Aromatic amide derivative and use thereof

Abstract

An aromatic amide derivative, a preparation method therefor, and a use of said compound in preventing and / or treating diseases, especially in tumor treatment. The aromatic amide derivative is a MEK / RAF inhibitor having advantages such as relatively good activity and safety, and shows good application prospects in preventing and / or treating tumors related to the MAPK pathway.

Description

Aromatic amide derivatives and uses thereof Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry and relates to a class of aromatic amide derivatives, a preparation method thereof and the application of the compounds in preventing and / or treating diseases, in particular tumor treatment. Background Art

[0002] Aromatic amide structures are widely present in drug molecules and serve as important pharmacophores, interacting with drug target proteins and improving drug performance. For example, the following drugs, either marketed or in clinical trials, all contain aromatic amide structures.

[0003] The RAS-RAF-MEK-ERK cascade is a crucial signaling pathway and one of the most actively studied. Aberrant activation of this pathway affects normal cell proliferation, differentiation, apoptosis, and metastasis. In addition to lung cancer, aberrant activation of this pathway is more prevalent and impacts high-mortality cancers such as pancreatic cancer (>90%) and colorectal cancer (>50%). RAF is a serine / threonine protein kinase, typically activated by the RAS protein kinase. MEK is a dual-specificity kinase that phosphorylates both serine / threonine and tyrosine residues. Activated MEK activates downstream ERK, allowing it to enter the cell nucleus and regulate various transcription factors, inducing gene expression and ultimately promoting cell proliferation. Blocking a single target in this pathway is often insufficient to achieve optimal anti-tumor effects, and single-target drugs have drawbacks such as susceptibility to mutational resistance and significant toxic side effects. Currently, combined Raf and MEK inhibitors are used clinically to block both key targets in this pathway to overcome drug resistance caused by pathway reactivation, thereby delaying the development of drug resistance.

[0004] Developing dual-target inhibitors of RAF and MEK is an effective anti-tumor strategy. Among the RAF / MEK inhibitors currently under development, VS-6766 (relevant literature, such as WO2007091736) has made rapid clinical progress. It has demonstrated efficacy in treating tumors with multiple MAPK pathway activations, with associated adverse reactions reported in clinical trials. Another type of compound has also shown activity in lung cancer models (relevant literature, such as WO2021149776).

[0005] The development of dual-target inhibitors for RAF and MEK requires, on the one hand, improving the inhibitory activity and efficacy of the compounds, and on the other hand, focusing on safety. The development of new dual-target inhibitors for RAF and MEK with improved efficacy and safety is of great significance.

[0006] Summary of the Invention

[0007] The present invention discloses an aromatic amide MEK / RAF inhibitor, whose stereoisomers, tautomers or pharmaceutically acceptable salts have the advantages of high activity and good safety, and show good application prospects in preventing and / or treating tumors related to the MAPK pathway.

[0008] The present invention provides a compound represented by formula (A), its stereoisomers, tautomers or pharmaceutically acceptable salts,

[0009] wherein M is selected from oxygen or sulfur;

[0010] X is selected from a bond, oxygen, sulfur, -C(O)-, -NR1C(O)-, -C(O)NR1-, -NR1S(O)-, -S(O)NR1-, -NR1SO2-, -SO2NR1-, -NR1- or -CR1R2-;

[0011] Ring A and Ring B are each independently selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

[0012] L is selected from a bond, oxygen, sulfur, -C(O)-, -NR1C(O)-, -C(O)NR1-, -NR1S(O)-, -S(O)NR1-, -NR1SO2-, -SO2NR1-, -NR1-, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0013] R 10 Selected from hydrogen, deuterium, halogen, aldehyde, cyano, hydroxyl, -OR a , -SR a , -NR a R b , -C(O)R a , -S(O)R a , -S(O)2R a ,-(CR 2a R 2b ) p SO2NR a R b ,-(CR 2a R 2b ) p NR a SO2NR b R c ,-(CR 2a R 2b ) p NR a SO2R b ,-(CR 2aR 2b ) p C(O)NR a R b ,-(CR 2a R 2b ) p NR a C(O)NR b R c ,-(CR 2a R 2b ) p NR a C(O)R b , substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0014] R 9a , R 9b Each independently selected from each independently selected from hydrogen, deuterium, halogen, aldehyde, cyano, hydroxyl, -OR a , -SR a , -NR a R b , -C(O)R a , -S(O)R a , -S(O)2R a , substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; or two adjacent substituents together form a substituted or unsubstituted 3-15 membered cyclic structure;

[0015] Each R1, R2, R 2a , R 2b , R 3a , R 3b , R a , R b , R c are each independently selected from hydrogen, deuterium, halogen, aldehyde, cyano, hydroxyl, -OR a , -SR a , -NR a R b , -C(O)R a , -S(O)R a , -S(O)2R a, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; or two adjacent substituents together form a substituted or unsubstituted 3-15 membered cyclic structure;

[0016] m is selected from 0, 1, 2, 3 or 4;

[0017] p is selected from 0, 1, 2, 3 or 4.

[0018] The present invention provides a compound represented by formula (A-1), its stereoisomers, tautomers or pharmaceutically acceptable salts,

[0019] wherein W is selected from a bond, oxygen or sulfur;

[0020] M is selected from oxygen or sulfur;

[0021] X is selected from a bond, oxygen, sulfur, -C(O)-, -NR1C(O)-, -C(O)NR1-, -NR1S(O)-, -S(O)NR1-, -NR1SO2-, -SO2NR1-, -NR1- or -CR1R2-;

[0022] Ring A and Ring B are each independently selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

[0023] L is selected from a bond, oxygen, sulfur, -C(O)-, -NR1C(O)-, -C(O)NR1-, -NR1S(O)-, -S(O)NR1-, -NR1SO2-, -SO2NR1-, -NR1-, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0024] R 10 Selected from hydrogen, deuterium, halogen, aldehyde, cyano, hydroxyl, -OR a , -SR a , -NR a R b , -C(O)R a , -S(O)R a , -S(O)2R a ,-(CR 2a R 2b ) p SO2NR a R b ,-(CR 2aR 2b ) p NR a SO2NR b R c ,-(CR 2a R 2b ) p NR a SO2R b ,-(CR 2a R 2b ) p C(O)NR a R b ,-(CR 2a R 2b ) p NR a C(O)NR b R c ,-(CR 2a R 2b ) p NR a C(O)R b , substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0025] Each R1, R2, R 2a , R 2b , R 3a , R 3b , R a , R b , R c are each independently selected from hydrogen, deuterium, halogen, aldehyde, cyano, hydroxyl, -OR a , -SR a , -NR a R b , -C(O)R a , -S(O)R a , -S(O)2R a , substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; or two adjacent substituents together form a substituted or unsubstituted 3-15 membered cyclic structure;

[0026] R 8a, R 8b , R 8c , R 8d , R 8e , R 9a are each independently selected from hydrogen, deuterium, halogen, aldehyde, cyano, hydroxyl, -OR a , -SR a , -NR a R b , -C(O)R a , -S(O)R a , -S(O)2R a , substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; or two adjacent substituents together form a substituted or unsubstituted 3-15 membered cyclic structure;

[0027] m is 0, 1, 2, 3 or 4;

[0028] n is 1, 2, 3, 4 or 5;

[0029] p is 0, 1, 2, 3 or 4.

[0030] The present invention provides a compound represented by formula (I), its stereoisomers, tautomers or pharmaceutically acceptable salts,

[0031] wherein W is selected from a bond, oxygen or sulfur;

[0032] V is selected from nitrogen or CR 4e ;

[0033] L is selected from -NR1C(O)-, -C(O)NR1-, C 3-6 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0034] R1 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl;

[0035] R 2a , R 2b , R 3a , R 3b , R4a , R 4b , R 4c , R 4d , R 4e , R 6a , R 6b , R 6c are independently selected from hydrogen, deuterium, halogen, aldehyde, cyano, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl; or two adjacent substituents together form a substituted or unsubstituted 3-10 membered ring structure;

[0036] R7 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl may be optionally selected from deuterium, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 One or more substituents in the cycloalkyl group;

[0037] R 8a , R 8b , R 8c , R 8d , R 8e are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3- 6-cycloalkyl;

[0038] m is 0, 1, 2 or 3;

[0039] n is 1, 2, 3 or 4;

[0040] p is 0, 1, 2 or 3.

[0041] The present invention provides a compound represented by formula (II), its stereoisomers, tautomers or pharmaceutically acceptable salts,

[0042] wherein W is selected from a bond, oxygen or sulfur;

[0043] V is selected from nitrogen or CR 4e ;

[0044] R1 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl;

[0045] R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R 4e , R 6a , R 6b , R 6c are independently selected from hydrogen, deuterium, halogen, aldehyde, cyano, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl; or two adjacent substituents together form a substituted or unsubstituted 3-10 membered ring structure;

[0046] R7 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl may be optionally selected from deuterium, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 One or more substituents in the cycloalkyl group;

[0047] R 8a , R 8b , R 8c , R 8d , R 8e are each independently selected from hydrogen, deuterium, halogen, C1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3- 6-cycloalkyl;

[0048] n is 1, 2, 3 or 4;

[0049] p is 0, 1, 2 or 3.

[0050] The present invention provides the following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,

[0051] The present invention provides a compound represented by formula (III), its stereoisomers, tautomers or pharmaceutically acceptable salts,

[0052] wherein W is selected from a bond, oxygen or sulfur;

[0053] V is selected from nitrogen or CR 4e ;

[0054] Ring A is selected from C 6-10 Aryl or 5-10 membered heteroaryl;

[0055] R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R 4e , R 6a , R 6b , R 6c are independently selected from hydrogen, deuterium, halogen, aldehyde, cyano, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl; or two adjacent substituents together form a substituted or unsubstituted 3-10 membered ring structure;

[0056] R7 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6Alkynyl, wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl can be optionally selected from deuterium, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 One or more substituents in the cycloalkyl group;

[0057] R 8a , R 8b , R 8c , R 8d , R 8e are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3- 6-cycloalkyl;

[0058] m is 0, 1, 2 or 3;

[0059] n is 1, 2, 3 or 4;

[0060] p is 0, 1, 2 or 3.

[0061] The present invention provides the following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,

[0062] The present invention provides a compound represented by formula (IV), its stereoisomers, tautomers or pharmaceutically acceptable salts,

[0063] Wherein, U is selected from nitrogen or CR 5d ;

[0064] V is selected from nitrogen or CR 4e ;

[0065] R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R 4e , R 5a , R 5b , R 5c , R 5d , R 6a , R 6b , R 6c are independently selected from hydrogen, deuterium, halogen, aldehyde, cyano, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl; or two adjacent substituents together form a substituted or unsubstituted 3-10 membered ring structure;

[0066] R7 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl may be optionally selected from deuterium, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 One or more substituents in the cycloalkyl group;

[0067] R 8a , R 8b , R 8c , R 8d , R 8e are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl;

[0068] n is 1, 2, 3 or 4.

[0069] The present invention provides a compound represented by formula (IV-1), its stereoisomers, tautomers or pharmaceutically acceptable salts,

[0070] wherein U is selected from nitrogen or CH;

[0071] V is selected from nitrogen or CR 4e ;

[0072] R 4a , R 4b , R 4c , R 4d , R 4e are independently selected from hydrogen, deuterium, halogen, aldehyde, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl;

[0073] R 5c , R 6b , R 6c are each independently selected from hydrogen, halogen or C 1-6 alkyl;

[0074] R7 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 3-6 Cycloalkyl;

[0075] R 8a , R 8b , R 8c , R 8d , R 8e are each independently selected from hydrogen, deuterium or C 1-6 alkyl;

[0076] n is 1, 2 or 3.

[0077] The present invention provides the following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,

[0078] The present invention provides the following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,

[0079] The present invention provides the following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,

[0080] The present invention provides a compound represented by formula (V), its stereoisomers, tautomers or pharmaceutically acceptable salts,

[0081] wherein U is selected from nitrogen or CH;

[0082] V is selected from nitrogen or CR 4e ;

[0083] R 4a , R 4b , R 4c , R 4d , R 4e , R 5c , R 6b , R 6c are independently selected from hydrogen, deuterium, halogen, aldehyde, cyano, amino, hydroxyl, C 1- 6 alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-6 Cycloalkyl; or two adjacent substituents together form a substituted or unsubstituted 3-10 membered ring structure;

[0084] R7 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl may be optionally selected from deuterium, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 substituted by one or more substituents in the cycloalkyl group;

[0085] R 8a , R 8b , R 8c , R 8d , R 8e are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 3- 6-cycloalkyl;

[0086] n is 1, 2, 3 or 4.

[0087] The present invention provides the following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,

[0088] The present invention provides a pharmaceutical composition comprising a therapeutically effective dose of any one of the compounds of the present invention, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0089] Use of any one of the compounds of the present invention, its stereoisomers, tautomers or pharmaceutically acceptable salts, or the pharmaceutical composition of the present invention in the preparation of drugs for preventing and / or treating tumors.

[0090] Use of any one of the compounds of the present invention, its stereoisomers, tautomers or pharmaceutically acceptable salts, or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing and / or treating diseases mediated by RAF or MEK, particularly tumors.

[0091] The application of the present invention, wherein the tumor includes renal cancer, liver cancer, breast cancer, pancreatic cancer, prostate cancer, melanoma, leukemia, malignant lymphoma, ovarian cancer, head and neck cancer, lung cancer, colorectal cancer, bladder cancer, uterine cancer, etc.

[0092] The present invention also provides a method for inhibiting RAF / MEK protein in cells, comprising contacting the cells with an effective amount of the compound of the present invention, its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of the present invention.

[0093] Detailed description of the invention:

[0094] All technical and scientific terms used in this specification have the same meanings as commonly understood by those skilled in the art.

[0095] The term "hydrogen" refers to H herein.

[0096] The term "deuterium" refers to D herein.

[0097] The term "nitrogen" refers to N herein.

[0098] The term "cyano" refers herein to -CN.

[0099] The term "halogen" as used herein refers to -F, -Cl, -Br and -I.

[0100] The term "aldehyde group" refers herein to -CHO.

[0101] The term "hydroxy" refers herein to -OH.

[0102] The term "amino" or "amine" refers interchangeably to a -NR2 group, wherein each R is, for example, H or a substituent. In some embodiments, the amino group is further substituted to form an ammonium ion, for example, NR 3+ Ammonium moieties are specifically included in the definition of "amino" or "amine." Substituents can be, for example, alkyl, deuterated alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amide, or carboxylate. The R group can be further substituted with one or more (e.g., 1 to 4) groups selected from the group consisting of halogen, cyano, alkenyl, alkynyl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, urea, carbonyl, carboxylate, amine, and amide.

[0103] The term "alkyl" herein refers to a saturated aliphatic hydrocarbon group having a plurality of carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and includes straight-chain and branched hydrocarbon groups. When the alkyl group is preceded by a carbon number limit, such as C 1-6Alkyl refers to an alkyl group having 1 to 6 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, etc. Alkyl groups as described herein may be optionally substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, acyloxy, oxo, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, heterocyclyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aryl or heteroaryl.

[0104] The term "deuterated alkyl" as used herein refers to an alkyl group substituted with deuterium as defined above. Non-limiting examples of deuterated alkyl groups include deuterated methyl, deuterated ethyl, and the like.

[0105] The term "haloalkyl" as used herein refers to an alkyl group substituted with a halogen, wherein halogen includes fluorine, chlorine, bromine, iodine, etc. Non-limiting examples of haloalkyl include monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, etc.

[0106] The term "alkoxy" refers to a group of the formula -OR a Group, where R a When the number of carbon atoms before the alkoxy group is limited, such as C 1-6 Alkoxy refers to an alkoxy group containing 1 to 6 carbon atoms. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

[0107] Alkenyl is an unsaturated hydrocarbon group containing a carbon-carbon double bond. The term "alkenyl" herein refers to an alkyl group containing a carbon-carbon double bond in the molecule, wherein the alkyl group is as defined above. It has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, and more preferably 2 to 6 carbon atoms. When the number of carbon atoms in the alkenyl group is specified, such as C 2-6 Alkenyl refers to that the alkenyl contains 2-6 carbon atoms.Alkenyl described herein can be optionally substituted by one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano group, nitro, hydroxyl, carboxyl, amino, oxo, alkyl, alkoxy, acyl, amide, ester group, amido, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkyloxy, sulfydryl, alkyl mercapto, deuterated alkyl mercapto, sulfone, sulfoxide, silicon, phosphono, deuterated alkyl, heterocyclic radical, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl.Alkenyl non-limiting examples include vinyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, deuterovinyl, deuteropropenyl, deuteroallyl etc.

[0108] Alkynyl is an unsaturated hydrocarbon group containing a carbon-carbon triple bond. The term "alkynyl" herein refers to an alkyl group containing a carbon-carbon triple bond in the molecule, wherein the alkyl group is as defined above. It has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, and more preferably 2 to 6 carbon atoms. When the number of carbon atoms before the alkynyl group is limited, such as C 2-6 Alkynyl refers to that the alkynyl contains 2-6 carbon atoms.Alkynyl can be optionally substituted by one or more following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano group, nitro, hydroxyl, carboxyl, amino, alkyl, oxo, alkoxyl, acyl group, amide groups, ester groups, amido, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkyloxy, sulfydryl, alkyl sulfydryl, deuterated alkyl sulfydryl, sulfone group, sulfoxide group, silicon radical, phosphono, deuterated alkyl, heterocyclic radical, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl.Alkynyl non-limiting examples comprises ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, deuterated 1-propynyl, deuterated 2-propynyl, deuterated propargyl etc.

[0109] The term "cycloalkyl" refers to a stable monovalent non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon atoms and hydrogen atoms, which may include a fused ring system or a bridged ring system, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8, 3 to 6 carbon atoms, and which is saturated or unsaturated and can be connected to the rest of the molecule through a single bond via any suitable carbon atom. When the cycloalkyl group is preceded by a carbon atom number limit, such as C 3-6 Cycloalkyl means that the cycloalkyl group contains 3-6 carbon atoms. Cycloalkyl includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2,3-dihydroindanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-hydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo [2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, adamantyl, octahydro-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-pentalenyl, etc. The cycloalkyl groups described herein may be optionally substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, oxo, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, heterocyclyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkoxy, aryl and heteroaryl.

[0110] The term "heterocyclyl" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring containing at least 1 to 5 heteroatoms selected from nitrogen, oxygen, or sulfur. Aromatic and non-aromatic rings may be 3- to 10-membered monocyclic rings, 4- to 20-membered spirocyclic rings, cyclic rings, or bridged rings. The nitrogen and sulfur atoms optionally substituted in the heterocyclyl ring may be oxidized to various oxidation states. 3- to 12-membered and 5- to 10-membered heterocyclic rings are preferred. Non-limiting examples include oxirane, oxetanyl, oxolanyl, oxhexyl, oxepanyl, oxocanyl, aziridinyl, azetidinyl, azirol, azihexyl, azirinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dithiolanyl, 1,3-dioxohexanyl, 1,3-dithiohexanyl, azepinyl, morpholinyl, piperazinyl, pyridinyl, furanyl, thienyl, pyrrolyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, thiomorpholinyl, dihydropyran, thiadiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, 1,4-dioxadienyl, and the like. The heterocyclyl groups described herein may be optionally substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, heterocyclyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkoxy, aryl, and heteroaryl.

[0111] The term "aryl" herein refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6-10 members, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring connected to the parent core structure is the aryl ring. The aryl groups described herein may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, sulfonyl, sulfinyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, alkenyl, alkynyl, heterocyclyl, cycloalkoxy, aryl, and heteroaryl.

[0112] The term "heteroaryl" as used herein refers to an aromatic group consisting of 5 to 10 atoms and containing at least one heteroatom selected from N, O, or S. The term can have a single ring (non-limiting examples include furan, thiophene, imidazole, triazole, pyrazole, pyridine, pyrazine, oxazole, thiazole, etc.) or multiple fused rings (non-limiting examples include benzothiophene, benzofuran, indole, isoindole, etc.), wherein the fused rings may or may not be aromatic groups containing heteroatoms, provided that the point of attachment is through an atom of the aromatic heteroaryl group. The heteroaryl groups described herein may be optionally substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, amino, oxo, alkyl, alkoxy, acyl, acyloxy, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, alkenyl, alkynyl, heterocyclyl, cycloalkoxy, aryl, and heteroaryl.

[0113] The present invention also includes isotopically labeled compounds of the present invention, i.e., compounds having the same structure as disclosed above, but with one or more atoms in the structure replaced by atoms having the same number of protons but a different number of neutrons. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl and 131 I, etc. The compounds of the present invention, their stereoisomers, tautomers or pharmaceutically acceptable salts, and compounds of the above forms containing the above isotopes and / or other atomic isotopes, are all within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as 3 H or 14 Compounds labeled with C can be used in drug tissue distribution studies. 3 H or 14 C isotopes are particularly preferred due to their ease of preparation and detection. 2 H, 18 O replaces some of the compounds of the present invention due to better metabolic stability and have certain therapeutic advantages, such as increased half-life in vivo and lower dosage and other comprehensive properties, therefore, 2 H, 18 O is also preferred in some cases.

[0114] The term "optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0115] The term "compound of the present invention" (unless otherwise specifically stated) refers to the compounds of formula (A), formula (A-1), formula (I)-formula (V) and all pure and mixed stereoisomers, geometric isomers, tautomers, solvates, hydrates, prodrugs and isotopically labeled compounds and any pharmaceutically acceptable salts thereof. A solvate of a compound of the present invention refers to a compound or a salt thereof in combination with a stoichiometric or non-stoichiometric amount of a solvent, such as a hydrate, ethanolate, methanolate, etc. The compound may also exist in one or more crystalline states, i.e., as a co-crystal, polymorph, or it may exist as an amorphous solid. All such forms are encompassed by the claims.

[0116] The term "pharmaceutically acceptable" means that the substance or composition must be compatible chemically and / or toxicologically with the other ingredients comprising the formulation and / or the mammal to be treated therewith.

