Aromatic amide derivatives and their uses

Abstract

Aromatic amide derivatives, methods for preparing the same, and the use of such compounds in the prevention and / or treatment of diseases, particularly in the treatment of tumors. Aromatic amide derivatives are MEK / RAF inhibitors with advantages such as relatively good activity and safety, and show promising application prospects in the prevention and / or treatment of tumors related to the MAPK pathway.

Description

Detailed description of the invention

[0001] [Technical Field] This invention belongs to the field of medicinal chemistry and relates to aromatic amide derivatives, methods for preparing them, and the use of such compounds in the treatment of diseases, particularly tumors.

[0002] [Background technology] Aromatic amide structures are widely found in drug molecules and are important pharmacophores that can interact with drug target proteins and potentially improve drug performance. For example, all of the following commercially available or clinically-staged molecular structures contain aromatic amide structures. [ka]

[0003] The RAS-RAF-MEK-ERK cascade is a crucial signaling pathway and one of the most actively studied. Abnormal activation of this signaling pathway affects the proliferation, differentiation, apoptosis, and metastasis of normal cells. In addition to lung cancer, abnormal activation of this pathway is more prevalent and has a greater impact in cancers with high mortality rates, such as pancreatic cancer (over 90%) and colorectal cancer (over 50%). RAF is a serine / threonine protein kinase, normally activated by RAS protein kinase. MEK is a bispecific kinase that can phosphorylate serine / threonine and tyrosine residues. Activated MEK activates downstream ERK, causing the kinase to translocate into the cell nucleus, thereby regulating various transcription factors and inducing specific gene expression to trigger cell proliferation. Inhibiting only a single target of this pathway is often insufficient to achieve the ideal antitumor effect, and single-target drugs have drawbacks such as a high likelihood of mutation and drug resistance, as well as high toxicity and side effects. Currently, by using Raf and MEK inhibitors in combination to inhibit two key targets in this pathway, we are overcoming drug resistance caused by pathway reactivation and delaying the emergence of resistance.

[0004] Developing dual-target inhibitors of RAF and MEK is an effective antitumor strategy. Among the RAF / MEK inhibitors currently under investigation, VS-6766 (related literature: WO2007091736, etc.) is rapidly progressing in clinical development, showing efficacy in treating various tumors activated by the MAPK pathway, and related side effects have also been reported in clinical trials. In addition, another type of compound has shown activity in lung cancer models (related literature: WO2021149776, etc.).

[0005] In developing dual-target inhibitors of RAF and MEK, it is necessary to improve the inhibitory activity and efficacy of the compound while paying attention to safety. Developing novel RAF and MEK dual-target inhibitors with superior efficacy and higher safety is extremely important.

[0006] 〔overview〕 This invention discloses aromatic amide MEK / RAF inhibitors, their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof. These possess advantages such as good activity and safety, and show promising prospects for application in the prevention and / or treatment of tumors associated with the MAPK pathway.

[0007] The present invention provides a compound represented by formula (A), or its stereoisomers, tautomers, or pharmaceutically acceptable salts. [ka] In the formula, M is selected from oxygen or sulfur; X is selected from bond, oxygen, sulfur, -C(O)-, -NR1C(O)-, -C(O)NR1-, -NR1S(O)-, -S(O)NR1-, -NR1SO2-, -SO2NR1-, -NR1-, or -CR1R2-; Rings A and B are independently selected from substituted or unsubstituted cycloalkyls, substituted or unsubstituted heterocyclines, substituted or unsubstituted aryls, and substituted or unsubstituted heteroaryls; L is selected from bonding, 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, and substituted or unsubstituted heteroaryl; R 10 is hydrogen, deuterium, halogen, aldehyde group, 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 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 bSelected from substituted or unsubstituted aminos, substituted or unsubstituted alkyls, substituted or unsubstituted deuterated alkyls, substituted or unsubstituted haloalkyls, substituted or unsubstituted alkoxys, substituted or unsubstituted alkenyls, substituted or unsubstituted alkynyls, substituted or unsubstituted cycloalkyls, substituted or unsubstituted heterocyclyls, substituted or unsubstituted aryls, and substituted or unsubstituted heteroaryls; R 9a and R 9b Each of these independently represents hydrogen, deuterium, halogen, aldehyde group, cyano, hydroxyl, and -OR. a , -SR a , -NR a R b , -C(O)R a ,-S(O)R a -S(O)2R a Selected from 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, and substituted or unsubstituted heteroaryl; or two adjacent substituents together form a substituted or unsubstituted 3- to 15-membered ring structure; R1, R2, R 2a , R 2b , R 3a , R 3b , R a , R b , and R c Each of these independently represents hydrogen, deuterium, halogen, aldehyde group, cyano, hydroxyl, and -OR. a , -SR a , -NR a R b , -C(O)R a ,-S(O)R a -S(O)2R aSelected from 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, and substituted or unsubstituted heteroaryl; or two adjacent substituents together form a substituted or unsubstituted 3- to 15-membered ring structure; m is selected from 0, 1, 2, 3, or 4; and, p is selected from 0, 1, 2, 3, or 4.

[0008] The present invention provides a compound represented by formula (A-1), or its stereoisomers, tautomers, or pharmaceutically acceptable salts. [ka] In the formula, W is selected from a bond, oxygen, or sulfur; M is selected from oxygen or sulfur; X is selected from bond, oxygen, sulfur, -C(O)-, -NR1C(O)-, -C(O)NR1-, -NR1S(O)-, -S(O)NR1-, -NR1SO2-, -SO2NR1-, -NR1-, or -CR1R2-; Rings A and B are independently selected from substituted or unsubstituted cycloalkyls, substituted or unsubstituted heterocyclines, substituted or unsubstituted aryls, and substituted or unsubstituted heteroaryls; L is selected from bonded, 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, and substituted or unsubstituted heteroaryl; R 10 These are hydrogen, deuterium, halogens, aldehydes, 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 2a R 2b ) p C(O)NR a R b , -(CR 2a R 2b ) p NR a C(O)NR b R[[ID=6​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​b , -C(O)R a ,-S(O)R a -S(O)2R a Selected from 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, and substituted or unsubstituted heteroaryl; or two adjacent substituents together form a substituted or unsubstituted 3- to 15-membered ring structure; R 8a , R 8b , R 8c , R 8d , R 8e and R 9a These are, independently, hydrogen, deuterium, halogen, aldehyde group, cyano, hydroxyl, -ORa, and -SR. a , -NR a R b , -C(O)R a ,-S(O)R a -S(O)2R a Selected from 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, and substituted or unsubstituted heteroaryl; or two adjacent substituents together form a substituted or unsubstituted 3-15 membered ring structure; m is 0, 1, 2, 3, or 4; n is 1, 2, 3, 4, or 5; and, p is 0, 1, 2, 3, or 4.

[0009] The present invention provides a compound represented by formula (I), or its stereoisomers, tautomers, or pharmaceutically acceptable salts. [ka] In the formula, W is selected from a bond, oxygen, or sulfur; V is nitrogen or CR 4e Selected from; L is -NR1C(O)-, -C(O)NR1-, C 3-6 Cycloalkyl, 5-10 membered heterocyclyl, C 6-10 Selected from aryls or 5-10 member heteroaryls; R1 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkyl deuterated, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, or C 3-6 Selected from cycloalkyl groups; R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R 4e , R 6a , R 6b and R 6c Each of these is independently hydrogen, deuterium, halogen, aldehyde group, cyano, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkyl deuterated, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, or C 3-6 Selected from cycloalkyl groups; or, two adjacent substituents together form a substituted or unsubstituted 3- to 10-membered ring structure; R7 is hydrogen, C 1-6 Alkyl, C 1-6 Alkyl deuterated, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-6 Alkenyl, or C 2-6Selected from alkynyl, alkyl, alkoxy, alkenyl, alkynyl, and cycloalkyl are optional, and deuterium, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl and C 3-6 Substituted with one or more substituents selected from cycloalkyl groups; R 8a , R 8b , R 8c , R 8d and R 8e These are, independently, hydrogen, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Alkyl deuterated, C 1-6 Haloalkyl, or C 3-6 Selected from cycloalkyl groups; m is 0, 1, 2, or 3; n is 1, 2, 3, or 4; and, p is 0, 1, 2, or 3.

[0010] The present invention provides a compound represented by formula (II), or its stereoisomer, tautomer, or pharmaceutically acceptable salt. [ka] In the formula, W is selected from a bond, oxygen, or sulfur; V is nitrogen or CR 4e Selected from; R1 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkyl deuterated, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, or C 3-6 Selected from cycloalkyl groups; R 2a , R 2b , R 3a , R 3b , R 4a , R4b , R 4c , R 4d , R 4e , R 6a , R 6b and R 6c Each of these is independently hydrogen, deuterium, halogen, aldehyde group, cyano, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkyl deuterated, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, or C 3-6 Selected from cycloalkyl groups; or, two adjacent substituents together form a substituted or unsubstituted 3- to 10-membered ring structure; R7 is hydrogen, C 1-6 Alkyl, C 1-6 Alkyl deuterated, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-6 Alkenyl, or C 2-6 Selected from alkynyl, alkyl, alkoxy, alkenyl, alkynyl and cycloalkyl are optional, and deuterium, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl and C 3-6 Substituted with one or more substituents selected from cycloalkyl groups; R 8a , R 8b , R 8c , R 8d and R 8e These are, independently, hydrogen, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Alkyl deuterated, C 1-6 Haloalkyl or C 3-6 Selected from cycloalkyl groups; n is 1, 2, 3, or 4; and, p is 0, 1, 2, or 3.

[0011] The present invention provides the following compounds, or their stereoisomers, tautomers, or pharmaceutically acceptable salts. [ka]

[0012] The present invention provides a compound represented by formula (III), or its stereoisomer, tautomer, or pharmaceutically acceptable salt. [ka] In the formula, W is selected from a bond, oxygen, or sulfur; V is nitrogen or CR 4e Selected from; Ring A is C 6-10 Selected from aryl or 5-10 member heteroaryl; R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R 4e , R 6a , R 6b and R 6c Each of these is independently hydrogen, deuterium, halogen, aldehyde group, cyano, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkyl deuterated, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, or C 3-6 Selected from cycloalkyl groups; or, two adjacent substituents together form a substituted or unsubstituted 3- to 10-membered ring structure; R7 is hydrogen, C 1-6 Alkyl, C 1-6 Alkyl deuterated, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-6 Alkenyl, or C2-6 Selected from alkynyl, alkyl, alkoxy, alkenyl, alkynyl and cycloalkyl are optional, and deuterium, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl and C 3-6 Substituted with one or more substituents selected from cycloalkyl groups; R 8a , R 8b , R 8c , R 8d and R 8e These are, independently, hydrogen, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Alkyl deuterated, C 1-6 Haloalkyl or C 3-6 Selected from cycloalkyl groups; m is 0, 1, 2, or 3; n is 1, 2, 3, or 4; and, p is 0, 1, 2, or 3.

[0013] The present invention provides the following compounds, or their stereoisomers, tautomers, or pharmaceutically acceptable salts. [ka]

[0014] The present invention provides a compound represented by formula (IV), or its stereoisomer, tautomer, or pharmaceutically acceptable salt. [ka] In the formula, U is nitrogen or CR 5d Selected from; V is nitrogen or CR 4e Selected from; R 3a , R 3b , R 4a , R 4b , R 4c , R 4d , R4e , R 5a , R 5b , R 5c , R 5d , R 6a , R 6b and R 6c Each of these is independently hydrogen, deuterium, halogen, aldehyde group, cyano, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkyl deuterated, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, or C 3-6 Selected from cycloalkyl groups; or, two adjacent substituents together form a substituted or unsubstituted 3- to 10-membered ring structure; R7 is hydrogen, C 1-6 Alkyl, C 1-6 Alkyl deuterated, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-6 Alkenyl, or C 2-6 Selected from alkynyl, alkyl, alkoxy, alkenyl, alkynyl and cycloalkyl are optional, and deuterium, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl and C 3-6 Substituted with one or more substituents selected from cycloalkyl groups; R 8a , R 8b , R 8c , R 8d and R 8e These are, independently, hydrogen, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Alkyl deuterated, C 1-6 Haloalkyl or C 3-6 Selected from cycloalkyl groups; and, n is 1, 2, 3, or 4.

[0015] The present invention provides a compound represented by formula (IV-1), or its stereoisomers, tautomers, or pharmaceutically acceptable salts. [ka] In the formula, U is selected from nitrogen or CH; V is nitrogen or CR 4e Selected from; R 4a , R 4b , R 4c , R 4d and R 4e Each of these is independently hydrogen, deuterium, halogen, aldehyde group, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, or C 3-6 Selected from cycloalkyl groups; R 5c , R 6b and R 6c Each of these is independently hydrogen, halogen, or C 1-6 Selected from alkyl groups; R7 is hydrogen, C 1-6 Alkyl, C 1-6 Alkyl deuterated, or C 3-6 Selected from cycloalkyl groups; R 8a , R 8b , R 8c , R 8d and R 8e Each of these is independently hydrogen, deuterium, or C 1-6 Selected from alkyl groups; and, n is 1, 2, or 3.

[0016] The present invention provides the following compounds, or their stereoisomers, tautomers, or pharmaceutically acceptable salts. [ka]

[0017] The present invention provides the following compounds, or their stereoisomers, tautomers, or pharmaceutically acceptable salts. [ka]

[0018] The present invention provides the following compounds, or their stereoisomers, tautomers, or pharmaceutically acceptable salts. [ka] [ka]

[0019] The present invention provides a compound represented by formula (V), or its stereoisomer, tautomer, or pharmaceutically acceptable salt. [ka] In the formula, U is selected from nitrogen or CH; V is nitrogen or CR 4e Selected from; R 4a , R 4b , R 4c , R 4d , R 4e , R 5c , R 6b and R 6c Each of these is independently hydrogen, deuterium, halogen, aldehyde group, cyano, amino, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkyl deuterated, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl, or C 3-6 Selected from cycloalkyl groups; or, two adjacent substituents together form a substituted or unsubstituted 3- to 10-membered ring structure; R7 is hydrogen, C 1-6 Alkyl, C 1-6Alkyl deuterated, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-6 Alkenyl, or C 2-6 Selected from alkynyl, alkyl, alkoxy, alkenyl, alkynyl and cycloalkyl are optional, and deuterium, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenil, C 2-6 Alkinyl and C 3-6 Substituted with one or more substituents selected from cycloalkyl groups; R 8a , R 8b , R 8c , R 8d and R 8e These are, independently, hydrogen, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Alkyl deuterated, C 1-6 Haloalkyl or C 3-6 Selected from cycloalkyl groups; and, n is 1, 2, 3, or 4.

[0020] The present invention provides the following compounds, or their stereoisomers, tautomers, or pharmaceutically acceptable salts. [ka]

[0021] The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any item of the present invention, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0022] The present invention provides for the use of compounds according to any item of the present invention, or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present invention, in the preparation of pharmaceuticals for the prevention and / or treatment of tumors.

[0023] The present invention provides for the use of compounds according to any item of the present invention, or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present invention, in the preparation of pharmaceuticals for the prevention and / or treatment of diseases, preferably tumors, mediated by RAF and / or MEK.

[0024] In the use of the present invention, tumors include kidney 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, and the like.

[0025] The present invention further provides a method for inhibiting intracellular RAF / MEK proteins. The method involves contacting cells with an effective amount of the compound of the present invention, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, or a pharmaceutical composition according to the present invention.

[0026] [Detailed explanation] All technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art.

[0027] In this specification, the term "hydrogen" refers to H.

[0028] In this specification, the term "deuterium" refers to D.

[0029] In this specification, the term "nitrogen" refers to N.

[0030] In this specification, the term "cyano" refers to -CN.

[0031] In this specification, the term "halogen" refers to -F, -Cl, -Br, and -I.

[0032] In this specification, the term "aldehyde group" refers to -CHO.

[0033] In this specification, the term "hydroxyl" refers to the -OH group.

[0034] The term "amino" or "amine" interchangeably refers to an -NR2 group, where each R is, for example, H or a substituent. In some embodiments, the amino is further substituted, for example, NR 3+ The ammonium ion is formed by the following: The ammonium portion is specifically included in the definition of "amino" or "amine". Substituents are, for example, alkyl, deuterated alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amide, or carboxylate. The R group may be further substituted by one or more (e.g., 1 to 4) groups selected from halogen, cyano, alkenyl, alkynyl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, urea, carbonyl, carboxylate, amine, and amide.

[0035] In this specification, the term "alkyl" refers to a saturated aliphatic hydrocarbon group having multiple carbon atoms, preferably having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and the term includes linear hydrocarbon groups and branched hydrocarbon groups. 1-6 When there is a limitation on the number of carbon atoms before an alkyl group, such as alkyl, it means that the alkyl group contains 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 used herein may optionally be 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 group, ester group, amine, sulfonyl, sulfinyl, cycloalkyl, heterocyclyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenoxy, alkynyl, cycloalkoxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aryl, or heteroaryl.

[0036] In this specification, the term "deuterated alkyl" refers to alkyl obtained by substituting the "alkyl" defined above with deuterium. Non-exclusive examples of deuterated alkyl include methyl deuterated and ethyl deuterated.

[0037] In this specification, the term "haloalkyl" refers to an alkyl group obtained by substituting the alkyl group defined above with a halogen, and halogens include fluorine, chlorine, bromine, iodine, etc. Non-limiting examples of haloalkyls include monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, etc.

[0038] The term "alkoxy" is -OR a It refers to the base, R a C is the alkyl group defined above. 1-6 When there is a limitation on the number of carbon atoms before "alkoxy," it means that the alkoxy contains 1 to 6 carbon atoms. Examples of alkoxys include, but are not limited to, methoxy, ethoxy, and isopropoxy.

[0039] Alkenyls are unsaturated hydrocarbon groups containing a carbon-carbon double bond. In this specification, the term "alkenyl" refers to an alkyl group containing a carbon-carbon double bond in its molecule, where an alkyl group is defined as above and has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms. 2-6When there is a limitation on the number of carbon atoms before an alkenyl, such as an alkenyl, it means that the alkenyl contains 2 to 6 carbon atoms. Alkenyls in this specification may optionally be substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, oxo, alkyl, alkoxy, acyl, amide group, ester group, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, alkylmercapto, deuterated alkylmercapto, sulfonyl, sulfinyl, silyl, phosphonyl, deuterated alkyl, heterocyclyl, aryl, heteroaryl, alkynyl, alkenyl, and arylalkyl. Non-limiting examples of alkenyls include, but are not limited to, vinyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, deuterated vinyl, deuterated propenyl, deuterated allyl, etc.

[0040] Alkynnyls are unsaturated hydrocarbon groups containing a carbon-carbon triple bond. In this specification, the term "alkynyl" refers to an alkyl group containing a carbon-carbon triple bond in its molecule, where alkyl is defined as above and has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms. 2-6When there is a limitation on the number of carbon atoms before an alkynyl, such as alkynyl, it means that the alkynyl contains 2 to 6 carbon atoms. Alkynnyls in this specification may optionally be substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, oxo, alkoxy, acyl, amide group, ester group, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, alkylmercapto, deuterated alkylmercapto, sulfonyl, sulfinyl, silyl, phosphonyl, deuterated alkyl, heterocyclyl, aryl, heteroaryl, alkynyl, alkenyl, and arylalkyl. Non-limiting examples of alkynyls include ethynyl, propargyl, 1-propargyl, 2-propargyl, 1-, 2- or 3-butynyl, deuterated 1-propargyl, deuterated 2-propargyl, deuterated propargyl, etc.

[0041] The term "cycloalkyl" refers to a stable, monovalent, non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, which may include fused or bridging ring systems having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 and 3 to 6 carbon atoms, and may be saturated or unsaturated, and may be linked to the rest of the molecule by single bonds via any suitable carbon atoms. 3-6When there is a limitation on the number of carbon atoms before "cycloalkyl," such as in "cycloalkyl," it means that the cycloalkyl contains 3 to 6 carbon atoms. Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2,3-dihydroindenyl, 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, This includes, but is not limited to, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]heptyl, 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, octahydro-2,5-methylene-cyclopentadienyl, etc. In this specification, cycloalkyls may optionally be substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, oxo, carboxyl, amino, alkyl, alkoxy, acyl, amide group, ester group, amine, sulfonyl, sulfinyl, cycloalkyl, heterocyclyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkoxy, aryl, and heteroaryl.

[0042] The term "heterocyclyl" refers to a substituted or unsubstituted, saturated or unsaturated aromatic or aromatic ring containing at least 1 to 5 heteroatoms selected from N, O, or S. The aromatic or aromatic ring may be a 3- to 10-membered monoring, a 4- to 20-membered spiroring, a fused ring, or a bridging ring, and the optionally substituted N and S within the heterocyclyl ring may be oxidized to various oxidation states, preferably 3- to 12-membered and 5- to 10-membered heterocyclyl rings. Non-limiting examples of heterocyclyls include oxiran-2-yl, oxetan-2-yl, oxolan-2-yl, oxan-2-yl, oxepan-2-yl, oxocan-2-yl, aziridin-2-yl, azetidine-2-yl, azolidin-2-yl, piperidine-2-yl, azirin-2-yl, 1,3-dioxolan-2-yl, 1,4-dioxolan-2-yl, 1,3-dithiolan-2-yl, 1 These include 3-dioxan-2-yl, 1,3-dithian-2-yl, azepinyl, morpholinyl, piperazinyl, pyridinyl, furanyl, thiophenyl, pyrrolyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridadinyl, imidazolyl, piperidinyl, thiomorpholinyl, dihydropyranyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, 1,4-dioxynyl, etc. Heterocyclyls in this specification may optionally be substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide group, ester group, amine, sulfonyl, sulfinyl, cycloalkyl, heterocyclyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkoxy, aryl, and heteroaryl.

[0043] In this specification, the term "aryl" refers to a 6- to 14-membered monocyclic or fused polycyclic group of all carbon atoms having a conjugated π-electron system (for example, a ring sharing a pair of adjacent carbon atoms), preferably a 6- to 10-membered ring, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused with a heteroaryl ring, a heterocyclyl ring, or a cycloalkyl ring, and the ring linked to the parent structure is an aryl ring. In this specification, aryls may be substituted or unsubstituted. If substituted, the substituent is 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.

