Compound acting as WRN inhibitor and use thereof

Abstract

Provided are a class of compounds acting as WRN inhibitors and a use thereof, in the field of medicinal chemistry. Specifically, provided are compounds represented by formulas (I) and (II), or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, as well as preparation methods therefor, pharmaceutical compositions containing said compounds, and a use of the compounds or compositions for treating WRN-related diseases.

Description

Compounds as wrn inhibitors and uses thereof TECHNICAL FIELD

[0001] The present invention is in the field of medicinal chemistry and relates specifically to compounds or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof as WRN inhibitors, their methods of preparation, and pharmaceutical compositions containing these compounds and the use of these compounds or compositions for the treatment of diseases associated with WRN. BACKGROUND

[0002] Microsatellite is a kind of short tandem repeat DNA sequence in the genome, generally composed of 1-6 nucleotides. Due to the difference in the number of core repeat units, microsatellite usually has population polymorphism. The phenomenon that a new microsatellite allele appears at a certain microsatellite site in tumor due to the insertion or deletion of repeat units compared with normal tissue is called microsatellite instability (MSI). The occurrence of MSI is due to the functional defect of DNA mismatch repair (DNA Mismatch Repair, dMMR) in tumor tissue. With the continuous deepening of preclinical and clinical research, MSI accompanied by DNA mismatch repair defect is an important tumor marker in clinic. In clinic, dMMR and MSI-H usually have the same clinical significance. MSI occurs in cancers including colorectal cancer, gastric cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, urethral cancer, brain cancer and skin cancer. Among them, colorectal cancer is the most common (MSI-H ≈ 15%). In a number of clinical experiments, PD-1 mAb represented by pembrolizumab was found to have good therapeutic effect on MSI-H tumors, but in the study, a certain proportion of MSI patients did not respond to immunotherapy and some MSI-H tumor patients developed primary drug resistance to immunotherapy. The clinical needs of this part of patients have not been met so far.

[0003] A series of studies in recent years found that the WRN protein (Werner Protein) in the RNA / DNA helicase RecQ family has a strong correlation with the occurrence and development of MSI-H tumors. Knocking out or knocking down WRN in MSI-H tumor cells can significantly inhibit the proliferation, invasion and migration of tumor cells, and promote the apoptosis of tumor cells. These research results show that WRN and MSI-H may have a synthetic lethal relationship in tumors. At present, the mechanism of knocking down WRN to promote the apoptosis of MSI-H tumors has also been relatively clearly described: TA-dinucleotide repeats are highly unstable in MSI cells and can undergo large-scale expansion. These large amounts of increased TArep ethyl acetate t form non-B DNA secondary structures, stop replication forks, and activate ATR checkpoint kinases, which require the participation of WRN helicase to reactivate DNA replication forks to continue DNA replication. When there is no WRN, the expanded TA-dinucleotide repeat sequence is easily cut and broken by MUS81 nuclease, thereby causing a large number of chromosome breaks and inducing cell apoptosis.

[0004] Therefore, the development of WRN small molecule inhibitors is expected to provide a new means for anti-tumor treatment, so that MSI-H tumor patients can obtain clinical benefits. SUMMARY

[0005] The present application provides a compound represented by general formula (I) or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

[0006] wherein,

[0007] Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, which is optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, haloalkylacyl, hydroxyalkylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0008] X and Y are each independently selected from CH and N;

[0009] W is selected from halogen, cyano, amino, alkyl, cycloalkyl, heterocyclyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, alkylamino, aryl and heteroaryl, which is optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy;

[0010] R 1selected from the group consisting of halogen, cyano, amino, alkyl, cycloalkyl, heterocyclyl, heterocyclenyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, monoalkylamino, dialkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylaminoacyl, aryl, and heteroaryl, m is selected from 0, 1, 2, and 3; and

[0011] R 2 selected from the group consisting of alkyl, haloalkyl, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0012] In some embodiments, the compounds of the present application are compounds of general formula (I) or pharmaceutically acceptable salts, isomers, solvates, crystals, or prodrugs thereof, wherein general formula (I) is the structure of general formula (la):

[0013] wherein ring A, X, Y, W, R 1 , m, R 2 are as defined in general formula (I).

[0014] In some specific embodiments, the compounds of the present application are compounds of general formula (I) or (la) or pharmaceutically acceptable salts, isomers, solvates, crystals, or prodrugs thereof, wherein:

[0015] ring A is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, and 5-12 membered heteroaryl, optionally substituted with one or more groups selected from halogen, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, hydroxyC 1-6 alkoxy, and a heteroatom selected from N, O, S, and P;

[0016] Further preferably, ring A is selected from C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-8 membered heteroaryl, optionally substituted with one or more groups selected from halogen, hydroxy, C 1-3 alkyl, haloC 1-3 alkyl, hydroxyC 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, hydroxyC 1-3 alkoxy, and a heteroatom selected from N, O, S, and P.

[0017] In some specific embodiments, the compound according to the application of general formula (I) or (la), or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein ring A is selected from cyclopropyl, cyclobutyl,

[0018] In some specific embodiments, the compound of the application is a compound of general formula (I) or (la), or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein X and Y are both CH, X is CH and Y is N, or X and Y are both N.

[0019] In some specific embodiments, the compound of the application is a compound of general formula (I) or (la), or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein W is selected from halogen, cyano, amino, C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, C 1-6 alkylamino, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more groups selected from halogen, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, C

[0020] In some specific embodiments, the compound according to the application of general formula (I) or (la), or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein:

[0021] R 1 selected from halogen, cyano, amino, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclenyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, mono C 1-6 alkylamino, bis C 1-6 alkylamino, C 1-6 alkylacylamino, C1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, bis-C 1-6 alkylamino, C 6-10 aryl and 5-10 membered heteroaryl, the heteroatoms being selected from N, O, S and P, m being selected from 0, 1, 2 and 3.

[0022] In some specific embodiments, the compound according to the application of general formula (I) or (la), or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 1 selected from fluorine, chlorine, bromine.

[0023] In some specific embodiments, the compound according to the application of general formula (I) or (la), or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein:

[0024] R 2 selected from C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxyC 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, the heteroatoms being selected from N, O, S and P;

[0025] Further preferably, R 2 selected from C 1-3 alkyl, haloC 1-4 alkyl, haloC 1-3 alkoxy, hydroxyC 1-3 alkoxy, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, the heteroatoms being selected from N, O, S and P.

[0026] In some specific embodiments, the compound according to the application of general formula (I) or (la), or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 2 selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, phenyl, trifluoromethyl and

[0027] The present application provides a compound represented by general formula (II) or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,

[0028] wherein,

[0029] Ring B is absent or selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally substituted with one or more groups selected from halo, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, alkylamino;

[0030] Ring C and Ring D together with the atoms to which they are attached form aryl and aryl, aryl and heteroaryl, heteroaryl and heteroaryl;

[0031] L1is selected from -C(O)-NH-, -NH-, and -C(O)-CH=C-;

[0032] L2is selected from -CH=CH- and and

[0033] R 3 and R 4 are each independently selected from the group consisting of hydrogen, halo, amino, alkyl, cycloalkyl, heterocyclyl, haloalkyl, aryloxy, cycloalkylalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, aryl, and heteroaryl, optionally substituted with one or more groups selected from halo, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, p and q are each independently selected from 0, 1, 2, and 3.

[0034] In some embodiments, the compounds of the present application are compounds of general formula (II) or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, wherein general formula (II) is the structure of general formula (IIa) below:

[0035] wherein Ring B, Ring C, Ring D, L1, L2, R 3 , R 4 , p, q are as defined in general formula (II).

[0036] In some specific embodiments, the compounds of the present application are compounds of general formula (II) or (IIa) or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, wherein:

[0037] Ring B is absent or selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, and 5-12 membered heteroaryl, optionally substituted with one or more groups selected from halo, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, hydroxyC 1-6 alkoxy, amino, C 1-6The alkylamino group is substituted, wherein the heteroatom is selected from N, O, S and P;

[0038] More preferably, ring B is absent or selected from C. 3-6 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 aryl and 5-8 heteroaryl groups, optionally separated by one or more elements selected from halogen, hydroxyl, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, hydroxy C 1-3 Alkoxy, amino, C 1-3 The alkylamino group is substituted, and the heteroatom is selected from N, O, S and P.

[0039] In some specific embodiments, the compounds of the present invention are compounds of general formula (II) or (IIa) or pharmaceutically acceptable salts, isomers, solvates, crystals, or prodrugs thereof, wherein ring C and ring D, together with the atoms to which they are attached, constitute a 6-membered aryl and 6-membered aryl, a 6-membered aryl and 5-6-membered heteroaryl, or a 5-6-membered heteroaryl and 5-6-membered heteroaryl. In some specific embodiments, ring C and ring D, together with the atoms to which they are attached, constitute

[0040] In some specific embodiments, the compounds of the present invention are compounds of general formula (II) or (IIa) or pharmaceutically acceptable salts, isomers, solvates, crystals, or prodrugs thereof, wherein R 3 and R 4 Each is independently selected from hydrogen, halogen, amino, oxygen, and C. 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, halogenated C 1-6 Alkyl, C 6-12 aryloxy, cycloalkyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, C 6-12 aryl and 5-12 heteroaryl groups, optionally separated by one or more elements selected from halogen, hydroxyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, amino, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12The substitution is by aryl or 5-12 heteroaryl groups, wherein the heteroatoms are selected from N, O, S, and P, and p and q are each independently selected from 0, 1, 2, and 3. In some specific embodiments, R 3 and R 4 Each is independently selected from hydrogen, fluorine, chlorine, bromine, amino, oxygen, and C. 1-4 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, halogenated C 1-6 Alkyl, phenoxy, cycloalkyl C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, C 6-12 aryl and 5-10 heteroaryl groups, optionally bonded by one or more elements selected from fluorine, chlorine, bromine, hydroxyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-12 The heteroatom is selected from N, O, S and P, and p and q are each independently selected from 0, 1, 2 and 3.

[0041] This invention provides the following specific compounds or their pharmaceutically acceptable salts, isomers, solvates, crystals, or prodrugs:

[0042] On the other hand, the present invention provides pharmaceutical compositions comprising the compounds of the present invention or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof.

[0043] In some embodiments, the present invention provides compounds of the present invention or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, and pharmaceutical compositions comprising compounds of the present invention or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, said compounds or pharmaceutical compositions for treating diseases associated with WRN.

[0044] In some embodiments, the present invention provides pharmaceutical compositions comprising the compound of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug and a pharmaceutically acceptable carrier.

[0045] The compounds of the present application, or pharmaceutically acceptable salts, isomers, solvates, crystals, or prodrugs thereof, can be mixed with a pharmaceutically acceptable carrier, diluent or excipient to produce a pharmaceutical preparation for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The preparation can be administered by any route, such as by infusion or bolus injection, by a route through the epithelial or mucosal membranes (e.g., oral mucosa or rectal membranes, etc.). Administration can be systemic or local. Examples of preparations for oral administration include solid or liquid dosage forms, and in particular, including tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions, etc. The preparation can be prepared by methods known in the art, and includes carriers, diluents or excipients conventionally used in the field of pharmaceutical preparations.