[0117] The term "optionally substituted by..." means that the structure is unsubstituted or substituted by one or more substituents described herein. The term "substituted" in this article means that any group is monosubstituted or polysubstituted by a specified substituent to the extent that such monosubstituted or polysubstituted (including multiple substitutions on the same part) is chemically allowed, and each substituent can be located at any available position on the group and can be connected by any available atom on the substituent. "Any available position" refers to any position on the group that can be chemically obtained by methods known in the art or methods taught herein and does not produce excessively unstable molecules. When there are two or more substituents on any group, each substituent is defined independently of any other substituent and can therefore be the same or different.

[0118] At various places in this specification, substituents of the compounds of the invention are disclosed in the form of groups or ranges. This specifically means that the invention includes each member of such groups and ranges or each individual subcombination of the members. For example, the term "C 1-6 "Alkyl" specifically means methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl are disclosed individually.

[0119] The term "stereoisomer" as used herein refers to compounds having one or more stereocenters that differ in chirality. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, and the like.

[0120] The term "tautomer" as used herein refers to structures having different energies, isomers that can interconvert across a low energy barrier. Examples include proton tautomers, such as enol-keto tautomers and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms attached to both the ring-NH- portion and the ring=N- portion, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. Valence tautomers include interconversion due to reorganization of some of the bonding electrons.

[0121] The compounds of the present invention may be used in the form of salts, such as "pharmaceutically acceptable salts" derived from inorganic or organic acids. These include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, sodium salt, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, sodium dodecylbenzenesulfonate sulfate, ethanesulfonate, glucose heptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, hydrochloride, 2-naphthalenesulfonate, oxalate, pectinate, sulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate, and quinate salts.

[0122] In this application, "tumor" or "cancer" includes but is not limited to: leukemia, malignant lymphoma, multiple myeloma, myelodysplastic syndrome and other blood and lymphatic cancers; as well as brain tumors, nerve tumors, head and neck cancer, esophageal cancer, gastric cancer, colorectal cancer, lung cancer, thyroid cancer, breast cancer, gallbladder cancer, pancreatic cancer, liver cancer, prostate cancer, ovarian cancer, uterine cancer, testicular cancer, ovarian cancer, renal cell carcinoma, bladder cancer, renal pelvis-ureter cancer, malignant melanoma, skin cancer, colorectal cancer, breast cancer, kidney cancer and other solid tumors. DETAILED DESCRIPTION

[0123] The present invention is further illustrated below with examples, but the present invention is not limited thereto. Throughout this application, multiple embodiments of the compounds and methods of the present invention are mentioned herein. The multiple embodiments described are intended to provide multiple illustrative examples and should not be construed as descriptions of alternatives. It should also be noted that the embodiments discussed herein (including various methods and parameters) are only for the purpose of illustrating the present invention and do not limit the scope of the present invention in any way. To describe the present invention, specific examples are listed below. However, it should be understood that the present invention is not limited to these examples. The following examples are merely provided to provide methods for practicing the present invention and do not limit the scope of the present invention in any way.

[0124] The preparation process of the compound of formula (IV), its stereoisomers, tautomers and pharmaceutically acceptable salts thereof of the present invention is as follows:

[0125] Under alkaline conditions, a fluorobenzene derivative a reacts with an aromatic amine derivative b to produce compound c, which is then methylated and oxidized to produce compound d; an aldehyde derivative d reacts with an arylsulfonylhydrazine to produce compound e; under alkaline conditions, a hydrazine derivative e reacts with an aromatic boronic acid derivative f to produce compound g; under acidic conditions, compound g is deprotected to produce compound h; the ester derivative h is hydrolyzed in the presence of a hydroxide to produce compound i; in the presence of a condensing agent, a benzoic acid derivative i reacts with a corresponding amine or amine hydrochloride to produce compound j; and under alkaline conditions, compound j reacts with a corresponding sulfonyl compound to prepare a compound of formula I. The substituents are as defined above.

[0126] The compounds provided by the present invention can be prepared by standard synthetic methods known in the art. This specification provides a general method for preparing the compounds of the present invention. The starting materials or reagents can usually be obtained commercially, for example, by Alfa It can be purchased from companies such as TCI, or prepared by methods well known to those skilled in the art.

[0127] The compounds of the present invention and corresponding preparation methods are further explained and listed below by examples and preparations. It should be understood that although typical or preferred reaction conditions (such as reaction temperature, time, molar ratio of reactants, reaction solvent, etc.) are given in the specific examples, those skilled in the art may also use other reaction conditions. Optimum reaction conditions may vary with the specific reaction substrate or solvent used, but the conditions may be determined by conventional optimization by those skilled in the art.

[0128] The structures of the following example compounds were characterized by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). 1H-NMR analyses were performed on a Bruker Ascend 400 MHz NMR spectrometer at ambient temperature using TMS as the internal standard and the compounds dissolved in the appropriate deuterated reagent. NMR chemical shifts (δ) are reported in ppm and are abbreviated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; brs, broad singlet.

[0129] The reaction starting materials, intermediates and example compounds can be separated and purified by precipitation, filtration, crystallization, evaporation, distillation and chromatography (eg, silica gel column chromatography, preparative chromatography, etc.).

[0130] Preparation of Intermediate 1

[0131] Step 1: Preparation of 2,3,4-trifluoro-5-iodobenzoic acid

[0132] To a 3L three-necked flask, add acetic acid (928mL) and acetic anhydride (538.0g) and cool to 0°C in an ice bath. Slowly add concentrated sulfuric acid (2116.0g) dropwise to the system, maintaining the system temperature above 40°C. After completion of the addition, cool the system to room temperature again. Then add 2,3,4-trifluorobenzoic acid (115.0g), iodine (66.9g), and manganese dioxide (68.7g). After addition, raise the temperature to 50°C and react for 3 hours. Stop heating, allow the system to cool to room temperature, then add additional iodine (66.9g) and manganese dioxide (68.7g), then raise the temperature to 50°C and react for 3 hours. Stop heating, allow the system to cool to room temperature, then add additional iodine (33.4g) and manganese dioxide (34.4g), then raise the temperature to 50°C again and react for 21 hours. Stop the reaction, allow the system to cool to room temperature, and then slowly pour into ice water to quench the reaction. Extract with dichloromethane, combine the organic phases, wash with aqueous sodium sulfite solution and saturated brine, and dry over anhydrous sodium sulfate. After concentrating the organic phase, add n-heptane and stir in an ice bath to precipitate a large amount of solid. Filter and wash the filter cake with n-heptane to obtain 178.1 g of a white solid. ESI-MS: [MH] - =300.9.

[0133] Step 2: Preparation of 2,3,4-trifluoro-5-vinylbenzoic acid

[0134] In a 3L three-necked flask, 2,3,4-trifluoro-5-iodobenzoic acid (89.0g), potassium vinyl trifluoroborate (47.4g), potassium phosphate (93.8g), methanol (1780mL), water (890mL) and [1,1′-bis(diphenylphosphino)ferrocene] palladium dichloride (21.6g) were added in sequence. The system was replaced with a nitrogen environment and heated to 60°C for 3h. After the system was cooled to room temperature, it was filtered through diatomaceous earth, the filtrate was collected, concentrated, and 1M HCl was added to adjust the pH of the system to 4-5. Then, methyl tert-ether was used for extraction, the organic phases were combined, washed with saturated brine, dried and concentrated. N-heptane and dichloromethane were added to the concentrate, stirred at room temperature for 2h, filtered, and the filter cake was washed with n-heptane to obtain 48.2g of white solid. ESI-MS: [MH] - =201.0.

[0135] Step 3: Preparation of 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-vinylbenzoic acid

[0136] In a 3L three-necked flask, 2,3,4-trifluoro-5-vinylbenzoic acid (65.0g), 2-fluoro-4-iodoaniline (76.3g) and tetrahydrofuran (1300mL) were added, and then the system was replaced with a nitrogen environment and cooled to -15 to -20°C. Lithium bis(trimethylsilyl)amide (1M, 965mL) was slowly added dropwise to the system, ensuring that the system temperature did not exceed -15°C. After the dropwise addition, the system was slowly restored to room temperature, and then 1M hydrochloric acid was added to adjust the pH of the system to 1 to 2. Extracted with tert-methyl ether, the organic phases were combined, washed with saturated brine, dried and concentrated. Slowly add n-heptane to the concentrate, precipitate the solid, filter, and obtain 99.0g of off-white solid. ESI-MS: [MH] - =418.0.

[0137] Step 4: Preparation of methyl 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-vinylbenzoate

[0138] 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-vinylbenzoic acid (20.0 g) and N,N-dimethylformamide (200 mL) were added to a 1L three-necked flask and stirred at room temperature until the solution became clear. Potassium carbonate (7.9 g) and iodomethane (8.1 g) were added to the system, and the system was then reacted at room temperature for 12 h. The suspended matter in the system was filtered out and the filtrate was collected. The filtrate was slowly added dropwise to water to precipitate a solid. After the addition was complete, the system was stirred for 1 h. Filtered and the filter cake was washed with 250 mL of ethanol to obtain 15.1 g of a light yellow solid.

[0139] Step 5: Preparation of methyl 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-formylbenzoate

[0140] In a 1L three-necked flask, methyl 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-vinylbenzoate (11.6g) and tetrahydrofuran (200mL) were added and stirred in an ice bath until dissolved. Potassium osmate dihydrate (494mg) was added to the system and the reaction was continued by stirring in an ice bath. After 15min, water (200mL), sodium periodate (17.2g) and 2,6-lutidine (2.9g) were added to the system, and the system was heated to room temperature and stirred for 4h. The reaction system was poured into a saturated aqueous sodium sulfite solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and the organic phases were concentrated to obtain a solid crude product. The crude product was washed with anhydrous ethanol and filtered to obtain 9.0g of a light brown solid. 1H NMR (400MHz, DMSO-d6): δ10.00(s,1H),9.52(s,1H),8.21(dd,J1=7.2Hz,J2=1.2Hz,1H),7.71(d d, J1=10.4Hz, J2=1.6Hz,1H),7.54-7.51(m,1H),7.13-7.07(m,1H),3.86(s,3H).ESI-MS:[M+H] + =436.0.

[0141] Step 6: Preparation of methyl (E)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-((2-toluenesulfonylhydrazono)methyl)benzoate

[0142] Methyl 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-formylbenzoate (50.7 g), p-methylbenzenesulfonylhydrazide (21.7 g), and ethanol (1500 mL) were added to a 2L three-necked flask and the mixture was heated to 50°C for 5 h. The mixture was then cooled to 0°C in an ice bath to precipitate a large amount of solid. The solid was filtered and the filter cake was washed with ethanol to obtain 53.1 g of a light yellow solid. 1 H NMR (400MHz, DMSO-d6): δ11.76(s,1H),8.97(s,1H),8.00-7.99(m,2H),7.75(d,J=8.0Hz,2H),7.64(dd,J1 =10.4Hz, J2=1.6Hz,1H),7.43(d,J=8.4Hz,3H),6.92-6.89(m,1H),3.85(s,3H),2.37(s,3H).ESI-MS:[M+H] + =604.0.

[0143] Step 7: Preparation of N-(2,4-dimethoxybenzyl)-3-fluoro-4-iodopyridin-2-amine

[0144] In a 1L single-necked flask, add 2,3-difluoro-4-iodopyridine (45.0g), (2,4-dimethoxyphenyl)methylamine (78.0g), N-methylpyrrolidone (675mL), and triethylamine (56.7g), and replace the system with a nitrogen atmosphere. Heat the system to 100°C and react for 2h. After the system cools to room temperature, pour it into water and extract with tertiary methyl ether. The organic phases are combined, washed with saturated brine, dried, and concentrated to obtain a crude product. The crude product is washed with tertiary methyl ether / petroleum ether (1 / 4) to obtain 56.8g of an off-white solid. 1H NMR (400MHz, DMSO-d6): δ7.45(d,J=5.6Hz,1H),7.11-7.08(m,1H),7.03(d,J=8.4Hz,1H),6.89-6.86(m,1H) ,6.54(d,J=2.4Hz,1H),6.43(dd,J1=8.4Hz,J2=2.4Hz,1H),4.44(d,J=6.0Hz,2H),3.80(s,3H),3.72(s,3H).

[0145] Step 8: Preparation of N-(2,4-dimethoxybenzyl)-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine

[0146] In a 2L three-necked flask, add N-(2,4-dimethoxybenzyl)-3-fluoro-4-iodopyridin-2-amine (56.5 g), pinacol diboron (147.8 g), potassium pivalate (44.9 g), toluene (1400 mL), dimethyl sulfoxide (20 mL), and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (10.6 g). The system is then replaced with a nitrogen atmosphere. The system is then heated to 55°C and reacted for 15 hours. After cooling to room temperature, the mixture is poured into water and extracted with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate is then diluted with n-hexane, dried, filtered through celite, and the filtrate is concentrated to obtain the product. The product from this step is carried on to the next step without further purification. 1 H NMR (400MHz, DMSO-d6): δ7.75 (dd, J1=4.8Hz, J2=0.8Hz, 1H), 7.01 (d, J=8.4Hz, 1H), 6.87-6.84 (m, 1H), 6.59-6.56 (m, 1H), 6.54(d,J=2.4Hz,1H),6.42(dd,J1=8.4Hz,J2=2.4Hz,1H),4.45(d,J=6.0Hz,2H),3.80(s,3H),3.72(s,3H),1.30(s,12H).

[0147] Step 9: Preparation of (2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)boronic acid

[0148] In a 2L single-necked bottle, N-(2,4-dimethoxybenzyl)-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine and THF (500mL) were added and stirred until clear. 1M aqueous hydrochloric acid solution was slowly added to the system and the reaction was stirred at room temperature for 1h. The system was extracted with petroleum ether and the aqueous phase was collected. Methylboric acid (17.4g) was added to the aqueous phase and the reaction was stirred at room temperature for 1h. The system was then extracted with a mixed solution of ethyl acetate / petroleum ether (3 / 1) and the aqueous phase was collected. Ethyl acetate was added to the aqueous phase and the pH of the system was adjusted to 8 with sodium bicarbonate aqueous solution. The organic phase was collected, washed with water, dried and concentrated to give 37.0g of an off-white solid. ESI-MS: [M+H] + =307.1.

[0149] Step 10: Preparation of methyl 5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate

[0150] In a 1L single-necked flask, (2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)boric acid (15.0 g), (E)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-((2-toluenesulfonylhydrazono)methyl)benzoate (35.4 g), potassium carbonate (8.1 g), and toluene (600 mL) were added, and the system was replaced with a nitrogen atmosphere. The system was heated to 100°C and reacted for 5 hours. After the system was cooled to room temperature, saturated aqueous ammonium chloride was added, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed by filtration, and the crude product was then purified by silica gel column chromatography to obtain 17.9 g of a light yellow liquid. 1 H NMR (400MHz, DMSO-d6): δ8.65(s,1H),7.73(d,J=7.2Hz,1H),7.68(d,J=5.2Hz,1H),7.62(dd,J1 =10.8Hz,J2=3.0Hz,1H),7.39(dd,J1=8.4Hz,J2=0.8Hz,1H),7.03(d,J=8.4Hz,1H),6.92-6.88(m ,1H),6.80-6.75(m,1H),6.54(d,J=2.4Hz,1H),6.42(dd,J1=8.4Hz,J2=2.4Hz,1H),6.38(t,J=4 .8Hz,1H),4.44(d,J=6.0Hz,2H),4.01(s,2H),3.80(d,J=1.2Hz,6H),3.72(s,3H).ESI-MS:[M+H] + =682.1.

[0151] Step 11: Preparation of methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate

[0152] In a 500mL single-necked bottle, 5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid methyl ester (10.0g) and dichloromethane (150mL) were added and stirred at room temperature until clear. The system was then placed in an ice bath and trifluoroacetic acid (150mL) was slowly added. After the addition was completed, the system was warmed to room temperature and stirred for 1.5h. The system was slowly added to a saturated aqueous sodium carbonate solution and the pH was adjusted to 8. Extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate. Filtered and the solvent was spun off, and the crude product was then purified by silica gel column chromatography to obtain 5.8g of a light yellow solid. 1 H NMR (400MHz, DMSO-d6): δ8.64(s,1H),7.71(d,J=7.2Hz,1H),7.67(d,J=5.2Hz,1H),7.62(dd,J1=10.8Hz,J2=1.6Hz,1H),7.39 (dd,J1=8.4Hz, J2=1.2Hz,1H),6.80-6.74(m,1H),6.40(t,J=4.8Hz,1H),6.22(s,2H),3.99(s,2H),3.79(s,3H).ESI-MS:[M+H] + =532.0.

[0153] Step 12: Preparation of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride

[0154] In a 1L single-necked flask, methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate (6.9g), tetrahydrofuran (100mL) and water (50mL) were added in sequence, and the system was placed in an ice bath and stirred. Lithium hydroxide monohydrate (1.6g) was slowly added to the system. After the addition was complete, it was warmed to room temperature and stirred for 2.5h. Subsequently, aqueous hydrochloric acid solution (6M, 20mL) was added to adjust the pH to 1-2 and stirred for 5min. The tetrahydrofuran was removed by concentration under reduced pressure, and then the concentrate was diluted with water and stirred for 10min. Filter, collect the filter cake, and wash it once with water and tertiary methyl ether to obtain 6.2g of purple-red solid. ESI-MS: [M+H] + =518.0.

[0155] Preparation of Intermediate 2

[0156] Step 1: Preparation of 3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)-5-vinylbenzoic acid

[0157] In a 2L three-necked flask, 2,3,4-trifluoro-5-vinylbenzoic acid (24.2g), 2-fluoro-4-methylaniline (15.0g) and tetrahydrofuran (485mL) were added, and then the system was replaced with a nitrogen environment and cooled to -70~-80°C. Lithium bis(trimethylsilyl)amide (1M, 360mL) was slowly added dropwise to the system, ensuring that the system temperature did not exceed -70°C. After the dropwise addition, the system was slowly restored to room temperature, and 600mL of hydrochloric acid (1M) was added to adjust the pH to 1~2. Extracted with tert-methyl ether, the organic phases were combined, washed with saturated brine, dried and concentrated. Slowly add n-heptane to the concentrate, stir at room temperature for 30min, filter, and obtain 30.4g of light yellow solid. ESI-MS: [MH] - =306.1.

[0158] Step 2: Preparation of 3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)-5-formylbenzoic acid

[0159] In a 2L three-necked flask, water (100mL), tetrahydrofuran (300mL) and acetonitrile (300mL) were added and stirred at room temperature. Subsequently, concentrated sulfuric acid (2.0g) was slowly added dropwise to the reaction flask. After the system temperature returned to room temperature, sodium periodate (34.9g) and anhydrous ruthenium trichloride (0.5g) were slowly added thereto and the reaction was continued to stir at room temperature. After 5min, 3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)-5-vinylbenzoic acid (10.0g) was added to the system and the reaction was stirred at room temperature for 2h. The insoluble matter was removed by filtration, the filtrate was collected, extracted with ethyl acetate, the organic phases were combined, washed with saturated sodium sulfite aqueous solution, then washed with saturated brine, the organic phases were collected and dried, filtered, and concentrated to obtain 7.0g of a yellow solid. ESI-MS: [MH] - =308.1.

[0160] Step 3: Preparation of methyl 3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)-5-formylbenzoate

[0161] 3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)-5-formylbenzoic acid (3.1 g) and N,N-dimethylformamide (31 mL) were added to a 250 mL three-necked flask and stirred at room temperature until the mixture became clear. Potassium carbonate (1.5 g) and iodomethane (1.6 g) were added to the system, and the temperature was then raised to 50°C for 4 h. The suspended solids were removed by filtration, and the filtrate was collected. The filtrate was slowly added dropwise to water to precipitate a solid. Stirring was continued for 1 h after the addition was complete. The filter cake was washed with water and dried to obtain 1.3 g of a yellow solid. ESI-MS: [M+H] + =324.1.

[0162] Step 4: Preparation of methyl (E)-3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)-5-((2-toluenesulfonylhydrazono)methyl)benzoate

[0163] To a 2L three-necked flask, add methyl 3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)-5-formylbenzoate (1.8 g), p-methylbenzenesulfonylhydrazide (1.1 g), and ethanol (54 mL). The system was heated to 50°C and reacted for 2 h. The system was placed in an ice bath and cooled to 0°C. A large amount of solid precipitated, which was filtered and the filter cake washed with ethanol to obtain 1.7 g of a light yellow solid. 1 H NMR (400MHz, DMSO-d6): δ11.69(s,1H),9.04(s,1H),8.01-7.98(m,2H),7.75(d,J=8.0Hz,2H),7.43(d,J=8 .0Hz,2H),7.09-7.03(m,2H),6.93(d,J=8.0Hz,1H),3.87(s,3H),2.38(s,3H),2.28(s,3H).ESI-MS:[M+H] + =492.1.

[0164] Step 5: Preparation of methyl 5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)benzoate

[0165] In a 1L single-necked flask, (2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)boric acid (2.7 g), (E)-3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)-5-((2-toluenesulfonylhydrazono)methyl)benzoic acid methyl ester (3.6 g), potassium carbonate (1.2 g) and toluene (144 mL) were added, and the system was replaced with a nitrogen atmosphere. The system was heated to 100°C and reacted for 4 hours. After the system was cooled to room temperature, saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed by filtration, and the crude product was then purified by silica gel column chromatography to obtain 3.2 g of a light yellow liquid. ESI-MS: [M+H] + =570.2.

[0166] Step 6: Preparation of methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)benzoate

[0167] In a 250mL single-necked bottle, 5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)benzoic acid methyl ester (3.2g) and dichloromethane (60mL) were added and stirred at room temperature until clear. The system was then placed in an ice bath and trifluoroacetic acid (60mL) was slowly added. After the addition was completed, the system was warmed to room temperature and stirred for 1.5h. Saturated aqueous sodium carbonate solution was slowly added to the system to adjust the pH to 8. Extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate. Filtered and the solvent was spun off, and the crude product was then purified by silica gel column chromatography to obtain 2.1g of a light yellow solid. ESI-MS: [M+H] + =420.1.