[0044] In this specification, the term "heteroaryl" refers to an aromatic group consisting of 5 to 10 atoms and containing at least one heteroatom selected from N, O, or S. This term may have a monocycle (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.), and the fused ring may or may not be an aromatic group containing a heteroatom, provided that the linking point is an atom of an aromatic heteroaryl group. In this specification, heteroaryls may optionally be substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, amino, oxo, alkyl, alkoxy, acyl, acyloxy, amide group, ester group, amine, sulfonyl, sulfinyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, alkenyl, alkynyl, heterocyclyl, cycloalkoxy, aryl, and heteroaryl.

[0045] The present invention further includes isotope-labeled compounds having, for example, the structure disclosed above, but in which one or more atoms in the structure are substituted with atoms having the same number of protons but different numbers of neutrons. Examples of isotopes incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine, for example. 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl, and 131 For example, I. All compounds of the present invention, their stereoisomers, tautomers, or pharmaceutically acceptable salts, as well as compounds of the above forms containing the above isotopes and / or other atomic isotopes, are included in the scope of the present invention. 3 H or 14 Some isotope-labeled compounds of the present invention, such as compounds labeled with 1C, may be used in drug tissue distribution studies. Therefore, these 3 H or 14 13C isotopes are particularly preferred because they are easy to prepare and detect. 2 H and 18 Some compounds of the present invention, substituted with heavier isotopes such as O, offer therapeutic advantages due to superior metabolic stability, including increased in vivo half-life, reduced dosage, and other overall performance benefits. Therefore, 2 H and 18 O is also preferable in some cases.

[0046] The terms "optional" or "at will" mean that the events or situations described below may occur but are not necessarily guaranteed to occur, and the descriptions include both cases in which such events or situations occur and cases in which they do not.

[0047] The term "compounds of the present invention" (unless otherwise specified) refers to the compounds shown in formulas (A), (A-1), and (I) to (V), as well as all of their pure and mixed stereoisomers, geometric isomers, tautomers, solvates, hydrates, prodrugs, isotope-labeled compounds, and pharmaceutically acceptable salts. Solvates of the compounds of the present invention refer to compounds or salts thereof combined with stoichiometric and non-stoichiometric solvents, such as hydrates, ethanol solvates, and methanol solvates. The compounds may also exist in one or more crystalline states, such as cocrystals and polymorphs, or in an amorphous solid state. All of these forms are covered in the claims.

[0048] The term "pharmaceutically acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with the other components of the formulation and / or with the mammal being treated by the formulation.

[0049] The term "may be optionally substituted with ~" means that the structure is either unsubstituted or substituted with one or more substituents of the present invention. In this specification, "substituted" means that, to the extent chemically permissible, any group is monosubstituted or polysubstituted (including multiple substitutions at the same site) by a particular substituent, each substituent may be located at any available position on the group and may be linked by any available atom of the substituent. "Any available position" means any position on the group that may be chemically obtained by methods well known in the art or taught herein, and that does not result in an excessively unstable molecule. If any group has two or more substituents, each substituent is defined independently of the others, and therefore the substituents may be identical or different.

[0050] In various parts of the specification, substituents of the compounds of the present invention are disclosed in the form of groups or ranges, specifically meaning that the present invention includes each configuration or each individual subcombination of such groups and ranges. For example, the term "C 1-6Specifically, "alkyl" means that methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl are disclosed individually.

[0051] In this specification, the term "stereoisomer" refers to a compound having one or more stereocenters and different chiral properties. Stereoiomers include enantiomers, diastereomers, stereoisomers (rotational isomers), geometric isomers (cis / trans isomers), atropisomers, and the like.

[0052] In this specification, the term "tautomer" refers to structures having different energies, and isomers may achieve interconversion over low energy barriers. For example, proton tautomers include tautomers that exhibit interconversion by proton dissociation (e.g., enol-ketone tautomers and imine-enamine tautomers), or tautomer forms containing heteroaryl groups linked to ring atoms in the ring-NH and ring-=N moieties (e.g., pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles). Valence tautomers include tautomers that exhibit interconversion by recombination of bonding electrons.

[0053] 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 salts include, but are not limited to, acetates, adipines, alginates, citrates, aspartates, sodium salts, benzoates, benzenesulfons, bisulfates, butyrates, camphorates, camphor sulfons, diglucons, cyclopentanepropionates, sodium dodecylbenzenesulfonate sulfate, ethanesulfons, glucosylheptanoates, glycerophosphates, hemisulfons, heptanoates, capronates, fumarates, hydrochlorides, hydrobroms, hydroiodides, 2-hydroxyethylsulfons, lactates, maleates, methanesulfons, hydrochlorides, 2-naphthalenesulfons, oxalates, pectins, sulfates, 3-phenylpropionates, picrinates, pivalates, propions, succinates, tartrates, thiocyans, p-toluenesulfons, quinines, and others.

[0054] In this application, “tumor” or “cancer” includes, but is not limited to, leukemia, malignant lymphoma, multiple myeloma, myelodysplastic syndrome and other hematological and lymphomas; as well as brain tumors, neurological tumors, head and neck cancers, esophageal cancers, gastric cancers, colorectal cancers, lung cancers, thyroid cancers, breast cancers, gallbladder cancers, pancreatic cancers, liver cancers, prostate cancers, ovarian cancers, uterine cancers, testicular cancers, renal cell carcinomas, bladder cancers, renal pelvis and ureteral cancers, malignant melanomas, skin cancers, colorectal cancers, breast cancers, kidney cancers and other solid tumors.

[0055] [Detailed explanation] The present invention will be further described below with reference to examples. However, the present invention is not limited by examples. Throughout this application, several examples of the compounds and methods of the present invention are described. These examples are intended to provide illustrative examples and should not be construed as descriptions of alternatives. Rather, the examples shown herein (including various methods and parameters) are for illustrative purposes only and do not limit the scope of protection of the present invention in any sense. Specific examples are listed below to illustrate the present invention. However, the present invention is not limited to these examples, and the following examples merely illustrate methods for carrying out the present invention and do not limit the scope of the present invention in any sense.

[0056] The process for preparing the compound represented by formula (IV) of the present invention, its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof is as follows: [ka]

[0057] Under alkaline conditions, fluorobenzene derivative a reacts with aromatic amine derivative b to form compound c, which is then methylated and oxidized to obtain compound d. Aldehyde derivative d reacts with arylsulfonylhydrazine to form compound e. Under alkaline conditions, hydrazine derivative e reacts with arylboronic acid derivative f to form compound g. Under acidic conditions, compound g is deprotected to form compound h. Ester derivative h is hydrolyzed in the presence of hydroxide to form compound i. In the presence of a coupling agent, benzoic acid derivative i reacts with the corresponding amine or amine hydrochloride to form compound j. Under alkaline conditions, compound j reacts with the corresponding sulfonyl compound to obtain the compound of general formula I. The definitions of each substituent are as described above.

[0058] The compounds provided by the present invention may be prepared by standard synthetic methods well-known in the art, and general methods for preparing the compounds of the present invention are described herein. Starting materials or reagents are usually commercially available and are purchased from, for example, Alfa Aesar®, Sigma-Aldrich®, TCI and other companies, or are prepared by methods well-known to those skilled in the art.

[0059] The compounds of the present invention and the corresponding preparation methods will be further illustrated and enumerated through the following examples and preparation methods. Although typical or preferred reaction conditions (reaction temperature and time, molar ratio of reactants, reaction solvent, etc.) are shown in specific examples, it should be understood that those skilled in the art may also use other reaction conditions. The optimal reaction conditions may vary depending on the specific reaction substrate or solvent used, but those skilled in the art may determine the conditions by routine optimization.

[0060] The structures of the compounds in the following examples were characterized by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). Using a Bruker Ascend 400 MHz NMR spectrometer, the compounds were dissolved in an appropriate deuterated reagent and analyzed by 1H-NMR at room temperature with TMS as the internal standard. NMR chemical shifts (δ) are shown in ppm units, and the following abbreviations were used: s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, and brs: broad singlet.

[0061] The starting materials, intermediates and compounds of the examples of the reaction may be separated and purified by precipitation, filtration, crystallization, evaporation, distillation, chromatography (such as silica gel column chromatography and preparative chromatography), and other techniques.

[0062] [Preparation of Intermediate 1]

Chemical formula

Chemical formula

[0063] (Step 1: Preparation of 2,3,4-trifluoro-5-iodobenzoic acid) Acetic acid (928 mL) and acetic anhydride (538.0 g) were added to a 3 L three-necked flask and cooled to 0°C in an ice bath. Concentrated sulfuric acid (2116.0 g) was slowly added to this system, maintaining the internal temperature of the system below 40°C. After the dropwise addition was complete, the system was cooled again to room temperature. Subsequently, 2,3,4-trifluorobenzoic acid (115.0 g), iodine (66.9 g), and manganese dioxide (68.7 g) were added. After the addition was complete, the system was heated to 50°C and reacted for 3 hours. After stopping the heating, the system was cooled to room temperature and iodine (66.9 g) and manganese dioxide (68.7 g) were added. Then, the system was heated to 50°C and reacted for 3 hours. After stopping the heating, the system was cooled to room temperature and iodine (33.4 g) and manganese dioxide (34.4 g) were added. Subsequently, the system was heated again to 50°C and reacted for 21 hours. After the reaction stopped, it was cooled to room temperature, and the system was slowly poured into ice water to halt the reaction. Extraction was performed using dichloromethane. The organic phases were combined, washed with sodium sulfite aqueous solution and saturated brine respectively, and then dried over anhydrous sodium sulfate. The organic phases were concentrated, n-heptane was added, and the mixture was stirred in an ice bath to precipitate a large amount of solid, which was then subjected to suction filtration. The filtration cake was washed with n-heptane to obtain 178.1 g of a white solid. ESI-MS: [MH] - = 300.9.

[0064] (Step 2: Preparation of 2,3,4-trifluoro-5-vinylbenzoic acid) 2,3,4-trifluoro-5-iodobenzoic acid (89.0 g), potassium vinyl trifluoroborate (47.4 g), potassium phosphate (93.8 g), methanol (1780 mL), water (890 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (21.6 g) were sequentially added to a 3 L three-necked flask. This system was subjected to nitrogen purging and heated to 60 °C for 3 hours. After cooling to room temperature, the system was filtered through diatomaceous earth. The filtrate was collected and concentrated, and the pH of the system was adjusted to 4-5 by adding 1 M HCl. Subsequently, the system was extracted using methyl tert-butyl ether. The organic phases were combined, washed with saturated brine, dried, and concentrated. n-heptane and dichloromethane were added to the concentrate, and the mixture was stirred at room temperature for 2 hours before being filtered. The filtered cake was washed with n-heptane to obtain 48.2 g of a white solid. ESI-MS: [MH] - = 201.0.

[0065] (Step 3: Preparation of 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-vinylbenzoic acid) 2,3,4-trifluoro-5-vinylbenzoic acid (65.0 g), 2-fluoro-4-iodoaniline (76.3 g), and tetrahydrofuran (1300 mL) were added to a 3 L three-necked flask. The system was then purged with nitrogen and cooled to -15°C to -20°C. Lithium bis(trimethylsilyl)amide (1 M, 965 mL) was slowly added to the system, ensuring the temperature did not exceed -15°C. After the addition was complete, the temperature of the system was slowly raised to room temperature. Next, 1 M hydrochloric acid was added to adjust the pH of the system to 1-2, and the system was extracted using methyl tert-butyl ether. The organic phases were combined, washed with saturated brine, dried, and concentrated. N-heptane was slowly added to the concentrate to precipitate the solid, which was then filtered to obtain 99.0 g of an off-white solid. ESI-MS: [MH] - = 418.0.

[0066] (Step 4: Preparation of methyl 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-vinylbenzoate) 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 1 L three-necked flask, and the system was stirred at room temperature until a clear solution was obtained. Potassium carbonate (7.9 g) and methyl iodide (8.1 g) were added to the system. The system was then reacted at room temperature for 12 hours. The suspension 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 dropwise addition was complete, the system was stirred for 1 hour, and then subjected to suction filtration. The filtration cake was washed with 250 mL of ethanol to obtain 15.1 g of a pale yellow solid.

[0067] (Step 5: Preparation of 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-formylmethyl benzoate) 3,4-Difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-vinylmethyl benzoate (11.6 g) and tetrahydrofuran (200 mL) were added to a 1 L three-necked flask and stirred in an ice bath until a clear solution was obtained. Potassium osmate dihydrate (494 mg) was added to the system and the mixture was reacted while continuing to stir in an ice bath. After 15 minutes, water (200 mL), sodium periodate (17.2 g), and 2,6-dimethylpyridine (2.9 g) were added to the system and the system was heated to room temperature and stirred for 4 hours. The reaction system was poured into a saturated sodium sulfite aqueous solution and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and concentrated to obtain a crude solid product. The crude product was washed with anhydrous ethanol and filtered to obtain 9.0 g of a light brown solid. 1H NMR (400 MHz, DMSO-d6): δ 10.00 (s, 1H), 9.52 (s, 1H), 8.21 (dd, J1= 7.2 Hz, J2= 1.2 Hz, 1H), 7.71 (dd, J1= 10.4 Hz, J2= 1.6 Hz, 1H), 7.54-7.51 (m, 1H), 7.13-7.07 (m, 1H), 3.86 (s, 3H). ESI-MS: [M+H] + = 436.0.

[0068] (Step 6: Preparation of (E)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-((2-p-toluenesulfonylhydrazinyl)methyl)benzoate) 50.7 g of 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-formylmethyl benzoate, 21.7 g of p-toluenesulfonic acid hydrazide, and 1500 mL of ethanol were added to a 2 L three-necked flask, and the system was heated to 50°C and reacted for 5 hours. The system was cooled to 0°C in an ice bath to precipitate a large amount of solid, which was then subjected to suction filtration. The filtration cake was washed with ethanol to obtain 53.1 g of a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.76 (s, 1H), 8.97 (s, 1H), 8.00-7.99 (m, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.64 (dd, J1= 10.4 Hz, J2= 1.6 Hz, 1H), 7.43 (d, J = 8.4 Hz, 3H), 6.92-6.89 (m, 1H), 3.85 (s, 3H), 2.37 (s, 3H). ESI-MS: [M+H] + = 604.0.

[0069] (Step 7: Preparation of N-(2,4-dimethoxybenzyl)-3-fluoro-4-iodopyridine-2-amine) 2,3-difluoro-4-iodopyridine (45.0 g), (2,4-dimethoxyphenyl)methylamine (78.0 g), N-methylpyrrolidone (675 mL), and triethylamine (56.7 g) were added to a 1 L necked flask, and the system was subjected to nitrogen purging. The system was heated to 100 °C and reacted for 2 hours. After cooling to room temperature, the system was poured into water and extracted with methyl tert-butyl ether. The organic phases were combined, washed with saturated brine, dried, and concentrated to obtain the crude product. The crude product was washed with methyl tert-butyl ether / petroleum ether (1 / 4) to obtain 56.8 g of an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 7.45 (d, J = 5.6 Hz, 1H), 7.11-7.08 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.89-6.86 (m, 1H), 6.54 (d, J = 2.4 Hz, 1H), 6.43 (dd, J1= 8.4 Hz, J2= 2.4 Hz, 1H), 4.44 (d, J = 6.0 Hz, 2H), 3.80 (s, 3H), 3.72 (s, 3H).

[0070] (Step 8: Preparation of N-(2,4-dimethoxybenzyl)-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-amine) N-(2,4-dimethoxybenzyl)-3-fluoro-4-iodopyridine-2-amine (56.5 g), bis(pinacolate)diborone (147.8 g), potassium pivalate (44.9 g), toluene (1400 mL), dimethyl sulfoxide (20 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (10.6 g) were added to a 2 L three-necked flask, and the system was subjected to nitrogen purging. The system was then heated to 55 °C and reacted for 15 hours. After cooling to room temperature, the system 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, filtered through diatomaceous earth, and the filtrate was concentrated to obtain the product. The product from this step was used directly in the next reaction without further purification. 1 H NMR (400 MHz, DMSO-d6): δ 7.75 (dd, J1= 4.8 Hz, J2= 0.8 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.87-6.84 (m, 1H), 6.59-6.56 (m, 1H), 6.54 (d, J = 2.4 Hz, 1H), 6.42 (dd, J1= 8.4 Hz, J2= 2.4 Hz, 1H), 4.45 (d, J = 6.0 Hz, 2H), 3.80 (s, 3H), 3.72 (s, 3H), 1.30 (s, 12H).

[0071] (Step 9: Preparation of (2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)boronic acid) N-(2,4-dimethoxybenzyl)-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-amine and THF (500 mL) were added to a 2 L necked flask and stirred until a clear solution was obtained. 1 M aqueous hydrochloric acid was slowly added to the system and stirred at room temperature for 1 hour to allow the reaction to proceed. The system was extracted using petroleum ether, and the aqueous phase was recovered. Methylboronic acid (17.4 g) was added to the aqueous phase, and the mixture was stirred at room temperature for 1 hour to allow the reaction to proceed. Subsequently, the system was extracted using a mixed solvent of ethyl acetate / petroleum ether (3 / 1), and the aqueous phase was recovered. Ethyl acetate was added to the aqueous phase, and aqueous sodium bicarbonate was added to adjust the pH of the system to 8. The organic phase was recovered, washed with water, dried, and concentrated to obtain 37.0 g of an off-white solid. ESI-MS: [M+H] + = 307.1.

[0072] (Step 10: Preparation of 5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)methyl benzoate) (2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)boronic acid (15.0 g), (E)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-((2-p-toluenesulfonylhydrazinyl)methyl)methyl benzoate (35.4 g), potassium carbonate (8.1 g), and toluene (600 mL) were added to a 1 L necked flask, and the system was subjected to nitrogen purging. The system was heated to 100 °C and reacted for 5 hours. After cooling to room temperature, saturated ammonium chloride aqueous solution was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. Subsequently, the crude product was purified by silica gel column chromatography to obtain 17.9 g of a pale yellow liquid. 1H NMR (400 MHz, DMSO-d6): δ 8.65 (s, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.68 (d, J = 5.2 Hz, 1H), 7.62 (dd, J1= 10.8 Hz, J2= 3.0 Hz, 1H), 7.39 (dd, J1= 8.4 Hz, J2= 0.8 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.92-6.88 (m, 1H), 6.80-6.75 (m, 1H), 6.54 (d, J = 2.4 Hz, 1H), 6.42 (dd, J1= 8.4 Hz, J2= 2.4 Hz, 1H), 6.38 (t, J = 4.8 Hz, 1H), 4.44 (d, J = 6.0 Hz, 2H), 4.01 (s, 2H), 3.80 (d, J = 1.2 Hz, 6H), 3.72 (s, 3H). ESI-MS: [M + H] + = 682.1.

[0073] (Step 11: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)methyl benzoate) 10.0 g of 5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)methyl benzoate and 150 mL of dichloromethane were added to a 500 mL necked flask and stirred at room temperature until a clear solution was obtained. The system was then placed in an ice bath and 150 mL of trifluoroacetic acid was slowly added. After the addition was complete, the system was heated to room temperature and stirred for 1.5 hours to allow the reaction to proceed. Slowly adding saturated sodium carbonate aqueous solution adjusted the pH of the system to 8, and the mixture was extracted using dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. The crude product was then purified by silica gel column chromatography to obtain 5.8 g of a pale yellow solid. 11H NMR (400 MHz, DMSO-d6): δ 8.64 (s, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 5.2 Hz, 1H), 7.62 (dd, J1 = 10.8 Hz, J2 = 1.6 Hz, 1H), 7.39 (dd, J1 = 8.4 Hz, J2 = 1.2 Hz, 1H), 6.80 - 6.74 (m, 1H), 6.40 (t, J = 4.8 Hz, 1H), 6.22 (s, 2H), 3.99 (s, 2H), 3.79 (s, 3H). ESI-MS: [M + H] + = 532.0。

[0074] (Step 12: Preparation of 5 - ((2 - amino - 3 - fluoropyridin - 4 - yl)methyl) - 3,4 - difluoro - 2 - ((2 - fluoro - 4 - iodophenyl)amino)benzoic acid hydrochloride) Methyl 5 - ((2 - amino - 3 - fluoropyridin - 4 - yl)methyl) - 3,4 - difluoro - 2 - ((2 - fluoro - 4 - iodophenyl)amino)benzoate (6.9 g), tetrahydrofuran (100 mL) and water (50 mL) were successively added to a 1 L single - neck flask. The system was placed in an ice bath and stirred. Lithium hydroxide monohydrate (1.6 g) was slowly added to this system. After the addition was complete, the system was heated to room temperature and stirred for 2.5 hours to react. Subsequently, aqueous hydrochloric acid solution (6 M, 20 mL) was added to adjust the pH value of this system to 1 - 2. After stirring for 5 minutes, it was concentrated under reduced pressure to remove tetrahydrofuran. Then, the concentrate was diluted with water, stirred for 10 minutes, and then filtered. The filter cake was recovered and washed once with water and once with methyl tert - butyl ether respectively to obtain 6.2 g of a magenta - colored solid. ESI - MS: [M + H] + = 518.0。

[0075] 〔Preparation of Intermediate 2〕

Chemical formula

[0076] (Step 1: Preparation of 3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)-5-vinylbenzoic acid) 2,3,4-trifluoro-5-vinylbenzoic acid (24.2 g), 2-fluoro-4-methylaniline (15.0 g), and tetrahydrofuran (485 mL) were added to a 2 L three-necked flask. The system was then purged with nitrogen and cooled to -70°C to -80°C. Lithium bis(trimethylsilyl)amide (1 M, 360 mL) was slowly added dropwise to the system, ensuring the temperature did not exceed -70°C. After the addition was complete, the system was slowly raised to room temperature, and 600 mL of hydrochloric acid (1 M) was added to adjust the pH to 1-2. Extraction was performed using methyl tert-butyl ether. The organic phases were combined, washed with saturated brine, dried, and concentrated. N-heptane was slowly added to the concentrate, and the mixture was stirred at room temperature for 30 minutes. The mixture was then filtered to obtain 30.4 g of a pale yellow solid. ESI-MS: [MH] - = 306.1.