[0046] In a third aspect, the present application provides the use of a compound of the present application represented by Formula (I), (Ia), (II) and (IIa), or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, or a pharmaceutical composition comprising the same, for treating a WRN-related disease, and for the manufacture of a medicament for treating a WRN-related disease.

[0047] In some preferred embodiments, the present application provides the use of a compound of the present application represented by Formula (I), (Ia), (II) and (IIa), or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, or a pharmaceutical composition comprising the same, for treating a WRN-related disease, and for the manufacture of a medicament for treating a WRN-related disease, wherein the WRN-related disease includes, but is not limited to, cancer, proliferative disease, hematological disease, or metabolic disease. In some embodiments, the WRN-related disease of the present application is cancer.

[0048] In some embodiments, the WRN-related disease of the present application includes, but is not limited to, pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma.

[0049] In some embodiments, the present application provides use of a compound of the present application of Formula (I), (Ia), (II) and (IIa) or a pharmaceutically acceptable salt, isomer, solvate, crystalline or prodrug thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for treating and / or preventing a microsatellite instability (MSI) or DNA mismatch repair (dMMR) cancer.

[0050] In some embodiments, the microsatellite instability (MSI) or DNA mismatch repair (dMMR) cancer of the present application includes, but is not limited to, colorectal cancer, gastric cancer, prostate cancer, endometrial cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, kidney cancer and ovarian cancer.

[0051] Definitions of terms

[0052] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0053] “Hydrogen”, “carbon”, “oxygen” in the compounds of the present application include all isotopes thereof. Isotopes are to be understood as including those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include protium, tritium, and deuterium, isotopes of carbon include 12 C, 13 C and 14 C, isotopes of oxygen include 16 O and 18 O, etc.

[0054] In this invention, "isomers" refers to molecules with the same atomic composition and bonding but different three-dimensional spatial arrangements, including but not limited to diastereomers, enantiomers, cis-trans isomers, and mixtures thereof, such as racemic mixtures. Many organic compounds exist in optically active forms, meaning they are capable of rotating the plane of polarized light. In describing optically active compounds, the prefixes D, L, or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The prefixes D, L, or (+), (-) are used to name the symbols for the plane polarization rotation of the compound; (-) or L indicates that the compound is levorotatory, and the prefix (+) or D indicates that the compound is dextrorotatory. These stereoisomers have the same chemical structure but different stereostructures. Specific stereoisomers can be enantiomers, and mixtures of isomers are usually called enantiomer mixtures. A 50:50 enantiomer mixture is called a racemic mixture or racemate, which may result in a lack of stereoselectivity or stereodirection during chemical reactions. The terms “racemic mixture” and “racemate” refer to a mixture of two equimolar enantiomers that lack optical activity.

[0055] Depending on the choice of starting materials and methods, the compounds of this invention can exist as one or a mixture of possible isomers, such as racemic mixtures and mixtures of non-corresponding isomers (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0056] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0057] In this invention, "halogen" refers to fluorine, chlorine, bromine, or iodine. "Halogenated" in this invention means substituted with fluorine, chlorine, bromine, or iodine.

[0058] In this invention, "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, preferably a straight-chain or branched group containing 1 to 6 carbon atoms, and more preferably a straight-chain or branched group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, etc. The alkyl group can be substituted or unsubstituted, and when substituted, the substituent can be at any usable connection point.

[0059] In this invention, "carbonyl" and "acyl" both refer to -C(O)-.

[0060] In this invention, "sulfonyl" refers to -S(O)2-.

[0061] "Sulfonamide" of the application refers to -S(O)2NH-.

[0062] "Haloalkyl" of the application refers to an alkyl group substituted with at least one halogen.

[0063] "Hydroxyalkyl" of the application refers to an alkyl group substituted with at least one hydroxyl group.

[0064] "Alkoxy" of the application refers to -O-alkyl. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propyloxy, n-propyloxy, isopropyloxy, isobutyloxy, sec-butyloxy, and the like. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituents can be on any available point of attachment.

[0065] "Cycloalkyl" of the application refers to cyclic, saturated hydrocarbon groups. Suitable cycloalkyl groups can be substituted or unsubstituted monocyclic, bicyclic, or tricyclic saturated hydrocarbon groups having 3-12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0066] "Heterocyclyl" of the application refers to a group of a 3- to 15-membered non-aromatic ring system having from 1 to 4 ring heteroatoms (where each heteroatom is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon) ("3-15 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heterocyclyl groups can either be monocyclic ("monocyclic heterocyclyl") or a fused, bridged, or spiro ring system (e.g., a bicyclic ring system (also referred to as "bicyclic heterocyclyl")) and can be saturated or can be partially unsaturated, wherein the bicyclic heterocyclyl includes, but is not limited to, benzazepinyl, benzoxazinyl, benzothiazinyl, benzodiazepinyl, benzodioxinyl, benzodithiinyl, benzoxazepinyl, benzothiazepinyl. Suitable heterocyclyl groups include, but are not limited to, piperidinyl, azetidinyl, aziridinyl, pyrrolidinyl, piperazinyl, dihydroquinazolinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydrobenzoxepinyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, and tetrahydroisoquinolinyl, and the like. Each instance of a heterocyclyl group can be optionally substituted or unsubstituted, and when substituted, the substituents can be on any available point of attachment.

[0067] "Aryl" of the present application refers to an aromatic system which can comprise a monocyclic or a fused polycyclic ring, preferably a monocyclic or a fused bicyclic ring, containing 6 to 12 carbon atoms, preferably containing about 6 to about 10 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, fluorenyl, indanyl. The aryl group can be optionally substituted or unsubstituted, and when substituted, the substituents can be on any available attachment point.

[0068] "Heteroaryl" of the present application refers to an aryl group in which at least one carbon atom has been replaced by a heteroatom, preferably from 5 to 12 atoms (5-12 membered heteroaryl), further preferably from 5 to 10 atoms (5-10 membered heteroaryl), the heteroatom being O, S, N. The heteroaryl group includes, but is not limited to, imidazolyl, pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, indolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, isoindolyl, benzopyrazolyl, benzimidazolyl, benzofuranyl, benzopyranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, quinoxalinyl, benzoxazinyl, benzothiazinyl, imidazopyridinyl, pyrimidopyrazolyl, pyrimidimidazolyl, pyridazinopyrrolyl, pyridazinimidazolyl, pyridinopyrrolyl, pyridinopyrazolyl, and the like. The heteroaryl group can be optionally substituted or unsubstituted, and when substituted, the substituents can be on any available attachment point.

[0069] "Cycloalkylalkoxy" of the present application refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group has been replaced by a cycloalkyl group as defined herein.

[0070] "Heterocyclylalkoxy" of the present application refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group has been replaced by a heterocyclyl group as defined herein.

[0071] "Pharmaceutically acceptable salt" of the present application refers to a salt of a compound of the present application which is safe and effective for use in a mammal and possesses the desirable biological activity.

[0072] "Solvate" of the present application refers in the conventional sense to a complex of a solute (such as an active compound, a salt of an active compound) and a solvent (such as water). The solvent refers to a solvent known or readily determined by one skilled in the art. If water, the solvate is commonly referred to as a hydrate, such as a hemihydrate, a monohydrate, a dihydrate, a trihydrate, or a salt thereof in alternative amounts.

[0073] The in vivo action of the compounds of the formula (I) can be exerted in part by one or more metabolites formed in the body of a human or animal after administration of the compounds of the formula (I). As described above, the in vivo action of the compounds of the formula (I) can also be exerted via metabolism of a precursor compound ("prodrug"). The "prodrugs" of the present application refer to compounds which are converted into the compounds of the present application in vivo due to reaction with enzymes, gastric acid, etc., i.e., compounds which are converted into the compounds of the present application by oxidation, reduction, hydrolysis, etc. of enzymes, and / or by hydrolysis reaction, etc. of gastric acid, etc.

[0074] The "crystal" of the present application refers to a solid whose internal structure is regularly repeated by atoms (or groups thereof) in three dimensions, unlike an amorphous solid which does not have such a regular internal structure.

[0075] The "pharmaceutical composition" of the present application refers to a mixture comprising any one of the compounds of the present application, including corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or more pharmaceutically acceptable carriers and / or another or more drugs. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism. The composition is generally used for the preparation of a medicament for the treatment and / or prevention of a disease mediated by one or more kinases.

[0076] The "pharmaceutically acceptable carrier" of the present application refers to a carrier which does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, including all solvents, diluents or other excipients, dispersants, surfactants, etc. isotonic agents, thickening agents or emulsifiers, preservatives, solid binders, lubricants, etc. Except for any conventional carrier medium which is not compatible with the compounds of the present application. Some examples which can be used as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, and cellulose and cellulose acetate; malt, gelatin, etc.

[0077] The "excipient" of the present application refers to an inert substance added to the pharmaceutical composition to further facilitate the administration of the compound. The excipient can include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycol. DETAILED DESCRIPTION

[0078] The present application is further illustrated in detail below with reference to examples, but the present application is not limited to these examples. The materials used in the following examples are commercially available unless otherwise specified.

[0079] Intermediate 1: (S, E)-1-cyclopropyl-3-(methylsulfonyl)propyl-2-ene-1-amine p-toluenesulfonate

[0080] Step 1: Preparation of (S)-(l-cyclopropyl-2-hydroxyethyl)carbamic acid tert-butyl ester

[0081] (S)-2-((tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid (2.25 g, 10 mmol) was dissolved in tetrahydrofuran (40 mL), and a corresponding amount of triethylamine (1.38 mL, 10 mmol) was added. The mixture was stirred in an ice water bath for 15 min, and isobutyl chloroformate (1.36 mL, 10 mmol) dissolved in tetrahydrofuran (5 mL) was added dropwise. The mixture was stirred in an ice water bath for 1 h, and then filtered under suction. A 20% aqueous solution of sodium borohydride in tetrahydrofuran was added to the filtrate in an ice water bath, and the mixture was stirred for another 2 h. Dilute hydrochloric acid was added to adjust the pH to 4-5 to quench the reaction, and then a saturated aqueous solution of sodium bicarbonate was added to adjust the pH to 7-8. The mixture was extracted with ethyl acetate, and the organic phases were combined and dried. Concentration gave a transparent oil 1.91 g. ESI-MS m / z: 146.1 [M+H-56] + .

[0082] Step 2: Preparation of (S)-(l-cyclopropyl-2-oxoethyl)carbamic acid tert-butyl ester

[0083] Dess-Martin periodinane (8.15 g, 19.0 mmol) was dissolved in dichloromethane (40 mL), and the mixture was stirred in an ice water bath for 15 min. Then a solution of (S)-(l-cyclopropyl-2-hydroxyethyl)carbamic acid tert-butyl ester (1.91 g, 9.5 mmol) in dichloromethane was added, and the mixture was stirred at room temperature for 3 h after 10 min. The reaction mixture was filtered, and the filtrate was washed with a saturated sodium chloride solution and extracted with ethyl acetate. The organic phases were combined and dried, and the product was purified by column chromatography to give a transparent oil 1.03 g. ESI-MS m / z: 144.1 [M+H-56] + .