[0168] Step 7: Preparation of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)benzoic acid hydrochloride

[0169] In a 250 mL single-necked bottle, methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)benzoate (2.5 g), tetrahydrofuran (60 mL) and water (30 mL) were added in sequence, and the system was placed in an ice bath and stirred. Lithium hydroxide monohydrate (0.8 g) was slowly added to the system. After the addition was complete, the mixture was warmed to room temperature and stirred for 4 hours. Aqueous hydrochloric acid solution (6 M, 10 mL) was then added to the system to adjust the pH to 1-2 and stirred for 5 minutes. The tetrahydrofuran in the system was removed by concentration under reduced pressure, and then the concentrate was diluted with water and stirred for 10 minutes. Filter, collect the filter cake, and wash it once with water and tertiary methyl ether respectively to obtain 1.4 g of purple-red solid. ESI-MS: [M+H] + =406.1.

[0170] Preparation of Intermediate 3

[0171] Step 1: Preparation of 3,4-difluoro-2-(phenylamino)-5-vinylbenzoic acid

[0172] In a 2L three-necked flask, add 2,3,4-trifluoro-5-vinylbenzoic acid (20.0g), aniline (9.2g) and tetrahydrofuran (400mL), then replace the system with a nitrogen atmosphere and cool to -15~-20℃. Slowly add lithium bis(trimethylsilyl)amide (1M, 297mL) dropwise to the system, ensuring that the system temperature does not exceed -15℃. After the addition is complete, slowly return the system to room temperature, then add hydrochloric acid (6M) to the system to adjust the pH of the system to 1~2. Use ethyl acetate to extract the system, combine the organic phases, wash with 1L of saturated brine, dry and concentrate to obtain 24.5g of yellow solid. 1 H NMR (400MHz, DMSO-d6): δ13.69(s,1H),9.13(s,1H),7.97(d,J=7.2Hz,1H),7.27(t,J=8.0Hz,2H),7.00-6.96 (m,3H),6.78(dd,J1=17.6Hz,J2=11.2Hz,1H),5.89(d,J=18.0Hz,1H),5.44(d,J=11.6Hz,1H).ESI-MS:[M+H] + =276.1.

[0173] Step 2: Preparation of methyl 3,4-difluoro-2-(phenylamino)-5-vinylbenzoate

[0174] 3,4-difluoro-2-(phenylamino)-5-vinylbenzoic acid (30.0 g) and N,N-dimethylformamide (300 mL) were added to a 1 L three-necked flask and stirred at room temperature until the solution became clear. Potassium carbonate (22.6 g) and iodomethane (20.1 g) were added to the system, and the system was then reacted at room temperature for 16 h. The suspended matter in the system was filtered out, and the filtrate was collected. The filtrate was slowly added dropwise to water to precipitate a solid. After the addition was complete, the system was stirred for another 1 h. Filtered with suction, and the filter cake was washed with ethanol to obtain 21.0 g of a light yellow solid. 1 H NMR (400MHz, DMSO-d6): δ8.77(s,1H),7.91(d,J=6.8Hz,1H),7.25(t,J=8.0Hz,2H),6.97-6.96(m,3H),6.78 (dd, J1=17.6Hz, J2=11.2Hz, 1H), 5.91 (d, J=17.6Hz, 1H), 5.46 (d, J=11.6Hz, 1H), 3.78 (s, 3H).ESI-MS: [M+H] + =290.1.

[0175] Step 3: Preparation of methyl 3,4-difluoro-2-(phenylamino)-5-formylbenzoate

[0176] In a 1L three-necked flask, methyl 3,4-difluoro-2-(phenylamino)-5-vinylbenzoate (20.8g) and tetrahydrofuran (312mL) were added and stirred in an ice bath until dissolved. Potassium osmate dihydrate (1.3g) was added to the system and the reaction was continued by stirring in an ice bath. After 15min, water (312mL), sodium periodate (46.2g) and 2,6-lutidine (7.7g) were added to the system, and the system was heated to room temperature and stirred for 4h. The reaction system was poured into a saturated aqueous sodium sulfite solution, extracted with ethyl acetate, the organic phases were combined, washed twice with saturated brine, and the organic phase was concentrated to obtain 20.0g of a yellow solid. ESI-MS: [M+H] + =292.1.

[0177] Step 4: Preparation of methyl (E)-3,4-difluoro-2-(phenylamino)-5-((2-toluenesulfonylhydrazono)methyl)benzoate

[0178] Methyl 3,4-difluoro-2-(phenylamino)-5-formylbenzoate (20.0 g), p-methylbenzenesulfonylhydrazide (12.8 g), and ethanol (600 mL) were added to a 2 L three-necked flask and the reaction was heated to 50°C for 15 h. The system was cooled to 0°C in an ice bath to precipitate a large amount of solid. The solid was filtered and the filter cake was washed with 50 mL of ethanol to obtain 26.0 g of an off-white solid. 1H NMR (400MHz, DMSO-d6): δ11.71(s,1H),8.98(s,1H),8.00-7.97(m,2H),7.75(d,J=8.0Hz,2H),7.43 (d,J=8.0Hz,2H),7.26(t,J=8.0Hz,2H),6.99-6.98(m,3H),3.80(s,3H),2.38(s,3H).ESI-MS:[M+H] + =460.1.

[0179] Step 5: Preparation of methyl 5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-(phenylamino)benzoate

[0180] In a 1L single-necked flask, (2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)boric acid (6.9 g), (E)-3,4-difluoro-2-(phenylamino)-5-((2-toluenesulfonylhydrazono)methyl)benzoate (8.0 g), potassium carbonate (3.6 g) and toluene (320 mL) were added, and the system was replaced with a nitrogen atmosphere. The system was heated to 100°C and reacted for 5 h. After the system was cooled to room temperature, saturated aqueous ammonium chloride was added, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed by filtration to obtain 4.7 g of a light yellow liquid. ESI-MS: [M+H] + =538.2.

[0181] Step 6: Preparation of methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-(phenylamino)benzoate

[0182] In a 500mL single-necked bottle, methyl 5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-(phenylamino)benzoate (4.7g) and dichloromethane (220mL) were added and stirred at room temperature until dissolved. The system was then placed in an ice bath and trifluoroacetic acid (110mL) was slowly added. After the addition was completed, the system was warmed to room temperature and stirred for 1.5h. The system was slowly added to a saturated aqueous sodium carbonate solution and the pH of the system was adjusted to 8. Extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate. Filtered and the solvent was spun off, and the crude product was then purified by silica gel column chromatography to obtain 1.8g of a yellow solid.

[0183] Step 7: Preparation of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-(phenylamino)benzoic acid hydrochloride

[0184] In a 500 mL single-necked flask, methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-(phenylamino)benzoate (1.8 g), tetrahydrofuran (40 mL), and water (40 mL) were added sequentially and the system was stirred in an ice bath. Lithium hydroxide monohydrate (586 mg) was slowly added to the system. After addition, the mixture was warmed to room temperature and stirred for 2 hours. Aqueous hydrochloric acid (6 M, 20 mL) was then added to the system to adjust the pH to 1-2 and stirred for 5 minutes. The tetrahydrofuran in the system was removed by concentration under reduced pressure, and then the concentrate was diluted with water and stirred for 10 minutes. The filter cake was collected by filtration and washed with an acetone / n-hexane mixed solvent to obtain 1.4 g of a light yellow solid.

[0185] Preparation of Intermediate 4

[0186] Step 1: Preparation of 3,4-difluoro-2-(2-fluoro-4-methoxyphenylamino)-5-vinylbenzoic acid

[0187] In a 1L three-necked flask, 2,3,4-trifluoro-5-vinylbenzoic acid (10.0g), 2-fluoro-4-methoxyaniline (7.0g) and tetrahydrofuran (250mL) were added, and then the system was replaced with a nitrogen environment and cooled to -15 to -20°C. Lithium bis(trimethylsilyl)amide (1M, 150mL) was slowly added dropwise to the system, ensuring that the system temperature did not exceed -15°C. After the dropwise addition, the system was slowly restored to room temperature, and then sodium bisulfate aqueous solution (1.5M) was added to the system to adjust the pH of the system to 1 to 2. The system was extracted with tert-methyl ether, the organic phases were combined, washed with 1L saturated brine, dried and concentrated to obtain 15.1g of a yellow solid. ESI-MS: [MH] - =322.1.

[0188] Step 2: Preparation of methyl 3,4-difluoro-2-(2-fluoro-4-methoxyphenylamino)-5-vinylbenzoate

[0189] 3,4-difluoro-2-(2-fluoro-4-methoxyphenylamino)-5-vinylbenzoic acid (16.2 g) and N,N-dimethylformamide (160 mL) were added to a 1L three-necked flask and the system was stirred at room temperature until dissolved. Potassium carbonate (8.3 g) and iodomethane (8.5 g) were added to the system, and the system was then reacted at 35°C for 4 h. The suspended matter in the system was removed by filtration, and the filtrate was collected. The filtrate was slowly added dropwise to water to precipitate a solid. After the addition was complete, the system was stirred for 1 h. Filtered and the filter cake was washed with n-heptane to obtain 16.1 g of a light yellow solid. ESI-MS: [M+H] + =338.1.

[0190] Step 3: Preparation of methyl 3,4-difluoro-2-((2-fluoro-4-methoxyphenyl)amino)-5-formylbenzoate

[0191] In a 500ml three-necked flask, add 3,4-difluoro-2-(2-fluoro-4-methoxyphenylamino)-5-vinylbenzoic acid methyl ester (15.8g) and tetrahydrofuran (314mL) and stir in an ice bath until dissolved. Add potassium osmate dihydrate (0.86g) to the system and continue stirring the reaction in an ice bath. After 15min, add water (312mL), sodium periodate (30.0g) and 2,6-lutidine (5.1g) to the system, and warm the system to room temperature and stir the reaction for 4h. Pour the reaction system into a saturated aqueous sodium sulfite solution, extract with ethyl acetate, combine the organic phases, wash with saturated brine, and concentrate. Dilute the concentrate with acetone, slowly add water to the system, stir, filter, and dry the filter cake to obtain 12.7g of light yellow solid.

[0192] Step 4: Preparation of methyl (E)-3,4-difluoro-2-((2-fluoro-4-methoxyphenyl)amino)-5-((2-toluenesulfonylhydrazono)methyl)benzoate

[0193] To a 500 mL three-necked flask, add methyl 3,4-difluoro-2-((2-fluoro-4-methoxyphenyl)amino)-5-formylbenzoate (4.0 g), p-methylbenzenesulfonylhydrazide (2.2 g), and ethanol (120 mL). The system was heated to 60°C and reacted for 1 h. The system was placed in an ice bath and cooled to 0°C. A large amount of solid precipitated, which was filtered and the filter cake washed with ethanol to obtain 5.1 g of a light yellow solid. ESI-MS: [M+H] + =508.1.

[0194] Step 5: Preparation of methyl 5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methoxyphenyl)amino)benzoate

[0195] In a 500 mL single-necked flask, (2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)boric acid (3.6 g), (E)-3,4-difluoro-2-((2-fluoro-4-methoxyphenyl)amino)-5-((2-toluenesulfonylhydrazono)methyl)benzoate (5.0 g), potassium carbonate (1.63 g), and toluene (150 mL) were added, and the system was replaced with a nitrogen atmosphere. The system was heated to 105°C and reacted for 3 hours. After the system was cooled to room temperature, saturated aqueous ammonium chloride was added, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed by filtration, and the crude product was purified by silica gel column chromatography to obtain 4.4 g of a light yellow liquid. ESI-MS: [M+H]+ =586.2.

[0196] Step 6: Preparation of methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methoxyphenyl)amino)benzoate

[0197] In a 500mL single-necked bottle, 5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methoxyphenyl)amino)benzoic acid methyl ester (4.4g) and dichloromethane (27mL) were added and stirred at room temperature until dissolved. The system was then placed in an ice bath and trifluoroacetic acid (9.1mL) was slowly added. After the addition was completed, the system was warmed to room temperature and stirred for 1.5h. The system was slowly added to a saturated aqueous sodium carbonate solution and the pH of the system was adjusted to 8. Extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate. Filtered and the solvent was removed by spin to obtain 3.1g of a light yellow solid. ESI-MS: [M+H] + =436.1.

[0198] Step 7: Preparation of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methoxyphenyl)amino)benzoic acid hydrochloride

[0199] In a 50 mL single-necked bottle, methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methoxyphenyl)amino)benzoate (3.0 g), acetonitrile (18 mL) and ethanol (12 mL) were added in sequence, and the system was placed in an ice bath and stirred. An aqueous solution (18 mL) of lithium hydroxide monohydrate (870 mg) was slowly added dropwise to the system. After the addition was complete, the mixture was heated to room temperature and stirred for 2.5 hours. A 1.5 M aqueous sodium bisulfate solution was then added to the system to adjust the pH to 1-2 and stirred for 5 minutes. The filter cake was collected by filtration and washed once with water and tertiary methyl ether to obtain 2.7 g of an off-white solid. ESI-MS: [M+H] + =422.1.

[0200] Preparation of Intermediate 5

[0201] Step 1: Preparation of 3-bromo-2-fluoro-N-(2,3,4-trimethoxybenzyl)aniline

[0202] In a 250 mL single-necked flask, add 3-bromo-2-fluoroaniline (10.1 g), 2,3,4-trimethoxybenzaldehyde (10.0 g), and toluene (200 mL). Heat the mixture to reflux and stir for 2 hours. Remove from heat, cool the mixture to room temperature, concentrate, and dilute the concentrate with 150 mL of 1,2-dichloroethane. Add 3 mL of acetic acid and sodium triacetoxyborohydride (21.0 g) to the mixture and stir for 12 hours at room temperature. Pour the mixture into water and extract with dichloromethane. Combine the organic phases, dry, and concentrate to yield 17.0 g of a brown solid.

[0203] Step 2: Preparation of 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(2,3,4-trimethoxybenzyl)aniline

[0204] To a 250 mL single-necked flask, add 3-bromo-2-fluoro-N-(2,3,4-trimethoxybenzyl)aniline (5.2 g), pinacol diboron (7.2 g), potassium pivalate (4.0 g), toluene (125 mL), dimethyl sulfoxide (2.2 g), and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (1.0 g). The system was then replaced with a nitrogen atmosphere. The system was then heated to 55°C and reacted for 19 hours. After cooling to room temperature, the mixture was poured into water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was then diluted with n-hexane, dried, and filtered through celite. The filtrate was concentrated to yield 4.7 g of a yellow solid.

[0205] Step 3: Preparation of (2-fluoro-3-((2,3,4-trimethoxybenzyl)amino)phenyl)boronic acid

[0206] 2-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(2,3,4-trimethoxybenzyl)aniline (4.7 g) and tetrahydrofuran (100 mL) were added to a 250 mL single-necked bottle and stirred until dissolved. 1 M aqueous hydrochloric acid solution (50 mL) was slowly added to the system and stirred at room temperature for 1 hour. Methylboric acid (2.4 g) was added to the system and stirred at room temperature for 24 hours. The system was then extracted with petroleum ether, the organic phases were combined, dried, and concentrated to obtain 1.1 g of a light yellow solid. ESI-MS: [M+H] + =336.1.

[0207] Step 4: Preparation of methyl 3,4-difluoro-5-(2-fluoro-3-((2,3,4-trimethoxybenzyl)amino)benzyl)-2-((2-fluoro-4-iodophenyl)amino)benzoate

[0208] In a 100 mL single-necked flask, (2-fluoro-3-((2,3,4-trimethoxybenzyl)amino)phenyl)boronic acid 1.1 g), (E)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-((2-toluenesulfonylhydrazono)methyl)benzoate (2.4 g), potassium carbonate (540 mg), and toluene (440 mL) were added, and the system was replaced with a nitrogen atmosphere. The system was heated to 100°C and reacted for 5 h. After the system was cooled to room temperature, saturated aqueous ammonium chloride was added, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed by filtration, and the crude product was purified by silica gel column chromatography to obtain 1.1 g of a light yellow liquid. ESI-MS: [M+H] + =711.1.

[0209] Step 5: Preparation of methyl 5-(3-amino-2-fluorobenzyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate

[0210] In a 100 mL single-necked bottle, methyl 3,4-difluoro-5-(2-fluoro-3-((2,3,4-trimethoxybenzyl)amino)benzyl)-2-((2-fluoro-4-iodophenyl)amino)benzoate (1.9 g) and dichloromethane (30 mL) were added and stirred at room temperature until dissolved. The system was then placed in an ice bath and trifluoroacetic acid (30 mL) was slowly added. After the addition was completed, the system was heated to room temperature and stirred for 3.5 hours. p-Toluenesulfonic acid (515 mg) was added to the system, and the system was heated to 40 ° C and stirred for 24 hours. After concentrating the system, the concentrate was diluted with saturated aqueous sodium carbonate solution and its pH was adjusted to 8. Extracted with ethyl acetate, the organic phases were combined, dried, filtered and concentrated. The concentrate was purified by silica gel column chromatography to obtain 670 mg of a light yellow solid. ESI-MS: [M+H] + =531.0.

[0211] Step 6: Preparation of 5-(3-amino-2-fluorobenzyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride

[0212] In a 100 mL single-necked bottle, methyl 5-(3-amino-2-fluorobenzyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate (670 mg), tetrahydrofuran (20 mL) and water (10 mL) were added in sequence, and the system was placed in an ice bath and stirred. Lithium hydroxide monohydrate (160 g) was slowly added to the system. After the addition was complete, the mixture was warmed to room temperature and stirred for 13 hours. Aqueous hydrochloric acid solution (2 M) was then added to the system to adjust the pH to 1-2 and stirred for 5 minutes. The tetrahydrofuran in the system was removed by concentration under reduced pressure, and then water was added to the system to dilute the concentrate and stir for 10 minutes. Filtering gave 630 mg of a light yellow solid. ESI-MS: [M+H] + =517.0.

[0213] Preparation of Intermediate 6

[0214] Preparation of N-ethyl-2-oxoxazoline-3-sulfonamide

[0215] Under ice bath conditions, 120 mL of acetonitrile and chlorosulfonyl isocyanate (3.2 g) were added to a 500 mL single-necked bottle. 2-bromoethanol (2.8 g) was then slowly added to the system. The system was kept stirring under ice bath for 30 minutes, then heated to room temperature and stirred for 1 hour. N-methylmorpholine (15.1 g) was then slowly added to the system and stirred for 10 minutes, and then ethylamine hydrochloride (1.8 g) was slowly added to the system. After the addition, the system was heated to 50°C and stirred for 5 hours. The system was then gradually cooled to room temperature and continued to stir for 15 hours. Filter and concentrate the filtrate. Ethyl acetate was added to dilute the concentrate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain 1.8 g of a white solid. 1 H NMR (400MHz, DMSO-d6, δ): 8.34 (t, J = 5.2 Hz, 1H), 4.41-4.37 (m, 2H), 3.96-3.92 (m, 2H), 3.08-3.01 (m, 2H), 1.08 (t, J = 7.2 Hz, 3H).

[0216] Preparation of Intermediate 7

[0217] Preparation of N-cyclopropyl-2-oxoxazoline-3-sulfonamide

[0218] Under ice bath conditions, add 500mL of acetonitrile and chlorosulfonyl isocyanate (11.6g) to a 1L single-necked flask. Then slowly add 2-bromoethanol (10.3g) to the system. Keep the system under ice bath and stir for 30 minutes, then warm it to room temperature and stir for 1 hour. Then slowly add N-methylmorpholine (50.0g) to the system and stir for 10 minutes, and then slowly add cyclopropylamine (4.7g) to the system. After the addition, warm the system to 50°C and stir for 5 hours. Then gradually cool the system to room temperature and continue stirring for 15 hours. Filter and concentrate the filtrate to obtain a light orange solid. Add ethyl acetate to dissolve most of the solid, wash with saturated brine, separate the organic phase and dry it over anhydrous sodium sulfate, filter and spin-dry the solvent to obtain a crude product. The crude product is washed with tert-methyl ether to obtain 4.4g of off-white solid. 1 H NMR (400MHz, DMSO-d6, δ): 8.72 (s, 1H), 4.44-4.40 (m, 2H), 4.00-3.96 (m, 2H), 2.50-2.45 (m, 1H), 0.65-0.58 (m, 2H), 0.56-0.52 (m, 2H).

[0219] Preparation of Intermediate 8

[0220] Preparation of N-methyl-d3-2-oxoxazoline-3-sulfonamide

[0221] Under ice bath conditions, 720mL of acetonitrile and chlorosulfonyl isocyanate (20.6g) were added to a 2L single-necked flask. 2-bromoethanol (18.2g) was then slowly added to the system. The system was kept stirring under ice bath for 30min, then heated to room temperature and stirred for 1h. N-methylmorpholine (58.4g) was then slowly added to the system and stirred for 10min, after which deuterated methylamine hydrochloride (10.2g) was slowly added to the system. After the addition, the system was heated to 50°C and stirred for 5h. The system was then gradually cooled to room temperature and stirred for 15h. Filtered and the filtrate was concentrated. Water was added to dilute the concentrate, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Filtered and the solvent was removed by spinning to obtain 11.9g of a light yellow solid. 1 H NMR (400MHz, DMSO-d6, δ): 8.17 (s, 1H), 4.42-4.38 (m, 2H), 3.96-3.93 (m, 2H).

[0222] Compound preparation

[0223] Example 1

[0224] Step 1: Preparation of N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide

[0225] In a 100 mL single-necked flask, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride (1.1 g), 1-hydroxybenzotriazole (646 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (763 mg), and N,N-dimethylformamide (11 mL) were added, and the system was stirred at room temperature for 2 hours. Allylamine hydrochloride (560 mg) and N,N-diisopropylethylamine (1.0 g) were then added to the system, and the reaction was continued by stirring at room temperature for 2 hours. The reaction system was added to a saturated aqueous sodium bicarbonate solution to precipitate a solid. The filter cake was filtered and purified by silica gel column chromatography to obtain 300 mg of a light yellow solid. ESI-MS: [M+H] + =557.1.