[0077] (Step 2: Preparation of 3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)-5-formylbenzoic acid) Water (100 mL), tetrahydrofuran (300 mL), and acetonitrile (300 mL) were added to a 2 L three-necked flask and stirred at room temperature. Concentrated sulfuric acid (2.0 g) was then slowly added dropwise to the reaction flask. After the system returned to room temperature, sodium periodate (34.9 g) and anhydrous ruthenium(III) chloride (0.5 g) were slowly added to the system, and the mixture was stirred at room temperature to allow it to react. After 5 minutes, 3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)-5-vinylbenzoic acid (10.0 g) was added to the system, and the mixture was stirred at room temperature for 2 hours to allow it to react. Insoluble substances were removed by filtration. The filtrate was collected and extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium sulfite aqueous solution, and then washed with saturated brine. The organic phases were collected, dried, filtered, and concentrated to obtain 7.0 g of a yellow solid. ESI-MS: [MH] - = 308.1.

[0078] (Step 3: Preparation of 3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)-5-formylmethyl benzoate) 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 the system was stirred at room temperature until a clear solution was obtained. Potassium carbonate (1.5 g) and methyl iodide (1.6 g) were added to the system, and the mixture was heated to 50 °C and reacted for 4 hours. The suspension was removed by filtration. The filtrate was collected. The filtrate was slowly added dropwise to water to precipitate a solid. After the dropwise addition was complete, the system was stirred for 1 hour, and then subjected to suction filtration. The filtration cake was washed with water and dried to obtain 1.3 g of a yellow solid. ESI-MS: [M+H] + = 324.1.

[0079] (Step 4: Preparation of (E)-3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)-5-((2-p-toluenesulfonylhydrazinyl)methyl)benzoate) 3,4-Difluoro-2-((2-fluoro-4-methylphenyl)amino)-5-formylmethyl benzoate (1.8 g), p-toluenesulfonyl hydrazide (1.1 g), and ethanol (54 mL) were added to a 2 L three-necked flask, and the system was heated to 50 °C and reacted for 2 hours. The system was cooled to 0 °C in an ice bath to precipitate a large amount of solid, which was then subjected to suction filtration. The filtration cake was washed with ethanol to obtain 1.7 g of a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.69 (s, 1H), 9.04 (s, 1H), 8.01-7.98 (m, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.09-7.03 (m, 2H), 6.93 (d, J = 8.0 Hz, 1H), 3.87 (s, 3H), 2.38 (s, 3H), 2.28 (s, 3H). ESI-MS: [M+H] + = 492.1.

[0080] (Step 5: Preparation of 5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)methyl benzoate) (2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)boronic acid (2.7 g), (E)-3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)-5-((2-p-toluenesulfonylhydrazinyl)methyl)methyl benzoate (3.6 g), potassium carbonate (1.2 g), and toluene (144 mL) were added to a 1 L necked flask, and the system was subjected to nitrogen purging. The system was heated to 100 °C and reacted for 4 hours. After cooling to room temperature, saturated ammonium chloride aqueous solution was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. Subsequently, the crude product was purified by silica gel column chromatography to obtain 3.2 g of a pale yellow liquid. ESI-MS: [M+H] + = 570.2.

[0081] (Step 6: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)methyl benzoate) 5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)methyl benzoate (3.2 g) and dichloromethane (60 mL) were added to a 250 mL necked flask and stirred at room temperature until a clear solution was obtained. Then, the system was placed in an ice bath and trifluoroacetic acid (60 mL) was slowly added. After the addition was complete, the system was heated to room temperature and stirred for 1.5 hours to allow the reaction to proceed. Saturated sodium carbonate aqueous solution was slowly added to adjust the pH to 8, and the mixture was extracted using dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and subjected to rotary evaporation to remove the solvent. The crude product was then purified by silica gel column chromatography to obtain 2.1 g of a pale yellow solid. ESI-MS: [M+H] + = 420.1.

[0082] (Step 7: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)benzoate) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)methyl benzoate (2.5 g), tetrahydrofuran (60 mL), and water (30 mL) were sequentially added to a 250 mL necked flask, 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 system was heated to room temperature and stirred for 4 hours to allow the reaction to proceed. Subsequently, aqueous hydrochloric acid (6 M, 10 mL) was added to adjust the pH to 1-2, and the mixture was stirred for 5 minutes. After that, the system was concentrated under reduced pressure to remove the tetrahydrofuran. Subsequently, the concentrate was diluted with water, stirred for 10 minutes, and then filtered. The filtered cake was collected and washed once with water and once with methyl tert-butyl ether to obtain 1.4 g of magenta solid. ESI-MS: [M+H] + = 406.1.

[0083] [Preparation of Intermediate 3] [ka]

[0084] (Step 1: Preparation of 3,4-difluoro-2-(phenylamino)-5-vinylbenzoic acid) 2,3,4-trifluoro-5-vinylbenzoic acid (20.0 g), aniline (9.2 g), and tetrahydrofuran (400 mL) were added to a 2 L three-necked flask. The system was then purged with nitrogen and cooled to -15°C to -20°C. Lithium bis(trimethylsilyl)amide (1 M, 297 mL) was slowly added dropwise to the system, ensuring that the temperature of the system did not exceed -15°C. After the addition was complete, the temperature of the system was slowly raised to room temperature, and hydrochloric acid (6 M) was added to adjust the pH of the system to 1-2. The system was then extracted using ethyl acetate. The organic phases were combined, washed with 1 L saturated brine, dried, and concentrated to obtain 24.5 g of a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 13.69 (s, 1H), 9.13 (s, 1H), 7.97 (d, J = 7.2 Hz, 1H), 7.27 (t, J = 8.0 Hz, 2H), 7.00-6.96 (m, 3H), 6.78 (dd, J1 = 17.6 Hz, J2 = 11.2 Hz, 1H), 5.89 (d, J = 18.0 Hz, 1H), 5.44 (d, J = 11.6 Hz, 1H). + = 276.1.

[0085] (Step 2: Preparation of methyl 3,4-difluoro-2-(phenylamino)-5-vinylbenzoate) 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 the system was stirred at room temperature until a clear solution was obtained. Potassium carbonate (22.6 g) and methyl iodide (20.1 g) were added to the system. The system was then reacted at room temperature for 16 hours. The suspension 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 dropwise addition was complete, the system was stirred for 1 hour, and then subjected to suction filtration. The filtration cake was washed with ethanol to obtain 21.0 g of a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.77 (s, 1H), 7.91 (d, J = 6.8 Hz, 1H), 7.25 (t, J = 8.0 Hz, 2H), 6.97-6.96 (m, 3H), 6.78 (dd, J1= 17.6 Hz, J2= (11.2 Hz, 1H), 5.91 (d, J = 17.6 Hz, 1H), 5.46 (d, J = 11.6 Hz, 1H), 3.78 (s, 3H). + = 290.1.

[0086] (Step 3: Preparation of 3,4-difluoro-2-(phenylamino)-5-formylmethyl benzoate) 3,4-Difluoro-2-(phenylamino)-5-vinylmethyl benzoate (20.8 g) and tetrahydrofuran (312 mL) were added to a 1 L three-necked flask and stirred in an ice bath until a clear solution was obtained. Potassium osmate dihydrate (1.3 g) was added to this system and the mixture was reacted by continuing to stir in an ice bath. After 15 minutes, water (312 mL), sodium periodate (46.2 g), and 2,6-dimethylpyridine (7.7 g) were added to this system and the mixture was heated to room temperature and reacted by stirring for 4 hours. This reaction system was poured into a saturated sodium sulfite aqueous solution and extracted with ethyl acetate. The organic phases were combined, washed twice with saturated brine, and concentrated to obtain 20.0 g of a yellow solid. ESI-MS: [M+H] + = 292.1.

[0087] (Step 4: Preparation of (E)-3,4-difluoro-2-(phenylamino)-5-((2-p-toluenesulfonylhydrazinyl)methyl)benzoate) 3,4-Difluoro-2-(phenylamino)-5-formylmethyl benzoate (20.0 g), p-toluenesulfonyl hydrazide (12.8 g), and ethanol (600 mL) were added to a 2 L three-necked flask, and the system was heated to 50 °C and reacted for 15 hours. The system was cooled to 0 °C in an ice bath to precipitate a large amount of solid, which was then subjected to suction filtration. The filtered cake was washed with 50 mL of ethanol to obtain 26.0 g of an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.71 (s, 1H), 8.98 (s, 1H), 8.00-7.97 (m, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.26 (t, J = 8.0 Hz, 2H), 6.99-6.98 (m, 3H), 3.80 (s, 3H), 2.38 (s, 3H). ESI-MS: [M+H] + = 460.1.

[0088] (Step 5: Preparation of 5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-(phenylamino)benzoate methyl) (2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)boronic acid (6.9 g), (E)-3,4-difluoro-2-(phenylamino)-5-((2-p-toluenesulfonylhydrazinyl)methyl)methyl benzoate (8.0 g), potassium carbonate (3.6 g), and toluene (320 mL) were added to a 1 L necked flask, and the system was subjected to nitrogen purging. The system was heated to 100 °C and reacted for 5 hours. After cooling to room temperature, saturated ammonium chloride aqueous solution was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent, yielding 4.7 g of pale yellow liquid. ESI-MS: [M+H]+ = 538.2.

[0089] (Step 6: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-(phenylamino)benzoate methyl) 5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-(phenylamino)benzoate methyl (4.7 g) and dichloromethane (220 mL) were added to a 500 mL necked flask, and the mixture was stirred at room temperature until a clear solution was obtained. Then, the system was placed in an ice bath, and trifluoroacetic acid (110 mL) was slowly added. After the addition was complete, the system was heated to room temperature and stirred for 1.5 hours to allow the reaction to proceed. Slowly, saturated sodium carbonate aqueous solution was added to adjust the pH to 8, and the mixture was extracted using dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. The crude product was then purified by silica gel column chromatography to obtain 1.8 g of a yellow solid.

[0090] (Step 7: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-(phenylamino)benzoate) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-(phenylamino)benzoate methyl (1.8 g), tetrahydrofuran (40 mL), and water (40 mL) were sequentially added to a 500 mL necked flask, and the system was stirred in an ice bath. Lithium hydroxide monohydrate (586 mg) was slowly added to the system. After the addition was complete, the system was heated to room temperature and stirred for 2 hours to allow the reaction to proceed. Subsequently, hydrochloric acid aqueous solution (6 M, 20 mL) was added to adjust the pH of the system to 1-2, and after stirring for 5 minutes, the system was concentrated under reduced pressure to remove the tetrahydrofuran. Then, water was added to the system to dilute the concentrate, and after stirring for 10 minutes, it was filtered. The filtered cake was collected and washed with an acetone / n-hexane mixed solvent to obtain 1.4 g of a pale yellow solid.

[0091] [Preparation of Intermediate 4] [ka]

[0092] (Step 1: Preparation of 3,4-difluoro-2-(2-fluoro-4-methoxyphenylamino)-5-vinylbenzoic acid) 10.0 g of 2,3,4-trifluoro-5-vinylbenzoic acid, 7.0 g of 2-fluoro-4-methoxyaniline, and 250 mL of tetrahydrofuran were added to a 1 L three-necked flask. The system was then subjected to nitrogen purging and cooled to -15°C to -20°C. 150 mL of lithium bis(trimethylsilyl)amide (1 M) was slowly added dropwise to the system, ensuring the temperature did not exceed -15°C. After the addition was complete, the temperature of the system was slowly raised to room temperature, and 1.5 M of sodium bisulfate solution was added to adjust the pH of the system to 1-2. The mixture was extracted using methyl tert-butyl ether. The organic phases were combined, washed with 1 L of saturated brine, dried, and concentrated to obtain 15.1 g of a yellow solid. ESI-MS: [MH] - = 322.1.

[0093] (Step 2: Preparation of methyl 3,4-difluoro-2-(2-fluoro-4-methoxyphenylamino)-5-vinylbenzoate) 3,4-Difluoro-2-(2-fluoro-4-methoxyphenylamino)-5-vinylbenzoic acid (16.2 g) and N,N-dimethylformamide (160 mL) were added to a 1 L three-necked flask, and the system was stirred at room temperature until a clear solution was obtained. Potassium carbonate (8.3 g) and methyl iodide (8.5 g) were added to the system. The system was then reacted at 35 °C for 4 hours. The suspension 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 mixture was stirred for 1 hour, and then subjected to suction filtration. The filtration cake was washed with n-heptane to obtain 16.1 g of a pale yellow solid. ESI-MS: [M+H] + = 338.1.

[0094] (Step 3: Preparation of 3,4-difluoro-2-((2-fluoro-4-methoxyphenyl)amino)-5-formylmethyl benzoate) 3,4-Difluoro-2-(2-fluoro-4-methoxyphenylamino)-5-vinylmethyl benzoate (15.8 g) and tetrahydrofuran (314 mL) were added to a 500 mL three-necked flask and stirred in an ice bath until a clear solution was obtained. Potassium osmate dihydrate (0.86 g) was added to the system and the mixture was continued to react while stirring in an ice bath. After 15 minutes, water (312 mL), sodium periodate (30.0 g), and 2,6-dimethylpyridine (5.1 g) were added to the system and the system was heated to room temperature and stirred for 4 hours. This reaction system was poured into a saturated sodium sulfite aqueous solution and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and concentrated. The concentrate was diluted with acetone. Water was slowly added dropwise to the system, the mixture was stirred, and the solution was subjected to suction filtration. The filtration cake was dried to obtain 12.7 g of a pale yellow solid.

[0095] (Step 4: Preparation of (E)-3,4-difluoro-2-((2-fluoro-4-methoxyphenyl)amino)-5-((2-p-toluenesulfonylhydrazinyl)methyl)benzoate) 3,4-Difluoro-2-((2-fluoro-4-methoxyphenyl)amino)-5-formylmethyl benzoate (4.0 g), p-toluenesulfonyl hydrazide (2.2 g), and ethanol (120 mL) were added to a 500 mL three-necked flask, and the system was heated to 60 °C and reacted for 1 hour. The system was cooled to 0 °C in an ice bath to precipitate a large amount of solid, which was then subjected to suction filtration. The filtration cake was washed with ethanol to obtain 5.1 g of a pale yellow solid. ESI-MS: [M+H] + = 508.1.

[0096] (Step 5: Preparation of 5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methoxyphenyl)amino)methyl benzoate) (2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)boronic acid (3.6 g), (E)-3,4-difluoro-2-((2-fluoro-4-methoxyphenyl)amino)-5-((2-p-toluenesulfonylhydrazinyl)methyl)methyl benzoate (5.0 g), potassium carbonate (1.63 g), and toluene (150 mL) were added to a 500 mL necked flask, and the system was subjected to nitrogen purging. The system was heated to 105 °C and reacted for 3 hours. After cooling to room temperature, saturated ammonium chloride aqueous solution was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. The crude product was purified by silica gel column chromatography to obtain 4.4 g of a pale yellow liquid. ESI-MS: [M+H] + = 586.2.

[0097] (Step 6: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methoxyphenyl)amino)methyl benzoate) 5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methoxyphenyl)amino)methyl benzoate (4.4 g) and dichloromethane (27 mL) were added to a 500 mL necked flask and stirred at room temperature until a clear solution was obtained. Then, the system was placed in an ice bath and trifluoroacetic acid (9.1 mL) was added. After the addition was complete, the system was heated to room temperature and stirred for 1.5 hours to allow the reaction to proceed. A saturated sodium carbonate aqueous solution was added to the system to adjust the pH to 8, and the mixture was extracted using dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent, yielding 3.1 g of a pale yellow solid. ESI-MS: [M+H] + = 436.1.

[0098] (Step 7: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methoxyphenyl)amino)benzoate) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methoxyphenyl)amino)methyl benzoate (3.0 g), acetonitrile (18 mL), and ethanol (12 mL) were sequentially added to a 50 mL necked flask, and the system was stirred in an ice bath. An aqueous solution of lithium hydroxide monohydrate (870 mg) (18 mL) was slowly added dropwise to the system. After the addition was complete, the system was heated to room temperature and stirred for 2.5 hours to allow the reaction to proceed. Subsequently, an aqueous solution of sodium bisulfate (1.5 M) was added to adjust the pH to 1-2, the mixture was stirred for 5 minutes, and then filtered. The filtered cake was collected and washed once with water and once with methyl tert-butyl ether to obtain 2.7 g of an off-white solid. ESI-MS: [M+H] + = 422.1.

[0099] [Preparation of Intermediate 5] [ka]

[0100] (Step 1: Preparation of 3-bromo-2-fluoro-N-(2,3,4-trimethoxybenzyl)aniline) 3-Bromo-2-fluoroaniline (10.1 g), 2,3,4-trimethoxybenzaldehyde (10.0 g), and toluene (200 mL) were added to a 250 mL necked flask. The system was heated under reflux and stirred for 2 hours. Heating was stopped, and the system was cooled to room temperature. The system was concentrated and diluted with 150 mL of 1,2-dichloroethane. 3 mL of acetic acid and sodium triacetoxyborohydride (21.0 g) were added to the system, and the mixture was stirred at room temperature for 12 hours. The system was poured into water and extracted with dichloromethane. The organic phases were combined, dried, and concentrated to obtain 17.0 g of a brown solid.

[0101] (Step 2: Preparation of 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(2,3,4-trimethoxybenzyl)aniline) 5.2 g of 3-bromo-2-fluoro-N-(2,3,4-trimethoxybenzyl)aniline, 7.2 g of bis(pinacolate)diborone, 4.0 g of potassium pivalate, 125 mL of toluene, 2.2 g of dimethyl sulfoxide, and 1.0 g of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium were added to a 250 mL necked flask, and the system was subjected to nitrogen purging. The system was then heated to 55 °C and reacted for 19 hours. After cooling to room temperature, the system 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 diatomaceous earth. The filtrate was concentrated to obtain 4.7 g of a yellow solid.

[0102] (Step 3: Preparation of (2-fluoro-3-((2,3,4-trimethoxybenzyl)amino)phenyl)boronic acid) 4.7 g of 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(2,3,4-trimethoxybenzyl)aniline and 100 mL of tetrahydrofuran were added to a 250 mL necked flask and stirred until a clear solution was obtained. 50 mL of 1 M aqueous hydrochloric acid was slowly added to the system, and the mixture was stirred at room temperature for 1 hour. 2.4 g of methylboronic acid was added to the system, and the mixture was stirred at room temperature for 24 hours. The system was then extracted using petroleum ether. The organic phases were combined, dried, and concentrated to obtain 1.1 g of a pale yellow solid. ESI-MS: [M+H] + = 336.1.

[0103] (Step 4: Preparation of 3,4-difluoro-5-(2-fluoro-3-((2,3,4-trimethoxybenzyl)amino)benzyl)-2-((2-fluoro-4-iodophenyl)amino)methyl benzoate) (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-p-toluenesulfonylhydrazinyl)methyl)methyl benzoate (2.4 g), potassium carbonate (540 mg), and toluene (440 mL) were added to a 100 mL necked flask, and the system was subjected to nitrogen purging. The system was heated to 100 °C and reacted for 5 hours. After cooling to room temperature, saturated ammonium chloride aqueous solution was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. The crude product was purified by silica gel column chromatography to obtain 1.1 g of a pale yellow liquid. ESI-MS: [M+H] + = 711.1.

[0104] (Step 5: Preparation of 5-(3-amino-2-fluorobenzyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)methyl benzoate) 3,4-Difluoro-5-(2-Fluoro-3-((2,3,4-trimethoxybenzyl)amino)benzyl)-2-((2-fluoro-4-iodophenyl)amino)methyl benzoate (1.9 g) and dichloromethane (30 mL) were added to a 100 mL necked flask and stirred at room temperature until a clear solution was obtained. The system was then placed in an ice bath and trifluoroacetic acid (30 mL) was slowly added. After the addition was complete, 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 mixture was heated to 40°C and stirred for 24 hours. The system was concentrated, the concentrate was diluted with saturated sodium carbonate aqueous solution, the pH was adjusted to 8, and then 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 pale yellow solid. ESI-MS: [M+H] + = 531.0.

[0105] (Step 6: Preparation of 5-(3-amino-2-fluorobenzyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate) 670 mg of methyl 5-(3-amino-2-fluorobenzyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate, 20 mL of tetrahydrofuran, and 10 mL of water were sequentially added to a 100 mL necked flask. The system was placed in an ice bath and stirred. 160 g of lithium hydroxide monohydrate was slowly added to the system. After the addition was complete, the system was heated to room temperature and stirred for 13 hours. Subsequently, 2 M hydrochloric acid solution was added to the system to adjust the pH to 1-2. After stirring for 5 minutes, the system was concentrated under reduced pressure to remove the tetrahydrofuran. Then, water was added to the system to dilute the concentrate, stirred for 10 minutes, and filtered to obtain 630 mg of a pale yellow solid. ESI-MS: [M+H] + = 517.0.

[0106] [Preparation of Intermediate 6] [ka]

[0107] (Preparation of N-ethyl-2-oxoxazoline-3-sulfonamide) In an ice bath, 120 mL of acetonitrile and chlorosulfonyl isocyanate (3.2 g) were added to a 500 mL necked flask. Subsequently, 2-bromoethanol (2.8 g) was slowly added to the system. The system was reacted in an ice bath with stirring for 30 minutes, then heated to room temperature and stirred for 1 hour. Next, N-methylmorpholine (15.1 g) was slowly added to the system, and the mixture was stirred for 10 minutes, after which ethylamine hydrochloride (1.8 g) was slowly added to the system. After the addition was complete, the system was heated to 50°C and stirred for 5 hours. Then, the system was gradually cooled to room temperature and stirred for another 15 hours, after which it was subjected to suction filtration and the filtrate was concentrated. The concentrate was diluted with ethyl acetate and 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 (400 MHz, 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).