[0084] Step 3: Preparation of (S,E)-(l-cyclopropyl-3-(methylsulfonyl)allyl)carbamic acid tert-butyl ester

[0085] Diethyl ((methylsulfonyl)methyl)phosphonate (1.18 g, 5.12 mmol) was dissolved in tetrahydrofuran (20 mL) and stirred at -30 °C for 15 min, sodium hydride (400 mg, 10 mmol) was added, stirred for 1 h, then a solution of (S)-(l-cyclopropyl-2-oxoethyl) carbamic acid tert-butyl ester (1.03 g, 5.12 mmol) in tetrahydrofuran was added dropwise, and the stirring was continued at -30 °C for 2-3 h. The reaction was quenched with water at low temperature, extracted with ethyl acetate, the organic phases were combined and dried, and purified by column chromatography to give 600 mg of an oil, ESI-MS m / z: 220.0 [M+H-56] + .

[0086] Step 4: Preparation of (S,E)-l-cyclopropyl-3-(methylsulfonyl)propyl-2- en-l-amine p-toluenesulfonic acid salt

[0087] (S,E)-(l-cyclopropyl-3-(methylsulfonyl)allyl)carbamic acid tert-butyl ester (600 mg, 2.18 mmol) was dissolved in acetonitrile (15 mL), p-toluenesulfonic acid (450.5 mg, 2.62 mmol) was added, and the reaction was transferred to 50 °C overnight. The reaction was checked by LC-MS and was complete, and the reaction mixture was concentrated for use. ESI-MS m / z: 176.0 [M+H] + .

[0088] Example 1: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-fluoro-4- (methylsulfonyl)-2-phenoxybenzamide

[0089] Step 1: Preparation of methyl 4-bromo-5-fluoro-2-phenoxybenzoate

[0090] Methyl 4-bromo-2,5-difluorobenzoate (5.0 g, 19.92 mmol), phenol (2.1 g, 21.91 mmol), copper powder (7.6 g, 119.52 mmol), potassium carbonate (5.5 g, 39.83 mmol) were dissolved in 60 mL of N,N-dimethylformamide and stirred at 100 °C for 3 hours. The reaction was complete. The reaction was filtered, the organic phase was concentrated, and the product was purified by column chromatography to give 3.0 g. ESI-MS m / z: 324.9 [M+H] + .

[0091] Step 2: Preparation of methyl 5-fluoro-4-(methylsulfonyl)-2-phenoxybenzoate

[0092] Methyl 4-bromo-5-fluoro-2-phenoxybenzoate (2.0 g, 6.15 mmol) was dissolved in 30 mL of dimethyl sulfoxide, and then sodium methanesulfinate (960 mg, 9.23 mmol), cuprous iodide (117 mg, 0.615 mmol), L-proline (141 mg, 1.23 mmol), potassium carbonate (1.69 g, 12.3 mmol) were added, and stirred at 100 °C for 12 hours. The reaction was monitored by LC-MS. After the reaction was completed, the organic phase was filtered and concentrated, and then purified by column chromatography to obtain 600 mg of the product. ESI-MS m / z: 325.1 [M+H] + .

[0093] Step 3: Preparation of 5-fluoro-4-(methylsulfonyl)-2-phenoxybenzoic acid

[0094] Methyl 5-fluoro-4-(methylsulfonyl)-2-phenoxybenzoate (600 mg, 1.85 mmol) was dissolved in 10 mL of tetrahydrofuran and 10 mL of water, and then lithium hydroxide (222 mg, 9.25 mmol) was added, and stirred at room temperature for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the pH was adjusted to about 3.0, and then extracted with EA, and concentrated to obtain 510 mg of the product. ESI-MS m / z: 310.9 [M+H] + .

[0095] Step 4: Preparation of (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-fluoro-4- (methylsulfonyl)-2-phenoxybenzamide

[0096] 5-Fluoro-4-(methylsulfonyl)-2-phenoxybenzoic acid (150 mg, 0.485 mmol) was dissolved in 10 mL of N,N-dimethylformamide, and then (S,E)-1-cyclopropyl-3- (methylsulfonyl)propyl-2-en-1-amine (210 mg, 0.485 mmol as p-toluenesulfonate salt), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (188 mg, 0.485 mmol), and N,N-diisopropyl ethylamine (187 mg, 3.0 mmol) were added, and stirred at room temperature for 1 hour. Purification by column chromatography to obtain 113 mg of the title product.

[0097] 1H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J = 8.2 Hz, 1H), 7.84 (d, J = 9.5 Hz, 1H), 7.50 - 7.41 (m, 2H), 7.31 - 7.19 (m, 2H), 7.13 (d, J = 7.7 Hz, 2H), 6.79 (s, 2H), 4.15 (t, J = 8.3 Hz, 1H), 3.36 (s, 3H), 2.93 (s, 3H), 1.00 - 0.93 (m, 1H), 0.56 - 0.0.46 (m, 1H), 0.45 - 0.33 (m, 2H), 0.30 - 0.23 (m, 1H).

[0098] ESI-MS m / z: 467.8 [M+H] + .

[0099] Example 2: (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-fluoro-4- (cyclopropylsulfonyl)-2-phenoxybenzamide

[0100] The preparation method is the same as that of Example 1 except that the raw material sodium methylsulfinyl is replaced by sodium cyclopropylsulfinyl to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J = 8.2 Hz, 1H), 7.84 (d, J = 9.5 Hz, 1H), 7.50 - 7.41 (m, 2H), 7.31 - 7.19 (m, 2H), 7.13 (d, J = 7.7 Hz, 2H), 6.79 (s, 2H), 4.15 (t, J = 8.3 Hz, 1H), 3.36 (s, 3H), 2.93 (s, 3H), 1.00 - 0.93 (m, 1H), 0.56 - 0.0.46 (m, 1H), 0.45 - 0.33 (m, 2H), 0.30 - 0.23 (m, 1H).

[0101] ESI-MS m / z: 493.8 [M+H] + .

[0102] Example 3: (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-fluoro-4- (ethylsulfonyl)-2-phenoxybenzamide

[0103] The preparation method is the same as that of Example 1 except that the raw material sodium methylsulfinyl is replaced by sodium ethylsulfinyl to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.92 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 9.5 Hz, 1H), 7.49 - 7.42 (m, 2H), 7.28 - 7.19 (m, 2H), 7.13 (d, J = 8.6 Hz, 2H), 6.80 (s, 2H), 4.19 - 4.11 (m, 1H), 3.48 - 3.43 (m, 2H), 2.94 (s, 3H), 1.14 (t, J = 7.3 Hz, 3H), 1.05 - 0.96 (m, 1H), 0.55 - 0.47 (m, 1H), 0.44 - 0.34 (m, 2H), 0.29 - 0.22 (m, 1H).

[0104] ESI-MS m / z: 481.9 [M+H] + .

[0105] Example 4: (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-fluoro-4- (isopropylsulfonyl)-2-phenoxybenzamide

[0106] The preparation method is the same as that of Example 1 except that the raw material sodium methylsulfinyl sodium is replaced by sodium isopropylsulfinyl sodium to obtain the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 9.5 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.23 - 7.13 (m, 2H), 7.07 (d, J = 8.4 Hz, 2H), 6.76 (s, 2H), 4.11 (t, J = 8.3 Hz, 1H), 3.54 - 3.45 (m, 1H), 2.90 (s, 3H), 1.16 (d, J = 6.8 Hz, 6H), 1.01 - 0.92 (m, 1H), 0.52 - 0.42 (m, 1H), 0.41 - 0.33 (m, 2H), 0.25 - 0.16 (m, 1H).

[0107] ESI-MS m / z: 495.9 [M+H] + .

[0108] Example 5: (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-fluoro-4-(tert- butylsulfonyl)-2-phenoxybenzamide

[0109] Step 1: Preparation of methyl 4-bromo-5-fluoro-2-phenoxybenzoate

[0110] Methyl 4-bromo-2,5-difluorobenzoate (5.0 g, 19.92 mmol), phenol (2.06 g, 21.91 mmol), copper powder (7.6 g, 119.52 mmol), potassium carbonate (5.5 g, 39.83 mmol) were dissolved in 60 mL of N,N-dimethylformamide, stirred at 100 °C for 3 hours. The reaction was completed. Filtration, the organic phase was concentrated and column chromatography to give the product 3.0 g. ESI-MS m / z: 324.9 [M+H] + .

[0111] Step 2: Preparation of methyl 4-(tert-butylsulfinyl)-5-fluoro-2-phenoxybenzoate

[0112] Methyl 4-bromo-5-fluoro-2-phenoxybenzoate (2.0 g, 6.15 mmol) was dissolved in 100 mL of N,N-dimethylformamide, then tert-butyl mercaptan (832 mg, 9.22 mmol), sodium carbonate (1.3 g, 12.3 mmol) and tetrakis(triphenylphosphine)palladium (426 mg, 0.369 mmol) were added, argon protection, stirred at 100 °C for 12 hours, LC-MS tracking monitoring reaction, the reaction was completed. Column chromatography to give the product. ESI-MS m / z: 334.9 [M+H] + .

[0113] Step 3: Preparation of methyl 4-(tert-butylsulfonyl)-5-fluoro-2-phenoxybenzoate

[0114] Methyl 4-(tert-butylsulfinyl)-5-fluoro-2-phenoxybenzoate (1.7 g, 5.09 mmol) was dissolved in 100 mL of dichloromethane, then m-chloroperoxybenzoic acid (2.63 g, 15.26 mmol) was added, stirred at room temperature for 12 hours, LC-MS tracking monitoring reaction, the reaction was completed. Column chromatography to give the product. ESI-MS m / z: 366.9 [M+H] + .

[0115] Step 4: Preparation of 4-(tert-butylsulfonyl)-5-fluoro-2-phenoxybenzoic acid

[0116] Methyl 4-(tert-butylsulfonyl)-5-fluoro-2-phenoxybenzoate (700 mg, 1.91 mmol) was dissolved in 20 mL of tetrahydrofuran and 20 mL of water, then lithium hydroxide (150 mg, 5.72 mmol) was added, stirred at room temperature for 2 hours, LC-MS tracking monitoring reaction, the reaction was completed. The pH of the aqueous phase was adjusted to about 3.0, extracted with ethyl acetate, concentrated to give the product. ESI-MS m / z: 352.9 [M+H] + .

[0117] Step 5: Preparation of (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-fluoro-4-(tert- butylsulfonyl)-2-phenoxybenzamide

[0118] To a solution of 4-(tert-butylsulfonyl)-5-fluoro-2-phenoxybenzoic acid (100 mg, 0.285 mmol) in 10 mL of N,N-dimethylformamide was added (S,E)-l-cyclopropyl-3-(methylsulfonyl)propyl-2- en-l-amine (110 mg, 0.285 mmol as p-toluenesulfonate salt), 2-(7-azabenzotriazol-l- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (110 mg, 0.285 mmol) and N,N- diisopropylethylamine (110 mg, 0.855 mmol) and stirred at room temperature for 1 h. The title product was isolated by preparative TLC.