[0226] Step 2: Preparation of N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)benzamide

[0227] In a 50 mL single-necked bottle, N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (300 mg), N,N-dimethylformamide (5.0 mL) and pyridine (422 mg) were added, and the system was placed in an ice bath and stirred. When the system dropped below 0°C, methylaminosulfonyl chloride (210 mg) was slowly added dropwise. After 30 minutes, the reaction was stopped, and the system was poured into a saturated aqueous sodium bicarbonate solution and stirred at room temperature for 10 minutes. Extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. Filtered and the solvent was removed by rotation, and the crude product was purified by silica gel column chromatography to obtain 100 mg of an off-white solid. 1H NMR (400MHz, DMSO-d6): δ10.40(s,1H),9.05(s,1H),8.87(t,J=5.6Hz,1H), 8.02(d,J=4.8Hz,1H),7.59-7.57(m,2H),7.36(d,J=8.4Hz,1H),7.04-7.00( m,1H),6.95-6.93(m,1H),6.72-6.66(m,1H),5.87-5.77(m,1H),5.17-5.06( m,2H),4.07(s,2H),3.84(t,J=5.2Hz,2H),2.53-2.51(m,3H).ESI-MS:[M+H] + =650.0.

[0228] Example 2

[0229] Step 1: Preparation of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-(but-3-en-1-yl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide

[0230] In a 100 mL single-necked flask, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride (300 mg), 1-hydroxybenzotriazole (149 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (414 mg), and N,N-dimethylformamide (5 mL) were added, and the system was stirred at room temperature for 2 hours. Subsequently, but-3-en-1-amine hydrochloride (117 mg) and N,N-diisopropylethylamine (348 mg) were added to the system, and the reaction was stirred at room temperature for another 2 hours. The reaction system was added to saturated sodium bicarbonate aqueous solution, and a solid precipitated. The filter cake was filtered and purified by silica gel column chromatography to obtain 148 mg of an off-white solid. ESI-MS: [M+H] + =571.2.

[0231] Step 2: Preparation of N-(but-3-en-1-yl)-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)benzamide

[0232] In a 50 mL single-necked bottle, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-(but-3-en-1-yl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (148 mg), N,N-dimethylformamide (5 mL) and pyridine (205 mg) were added, and the system was placed in an ice bath and stirred. After the system dropped below 0°C, methylaminosulfonyl chloride (326 mg) was slowly added dropwise. After 30 minutes, the reaction was stopped, and the system was poured into a saturated aqueous sodium bicarbonate solution and stirred at room temperature for 10 minutes. Extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. Filtered and the solvent was removed by rotation, and the crude product was purified by silica gel column chromatography to obtain 70 mg of an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ10.42(s,1H),9.00(s,1H),8.69(t,J=5.6Hz,1H),8.02(d,J=5. 2Hz,1H),7.60-7.57(m,1H),7.48(d,J=7.2Hz,1H),7.36(d,J=8.4Hz,1H),7.05-7.01(m, 1H),6.93(t,J=4.4Hz,1H),7.00-6.64(m,1H),5.81-5.71(m,1H),5.04-4.94(m,2H),4.0 7(s,2H),3.25(q,J=6.4Hz,2H),2.52-2.51(m,3H),2.21(q,J=6.8Hz,2H).ESI-MS:[M+H] + =664.2.

[0233] Example 3

[0234] Step 1: Preparation of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(pent-4-en-1-yl)benzamide

[0235] In a 100 mL single-necked bottle, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride (400 g), 1-hydroxybenzotriazole (105 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (177 mg) and N,N-dimethylformamide (15 mL) were added, and the system was stirred at room temperature for 2 hours. Subsequently, 4-penten-1-amine hydrochloride (113 mg) and N,N-diisopropylethylamine (250 g) were added to the system, and the reaction was continued to stir at room temperature for 2 hours. The reaction system was added to a saturated sodium bicarbonate aqueous solution to precipitate a solid. Filtered to obtain 400 mg of a light yellow solid. ESI-MS: [M+H] + =585.3.

[0236] Step 2: Preparation of 3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)-N-(pent-4-en-1-yl)benzamide

[0237] In a 50 mL single-necked bottle, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(pent-4-en-1-yl)benzamide (400 mg), N,N-dimethylformamide (4 mL), dichloromethane (4 mL) and pyridine (270 mg) were added, and the system was placed in an ice bath and stirred. When the system dropped below 0°C, methylaminosulfonyl chloride (355 mg) was slowly added dropwise. After the addition was completed, the reaction was continued for 30 minutes and then stopped. The system was poured into a saturated sodium bicarbonate aqueous solution and stirred at room temperature for 10 minutes. Extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. Filtered and the solvent was removed by rotation, and the crude product was purified by silica gel column chromatography to obtain 110 mg of an off-white solid. 1H NMR (400MHz, DMSO-d6): δ10.41(s,1H),9.02(s,1H),8.67(t,J=5.2Hz,1H),8.02(d,J=4.8Hz,1H), 7.58(dd,J1=10.8Hz,J2=1.6Hz,1H),7.52(d,J=6.8Hz,1H),7.36(d,J=8.8Hz,1H),7.03(q,J=5.2Hz ,1H),6.93(t,J=4.8Hz,1H),7.00-6.64(m,1H),5.84-5.74(m,1H),5.02-4.93(m,2H),4.08(s,2H) ,3.19(q,J=6.4Hz,2H),2.52-2.51(m,3H),2.01(q,J=7.2Hz,2H),1.57-1.50(m,2H).ESI-MS:[M+H] + =678.3.

[0238] Example 4

[0239] Step 1: Preparation of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(3-methylbut-2-en-1-yl)benzamide

[0240] In a 100 mL single-necked bottle, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride (400 mg), 3-methylbut-2-en-1-amine (63 mg), N,N-diisopropylethylamine (373 mg) and N,N-dimethylformamide (8 mL) were added, and the system was stirred at room temperature for 5 minutes. Subsequently, O-benzotriazole-N,N,N',N',-tetramethyluronium tetrafluoroborate (763 mg) was added to the system, and the reaction was continued to stir at room temperature for 1.5 hours. The reaction system was added to a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was filtered and removed by rotation, and the crude product was purified by silica gel column chromatography to obtain 310 mg of an off-white solid. ESI-MS: [M+H] + =585.3.

[0241] Step 2: Preparation of 3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)-N-(3-methylbut-2-en-1-yl)benzamide

[0242] In a 50 mL single-necked bottle, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(3-methylbut-2-en-1-yl)benzamide (310 mg), N,N-dimethylformamide (6 mL) and pyridine (335 mg) were added, and the system was placed in an ice bath and stirred. When the system dropped below 0°C, methylaminosulfonyl chloride (272 mg) was slowly added dropwise. After 30 minutes, the reaction was stopped, and the system was poured into a saturated aqueous sodium bicarbonate solution and stirred at room temperature for 10 minutes. Extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. Filtered and the solvent was removed by rotation, and the crude product was purified by silica gel column chromatography to obtain 200 mg of an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ10.41(s,1H),9.11(s,1H),8.74(t,J=5.2Hz,1H),8.20(d,J=4. 8Hz,1H),7.59(dd,J1=10.8Hz,J2=2.0Hz,1H),7.54(d,J=6.8Hz,1H),7.36(d,J=5.2Hz,1 H),7.03(d,J=4.8Hz,1H),6.93(s,1H),6.70-6.65(m,1H),5.14(t,J=6.8Hz,1H),4.07(s ,2H),3.79(t,J=6.0Hz,2H),2.52-2.51(m,3H),1.67(s,3H),1.63(s,3H).ESI-MS:[M+H] + =678.3.

[0243] Example 5

[0244] Step 1: Preparation of (R)-5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-(but-3-en-2-yl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide

[0245] To a 100 mL single-necked flask, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride (500 mg), 1-hydroxybenzotriazole (232 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (641 mg), and N,N-dimethylformamide (20 mL) were added, and the reaction was stirred at room temperature for 2 hours. Subsequently, (R)-but-3-en-2-amine hydrochloride (195 mg) and N,N-diisopropylethylamine (350 mg) were added to the system, and the reaction was stirred at room temperature for another 2 hours. The reaction system was added to saturated aqueous sodium bicarbonate solution, and a solid precipitated. The filter cake was filtered, and purified by silica gel column chromatography to obtain 340 mg of a light yellow solid. ESI-MS: [M+H] + =571.2.

[0246] Step 2: Preparation of (R)-N-(but-3-en-2-yl)-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)benzamide

[0247] In a 50 mL single-necked flask, (R)-5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-(but-3-en-2-yl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (330 mg), N,N-dimethylformamide (15 mL), and pyridine (458 mg) were added, and the system was placed in an ice bath and stirred. After the system cooled to below 0°C, methylaminosulfonyl chloride (225 mg) was slowly added dropwise. After the addition was completed and the reaction was stopped after 30 minutes, the system was poured into a saturated aqueous sodium bicarbonate solution and stirred at room temperature for 10 minutes. Extraction was performed with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed by filtration, and the crude product was purified by silica gel column chromatography to obtain 320 mg of an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ10.41(s,1H),8.95(s,1H),8.64(d,J=8.0Hz,1H),8.02(d, J=5.2Hz,1H),7.58(d,J=8.8Hz,2H),7.36(d,J=8.8Hz,1H),7.02(q,J=5.2Hz,1H),6 .93(t,J=4.8Hz,1H),7.00-6.64(m,1H),5.89-5.81(m,1H),5.13-5.01(m,2H),4.54 -4.46(m,1H),4.09(s,2H),2.52-2.51(m,3H),1.18(d,J=6.8Hz,3H).ESI-MS:[M+H]+ =664.2.

[0248] Example 6

[0249] Step 1: Preparation of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-methylallyl)benzamide

[0250] In a 100 mL single-necked flask, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride (400 mg), 1-hydroxybenzotriazole (195 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (552 mg), and N,N-dimethylformamide (5 mL) were added, and the system was stirred at room temperature for 2 hours. 2-Methylprop-2-en-1-amine (102 mg) and N,N-diisopropylethylamine (464 mg) were then added to the system, and the reaction was continued by stirring at room temperature for 2 hours. The reaction system was added to a saturated aqueous sodium bicarbonate solution to precipitate a solid. The filter cake was filtered and purified by silica gel column chromatography to obtain 200 mg of a white solid. ESI-MS: [M+H] + =571.1.

[0251] Step 2: Preparation of 3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)-N-(2-methylallyl)benzamide

[0252] In a 50 mL single-necked bottle, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-methylallyl)benzamide (200 mg), N,N-dimethylformamide (3 mL) and pyridine (278 mg) were added, and the system was placed in an ice bath and stirred. When the system dropped below 0°C, methylaminosulfonyl chloride (208 mg) was slowly added dropwise. After 30 minutes, the reaction was stopped, and the system was poured into a saturated aqueous sodium bicarbonate solution and stirred at room temperature for 10 minutes. Extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. Filtered and the solvent was removed by rotation, and the crude product was purified by silica gel column chromatography to obtain 170 mg of an off-white solid. 1H NMR (400MHz, DMSO-d6): δ10.43(s,1H),9.00(s,1H),8.92(t,J=5.6Hz,1H),8.02(d,J=4.8Hz,1H),7.60-7.57(m,2H),7.36(d,J=8.4Hz,1H),7.06-7. 02(m,1H),6.95(t,J=4.8Hz,1H),6.71-6.65(m,1H),4.78(s,2H),4.08(s, 2H),3.76(d,J=5.6Hz,2H),2.51-2.50(m,3H),1.67(s,3H).ESI-MS:[M+H] + =664.0.

[0253] Example 7

[0254] Step 1: Preparation of ethyl 3-(trimethylsilyl)propionate

[0255] To a 3L reaction flask, add 1000mL of dichloromethane, trimethylsilyl trifluoromethanesulfonate (271.8g), triethylamine (123.7g), and silver trifluoromethanesulfonate (10g). Slowly add a solution of ethyl propargyl acid (100g) in dichloromethane (100mL) dropwise. After the addition is complete, stir at room temperature for 30 minutes and concentrate under reduced pressure to remove the dichloromethane. Add n-hexane to the concentrated residue and extract twice. Combine the n-hexanes and wash twice with saturated ammonium chloride solution. Dry the n-hexane phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a light yellow liquid.

[0256] Step 2: Preparation of 3-(trimethylsilyl)prop-2-yn-1,1-d2-1-ol

[0257] In a 1000mL three-necked flask, add ethyl 3-(trimethylsilyl)propionate (50g), 500mL of ether, sodium borodeuteride (17.3g), lithium chloride (17.4g), and heavy water (8.2g). Stir at room temperature for 40 minutes, then warm to 33°C and react for 8 hours. Slowly add the reaction solution to a 10% aqueous acetic acid solution; extract with n-hexane, separate the layers, and extract the aqueous layer again with n-hexane. Combine the organic phases, wash with 1N hydrochloric acid solution, and then wash the organic phase with water until neutral. Dry over anhydrous sodium sulfate and concentrate under reduced pressure to obtain a light yellow liquid. 1 H NMR (400MHz, DMSO-d6): δ5.20 (brs, 1H), 0.13 (s, 9H).

[0258] Step 3: Preparation of (3-bromoprop-1-yn-1-yl-3,3-d2)trimethylsilane

[0259] In a 100 mL single-necked flask, add 3-(trimethylsilyl)prop-2-yn-1,1-d2-1-ol (6.0 g) and dichloromethane (75 mL) and cool the system to -10°C. Phosphorus tribromide (30.0 g) is then added dropwise. After addition, warm the reaction system to room temperature for 1 hour. Pour the mixture into ice, adjust the pH to neutral with saturated sodium bicarbonate aqueous solution, extract with dichloromethane, combine the organic phases, dry, and concentrate to yield 5.1 g of a colorless, transparent liquid.

[0260] Step 4: Preparation of 2-(3-(trimethylsilyl)prop-2-yn-1-yl-1,1-d2)isoindoline-1,3-dione

[0261] In a 250 mL single-necked flask, add (3-bromoprop-1-yn-1-yl-3,3-d2)trimethylsilane (10.0 g), potassium phthalimide (10.5 g), potassium carbonate (8.6 g), and N,N-dimethylformamide (100 mL). Stir the reaction at room temperature for 16 hours. Pour the mixture into water, extract with ethyl acetate, combine the organic phases, and dry over anhydrous sodium sulfate. Filter and concentrate to obtain 12.0 g of an off-white solid.

[0262] Step 5: Preparation of 2-(prop-2-yn-1-yl-1,1-d2)isoindoline-1,3-dione

[0263] In a 250 mL single-necked flask, add 2-(3-(trimethylsilyl)prop-2-yn-1-yl-1,1-d2)isoindoline-1,3-dione (3.4 g), tetrahydrofuran (15 mL), and tetra-n-butylammonium fluoride trihydrate (10.8 g) and stir at room temperature for 10 minutes. Pour the mixture into water, extract with ethyl acetate, combine the organic phases, and dry over anhydrous sodium sulfate. Concentrate to obtain 900 mg of an off-white solid.

[0264] Step 6: Preparation of 2-(allyl-1,1-d2)isoindoline-1,3-dione

[0265] In a 100 mL single-necked flask, add 2-(prop-2-yn-1-yl-1,1-d2)isoindoline-1,3-dione (1.8 g), methanol (45 mL), and Lindela's catalyst (180 mg). The system was replaced with a hydrogen atmosphere and stirred at room temperature for 10 minutes. The filtrate was collected by suction and concentrated to yield 1.0 g of an off-white solid.

[0266] Step 7: Preparation of prop-2-en-1,1-d2-1-amine hydrochloride

[0267] In a 100 mL single-necked flask, add 2-(allyl-1,1-d2)isoindoline-1,3-dione (1.0 g) and concentrated hydrochloric acid (30 mL). Stir the reaction at 100°C for 19 h. Collect the filtrate by suction, wash with diethyl ether, and collect the aqueous phase, concentrate, and dry to obtain 325 mg of an off-white solid.

[0268] Step 8: Preparation of N-(allyl-1,1-d2)-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide

[0269] In a 100 mL single-necked bottle, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride (700 mg), 1-hydroxybenzotriazole (205 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (483 mg) and N,N-dimethylformamide (10 mL) were added, and the system was stirred at room temperature for 2 hours. Subsequently, prop-2-en-1,1-d2-1-amine hydrochloride (325 mg) and N,N-diisopropylethylamine (325 mg) were added to the system, and the reaction was continued to stir at room temperature for 2 hours. The reaction system was added to saturated brine to precipitate a solid. The filter cake was filtered and purified by silica gel column chromatography to obtain 500 mg of a yellow solid. ESI-MS: [M+H] + =559.1.

[0270] Step 9: Preparation of N-(allyl-1,1-d2)-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)benzamide

[0271] In a 50 mL single-necked bottle, N-(allyl-1,1-d2)-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (250 mg), N,N-dimethylformamide (5 mL) and pyridine (351 mg) were added, and the system was placed in an ice bath and stirred. When the system dropped below 0°C, methylaminosulfonyl chloride (175 mg) was slowly added dropwise. After the addition was completed, the reaction was continued for 30 minutes and then stopped. The system was poured into saturated brine and stirred at room temperature for 10 minutes. Extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. Filtered and the solvent was removed by rotation, and the crude product was then purified by silica gel column chromatography to obtain 180 mg of an off-white solid. 1H NMR (400MHz, DMSO-d6): δ10.42(s,1H),9.06(s,1H),8.88(s,1H),8.02(d, J=5.2Hz,1H),7.60-7.57(m,2H),7.36(d,J=8.8Hz,1H),7.03(q,J=4.8Hz,1 H), 6.95 (t, J=4.8Hz, 1H), 6.72-6.66 (m, 1H), 5.81 (dd, J1=17.2Hz, J2=10. 4Hz,1H),5.18-5.06(m,2H),4.07(s,2H),2.52-2.51(m,3H).ESI-MS:[M+H] + =652.1.

[0272] Example 8

[0273] Preparation of N-allyl-5-((2-((N-ethylaminosulfonyl)amino)-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-(((2-fluoro-4-iodophenyl)amino)benzamide

[0274] To a 100 mL single-necked flask, add N-ethyl-2-oxoxazoline-3-sulfonamide (1.1 g), N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (350 mg), triethylamine (699 mg), and 1,2-dichloroethane (20 mL). The reaction system was heated to 80°C for 5.5 h. After cooling to room temperature, the mixture was poured into a water / tetrahydrofuran mixture and extracted with ethyl acetate. The organic phases were combined, dried, concentrated, and purified by silica gel column chromatography. The crude product was washed with a n-hexane / acetone mixture (4 / 1, v / v) to yield 110 mg of an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ10.40(s,1H),9.05(s,1H),8.89(t,J=5.6Hz,1H),8.03(d, J=5.2Hz,1H),7.60-7.56(m,2H),7.36(d,J=8.4Hz,1H),7.17(t,J=5.6Hz,1H),6.93 (t,J=4.8Hz,1H),6.72-6.66(m,1H),5.87-5.77(m,1H),5.17-5.06(m,2H),4.07(s, 2H),3.84(t,J=5.2Hz,2H),2.96-2.90(m,2H),1.02(t,J=7.2Hz,3H).ESI-MS:[M+H] + =664.2.

[0275] Example 9

[0276] Preparation of N-allyl-5-((2-((N-cyclopropylaminosulfonyl)amino)-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide

[0277] To a 100 mL single-necked flask, add N-cyclopropyl-2-oxoxazoline-3-sulfonamide (1.5 g), N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (400 mg), triethylamine (729 mg), and 1,2-dichloroethane (20 mL). Heat the reaction system to 80°C for 5.5 hours. After cooling to room temperature, pour the mixture into a water / tetrahydrofuran mixture and extract with ethyl acetate. The organic phases are combined, dried, concentrated, and purified by silica gel column chromatography. The crude product is washed with a n-hexane / acetone mixture to obtain 150 mg of an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ10.54(s,1H),9.05(s,1H),8.89(t,J=5.6Hz,1H),8 .03(d,J=5.2Hz,1H),7.61-7.56(m,3H),7.36(d,J=8.4Hz,1H),6.95(t,J=4.8 Hz,1H),6.72-6.66(m,1H),5.87-5.77(m,1H),5.17-5.06(m,2H),4.08(s,2H ),3.84(t,J=5.2Hz,2H),2.32-2.30(m,1H),0.56-0.47(m,4H).ESI-MS:[M+H] + =676.1.

[0278] Example 10

[0279] Preparation of N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methyl-d3-aminosulfonyl)amino)pyridin-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)benzamide

[0280] To a 100 mL single-necked flask, add N-methyl-d3-2-oxoxazoline-3-sulfonamide (1.0 g), N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (310 mg), triethylamine (621 mg), and 1,2-dichloroethane (30 mL). The reaction system was heated to 80°C for 5.5 hours. After cooling to room temperature, the mixture was poured into a water / tetrahydrofuran mixture and extracted with ethyl acetate. The organic phases were combined, dried, concentrated, and purified by silica gel column chromatography. The crude product was washed with a hexane / acetone mixture to yield 110 mg of an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ10.41(s,1H),9.05(s,1H),8.89(t,J=5.6Hz,1H),8.02(d,J=5.2Hz,1H),7.60-7.57(m,2H),7.36(d,J=8.4Hz,1H),7 .00(s,1H),6.94(t,J=4.8Hz,1H),6.72-6.66(m,1H),5.87-5.77(m,1H),5.17-5.06(m,2H),4.07(s,2H),3.84(t,J=5.2Hz,2H).ESI-MS:[M+H] + =653.2.

[0281] Example 11

[0282] Step 1: Preparation of 5-(3-amino-2-fluorobenzyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-allylbenzamide

[0283] In a 100 mL single-necked bottle, 5-(3-amino-2-fluorobenzyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride (310 mg), 1-hydroxybenzotriazole (170 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (322 mg) and N,N-dimethylformamide (6 mL) were added, and the system was stirred at room temperature for 2 hours. Subsequently, allylamine hydrochloride (93 mg) and N,N-diisopropylethylamine (217 mg) were added to the system, and the reaction was continued to stir at room temperature for 2 hours. The reaction system was added to a saturated sodium bicarbonate aqueous solution to precipitate a solid. The filter cake was filtered and purified by silica gel column chromatography to obtain 220 mg of an off-white solid. ESI-MS: [M+H] + =556.0.