[0108] [Preparation of Intermediate 7] [ka]

[0109] (Preparation of N-cyclopropyl-2-oxoxazoline-3-sulfonamide) 500 mL of acetonitrile and 11.6 g of chlorosulfonyl isocyanate were added to a 1 L necked flask in an ice bath. Subsequently, 10.3 g of 2-bromoethanol was slowly added to the system. The system was kept in the ice bath and stirred for 30 minutes. Then, it was heated to room temperature and stirred for 1 hour. Next, 50.0 g of N-methylmorpholine was slowly added to the system and the mixture was stirred for 10 minutes. Then, 4.7 g of cyclopropylamine was slowly added to the system. After the addition was complete, the system was heated to 50°C and stirred for 5 hours. Then, the system was gradually cooled to room temperature and stirred for 15 hours. After that, it was subjected to suction filtration, and the filtrate was concentrated to obtain a pale orange solid. Most of the solid was dissolved in ethyl acetate and washed with saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent and obtain the crude product. The crude product was washed with methyl tert-butyl ether to obtain 4.4 g of an off-white solid. 1 H NMR (400 MHz, 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).

[0110] [Preparation of Intermediate 8] [ka]

[0111] (Preparation of N-methyl-d3-2-oxoxazoline-3-sulfonamide) 720 mL of acetonitrile and 20.6 g of chlorosulfonyl isocyanate were added to a 2 L necked flask in an ice bath. Subsequently, 18.2 g of 2-bromoethanol was slowly added to the system. The system was kept in the ice bath and stirred for 30 minutes. Then, it was heated to room temperature and stirred for 1 hour. Next, 58.4 g of N-methylmorpholine was slowly added to the system and the mixture was stirred for 10 minutes. Subsequently, 10.2 g of deuterated methylamine hydrochloride was slowly added to the system. After the addition was complete, the system was heated to 50°C and stirred for 5 hours. Then, the system was gradually cooled to room temperature and stirred for 15 hours, after which it was subjected to suction filtration and the filtrate was concentrated. The concentrate was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed by rotary evaporation, yielding 11.9 g of a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6, δ): 8.17 (s, 1H), 4.42-4.38 (m, 2H), 3.96-3.93 (m, 2H).

[0112] [Preparation of compounds] [Example 1] [ka]

[0113] (Step 1: Preparation of N-allyl-5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate (1.1 g), 1-hydroxybenzotriazole (646 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (763 mg), and N,N-dimethylformamide (11 mL) were added to a 100 mL necked flask and stirred at room temperature for 2 hours. Subsequently, allylamine hydrochloride (560 mg) and N,N-diisopropylethylamine (1.0 g) were added to the system, and the mixture was stirred at room temperature for 2 hours. This reaction system was added to saturated sodium bicarbonate aqueous solution to precipitate a solid, and the mixture was subjected to suction filtration. The filtration cake was purified by silica gel column chromatography to obtain 300 mg of a pale yellow solid. ESI-MS: [M+H] + = 557.1.

[0114] (Step 2: Preparation of N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)benzamide) N-allyl-5-((2-amino-3-fluoropyridine-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 to a 50 mL necked flask, and the system was stirred in an ice bath. After cooling to below 0°C, methylaminosulfonyl chloride (210 mg) was slowly added dropwise to the system. After 30 minutes, the reaction was stopped, and the system was poured into a saturated sodium bicarbonate aqueous solution, stirred at room temperature for 10 minutes, and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. The crude product was purified by silica gel column chromatography to obtain 100 mg of an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.40 (s, 1H), 9.05 (s, 1H), 8.87 (t, J = 5.6 Hz, 1H), 8.02 (d, J = 4.8 Hz, 1H), 7.59-7.57 (m, 2H), 7.36 (d, J = 8.4 Hz, 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 = 5.2 Hz, 2H), 2.53-2.51 (m, 3H). ESI-MS: [M+H] + = 650.0.

[0115] [Example 2] [ka]

[0116] (Step 1: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-N-(buta-3-en-1-yl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate (300 mg), 1-hydroxybenzotriazole (149 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (414 mg), and N,N-dimethylformamide (5 mL) were added to a 100 mL necked flask, and the system was stirred at room temperature for 2 hours. Subsequently, buta-3-en-1-amine hydrochloride (117 mg) and N,N-diisopropylethylamine (348 mg) were added to the system, and the mixture was stirred at room temperature for 2 hours. This reaction system was added to a saturated sodium bicarbonate aqueous solution to precipitate a solid, which was then subjected to suction filtration. The filtration cake was purified by silica gel column chromatography to obtain 148 mg of an off-white solid. ESI-MS: [M+H] + = 571.2.

[0117] (Step 2: Preparation of N-(buta-3-en-1-yl)-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)benzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-N-(buta-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 to a 50 mL necked flask, and the system was stirred in an ice bath. After cooling to below 0°C, methylaminosulfonyl chloride (326 mg) was slowly added dropwise to the system. After 30 minutes, the reaction was stopped, and the system was poured into a saturated sodium bicarbonate aqueous solution, stirred at room temperature for 10 minutes, and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. The crude product was purified by silica gel column chromatography to obtain 70 mg of an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1H), 9.00 (s, 1H), 8.69 (t, J = 5.6 Hz, 1H), 8.02 (d, J = 5.2 Hz, 1H), 7.60-7.57 (m, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.05-7.01 (m, 1H), 6.93 (t, J = 4.4 Hz, 1H), 7.00-6.64 (m, 1H), 5.81-5.71 (m, 1H), 5.04-4.94 (m, 2H), 4.07 (s, 2H), 3.25 (q, J = 6.4 Hz, 2H), 2.52-2.51 (m, 3H), 2.21 (q, J = 6.8 Hz, 2H). ESI-MS: [M+H] + = 664.2.

[0118] [Example 3] [ka]

[0119] (Step 1: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(penta-4-en-1-yl)benzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate (400 g), 1-hydroxybenzotriazole (105 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (177 mg), and N,N-dimethylformamide (15 mL) were added to a 100 mL necked flask, and the system was stirred at room temperature and reacted for 2 hours. Subsequently, 4-penten-1-amine hydrochloride (113 mg) and N,N-diisopropylethylamine (250 g) were added to the system, and the mixture was stirred at room temperature and reacted for 2 hours. This reaction system was added to a saturated sodium bicarbonate aqueous solution to precipitate a solid, which was then subjected to suction filtration to obtain 400 mg of a pale yellow solid. ESI-MS: [M+H] + = 585.3.

[0120] (Step 2: Preparation of 3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)-N-(penta-4-en-1-yl)benzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(penta-4-en-1-yl)benzamide (400 mg), N,N-dimethylformamide (4 mL), dichloromethane (4 mL), and pyridine (270 mg) were added to a 50 mL necked flask, and the system was stirred in an ice bath. After cooling to below 0°C, methylaminosulfonyl chloride (355 mg) was slowly added dropwise to the system. After the addition was complete, the reaction was continued for 30 minutes and then stopped. The system was poured into a saturated sodium bicarbonate aqueous solution, stirred at room temperature for 10 minutes, and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. The crude product was purified by silica gel column chromatography to obtain 110 mg of an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.41 (s, 1H), 9.02 (s, 1H), 8.67 (t, J = 5.2 Hz, 1H), 8.02 (d, J = 4.8 Hz, 1H), 7.58 (dd, J1= 10.8 Hz, J2= 1.6 Hz, 1H), 7.52 (d, J = 6.8 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.03 (q, J = 5.2 Hz, 1H), 6.93 (t, J = 4.8 Hz, 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 = 6.4 Hz, 2H), 2.52-2.51 (m, 3H), 2.01 (q, J = 7.2 Hz, 2H), 1.57-1.50 (m, 2H). ESI-MS: [M+H] + = 678.3.

[0121] [Example 4] [ka]

[0122] (Step 1: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(3-methylbuta-2-en-1-yl)benzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate (400 mg), 3-methylbuta-2-en-1-amine (63 mg), N,N-diisopropylethylamine (373 mg), and N,N-dimethylformamide (8 mL) were added to a 100 mL necked flask and 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 mixture was stirred at room temperature for 1.5 hours. This reaction system was added to saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. 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.

[0123] (Step 2: Preparation of 3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)-N-(3-methylbuta-2-en-1-yl)benzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(3-methylbuta-2-en-1-yl)benzamide (310 mg), N,N-dimethylformamide (6 mL), and pyridine (335 mg) were added to a 50 mL necked flask, and the system was stirred in an ice bath. After cooling to below 0°C, methylaminosulfonyl chloride (272 mg) was slowly added dropwise to the system. After 30 minutes, the reaction was stopped, and the system was poured into a saturated sodium bicarbonate aqueous solution, stirred at room temperature for 10 minutes, and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. The crude product was purified by silica gel column chromatography to obtain 200 mg of an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.41 (s, 1H), 9.11 (s, 1H), 8.74 (t, J = 5.2 Hz, 1H), 8.20 (d, J = 4.8 Hz, 1H), 7.59 (dd, J1= 10.8 Hz, J2= 2.0 Hz, 1H), 7.54 (d, J = 6.8 Hz, 1H), 7.36 (d, J = 5.2 Hz, 1H), 7.03 (d, J = 4.8 Hz, 1H), 6.93 (s, 1H), 6.70-6.65 (m, 1H), 5.14 (t, J = 6.8 Hz, 1H), 4.07 (s, 2H), 3.79 (t, J = 6.0 Hz, 2H), 2.52-2.51 (m, 3H), 1.67 (s, 3H), 1.63 (s, 3H). ESI-MS: [M+H] + = 678.3.

[0124] [Example 5] [ka]

[0125] (Step 1: Preparation of (R)-5-((2-amino-3-fluoropyridine-4-yl)methyl)-N-(buta-3-en-2-yl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate (500 mg), 1-hydroxybenzotriazole (232 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (641 mg), and N,N-dimethylformamide (20 mL) were added to a 100 mL necked flask, and the system was stirred at room temperature and reacted for 2 hours. Subsequently, (R)-buta-3-en-2-amine hydrochloride (195 mg) and N,N-diisopropylethylamine (350 mg) were added to the system, and the mixture was stirred at room temperature and reacted for 2 hours. This reaction system was added to a saturated sodium bicarbonate aqueous solution to precipitate a solid, which was then subjected to suction filtration. The filtration cake was purified by silica gel column chromatography to obtain 340 mg of a pale yellow solid. ESI-MS: [M+H] + = 571.2.

[0126] (Step 2: Preparation of (R)-N-(buta-3-en-2-yl)-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)benzamide) (R)-5-((2-amino-3-fluoropyridine-4-yl)methyl)-N-(buta-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 to a 50 mL necked flask, and the system was stirred in an ice bath. After cooling to below 0°C, methylaminosulfonyl chloride (225 mg) was slowly added dropwise to the system. The reaction was stopped 30 minutes after the end of the addition, and the system was poured into a saturated sodium bicarbonate aqueous solution, stirred at room temperature for 10 minutes, and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. The crude product was purified by silica gel column chromatography to obtain 320 mg of an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.41 (s, 1H), 8.95 (s, 1H), 8.64 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 5.2 Hz, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.8 Hz, 1H), 7.02 (q, J = 5.2 Hz, 1H), 6.93 (t, J = 4.8 Hz, 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 = 6.8 Hz, 3H). ESI-MS: [M+H] + = 664.2.

[0127] [Example 6] [ka]

[0128] (Step 1: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-methylallyl)benzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate (400 mg), 1-hydroxybenzotriazole (195 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (552 mg), and N,N-dimethylformamide (5 mL) were added to a 100 mL necked flask, and the system was stirred at room temperature for 2 hours. Subsequently, 2-methylpropa-2-en-1-amine (102 mg) and N,N-diisopropylethylamine (464 mg) were added to the system, and the system was stirred at room temperature for 2 hours. This reaction system was added to a saturated sodium bicarbonate aqueous solution to precipitate a solid, which was then subjected to suction filtration. The filtration cake was purified by silica gel column chromatography to obtain 200 mg of a white solid. ESI-MS: [M+H] + = 571.1.

[0129] (Step 2: Preparation of 3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)-N-(2-methylallyl)benzamide) 5-((2-amino-3-fluoropyridine-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 to a 50 mL necked flask, and the system was stirred in an ice bath. After cooling to below 0°C, methylaminosulfonyl chloride (208 mg) was slowly added dropwise to the system. After 30 minutes, the reaction was stopped, and the system was poured into a saturated sodium bicarbonate aqueous solution, stirred at room temperature for 10 minutes, and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. The crude product was purified by silica gel column chromatography to obtain 170 mg of an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1H), 9.00 (s, 1H), 8.92 (t, J = 5.6 Hz, 1H), 8.02 (d, J = 4.8 Hz, 1H), 7.60-7.57 (m, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.06-7.02 (m, 1H), 6.95 (t, J = 4.8 Hz, 1H), 6.71-6.65 (m, 1H), 4.78 (s, 2H), 4.08 (s, 2H), 3.76 (d, J = 5.6 Hz, 2H), 2.51-2.50 (m, 3H), 1.67 (s, 3H). ESI-MS: [M+H] + = 664.0.

[0130] [Example 7] [ka]

[0131] (Step 1: Preparation of ethyl 3-(trimethylsilyl)propionate) 1000 mL of dichloromethane, trimethylsilyltrifluoromethanesulfonate (271.8 g), triethylamine (123.7 g), and silver trifluoromethanesulfonate (10 g) were added to a 3 L reaction flask. A solution of ethyl propioate (100 g) in dichloromethane (100 mL) was slowly added dropwise to this system. After the addition was complete, the system was stirred at room temperature for 30 minutes and concentrated under reduced pressure to remove the dichloromethane. The concentrated residue was extracted twice with n-hexane. The n-hexane extracts were combined and washed twice with saturated ammonium chloride solution. The n-hexane phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a pale yellow liquid.

[0132] (Step 2: Preparation of 3-(trimethylsilyl)propa-2-in-1,1-d2-1-ol) Ethyl 3-(trimethylsilyl)propionate (50 g), ether (500 mL), sodium boron deuterate (17.3 g), lithium chloride (17.4 g), and heavy water (8.2 g) were added to a 1000 mL three-necked flask. After the addition was complete, the system was stirred at room temperature for 40 minutes, then heated to 33 °C and reacted for 8 hours. This reaction system was slowly added to a 10% aqueous acetic acid solution, extracted with n-hexane, and then subjected to liquid-liquid separation. The aqueous layer was extracted with n-hexane. The organic phases were combined, washed with 1 N hydrochloric acid solution, washed until neutral, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a pale yellow liquid. 1 H NMR (400 MHz, DMSO-d6): δ 5.20 (brs, 1H), 0.13 (s, 9H).

[0133] (Step 3: Preparation of (3-bromopropa-1-in-1-yl-3,3-d2)trimethylsilane) 6.0 g of 3-(trimethylsilyl)propa-2-in-1,1-d2-1-ol and 75 mL of dichloromethane were added to a 100 mL necked flask, and the system was cooled to -10°C. Subsequently, 30.0 g of phosphorus tribromide was added dropwise to the system. After the addition was complete, the system was heated to room temperature and reacted for 1 hour. The system was poured onto ice, saturated sodium bicarbonate solution was added to adjust the pH to neutral, and the mixture was extracted using dichloromethane. The organic phases were combined, dried, and concentrated to obtain 5.1 g of a colorless, transparent liquid.

[0134] (Step 4: Preparation of 2-(3-(trimethylsilyl)propa-2-in-1-yl-1,1-d2)isoindoline-1,3-dione) (3-bromopropa-1-in-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) were added to a 250 mL necked flask, and the system was stirred at room temperature and reacted for 16 hours. The system was poured into water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 12.0 g of an off-white solid.

[0135] (Step 5: Preparation of 2-(propa-2-in-1-yl-1,1-d2)isoindoline-1,3-dione) 2-(3-(trimethylsilyl)propa-2-in-1-yl-1,1-d2)isoindorin-1,3-dione (3.4 g), tetrahydrofuran (15 mL), and tetra-n-butylammonium fluoride trihydrate (10.8 g) were added to a 250 mL necked flask and stirred, reacting at room temperature for 10 minutes. This system was poured into water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 900 mg of an off-white solid.

[0136] (Step 6: Preparation of 2-(allyl-1,1-d2)isoindoline-1,3-dione) 1.8 g of 2-(propa-2-in-1-yl-1,1-d2)isoindorin-1,3-dione, 45 mL of methanol, and 180 mg of Lindler catalyst were added to a 100 mL necked flask. The system was subjected to hydrogen purging, stirred, and reacted at room temperature for 10 minutes, after which it was subjected to suction filtration. The filtrate was collected and concentrated to obtain 1.0 g of an off-white solid.

[0137] (Step 7: Preparation of propa-2-ene-1,1-d2-1-amine hydrochloride) 1.0 g of 2-(allyl-1,1-d2)isoindoline-1,3-dione and 30 mL of concentrated hydrochloric acid were added to a 100 mL necked flask and reacted with stirring at 100°C for 19 hours, after which the mixture was subjected to suction filtration. The filtrate was collected and washed with diethyl ether. The aqueous phase was collected, concentrated and dried to obtain 325 mg of an off-white solid.

[0138] (Step 8: Preparation of N-(allyl-1,1-d2)-5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate (700 mg), 1-hydroxybenzotriazole (205 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (483 mg), and N,N-dimethylformamide (10 mL) were added to a 100 mL necked flask and reacted with stirring at room temperature for 2 hours. Subsequently, propa-2-en-1,1-d2-1-amine hydrochloride (325 mg) and N,N-diisopropylethylamine (325 mg) were added to this system, and the mixture was reacted with continued stirring at room temperature for 2 hours. This reaction system was added to saturated saline to precipitate a solid, which was then subjected to suction filtration. The filtration cake was purified by silica gel column chromatography to obtain 500 mg of a yellow solid. ESI-MS: [M+H] + = 559.1.

[0139] (Step 9: Preparation of N-(allyl-1,1-d2)-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)benzamide) N-(allyl-1,1-d2)-5-((2-amino-3-fluoropyridine-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 to a 50 mL necked flask, and the system was stirred in an ice bath. After cooling to below 0°C, methylaminosulfonyl chloride (175 mg) was slowly added dropwise to the system. After the addition was complete, the reaction was continued for 30 minutes and then stopped. The system was poured into saturated saline solution, stirred at room temperature for 10 minutes, and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. Subsequently, the crude product was purified by silica gel column chromatography to obtain 180 mg of an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1H), 9.06 (s, 1H), 8.88 (s, 1H), 8.02 (d, J = 5.2 Hz, 1H), 7.60-7.57 (m, 2H), 7.36 (d, J = 8.8 Hz, 1H), 7.03 (q, J = 4.8 Hz, 1H), 6.95 (t, J = 4.8 Hz, 1H), 6.72-6.66 (m, 1H), 5.81 (dd, J1= 17.2 Hz, J2= 10.4 Hz, 1H), 5.18-5.06 (m, 2H), 4.07 (s, 2H), 2.52-2.51 (m, 3H). ESI-MS: [M+H] + = 652.1.

[0140] [Example 8] [ka]

[0141] (Preparation of N-allyl-5-((2-((N-ethylaminosulfonyl)amino)-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide) N-ethyl-2-oxoxazoline-3-sulfonamide (1.1 g), N-allyl-5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (350 mg), triethylamine (699 mg), and 1,2-dichloroethane (20 mL) were added to a 100 mL necked flask. The reaction system was heated to 80 °C and reacted for 5.5 hours. After cooling to room temperature, the system was poured into a water / tetrahydrofuran mixed solvent 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 mixed solvent (4 / 1, v / v) to obtain 110 mg of an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.40 (s, 1H), 9.05 (s, 1H), 8.89 (t, J = 5.6 Hz, 1H), 8.03 (d, J = 5.2 Hz, 1H), 7.60-7.56 (m, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.17 (t, J = 5.6 Hz, 1H), 6.93 (t, J = 4.8 Hz, 1H), 6.72-6.66 (m, 1H), 5.87-5.77 (m, 1H), 5.17-5.06 (m, 2H), 4.07 (s, 2H), 3.84 (t, J = 5.2 Hz, 2H), 2.96-2.90 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H). ESI-MS: [M+H] + = 664.2.

[0142] [Example 9] [ka]

[0143] (Preparation of N-allyl-5-((2-((N-cyclopropylaminosulfonyl)amino)-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide) N-cyclopropyl-2-oxoxazoline-3-sulfonamide (1.5 g), N-allyl-5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (400 mg), triethylamine (729 mg), and 1,2-dichloroethane (20 mL) were added to a 100 mL necked flask. The reaction system was heated to 80 °C and reacted for 5.5 hours. After cooling to room temperature, the system was poured into a water / tetrahydrofuran mixed solvent 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 n-hexane / acetone mixed solvent to obtain 150 mg of an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1H), 9.05 (s, 1H), 8.89 (t, J = 5.6 Hz, 1H), 8.03 (d, J = 5.2 Hz, 1H), 7.61-7.56 (m, 3H), 7.36 (d, J = 8.4 Hz, 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 = 5.2 Hz, 2H), 2.32-2.30 (m, 1H), 0.56-0.47 (m, 4H). ESI-MS: [M+H] + = 676.1.

[0144] [Example 10] [ka]

[0145] (Preparation of N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methyl-d3-aminosulfonyl)amino)pyridine-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)benzamide) N-methyl-d3-2-oxoxazoline-3-sulfonamide (1.0 g), N-allyl-5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (310 mg), triethylamine (621 mg), and 1,2-dichloroethane (30 mL) were added to a 100 mL necked flask. The reaction system was heated to 80 °C and reacted for 5.5 hours. After cooling to room temperature, the system was poured into a water / tetrahydrofuran mixed solvent 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 an n-hexane / acetone mixed solvent to obtain 110 mg of an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.41 (s, 1H), 9.05 (s, 1H), 8.89 (t, J = 5.6 Hz, 1H), 8.02 (d, J = 5.2 Hz, 1H), 7.60-7.57 (m, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.00 (s, 1H), 6.94 (t, J = 4.8 Hz, 1H), 6.72-6.66 (m, 1H), 5.87-5.77 (m, 1H), 5.17-5.06 (m, 2H), 4.07 (s, 2H), 3.84 (t, J = 5.2 Hz, 2H). ESI-MS: [M+H] + = 653.2.