[0119] 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 9.7 Hz, 1H), 7.50 - 7.39 (m, 2H), 7.26 - 7.16 (m, 2H), 7.13 - 7.05 (m, 2H), 6.80 (s, 2H), 4.14 (t, J = 8.3 Hz, 1H), 2.93 (s, 3H), 1.26 (s, 9H), 1.05 - 0.96 (m, 1H), 0.56 - 0.47 (m, 1H), 0.45 - 0.34 (m, 2H), 0.29 - 0.21 (m, 1H).

[0120] ESI-MS m / z: 509.8 [M+H] + .

[0121] Example 6: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-fluoro-6-(methylsulfonyl)-2- phenoxy nicotinamide

[0122] Step 1: Preparation of methyl 2-chloro-5-fluoro-6-(methylthio)nicotinate

[0123] To a solution of methyl 2,6-dichloro-5-fluoronicotinate (5.0 g, 22.32 mmol) and sodium methanethiolate (1.56 g, 22.32 mmol) in 100 mL of tetrahydrofuran was stirred at room temperature for 12 h. The reaction was complete. The product was isolated by column chromatography. ESI-MS m / z: 235.9 [M+H] + .

[0124] Step 2: Preparation of methyl 5-fluoro-6-(methylthio)-2-phenoxy nicotinate

[0125] Methyl 2-chloro-5-fluoro-6-(methylthio)nicotinate (3.0 g, 12.76 mmol) was dissolved in 100 mL of N,N-dimethylformamide, then phenol (1.8 g, 19.14 mmol) and potassium carbonate (5.28 g, 38.28 mmol) were added, and stirred at 80 °C for 12 hours. The reaction was monitored by LC-MS. After the reaction was completed, the product was obtained by column chromatography. ESI-MS m / z: 293.9 [M+H] + .

[0126] Step 3: Preparation of methyl 5-fluoro-6-(methylsulfonyl)-2-phenoxy nicotinate

[0127] Methyl 5-fluoro-6-(methylthio)-2-phenoxy nicotinate (2.0 g, 6.82 mmol) was dissolved in 100 mL of dichloromethane, then m-chloroperoxybenzoic acid (3.53 g, 20.46 mmol) was added, and stirred at room temperature for 12 hours. The reaction was monitored by LC-MS. After the reaction was completed, the product was obtained by column chromatography. ESI-MS m / z: 326.1 [M+H] + .

[0128] Step 4: Preparation of 5-fluoro-6-(methylsulfonyl)-2-phenoxy nicotinic acid

[0129] Methyl 5-fluoro-6-(methylsulfonyl)-2-phenoxy nicotinate (800 mg, 2.46 mmol) was dissolved in 25 mL of tetrahydrofuran and 25 mL of water, then lithium hydroxide (177 mg, 7.38 mmol) was added, and stirred at room temperature for 2 hours. The reaction was monitored by LC-MS. After the reaction was completed, the product was obtained by first extracting the impurities with ethyl acetate, and then adjusting the pH of the aqueous phase to about 3.0 and extracting with ethyl acetate. ESI-MS m / z: 312.1 [M+H] + .

[0130] Step 5: Preparation of (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-fluoro-6- (methylsulfonyl)-2-phenoxy nicotinamide

[0131] To a solution of 5-fluoro-6-(methylsulfonyl)-2-phenoxybenzoic acid (150 mg, 0.48 mmol) in 10 mL of N,N-dimethylformamide was added (S,E)-1-cyclopropyl-3- (methylsulfonyl)propyl-2-en-1-amine (225 mg, 0.48 mmol), 2-(7-azabenzotriazol-1- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (190 mg, 0.48 mmol) and N,N- diisopropylethylamine (195 mg, 1.36 mmol) and stirred at room temperature for 1 h. The title product was isolated by prep HPLC.

[0132] 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 8.2 Hz, 1H), 8.43 (d, J = 9.0 Hz, 1H), 7.52 - 7.41 (m, 2H), 7.36 - 7.23 (m, 3H), 6.96 - 6.79 (m, 2H), 4.33 - 4.26 (m, 1H), 3.16 (s, 3H), 2.98 (s, 3H), 1.16 - 1.05 (m, 1H), 0.66 - 0.57 (m, 1H), 0.52 - 0.43 (m, 2H), 0.37 - 0.28 (m, 1H).

[0133] ESI-MS m / z: 469.0 [M+H] + .

[0134] Example 7: (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6-(cyclopropylsulfonyl)-4- phenoxy nicotinamide

[0135] The preparation method is the same as that of Example 1, except that the raw material 4-bromo-2,5-difluorobenzoic acid methyl ester is replaced by 6-bromo-4-chloronicotinic acid methyl ester, and sodium methanesulfinate is replaced by sodium cyclopropylsulfinate, to obtain the title compound.

[0136] 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 8.2 Hz, 1H), 8.43 (d, J = 9.0 Hz, 1H), 7.52 - 7.41 (m, 2H), 7.36 - 7.23 (m, 3H), 6.96 - 6.79 (m, 2H), 4.33 - 4.26 (m, 1H), 3.16 (s, 3H), 2.98 (s, 3H), 1.16 - 1.05 (m, 1H), 0.66 - 0.57 (m, 1H), 0.52 - 0.43 (m, 2H), 0.37 - 0.28 (m, 1H).

[0137] ESI-MS m / z: 476.8 [M+H] + .

[0138] Example 8: (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4- (cyclopropylsulfonyl)-2-phenoxybenzamide

[0139] The preparation method is the same as that of Example 1, except that the raw material 4-bromo-2,5-difluorobenzoic acid methyl ester is replaced by 4-bromo-2-fluorobenzoic acid methyl ester, and methyl sulfinate sodium is replaced by cyclopropyl sulfinate sodium, to obtain the title compound.

[0140] 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 9.5 Hz, 1H), 7.47 (t, J = 8.0 Hz, 2H), 7.31 (s, 1H), 7.25 (t, J = 7.4 Hz, 1H), 7.16 (d, J = 7.8 Hz, 2H), 6.82-6.77 (m, 2H), 4.25-4.15 (m, 1H), 2.94-2.89 (m, 4H), 1.10-0.99 (m, 5H), 0.57-0.48 (m, 1H), 0.47-0.37 (m, 2H), 0.36-0.26 (m, 1H).

[0141] ESI-MS m / z 475.9 [M+H] + .

[0142] Example 9: (S,E)-5-chloro-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4- (cyclopropylsulfonyl)-2-phenoxybenzamide

[0143] Step 1: Preparation of 4-bromo-5-chloro-2-fluorobenzoic acid

[0144] 1-bromo-2-chloro-5-fluoro-4-methylbenzene (10 g, 44.8 mmol) was added to a reaction bottle, pyridine (80 mL) and water (80 mL) were added, then potassium permanganate (21.2 g, 134.3 mmol) was added at 90°C, and stirred for 12 hours. After cooling to room temperature, suction filtration was performed, the filtrate was adjusted to pH 3 with 2M hydrochloric acid, and a solid was precipitated, suction filtration was performed to obtain a solid, which was dried to obtain the product 6.3 g. ESI-MS m / z: 252.9 [M+H] + .

[0145] Step 2: Preparation of methyl 4-bromo-5-chloro-2-fluorobenzoate

[0146] Methyl 4-bromo-5-chloro-2-fluorobenzoate (3.0 g, 11.2 mmol) was added to a reaction flask, N,N-dimethylformamide (10 mL) and copper (4.3 g, 67.4 mmol) were added, then phenol (1.26 g, 13.5 mmol) and potassium carbonate (3.1 g, 22.5 mmol) were added, then stirred at 100 °C for 12 hours. After cooling to room temperature, water and ethyl acetate were added, the aqueous phase was adjusted to pH 3 with 2M hydrochloric acid, extracted with ethyl acetate, the organic phase was concentrated and purified by column chromatography to obtain 800 mg of product. ESI-MS m / z: 326.8 [M+H] + .

[0147] Step 3: Preparation of 4-bromo-5-chloro-2-phenoxybenzoic acid

[0148] Methyl 4-bromo-5-chloro-2-fluorobenzoate (3.0 g, 11.2 mmol) was added to a reaction flask, N,N-dimethylformamide (10 mL) and copper (4.3 g, 67.4 mmol) were added, then phenol (1.26 g, 13.5 mmol) and potassium carbonate (3.1 g, 22.5 mmol) were added, then stirred at 100 °C for 12 hours. After cooling to room temperature, water and ethyl acetate were added, the aqueous phase was adjusted to pH 3 with 2M hydrochloric acid, extracted with ethyl acetate, the organic phase was concentrated and purified by column chromatography to obtain 800 mg of product. ESI-MS m / z: 326.8 [M+H] + .

[0149] Step 4: Preparation of 5-chloro-4-(cyclopropylsulfonyl)-2-phenoxybenzoic acid

[0150] Methyl 4-bromo-5-chloro-2-fluorobenzoate (3.0 g, 11.2 mmol) was added to a reaction flask, N,N-dimethylformamide (10 mL) and copper (4.3 g, 67.4 mmol) were added, then phenol (1.26 g, 13.5 mmol) and potassium carbonate (3.1 g, 22.5 mmol) were added, then stirred at 100 °C for 12 hours. After cooling to room temperature, water and ethyl acetate were added, the aqueous phase was adjusted to pH 3 with 2M hydrochloric acid, extracted with ethyl acetate, the organic phase was concentrated and purified by column chromatography to obtain 800 mg of product. ESI-MS m / z: 326.8 [M+H] + .

[0151] Step 5: Preparation of (S,E)-5-chloro-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4- (cyclopropylsulfonyl)-2-phenoxybenzamide

[0152] Into a round bottom flask was placed 5-chloro-4-(cyclopropylsulfonyl)-2- phenoxybenzoic acid (0.10 g, 0.28 mmol) and N,N-dimethylformamide (2 mL) was added to dissolve. Then (S,E)-l-cyclopropyl-3-(methylsulfonyl)propyl-2- en-l-amine p-toluenesulfonate (0.12 g, 0.71 mmol) was added to the reaction system, followed by the addition of 2-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (0.16 g, 0.41 mmol) and N,N- diisopropylethylamine (0.11 g, 85 mmol). The reaction was allowed to proceed at room temperature overnight. After the reaction was completed, the title product was obtained by purification, 65 mg.

[0153] 1 H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J = 8.2 Hz, 1H), 7.98 (s, 1H), 7.51-7.43 (m, 2H), 7.36 (s, 1H), 7.29-7.22 (m, 1H), 7.16 (d, J = 8.2 Hz, 2H), 6.82 (s, 2H), 4.23-4.12 (m, 1H), 3.22-3.12 (m, 1H), 2.95 (s, 3H), 1.18-0.95 (m, 5H), 0.55-0.48 (m, 1H), 0.46-0.35 (m, 2H), 0.34-0.24 (m, 1H).