[0284] Step 2: Preparation of N-allyl-3,4-difluoro-5-(2-fluoro-3-((N-methylaminosulfonyl)amino)benzyl)-2-((2-fluoro-4-iodophenyl)amino)benzamide

[0285] In a 50 mL single-necked flask, 5-(3-amino-2-fluorobenzyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-allylbenzamide (274 mg), N,N-dimethylformamide (10 mL), and pyridine (391 mg) were added and the system was stirred in an ice bath. After the system cooled to below 0°C, methylaminosulfonyl chloride (192 mg) was slowly added dropwise. The reaction was stopped after 30 minutes, and the system was poured into a saturated aqueous sodium bicarbonate solution and stirred at room temperature for 10 minutes. Extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. Filtered and the solvent was removed by swirl. The crude product was purified by silica gel column chromatography to obtain 180 mg of an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ9.43(s,1H),8.99(s,1H),8.86(t,J=5.6Hz,1H),7.58(dd,J1= 10.8Hz,J2=2.0Hz,1H),7.54(d,J=7.2Hz,1H),7.37-7.31(m,2H),7.25(q,J=4.8Hz,1H), 7.11(t,J=8.0Hz,1H),7.02(t,J=6.8Hz,1H),6.68-6.63(m,1H),5.86-5.76(m,1H),5.16 -5.05(m,2H),4.03(s,2H),3.83(t,J=5.4Hz,2H),2.52(d,J=4.8Hz,3H).ESI-MS:[M+Na] + =671.0.

[0286] Example 12

[0287] Step 1: Preparation of N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-(phenylamino)benzamide

[0288] To a 100 mL single-necked flask, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-(phenylamino)benzoic acid hydrochloride (350 mg), 1-hydroxybenzotriazole (220 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (606 mg), and N,N-dimethylformamide (10 mL) were added and the reaction was stirred at room temperature for 2 hours. Allylamine hydrochloride (160 mg) and N,N-diisopropylethylamine (331 mg) were then added and the reaction was stirred at room temperature for another 2 hours. The reaction system was added to saturated aqueous sodium bicarbonate solution to precipitate a solid. The filter cake was filtered and purified by silica gel column chromatography to obtain 250 mg of a light yellow solid.

[0289] Step 2: Preparation of N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)-2-(phenylamino)benzamide

[0290] In a 50 mL single-necked flask, add N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-(phenylamino)benzamide (250 mg), N,N-dimethylformamide (10 mL), and pyridine (480 mg), and place the system in an ice bath and stir. When the system drops below 0°C, slowly add methylaminosulfonyl chloride (236 mg) dropwise. After the addition is complete, continue the reaction for 30 minutes, then stop the reaction. Pour the system into saturated sodium bicarbonate aqueous solution and stir at room temperature for 10 minutes. Extract with ethyl acetate, combine the organic phases, and dry over anhydrous sodium sulfate. Filter and spin to remove the solvent. The crude product is purified by silica gel column chromatography to obtain 165 mg of the product as an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ10.42(s,1H),8.83(s,1H),8.78(t,J=5.6Hz,1H),8.02(d,J=4.8Hz,1H),7.52(d,J=6.8Hz,1H),7.22-7.18(m,2H),7. 03(d,J=4.8Hz,1H),6.96-6.82(m,4H),5.83-5.74(m,1H),5.14-5.03(m ,2H),4.07(s,2H),3.82-3.80(m,2H),2.52-2.51(m,3H).ESI-MS:[M+H] + =506.2.

[0291] Example 13

[0292] Step 1: Preparation of N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)benzamide

[0293] In a 100 mL single-necked flask, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)benzoic acid hydrochloride (500 mg), 1-hydroxybenzotriazole (344 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (433 mg) and N,N-dimethylformamide (5 mL) were added, and the system was stirred at room temperature for 2 hours. Subsequently, allylamine hydrochloride (317 mg) and N,N-diisopropylethylamine (875 mg) were added to the system, and the reaction was continued to stir at room temperature for 2 hours. The reaction system was added to a saturated sodium bicarbonate aqueous solution to precipitate a solid. The filter cake was filtered and purified by silica gel column chromatography to obtain 350 mg of a light yellow solid. ESI-MS: [M+H] + =445.3.

[0294] Step 2: Preparation of N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)-2-(((2-fluoro-4-methylphenyl)amino)benzamide

[0295] In a 50 mL single-necked bottle, N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)benzamide (350 mg), N,N-dimethylformamide (5 mL) and pyridine (617 mg) were added, and the system was placed in an ice bath and stirred. When the system dropped below 0°C, methylaminosulfonyl chloride (307 mg) was slowly added dropwise. After 30 minutes, the reaction was stopped, and the system was poured into a saturated aqueous sodium bicarbonate solution and stirred at room temperature for 10 minutes. Extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. Filtered and the solvent was removed by rotation, and the crude product was purified by silica gel column chromatography to obtain 180 mg of an off-white solid. 1H NMR (400MHz, DMSO-d6): δ10.41(s,1H),9.08(s,1H),8.90(t,J=5.6Hz,1H), 8.02(d,J=4.8Hz,1H),7.58(d,J=6.8Hz,1H),7.05-7.02(m,2H),6.93(t,J= 4.8Hz,1H),6.88-6.79(m,2H),5.88-5.80(m,1H),5.18-5.07(m,2H),4.05( s,2H),3.85(t,J=5.2Hz,2H),2.52-2.51(m,3H),2.25(s,3H).ESI-MS:[M+H] + =538.3.

[0296] Example 14

[0297] Step 1: Preparation of methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzoate

[0298] In a 50 mL single-necked bottle, methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate (1.3 g), potassium vinyl fluoroborate (636 mg), potassium carbonate (984 mg), 1,4-dioxane (12 mL), water (4 mL) and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (86 mg) were added, and the system was replaced with a nitrogen atmosphere and heated to 95 ° C. The reaction was stirred for 2 hours. After the system was cooled to room temperature, it was poured into water to quench the reaction. It was extracted with ethyl acetate, the organic phases were combined, and dried over anhydrous sodium sulfate. Filtered and the solvent was removed by rotation to obtain 950 mg of a brown solid. ESI-MS: [M+H] + =432.2.

[0299] Step 2: Preparation of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzoic acid hydrochloride

[0300] In a 50 mL single-necked flask, methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzoate (950 mg), tetrahydrofuran (20 mL), and water (10 mL) were added and stirred at room temperature until the solution became clear. The system was then placed in an ice bath and lithium hydroxide monohydrate (360 mg) was slowly added. After the addition, the system was warmed to room temperature and stirred for 3 hours. Hydrochloric acid (6 M, 5 mL) was then slowly added dropwise to the system to adjust the pH to 1-2, and the mixture was stirred for 5 minutes. The tetrahydrofuran was removed from the system under reduced pressure, and the concentrate was diluted with water and stirred for 10 minutes. The filter cake was collected by filtration and washed once with water and once with methyl tert-ether to yield 700 mg of a brown solid. The product from this step was used directly in the next step without further characterization or purification.

[0301] Step 3: Preparation of N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzamide

[0302] In a 100 mL single-necked flask, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzoic acid hydrochloride (300 mg), 1-hydroxybenzotriazole (107 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (253 mg), and N,N-dimethylformamide (5 mL) were added, and the system was stirred at room temperature for 2 hours. Allylamine hydrochloride (126 mg) and N,N-diisopropylethylamine (426 mg) were then added to the system, and the reaction was continued by stirring at room temperature for 2 hours. The reaction system was added to a saturated aqueous sodium bicarbonate solution to precipitate a solid. The filter cake was filtered and purified by silica gel column chromatography to obtain 150 mg of a light yellow solid. ESI-MS: [M+H] + =457.3.

[0303] Step 4: Preparation of N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)-2-((2-fluoro-4-vinylphenyl)amino)benzamide

[0304] In a 50 mL single-necked bottle, N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzamide (146 mg), N,N-dimethylformamide (5 mL) and pyridine (250 mg) were added, and the system was placed in an ice bath and stirred. After the system dropped below 0°C, methylaminosulfonyl chloride (240 mg) was slowly added dropwise. After 30 minutes, the reaction was stopped, and the system was poured into a saturated aqueous sodium bicarbonate solution and stirred at room temperature for 10 minutes. Extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. Filtered and the solvent was removed by rotation, and the crude product was purified by silica gel column chromatography to obtain 70 mg of an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ10.42(s,1H),9.13(s,1H),8.91(t,J=5.6Hz,1H),8.03(d,J=4.8Hz,1H),7.59(d,J=6.8 Hz,1H),7.39(dd,J1=12.8Hz,J2=1.2Hz,1H),7.13(d,J=8.0Hz,1H),7.03(q,J=5.2Hz,1H),6.95(t,J=4.8Hz,1H), 6.87-6.82(m,1H),6.64(dd,J1=17.6Hz,J2=10.8Hz,1H),5.88-5.79(m,1H),5.74(d,J=17.6Hz,1H),5.19-5.13( m,2H),5.07(dd,J1=10.4Hz,J2=5.6Hz,1H),4.08(s,2H),3.85(t,J=5.2Hz,2H),2.53-2.51(m,3H).ESI-MS:[M+H] + =550.3.

[0305] Example 15

[0306] Step 1: Preparation of methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-formylphenyl)amino)benzoate

[0307] In a 100 mL single-necked bottle, methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzoate (1.1 g), potassium osmate dihydrate (91 mg), sodium periodate (2.7 g), 1,4-dioxane (30 mL) and water (12 mL) were added, and the system was stirred at room temperature for 2 h. The reaction system was poured into water, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was filtered and removed by rotation to obtain 950 mg of a solid. The solid was diluted with acetic acid (20 mL), and then iron powder (9.0 g) was added to the system and the reaction was stirred at room temperature for 1 h. 50 mL of ethyl acetate was added to the system and the insoluble matter was removed by suction. The filtrate was collected and concentrated. Water was added to dilute the concentrate, and the pH of the system was adjusted to 7-8 with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The crude product was filtered and the solvent was removed by spin-drying to obtain the crude product. The product was purified by silica gel column chromatography to obtain 450 mg of a yellow solid. ESI-MS: [M+H] + =434.1.

[0308] Step 2: Preparation of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-formylphenyl)amino)benzoic acid hydrochloride

[0309] In a 50 mL single-necked flask, methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-formylphenyl)amino)benzoate (450 mg), tetrahydrofuran (10 mL) and water (5 mL) were added and the system was stirred at room temperature until clear. The system was then placed in an ice bath and lithium hydroxide monohydrate (131 mg) was slowly added to the system. After the addition was complete, the system was warmed to room temperature and stirred for 2 hours. Hydrochloric acid (6 M, 3 mL) was then slowly added dropwise to the system to adjust the pH to 1-2 and stirred for 5 minutes. The tetrahydrofuran in the system was removed under reduced pressure, and the concentrate was then diluted with water and stirred for 10 minutes. The filter cake was collected by filtration and washed once with water and tertiary methyl ether to obtain 390 mg of a light yellow solid. This step was not further purified or characterized and was directly carried out to the next step.

[0310] Step 3: Preparation of N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-formylphenyl)amino)benzamide

[0311] In a 100 mL single-necked bottle, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-formylphenyl)amino)benzoic acid hydrochloride (440 mg), 1-hydroxybenzotriazole (248 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (686 mg) and N,N-dimethylformamide (15 mL) were added, and the system was stirred at room temperature for 2 hours. Subsequently, allylamine hydrochloride (90 mg) and N,N-diisopropylethylamine (374 g) were added to the system, and the reaction was continued to stir at room temperature for 2 hours. The reaction system was added to a saturated sodium bicarbonate aqueous solution to precipitate a solid. The filter cake was filtered and purified by silica gel column chromatography to obtain 290 mg of an off-white solid. ESI-MS: [M+H] + =459.2.

[0312] Step 4: Preparation of N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)-2-((2-fluoro-4-formylphenyl)amino)benzamide

[0313] In a 50 mL single-necked bottle, N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-formylphenyl)amino)benzamide (280 mg), N,N-dimethylformamide (10 mL) and pyridine (483 mg) were added, and the system was placed in an ice bath and stirred. When the system dropped below 0°C, methylaminosulfonyl chloride (238 mg) was slowly added dropwise. After 30 minutes, the reaction was stopped, and the system was poured into a saturated aqueous sodium bicarbonate solution and stirred at room temperature for 10 minutes. Extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. Filtered and the solvent was removed by rotation, and the crude product was purified by silica gel column chromatography to obtain 270 mg of a white solid. 1H NMR (400MHz, DMSO-d6): δ10.44(s,1H),9.79(d,J=1.6Hz,1H),9.22(s,1H),8.85(t,J=5.6Hz,1H ),8.04(d,J=5.2Hz,1H),7.67(dd,J1=12.0Hz,J2=1.6Hz,1H),7.61(dd,J1=8.4Hz,J2=1.2Hz,1H) ,7.57(d,J=6.8Hz,1H),7.06-7.03(m,1H),6.98(t,J=4.8Hz,1H),6.95-6.89(m,1H),5.84-5.75 (m,1H),5.16-5.03(m,2H),4.13(s,2H),3.82(t,J=5.2Hz,2H),2.53-2.51(m,3H).ESI-MS:[M+H] + =552.1.

[0314] Example 16

[0315] Step 1: Preparation of N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)-2-((2-fluoro-4-((trimethylsilyl)ethynyl)phenyl)amino)benzamide

[0316] In a 100 mL single-necked flask, N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)benzamide (140 mg), trimethylsilylacetylene (85 mg), cuprous iodide (1 mg), bis(triphenylphosphine)palladium dichloride (3 mg), tetrahydrofuran (20 mL), and triethylamine (0.5 mL) were added. The system was then replaced with a nitrogen atmosphere and the reaction was stirred at room temperature for 16 h. Filtration, concentration, and purification by silica gel column chromatography afforded 120 mg of a yellow solid. ESI-MS: [M+H] + =620.4.

[0317] Step 2: Preparation of N-allyl-2-((4-ethynyl-2-fluorophenyl)amino)-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)benzamide

[0318] In a 50 mL single-necked flask, N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)-2-((2-fluoro-4-((trimethylsilyl)ethynyl)phenyl)amino)benzamide (120 mg), ethanol (5 mL), and potassium fluoride (50 mg) were added, and the system was stirred at room temperature for 21 hours. Water was added to the system and stirred at room temperature for 10 minutes. Extraction was performed with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by spin-drying. Purification by silica gel column chromatography gave 50 mg of a light yellow solid. 1 H NMR (400MHz, DMSO-d6): δ10.42(s,1H),9.12(s,1H),8.89(t,J=5.6Hz,1H),8.01(d, J=3.6Hz,1H),7.58(d,J=6.8Hz,1H),7.34(d,J=12.0Hz,1H),7.15(d,J=8.4Hz,1H),7 .02(brs,1H),6.94(brs,1H),6.85-6.79(m,1H),5.87-5.77(m,1H),5.17-5.06(m,2H ),4.13(s,1H),4.09(s,2H),3.84(t,J=5.2Hz,2H),2.52-2.51(m,3H).ESI-MS:[M+H] + =548.3.

[0319] Example 17

[0320] Step 1: Preparation of methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluorobenzoate

[0321] To a 100 mL single-necked flask, add methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate (1.9 g), potassium cyclopropylfluoroborate (799 mg), cesium carbonate (3.5 g), toluene (38 mL), water (4 mL), and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (294 mg). The atmosphere was purged with nitrogen. The temperature was raised to 100°C and stirred for 23 hours. The reaction system was cooled to room temperature, ethyl acetate was added, and the reaction system was washed with saturated brine. The organic phase was collected and dried over anhydrous sodium sulfate. The solvent was removed by filtration, and the concentrate was purified by silica gel column chromatography to yield 1.0 g of a yellow solid. ESI-MS: [M+H]+ = 446.2.

[0322] Step 2: Preparation of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluorobenzoic acid hydrochloride

[0323] To a 50 mL single-necked flask, add methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluorobenzoate (1.0 g), tetrahydrofuran (14 mL), and water (7 mL). Stir at room temperature until the solution becomes clear. The solution is then placed in an ice bath and slowly added with lithium hydroxide monohydrate (283 mg). After addition, warm the solution to room temperature and stir for 19 hours. Hydrochloric acid (6 M, 6 mL) is slowly added dropwise to adjust the pH to 1-2, and the solution is stirred for 5 minutes. The tetrahydrofuran is removed by concentration under reduced pressure, and the concentrate is then diluted with water and stirred for 10 minutes. The filter cake is collected by filtration and washed with water and then methyl tert-ether to yield 1.0 g of an off-white solid. ESI-MS: [M+H]+ = 432.2.

[0324] Step 3: Preparation of N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluorobenzamide

[0325] To a 100 mL single-necked flask, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluorobenzoic acid hydrochloride (320 mg), 1-hydroxybenzotriazole (110 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (261 mg), and N,N-dimethylformamide (5 mL) were added and stirred at room temperature for 2 hours. Allylamine hydrochloride (127 mg) and N,N-diisopropylethylamine (439 mg) were then added, and the reaction was stirred at room temperature for another 2 hours. The reaction system was added to saturated aqueous sodium bicarbonate solution, resulting in the precipitation of a solid. The filter cake was filtered, and purified by silica gel column chromatography to yield 250 mg of the product as an off-white solid. ESI-MS: [M+H]+ = 471.2.

[0326] Step 4: Preparation of N-allyl-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)benzamide

[0327] In a 50 mL single-necked bottle, N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluorobenzamide (250 mg), N,N-dimethylformamide (10 mL) and pyridine (414 mg) were added, and the system was placed in an ice bath and stirred. When the system dropped below 0°C, methylaminosulfonyl chloride (206 mg) was slowly added dropwise. After 30 minutes, the reaction was stopped, and the system was poured into a saturated aqueous sodium bicarbonate solution and stirred at room temperature for 10 minutes. Extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. Filtered and the solvent was removed by rotation, and the crude product was purified by silica gel column chromatography to obtain 200 mg of an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ10.41(s,1H),9.07(s,1H),8.90(t,J=5.6Hz,1H),8.02(d,J= 4.8Hz,1H),7.58(d,J=6.8Hz,1H),7.03(q,J=5.2Hz,1H),6.94-6.89(m,2H),6.81-6.80 (m,2H),5.89-5.79(m,1H),5.18-5.07(m,2H),4.05(s,2H),3.85(t,J=5.6Hz,2H),2.52 -2.51(m,3H),1.91-1.84(m,1H),0.93-0.88(m,2H),0.64-0.60(m,2H).ESI-MS:[M+Na] + =586.2.

[0328] Example 18

[0329] Step 1: Preparation of N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methoxyphenyl)amino)-benzamide

[0330] In a 100 mL single-necked flask, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methoxyphenyl)amino)benzoic acid hydrochloride (300 mg), allylamine hydrochloride (67 mg), N,N-diisopropylethylamine (366 mg), and N,N-dimethylformamide (6 mL) were added. The system was then replaced with a nitrogen atmosphere, and O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (a total of 228 mg) was added portionwise. The reaction mixture was stirred at room temperature for 3 hours. Saturated brine was added to the reaction solution, and the system was extracted with ethyl acetate. The organic phases were combined, washed with aqueous citric acid solution and saturated brine, dried, and concentrated. The crude product was purified by silica gel column chromatography to obtain 230 mg of a yellow solid. ESI-MS: [M+H] + =461.2.

[0331] Step 2: Preparation of N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)-2-((2-fluoro-4-methoxyphenyl)amino)benzamide

[0332] In a 50 mL single-necked flask, add N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methoxyphenyl)amino)-benzamide (200 mg), N,N-dimethylformamide (6 mL), and pyridine (275 mg). The system is cooled to -16°C to -20°C under a nitrogen atmosphere. Methylaminosulfonyl chloride (334 mg) is slowly added dropwise and reacted for 2 hours. Water is added to the system and stirred at room temperature for 10 minutes. Extract with ethyl acetate, combine the organic phases, and dry over anhydrous sodium sulfate. Filter and spin off the solvent. The crude product is purified by silica gel column chromatography to obtain 190 mg of a light yellow solid. 1 H NMR (400MHz, DMSO-d6): δ10.41(s,1H),9.10(s,1H),8.89(t,J=5.6Hz,1H),8.01(d,J=4.8Hz,1H),7.57 (d,J=6.8Hz,1H),7.03(brs,1H),7.0-6.86(m,3H),6.68-6.66(m,1H),5.90-5.81(m,1H),5.20-5.07(m 2H),4.03(s,2H),3.87-3.84(m,2H),3.73(s,3H),2.52-2.51(m,3H).ESI-MS:[M+H] + =554.2.

[0333] Example 19

[0334] Step 1: Preparation of N-(allyloxy)-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide

[0335] In a 100 mL single-necked bottle, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride (400 mg), 1-hydroxybenzotriazole (195 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (552 mg) and N,N-dimethylformamide (5 mL) were added, and the system was stirred at room temperature for 2 hours. Subsequently, allylhydroxylamine hydrochloride (158 mg) and N,N-diisopropylethylamine (464 mg) were added to the system, and the reaction was continued to stir at room temperature for 2 hours. The reaction system was added to a saturated sodium bicarbonate aqueous solution to precipitate a solid. The filter cake was filtered and purified by silica gel column chromatography to obtain 200 mg of an off-white solid. ESI-MS: [M+H] + =573.1.