[0146] [Example 11] [ka]

[0147] (Step 1: Preparation of 5-((3-amino-2-fluorobenzyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-allylbenzamide) 5-(3-amino-2-fluorobenzyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate (310 mg), 1-hydroxybenzotriazole (170 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (322 mg), and N,N-dimethylformamide (6 mL) were added to a 100 mL necked flask, and the system was stirred at room temperature and reacted for 2 hours. Subsequently, allylamine hydrochloride (93 mg) and N,N-diisopropylethylamine (217 mg) were added to the system, and the mixture was stirred at room temperature and reacted for another 2 hours. This reaction system was added to a saturated sodium bicarbonate aqueous solution to precipitate a solid, which was then subjected to suction filtration. The filtration cake was purified by silica gel column chromatography to obtain 220 mg of an off-white solid. ESI-MS: [M+H] + = 556.0.

[0148] (Step 2: Preparation of N-allyl-3,4-difluoro-5-(2-fluoro-3-((N-methylaminosulfonyl)amino)benzyl)-2-((2-fluoro-4-iodophenyl)amino)benzamide) 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 to a 50 mL necked flask, and the system was stirred in an ice bath. After cooling to below 0°C, methylaminosulfonyl chloride (192 mg) was slowly added dropwise. After 30 minutes, the reaction was stopped, and the system was poured into a saturated sodium bicarbonate aqueous solution, stirred at room temperature for 10 minutes, and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. The crude product was purified by silica gel column chromatography to obtain 180 mg of an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H), 8.99 (s, 1H), 8.86 (t, J = 5.6 Hz, 1H), 7.58 (dd, J1= 10.8 Hz, J2= 2.0 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.37-7.31 (m, 2H), 7.25 (q, J = 4.8 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 7.02 (t, J = 6.8 Hz, 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 = 5.4 Hz, 2H), 2.52 (d, J = 4.8 Hz, 3H). ESI-MS: [M+Na] + = 671.0.

[0149] [Example 12] [ka]

[0150] (Step 1: Preparation of N-allyl-5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-(phenylamino)benzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-(phenylamino)benzoate (350 mg), 1-hydroxybenzotriazole (220 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (606 mg), and N,N-dimethylformamide (10 mL) were added to a 100 mL necked flask, and the system was stirred at room temperature and reacted for 2 hours. Subsequently, allylamine hydrochloride (160 mg) and N,N-diisopropylethylamine (331 mg) were added to the system, and the system was stirred at room temperature and reacted for 2 hours. This reaction system was added to a saturated sodium bicarbonate aqueous solution to precipitate a solid, which was then subjected to suction filtration. The filtration cake was purified by silica gel column chromatography to obtain 250 mg of a pale yellow solid.

[0151] (Step 2: Preparation of N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)-2-(phenylamino)benzamide) N-allyl-5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-(phenylamino)benzamide (250 mg), N,N-dimethylformamide (10 mL), and pyridine (480 mg) were added to a 50 mL necked flask, and the system was stirred in an ice bath. After cooling to below 0°C, methylaminosulfonyl chloride (236 mg) was slowly added dropwise to the system. After the addition was complete, the reaction was continued for 30 minutes and then stopped. The system was poured into a saturated sodium bicarbonate aqueous solution, stirred at room temperature for 10 minutes, and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. The crude product was purified by silica gel column chromatography to obtain 165 mg of an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1H), 8.83 (s, 1H), 8.78 (t, J = 5.6 Hz, 1H), 8.02 (d, J = 4.8 Hz, 1H), 7.52 (d, J = 6.8 Hz, 1H), 7.22-7.18 (m, 2H), 7.03 (d, J = 4.8 Hz, 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.

[0152] [Example 13] [ka]

[0153] (Step 1: Preparation of N-allyl-5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)benzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methylphenyl)amino)benzoate (500 mg), 1-hydroxybenzotriazole (344 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (433 mg), and N,N-dimethylformamide (5 mL) were added to a 100 mL necked flask, and the system was stirred and reacted at room temperature for 2 hours. Subsequently, allylamine hydrochloride (317 mg) and N,N-diisopropylethylamine (875 mg) were added to the system, and the mixture was stirred and reacted for 2 hours. This reaction system was added to a saturated sodium bicarbonate aqueous solution to precipitate a solid, which was then subjected to suction filtration. The filtration cake was purified by silica gel column chromatography to obtain 350 mg of a pale yellow solid. ESI-MS: [M+H] + = 445.3.

[0154] (Step 2: Preparation of N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)-2-((2-fluoro-4-methylphenyl)amino)benzamide) N-allyl-5-((2-amino-3-fluoropyridine-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 to a 50 mL necked flask, and the system was stirred in an ice bath. After cooling to 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 sodium bicarbonate aqueous solution, stirred at room temperature for 10 minutes, and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. The crude product was purified by silica gel column chromatography to obtain 180 mg of an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.41 (s, 1H), 9.08 (s, 1H), 8.90 (t, J = 5.6 Hz, 1H), 8.02 (d, J = 4.8 Hz, 1H), 7.58 (d, J = 6.8 Hz, 1H), 7.05-7.02 (m, 2H), 6.93 (t, J = 4.8 Hz, 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 = 5.2 Hz, 2H), 2.52-2.51 (m, 3H), 2.25 (s, 3H). ESI-MS: [M+H] + = 538.3.

[0155] [Example 14] [ka]

[0156] (Step 1: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)methyl benzoate) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)methyl benzoate (1.3 g), potassium vinyltrifluoroborate (636 mg), potassium carbonate (984 mg), 1,4-dioxane (12 mL), water (4 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (86 mg) were added to a 50 mL necked flask. The system was purged with nitrogen, heated to 95 °C, and stirred for 2 hours. After cooling to room temperature, the system was poured into water to stop the reaction, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and subjected to rotary evaporation to remove the solvent, yielding 950 mg of a yellowish-brown solid. ESI-MS: [M+H] + = 432.2.

[0157] (Step 2: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzoate) 950 mg of methyl 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzoate, 20 mL of tetrahydrofuran, and 10 mL of water were added to a 50 mL necked flask and stirred at room temperature until a clear solution was obtained. The system was then placed in an ice bath and lithium hydroxide monohydrate (360 mg) was slowly added. After the addition was complete, the system was heated to room temperature and stirred for 3 hours. Then, 5 mL of hydrochloric acid (6 M) was slowly added dropwise to the system to adjust the pH to 1-2 and stirred for 5 minutes. Tetrahydrofuran was removed from the system under reduced pressure. The concentrate was then diluted with water, the mixture was stirred for 10 minutes, and then filtered. The filtered cake was collected and washed once with water and once with methyl tert-butyl ether to obtain 700 mg of a brown solid. The product from this step was used directly in the next step without further characterization or purification.

[0158] (Step 3: Preparation of N-allyl-5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzoate (300 mg), 1-hydroxybenzotriazole (107 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (253 mg), and N,N-dimethylformamide (5 mL) were added to a 100 mL necked flask, and the system was stirred at room temperature and reacted for 2 hours. Subsequently, allylamine hydrochloride (126 mg) and N,N-diisopropylethylamine (426 mg) were added to the system, and the mixture was stirred at room temperature and reacted for 2 hours. This reaction system was added to a saturated sodium bicarbonate aqueous solution to precipitate a solid, which was then subjected to suction filtration. The filtration cake was purified by silica gel column chromatography to obtain 150 mg of a pale yellow solid. ESI-MS: [M+H] + = 457.3.

[0159] (Step 4: Preparation of N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)-2-((2-fluoro-4-vinylphenyl)amino)benzamide) N-allyl-5-((2-amino-3-fluoropyridine-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 to a 50 mL necked flask, and the system was stirred in an ice bath. After cooling to below 0°C, methylaminosulfonyl chloride (240 mg) was slowly added dropwise to the system. After 30 minutes, the reaction was stopped, and the system was poured into a saturated sodium bicarbonate aqueous solution, stirred at room temperature for 10 minutes, and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. The crude product was purified by silica gel column chromatography to obtain 70 mg of an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1H), 9.13 (s, 1H), 8.91 (t, J = 5.6 Hz, 1H), 8.03 (d, J = 4.8 Hz, 1H), 7.59 (d, J = 6.8 Hz, 1H), 7.39 (dd, J1= 12.8 Hz, J2= 1.2 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.03 (q, J = 5.2 Hz, 1H), 6.95 (t, J = 4.8 Hz, 1H), 6.87-6.82 (m, 1H), 6.64 (dd, J1= 17.6 Hz, J2= 10.8 Hz, 1H), 5.88-5.79 (m, 1H), 5.74 (d, J = 17.6 Hz, 1H), 5.19-5.13 (m, 2H), 5.07 (dd, J1= 10.4 Hz, J2= 5.6 Hz, 1H), 4.08 (s, 2H), 3.85 (t, J = 5.2 Hz, 2H), 2.53-2.51 (m, 3H). ESI-MS: [M+H] += 550.3.

[0160] [Example 15] [ka]

[0161] (Step 1: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-formylphenyl)amino)methyl benzoate) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)methyl 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 to a 100 mL necked flask, and the system was stirred at room temperature and reacted for 2 hours. This reaction system was poured into water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The solvent was removed by rotary evaporation to obtain 950 mg of solid. The solid was diluted with acetic acid (20 mL). Subsequently, iron powder (9.0 g) was added to the system, and the mixture was stirred at room temperature and reacted for 1 hour. 50 mL of ethyl acetate was added to the system, and the mixture was subjected to suction filtration to remove insoluble substances. The filtrate was collected and concentrated. The concentrate was diluted with water, and an aqueous sodium bicarbonate solution was added to adjust the pH of the system to 7-8. Extraction was then performed using ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent and obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 450 mg of a yellow solid. ESI-MS: [M+H] + = 434.1.

[0162] (Step 2: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-formylphenyl)amino)benzoate) 450 mg of methyl 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-formylphenyl)amino)benzoate, 10 mL of tetrahydrofuran, and 5 mL of water were added to a 50 mL necked flask and stirred at room temperature until a clear solution was obtained. 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 heated to room temperature and stirred for 2 hours. Then, hydrochloric acid (6 M, 3 mL) was slowly added dropwise to adjust the pH to 1-2, and the mixture was stirred for 5 minutes. Tetrahydrofuran was removed from the system under reduced pressure. The concentrate was then diluted with water, stirred for 10 minutes, and filtered. The filter cake was collected and washed once with water and once with methyl tert-butyl ether to obtain 390 mg of a pale yellow solid. The product of this step was used directly in the reaction of the next step without further purification or characterization.

[0163] (Step 3: Preparation of N-allyl-5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-formylphenyl)amino)benzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-formylphenyl)amino)benzoate (440 mg), 1-hydroxybenzotriazole (248 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (686 mg), and N,N-dimethylformamide (15 mL) were added to a 100 mL necked flask, and the system was stirred at room temperature and reacted for 2 hours. Subsequently, allylamine hydrochloride (90 mg) and N,N-diisopropylethylamine (374 g) were added to the system, and the mixture was stirred at room temperature and reacted for 2 hours. This reaction system was added to a saturated sodium bicarbonate aqueous solution to precipitate a solid, which was then subjected to suction filtration. The filtration cake was purified by silica gel column chromatography to obtain 290 mg of an off-white solid. ESI-MS: [M+H] + = 459.2.

[0164] (Step 4: Preparation of N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)-2-((2-fluoro-4-formylphenyl)amino)benzamide) N-allyl-5-((2-amino-3-fluoropyridine-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 to a 50 mL necked flask, and the system was stirred in an ice bath. After cooling to below 0°C, methylaminosulfonyl chloride (238 mg) was slowly added dropwise to the system. After 30 minutes, the reaction was stopped, and the system was poured into a saturated sodium bicarbonate aqueous solution, stirred at room temperature for 10 minutes, and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. The crude product was purified by silica gel column chromatography to obtain 270 mg of a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1H), 9.79 (d, J = 1.6 Hz, 1H), 9.22 (s, 1H), 8.85 (t, J = 5.6 Hz, 1H), 8.04 (d, J = 5.2 Hz, 1H), 7.67 (dd, J1= 12.0 Hz, J2= 1.6 Hz, 1H), 7.61 (dd, J1= 8.4 Hz, J2= 1.2 Hz, 1H), 7.57 (d, J = 6.8 Hz, 1H), 7.06-7.03 (m, 1H), 6.98 (t, J = 4.8 Hz, 1H), 6.95-6.89 (m, ESI-MS: [M+H] + = 552.1.

[0165] [Example 16] [ka]

[0166] (Step 1: Preparation of N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)-2-((2-fluoro-4-((trimethylsilyl)ethynyl)phenyl)amino)benzamide) N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-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 to a 100 mL necked flask. The system was then purged with nitrogen, stirred at room temperature, and reacted for 16 hours. After filtration and concentration, the mixture was purified by silica gel column chromatography to obtain 120 mg of a yellow solid. ESI-MS: [M+H] + = 620.4.

[0167] (Step 2: Preparation of N-allyl-2-((4-ethynyl-2-fluorophenyl)amino)-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)benzamide) N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)-2-((2-fluoro-4-((trimethylsilyl)ethynyl)phenyl)amino)benzamide (120 mg), ethanol (5 mL), and potassium fluoride (50 mg) were added to a 50 mL necked flask, and the system was stirred at room temperature and reacted for 21 hours. Water was added to the system, and the mixture was stirred at room temperature for 10 minutes, after which it was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and subjected to rotary evaporation to remove the solvent. The mixture was purified by silica gel column chromatography to obtain 50 mg of a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1H), 9.12 (s, 1H), 8.89 (t, J = 5.6 Hz, 1H), 8.01 (d, J = 3.6 Hz, 1H), 7.58 (d, J = 6.8 Hz, 1H), 7.34 (d, J = 12.0 Hz, 1H), 7.15 (d, J = 8.4 Hz, 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 = 5.2 Hz, 2H), 2.52-2.51 (m, 3H). ESI-MS: [M+H] + = 548.3.

[0168] [Example 17] [ka]

[0169] (Step 1: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluorobenzoate methyl) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)methyl benzoate (1.9 g), potassium cyclopropyltrifluoroborate (799 mg), cesium carbonate (3.5 g), toluene (38 mL), water (4 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (294 mg) were added to a 100 mL necked flask, and the system was subjected to nitrogen purging. The system was heated to 100 °C and stirred and reacted for 23 hours. The reaction system was cooled to room temperature, ethyl acetate was added, and the mixture was washed with saturated brine. The organic phase was recovered, dried over anhydrous sodium sulfate, filtered, and subjected to rotary evaporation to remove the solvent. The concentrate was purified by silica gel column chromatography to obtain 1.0 g of yellow solid. ESI-MS: [M+H] + = 446.2.

[0170] (Step 2: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluorobenzoate) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluorobenzoate methyl (1.0 g), tetrahydrofuran (14 mL), and water (7 mL) were added to a 50 mL necked flask, and the system was stirred at room temperature until a clear solution was obtained. Then, the system was placed in an ice bath, and lithium hydroxide monohydrate (283 mg) was slowly added to the system. After the addition was complete, the system was heated to room temperature and stirred for 19 hours. Hydrochloric acid (6 M, 6 mL) was slowly added dropwise to adjust the pH to 1-2, and the mixture was stirred for 5 minutes. The system was then concentrated under reduced pressure to remove the tetrahydrofuran. The concentrate was then diluted with water, stirred for 10 minutes, and filtered. The filtered cake was collected and washed with water and methyl tert-butyl ether, respectively, to obtain 1.0 g of an off-white solid. ESI-MS: [M+H] + = 432.2.

[0171] (Step 3: Preparation of N-allyl-5-((2-amino-3-fluoropyridine-4-yl)methyl)-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluorobenzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluorobenzoate (320 mg), 1-hydroxybenzotriazole (110 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (261 mg), and N,N-dimethylformamide (5 mL) were added to a 100 mL necked flask, and the system was stirred at room temperature and reacted for 2 hours. Subsequently, allylamine hydrochloride (127 mg) and N,N-diisopropylethylamine (439 mg) were added to the system, and the mixture was stirred at room temperature and reacted for 2 hours. This reaction system was added to a saturated sodium bicarbonate aqueous solution to precipitate a solid, which was then subjected to suction filtration. The filtration cake was purified by silica gel column chromatography to obtain 250 mg of an off-white solid. ESI-MS: [M+H] + = 471.2.

[0172] (Step 4: Preparation of N-allyl-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)benzamide) N-allyl-5-((2-amino-3-fluoropyridine-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 to a 50 mL necked flask, and the system was stirred in an ice bath. After cooling to below 0°C, methylaminosulfonyl chloride (206 mg) was slowly added dropwise to the system. After 30 minutes, the reaction was stopped, and the system was poured into a saturated sodium bicarbonate aqueous solution, stirred at room temperature for 10 minutes, and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. The crude product was purified by silica gel column chromatography to obtain 200 mg of an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.41 (s, 1H), 9.07 (s, 1H), 8.90 (t, J = 5.6 Hz, 1H), 8.02 (d, J = 4.8 Hz, 1H), 7.58 (d, J = 6.8 Hz, 1H), 7.03 (q, J = 5.2 Hz, 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 = 5.6 Hz, 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.

[0173] [Example 18] [ka]

[0174] (Step 1: Preparation of N-allyl-5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methoxyphenyl)amino)benzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methoxyphenyl)amino)benzoate (300 mg), allylamine hydrochloride (67 mg), N,N-diisopropylethylamine (366 mg), and N,N-dimethylformamide (6 mL) were added to a 100 mL necked flask. The system was then subjected to nitrogen purging, and O-benzotriazole-N,N,N',N'-tetramethylureatetrafluoroborate (total 228 mg) was added in portions. The mixture was stirred at room temperature and reacted for 3 hours. Saturated brine was added to the reaction solution, and the system was extracted using ethyl acetate. The organic phases were combined, washed with citric acid aqueous solution and saturated brine, dried, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 230 mg of a yellow solid. ESI-MS: [M+H] + = 461.2.

[0175] (Step 2: Preparation of N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)-2-((2-fluoro-4-methoxyphenyl)amino)benzamide) N-allyl-5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-methoxyphenyl)amino)benzamide (200 mg), N,N-dimethylformamide (6 mL), and pyridine (275 mg) were added to a 50 mL necked flask. The system was cooled to -16°C to -20°C under a nitrogen atmosphere, and methylaminosulfonyl chloride (334 mg) was slowly added dropwise, reacting for 2 hours. Water was added to the system, and the mixture was stirred at room temperature for 10 minutes, after which it was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. The crude product was purified by silica gel column chromatography to obtain 190 mg of a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.41 (s, 1H), 9.10 (s, 1H), 8.89 (t, J = 5.6 Hz, 1H), 8.01 (d, J = 4.8 Hz, 1H), 7.57 (d, J = 6.8 Hz, 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.

[0176] [Example 19] [ka]

[0177] (Step 1: Preparation of N-(allyloxy)-5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate (400 mg), 1-hydroxybenzotriazole (195 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (552 mg), and N,N-dimethylformamide (5 mL) were added to a 100 mL necked flask, and the system was stirred at room temperature and reacted for 2 hours. Subsequently, allylhydroxylamine hydrochloride (158 mg) and N,N-diisopropylethylamine (464 mg) were added to the system, and the mixture was stirred at room temperature and reacted for 2 hours. This reaction system was added to a saturated sodium bicarbonate aqueous solution to precipitate a solid, which was then subjected to suction filtration. The filtration cake was purified by silica gel column chromatography to obtain 200 mg of an off-white solid. ESI-MS: [M+H] + = 573.1.

[0178] (Step 2: Preparation of N-(allyloxy)-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)benzamide) N-(allyloxy)-5-((2-amino-3-fluoropyridine-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 to a 50 mL necked flask, and the system was stirred in an ice bath. After cooling to 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 sodium bicarbonate aqueous solution, stirred at room temperature for 10 minutes, and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. The crude product was purified by silica gel column chromatography to obtain 100 mg of an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.76 (s, 1H), 10.41 (s, 1H), 8.49 (s, 1H), 8.02 (d, J = 2.8 Hz, 1H), 7.57 (d, J = 10.8 Hz, 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.

[0179] [Example 20] [ka]

[0180] (Step 1: Preparation of 2-(buta-3-en-1-yloxy)isoindoline-1,3-dione) Buta-3-en-1-ol (5.0 g), triphenylphosphine (23.7 g), N-hydroxyphthalimide (12.5 g), and tetrahydrofuran (250 mL) were added to a 500 mL three-necked flask, and the system was subjected to nitrogen purging. The system was cooled to below 0°C, and a solution of diisopropyl azodicarboxylate in tetrahydrofuran (18.2 g in 100 mL of tetrahydrofuran) was added dropwise. After the addition was complete, the system was removed from the condenser and reacted with stirring at room temperature for 16 hours. The reaction system was concentrated, added to saturated brine, and extracted with ethyl acetate. The organic phases were combined, dried, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 14.0 g of a pale yellow oily substance.

[0181] (Step 2: Preparation of O-(buta-3-en-1-yl)hydroxylamine hydrochloride) 7.0 g of 2-(buta-3-en-1-yloxy)isoindoline-1,3-dione and 168 mL of dichloromethane / methanol (2 / 1, v / v) were added to a 250 mL necked flask, and the system was subjected to nitrogen purging. 1.8 g of hydrazine hydrate was slowly added dropwise to the system. After the addition was complete, the system was stirred and reacted for 3 hours, then subjected to suction filtration. The filtrate cake was washed with dichloromethane. The organic phases were combined and concentrated. The concentrate was diluted with methyl tert-butyl ether and subjected to suction filtration. Ethyl ethyl chloride solution was added to the filtrate to adjust the pH to 1, and the filtrate was concentrated to obtain 1.7 g of an off-white solid.

[0182] (Step 3: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-N-(buta-3-en-1-yloxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate (400 mg), 1-hydroxybenzotriazole (147 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (416 mg), and N,N-dimethylformamide (10 mL) were added to a 100 mL necked flask, and the system was stirred at room temperature and reacted for 2 hours. Subsequently, O-(buta-3-en-1-yl)hydroxylamine hydrochloride (178 mg) and N,N-diisopropylethylamine (280 mg) were added to the system, and the mixture was stirred at room temperature and reacted for 2 hours. This reaction system was added to saturated saline to precipitate a solid, which was then subjected to suction filtration. The filtration cake was purified by silica gel column chromatography to obtain 70 mg of a pale yellow solid. ESI-MS: [M+H] + = 587.1.