[0154] ESI-MS m / z: 509.9 [M+H] + .

[0155] Example 10: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-(phenylsulfonyl)-5- fluoro-2-phenoxybenzamide

[0156] The preparation method is the same as that of Example 1, except that the raw material sodium methylsulfinate is replaced by sodium phenylsulfinate, to obtain the title compound.

[0157] 1H NMR (400 MHz, CDC13) δ 7.90 (m, 3H), 7.84 (d, J = 7.3 Hz, 1H), 7.67-7.64 (m, 2H), 7.55 (t, J = 7.7 Hz, 2H), 7.48 (t, J = 7.9 Hz, 2H), 7.33-7.28 (m, 1H), 7.10-7.05 (m, 2H), 6.91 (dd, J = 15.1, 4.6 Hz, 1H), 6.39 (d, J = 15.5 Hz, 1H), 4.20-4.10 (m, 1H), 2.85 (s, 3H), 1.00-0.90 (m, 1H), 0.70-0.60 (m, 1H), 0.54-0.45 (m, 1H), 0.45-0.30 (m, 2H).

[0158] ESI-MS m / z: 530.9 [M+H] + .

[0159] Example 11: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4- (trifluoromethylsulfonyl)-5-fluoro-2-phenoxybenzamide

[0160] Step 1: Preparation of methyl 5-fluoro-2-phenoxy-4-((trifluoromethyl)thio)benzoate

[0161] Methyl 4-bromo-5-fluoro-2-phenoxybenzoate (1.5 g, 4.6 mmol) was dissolved in 10 mL of N-methylpyrrolidine, and copper trifluoromethanesulfide (2.3 g, 13.9 mmol) was added. The mixture was stirred at 150 °C for 9 hours under microwave. The reaction was monitored by LC-MS. The product was obtained by column chromatography. ESI-MS m / z: 346.8 [M+H] + .

[0162] Step 2: Preparation of methyl 5-fluoro-2-phenoxy-4-((trifluoromethyl)sulfonyl)benzoate

[0163] Methyl 5-fluoro-2-phenoxy-4-((trifluoromethyl)thio)benzoate (300 mg, 0.867 mmol) was dissolved in 10 mL of dichloromethane / 10 mL of acetonitrile / 20 mL of water, and sodium periodate (556 mg, 2.6 mmol) was added. The mixture was cooled to 0 °C, and ruthenium trichloride monohydrate (4 mg, 0.017 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LC-MS. The product was obtained by column chromatography. ESI-MS m / z: 378.9 [M+H] + .

[0164] Step 3: Preparation of 5-fluoro-2-phenoxy-4-((trifluoromethyl)sulfonyl)benzoic acid

[0165] Methyl 5-fluoro-2-phenoxy-4-((trifluoromethyl)sulfonyl)benzoate (380 mg, 1.0 mmol) was dissolved in 20 mL of tetrahydrofuran and 20 mL of water, and lithium hydroxide (72 mg, 3.0 mmol) was added, and stirred at room temperature for 2 hours. The reaction was monitored by LC-MS, and the reaction was completed. The pH of the aqueous phase was adjusted to about 3.0, and extracted with ethyl acetate, and concentrated to obtain the product. ESI-MS m / z: 364.8 [M+H] + .

[0166] Step 4: Preparation of (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4- (trifluoromethylsulfonyl)-5-fluoro-2-phenoxybenzamide

[0167] 5-Fluoro-2-phenoxy-4-((trifluoromethyl)sulfonyl)benzoic acid (100 mg, 0.27 mmol) was dissolved in 10 mL of N,N-dimethylformamide, and (S,E)-1-cyclopropyl-3- (methylsulfonyl)propyl-2-en-1-amine p-toluenesulfonate (120 mg, 0.27 mmol), 2-(7- azobenzo triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (110 mg, 0.27 mmol), and N,N-diisopropyl ethylamine (110 mg, 0.81 mmol) were added, and stirred at room temperature for 1 hour. Separation by preparation gave 61 mg of the title product.

[0168] 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 8.2 Hz, 1H), 8.09 (d, J = 9.7 Hz, 1H), 7.54-7.38 (m, 3H), 7.25 (t, J = 7.4 Hz, 1H), 7.19-7.11 (m, 2H), 6.90-6.73 (m, 2H), 4.23-4.03 (m, 1H), 2.95 (s, 3H), 1.07-0.96 (m, 1H), 0.57-0.47 (m, 1H), 0.47-0.35 (m, 2H), 0.30-0.19 (m, 1H).

[0169] ESI-MS m / z: 521.8 [M+H] + .

[0170] Example 12: (S, E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-7-(1,1- difluoroethyl)-8-fluoro-5-phenoxyquinazolin-4-amine

[0171] Step 1: Preparation of 7-bromo-5,8-difluoroquinazolin-4(3H)-one

[0172] Into a reaction flask was placed 2-amino-4-bromo-3,6-difluorobenzoic acid (5.0 g, 19.84 mmol) and a solution of formamidine acetate (24.8 g, 238.1 mmol) in ethanol (100 mL), and then stirred at reflux for 16 h. Concentrated under reduced pressure, and purified by column chromatography to give the product as a solid 5 g. ESI-MS m / z: 261.0 [M+H] + .

[0173] Step 2: Preparation of 7-bromo-8-fluoro-5-phenoxyquinazolin-4(3H)-one

[0174] Into a solution of N,N-dimethylformamide (80 mL) was placed 7-bromo-5,8- difluoroquinazolin-4(3H)-one (4.0 g, 15.3 mmol), phenol (1.73 g, 18.4 mmol) and potassium carbonate (3.2 g, 22.9 mmol), and the resulting mixture was heated at 150 °C and stirred for 18 h. Upon completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give the product as a solid 1.8 g. ESI-MS m / z: 335.0 [M+H] + .

[0175] Step 3: Preparation of 7-(1-ethoxyvinyl)-8-fluoro-5-phenoxyquinazolin-4(3H)-one

[0176] Into a reaction flask was placed 7-bromo-8-fluoro-5-phenoxyquinazolin-4(3H)-one (1.8 g, 5.4 mmol), tributyl(1-ethoxyvinyl)tin (5.8 g, 16.1 mmol) and tetrakis(triphenylphosphine)palladium (0.19 g, 0.16 mmol), and then replaced with argon. 1,4-Dioxane (110 mL) was added, and the resulting mixture was heated at 100 °C for 12 h. Upon completion of the reaction, the mixture was concentrated under reduced pressure, and purified by column chromatography on silica gel to give the product 1.6 g. ESI-MS m / z: 327.1 [M+H] + .

[0177] Step 4: Preparation of 7-acetyl-8-fluoro-5-phenoxyquinazolin-4(3H)-one

[0178] Into a reaction flask was placed 7-(1-ethoxyvinyl)-8-fluoro-5-phenoxyquinazolin-4(3H)-one (1.6 g, 4.9 mmol), hydrochloric acid / 1,4-dioxane (35 mL) and stirred at room temperature for 1 h. The product was concentrated under reduced pressure and used directly in the next step. ESI-MS m / z: 299.1 [M+H] + .

[0179] Step 5: Preparation of 7-(1,1-difluoroethyl)-8-fluoro-5-phenoxyquinazolin-4(3H)-one

[0180] Into a reaction flask was placed 7-acetyl-8-fluoro-5-phenoxyquinazolin-4(3H)-one (1.5 g, 5.2 mmol), diethylamine sulfide (10 mL) and stirred at 25 °C for 16 h. The reaction was quenched with ice water, extracted with dichloromethane, washed with water, saturated sodium chloride, concentrated under reduced pressure and purified on a silica gel column to give the product 0.9 g. ESI-MS m / z: 321.1 [M+H] +

[0181] Step 6: Preparation of 4-chloro-7-(1,1-difluoroethyl)-8-fluoro-5-phenoxyquinazoline

[0182] Into a reaction flask was placed 7-(1,1-difluoroethyl)-8-fluoro-5-phenoxyquinazolin-4(3H)-one (0.4 g, 1.25 mmol), 1,2-dichloroethane (24 mL), phosphorus oxychloride (0.96 g, 6.25 mmol) and N,N-diisopropylethylamine (0.8 g, 6.25 mmol), and stirred at 90 °C for 3 h. The reaction was complete and the product was used directly in the next step, ESI-MS m / z: 339.0 [M+H] + .

[0183] Step 7: Preparation of (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-7-(1,1-difluoroethyl)-8-fluoro-5-phenoxyquinazolin-4-amine

[0184] Take (S, E)-1-cyclopropyl-3-(methylsulfonyl)propyl-2-en-1-amine p-toluenesulfonic acid salt (0.1 g, 0.591 mmol) into a round-bottom flask, dissolve in acetonitrile (15 mL), add 4-chloro-7-(1,1-difluoroethyl)-8-fluoro-5-phenoxyquinazoline (0.2 g, 0.591 mmol) and N,N-diisopropylethylamine (4 mL) to the reaction system, react at room temperature, after the reaction is completed, add water, extract with ethyl acetate, wash with water, dry over anhydrous sodium sulfate, purify to obtain 5 mg of the title product. ESI-MS m / z: 478.1 [M+H] + .

[0185] 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.56-7.42 (m, 1H), 7.41-7.30 (m, 2H), 7.13-7.07 (m, 1H), 6.93-6.88 (m, 2H), 4.62-4.55 (m, 1H), 3.94-3.68 (m, 2H), 3.51 (s, 1H), 3.12 (s, 3H), 2.29 (s, 1H), 1.99 (d, J = 19.3 Hz, 3H), 0.98-0.78 (m, 4H).

[0186] Example 13: (S, E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxy-pyrrolo[1,2-b]pyridazine-3-carboxamide

[0187] Step 1: Preparation of 1-amino-5-bromo-1H-pyrrole-2-carboxylic acid methyl ester

[0188] Take 5-bromo-1H-pyrrole-2-carboxylic acid methyl ester (2.0 g, 9.9 mmol) into a 250 mL flask, add sodium hydride (0.47 g, 11.8 mmol) under ice bath conditions, react for 1 h, then add aminooxydiphenylphosphine oxide (2.75 g, 11.8 mmol) to it, stir at room temperature overnight, after the reaction is completed, extract with ethyl acetate twice, collect the organic phase, wash with water twice, wash with saturated brine once, dry over anhydrous sodium sulfate, concentrate and pass through a column to obtain the target product. ESI-MS m / z: 219.1 [M+H] + .

[0189] Step 2: Preparation of (E)-5-bromo-1-((3-ethoxy-3-oxoprop-1-en-1-yl)amino)-1H-pyrrole-2-carboxylic acid methyl ester

[0190] Take 1-amino-5-bromo-1H-pyrrole-2-carboxylic acid methyl ester (2.2 g, 10.09 mmol) into a 100 mL pressure bottle, dissolve with ethanol and add excess ethyl propiolate (4.9 g, 50 mmol) to it, seal and reflux at 100°C overnight, after TLC spotting shows that the reaction is complete, extract with ethyl acetate twice, collect the organic phase, wash with water twice, saturated brine once, dry over anhydrous sodium sulfate, concentrate and pass through a column to obtain 1.2 g of the title compound. ESI-MS m / z: 317.0 [M+H] + .