[0336] Step 2: Preparation of N-(allyloxy)-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)benzamide

[0337] In a 50 mL single-necked bottle, N-(allyloxy)-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (200 mg), N,N-dimethylformamide (3 mL) and pyridine (278 mg) were added, and the system was placed in an ice bath and stirred. When the system dropped below 0°C, methylaminosulfonyl chloride (208 mg) was slowly added dropwise. After 30 minutes, the reaction was stopped, and the system was poured into a saturated aqueous sodium bicarbonate solution and stirred at room temperature for 10 minutes. Extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. Filtered and the solvent was removed by rotation, and the crude product was purified by silica gel column chromatography to obtain 100 mg of an off-white solid. 1H NMR (400MHz, DMSO-d6): δ11.76(s,1H),10.41(s,1H),8.49(s,1H),8.02(d,J=2.8Hz,1H),7.57(d,J=10.8Hz,1H),7.36-7.34(m,2H),7.03-7. 02(m,1H),6.94(s,1H),6.68-6.62(m,1H),5.95-5.87(m,1H),5.30-5. 19(m,2H),4.30(s,2H),4.07(s,2H),2.51-2.50(m,3H).ESI-MS:[M+H] + =666.0.

[0338] Example 20

[0339] Step 1: Preparation of 2-(but-3-en-1-yloxy)isoindoline-1,3-dione

[0340] In a 500mL three-necked flask, add but-3-en-1-ol (5.0g), triphenylphosphine (23.7g), N-hydroxyphthalimide (12.5g) and tetrahydrofuran (250mL), and replace the system with a nitrogen atmosphere. Cool the system to below 0°C, and add a tetrahydrofuran solution of diisopropyl azodicarboxylate (18.2g, 100mL tetrahydrofuran) dropwise to the system. After the addition is complete, remove the low-temperature bath and stir the system at room temperature for 16 hours. Concentrate the reaction system, then add it to saturated brine, extract the combined organic phases with ethyl acetate, dry and concentrate. Purify the concentrate by silica gel column chromatography to obtain 14.0g of a light yellow oil.

[0341] Step 2: Preparation of O-(but-3-en-1-yl)hydroxylamine hydrochloride

[0342] In a 250 mL single-necked flask, add 2-(but-3-en-1-yloxy)isoindoline-1,3-dione (7.0 g) and dichloromethane / methanol (2 / 1, v / v, 168 mL total) and replace the system with a nitrogen atmosphere. Slowly add hydrazine hydrate (1.8 g) dropwise to the system. After addition, continue stirring the reaction for 3 hours. Filter with suction, wash the filter cake with dichloromethane, and combine the organic phases. Concentrate, dilute the concentrate with tertiary methyl ether, filter with suction, and adjust the filtrate pH to 1 with a solution of hydrogen chloride in ethyl acetate. Concentrate the filtrate to obtain 1.7 g of an off-white solid.

[0343] Step 3: Preparation of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-(but-3-en-1-yloxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide

[0344] In a 100 mL single-necked flask, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride (400 mg), 1-hydroxybenzotriazole (147 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (416 mg), and N,N-dimethylformamide (10 mL) were added, and the system was stirred at room temperature for 2 hours. Subsequently, O-(but-3-en-1-yl)hydroxylamine hydrochloride (178 mg) and N,N-diisopropylethylamine (280 mg) were added to the system, and the reaction was continued to stir at room temperature for 2 hours. The reaction system was added to saturated brine to precipitate a solid. The filter cake was filtered and purified by silica gel column chromatography to obtain 70 mg of a light yellow solid. ESI-MS: [M+H] + =587.1.

[0345] Step 4: Preparation of N-(but-3-en-1-yloxy)-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)benzamide

[0346] In a 50 mL single-necked bottle, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-(but-3-en-1-yloxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (75 mg), N,N-dimethylformamide (8 mL) and pyridine (101 mg) were added, and the system was placed in an ice bath and stirred. When the system dropped below 0°C, methylaminosulfonyl chloride (50 mg) was slowly added dropwise. After 30 minutes, the reaction was stopped, and the system was poured into a saturated aqueous sodium bicarbonate solution and stirred at room temperature for 10 minutes. Extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. Filtered and the solvent was removed by rotation, and the crude product was purified by silica gel column chromatography to obtain 50 mg of an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ11.76(s,1H),10.42(s,1H),8.52(s,1H),8.02(d,J=4.8H z,1H),7.57(dd,J1=10.8Hz,J2=1.6Hz,1H),7.38-7.34(m,2H),7.05-7.01(m,1H),6 .95(t,J=4.8Hz,1H),6.68-6.63(m,1H),5.86-5.76(m,1H),5.14-5.02(m,2H),4.08 (s,2H),3.81(t,J=6.8Hz,2H),2.52-2.51(m,3H),2.33-2.28(m,2H).ESI-MS:[M+H] + =680.1.

[0347] Example 21

[0348] Step 1: Preparation of N-(allyloxy)-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzamide

[0349] In a 50 mL single-necked flask, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzoic acid hydrochloride (300 mg), 1-hydroxybenzotriazole (134 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (380 mg), and N,N-dimethylformamide (10 mL) were added, and the system was stirred at room temperature for 1 hour. Allylhydroxylamine hydrochloride (145 mg) and N,N-diisopropylethylamine (256 mg) were then added to the system, and the reaction was continued by stirring at room temperature for 2 hours. The reaction system was added to saturated brine to precipitate a solid. The filter cake was filtered and purified by silica gel column chromatography to obtain 254 mg of a light yellow solid.

[0350] Step 2: Preparation of N-(allyloxy)-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)-2-((2-fluoro-4-vinylphenyl)amino)benzamide

[0351] In a 50 mL single-necked bottle, N-(allyloxy)-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzamide (254 mg), N,N-dimethylformamide (10 mL) and pyridine (425 mg) were added, and the system was placed in an ice bath and stirred. When the system dropped below 0°C, methylaminosulfonyl chloride (210 mg) was slowly added dropwise. After 30 minutes, the reaction was stopped, the system was poured into saturated brine and stirred at room temperature for 10 minutes. Extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. Filtered and the solvent was removed by rotation, and the crude product was purified by silica gel column chromatography to obtain 101 mg of an off-white solid. 1H NMR (400MHz, DMSO-d6): δ11.81(s,1H),10.42(s,1H),8.57(s,1H),8.03(d,J=4.0Hz,1H),7.39-7. 34(m,2H),7.12(dd,J1=8.4Hz,J2=1.2Hz,1H),7.03(d,J=4.0Hz,1H),6.95(s,1H),6.85-6.79(m,1 H),6.64(dd,J1=17.6Hz,J2=11.2Hz,1H),5.98-5.88(m,1H),5.74(d,J=17.6Hz,1H),5.28(d,J=17 .2Hz,1H),5.22-5.16(m,2H),4.31(d,J=4.8Hz,2H),4.07(s,2H),2.53-2.51(m,3H).ESI-MS:[M+H] + =566.2.

[0352] Example 22

[0353] Step 1: Preparation of 2-(pent-4-en-1-yloxy)isoindoline-1,3-dione

[0354] In a 1L three-necked flask, add pent-4-en-1-ol (5.0g), triphenylphosphine (19.8g), N-hydroxyphthalimide (10.4g) and tetrahydrofuran (250mL), and replace the system with a nitrogen atmosphere. Cool the system to below 0°C, and add a tetrahydrofuran solution of diisopropyl azodicarboxylate (15.3g, 150mL tetrahydrofuran) dropwise to the system. After the addition is complete, remove the low-temperature bath and stir the system at room temperature for 16h. Concentrate the reaction system, then add it to saturated brine, extract the combined organic phases with ethyl acetate, dry and concentrate. Purify the concentrate by silica gel column chromatography to obtain 10.0g of a light yellow oil.

[0355] Step 2: Preparation of O-(pent-4-en-1-yl)hydroxylamine hydrochloride

[0356] In a 250 mL single-necked flask, add 2-(pent-4-en-1-yloxy)isoindoline-1,3-dione (5.0 g) and dichloromethane / methanol (2 / 1, v / v, 120 mL total), replace the system with a nitrogen atmosphere, and stir until the solution is clear. Slowly add hydrazine hydrate (1.2 g) dropwise to the system. After addition, continue stirring the reaction for 3 hours. Filter with suction, wash the filter cake with dichloromethane, and combine the organic phases. Concentrate, dilute the concentrate with tertiary methyl ether, filter with suction, and adjust the filtrate pH to 1 with a solution of hydrogen chloride in ethyl acetate. Concentrate the filtrate to obtain 1.2 g of an off-white solid.

[0357] Step 3: Preparation of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(pent-4-en-1-yloxy)benzamide

[0358] In a 100 mL single-necked flask, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride (500 mg), 1-hydroxybenzotriazole (180 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (520 mg), and N,N-dimethylformamide (10 mL) were added, and the system was stirred at room temperature for 2 hours. Subsequently, O-(pent-4-en-1-yl)hydroxylamine hydrochloride (250 mg) and N,N-diisopropylethylamine (350 mg) were added to the system, and the reaction was continued to stir at room temperature for 2 hours. The reaction system was added to saturated sodium bicarbonate aqueous solution to precipitate a solid. The filter cake was filtered and purified by silica gel column chromatography to obtain 120 mg of the product as a light yellow oil. ESI-MS: [M+H] + =601.1.

[0359] Step 4: Preparation of 3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)-N-(pent-4-en-1-yloxy)benzamide

[0360] In a 50 mL single-necked flask, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(pent-4-en-1-yloxy)benzamide (120 mg), N,N-dimethylformamide (3 mL), and pyridine (160 mg) were added and stirred in an ice bath. Methylaminosulfonyl chloride (120 mg) was slowly added dropwise after the temperature dropped below 0°C. After the addition was complete and the reaction was continued for 30 minutes, the reaction was stopped and the system was poured into a saturated aqueous sodium bicarbonate solution and stirred at room temperature for 10 minutes. Extraction was performed with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. Filtering and removing the solvent, the crude product was then purified by silica gel column chromatography to obtain 20 mg of a light yellow solid. 1H NMR (400MHz, DMSO-d6): δ11.73(s,1H),10.42(s,1H),8.51(s,1H),8.02(d,J=4.8Hz,1H) ,7.57(dd,J1=10.8Hz,J2=1.6Hz,1H),7.37-7.33(m,2H),7.03(d,J=5.6Hz,1H),6.95-6.9 3(m,1H),6.67-6.62(m,1H),5.85-5.75(m,1H),5.04-4.95(m,2H),4.07(b,2H),3.75(t, J=6.4Hz,2H),2.52-2.51(m,3H),2.09(q,J=7.2Hz,2H),1.64-1.58(m,2H).ESI-MS:[M+H] + =694.1.

[0361] Example 23

[0362] Step 1: Preparation of 2-(hex-5-en-1-yloxy)isoindoline-1,3-dione

[0363] In a 500mL three-necked flask, add hex-5-en-1-ol (5.0g), triphenylphosphine (17.0g), N-hydroxyphthalimide (9.0g) and tetrahydrofuran (250mL), and replace the system with a nitrogen atmosphere. Cool the system to below 0°C, and add a tetrahydrofuran solution of diisopropyl azodicarboxylate (13.1g, 100mL tetrahydrofuran) dropwise to the system. After the addition is complete, remove the low-temperature bath and stir the system at room temperature for 16h. Concentrate the reaction system and then add it to saturated brine. Extract the combined organic phases with ethyl acetate, dry and concentrate. Purify the concentrate by silica gel column chromatography to obtain 9.2g of a light yellow oil.

[0364] Step 2: Preparation of O-(hex-5-en-1-yl)hydroxylamine hydrochloride

[0365] In a 250 mL single-necked flask, add 2-(hex-5-en-1-yloxy)isoindoline-1,3-dione (9.2 g) and dichloromethane / methanol (2 / 1, v / v, 213 mL total), replace the system with a nitrogen atmosphere, and stir until the solution is clear. Slowly add hydrazine hydrate (2.6 g) dropwise to the system. After addition, continue stirring the reaction for 3 hours. Filter with suction, wash the filter cake with dichloromethane, and combine the organic phases. Concentrate, dilute the concentrate with tertiary methyl ether, filter with suction, and adjust the filtrate pH to 1 with a solution of hydrogen chloride in ethyl acetate. Concentrate the filtrate to obtain 3.7 g of an off-white solid.

[0366] Step 3: Preparation of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(hex-5-en-1-yloxy)benzamide

[0367] In a 100 mL single-necked flask, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride (400 mg), 1-hydroxybenzotriazole (126 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (296 mg), and N,N-dimethylformamide (10 mL) were added, and the system was stirred at room temperature for 2 hours. Subsequently, O-(hex-5-en-1-yl)hydroxylamine hydrochloride (129 mg) and N,N-diisopropylethylamine (274 mg) were added to the system, and the reaction was continued to stir at room temperature for 2 hours. The reaction system was added to saturated brine to precipitate a solid. The filter cake was filtered and purified by silica gel column chromatography to obtain 200 mg of a light yellow solid. ESI-MS: [M+H] + =615.1.

[0368] Step 4: Preparation of 3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)-2-((2-fluoro-4-iodo)amino)-N-(hex-5-en-1-yloxy)benzamide

[0369] In a 50 mL single-necked bottle, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(hex-5-en-1-yloxy)benzamide (200 mg), N,N-dimethylformamide (5 mL) and pyridine (257 mg) were added, and the system was placed in an ice bath and stirred. When the system dropped below 0°C, methylaminosulfonyl chloride (175 mg) was slowly added dropwise. After 30 minutes, the reaction was stopped, and the system was poured into a saturated aqueous sodium bicarbonate solution and stirred at room temperature for 10 minutes. Extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. Filtered and the solvent was removed by rotation, and the crude product was purified by silica gel column chromatography to obtain 140 mg of an off-white solid. 1H NMR (400MHz, DMSO-d6): δ11.70(s,1H),10.41(s,1H),8.50(s,1H),8.02(d,J=4.8Hz,1H),7. 57(dd,J1=10.8Hz,J2=1.6Hz,1H),7.37-7.33(m,2H),7.05-7.01(m,1H),6.94(t,J=4.8Hz,1 H),6.67-6.63(m,1H),5.83-5.73(m,1H),5.02-4.93(m,2H),4.07(s,2H),3.75-3.72(m,2H) ,2.52-2.50(m,3H),2.05-2.00(m,2H),1.54-1.50(m,2H),1.44-1.35(m,2H).ESI-MS:[M+H] + =708.1.

[0370] Example 24

[0371] Step 1: Preparation of N-(allyloxy)-5-(3-amino-2-fluorobenzyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide

[0372] In a 100 mL single-necked flask, 5-(3-amino-2-fluorobenzyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride (400 mg), 1-hydroxybenzotriazole (104 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (294 mg), and N,N-dimethylformamide (12 mL) were added and the reaction mixture was stirred at room temperature for 2 hours. Allylhydroxylamine hydrochloride (93 mg) and N,N-diisopropylethylamine (298 mg) were then added to the mixture, and the reaction mixture was stirred at room temperature for another 2 hours. The reaction mixture was added to saturated brine to precipitate a solid. The mixture was filtered, and the filter cake was purified by silica gel column chromatography to obtain 128 mg of a light yellow oil.

[0373] Step 2: Preparation of N-(allyloxy)-3,4-difluoro-5-(2-fluoro-3-((N-methylaminosulfonyl)amino)benzyl)-2-((2-fluoro-4-iodophenyl)amino)benzamide

[0374] In a 50 mL single-necked bottle, add N-(allyloxy)-5-(3-amino-2-fluorobenzyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (120 mg), N,N-dimethylformamide (3 mL) and pyridine (265 mg), and place the system in an ice bath and stir. When the system drops below 0°C, slowly add methylaminosulfonyl chloride (272 mg) dropwise. After 30 minutes, stop the reaction, pour the system into saturated brine and stir at room temperature for 10 minutes. Use ethyl acetate to extract, combine the organic phases, and dry over anhydrous sodium sulfate. Filter and spin to remove the solvent, and the crude product is purified by silica gel column chromatography to obtain 90 mg of a light yellow solid. 1 H NMR (400MHz, DMSO-d6): δ11.74(s,1H),9.43(s,1H),8.43(s,1H),7.57(dd,J1=10.8Hz,J2=1.6Hz,1H),7.36-7.25(m,4H),7.11(t,J=8.0Hz,1H),7. 02(t,J=6.8Hz,1H),6.65-6.59(m,1H),5.96-5.86(m,1H),5.29-5.18(m, 2H),4.28(d,J=6.0Hz,2H),4.03(s,2H),2.53-2.51(m,3H).ESI-MS:[M+H] + =665.1.

[0375] Example 25

[0376] Preparation of N-(allyloxy)-5-((2-((N-ethylaminosulfonyl)amino)-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide

[0377] To a 100 mL single-necked flask, add N-ethyl-2-oxoxazoline-3-sulfonamide (848 mg), N-(allyloxy)-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (250 mg), triethylamine (487 mg), and 1,2-dichloroethane (20 mL). The reaction system was heated to 80°C for 16.5 hours. After cooling to room temperature, the system was poured into 100 mL of a water / tetrahydrofuran mixture (90 / 10, v / v). The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 8 mg of a yellow solid. 1H NMR (400MHz, DMSO-d6): δ11.78(s,1H),10.41(s,1H),8.49(s,1H),8.03(d,J=5.2 Hz,1H),7.57(d,J=10.8Hz,1H),7.36-7.32(m,2H),7.18(t,J=5.6Hz,1H),6.94(t, J=4.8Hz,1H),6.67-6.62(m,1H),5.97-5.87(m,1H),5.30-5.19(m,2H),4.29(d,J =6.0Hz,2H),4.07(s,2H),2.97-2.90(m,2H),1.02(t,J=7.2Hz,3H).ESI-MS:[M+H] + =680.1.

[0378] Example 26

[0379] Preparation of N-(allyloxy)-3,4-difluoro-5-((3-fluoro-2-((N-methyl-d3-aminosulfonyl)amino)pyridin-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)benzamide

[0380] To a 50 mL single-necked flask, N-methyl-d3-2-oxoxazoline-3-sulfonamide (800 mg), N-(allyloxy)-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (250 mg), triethylamine (486 mg), and 1,2-dichloroethane (20 mL) were added. The reaction system was heated to 80°C for 5 h. After cooling to room temperature, the system was poured into a water / tetrahydrofuran mixture (90 / 10, v / v), and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 35 mg of a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ11.78(s,1H),10.42(s,1H),8.50(s,1H),8.02(d,J=4.8Hz,1H),7.58(d,J=9.6Hz,1H),7.36-7.32(m,2H),7 .01(s,1H),6.94(s,1H),6.68-6.63(m,1H),5.97-5.89(m,1H),5.30-5.19(m,2H),4.29(d,J=5.6Hz,2H),4.07(s,2H).ESI-MS:[M+H] + =669.1.

[0381] Example 27

[0382] Step 1: Preparation of 2-fluoro-4-iodo-5-methylaniline

[0383] To a 250 mL three-necked flask, add 2-fluoro-5-methylaniline (10.0 g), sodium bicarbonate (13.4 g), methanol (50 mL), and dichloromethane (50 mL). Cool to -5°C and stir until dissolved. Slowly add a dichloromethane solution (50 mL) of benzyltrimethylammonium dichloroiodate (27.8 g) dropwise. Continue stirring at -5°C for 30 minutes, then gradually warm to room temperature and stir for 2 hours. Pour the reaction system into water, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry, and concentrate to yield 18.4 g of a brown liquid.

[0384] Step 2: Preparation of 3,4-difluoro-2-((2-fluoro-4-iodo-5-methylphenyl)amino)-5-vinylbenzoic acid

[0385] To a 250 mL three-necked flask, 2,3,4-trifluoro-5-vinylbenzoic acid (3.2 g), 2-fluoro-4-iodo-5-methylaniline (4.0 g), and tetrahydrofuran (64 mL) were added sequentially. The atmosphere was replaced with nitrogen and the temperature was lowered to -20°C. Lithium bistrimethylsilylamide (1 M, 48 mL) was added dropwise. After completion of the addition, the mixture was warmed to room temperature and stirred for 1 h. Aqueous sodium bisulfate solution was added dropwise to adjust the pH to 1-2. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried, and concentrated. The concentrate was slurried with a mixed solvent of ethyl acetate / n-hexane (v / v = 1 / 3) to obtain 5.0 g of a brown solid.

[0386] Step 3: Preparation of methyl 3,4-difluoro-2-((2-fluoro-4-iodo-5-methylphenyl)amino)-5-vinylbenzoate

[0387] To a 100 mL three-necked flask, add 3,4-difluoro-2-((2-fluoro-4-iodo-5-methylphenyl)amino)-5-vinylbenzoic acid (4.7 g), potassium carbonate (1.8 g), and N,N-dimethylformamide (47 mL) in sequence. Stir at room temperature, then add iodomethane (1.9 g) dropwise. After addition, heat the temperature to 35°C and stir for 2 h. Pour the mixture into water, filter, collect the filter cake, wash it with water, and dry it to obtain 4.6 g of a brownish-red solid. ESI-MS: [M+Na] + =470.0.

[0388] Step 4: Preparation of methyl 3,4-difluoro-2-((2-fluoro-4-iodo-5-methylphenyl)amino)-5-formylbenzoate

[0389] To a 250 mL three-necked flask, methyl 3,4-difluoro-2-((2-fluoro-4-iodo-5-methylphenyl)amino)-5-vinylbenzoate (4.1 g) and acetonitrile (80 mL) were added sequentially and the temperature was lowered to 0°C. Potassium osmate dihydrate (169 mg) was added and stirred for 15 minutes. Subsequently, water (80 mL), sodium periodate (5.9 g) and 2,6-lutidine (986 mg) were added to the reaction flask and the mixture was stirred at room temperature for 6 hours. The system was poured into a saturated aqueous sodium sulfite solution, filtered, and the filter cake was collected and washed with water to obtain 4.1 g of a brown-gray solid. ESI-MS: [MH] - =448.0.

[0390] Step 5: Preparation of methyl (E)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methylphenyl)amino)-5-((2-(4-methylphenyl)sulfonylhydrazono)methyl)benzoate

[0391] To a 250 mL three-necked flask, add methyl 3,4-difluoro-2-((2-fluoro-4-iodo-5-methylphenyl)amino)-5-formylbenzoate (4.2 g), p-methylbenzenesulfonylhydrazide (1.7 g), and anhydrous ethanol (130 mL). The temperature was raised to 60°C and the reaction was allowed to proceed for 2 h. The system was then cooled to -10°C and stirred for 1 h. The filter cake was collected and washed with cold ethanol and dried to yield 4.7 g of a light brown solid. ESI-MS: [M+Na] + =640.0.