[0183] (Step 4: Preparation of N-(buta-3-en-1-yloxy)-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)benzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-N-(buta-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 to a 50 mL necked flask, and the system was stirred in an ice bath. After cooling to below 0°C, methylaminosulfonyl chloride (50 mg) was slowly added dropwise to the system. After 30 minutes, the reaction was stopped, and the system was poured into a saturated sodium bicarbonate aqueous solution, stirred at room temperature for 10 minutes, and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. The crude product was purified by silica gel column chromatography to obtain 50 mg of an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.76 (s, 1H), 10.42 (s, 1H), 8.52 (s, 1H), 8.02 (d, J = 4.8 Hz, 1H), 7.57 (dd, J1= 10.8 Hz, J2= 1.6 Hz, 1H), 7.38-7.34 (m, 2H), 7.05-7.01 (m, 1H), 6.95 (t, J = 4.8 Hz, 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 = 6.8 Hz, 2H), 2.52-2.51 (m, 3H), 2.33-2.28 (m, 2H). ESI-MS: [M+H] + = 680.1.

[0184] [Example 21] [ka]

[0185] (Step 1: Preparation of N-(allyloxy)-5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzoate (300 mg), 1-hydroxybenzotriazole (134 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (380 mg), and N,N-dimethylformamide (10 mL) were added to a 50 mL necked flask, and the system was stirred at room temperature and reacted for 1 hour. Subsequently, allylhydroxylamine hydrochloride (145 mg) and N,N-diisopropylethylamine (256 mg) were added to the system, and the mixture was stirred at room temperature and reacted for 2 hours. This reaction system was added to saturated saline to precipitate a solid, which was then subjected to suction filtration. The filtration cake was purified by silica gel column chromatography to obtain 254 mg of a pale yellow solid.

[0186] (Step 2: Preparation of N-(allyloxy)-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)-2-((2-fluoro-4-vinylphenyl)amino)benzamide) N-(allyloxy)-5-((2-amino-3-fluoropyridine-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 to a 50 mL necked flask, and the system was stirred in an ice bath. After cooling to below 0°C, methylaminosulfonyl chloride (210 mg) was slowly added dropwise. After 30 minutes, the reaction was stopped. The system was poured into saturated saline solution and stirred at room temperature for 10 minutes, then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. The crude product was purified by silica gel column chromatography to obtain 101 mg of an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.81 (s, 1H), 10.42 (s, 1H), 8.57 (s, 1H), 8.03 (d, J = 4.0 Hz, 1H), 7.39-7.34 (m, 2H), 7.12 (dd, J1= 8.4 Hz, J2= 1.2 Hz, 1H), 7.03 (d, J = 4.0 Hz, 1H), 6.95 (s, 1H), 6.85-6.79 (m, 1H), 6.64 (dd, J1= 17.6 Hz, J2= 11.2 Hz, 1H), 5.98-5.88 (m, 1H), 5.74 (d, J = 17.6 Hz, ESI-MS: [M+H] + = 566.2.

[0187] [Example 22] [ka]

[0188] (Step 1: Preparation of 2-(penta-4-en-1-yloxy)isoindoline-1,3-dione) Penta-4-en-1-ol (5.0 g), triphenylphosphine (19.8 g), N-hydroxyphthalimide (10.4 g), and tetrahydrofuran (250 mL) were added to a 1 L three-necked flask, and the system was subjected to nitrogen purging. The system was cooled to below 0°C, and a solution of diisopropyl azodicarboxylate in tetrahydrofuran (15.3 g in 150 mL of tetrahydrofuran) was added dropwise. After the addition was complete, the system was removed from the condenser and reacted with stirring at room temperature for 16 hours. The reaction system was concentrated, added to saturated brine, and extracted with ethyl acetate. The organic phases were combined, dried, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 10.0 g of a pale yellow oily substance.

[0189] (Step 2: Preparation of O-(penta-4-en-1-yl)hydroxylamine hydrochloride) 5.0 g of 2-(penta-4-en-1-yloxy)isoindorin-1,3-dione and 120 mL of dichloromethane / methanol (2 / 1, v / v) were added to a 250 mL necked flask. The system was purged with nitrogen and stirred until a clear solution was obtained. 1.2 g of hydrazine hydrate was slowly added dropwise to the system. After the addition was complete, the system was stirred and reacted for 3 hours, then subjected to suction filtration. The filtration cake was washed with dichloromethane. The organic phases were combined and concentrated. The concentrate was diluted with methyl tert-butyl ether and subjected to suction filtration. Ethyl ethyl chloride solution was added to the filtrate to adjust the pH of the filtrate to 1. The mixture was concentrated to obtain 1.2 g of an off-white solid.

[0190] (Step 3: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(penta-4-en-1-yloxy)benzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate (500 mg), 1-hydroxybenzotriazole (180 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (520 mg), and N,N-dimethylformamide (10 mL) were added to a 100 mL necked flask, and the system was stirred at room temperature and reacted for 2 hours. Subsequently, O-(penta-4-en-1-yl)hydroxylamine hydrochloride (250 mg) and N,N-diisopropylethylamine (350 mg) were added to the system, and the mixture was stirred at room temperature and reacted for 2 hours. This reaction system was added to a saturated sodium bicarbonate aqueous solution to precipitate a solid, which was then subjected to suction filtration. The filtration cake was purified by silica gel column chromatography to obtain 120 mg of a pale yellow oily substance. ESI-MS: [M+H] + = 601.1.

[0191] (Step 4: Preparation of 3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)-N-(penta-4-en-1-yloxy)benzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(penta-4-en-1-yloxy)benzamide (120 mg), N,N-dimethylformamide (3 mL), and pyridine (160 mg) were added to a 50 mL necked flask, and the system was stirred in an ice bath. After cooling to below 0°C, methylaminosulfonyl chloride (120 mg) was slowly added dropwise to the system. After the addition was complete, the reaction was continued for 30 minutes and then stopped. The system was poured into a saturated sodium bicarbonate aqueous solution, stirred at room temperature for 10 minutes, and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. Subsequently, the crude product was purified by silica gel column chromatography to obtain 20 mg of a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 11.73 (s, 1H), 10.42 (s, 1H), 8.51 (s, 1H), 8.02 (d, J = 4.8 Hz, 1H), 7.57 (dd, J1= 10.8 Hz, J2= 1.6 Hz, 1H), 7.37-7.33 (m, 2H), 7.03 (d, J = 5.6 Hz, 1H), 6.95-6.93 (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 = 6.4 Hz, 2H), 2.52-2.51 (m, 3H), 2.09 (q, J = 7.2 Hz, 2H), 1.64-1.58 (m, 2H). ESI-MS: [M+H] + = 694.1.

[0192] [Example 23] [ka]

[0193] (Step 1: Preparation of 2-(hexa-5-en-1-yloxy)isoindoline-1,3-dione) Hexa-5-en-1-ol (5.0 g), triphenylphosphine (17.0 g), N-hydroxyphthalimide (9.0 g), and tetrahydrofuran (250 mL) were added to a 500 mL three-necked flask, and the system was subjected to nitrogen purging. The system was cooled to below 0°C, and a solution of diisopropyl azodicarboxylate in tetrahydrofuran (13.1 g in 100 mL of tetrahydrofuran) was added dropwise. After the addition was complete, the system was removed from the condenser and reacted with stirring at room temperature for 16 hours. The reaction system was concentrated, added to saturated saline solution, and extracted with ethyl acetate. The organic phases were combined, dried, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 9.2 g of a pale yellow oily substance.

[0194] (Step 2: Preparation of O-(hexa-5-en-1-yl)hydroxylamine hydrochloride) 9.2 g of 2-(hexa-5-en-1-yloxy)isoindoline-1,3-dione and 213 mL of dichloromethane / methanol (2 / 1, v / v, total) were added to a 250 mL necked flask. The system was purged with nitrogen and stirred until a clear solution was obtained. 2.6 g of hydrazine hydrate was slowly added dropwise to the system. After the addition was complete, the system was stirred and reacted for 3 hours, then subjected to suction filtration. The filtration cake was washed with dichloromethane. The organic phases were combined and concentrated. The concentrate was diluted with methyl tert-butyl ether and subjected to suction filtration. Ethyl ethyl hydroxide solution was added to the filtrate to adjust the pH of the filtrate to 1. The mixture was concentrated to obtain 3.7 g of an off-white solid.

[0195] (Step 3: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(hexa-5-en-1-yloxy)benzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate (400 mg), 1-hydroxybenzotriazole (126 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (296 mg), and N,N-dimethylformamide (10 mL) were added to a 100 mL necked flask, and the system was stirred at room temperature and reacted for 2 hours. Subsequently, O-(hexa-5-en-1-yl)hydroxylamine hydrochloride (129 mg) and N,N-diisopropylethylamine (274 mg) were added to the system, and the mixture was stirred at room temperature and reacted for 2 hours. This reaction system was added to saturated saline to precipitate a solid, which was then subjected to suction filtration. The filtration cake was purified by silica gel column chromatography to obtain 200 mg of a pale yellow solid. ESI-MS: [M+H] + = 615.1.

[0196] (Step 4: Preparation of 3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)-N-(hexa-5-en-1-yloxy)benzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(hexa-5-en-1-yloxy)benzamide (200 mg), N,N-dimethylformamide (5 mL), and pyridine (257 mg) were added to a 50 mL necked flask, and the system was stirred in an ice bath. After cooling to below 0°C, methylaminosulfonyl chloride (175 mg) was slowly added dropwise to the system. After 30 minutes, the reaction was stopped, and the system was poured into a saturated sodium bicarbonate aqueous solution, stirred at room temperature for 10 minutes, and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. The crude product was purified by silica gel column chromatography to obtain 140 mg of an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.70 (s, 1H), 10.41 (s, 1H), 8.50 (s, 1H), 8.02 (d, J = 4.8 Hz, 1H), 7.57 (dd, J1= 10.8 Hz, J2= 1.6 Hz, 1H), 7.37-7.33 (m, 2H), 7.05-7.01 (m, 1H), 6.94 (t, J = 4.8 Hz, 1H), 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.

[0197] [Example 24] [ka]

[0198] (Step 1: Preparation of N-(allyloxy)-5-(3-amino-2-fluorophenyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide) 5-(3-amino-2-fluorobenzyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoate (400 mg), 1-hydroxybenzotriazole (104 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (294 mg), and N,N-dimethylformamide (12 mL) were added to a 100 mL necked flask, and the system was stirred at room temperature and reacted for 2 hours. Subsequently, allylhydroxylamine hydrochloride (93 mg) and N,N-diisopropylethylamine (298 mg) were added to the system, and the mixture was stirred at room temperature and reacted for 2 hours. This reaction system was added to saturated saline to precipitate a solid, which was then subjected to suction filtration. The filtration cake was purified by silica gel column chromatography to obtain 128 mg of a pale yellow oily substance.

[0199] (Step 2: Preparation of N-(allyloxy)-3,4-difluoro-5-(2-fluoro-3-((N-methylaminosulfonyl)amino)benzyl)-2-((2-fluoro-4-iodophenyl)amino)benzamide) N-(allyloxy)-5-(3-amino-2-fluorophenyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (120 mg), N,N-dimethylformamide (3 mL), and pyridine (265 mg) were added to a 50 mL necked flask, and the system was stirred in an ice bath. After cooling to below 0°C, methylaminosulfonyl chloride (272 mg) was slowly added dropwise to the system. After 30 minutes, the reaction was stopped. The system was poured into saturated saline solution, stirred at room temperature for 10 minutes, and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then subjected to rotary evaporation to remove the solvent. The crude product was purified by silica gel column chromatography to obtain 90 mg of a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.74 (s, 1H), 9.43 (s, 1H), 8.43 (s, 1H), 7.57 (dd, J1= 10.8 Hz, J2= 1.6 Hz, 1H), 7.36-7.25 (m, 4H), 7.11 (t, J = 8.0 Hz, 1H), 7.02 (t, J = 6.8 Hz, 1H), 6.65-6.59 (m, 1H), 5.96-5.86 (m, 1H), 5.29-5.18 (m, 2H), 4.28 (d, J = 6.0 Hz, 2H), 4.03 (s, 2H), 2.53-2.51 (m, 3H). ESI-MS: [M+H] + = 665.1.

[0200] [Example 25] [ka]

[0201] (Preparation of N-(allyloxy)-5-((2-((N-ethylaminosulfonyl)amino)-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide) N-ethyl-2-oxoxazoline-3-sulfonamide (848 mg), N-(allyloxy)-5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (250 mg), triethylamine (487 mg), and 1,2-dichloroethane (20 mL) were added to a 100 mL necked flask. The reaction system was heated to 80 °C and reacted for 16.5 hours. After cooling to room temperature, the system was poured into 100 mL of water / tetrahydrofuran mixed solvent (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 8 mg of a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.78 (s, 1H), 10.41 (s, 1H), 8.49 (s, 1H), 8.03 (d, J = 5.2 Hz, 1H), 7.57 (d, J = 10.8 Hz, 1H), 7.36-7.32 (m, 2H), 7.18 (t, J = 5.6 Hz, 1H), 6.94 (t, J = 4.8 Hz, 1H), 6.67-6.62 (m, 1H), 5.97-5.87 (m, 1H), 5.30-5.19 (m, 2H), 4.29 (d, J = 6.0 Hz, 2H), 4.07 (s, 2H), 2.97-2.90 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H). ESI-MS: [M+H] + = 680.1.

[0202] [Example 26] [ka]

[0203] (Preparation of N-(allyloxy)-3,4-difluoro-5-((3-fluoro-2-((N-methyl-d3-aminosulfonyl)amino)pyridine-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)benzamide) N-methyl-d3-2-oxoxazoline-3-sulfonamide (800 mg), N-(allyloxy)-5-((2-amino-3-fluoropyridine-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 to a 50 mL neck flask. This reaction system was heated to 80 °C and reacted for 5 hours. After cooling to room temperature, the system was poured into a water / tetrahydrofuran mixed solvent (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 (400 MHz, DMSO-d6): δ 11.78 (s, 1H), 10.42 (s, 1H), 8.50 (s, 1H), 8.02 (d, J = 4.8 Hz, 1H), 7.58 (d, J = 9.6 Hz, 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 = 5.6 Hz, 2H), 4.07 (s, 2H). ESI-MS: [M+H] + = 669.1.

[0204] [Example 27] [ka]

[0205] (Step 1: Preparation of 2-fluoro-4-iodo-5-methylaniline) 10.0 g of 2-fluoro-5-methylaniline, 13.4 g of sodium bicarbonate, 50 mL of methanol, and 50 mL of dichloromethane were added to a 250 mL three-necked flask and stirred while cooling to -5°C until a clear solution was obtained. A 50 mL solution of benzyltrimethyldichloroiodide ammonium (27.8 g) in dichloromethane was slowly added dropwise to this system. After the addition was complete, the system was stirred at -5°C for 30 minutes, then gradually heated to room temperature and stirred for 2 hours. The reaction system was poured into water and extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried, and concentrated to obtain 18.4 g of brown liquid.

[0206] (Step 2: Preparation of 3,4-difluoro-2-((2-fluoro-4-iodo-5-methylphenyl)amino)-5-vinylbenzoic acid) 3.2 g of 2,3,4-trifluoro-5-vinylbenzoic acid, 4.0 g of 2-fluoro-4-iodo-5-methylaniline, and 64 mL of tetrahydrofuran were added to a 250 mL three-necked flask. After purging with nitrogen, the mixture was cooled to -20°C, and lithium bis(trimethylsilyl)amide (1 M, 48 mL) was added dropwise. After the dropwise addition was complete, the system was heated to room temperature and stirred for 1 hour. An aqueous solution of sodium bisulfate was added dropwise to the system to adjust the pH to 1-2, and the mixture was extracted using ethyl acetate. The organic phases were combined, washed with saturated brine, dried, and concentrated. The concentrate was pulverized with ethyl acetate / n-hexane (v / v=1 / 3) mixed solvent to obtain 5.0 g of a brown solid.

[0207] (Step 3: Preparation of 3,4-difluoro-2-((2-fluoro-4-iodo-5-methylphenyl)amino)-5-vinylbenzoate methyl benzoate) 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) were sequentially added to a 100 mL three-necked flask and stirred at room temperature. Methyl iodide (1.9 g) was then added dropwise. After the dropwise addition was complete, the system was heated to 35 °C and stirred and reacted for 2 hours. The system was poured into water and subjected to suction filtration. The filtration cake was collected, washed with water, and dried to obtain 4.6 g of a reddish-brown solid. ESI-MS: [M+Na] + = 470.0.

[0208] (Step 4: Preparation of 3,4-difluoro-2-((2-fluoro-4-iodo-5-methylphenyl)amino)-5-formylmethyl benzoate) 3,4-Difluoro-2-((2-fluoro-4-iodo-5-methylphenyl)amino)-5-vinylmethyl benzoate (4.1 g) and acetonitrile (80 mL) were sequentially added to a 250 mL three-necked flask. The mixture was cooled to 0°C, and potassium osmite dihydrate (169 mg) was added. The mixture was stirred and reacted for 15 minutes. Subsequently, water (80 mL), sodium periodate (5.9 g), and 2,6-dimethylpyridine (986 mg) were added to the system. The mixture was heated to room temperature and stirred and reacted for 6 hours. This system was poured into a saturated sodium sulfite aqueous solution and subjected to suction filtration. The filtration cake was collected and washed with water to obtain 4.1 g of a grayish-brown solid. ESI-MS: [MH] - = 448.0.

[0209] (Step 5: Preparation of (E)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methylphenyl)amino)-5-((2-(4-methylphenyl)sulfonylhydrazinylidene)methyl)benzoate) 3,4-Difluoro-2-((2-fluoro-4-iodo-5-methylphenyl)amino)-5-formylmethyl benzoate (4.2 g), p-toluenesulfonyl hydrazide (1.7 g), and anhydrous ethanol (130 mL) were added to a 250 mL three-necked flask and heated to 60 °C and reacted for 2 hours. The system was then cooled to -10 °C, stirred for 1 hour, and subjected to suction filtration. The filtration cake was collected, washed with cold ethanol, and dried to obtain 4.7 g of a light brown solid. ESI-MS: [M+Na] + = 640.0.

[0210] (Step 6: Preparation of 2-((2-fluoro-4-iodo-5-methylphenyl)amino)-5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)methyl)-3,4-difluorobenzoate methyl) (E)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methylphenyl)amino)-5-((2-(4-methylphenyl)sulfonylhydrazinylidene)methyl)methyl benzoate (4.7g), (2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)boronic acid (3.0g), anhydrous potassium carbonate (1.4g), and toluene (140mL) were added to a 250mL three-necked flask, purged with nitrogen, heated to 105°C, and stirred and reacted for 6 hours. This reaction system was poured into water and extracted with ethyl acetate. The organic phases were combined, dried, and concentrated to obtain 5.2g of a brown oily substance. The product of this step was used directly in the next reaction without further purification. ESI-MS: [M+H] + = 696.1.

[0211] (Step 7: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-2-((2-fluoro-4-iodo-5-methylphenyl)amino)-3,4-difluorobenzoate methyl) 6.0 g of 2-((2-fluoro-4-iodo-5-methylphenyl)amino)-5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)methyl)-3,4-difluorobenzoate methyl methyl and 120 mL of dichloromethane were added to a 250 mL three-necked flask. After cooling to 10°C, 90 mL of trifluoroacetic acid was added dropwise. After the dropwise addition was complete, the temperature of the system was returned to room temperature and the mixture was stirred and reacted for 1 hour. A saturated sodium bicarbonate aqueous solution was added to the system to adjust the pH to neutral, and the mixture was extracted using 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.

[0212] (Step 8: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methylphenyl)amino)benzoic acid) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-2-((2-fluoro-4-iodo-5-methylphenyl)amino)-3,4-difluorobenzoate methyl (3.0 g), acetonitrile (18 mL), and ethanol (18 mL) were added to a 100 mL necked flask and stirred until a clear solution was obtained. An aqueous solution of lithium hydroxide monohydrate (413 mg) (18 mL) was added dropwise to this system. After the addition was complete, the system was stirred at room temperature and allowed to react for 3 hours. An aqueous solution of sodium bisulfate was added to adjust the pH of the system to 1-2, and the mixture was subjected to suction filtration. The filtrate was extracted using ethyl acetate. The organic phases were combined, dried, and concentrated to obtain 1.3 g of a brown solid. ESI-MS: [MH] - = 530.0.

[0213] (Step 9: Preparation of N-allyl-5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methylphenyl)amino)benzamide) 5-((2-amino-3-fluoropyridine-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 to a 100 mL necked flask and cooled to 0°C. Subsequently, 1-hydroxybenzotriazole (305 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (863 mg) were added to the system, and the mixture was stirred and reacted for 5 minutes, then heated to room temperature and reacted for 2 hours. Allylamine hydrochloride (233 mg) and N,N-diisopropylethylamine (583 mg) were added to the reaction flask, and the system was stirred at room temperature and reacted for 2 hours. This reaction system was slowly added to a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined, dried, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 500 mg of yellow solid. ESI-MS: [M+H] + = 571.1.

[0214] (Step 10: Preparation of N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)-2-((2-fluoro-4-iodo-5-methylphenyl)amino)benzamide) N-allyl-5-((2-amino-3-fluoropyridine-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) were placed in a 25 mL necked flask and cooled to -20°C. Methylaminosulfonyl chloride (545 mg) was slowly added dropwise. After the addition was complete, the system was allowed to react for 30 minutes. The reaction system was poured into water and extracted with ethyl acetate. The organic phases were combined, dried, and concentrated. The concentrate was slurryed with methyl tert-butyl ether to obtain 150 mg of an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.41 (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.

[0215] [Example 28] [ka] [ka]

[0216] (Step 1: Preparation of 5-((tert-butyldimethylsilyl)oxy)-2-fluoroaniline) 3-amino-4-fluorophenol (5.0 g), imidazole (4.8 g), tert-butyldimethylchlorosilane (8.9 g), and dichloromethane (150 mL) were added to a 250 mL three-necked flask. After the addition was complete, the system was reacted at room temperature for 24 hours. The system was poured into water, the organic phase was separated, and the aqueous layer was extracted with dichloromethane. The organic phases were combined, dried, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 9.5 g of a colorless, transparent oily substance. ESI-MS: [M+H] + = 242.1.