[0191] Step 3: Preparation of 7-bromo-4-hydroxypyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester

[0192] Dissolve (E)-5-bromo-1-((3-ethoxy-3-oxoprop-1-en-1-yl)amino)-1H-pyrrole-2-carboxylic acid methyl ester (1.2 g, 3.8 mmol) in ethanol (20 mL) in a 100 mL single-neck flask, add potassium tert-butoxide (852.0 mg, 7.6 mmol) to it, condense and reflux at 80°C for 2 h, monitor the reaction completion by LCMS, adjust the pH to weakly acidic and extract with ethyl acetate twice, collect the organic phase, wash with water twice, saturated brine once, dry over anhydrous sodium sulfate, concentrate and pass through a column to obtain 0.9 g of the target product. ESI-MS m / z: 285.0 [M+H] + 。

[0193] Step 4: Preparation of 7-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxylic acid

[0194] Add 7-bromo-4-hydroxypyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (100 mg, 0.35 mmol) into a 100 mL single-neck flask, add excess phosphorus oxychloride and triethylamine (0.15 mL, 0.39 mmol) to it, stir at 110°C overnight, after LC-MS shows that the reaction is complete, slowly add the reaction solution to ice water, extract with ethyl acetate twice, collect the organic phase, wash with water twice, saturated brine once, dry over anhydrous sodium sulfate, concentrate to obtain the crude product. ESI-MS m / z: 274.9 [M-H] - .

[0195] Step 5: Preparation of 7-bromo-4-phenoxy-pyrrolo[1,2-b]pyridazine-3-carboxylic acid

[0196] 7-bromo-4-chloropyrrolo[l,2-b]pyridazine-3-carboxylic acid (241 mg, 0.88 mmol) was dissolved in tetrahydrofuran, phenol (124 mg, 1.32 mmol) and potassium tert-butoxide (198 mg, 1.76 mmol) were added, and the mixture was condensed and refluxed at 80 °C. After the reaction was completed by LC-MS monitoring, the reaction solution was extracted with ethyl acetate twice, the organic phase was collected, washed with water twice, saturated brine once, dried over anhydrous sodium sulfate, and concentrated to obtain the target crude product. ESI-MS m / z: 333.0 [M+H] + .

[0197] Step 6: Preparation of 4-phenoxy-pyrrolo[l,2-b]pyridazine-3-carboxylic acid

[0198] 7-bromo-4-phenoxy-pyrrolo[l,2-b]pyridazine-3-carboxylic acid (150 mg, 0.45 mmol) was added to a 100 mL single-neck flask, and palladium-carbon (7.5 mg, 10%) and triethylamine (23 mg, 0.23 mmol) were added. The mixture was protected with hydrogen and reacted at room temperature. After the reaction was completed by LC-MS monitoring, the mixture was filtered and concentrated to obtain the crude product. ESI-MS m / z: 255.0 [M+H] + .

[0199] Step 7: Preparation of (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenoxy- pyrrolo[l,2-b]pyridazine-3-carboxamide

[0200] The crude 4-phenoxy-pyrrolo[l,2-b]pyridazine-3-carboxylic acid was placed in a 100 mL single-neck flask, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (205 mg, 0.54 mmol), N,N-diisopropyl ethylamine (116 mg, 0.90 mmol), and 8 mL of N,N-dimethylformamide were added. After 10 min, (S,E)-l-cyclopropyl-3-(methylsulfonyl)prop-2-en-l-amine (78 mg, 0.45 mmol) was added, and the mixture was reacted at room temperature. After the reaction was completed by LC-MS monitoring, the reaction solution was extracted with ethyl acetate twice, the organic phase was collected, washed with water twice, saturated brine once, dried over anhydrous sodium sulfate, concentrated, and the target product was obtained by preparation. ESI-MS m / z: 410.0 [M-H] -

[0201] 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 8.2 Hz, 1H), 8.43 (s, 1H), 7.99 (dd, J = 2.6, 1.5 Hz, 1H), 7.50 - 7.35 (m, 2H), 7.25 - 7.15 (m, 3H), 6.83 - 6.71 (m, 3H), 5.99 (dd, J = 4.5, 1.5 Hz, 1H), 4.09 (td, J = 8.4, 4.0 Hz, 1H), 2.93 (s, 3H), 1.09 - 0.97 (m, 1H), 0.54 - 0.44 (m, 1H), 0.40 - 0.29 (m, 2H), 0.25 - 0.15 (m, 1H).

[0202] Example 14: (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6-fluoro-4- phenoxy-pyrrolo[1,2-b]pyridazine-3-carboxamide

[0203] The synthesis method refers to Example 13, except that 5-bromo-1H-pyrrole-2- carboxylic acid methyl ester is replaced by 4-fluoro-1H-pyrrole-2-carboxylic acid methyl ester.

[0204] ESI-MS m / z: 430.1 [M+H] + .

[0205] 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 8.2 Hz, 1H), 8.43 (s, 1H), 7.99 (dd, J = 2.6, 1.5 Hz, 1H), 7.50 - 7.35 (m, 2H), 7.25 - 7.15 (m, 3H), 6.83 - 6.71 (m, 3H), 5.99 (dd, J = 4.5, 1.5 Hz, 1H), 4.09 (td, J = 8.4, 4.0 Hz, 1H), 2.93 (s, 3H), 1.09 - 0.97 (m, 1H), 0.54 - 0.44 (m, 1H), 0.40 - 0.29 (m, 2H), 0.25 - 0.15 (m, 1H).

[0206] Example 15: 1-(2-(cyclopropyldifluoromethyl)-4-phenoxy-7,8-dihydropyrido[4,3- d]pyrimidin-6(5H)-yl)-3-(1-(methylsulfonyl)pyrrolidin-3-yl)prop-2-yn-1-one

[0207] Step 1: Preparation of tert-butyl 2-chloro-4-phenoxy-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carboxylate

[0208] Charge 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylic acid tert-butyl ester (1.0 g, 3.4 mmol) into a round bottom flask, add dropwise phenol (0.32 g, 3.4 mmol) in N,N-dimethylformamide, add potassium carbonate (0.56 g, 4.1 mmol), then stir at 50 °C for 12 hours. After cooling to room temperature, quench the reaction with water, extract with ethyl acetate, backwash with water, wash with saturated sodium chloride, concentrate under reduced pressure, and purify by column chromatography on silica gel to obtain the product as a yellow oily liquid 1.08 g. ESI-MS m / z: 361.9 [M+H] + .

[0209] Step 2: Preparation of 2-(1-cyclopropylethenyl)-4-phenoxy-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carboxylic acid tert-butyl ester

[0210] Charge 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylic acid tert-butyl ester (1.0 g, 3.4 mmol) into a round bottom flask, add dropwise phenol (0.32 g, 3.4 mmol) in N,N-dimethylformamide, add potassium carbonate (0.56 g, 4.1 mmol), then stir at 50 °C for 12 hours. After cooling to room temperature, quench the reaction with water, extract with ethyl acetate, backwash with water, wash with saturated sodium chloride, concentrate under reduced pressure, and purify by column chromatography on silica gel to obtain the product as a yellow oily liquid 1.08 g. ESI-MS m / z: 361.9 [M+H] + .

[0211] Step 3: Preparation of 2-(cyclopropanecarbonyl)-4-phenoxy-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carboxylic acid tert-butyl ester

[0212] tert-Butyl 2-(1-cyclopropylethenyl)-4-phenoxy-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carboxylate (0.51 g, 1.30 mmol), potassium osmate dihydrate (0.05 g, 0.13 mmol) and sodium periodate (1.38 g, 6.5 mmol) were added into a reaction flask, propyl alcohol (2 mL) and water (2 mL) were added, the mixture was stirred at room temperature for 1 hour under argon. The reaction mixture was extracted with dichloromethane, washed with water, washed with saturated sodium chloride, concentrated under reduced pressure, purified by silica gel column chromatography to obtain the product 0.34 g. ESI-MS m / z: 396.0 [M+H] + .

[0213] Step 4: Preparation of tert-butyl 2-(cyclopropanecarbonyl)-4-phenoxy-7,8- dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

[0214] tert-Butyl 2-(cyclopropanecarbonyl)-4-phenoxy-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carboxylate (0.18 g, 0.45 mmol) was added into diethylamine trifluoride (2 mL), stirred at 25 °C for 48 hours. The reaction was complete, quenched with ice water, extracted with dichloromethane, washed with water, washed with saturated sodium chloride, concentrated under reduced pressure, purified by silica gel column chromatography to obtain the product 0.15 g. ESI-MS m / z: 418.0 [M+H] + .

[0215] Step 5: Preparation of 2-(cyclopropanecarbonyl)-4-phenoxy-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidine

[0216] tert-Butyl 2-(cyclopropanecarbonyl)-4-phenoxy-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carboxylate (0.30 g, 0.78 mmol) was added into dichloromethane (3 mL) and trifluoroacetic acid (1 mL), stirred at 25 °C for 1 hour. After the reaction was complete, quenched with ice water, adjusted the solution pH to weak alkaline with potassium hydroxide, extracted with dichloromethane, washed with water, washed with saturated sodium chloride, concentrated under reduced pressure, purified by silica gel column chromatography to obtain the product. ESI-MS m / z: 318.0 [M+H] + .

[0217] Step 6: Preparation of tert-butyl 3-(3-(2-(cyclopropanecarbonyl)-4- phenoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-3-oxoprop-1-yn-1-yl)pyrrolidine-1- carboxylate

[0218] Into a round bottom flask was placed 2-(cyclopropyldifluoromethyl)-4- phenoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.54 g, 0.17 mmol) and N,N- dimethylformamide (5 mL) was added. To the reaction was added 3-(1-(tert- butyloxycarbonyl)pyrrolidin-3-yl)propynoic acid (0.05 g, 0.17 mmol), N,N,N,N- tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (0.11 g, 0.26 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.72 mmol) and the reaction was stirred at room temperature. Upon completion, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give the product. ESI-MS m / z: 483.1 [M-56+H] + .

[0219] Step 7: Preparation of 1-(2-(cyclopropyldifluoromethyl)-4-phenoxy-7,8- dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-3-(pyrrolidin-3-yl)prop-2-yn-1-one

[0220] Into a round bottom flask was placed 3-(3-(2-(cyclopropyldifluoromethyl)-4- phenoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-3-oxoprop-1-yn-1-yl)pyrrolidine- 1-carboxylic acid tert-butyl ester (0.34 g, 0.78 mmol) and dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was added. The reaction was stirred at 25 °C for 1 h. Upon completion, the reaction was quenched with ice water and the pH of the solution was adjusted to weak alkaline with potassium hydroxide. The reaction was extracted with dichloromethane, washed with water and saturated sodium chloride. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give the product 0.33 g. ESI-MS m / z: 439.1 [M+H] + .