[0392] Step 6: Preparation of methyl 2-((2-fluoro-4-iodo-5-methylphenyl)amino)-5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-3,4-difluorobenzoate

[0393] To a 250 mL three-necked flask, (E)-methyl 3,4-difluoro-2-((2-fluoro-4-iodo-5-methylphenyl)amino)-5-((2-(4-methylphenyl)sulfonylhydrazono)methyl)benzoate (4.7 g), (2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)boric acid (3.0 g), anhydrous potassium carbonate (1.4 g) and toluene (140 mL) were added. The atmosphere was replaced with nitrogen, and the temperature was raised to 105°C and stirred for 6 h. The reaction system was poured into water and extracted with ethyl acetate. The organic phases were combined, dried and concentrated to obtain 5.2 g of a brown oil. The product of this step was used directly in the next reaction without further purification. ESI-MS: [M+H] + =696.1.

[0394] Step 7: Preparation of methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((2-fluoro-4-iodo-5-methylphenyl)amino)-3,4-difluorobenzoate

[0395] To a 250 mL three-necked flask, add methyl 2-((2-fluoro-4-iodo-5-methylphenyl)amino)-5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-3,4-difluorobenzoate (6.0 g) and dichloromethane (120 mL). The temperature was lowered to 10°C, and trifluoroacetic acid (90 mL) was added dropwise. After the addition was complete, the mixture was returned to room temperature and stirred for 1 hour. The pH of the system was adjusted to neutral with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, and concentrated to obtain 3.0 g of a brown solid. ESI-MS: [M+H] + =546.0.

[0396] Step 8: Preparation of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methylphenyl)amino)benzoic acid To a 100 mL single-necked bottle, methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((2-fluoro-4-iodo-5-methylphenyl)amino)-3,4-difluorobenzoate (3.0 g), acetonitrile (18 mL) and ethanol (18 mL) were added and stirred until dissolved. An aqueous solution of lithium hydroxide monohydrate (413 mg) (18 mL) was added dropwise. After addition, the reaction was stirred at room temperature for 3 h. The pH of the system was adjusted to 1-2 with aqueous sodium bisulfate solution, filtered, and the filtrate was extracted with ethyl acetate. The organic phases were combined, dried, and concentrated to obtain 1.3 g of a brown solid. ESI-MS: [MH] - =530.0.

[0397] Step 9: Preparation of N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methylphenyl)amino)benzamide

[0398] In a 100 mL single-necked flask, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methylphenyl)amino)benzoic acid (1.2 g) and N,N-dimethylformamide (24 mL) were added and the temperature was lowered to 0°C. 1-Hydroxybenzotriazole (305 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (863 mg) were then added to the system, stirred for 5 minutes, and then warmed to room temperature for 2 hours. Allylamine hydrochloride (233 mg) and N,N-diisopropylethylamine (583 mg) were added to the reaction flask, and the reaction was continued by stirring at room temperature for 2 hours. The reaction system was slowly added to a saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases were combined, dried, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 500 mg of a yellow solid. ESI-MS: [M+H] + =571.1.

[0399] Step 10: Preparation of N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)-2-((2-fluoro-4-iodo-5-methylphenyl)amino)benzamide

[0400] To a 25 mL single-necked flask, add N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methylphenyl)amino)benzamide (480 mg), N,N-dimethylformamide (6 mL), and pyridine (666 mg). Cool to -20°C and slowly add methylaminosulfonyl chloride (545 mg) dropwise. Let react for 30 minutes. Pour the reaction solution into water, extract with ethyl acetate, and combine the organic phases, dry, and concentrate. The concentrate is slurried with tertiary methyl ether to obtain 150 mg of an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ10.41(s,1H),9.00(s,1H),8.87(t,J=5.6,1H),8.02 (d,J=4.8,1H),7.62(d,J=10.8,1H),7.56(d,J=7.2,1H),7.02(q,J=4.8,1H),6 .95(t,J=4.8,1H),6.89-6.86(m,1H),5.86-5.77(m,1H),5.17-5.06(m,2H),4 .07(s,2H),3.83(t,J=5.2,2H),2.52-2.51(m,3H),2.25(s,3H).ESI-MS:[M+H] + =664.1.

[0401] Example 28

[0402] Step 1: Preparation of 5-((tert-butyldimethylsilyl)oxy)-2-fluoroaniline

[0403] To a 250 mL three-necked flask, add 3-amino-4-fluorophenol (5.0 g), imidazole (4.8 g), tert-butyldimethylsilyl chloride (8.9 g), and dichloromethane (150 mL). The mixture was allowed to react at room temperature for 24 h. The mixture was poured into water, the organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried and concentrated. The concentrate was purified by silica gel column chromatography to obtain 9.5 g of a colorless, transparent oil. ESI-MS: [M+H] + =242.1.

[0404] Step 2: Preparation of 5-((tert-butyldimethylsilyl)oxy)-2-fluoro-4-iodoaniline

[0405] To a 250 mL three-necked flask, add 5-((tert-butyldimethylsilyl)oxy)-2-fluoroaniline (9.8 g), sodium bicarbonate (12.2 g), methanol (100 mL) and dichloromethane (100 mL), stir and cool to -5°C. Slowly add a dichloromethane solution (100 mL) of benzyltrimethylammonium dichloroiodate (10.6 g) dropwise. After completion of the addition, continue stirring at -5°C for 30 minutes, then gradually warm to room temperature and stir for 2 hours. Pour the reaction system into water, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry and concentrate. The concentrate is purified by silica gel column chromatography to obtain 9.8 g of an orange oily liquid. ESI-MS: [M+H] + =368.0.

[0406] Step 3: Preparation of N-(5-((tert-butyldimethylsilyl)oxy)-2-fluoro-4-iodophenyl)acetamide

[0407] To a 250 mL three-necked flask, add 5-((tert-butyldimethylsilyl)oxy)-2-fluoro-4-iodoaniline (7.0 g), acetic anhydride (3.0 g), and tetrahydrofuran (100 mL). Heat to 50°C and react for 3 h. Add the reaction solution to saturated sodium bicarbonate aqueous solution and extract with ethyl acetate. The combined organic phases are washed with saturated brine, dried, and concentrated. The concentrate is purified by silica gel column chromatography to obtain 9.8 g of a brown oily liquid.

[0408] Step 4: Preparation of N-(2-fluoro-5-hydroxy-4-iodophenyl)acetamide

[0409] To a 250 mL three-necked flask, add N-(5-((tert-butyldimethylsilyl)oxy)-2-fluoro-4-iodophenyl)acetamide (21.7 g), potassium fluoride (3.7 g), and N,N-dimethylformamide (200 mL). The mixture is allowed to react at room temperature for 2 h. The reaction system is poured into ice water and extracted with ethyl acetate. The organic phases are combined, washed with saturated brine, dried, and concentrated. The concentrate is purified by silica gel column chromatography to obtain 10.0 g of a brown solid. ESI-MS: [M+H] + =296.0.

[0410] Step 5: Preparation of N-(2-fluoro-4-iodo-5-methoxyphenyl)acetamide

[0411] To a 250 mL three-necked flask, add N-(2-fluoro-5-hydroxy-4-iodophenyl)acetamide (10.0 g), potassium carbonate (7.0 g), iodomethane (5.8 g), and acetone (100 mL). The mixture was allowed to react at room temperature for 17 h. The reaction solution was concentrated, diluted with tertiary methyl ether, and washed with water. The organic phase was dried and concentrated to yield 10.0 g of a brown solid. ESI-MS: [M+H] + =310.0.

[0412] Step 6: Preparation of 2-fluoro-5-methoxyaniline

[0413] To a 250 mL three-necked flask, add N-(2-fluoro-4-iodo-5-methoxyphenyl)acetamide (10.0 g), water (100 mL), and concentrated hydrochloric acid (100 mL). Heat to 90°C and stir for 4 h. Add water to the system, extract with tert-methyl ether, combine the organic phases, wash with saturated sodium bicarbonate aqueous solution until neutral, dry, and concentrate. The concentrate is purified by silica gel column chromatography to obtain 3.0 g of a brown solid. ESI-MS: [M+MeCN+H] + =183.1.

[0414] Step 7: Preparation of 2-fluoro-4-iodo-5-methoxyaniline

[0415] To a 250 mL three-necked flask, add 2-fluoro-5-methoxyaniline (2.0 g), sodium bicarbonate (8.9 g), methanol (30 mL), and dichloromethane (30 mL). Cool to -5°C and stir until dissolved. Slowly add a dichloromethane solution (30 mL) of benzyltrimethylammonium dichloroiodate (7.7 g) dropwise to the system. Continue stirring at -5°C for 30 minutes, then gradually warm to room temperature and stir for 2 hours. Pour the reaction system into water and extract with dichloromethane. The organic phases are combined, washed with saturated brine, dried, and concentrated to obtain 5.0 g of a brown oily liquid. The product from this step is used directly in the next reaction without further purification.

[0416] Step 8: Preparation of 3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)-5-vinylbenzoic acid

[0417] To a 250 mL three-necked flask, add 2-fluoro-4-iodo-5-methoxyaniline (5.0 g), 2,3,4-trifluoro-5-vinylbenzoic acid (3.8 g), and tetrahydrofuran (76 mL) and stir at room temperature for 5 minutes. Place the system in a low-temperature bath and cool to -20°C. Then add lithium bis(trimethylsilyl)amide (1 M, 56.1 mL) dropwise. After the addition is complete, continue stirring at -20°C for 20 minutes, then gradually warm to room temperature and stir for 2 hours. Pour the system into water, adjust the pH to 2-3 with dilute hydrochloric acid, extract with ethyl acetate, combine the organic phases, dry, and concentrate. The concentrate is slurried with a mixed solvent of petroleum ether / ethyl acetate (v / v = 10 / 1) to obtain 5.0 g of a brownish-yellow solid. ESI-MS: [MH] - =448.0.

[0418] Step 9: Preparation of methyl 3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)-5-vinylbenzoate

[0419] To a 250 mL three-necked flask, add 3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)-5-vinylbenzoic acid (5.0 g), potassium carbonate (2.3 g), iodomethane (1.9 g), and N,N-dimethylformamide (50 mL). Stir and react at 35°C for 4 h. Pour the mixture into water and extract with ethyl acetate. The combined organic phases are dried and concentrated to yield 5.0 g of a brown solid. The product is used directly in the next reaction without further purification.

[0420] Step 10: Preparation of methyl 3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)-5-formylbenzoate

[0421] In a 250 mL three-necked flask, add methyl 3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)-5-vinylbenzoate (5.0 g) and tetrahydrofuran (75 mL) and stir in an ice bath until dissolved. Add potassium osmate dihydrate (199 mg) to the system and continue stirring in an ice bath for 15 minutes. Add water (75 mL), sodium periodate (6.9 g), and 2,6-lutidine (1.2 g) to the system, warm to room temperature, and stir for 1 hour. Pour the reaction system into saturated aqueous sodium sulfite solution, extract with ethyl acetate, combine the organic phases, wash with saturated brine, and concentrate the organic phase to obtain 5.0 g of a gray solid. The product of this step is used directly in the next reaction without further purification.

[0422] Step 11: Preparation of methyl (E)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)-5-((2-(4-methylphenyl)sulfonylhydrazono)methyl)benzoate

[0423] To a 250 mL single-necked flask, add methyl 3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)-5-formylbenzoate (5.0 g), p-methylbenzenesulfonylhydrazide (2.0 g), and ethanol (150 mL). Heat to 50°C and react for 14 h. The reaction solution was concentrated and the concentrate was purified by silica gel column chromatography to obtain 6.8 g of an off-white solid. ESI-MS: [M+H] + =634.0.

[0424] Step 12: Preparation of methyl 5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)benzoate

[0425] To a 250 mL single-necked flask, add (E)-methyl 3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)-5-((2-(4-methylphenyl)sulfonylhydrazono)methyl)benzoate (6.8 g), (2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)boric acid (4.9 g), potassium carbonate (3.0 g), and toluene (210 mL). The temperature was raised to 100°C and stirred for 3 h. The reaction system was poured into water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 3.0 g of a white solid. ESI-MS: [M+H] + =712.1.

[0426] Step 13: Preparation of methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)benzoate

[0427] To a 100 mL single-necked bottle, methyl 5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)benzoate (2.0 g), 2,3-dichloro-5,6-dicyano-p-benzoquinone (2.5 g), dichloromethane (60 mL) and water (3 mL) were added and stirred at room temperature for 2 h. The reaction system was poured into an aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried and concentrated. The concentrate was purified by silica gel column chromatography to obtain 700 mg of an off-white solid. ESI-MS: [M+H] + =562.0.

[0428] Step 14: Preparation of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)benzoic acid

[0429] In a 100 mL single-necked bottle, methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)benzoate (700 mg), tetrahydrofuran (20 mL) and water (10 mL) were added in sequence and stirred in an ice bath. Lithium hydroxide monohydrate (169 mg) was slowly added to the system. After the addition was complete, the mixture was heated to room temperature and stirred for 2.5 hours. Hydrochloric acid was added to adjust the pH to 2-3 and stirred for 5 minutes. The tetrahydrofuran in the system was removed by concentration under reduced pressure, and then 50 mL of water was added to dilute the concentrate and stirred for 10 minutes. The filter cake was collected by filtration, washed with water and tertiary methyl ether, and dried to obtain 680 mg of a yellow solid.

[0430] Step 15: Preparation of N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)benzamide

[0431] To a 100 mL single-necked flask, add 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)benzoic acid (700 mg) and N,N-dimethylformamide (10 mL), and cool to 0°C in an ice bath. 1-Hydroxybenzotriazole (208 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (491 mg) were added, and the reaction was stirred for 5 minutes, then warmed to room temperature for 2 hours. Allylamine hydrochloride (240 mg) and N,N-diisopropylethylamine (330 mg) were added, and the reaction was continued by stirring at room temperature for 2 hours. The reaction system was slowly added to a saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases were combined, dried, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 700 mg of a white solid. ESI-MS:[M+H] + =587.1.

[0432] Step 16: Preparation of N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-5-hydroxy-4-iodophenyl)amino)benzamide

[0433] In a 500 mL single-necked flask, add N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)benzamide (500 mg) and dichloromethane (110 mL), and cool to -15°C. Add a dichloromethane solution of boron tribromide (1 M, 10 mL) dropwise to the system. After addition, stir at -15°C for 3 h. Pour the reaction system into a saturated sodium bicarbonate solution, extract with ethyl acetate, combine the organic phases, dry, and concentrate to obtain 450 mg of a yellow solid. ESI-MS: [MH] - =571.0.

[0434] Step 17: Preparation of N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((5-((tert-butyldimethylsilyl)oxy)-2-fluoro-4-iodophenyl)amino)-3,4-difluorobenzamide

[0435] To a 250 mL three-necked flask, add N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-5-hydroxy-4-iodophenyl)amino)benzamide (400 mg), imidazole (86 mg), tert-butyldimethylsilyl chloride (158 mg), and dichloromethane (50 mL). Stir the reaction at room temperature for 5.5 hours. The reaction solution was concentrated and the concentrate was purified by silica gel column chromatography to obtain 400 mg of a colorless, transparent oil. ESI-MS: [M+H] + =687.1.

[0436] Step 18: Preparation of N-allyl-2-((5-((tert-butyldimethylsilyl)oxy)-2-fluoro-4-iodophenyl)amino)-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)benzamide

[0437] In a 50 mL single-necked flask, add N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((5-((tert-butyldimethylsilyl)oxy)-2-fluoro-4-iodophenyl)amino)-3,4-difluorobenzamide (350 mg), N,N-dimethylformamide (7 mL), and pyridine (356 mg), and cool to -20°C. Slowly add methylaminosulfonyl chloride (175 mg) dropwise to the system. After addition, continue stirring at -20°C for 30 minutes. Pour the system into water, extract with ethyl acetate, and combine the organic phases, dry, and concentrate to obtain 350 mg of a yellow oil.

[0438] Step 19: Preparation of N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)-2-((2-fluoro-5-hydroxy-4-iodophenyl)amino)benzamide

[0439] In a 50 mL single-necked bottle, N-allyl-2-((5-((tert-butyldimethylsilyl)oxy)-2-fluoro-4-iodophenyl)amino)-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)benzamide (350 mg), N,N-dimethylformamide (10 mL), and potassium fluoride (31 mg) were added and stirred at room temperature for 30 minutes. The system was poured into water and extracted with ethyl acetate. The organic phases were combined, dried, and concentrated. The concentrate was purified by silica gel column chromatography to obtain a crude product, which was further purified by preparative HPLC to obtain 100 mg of an off-white solid. 1 H NMR (400MHz, DMSO): δ10.44(s,1H),9.98(s,1H),8.91-8.89(m,2H),8.03(d,J=4.4Hz,1H),7.61(d,J=6.4Hz,1H),7.46(d,J=10.4Hz,1H),7.03(d,J= 3.2Hz,1H),6.95(s,1H),6.35-6.32(m,1H),5.88-5.79(m,1H),5.18-5.06 (m,2H),4.09(s,2H),3.85(t,J=5.6,2H),2.51-2.50(m,3H).ESI-MS:[M+H] + =666.0.

[0440] Example 29

[0441] Step 1: Preparation of 2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluoro-5-vinylbenzoic acid

[0442] To a 250 mL three-necked flask, add 2,3,4-trifluoro-5-vinylbenzoic acid (3.2 g), 2,5-difluoro-4-iodoaniline (4.0 g), and tetrahydrofuran (78 mL). Replace the atmosphere with nitrogen, cool to -20°C, and stir the reaction. Add lithium bistrimethylsilylamide (1 M, 47.1 mL) dropwise. After completion, warm to room temperature and stir the reaction for 1 hour. Adjust the pH to 1-2 with aqueous sodium bisulfate solution, extract with tert-methyl ether, combine the organic phases, wash with saturated aqueous sodium chloride solution, dry, and concentrate. Slurry the concentrate with a tert-methyl ether / n-heptane mixture and dry to yield 3.9 g of a brown solid.

[0443] Step 2: Preparation of methyl 2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluoro-5-vinylbenzoate

[0444] To a 250 mL three-necked flask, add 2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluoro-5-vinylbenzoic acid (3.9 g), potassium carbonate (2.0 g), and N,N-dimethylformamide (46 mL). Add iodomethane (1.5 g) dropwise with stirring at room temperature. After addition, heat to 35°C and stir for 2 h. Pour the mixture into water, filter, and collect the filter cake to yield 3.8 g of a brown solid.

[0445] Step 3: Preparation of methyl 2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluoro-5-formylbenzoate

[0446] To a 250 mL three-necked flask, add methyl 2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluoro-5-vinylbenzoate (3.8 g), tetrahydrofuran (76 mL), and potassium osmate dihydrate (155 mg). Cool to 0°C and stir for 15 minutes. Add water (76 mL), sodium periodate (5.4 g), and 2,6-lutidine (911 mg) to the system, then warm to room temperature and stir for 2.5 hours. Pour the system into saturated aqueous sodium sulfite solution, filter, and collect the filter cake to obtain 3.3 g of a brown solid.

[0447] Step 4: Preparation of methyl (E)-2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluoro-5-((2-(4-methylphenyl)sulfonylhydrazono)methyl)benzoate

[0448] To a 250 mL three-necked flask, add methyl 2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluoro-5-formylbenzoate (3.3 g), p-methylbenzenesulfonylhydrazide (1.3 g), and anhydrous ethanol (100 mL). Heat to 60°C and react for 2 h. Cool to -10°C and stir for 30 min. Filter, collect the filter cake, and wash with cold ethanol to obtain 3.4 g of a light brown solid. ESI-MS: [M+H] + =622.0.

[0449] Step 5: Preparation of methyl 2-((2,5-difluoro-4-iodophenyl)amino)-5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-3,4-difluorobenzoate

[0450] To a 250 mL three-necked flask, add (E)-methyl 2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluoro-5-((2-(4-methylphenyl)sulfonylhydrazono)methyl)benzoate (3.4 g), (2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)boric acid (2.2 g), potassium carbonate (1.0 g), and toluene (102 mL). The temperature was raised to 100°C and stirred for 6 h. The reaction system was poured into water and extracted with ethyl acetate. The organic phases were combined, dried, and concentrated to obtain 3.8 g of a brown oil. The product was used directly in the next reaction without further purification. ESI-MS: [M+H] + =700.1.

[0451] Step 6: Preparation of methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluorobenzoate

[0452] To a 250 mL three-necked flask, add methyl 2-((2,5-difluoro-4-iodophenyl)amino)-5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-3,4-difluorobenzoate (5.0 g) and dichloromethane (100 mL). The temperature was lowered to 10°C, and trifluoroacetic acid (75 mL) was added dropwise. After the addition was complete, the mixture was returned to room temperature and stirred for 1 hour. The pH of the system was adjusted to neutral with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, and concentrated to obtain 1.8 g of a brown solid. ESI-MS: [M+H] + =550.0.

[0453] Step 7: Preparation of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluorobenzoic acid

[0454] To a 100 mL single-necked flask, methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluorobenzoate (1.8 g) and tetrahydrofuran (36 mL) were added dropwise with stirring at room temperature. A solution of lithium hydroxide monohydrate (413 mg) in water (18 mL) was added dropwise. After addition, the reaction was continued with stirring at room temperature for 3 h. The pH of the system was adjusted to 1-2 with hydrochloric acid, filtered, and the filtrate was extracted with ethyl acetate. The organic phases were combined, dried, and concentrated to yield 860 mg of a brown solid. ESI-MS: [MH] - =534.0.

[0455] Step 8: Preparation of N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluorobenzamide

[0456] In a 100 mL single-necked flask, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluorobenzoic acid (860 mg) and N,N-dimethylformamide (17 mL) were added and the temperature was lowered to 0°C. 1-Hydroxybenzotriazole (217 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (613 mg) were added and stirred for 5 minutes, then the temperature was raised to room temperature and the reaction was allowed to react for 2 hours. Allylamine hydrochloride (164 mg) and N,N-diisopropylethylamine (415 mg) were added and the reaction was continued to stir at room temperature for 2 hours. The reaction system was slowly added to a saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases were combined, dried, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 580 mg of a yellow solid. ESI-MS: [M+H] + =575.0.