[0217] (Step 2: Preparation of 5-((tert-butyldimethylsilyl)oxy)-2-fluoro-4-iodoaniline) 5-((tert-butyldimethylsilyl)oxy)-2-fluoroaniline (9.8 g), sodium bicarbonate (12.2 g), methanol (100 mL), and dichloromethane (100 mL) were added to a 250 mL three-necked flask, stirred, and cooled to -5°C. A 100 mL solution of benzyltrimethyldichloroiodide ammonium (10.6 g) in dichloromethane was slowly added dropwise to the system. After the addition was complete, the mixture was stirred at -5°C for 30 minutes, then gradually heated to room temperature and stirred for 2 hours. The reaction system was poured into water 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 9.8 g of an orange oily liquid. ESI-MS: [M+H] + = 368.0.

[0218] (Step 3: Preparation of N-(5-((tert-butyldimethylsilyl)oxy)-2-fluoro-4-iodophenyl)acetamide) 7.0 g of 5-((tert-butyldimethylsilyl)oxy)-2-fluoro-4-iodoaniline, 3.0 g of acetic anhydride, and 100 mL of tetrahydrofuran were added to a 250 mL three-necked flask and heated to 50°C for 3 hours. This reaction system was added to a saturated sodium bicarbonate aqueous 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 9.8 g of a brown oily liquid.

[0219] (Step 4: Preparation of N-(2-fluoro-5-hydroxy-4-iodophenyl)acetamide) N-(5-((tert-butyldimethylsilyl)oxy)-2-fluoro-4-iodophenyl)acetamide (21.7 g), potassium fluoride (3.7 g), and N,N-dimethylformamide (200 mL) were added to a 250 mL three-necked flask. After the addition was complete, the system was reacted at room temperature for 2 hours. The reaction system was poured into ice 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 10.0 g of a brown solid. ESI-MS: [M+H] + = 296.0.

[0220] (Step 5: Preparation of N-(2-fluoro-4-iodo-5-methoxyphenyl)acetamide) N-(2-fluoro-5-hydroxy-4-iodophenyl)acetamide (10.0 g), potassium carbonate (7.0 g), methyl iodide (5.8 g), and acetone (100 mL) were added to a 250 mL three-necked flask. After the addition was complete, the system was reacted at room temperature for 17 hours. The reaction system was concentrated, the concentrate was diluted with methyl tert-butyl ether, and then washed with water. The organic phase was dried and concentrated to obtain 10.0 g of a brown solid. ESI-MS: [M+H] + = 310.0.

[0221] (Step 6: Preparation of 2-fluoro-5-methoxyaniline) N-(2-fluoro-4-iodo-5-methoxyphenyl)acetamide (10.0 g), water (100 mL), and concentrated hydrochloric acid (100 mL) were added to a 250 mL three-necked flask and heated to 90°C, stirred, and reacted for 4 hours. Water was added to this system, and the mixture was extracted with methyl tert-butyl ether. The organic phases were combined, washed with saturated sodium bicarbonate aqueous solution to neutralize, dried, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 3.0 g of a brown solid. ESI-MS: [M+MeCN+H] + = 183.1.

[0222] (Step 7: Preparation of 2-fluoro-4-iodo-5-methoxyaniline) 2-Fluoro-5-methoxyaniline (2.0 g), sodium bicarbonate (8.9 g), methanol (30 mL), and dichloromethane (30 mL) were added to a 250 mL three-necked flask and cooled to -5°C, stirring until a clear solution was obtained. A solution of benzyltrimethyldichloroiodide ammonium (7.7 g) in dichloromethane (30 mL) was slowly added dropwise to this system. After the addition was complete, the system was stirred at -5°C for 30 minutes, then gradually heated to room temperature and stirred for 2 hours. The reaction system was poured into water and extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried, and concentrated to obtain 5.0 g of a brown oily liquid. The product of this step was used directly in the next reaction without further purification.

[0223] (Step 8: Preparation of 3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)-5-vinylbenzoic acid) 5.0 g of 2-fluoro-4-iodo-5-methoxyaniline, 3.8 g of 2,3,4-trifluoro-5-vinylbenzoic acid, and 76 mL of tetrahydrofuran were added to a 250 mL three-necked flask and stirred at room temperature for 5 minutes. The system was cooled to -20°C in a condenser, and lithium bis(trimethylsilyl)amide (1 M, 56.1 mL) was added dropwise. After the addition was complete, the system was stirred at -20°C for 20 minutes, then gradually heated to room temperature and stirred for 2 hours. The system was poured into water, dilute hydrochloric acid was added to adjust the pH of the system to 2-3, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, and concentrated. The concentrate was slurryed in a petroleum ether / ethyl acetate (v / v=10 / 1) mixed solvent to obtain 5.0 g of a yellowish-brown solid. ESI-MS: [MH] - = 448.0.

[0224] (Step 9: Preparation of 3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)-5-vinylbenzoate methyl benzoate) 5.0 g of 3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)-5-vinylbenzoic acid, 2.3 g of potassium carbonate, 1.9 g of methyl iodide, and 50 mL of N,N-dimethylformamide were added to a 250 mL three-necked flask and stirred at 35 °C for 4 hours. This system was poured into water and extracted with ethyl acetate. The organic phases were combined, dried, and concentrated to obtain 5.0 g of a brown solid. The product of this step was used directly in the next reaction without further purification.

[0225] (Step 10: Preparation of 3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)-5-formylmethyl benzoate) 5.0 g of 3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)-5-vinylmethyl benzoate and 75 mL of tetrahydrofuran were placed in a 250 mL three-necked flask and stirred in an ice bath until a clear solution was obtained. 199 mg of potassium osmite dihydrate was added to the system, and the mixture was reacted for 15 minutes with continued stirring in an ice bath. 75 mL of water, 6.9 g of sodium periodate, and 1.2 g of 2,6-dimethylpyridine were added to the system, and the mixture was heated to room temperature and stirred for 1 hour. This 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, and concentrated to obtain 5.0 g of a gray solid. The product of this step was used directly in the next reaction without further purification.

[0226] (Step 11: Preparation of (E)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)-5-((2-(4-methylphenyl)sulfonylhydrazinylidene)methyl)benzoate) 5.0 g of 3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)-5-formylmethyl benzoate, 2.0 g of p-toluenesulfonyl hydrazide, and 150 mL of ethanol were added to a 250 mL necked flask and heated to 50°C for 14 hours. 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.

[0227] (Step 12: Preparation of 5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)methyl benzoate) (E)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)-5-((2-(4-methylphenyl)sulfonylhydrazinylidene)methyl)methyl benzoate (6.8g), (2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)boronic acid (4.9g), potassium carbonate (3.0g), and toluene (210mL) were added to a 250mL necked flask and heated to 100°C, stirred, and reacted for 3 hours. This 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 3.0g of a white solid. ESI-MS: [M+H] + = 712.1.

[0228] (Step 13: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)methyl benzoate) 5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)methyl benzoate (2.0 g), 2,3-dichloro-5,6-dicyano-p-benzoquinone (2.5 g), dichloromethane (60 mL), and water (3 mL) were added to a 100 mL necked flask and stirred at room temperature for 2 hours. This 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.

[0229] (Step 14: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)benzoic acid) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)methyl benzoate (700 mg), tetrahydrofuran (20 mL), and water (10 mL) were sequentially added to a 100 mL necked flask and stirred in an ice bath. Lithium hydroxide monohydrate (169 mg) was slowly added to this system. After the addition was complete, the system was heated to room temperature, stirred, and reacted for 2.5 hours. Hydrochloric acid was added to adjust the pH to 2-3, and the mixture was stirred for 5 minutes. The system was then concentrated under reduced pressure to remove the tetrahydrofuran. Subsequently, the concentrate was diluted with 50 mL of water, stirred for 10 minutes, and then filtered. The filtered cake was collected, washed with water and methyl tert-butyl ether respectively, and dried to obtain 680 mg of yellow solid.

[0230] (Step 15: Preparation of N-allyl-5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)benzamide) 700 mg of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)benzoic acid and 10 mL of N,N-dimethylformamide were added to a 100 mL necked flask and cooled to 0°C in an ice bath. 208 mg of 1-hydroxybenzotriazole and 491 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to the system, and the mixture was stirred and reacted for 5 minutes. The mixture was then heated to room temperature and reacted for 2 hours. 240 mg of allylamine hydrochloride and 330 mg of N,N-diisopropylethylamine were added to the system, and the mixture was stirred at room temperature and reacted for 2 hours. The reaction system was slowly added to a saturated sodium bicarbonate solution and extracted with ethyl acetate. 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.

[0231] (Step 16: Preparation of N-allyl-5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-5-hydroxy-4-iodophenyl)amino)benzamide) N-allyl-5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodo-5-methoxyphenyl)amino)benzamide (500 mg) and dichloromethane (110 mL) were placed in a 500 mL necked flask and cooled to -15°C. A 1 M solution of boron tribromide in dichloromethane (10 mL) was added dropwise to the system. After the addition was complete, the system was stirred at -15°C and reacted for 3 hours. The reaction system was poured into a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined, dried, and concentrated to obtain 450 mg of a yellow solid. ESI-MS: [MH] - = 571.0.

[0232] (Step 17: Preparation of N-allyl-5-((2-amino-3-fluoropyridine-4-yl)methyl)-2-((5-((tert-butyldimethylsilyl)oxy)-2-fluoro-4-iodophenyl)amino)-3,4-difluorobenzamide) N-allyl-5-((2-amino-3-fluoropyridine-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-5-hydroxy-4-iodophenyl)amino)benzamide (400 mg), imidazole (86 mg), tert-butyldimethylchlorosilane (158 mg), and dichloromethane (50 mL) were added to a 250 mL three-necked flask and reacted at room temperature with stirring 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 oily substance. ESI-MS: [M+H] + = 687.1.

[0233] (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)pyridine-4-yl)methyl)benzamide) N-allyl-5-((2-amino-3-fluoropyridine-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) were added to a 50 mL necked flask and cooled to -20°C. Methylaminosulfonyl chloride (175 mg) was slowly added dropwise to this system. After the addition was complete, the system was stirred at -20°C and reacted for 30 minutes. The system was poured into water and extracted with ethyl acetate. The organic phases were combined, dried, and concentrated to obtain 350 mg of a yellow oily substance.

[0234] (Step 19: Preparation of N-allyl-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)-2-((2-fluoro-5-hydroxy-4-iodophenyl)amino)benzamide) N-allyl-2-((5-((tert-butyldimethylsilyl)oxy)-2-fluoro-4-iodophenyl)amino)-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)benzamide (350 mg), N,N-dimethylformamide (10 mL), and potassium fluoride (31 mg) were added to a 50 mL necked flask and reacted with stirring at room temperature for 30 minutes. This 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 the crude product. The crude product was further purified by preparative HPLC to obtain 100 mg of an off-white solid. 1 H NMR (400 MHz, DMSO): δ 10.44 (s, 1H), 9.98 (s, 1H), 8.91-8.89 (m, 2H), 8.03 (d, J = 4.4 Hz, 1H), 7.61 (d, J = 6.4 Hz, 1H), 7.46 (d, J = 10.4 Hz, 1H), 7.03 (d, J = 3.2 Hz, 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.

[0235] [Example 29] [ka]

[0236] (Step 1: Preparation of 2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluoro-5-vinylbenzoic acid) 2,3,4-trifluoro-5-vinylbenzoic acid (3.2 g), 2,5-difluoro-4-iodoaniline (4.0 g), and tetrahydrofuran (78 mL) were added to a 250 mL three-necked flask, purged with nitrogen, cooled to -20°C, and stirred to react. Lithium bis(trimethylsilyl)amide (1 M, 47.1 mL) was added dropwise. After the dropwise addition was complete, the system was heated to room temperature, stirred, and reacted for 1 hour. Sodium bisulfate aqueous solution was added to adjust the pH to 1-2, and the mixture was extracted with methyl tert-butyl ether. The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried, and concentrated. The concentrate was slurryed with methyl tert-butyl ether / n-heptane mixed solvent and dried to obtain 3.9 g of a yellowish-brown solid.

[0237] (Step 2: Preparation of 2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluoro-5-vinylbenzoate methyl benzoate) 3.9 g of 2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluoro-5-vinylbenzoic acid, 2.0 g of potassium carbonate, and 46 mL of N,N-dimethylformamide were added to a 250 mL three-necked flask and stirred at room temperature. 1.5 g of methyl iodide was then added dropwise. After the dropwise addition was complete, the system was heated to 35 °C and reacted for 2 hours. The system was poured into water and subjected to suction filtration. The filtration cake was collected to obtain 3.8 g of a brown solid.

[0238] (Step 3: Preparation of 2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluoro-5-formylmethyl benzoate) 2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluoro-5-vinylmethyl benzoate (3.8 g), tetrahydrofuran (76 mL), and potassium osmite dihydrate (155 mg) were added to a 250 mL three-necked flask, cooled to 0°C, and stirred for 15 minutes. Water (76 mL), sodium periodate (5.4 g), and 2,6-dimethylpyridine (911 mg) were added to the system, and the mixture was heated to room temperature and stirred for 2.5 hours. This system was poured into a saturated sodium sulfite aqueous solution and subjected to suction filtration. The filtration cake was collected to obtain 3.3 g of a brown solid.

[0239] (Step 4: Preparation of (E)-2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluoro-5-((2-(4-methylphenyl)sulfonylhydrazinylidene)methyl)benzoate) 3.3 g of 2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluoro-5-formylmethyl benzoate, 1.3 g of p-toluenesulfonyl hydrazide, and 100 mL of anhydrous ethanol were added to a 250 mL three-necked flask. The mixture was heated to 60°C and reacted for 2 hours. After cooling to -10°C and stirring for 30 minutes, the mixture was subjected to suction filtration. The filtration cake was collected and washed with cold ethanol to obtain 3.4 g of a light brown solid. ESI-MS: [M+H] + = 622.0.

[0240] (Step 5: Preparation of 2-((2,5-difluoro-4-iodophenyl)amino)-5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)methyl)-3,4-difluorobenzoate methyl) (E)-2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluoro-5-((2-(4-methylphenyl)sulfonylhydrazinylidene)methyl)methyl benzoate (3.4 g), (2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)boronic acid (2.2 g), potassium carbonate (1.0 g), and toluene (102 mL) were added to a 250 mL three-necked flask and heated to 100 °C, stirred, and reacted for 6 hours. This 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 yellowish-brown oily substance. The product of this step was used directly in the reaction of the next step without further purification. ESI-MS: [M+H] + = 700.1.

[0241] (Step 6: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluorobenzoate methyl) 5.0 g of 2-((2,5-difluoro-4-iodophenyl)amino)-5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)methyl)-3,4-difluorobenzoate methyl methyl ester and 100 mL of dichloromethane were placed in a 250 mL three-necked flask and cooled to 10°C. 75 mL of trifluoroacetic acid was then added dropwise. After the dropwise addition was complete, the system was allowed to return to room temperature and stirred for 1 hour. A saturated sodium bicarbonate aqueous solution was added to the system to adjust the pH to neutral, and the mixture was extracted using 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.

[0242] (Step 7: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluorobenzoic acid) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluorobenzoate methyl (1.8 g) and tetrahydrofuran (36 mL) were placed in a 100 mL necked flask and stirred at room temperature. An aqueous solution of lithium hydroxide monohydrate (413 mg) (18 mL) was added dropwise. After the dropwise addition was complete, the system was stirred at room temperature and reacted for 3 hours. Hydrochloric acid was added to adjust the pH of the system to 1-2, and the mixture was subjected to suction filtration. The filtrate was extracted using ethyl acetate. The organic phases were combined, dried, and concentrated to obtain 860 mg of a brown solid. ESI-MS: [MH] - = 534.0.

[0243] (Step 8: Preparation of N-allyl-5-((2-amino-3-fluoropyridine-4-yl)methyl)-2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluorobenzamide) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluorobenzoic acid (860 mg) and N,N-dimethylformamide (17 mL) were added to a 100 mL necked flask and cooled to 0°C. 1-hydroxybenzotriazole (217 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (613 mg) were added, and the mixture was stirred and reacted for 5 minutes. Then, it was heated to room temperature and reacted for 2 hours. Allylamine hydrochloride (164 mg) and N,N-diisopropylethylamine (415 mg) were added to this system, and the mixture was stirred at room temperature and reacted for 2 hours. This reaction system was slowly added to a saturated sodium bicarbonate solution and extracted with ethyl acetate. 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.

[0244] (Step 9: Preparation of N-allyl-2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)benzamide) N-allyl-5-((2-amino-3-fluoropyridine-4-yl)methyl)-2-((2,5-difluoro-4-iodophenyl)amino)-3,4-difluorobenzamide (580 mg), N,N-dimethylformamide (7 mL), and pyridine (799 mg) were placed in a 25 mL necked flask and cooled to -20°C. Methylaminosulfonyl chloride (654 mg) was slowly added dropwise. After the addition was complete, the system was stirred 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 slurryed with methyl tert-butyl ether to obtain 410 mg of an off-white solid. 1 HNMR (400 MHz, DMSO-d6): δ 10.41 (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.

[0245] [Example 30] [ka]

[0246] (Step 1: Preparation of 5-chloro-2-fluoro-4-iodoaniline) 7.0 g of 5-chloro-2-fluoroaniline, 8.1 g of sodium bicarbonate, 35 mL of methanol, and 35 mL of dichloromethane were added to a 250 mL three-necked flask and stirred, then cooled to -5°C. 100 mL of a dichloromethane solution of 16.7 g of benzyltrimethyldichloroiodide was slowly added dropwise to the system. After the addition was complete, the system was stirred at -5°C for 30 minutes, then gradually heated to room temperature and stirred for 2 hours. 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 5.5 g of a brown solid.

[0247] (Step 2: Preparation of 2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluoro-5-vinylbenzoic acid) 5.5 g of 5-chloro-2-fluoro-4-iodoaniline, 4.1 g of 2,3,4-trifluoro-5-vinylbenzoic acid, and 40 mL of tetrahydrofuran were added to a 250 mL three-necked flask, purged with nitrogen, cooled to -20°C, and lithium bis(trimethylsilyl)amide (1 M, 62 mL) was slowly added dropwise. After the addition was complete, the system was stirred at -20°C for 10 minutes, then gradually heated to room temperature and reacted for 30 minutes. The reaction system was poured into water, 1 M hydrochloric acid was added to adjust the pH to 3-4, and the mixture was extracted using ethyl acetate. The organic phases were combined, washed with saturated brine, dried, and concentrated. The concentrate was slurryed with methanol to obtain 5.0 g of a brown solid. ESI-MS: [MH] - = 451.9.

[0248] (Step 3: Preparation of 2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluoro-5-vinylbenzoate methyl) 5.0 g of 2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluoro-5-vinylbenzoic acid, 3.1 g of potassium carbonate, 40 mL of N,N-dimethylformamide, and 1.9 g of methyl iodide were added to a 100 mL necked flask and stirred at room temperature for 5 hours. This reaction system was poured into a saturated aqueous solution of ammonium chloride 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 3.9 g of a pale red product.

[0249] (Step 4: Preparation of 2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluoro-5-formylmethyl benzoate) 2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluoro-5-vinylmethyl benzoate (3.9 g), potassium osmate dihydrate (153 mg), and tetrahydrofuran (60 mL) were added to a 250 mL necked flask and stirred at room temperature for 5 minutes. Water (60 mL), sodium periodate (5.3 g), and 2,6-dimethylpyridine (890 mg) were added to the system, and the mixture was stirred at room temperature for 4 hours. This reaction system was poured into a saturated sodium sulfite aqueous 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 pale yellow solid.

[0250] (Step 5: Preparation of (E)-2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluoro-5-((2-(4-methylphenyl)sulfonylhydrazinylidene)methyl)benzoate) 2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluoro-5-formylmethyl benzoate (1.8 g), p-toluenesulfonyl hydrazide (715 mg), and ethanol (40 mL) were added to a 100 mL necked flask and heated to 50°C for 3 hours. After concentrating the reaction solution, it was slurryed with n-hexane to obtain 2.3 g of an off-white solid.

[0251] (Step 6: Preparation of 2-((5-chloro-2-fluoro-4-iodophenyl)amino)-5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)methyl)-3,4-difluorobenzoate methyl) (E)-2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluoro-5-((2-(4-methylphenyl)sulfonylhydrazinylidene)methyl)methyl benzoate (2.3g), (2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)boronic acid (1.4g), potassium carbonate (748mg), and toluene (80mL) were added to a 250mL necked flask and heated to 100°C, stirred, and reacted for 12 hours. This 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 1.1g of a pale yellow solid. ESI-MS: [M+H] + = 716.1.

[0252] (Step 7: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluorobenzoate methyl) 1.1 g of 2-((5-chloro-2-fluoro-4-iodophenyl)amino)-5-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridine-4-yl)methyl)-3,4-difluorobenzoate methyl ester (1.1 g) and 30 mL of dichloromethane were added to a 50 mL necked flask and stirred at room temperature until a clear solution was obtained. The system was placed in an ice bath and trifluoroacetic acid (5 mL) was slowly added dropwise. After the addition was complete, the system was heated to room temperature and stirred for 1.5 hours. The system was slowly added to a saturated sodium carbonate aqueous solution, the pH was adjusted to 8, and then extracted with dichloromethane. The organic phases were combined, dried, filtered, and concentrated to obtain 0.8 g of a pale yellow solid. ESI-MS: [M+H] + = 566.0.

[0253] (Step 8: Preparation of 5-((2-amino-3-fluoropyridine-4-yl)methyl)-2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluorobenzoic acid) 5-((2-amino-3-fluoropyridine-4-yl)methyl)-2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluorobenzoate methyl (1.1 g), tetrahydrofuran (20 mL), and water (20 mL) were sequentially added to a 100 mL necked flask and stirred in an ice bath. Lithium hydroxide monohydrate (250 mg) was slowly added to this system. After the addition was complete, the system was heated to room temperature and stirred and reacted for 2.5 hours. Hydrochloric acid (6 M) was added to the system to adjust the pH to 1-2, stirred for 5 minutes, and then concentrated under reduced pressure to remove the tetrahydrofuran from the system. Subsequently, the concentrate was diluted with water, stirred for 10 minutes, and then filtered. The filtered cake was collected and sequentially washed with water and methyl tert-butyl ether to obtain 900 mg of a pale yellow solid.