[0221] Step 8: Preparation of 1-(2-(cyclopropyldifluoromethyl)-4-phenoxy-7,8- dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-3-(1-(methylsulfonyl)pyrrolidin-3-yl)prop-2- yn-1-one

[0222] To a solution of (E)-4-(cyclopropylsulfonyl)-N-(1-(3,3-difluorocyclobutyl)-3- (methylsulfonyl)allyl)-5-fluoro-2-phenoxybenzamide (0.1 g, 0.16 mmol) in methanol (2 mL) was added sodium borohydride (0.01 g, 0.32 mmol) at 0 °C. The mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of water (0.2 mL) and methanol (0.2 mL). The mixture was concentrated under reduced pressure. The residue was diluted with water (2 mL) and extracted with dichloromethane (2 mL). The organic phase was washed with saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the product 0.01 g. ESI-MS m / z: 550.9 [M+H] + .

[0223] 1 H NMR (400 MHz, DMSO-d6) δ 7.55-7.40 (m, 2H), 7.40-7.17 (m, 3H), 4.98 (s, 1H), 4.74 (s, 1H), 4.13-3.89 (m, 2H), 3.66-3.35 (m, 4H), 3.09-2.86 (m, 5H), 2.31-2.23 (m, 1H), 2.03 (m, 1H), 1.66-1.36 (m, 2H), 0.65-0.43 (m, 4H).

[0224] Example 16: (E)-4-(cyclopropylsulfonyl)-N-(1-(3,3-difluorocyclobutyl)-3- (methylsulfonyl)allyl)-5-fluoro-2-phenoxybenzamide

[0225] Step 1: Preparation of 3,3-difluorocyclobutanecarboxaldehyde

[0226] To (3,3-difluorocyclobutyl)methanol (10 g, 81.9 mmol) and Dess-Martin periodinane (48.6 g, 114.7 mmol) was added dichloromethane (260 mL) and stirred for 14 hours. The mixture was filtered and the filter cake was rinsed with dichloromethane. The organic phase was then washed with saturated sodium thiosulfate solution, saturated sodium bicarbonate solution and saturated sodium chloride solution. It was dried over anhydrous sodium sulfate, filtered to give 3,3-difluorocyclobutanecarboxaldehyde crude 3.0 g.

[0227] Step 2: Preparation of (Z)-N-((3,3-difluorocyclobutyl)methylene)-2-methylpropane-2- sulfinamide

[0228] To a solution of 3,3-difluorocyclobutanecarboxaldehyde (3.0 g, 24.98 mmol) in dichloromethane (50 mL) was added tert-butylsulfinamide (2.52 g, 20.82 mmol) and anhydrous copper sulfate (8.3 g, 52.04 mmol) and stirred at room temperature for 60 h. The reaction was completed, the mixture was filtered, and then saturated sodium chloride was added, extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and purified by column chromatography on silica gel to give the product 2.5 g. ESI-MS m / z: 224.1 [M+H] + .

[0229] Step 3: Preparation of N-(1-(3,3-difluorocyclobutyl)allyl)-2-methylpropane-2- sulfinamide

[0230] To a solution of (Z)-N-((3,3-difluorocyclobutyl)methylene)-2-methylpropane-2- sulfinamide (2.5 g, 11.2 mmol, 1.0 eq) in dichloromethane (100 mL) was added vinylmagnesium bromide (33.6 mL, 33.6 mmol) dropwise slowly at -50 °C after replacing with argon. The reaction was slowly recovered to room temperature and stirred for 4 h. The reaction was completed, quenched with water, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and purified by column chromatography on silica gel to give the product 0.4 g. ESI-MS m / z: 252.0 [M+H] + .

[0231] Step 4: Preparation of 1-(3,3-difluorocyclobutyl)prop-2-en-1-amine hydrochloride

[0232] N-(1-(3,3-difluorocyclobutyl)allyl)-2-methylpropane-2-sulfinamide (0.22 g, 0.88 mmol) was dissolved in hydrogen chloride ethyl acetate solution (10 mL) and stirred at room temperature for 1 h. The reaction was completed, and the product was obtained by rotary evaporation. ESI-MS m / z: 148.0 [M+H] + .

[0233] Step 5: Preparation of 4-(cyclopropylsulfonyl)-N-(1-(3-3-difluorocyclobutyl)allyl)-5- fluoro-2-phenoxybenzamide

[0234] Take 1-(3,3-difluorocyclobutyl)prop-2-en-1-amine hydrochloride (60 mg, 0.32 mmol) into a round-bottom flask, dissolve in N,N-dimethylformamide (3 mL), add 4-(cyclopropylsulfonyl)-5-fluoro-2-phenoxybenzoic acid (90 mg, 0.27 mmol), N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (153 mg, 0.40 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.80 mmol) into the reaction system, react at room temperature, after the reaction is completed, add water, extract with ethyl acetate, wash with water, dry over anhydrous sodium sulfate, and purify by silica gel column chromatography to obtain 107 mg of the product. ESI-MS m / z: 465.9 [M+H] + .

[0235] Step 6: Preparation of 4-(cyclopropylsulfonyl)-N-(1-(3,3-difluorocyclobutyl)-2-oxoethyl)-5-fluoro-2-phenoxybenzamide

[0236] Put 4-(cyclopropylsulfonyl)-N-(1-(3,3-difluorocyclobutyl)allyl)-5-fluoro-2-phenoxybenzamide (70 mg, 0.15 mmol), potassium osmate dihydrate (5.5 mg, 0.015 mmol) and sodium periodate (64 mg, 0.30 mmol) into a reaction bottle, add propanol (1.2 mL) and water (1.2 mL), and stir the mixture at room temperature for 2 hours under argon replacement. Extract the reaction mixture with dichloromethane, wash with water, wash with saturated sodium chloride, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 47 mg of the title product. ESI-MS m / z: 465.9 [M-H] -

[0237] Step 7: Preparation of (E)-4-(cyclopropylsulfonyl)-N-(1-(3,3-difluorocyclobutyl)-3-(methylsulfonyl)allyl)-5-fluoro-2-phenoxybenzamide

[0238] Take diethyl(methylsulfonyl)phosphine (45 mg, 0.19 mmol) into a round-bottom flask, dissolve in tetrahydrofuran (3 mL), add sodium hydride (10 mg, 0.26 mmol) in an ice bath, and after 0.5 h, add a tetrahydrofuran solution of 4-(cyclopropylsulfonyl)-N-(1-(3,3-difluorocyclobutyl)-2-oxoethyl)-5-fluoro-2-phenoxybenzamide (60 mg, 0.13 mmol) at -10°C. Stir the mixture at -10°C for 2 hours. Extract the reaction mixture with dichloromethane, wash with water, wash with saturated sodium chloride, concentrate under reduced pressure, and prepare to obtain 19 mg of the title product.

[0239] 1 H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J = 8.7 Hz, 1H), 7.89 (d, J = 9.5 Hz, 1H), 7.50-7.41 (m, 2H), 7.26-7.20 (m, 2H), 7.15-7.09 (m, 2H), 6.90-6.83 (m, 1H), 6.74-6.65 (m, 1H), 4.88-4.73 (m, 1H), 3.06-2.98 (m, 1H), 2.89 (s, 3H), 2.66-2.55 (m, 2H), 2.44-2.30 (m, 3H), 1.14-1.05 (m, 4H). ESI-MS m / z: 544.1 [M+H] + .

[0240] (E)-4-(cyclopropylsulfonyl)-N-(1-(3,3-difluorocyclobutyl)-3- (methylsulfonyl)allyl)-5-fluoro-2-phenoxybenzamide was separated by preparative HPLC (C18 column; detection wavelength: 225 nm; mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile solution; elution program 0-15 min, 45%-90% B) to give isomer 1 and isomer 2 of the title compound.

[0241] Isomer 1 (Example 17): Retention time 10.142 min. 1 H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J = 8.7 Hz, 1H), 7.89 (d, J = 9.5 Hz, 1H), 7.50-7.41 (m, 2H), 7.26-7.20 (m, 2H), 7.15-7.09 (m, 2H), 6.90-6.83 (m, 1H), 6.74-6.65 (m, 1H), 4.88-4.73 (m, 1H), 3.06-2.98 (m, 1H), 2.89 (s, 3H), 2.66-2.55 (m, 2H), 2.44-2.30 (m, 3H), 1.14-1.05 (m, 4H).

[0242] ESI-MS m / z: 544.1 [M+H] + .

[0243] Isomer 2 (Example 18): Retention time 10.477 min. 1H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.88 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 9.5 Hz, 1H), 7.78 (d, J = 9.4 Hz, 1H), 7.28 - 7.24 (m, 1H), 7.16 - 7.12 (m, 1H), 7.11 - 7.06 (m, 1H), 6.91 - 6.82 (m, 1H), 6.65 - 6.60 (m, 1H), 6.17 - 6.09 (m, 1H), 3.88 (d, J = 7.5 Hz, 2H), 3.06 - 2.99 (m, 1H), 2.89 (s, 3H), 2.71 - 2.63 (m, 2H), 2.41 - 2.32 (m, 2H), 1.14 - 1.10 (m, 4H).

[0244] ESI-MS m / z: 544.1 [M+H] + .

[0245] Referring to the synthesis method of the above examples, using different raw materials, the compounds of examples 19-28 in table 1 were prepared.

[0246] Table 1

[0247] Experimental Example 1: WRN helicase activity assay

[0248] 1. Experimental materials

[0249] 1.1 Experimental reagents

[0250] Capture DNA (Genscript, Piscataway, NJ, USA); dsDNA-secquence 2 (Genscript, Piscataway, NJ, USA); WRN (517-1238) (ICE, S2212T-H56HZ);

[0251] ATP (Ark Pharm, Ak-54737).

[0252] 1.2 Preparation of compound solution

[0253] The above inventive example compounds were all prepared into 10 mM storage solution with DMSO.

[0254] 1.3 Experimental reaction conditions

[0255] 2 Experimental method

[0256] 2.1. 384-well dilution plate plus 40 μL compound;

[0257] 2.2. Compound was serially diluted with DMSO at 1:3 for 10 concentration gradients;

[0258] 2.3. 0.15 μL diluted compound solution per row was transferred to 384-well assay plate by Echo, 2 replicates;

[0259] 2.4. 5 μL enzyme working solution containing 0.2 mM ATP was added to 384-well assay plate, centrifuged at 1000 rpm for 1 min;

[0260] 2.5. Incubated at 25°C for 4 h;

[0261] 2.6. 5 μL working solution (dsDNA-sequence 2 and capture DNA) was added, centrifuged at 1000 rpm for 1 min;

[0262] 2.7. 5 μL ATP working solution was added to initiate the reaction, centrifuged at 1000 rpm for 1 min;

[0263] 2.8. Incubated at 25°C for 30 min;

[0264] 2.9. BMG was used to read Ex620 nm and Em685 nm fluorescence signals. Data fitting was performed to obtain IC50 value by using the formula: inh% = 100*(ave High control-cpd well) / (ave High control-ave Low control). 50 The experimental results are shown in Table 2.