[0457] Step 9: Preparation of N-allyl-2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)benzamide

[0458] In a 25 mL single-necked flask, add N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluorobenzamide (580 mg), N,N-dimethylformamide (7 mL), and pyridine (799 mg) and cool to -20°C. Slowly add methylaminosulfonyl chloride (654 mg) dropwise and stir for 30 minutes. Pour the mixture into water and extract with ethyl acetate. The organic phases are combined, dried, and concentrated. The concentrate is slurried with tertiary methyl ether to obtain 410 mg of an off-white solid. 1 HNMR (400MHz, DMSO-d6): δ10.41(s,1H),9.09(s,1H),8.86(t,J=5.6,1H), 8.02(d,J=4.8,1H),7.69-7.65(m,1H),7.54(d,J=7.2,1H),7.02(q,J=5.2, 1H),6.95(t,J=5.2,1H),6.85-6.80(m,1H),5.85-5.75(m,1H),5.16-5.05 (m,2H),4.08(s,2H),3.82(t,J=5.2,2H),2.52-2.51(m,3H).ESI-MS:[M+H]+ =668.0.

[0459] Example 30

[0460] Step 1: Preparation of 5-chloro-2-fluoro-4-iodoaniline

[0461] To a 250 mL three-necked flask, add 5-chloro-2-fluoroaniline (7.0 g), sodium bicarbonate (8.1 g), 35 mL of methanol, and 35 mL of dichloromethane. Stir and cool to -5°C. Slowly add a solution of benzyltrimethylammonium dichloroiodate (16.7 g) in dichloromethane (100 mL) dropwise. Continue stirring at -5°C for 30 minutes, then gradually warm to room temperature and stir for 2 hours. Pour the reaction system into water, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry, and concentrate. Purify the concentrate by silica gel column chromatography to obtain 5.5 g of a brown solid.

[0462] Step 2: Preparation of 2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluoro-5-vinylbenzoic acid

[0463] To a 250 mL three-necked flask, add 5-chloro-2-fluoro-4-iodoaniline (5.5 g), 2,3,4-trifluoro-5-vinylbenzoic acid (4.1 g) and tetrahydrofuran (40 mL), replace the atmosphere with nitrogen, and cool to -20 ° C. Slowly add lithium bis(trimethylsilyl)amide (1 M, 62 mL) dropwise. After the addition is complete, continue stirring and react at -20 ° C for 10 minutes, then gradually warm to room temperature for 30 minutes. Pour the reaction system into water, adjust the pH to 3-4 with 1 M hydrochloric acid, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry and concentrate. The concentrate is slurried with methanol to obtain 5.0 g of brown solid. ESI-MS: [MH] - =451.9.

[0464] Step 3: Preparation of methyl 2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluoro-5-vinylbenzoate

[0465] To a 100 mL single-necked flask, add 2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluoro-5-vinylbenzoic acid (5.0 g), potassium carbonate (3.1 g), N,N-dimethylformamide (40 mL), and iodomethane (1.9 g). Stir at room temperature for 5 h. Pour the reaction system into a saturated aqueous solution of ammonium chloride and extract with ethyl acetate. The combined organic phases are washed with saturated brine, dried, and concentrated. The concentrate is purified by silica gel column chromatography to yield 3.9 g of a light red product.

[0466] Step 4: Preparation of methyl 2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluoro-5-formylbenzoate

[0467] To a 250 mL single-necked flask, methyl 2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluoro-5-vinylbenzoate (3.9 g), potassium osmate dihydrate (153 mg), and tetrahydrofuran (60 mL) were added and stirred at room temperature for 5 minutes. Water (60 mL), sodium periodate (5.3 g), and 2,6-lutidine (890 mg) were added to the system, and the reaction was continued by stirring at room temperature for 4 hours. The reaction system was poured into a saturated aqueous sodium sulfite solution and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 1.8 g of a light yellow solid.

[0468] Step 5: Preparation of methyl (E)-2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluoro-5-((2-(4-methylphenyl)sulfonylhydrazonomethyl)benzoate

[0469] To a 100 mL single-necked flask, add methyl 2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluoro-5-formylbenzoate (1.8 g), p-methylbenzenesulfonylhydrazide (715 mg), and ethanol (40 mL). Heat to 50°C and react for 3 h. Concentrate the reaction solution and slurry with n-hexane to obtain 2.3 g of an off-white solid.

[0470] Step 6: Preparation of methyl 2-((5-chloro-2-fluoro-4-iodophenyl)amino)-5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-3,4-difluorobenzoate

[0471] To a 250 mL single-necked bottle, (E)-methyl 2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluoro-5-((2-(4-methylphenyl)sulfonylhydrazonomethyl)benzoate (2.3 g), (2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)boric acid (1.4 g), potassium carbonate (748 mg), and toluene (80 mL) were added. The temperature was raised to 100°C and stirred for 12 h. The reaction system was poured into water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 1.1 g of a light yellow solid. ESI-MS: [M+H] + =716.1.

[0472] Step 7: Preparation of methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluorobenzoate

[0473] In a 50 mL single-necked flask, methyl 2-((5-chloro-2-fluoro-4-iodophenyl)amino)-5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-3,4-difluorobenzoate (1.1 g) and dichloromethane (30 mL) were added and stirred at room temperature until dissolved. The system was placed in an ice bath and trifluoroacetic acid (5 mL) was slowly added dropwise. After the addition was complete, the temperature was raised to room temperature and stirred for 1.5 h. The system was slowly added to a saturated aqueous sodium carbonate solution, the pH was adjusted to 8, and the mixture was extracted with dichloromethane. The organic phases were combined, dried, filtered, and concentrated to obtain 0.8 g of a light yellow solid. ESI-MS: [M+H] + =566.0.

[0474] Step 8: Preparation of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluorobenzoic acid

[0475] In a 100 mL single-necked bottle, methyl 5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluorobenzoate (1.1 g), tetrahydrofuran (20 mL) and water (20 mL) were added in sequence and stirred in an ice bath. Lithium hydroxide monohydrate (250 mg) was slowly added to the system. After the addition was complete, the temperature was raised to room temperature and stirred for 2.5 hours. Hydrochloric acid (6 M) was added to the system to adjust the pH to 1-2 and stirred for 5 minutes. The tetrahydrofuran in the system was removed by concentration under reduced pressure, and the concentrate was diluted with water and stirred for 10 minutes. Filtered, the filter cake was collected, and the filter cake was washed with water and tert-methyl ether in sequence to obtain 900 mg of a light yellow solid.

[0476] Step 9: Preparation of N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluorobenzamide

[0477] In a 50 mL single-necked flask, 5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluorobenzoic acid (900 mg) and N,N-dimethylformamide (20 mL) were added and cooled to 0°C in an ice bath. 1-Hydroxybenzotriazole (240 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (627 mg) were added, and after stirring for 5 minutes, the temperature was raised to room temperature and the reaction was allowed to react for 2 hours. Allylamine hydrochloride (257 mg) and N,N-diisopropylethylamine (631 mg) were added, and the reaction was continued by stirring at room temperature for 2 hours. The reaction system was slowly added to a saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases were combined, dried, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 580 mg of a light yellow solid. ESI-MS: [M+H] + =591.0.

[0478] Step 10: Preparation of N-allyl-2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridin-4-yl)methyl)benzamide

[0479] In a 25 mL single-necked bottle, N-allyl-5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluorobenzamide (580 mg), N,N-dimethylformamide (10 mL) and pyridine (776 mg) were added and the temperature was lowered to -20°C. Methylaminosulfonyl chloride (382 mg) was slowly added dropwise to the system. After completion of the addition, the mixture was stirred for 30 minutes. The system was poured into water and stirred at room temperature for 10 minutes, then filtered. The filter cake was dissolved in ethyl acetate, washed with saturated brine, and the organic phase was dried and concentrated. The concentrate was purified by silica gel column chromatography and further slurried in a mixed solvent of acetone / n-hexane (v / v = 1 / 6, 105 mL) to obtain 320 mg of an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ10.41(s,1H),9.06(s,1H),8.85(t,J=5.2Hz,1H),8.02(d,J=4.8Hz,1H),7.77(d,J=10.4Hz,1H),7.53(d,J=6.8Hz,1H),7. 06-7.00(m,2H),6.95(t,J=4.8Hz,1H),5.83-5.77(m,1H),5.16-5.05(m,2 H),4.09(s,2H),3.82(t,J=5.2Hz,2H),2.52-2.51(m,3H).ESI-MS:[M+Na] + =706.1.

[0480] Preparation of control compounds

[0481] The reference compounds Ref A-1 and Ref A-7 were synthesized with reference to CN114929669A, which are compounds A-1 and A-7 in the reference, respectively, and their structures are as follows:

[0482] The therapeutic efficacy and safety of a drug in vivo are the result of the combined effects of the compound's inhibitory activity, various physicochemical properties, and absorption, metabolism, distribution, excretion, and other factors. The compounds of this invention demonstrate superior efficacy and safety and have promising therapeutic prospects.

[0483] Biological testing

[0484] 1. Proliferation inhibition activity test of colorectal cancer cell HCT116

[0485] Cell proliferation activity was assessed using the CellTiter-3D-Glo reagent assay. The assay procedure was as follows: HCT116 cells in the logarithmic growth phase were digested, diluted to an appropriate cell density using McCoy's 5A complete medium supplemented with 10% FBS and 1% PS, and seeded into low-adsorption 96-well U-bottom plates in a 5% CO2 incubator. A series of concentrations of the test compound were added and incubated in a 5% CO2 incubator. Following incubation, the cells were lysed and detected using the CellTiter-3D-Glo reagent. Chemiluminescence values ​​were measured using a microplate reader, and data were fitted using Graphpad Prism software to calculate the IC values ​​of the test compounds. 50 The test results are shown in the following table:

[0486] Where, “A” represents the inhibitory activity IC 50 <20 nM, "B" indicates inhibitory activity 20 nM ≤ IC 50 <50nM, “C” represents the inhibitory activity IC 50 ≥50nM.

[0487] As can be seen from the results in the above table, the compounds of the present invention exhibit significant cell proliferation inhibitory activity on colorectal cancer cell line HCT116.

[0488] 2. 3D model proliferation inhibition activity test of colorectal cancer cell SW480

[0489] Cell proliferation activity was detected using the CellTiter-3D-Glo reagent method. The specific method is as follows: SW480 cells in the logarithmic growth phase were digested and diluted to an appropriate cell density using DMEM complete medium containing 10% FBS and 1% PS. The cells were seeded into low-adsorption 96-well U-bottom plates and cultured in 5% CO2. A series of concentration gradients of the test compound were added and incubated in a 5% CO2 incubator. After incubation, the cells were lysed and detected using the CellTiter-3D-Glo reagent. The chemiluminescence value was measured using an enzyme reader. The data were fitted using Graphpad Prism software to calculate the IC value of the test compound. 50 The test results are shown in the following table:

[0490] The test results showed that the compound of the present invention exhibited significant cell proliferation inhibitory activity on colorectal cancer cell line SW480.

[0491] 3. 3D Model Proliferation Inhibitory Activity Test of Lung Cancer Cell A427

[0492] Cell proliferation activity was detected using the CellTiter-3D-Glo reagent method. The specific method is as follows: A427 cells in the logarithmic growth phase were digested and diluted to an appropriate cell density using MEM complete medium containing 10% FBS and 1% PS. The cells were seeded into low-adsorption 96-well U-bottom plates and cultured in 5% CO2. A series of concentration gradients of the test compound were added and incubated in a 5% CO2 incubator. After incubation, the cells were lysed and detected using the CellTiter-3D-Glo reagent. The chemiluminescence value was measured using a microplate reader. The data were fitted using Graphpad Prism software to calculate the IC value of the test compound. 50 The test results are shown in the following table:

[0493] The test results show that the compound of the present invention exhibits significant cell proliferation inhibition activity on lung cancer cell A427.

[0494] 4. Pharmacodynamics Study in a Subcutaneous Pancreatic Cancer Cell MIA PaCa-2 Xenograft Model

[0495] Animal species and number: BALB / c nude mice, 6 per group;

[0496] Test samples: Compound 4-1, Compound 5-1;

[0497] Test groups: blank solvent control group, compound 4-1 (0.2 mg / kg, QD×15 days), compound 5-1 (0.2 mg / kg, QD×15 days);

[0498] Animal model establishment: MIA PaCa-2 tumor cells in the logarithmic growth phase were cultured in vitro and collected, and subcutaneously inoculated into the right back of Balb / c Nude mice. 3 Around 24 hours after the start of the experiment, the tumor-bearing mice were randomly divided into groups. Subsequently, each group of animals was dosed, and the day of the first dose was defined as the first day of the experiment.

[0499] Administration route and frequency: Oral gavage, once a day for 15 consecutive days;

[0500] General status observation: Observe once a day. The observation contents include but are not limited to the animal's drug administration site, appearance signs, general behavior activities, mental state, death, and other abnormal manifestations.

[0501] Tumor volume calculation: V = 0.5a × b 2 , where a is the long diameter of the tumor and b is the short diameter of the tumor. The tumor growth inhibition rate (TGI) (%) was used to evaluate the anti-tumor effect of the compound. TGI (%) = [1 - (average tumor volume of the treatment group at the end of dosing - average tumor volume of the treatment group at the start of dosing) / (average tumor volume of the control group at the end of dosing - average tumor volume of the control group at the start of dosing)] × 100%.

[0502] “+” indicates a tumor inhibition rate of <60%; “++” indicates a tumor inhibition rate of 60% to 90%; and “+++” indicates a tumor inhibition rate of >90%.

[0503] The experimental results showed that compounds 4-1 and 5-1 had a significant inhibitory effect on the growth of subcutaneous transplanted tumors of pancreatic cancer MIA PaCa-2 cells in nude mice; during the administration period, the diet, body weight and activity of animals in each administration group were normal, showing good safety.

[0504] 5. Pharmacodynamics Study in Subcutaneous Xenograft Tumor Model of Colorectal Cancer Cells SW480

[0505] Animal species and number: BALB / c nude mice, 6 per group;

[0506] Test samples: Compound 4-1, Compound Ref A-1;

[0507] Test groups: blank solvent control group, compound 4-1 (0.2 mg / kg, QD×18 days), compound Ref A-1 (0.2 mg / kg, QD×18 days);

[0508] Animal model establishment: SW480 tumor cells in the logarithmic growth phase were cultured in vitro and collected, and subcutaneously inoculated into the right back of Balb / c Nude mice. 3Around 24 hours after the start of the experiment, the tumor-bearing mice were randomly divided into groups. Subsequently, each group of animals was dosed, and the day of the first dose was defined as the first day of the experiment.

[0509] Route and frequency of administration: Oral gavage, once a day for 18 consecutive days;

[0510] General status observation: Observe once a day. The observation contents include but are not limited to the animal's drug administration site, appearance signs, general behavior activities, mental state, death, and other abnormal manifestations.

[0511] Tumor volume calculation: V = 0.5a × b 2 , where a is the long diameter of the tumor and b is the short diameter of the tumor. The tumor growth inhibition rate (TGI) (%) was used to evaluate the anti-tumor efficacy of the compound. TGI (%) = [1 - (average tumor volume of the treatment group at the end of dosing - average tumor volume of the treatment group at the start of dosing) / (average tumor volume of the control group at the end of dosing - average tumor volume of the control group at the start of dosing)] × 100%.

[0512] “+” indicates a tumor inhibition rate of <60%; “++” indicates a tumor inhibition rate of 60% to 80%; “+++” indicates a tumor inhibition rate of 80% to 100%; and “++++” indicates a tumor inhibition rate of >100%.

[0513] The experimental results showed that compound 4-1 had a significant inhibitory effect on the growth of subcutaneous transplanted tumors of colorectal cancer SW480 cells in nude mice, which was significantly better than the control Ref A-1.

[0514] 6. In vivo pharmacokinetic studies

[0515] The pharmacokinetics of compound 4-1 in SD rats were studied. Twelve SD rats (half male and half female) were randomly divided into two groups (3 rats / sex / group) according to body weight. The groups were designated as Group 1 and Group 2. 0.2 mg / kg of compound 4-1 was administered intravenously and orally by gavage, respectively. All experimental animals received a single dose on Day 0, and the time of administration was designated as 0 h. Approximately 0.25 mL of whole blood (EDTA-K2) was collected from all experimental animals in Group 1 before administration and at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration to prepare plasma. Approximately 0.25 mL of whole blood (EDTA-K2) was collected from all experimental animals in Group 2 before administration and at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration to prepare plasma. The compounds in the plasma samples were quantified by LC-MS / MS, and the pharmacokinetic parameters were calculated using non-compartmental model analysis.

[0516] The test results showed that compound 4-1 had a high absolute bioavailability (F%>65%) and a fast absorption and clearance rate, indicating good safety.

Claims

1. A compound represented by formula (I), its stereoisomers, tautomers or pharmaceutically acceptable salts, in, W is selected from a bond, oxygen or sulfur; V is selected from nitrogen or CR 4e ; L is selected from -NR1C(O)-, -C(O)NR1-, C 3-6 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R1 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl; R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R 4e , R 6a , R 6b , R 6c are each independently selected from hydrogen, deuterium, halogen, aldehyde, cyano, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl; or two adjacent substituents together form a substituted or unsubstituted 3-10 membered ring structure; R7 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl may be selected from deuterium, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 One or more substituents in the cycloalkyl group; R 8a , R 8b , R 8c , R 8d , R 8e are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3- 6-cycloalkyl; m is 0, 1, 2 or 3; n is 1, 2, 3 or 4; p is 0, 1, 2 or 3.

2. A compound represented by formula (II), its stereoisomers, tautomers or pharmaceutically acceptable salts, in, W is selected from a bond, oxygen or sulfur; V is selected from nitrogen or CR 4e ; R1 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl; R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R 4e , R 6a , R 6b , R 6c are each independently selected from hydrogen, deuterium, halogen, aldehyde, cyano, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl; or two adjacent substituents together form a substituted or unsubstituted 3-10 membered ring structure; R7 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl may be selected from deuterium, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 One or more substituents in the cycloalkyl group; R 8a , R 8b , R 8c , R 8d , R 8e are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3- 6-cycloalkyl; n is 1, 2, 3 or 4; p is 0, 1, 2 or 3.

3. The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts, 4. A compound represented by formula (III), its stereoisomers, tautomers or pharmaceutically acceptable salts, in, W is selected from a bond, oxygen or sulfur; V is selected from nitrogen or CR 4e ; Ring A is selected from C 6-10 Aryl or 5-10 membered heteroaryl; R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R 4e , R 6a , R 6b , R 6c are each independently selected from hydrogen, deuterium, halogen, aldehyde, cyano, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl; or two adjacent substituents together form a substituted or unsubstituted 3-10 membered ring structure; R7 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl may be selected from deuterium, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 One or more substituents in the cycloalkyl group; R 8a , R 8b , R 8c , R 8d , R 8e are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3- 6-cycloalkyl; m is 0, 1, 2 or 3; n is 1, 2, 3 or 4; p is 0, 1, 2 or 3.

5. The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts, 6. A compound represented by formula (IV), its stereoisomers, tautomers or pharmaceutically acceptable salts, in, U is selected from nitrogen or CR 5d ; V is selected from nitrogen or CR 4e ; R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R 4e , R 5a , R 5b , R 5c , R 5d , R 6a , R 6b , R 6c are each independently selected from hydrogen, deuterium, halogen, aldehyde, cyano, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl; or two adjacent substituents together form a substituted or unsubstituted 3-10 membered ring structure; R7 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl may be selected from deuterium, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 One or more substituents in the cycloalkyl group; R 8a , R 8b , R 8c , R 8d , R 8e are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; n is 1, 2, 3 or 4.

7. A compound represented by formula (IV-1), its stereoisomers, tautomers or pharmaceutically acceptable salts, in, U is selected from nitrogen or CH; V is selected from nitrogen or CR 4e ; R 4a , R 4b , R 4c , R 4d , R 4e are each independently selected from hydrogen, deuterium, halogen, aldehyde, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl; R 5c , R 6b , R 6c are each independently selected from hydrogen, halogen or C 1-6 alkyl; R7 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 3-6 Cycloalkyl; R 8a , R 8b , R 8c , R 8d , R 8e are each independently selected from hydrogen, deuterium or C 1-6 alkyl; n is 1, 2 or 3.

8. The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts, 9. The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts, 10. The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts, 11. A compound represented by formula (V), its stereoisomers, tautomers or pharmaceutically acceptable salts, in, U is selected from nitrogen or CH; V is selected from nitrogen or CR 4e ; R 4a , R 4b , R 4c , R 4d , R 4e , R 5c , R 6b , R 6c are each independently selected from hydrogen, deuterium, halogen, aldehyde, cyano, amino, hydroxyl, C 1- 6 alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl; or two adjacent substituents together form a substituted or unsubstituted 3-10 membered ring structure; R7 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl may be selected from deuterium, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The cycloalkyl group is substituted by one or more substituents; R 8a , R 8b , R 8c , R 8d , R 8e are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl or C 3- 6-cycloalkyl; n is 1, 2, 3 or 4.

12. The following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts, 13. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1 to 12, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. Use of the compound according to any one of claims 1 to 12, its stereoisomer, tautomer or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 13 in the preparation of drugs for preventing and / or treating tumors.

15. Use of the compound according to any one of claims 1 to 12, its stereoisomers, tautomers or pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 13, in the preparation of a medicament for preventing and / or treating a disease mediated by RAF or MEK, wherein the disease is particularly a tumor.

16. The use according to claim 14 or 15, wherein the tumor comprises renal cancer, liver cancer, breast cancer, pancreatic cancer, prostate cancer, melanoma, leukemia, malignant lymphoma, ovarian cancer, head and neck cancer, lung cancer, colorectal cancer, bladder cancer, and uterine cancer.

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