[0254] (Step 9: Preparation of N-allyl-5-((2-amino-3-fluoropyridine-4-yl)methyl)-2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluorobenzamide) 5-((2-amino-3-fluoropyridine-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 to a 50 mL necked flask 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 the mixture was stirred for 5 minutes. The mixture was then heated to room temperature and reacted for 2 hours. Allylamine hydrochloride (257 mg) and N,N-diisopropylethylamine (631 mg) were added to this system, and the mixture was stirred at room temperature and reacted for 2 hours. This reaction system was slowly added to a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined, dried, and concentrated. The concentrate was purified by silica gel column chromatography to obtain 580 mg of a pale yellow solid. ESI-MS: [M+H] + = 591.0.

[0255] (Step 10: Preparation of N-allyl-2-((5-chloro-2-fluoro-4-iodophenyl)amino)-3,4-difluoro-5-((3-fluoro-2-((N-methylaminosulfonyl)amino)pyridine-4-yl)methyl)benzamide) N-allyl-5-((2-amino-3-fluoropyridine-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 to a 25 mL necked flask and cooled to -20°C. Methylaminosulfonyl chloride (382 mg) was slowly added dropwise to the system. After the addition was complete, the system was stirred for 30 minutes. The system was poured into water and stirred at room temperature for 10 minutes, then subjected to suction filtration. The filtration cake was dissolved in ethyl acetate and washed with saturated brine. The organic phase was dried and concentrated. The concentrate was purified by silica gel column chromatography and further slurryed in an acetone / n-hexane mixed solvent (v / v=1 / 6, 105 mL) to obtain 320 mg of an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.41 (s, 1H), 9.06 (s, 1H), 8.85 (t, J = 5.2 Hz, 1H), 8.02 (d, J = 4.8 Hz, 1H), 7.77 (d, J = 10.4 Hz, 1H), 7.53 (d, J = 6.8 Hz, 1H), 7.06-7.00 (m, 2H), 6.95 (t, J = 4.8 Hz, 1H), 5.83-5.77 (m, 1H), 5.16-5.05 (m, 2H), 4.09 (s, 2H), 3.82 (t, J = 5.2 Hz, 2H), 2.52-2.51 (m, 3H). ESI-MS: [M+Na] + = 706.1.

[0256] [Preparation of control compound] Control compounds RefA-1 and RefA-7 were synthesized according to reference CN114929669A, and the structures of compounds A-1 and A-7 are as follows. [ka]

[0257] The therapeutic effect and safety of a drug in vivo are the result of the combined effect of multiple factors, including the inhibitory activity of the compound, various physicochemical properties, and factors such as absorption, metabolism, distribution, and excretion. The compounds of the present invention exhibit excellent efficacy and safety, and have a good therapeutic outlook.

[0258] [Biological Tests] (1. Proliferation inhibitory activity test against HCT116 in colorectal cancer cells) Cell proliferation activity was detected using the CellTiter-3D-Glo reagent method. The test procedure was as follows: HCT116 cells in the logarithmic growth phase were digested, diluted to an appropriate cell density in McCoy's 5A complete medium containing 10% FBS and 1% PS, inoculated into a low-adhesion 96-well U-bottom plate, and cultured in 5% CO2; then, a series of test compounds with a concentration gradient were added, and the system was cultured in a 5% CO2 incubator. After incubation, the cells were lysed and detected using the CellTiter-3D-Glo reagent. Chemiluminescence values ​​were measured with a microplate reader, and the data were fitted using Graphpad Prism software to determine the IC of the test substance. 50 The values ​​were calculated. The test results are shown in the table below. "A" indicates inhibitory activity IC 50 <20nM represents inhibitory activity, and "B" indicates inhibitory activity. 20nM ≤ IC 50 <50nM represents the inhibitory activity IC2. 50 This represents ≥50nM.

[0259] [Table 1]

[0260] The results in the table above show that the compound of the present invention exhibited significant cell proliferation inhibitory activity against colorectal cancer cells HCT116.

[0261] (2. Proliferation inhibitory activity test in a 3D model against colorectal cancer cells SW480) Cell proliferation activity was measured using the CellTiter-3D-Glo reagent method. The specific procedure was as follows: SW480 cells in the logarithmic growth phase were digested, diluted to an appropriate cell density in DMEM complete medium containing 10% FBS and 1% PS, inoculated into a low-adhesion 96-well U-bottom plate, and cultured in 5% CO2; then, a series of test compounds with a concentration gradient were added and cultured in a 5% CO2 incubator. After incubation, the cells were lysed and detected using the CellTiter-3D-Glo reagent. Chemiluminescence values ​​were measured with a microplate reader, and the data were fitted using Graphpad Prism software to determine the IC of the test substance. 50 The values ​​were calculated. The test results are shown in the table below.

[0262] [Table 2]

[0263] The test results showed that the compound of the present invention exhibits significant cell proliferation inhibitory activity against colorectal cancer cells SW480.

[0264] (3. Proliferation inhibitory activity test in a 3D model against lung cancer cell A427) Cell proliferation activity was measured using the CellTiter-3D-Glo reagent method. The specific procedure was as follows: A427 cells in the logarithmic growth phase were digested, diluted to an appropriate cell density in MEM complete medium containing 10% FBS and 1% PS, inoculated into a low-adhesion 96-well U-bottom plate, and cultured in 5% CO2; then, a series of test compounds with a concentration gradient were added and cultured in a 5% CO2 incubator. After incubation, the cells were lysed and detected using the CellTiter-3D-Glo reagent. Chemiluminescence values ​​were measured with a microplate reader, and the data were fitted using Graphpad Prism software to determine the IC of the test substance. 50 The values ​​were calculated. The test results are shown in the table below.

[0265] [Table 3]

[0266] The test results showed that the compound of the present invention exhibits significant cell proliferation inhibitory activity against lung cancer cells A427.

[0267] (4. Pharmacological studies of a subcutaneous xenograft tumor model of MIA pancreatic cancer cells PaCa-2) Animal species and number: BALB / c nude mice, 6 per group.

[0268] Experimental samples: Compound 4-1 and Compound 5-1.

[0269] Experimental 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).

[0270] Establishment of an animal model: MIA PaCa-2 tumor cells in the logarithmic growth phase were cultured, isolated in vitro, and subcutaneously inoculated into the right dorsal region of Balb / c nude mice. The tumors were approximately 180-250 mm in size. 3 When the tumors grew to a certain size, the tumor-carrying mice were randomly divided into groups. Subsequently, drugs were administered to the animals in each group, and day 1 of drug administration was defined as day 1 of the experiment.

[0271] Drug administration route and frequency: Oral forced administration, once daily for 15 consecutive days.

[0272] General condition observation: Mice will be observed once daily, and observations will include, but are not limited to, the local injection site, physical signs, general behavior, mental state, death and other circumstances, as well as other abnormal symptoms in the animals.

[0273] Calculation of tumor volume: V = 0.5a × b 2, a is the longest diameter of the tumor, and b is the shortest diameter of the tumor. The tumor growth inhibition rate (TGI) (%) was used to evaluate the antitumor effect of the compound. TGI (%) = [1 - (average tumor volume of the treatment group at the end of drug administration - average tumor volume of the treatment group at the start of drug administration) / (average tumor volume of the control group at the end of drug administration - average tumor volume of the control group at the start of drug administration)] × 100%.

[0274] "+" indicates a tumor suppression rate <60%, "++" indicates a tumor suppression rate between 60% and 90%, and "+++" indicates a tumor suppression rate >90%.

[0275] [Table 4]

[0276] Experimental results showed that compounds 4-1 and 5-1 exhibited a significant inhibitory effect on the proliferation of subcutaneously transplanted tumors of pancreatic cancer MIA PaCa-2 cells in nude mice. Furthermore, during the drug administration period, the food intake, body weight, and activity levels of the animals in each drug administration group remained normal, demonstrating good safety.

[0277] (5. Pharmacological studies of SW480 colorectal cancer cells in a subcutaneous xenograft tumor model) Animal species and number: BALB / c nude mice, 6 per group.

[0278] Experimental samples: Compound 4-1 and Compound RefA-1.

[0279] Experimental groups: Blank solvent control group, Compound 4-1 (0.2 mg / kg, QD × 18 days), Compound RefA-1 (0.2 mg / kg, QD × 18 days).

[0280] Establishment of an animal model: SW480 tumor cells in the logarithmic growth phase were cultured, isolated in vitro, and subcutaneously inoculated into the right dorsal region of Balb / c nude mice. The tumors were approximately 180-250 mm in size. 3 When the mice grew to maturity, those carrying tumors were randomly divided into groups. Then, drugs were administered to the animals in each group, and day 1 after drug administration was defined as day 1 of the experiment.

[0281] Drug administration route and frequency: Oral forced administration, once daily for 18 consecutive days.

[0282] General condition observation: Mice will be observed once daily, and observations will include, but are not limited to, the local injection site, physical signs, general behavior, mental state, death and other circumstances, as well as other abnormal symptoms in the animals.

[0283] Calculation of tumor volume: V = 0.5a × b 2 , a is the longest diameter of the tumor, and b is the shortest diameter of the tumor. The tumor growth inhibition rate (TGI) (%) was used to evaluate the antitumor effect of the compound. TGI (%) = [1 - (average tumor volume of the treatment group at the end of drug administration - average tumor volume of the treatment group at the start of drug administration) / (average tumor volume of the control group at the end of drug administration - average tumor volume of the control group at the start of drug administration)] × 100%.

[0284] "+" indicates a tumor suppression rate <60%, "++" indicates a tumor suppression rate of 60% to 80%, "+++" indicates a tumor suppression rate of 80% to 100%, and "++++" indicates a tumor suppression rate >100%.

[0285] [Table 5]

[0286] The experimental results showed that compound 4-1 exhibited a significant inhibitory effect on the proliferation of subcutaneously transplanted tumors of colorectal cancer SW480 cells in nude mice, demonstrating its considerable superiority over the control compound RefA-1.

[0287] (6. In vivo pharmacokinetic studies) A pharmacokinetic study of compound 4-1 was conducted in SD rats. Twelve SD rats (half male, half female) were selected and randomly divided into two groups (3 rats / sex per group) based on body weight, and recorded as Group 1 and Group 2. Compound 4-1 was administered at a dose of 0.2 mg / kg to Group 1 by intravenous administration, and to Group 2 by oral forced administration. All experimental animals received a single dose on day 0, and the time of drug administration was recorded as hour 0. From all experimental animals in Group 1, approximately 0.25 mL of whole blood (EDTA-K2) was collected before drug administration and at 5, 15, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration, and plasma was prepared. Similarly, from all experimental animals in Group 2, approximately 0.25 mL of whole blood (EDTA-K2) was collected before drug administration and at 15, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration, and plasma was prepared. Compounds in plasma samples were quantitatively measured by LC-MS / MS, and pharmacokinetic parameters were analyzed and calculated using non-compartmental analysis.

[0288] Experimental results showed that compound 4-1 demonstrated higher safety due to its higher absolute bioavailability (F% > 65%), as well as higher absorption and clearance rates.

Claims

【Request Item 1】 【Chemistry 1】 In the formula, W is selected from a bond, oxygen, or sulfur; V is nitrogen or CR ４ｅ Selected from; L is -NR １ C(O)-, -C(O)NR １ -, C ３－６ Cycloalkyl, 5-10 membered heterocyclyl, C ６－１０ Selected from aryls or 5- to 10-membered heteroaryls; R １ 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 and R ６ｃ Each of these is independently hydrogen, deuterium, halogen, aldehyde group, cyano, amino, hydroxyl, and C. １－６ Alkyl, C １－６ Alkyl deuterated, C １－６ Haloalkyl, C １－６ Alkoxy, C ２－６ Alkenil, C ２－６ Alkinyl, or C ３－６ Selected from cycloalkyl groups; or, two adjacent substituents together form a substituted or unsubstituted 3- to 10-membered ring structure; R ７ is hydrogen, C １－６ Alkyl, C １－６ Alkyl deuterated, C １－６ Haloalkyl, C １－６ Alkoxy, C ３－６ Cycloalkyl, C ２－６ Alkenyl, or C ２－６ Selected from alkynyl, alkyl, alkoxy, alkenyl, alkynyl and cycloalkyl are optional, and deuterium, halogen, amino, C １－６ Alkyl, C １－６ Alkoxy, C ２－６ Alkenil, C ２－６ Alkinyl and C ３－６ Substituted with one or more substituents selected from cycloalkyl groups; R ８ａ , R ８ｂ , R ８ｃ , R ８ｄ and R ８ｅ These are, independently, hydrogen, deuterium, halogen, and C. １－６ Alkyl, C １－６ Alkyl deuterated, C １－６ Haloalkyl or C ３－６ Selected from cycloalkyl; m is 0, 1, 2, or 3; n is 1, 2, 3, or 4; and, p is 0, 1, 2, or 3. A compound represented by formula (I), or its stereoisomer, tautomer, or pharmaceutically acceptable salt. 【Request Item 2】 【Chemistry 2】 In the formula, W is selected from a bond, oxygen, or sulfur; V is nitrogen or CR ４ｅ Selected from; R １ is hydrogen, halogen, C １－６ Alkyl, C １－６ Alkyl deuterated, C １－６ Haloalkyl, C １－６ Alkoxy, C ２－６ Alkenil, C ２－６ Alkinyl, or C ３－６ Selected from cycloalkyl; R ２ａ , R ２ｂ , R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ４ｃ , R ４ｄ , R ４ｅ , R ６ａ , R ６ｂ and R ６ｃ Each of these is independently hydrogen, deuterium, halogen, aldehyde group, cyano, amino, hydroxyl, and C. １－６ Alkyl, C １－６ Alkyl deuterated, C １－６ Haloalkyl, C １－６ Alkoxy, C ２－６ Alkenil, C ２－６ Alkinyl, or C ３－６ Selected from cycloalkyl groups; or, two adjacent substituents together form a substituted or unsubstituted 3- to 10-membered ring structure; R ７ 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, and alkyl, alkoxy, alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more substituents selected from deuterium, halogen, amino, C １－６ alkyl, C １－６ alkoxy, C ２－６ alkenyl, C ２－６ alkynyl and C ３－６ cycloalkyl; R ８ａ 、 R ８ｂ 、 R ８ｃ 、 R ８ｄ 以及R ８ｅ 各自独立地为氢、氘、卤素、C １－６ 烷基、C １－６ 氘代烷基、C １－６ 卤代烷基或C ３－６ 环烷基中选择的; n is 1, 2, 3, or 4; and, p is 0, 1, 2, or 3. A compound represented by formula (II), or its stereoisomer, tautomer, or pharmaceutically acceptable salt.

3. The following compounds, or their stereoisomers, tautomers, or pharmaceutically acceptable salts. 【Transformation 3】 【Request Item 4】 【Chemistry 4】 In the formula, W is selected from a bond, oxygen, or sulfur; V is nitrogen or CR ４ｅ Selected from; Ring A is C ６－１０ Selected from aryl or 5- to 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 and R ６ｃ Each of these is independently hydrogen, deuterium, halogen, aldehyde group, cyano, amino, hydroxyl, and C. １－６ Alkyl, C １－６ Alkyl deuterated, C １－６ Haloalkyl, C １－６ Alkoxy, C ２－６ Alkenil, C ２－６ Alkinyl, or C ３－６ Selected from cycloalkyl groups; or, two adjacent substituents together form a substituted or unsubstituted 3- to 10-membered ring structure; R ７ is hydrogen, C １－６ Alkyl, C １－６ Alkyl deuterated, C １－６ Haloalkyl, C １－６ Alkoxy, C ３－６ Cycloalkyl, C ２－６ Alkenyl, or C ２－６ Selected from alkynyl, alkyl, alkoxy, alkenyl, alkynyl and cycloalkyl are optional, and deuterium, halogen, amino, C １－６ Alkyl, C １－６ Alkoxy, C ２－６ Alkenil, C ２－６ Alkinyl and C ３－６ Substituted with one or more substituents selected from cycloalkyl groups; R ８ａ , R ８ｂ , R ８ｃ , R ８ｄ and R ８ｅ These are, independently, hydrogen, deuterium, halogen, and C. １－６ Alkyl, C １－６ Alkyl deuterated, C １－６ Haloalkyl or C ３－６ Selected from cycloalkyl; m is 0, 1, 2, or 3; n is 1, 2, 3, or 4; p is 0, 1, 2, or 3. A compound represented by formula (III), or its stereoisomer, tautomer, or pharmaceutically acceptable salt.

5. The following compounds, or their stereoisomers, tautomers, or pharmaceutically acceptable salts. 【Transformation 5】 【Request Item 6】 【Transformation 6】 In the formula, U is nitrogen or CR ５ｄ Selected from; V is nitrogen or CR ４ｅ Selected from; 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 and R ６ｃ Each of these is independently hydrogen, deuterium, halogen, aldehyde group, cyano, amino, hydroxyl, and C. １－６ Alkyl, C １－６ Alkyl deuterated, C １－６ Haloalkyl, C １－６ Alkoxy, C ２－６ Alkenil, C ２－６ Alkinyl, or C ３－６ Selected from cycloalkyl groups; or, two adjacent substituents together form a substituted or unsubstituted 3- to 10-membered ring structure; R ７ is hydrogen, C １－６ Alkyl, C １－６ Alkyl deuterated, C １－６ Haloalkyl, C １－６ Alkoxy, C ３－６ Cycloalkyl, C ２－６ Alkenyl, or C ２－６ Selected from alkynyl, alkyl, alkoxy, alkenyl, alkynyl and cycloalkyl are optional, and deuterium, halogen, amino, C １－６ Alkyl, C １－６ Alkoxy, C ２－６ Alkenil, C ２－６ Alkinyl, or C ３－６ Substituted with one or more substituents selected from cycloalkyl groups; R ８ａ , R ８ｂ , R ８ｃ , R ８ｄ and R ８ｅ These are, independently, hydrogen, deuterium, halogen, and C. １－６ Alkyl, C １－６ Alkyl deuterated, C １－６ Haloalkyl or C ３－６ Selected from cycloalkyl groups; and, n is 1, 2, 3, or 4. A compound represented by formula (IV), or its stereoisomer, tautomer, or pharmaceutically acceptable salt. 【Request Item 7】 【Chemistry 7】 In the formula, U is selected from nitrogen or CH; V is nitrogen or CR ４ｅ Selected from; R ４ａ , R ４ｂ , R ４ｃ , R ４ｄ and R ４ｅ Each of these is independently hydrogen, deuterium, halogen, aldehyde group, hydroxyl, and C. １－６ Alkyl, C １－６ Alkoxy, C ２－６ Alkenil, C ２－６ Alkinyl, or C ３－６ Selected from cycloalkyl; R ５ｃ , R ６ｂ and R ６ｃ Each of these is independently hydrogen, halogen, or C １－６ Selected from alkyl groups; R ７ is hydrogen, C １－６ Alkyl, C １－６ Alkyl deuterated, or C ３－６ Selected from cycloalkyl; R ８ａ , R ８ｂ , R ８ｃ , R ８ｄ and R ８ｅ Each of these is independently hydrogen, deuterium, or C １－６ Selected from alkyl groups; and, n is 1, 2, or 3. A compound represented by formula (IV-1), or its stereoisomer, tautomer, or pharmaceutically acceptable salt.

8. The following compounds, or their stereoisomers, tautomers, or pharmaceutically acceptable salts. 【Transformation 8】

9. The following compounds, or their stereoisomers, tautomers, or pharmaceutically acceptable salts. 【Chemistry 9】

10. The following compounds, or their stereoisomers, tautomers, or pharmaceutically acceptable salts. 【Chemistry 10】 【Chemistry 11】 【Request Item 11】 【Chemistry 12】 In the formula, U is selected from nitrogen or CH; V is nitrogen or CR ４ｅ Selected from; R ４ａ , R ４ｂ , R ４ｃ , R ４ｄ , R ４ｅ , R ５ｃ , R ６ｂ and R ６ｃ Each of these is independently hydrogen, deuterium, halogen, aldehyde group, cyano, amino, hydroxyl, and C. １－６ Alkyl, C １－６ Alkyl deuterated, C １－６ Haloalkyl, C １－６ Alkoxy, C ２－６ Alkenil, C ２－６ Alkinyl, or C ３－６ Selected from cycloalkyl groups; or, two adjacent substituents together form a substituted or unsubstituted 3- to 10-membered ring structure; R ７ is hydrogen, C １－６ Alkyl, C １－６ Alkyl deuterated, C １－６ Haloalkyl, C １－６ Alkoxy, C ３－６ Cycloalkyl, C ２－６ Alkenyl, or C ２－６ Selected from alkynyl, alkyl, alkoxy, alkenyl, alkynyl and cycloalkyl are optional, and deuterium, halogen, amino, C １－６ Alkyl, C １－６ Alkoxy, C ２－６ Alkenil, C ２－６ Alkinyl and C ３－６ Substituted with one or more substituents selected from cycloalkyl groups; R ８ａ , R ８ｂ , R ８ｃ , R ８ｄ and R ８ｅ These are, independently, hydrogen, deuterium, halogen, and C. １－６ Alkyl, C １－６ Alkyl deuterated, C １－６ Haloalkyl or C ３－６ Selected from cycloalkyl groups; and, n is 1, 2, 3, or 4. A compound represented by formula (V), or its stereoisomer, tautomer, or pharmaceutically acceptable salt.

12. The following compounds, or their stereoisomers, tautomers, or pharmaceutically acceptable salts. 【Chemistry 13】

13. A pharmaceutical composition comprising a therapeutically effective amount of a 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 a compound according to any one of claims 1 to 12, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13, in the preparation of a pharmaceutical for the prevention and / or treatment of tumors.

15. Use of a compound according to any one of claims 1 to 12, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13, in the preparation of a pharmaceutical for the prevention and / or treatment of a disease mediated by RAF and / or MEK, wherein the disease is preferably a tumor.

16. The use according to claim 14 or claim 15, wherein the tumor includes kidney 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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