[0265] Table 2

[0266] Experimental Example 2: In vitro cell activity evaluation of compounds

[0267] 1. Experimental materials

[0268] Experimental cell: Human colorectal cancer cell HCT116 was purchased from Wuhan Pons Life Science Co., Ltd.

[0269] Tested compound: The compound of the application prepared in the above examples, each compound was prepared into 20 mM stock solution with DMSO, and the drug was diluted with complete culture medium, and the final concentration of the drug was started from 5 μM as the highest concentration, and was serially diluted at 1:3 gradient to 9 concentration gradients: 5 μM, 1.25 μM, 1.11 μM, 0.313 μM, 0.0195 μM, 0.00488 μM, 0.00122 μM, 0.000305 μM, 0.000076 μM.

[0270] Reagents: McCoy's 5A (Gibco, 16600-082); Fetal Bovine Serum (Gibco, 10099-141); Penicillin-Streptomycin (Gibco, 15140-122); CellTiter-Glo Luminescent Cell Viability Assay (Promega, G7571).

[0271] 2. Experimental method

[0272] 2.1 Cell resuscitation:

[0273] Take the HCT116 cell cryopreservation tube from the liquid nitrogen tank and place it in a 37°C water bath. Gently shake it to thaw it as quickly as possible. After thawing, remove the cryopreservation tube, sterilize it with an alcohol cotton ball, and unscrew the cap. Suck the cell liquid into a centrifuge tube and add 1 mL of McCoy's 5A medium containing 10% FBS. Mix well and centrifuge in a centrifuge at 1000 rpm for 5 min. Then discard the supernatant and resuspend the cells in complete medium. Inoculate the culture dish with the appropriate concentration. Place it in a 37°C, 5% CO2 incubator.

[0274] 2.2 Cell culture and passage:

[0275] When the cells grow to about 80-90% confluence, discard the original culture medium (McCoy's 5A medium + 10% FBS + 1% penicillin-streptomycin), wash the residual medium with 1 mL of PBS and discard it. Add 1 mL of trypsin digestion solution and digest for 2-3 min. Under a microscope, observe that the cell pseudopods retract and round, but the cells have not yet detached in patches. At this time, discard the trypsin and terminate the digestion with 1-2 mL of complete medium. Gently blow and collect the cell suspension, centrifuge at 1000 rpm for 5 min. Remove the supernatant and resuspend the cells in complete medium. Inoculate the culture dish with the desired density and place it in a 37°C, 5% CO2 incubator. Replace the culture medium or passage every 2-3 days according to the growth of the cells.

[0276] 2.3 Experimental procedure:

[0277] Day 1 of the experiment:

[0278] After the HCT116 cells are passaged, resuspend them in complete medium at the corresponding density and inoculate them into a 96-well culture plate: fill the outermost 36 wells of the 96-well plate with 200 μL of PBS to prevent the evaporation of the edge medium from being too fast, causing the culture conditions in the inner wells to differ too much; the remaining 60 wells are plated; each well contains 750 cells in 100 μL of complete medium, and 2 replicate wells are set up for each concentration. Place it in a 5% CO2 incubator at 37°C for 24 h.

[0279] Day 2 of the experiment:

[0280] HCT116 cells were treated with 100 μL of (2x) drug in addition to the original media (100 μL) and two replicates were set up for each concentration. The cells were then incubated in a 5% CO2 incubator for 4 days.

[0281] On day 5 of the experiment:

[0282] After 4 days of treatment, the CellTiter-Glo Luminescent Cell Viabillity Assay was removed from the freezer and allowed to equilibrate to room temperature for 30 min. The media was aspirated from the wells and the Celltiter-Glo reagent was diluted 1:1 (equal volumes) with complete media. 150 μL of the diluted Celltiter-Glo reagent was added to each well and the plate was shaken for 2 min at room temperature. After a 10 min incubation at room temperature, 100 μL of the luminescent signal was removed from each well and shaken. The samples were read in the luminometer under the following conditions: 500 ms. The percent inhibition for each well was calculated relative to the solvent control well using the A.U. values derived from the luminometer: Inhibition (%) = 100 - (A.U. experimental well - A.U. blank well) / (A.U. solvent control well - A.U. blank well)*100. The IC50 values were determined by fitting a four parameter logistic S-shaped curve to the data using GraphPad 6.0 software. 50 The results of the experiment are shown in Table 3.

[0283] Table 3

[0284] The results of the experiment show that the compounds of the application have good proliferative inhibitory activity on human colorectal cancer cells HCT116.

[0285] Experimental Example 3: Pharmacokinetic experiment

[0286] 1. Experimental materials

[0287] Compound: The compound of the application prepared in the above examples. The drug vehicle was 10% Solutol / 20% PG / 70% Saline (v / v / v). The oral drug was prepared as a 0.5 mg / mL clear solution; the intravenous drug was prepared as a 0.1 mg / mL clear solution.

[0288] Animals: Male BALB / c mice, weighing 18-20 g. An acclimation period of 2-3 days was given before the experiment.

[0289] Instrument: AB API4500 triple quadrupole liquid chromatography-mass spectrometer with an electrospray ion source (ESI), LC-30AD double pump; SIL-30AC automatic sampler; CTO-30AC column oven; DGU-20A3R degasser; Analyst QSA01.01 chromatography workstation; Milli-Q ultrapure water generator (Millipore Inc); Qilinbeier Vortex-5 shaker; HITACHI CF16RⅩⅡtabletop high-speed refrigerated centrifuge.

[0290] 2. Experimental method

[0291] (1) 3 mice per group, intragastrically (IG) administered with 10 mg / kg of the compound of the present application, and intravenously (IV) administered with 1 mg / kg of the compound of the present application;

[0292] (2) After intravenous or oral administration, blood was collected from the orbital venous plexus into heparinized EP tubes (0.6 mL) at 5 min, 15 min, 30 min, 1 h, 2 h, 6 h, 10 h, and 24 h, and the upper plasma was taken after centrifugation at 8000 rpm / min for 5 min, and stored at -20℃, and analyzed by LC-MS / MS;

[0293] (3) The blood concentration-time curve was plotted according to the blood concentration data obtained by the above steps, and the pharmacokinetic parameters were calculated using WinNonlin software.

[0294] 3. Experimental results

[0295] The experimental results are shown in Tables 4 and 5.

[0296] Table 4 Intravenous administration

[0297] Table 5 Oral administration

[0298] From the above experiments, it can be seen that the compound of the present application has good half-life, in vivo exposure, and bioavailability when administered orally.

[0299] Although the present application has been described in detail above, those skilled in the art will understand that various modifications and changes can be made to the present application without departing from the spirit and scope of the present application. The scope of the present application is not limited to the detailed description above, but should be attributed to the claims.

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, ###0001### (I) wherein Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally substituted with one or more groups selected from halo, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl, alkylaminoacyl, dialkylamino, haloalkylacyl, hydroxyalkylacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; X and Y are each independently selected from CH and N; W is selected from halo, cyano, amino, alkyl, cycloalkyl, heterocyclyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, alkylamino, aryl and heteroaryl, optionally substituted with one or more groups selected from halo, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy; R 1 selected from the group consisting of halogen, cyano, amino, alkyl, cycloalkyl, heterocyclyl, heterocyclenyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, monoalkylamino, dialkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylaminoacyl, aryl, and heteroaryl, m is selected from 0, 1, 2, and 3; and R 2 is selected from alkyl, haloalkyl, haloalkoxy, hydroxyalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

2. The compound of claim 1 or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, wherein ring A is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl and 5-12 membered heteroaryl, optionally substituted with one or more groups selected from halogen, hydroxyl, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxyl C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxyl C 1-6 alkoxy, the heteroatom selected from N, O, S, and P.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isomer, solvate, crystalline or prodrug thereof, wherein W is selected from the group consisting of halogen, cyano, amino, C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, C 1-6 alkylamino, C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more groups selected from halogen, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, and the heteroatom is selected from the group consisting of N, O, S and P.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, wherein R 1 selected from halo, cyano, amino, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, 3-10 membered heterocyclenyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, monoC 1-6 alkylamino, diC 1-6 alkylamino, C 1-6 alkylcarbonylamino, C 1-6 alkylcarbonyl, aminoacyl, C 1-6 alkylaminoacyl, diC 1-6 alkylamino, C 6-10 aryl and 5-10 membered heteroaryl, the heteroatoms selected from N, O, S, and P, m is selected from 0, 1, 2, and 3; and R 2 selected from C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, hydroxyC 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, the heteroatoms selected from N, O, S, and P.

5. A compound of Formula (II) or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, wherein Ring B is absent or is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally substituted with one or more groups selected from halo, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, alkylamino; Ring C and Ring D together with the atoms to which they are attached form aryl and aryl, aryl and heteroaryl, heteroaryl and heteroaryl; L1is selected from -C(O)-NH-, -NH- and -C(O)-CH=C-; L2is selected from -CH=CH- and and R 3 and R 4 each independently is selected from the group consisting of hydrogen, halogen, amino, alkyl, cycloalkyl, heterocyclyl, haloalkyl, aryloxy, cycloalkylalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, aryl, and heteroaryl, optionally substituted with one or more groups selected from halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, p and q are each independently selected from 0, 1, 2, and 3.

6. The compound of claim 5 or a pharmaceutically acceptable salt, isomer, solvate, crystalline or prodrug thereof, wherein ring B is absent or is selected from C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-8 membered heteroaryl, optionally substituted with one or more groups selected from halogen, hydroxyl, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxyl C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxyl C 1-6 alkoxy, amino, C 1-6 alkylamino, the heteroatom selected from N, O, S and P, ring C and ring D together with the atoms to which they are attached form a 6 membered aryl and 6 membered aryl, 6 membered aryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl.

7. The compound of claim 5 or 6, or a pharmaceutically acceptable salt, isomer, solvate, crystalline or prodrug thereof, wherein R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, amino, oxo, C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, halogenoC 1-6 alkyl, C 6-12 aryloxy, cycloalkylC 1-6 alkyl, C 1-6 alkoxy, halogenoC 1-6 alkoxy, hydroxyC 1-6 alkoxy, C 6-12 aryl, and 5-12 membered heteroaryl, optionally substituted with one or more groups selected from halogen, hydroxy, C 1-6 alkyl, halogenoC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxy, halogenoC 1-6 alkoxy, hydroxyC 1-6 alkoxy, amino, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, said heteroatoms selected from N, O, S and P, p and q are each independently selected from 0, 1, 2 and 3.

8. A compound, or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof, wherein the compound is a compound selected from the group consisting of:

9. A pharmaceutical composition comprising a compound of any one of claims 1-8, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.

10. Use of a compound of any one of claims 1-8, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, or a pharmaceutical composition of claim 9, for the manufacture of a medicament for the treatment of a disease associated with WRN, preferably the disease is cancer.

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