Drak2 inhibitors, their manufacturing methods, and uses

Abstract

Provided are compounds of formula I or stereoisomers or optical isomers, pharma- ceutically acceptable salts, prodrugs or solvates thereof that are useful as Drak2 inhibitors, as well as methods for making said compounds, pharmaceutical compositions, their use as Drak2 inhibitors, and their use in the manufacture of a medicament for preventing and / or treating diseases associated with Drak2. [Formula 1] JPEG2024544556000170.jpg3972

Description

[Technical Field]

[0001] This invention belongs to the field of drug chemistry and specifically relates to Drak2 inhibitors, methods for producing the same, and their use. [Background technology]

[0002] Drak2 (Death-Associated Related Apoptotic Protein Kinase 2) is a member of the DAPK family of cell death-associated protein kinases, and is abundantly expressed in the thymus, spleen, and lymph nodes, primarily involved in regulating apoptosis.

[0003] The literature has shown that in pancreatic islet β-cells treated with free fatty acids (FFA) and inflammatory cytokines (IL-1β, IFNγ, TNFα), both Drak2 gene and protein levels rise sharply, accompanied by increases in anti-apoptotic factors such as Bcl-2, Bcl-xL, and Flip. Upregulation of these gene and protein levels promotes increased apoptosis in pancreatic islet β-cells and reduces insulin secretion. Simultaneously, Drak2-gene-modified mice exhibited inferior glucose tolerance after obesity was induced with a high-fat diet, demonstrating that Drak2 is detrimental to pancreatic islet β-cell survival under simulated inflammatory and hyperlipidemia pathological conditions. Therefore, Drak2 may be a novel target for preventing apoptosis in pancreatic islet β-cells, restoring their function, and fundamentally treating type 2 diabetes.

[0004] In addition to its involvement in regulating apoptosis, Drak2 also possesses immunomodulatory functions, playing a role in the negative regulation of T cell activation and being closely involved in T cell survival and differentiation, tumor immunomodulation, and autoimmunity. Therefore, the development of new Drak2 inhibitors is necessary. [Overview of the project] [Problems that the invention aims to solve]

[0005] An object of the present invention is to provide a novel Drak2 inhibitor with broad prospects for clinical applications in the future.

Means for Solving the Problems

[0006] In a first aspect of the present invention, there is provided a compound represented by formula I or a stereoisomer or optical isomer thereof, a pharmaceutically acceptable salt, prodrug or solvate.

Chemical formula

[0007] In another preferred example, the compound or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate has a structure represented by formula II. [ka] (Here, X1, X2, X3, X5, ring A, ring B, R m , R p The definitions of n and n are as described above.

[0008] In another preferred example, ring A is selected from a phenyl group, a C5-C6 cycloalkyl group, a 5-6 membered heteroaryl group, or a 5-6 membered heteroaryl group, and is preferably a phenyl group. In another preferred example, ring B is a 5-6 membered heteroaryl group, preferably a thienyl group or a thiazolyl group.

[0009] In another preferred example, the compound or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs, or solvates have a structure represented by formula III. [ka] (Here, X4 is N or CR m10 Selected from, here, R m10 is selected from H, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkylamine groups, C3-C12 cycloalkyl groups, 3-12 membered heterocyclic groups, C6-C10 aryl groups, or 5-12 membered heteroaryl groups, or R m6 and R m7 These, together with adjacent N atoms, constitute a 3-12 membered heterocyclic group, where the C1-C6 alkyl group, C1-C6 alkoxy group, C3-C12 cycloalkyl group, 3-12 membered heterocyclic group, C6-C10 aryl group, or 5-12 membered heteroaryl group are optionally substituted with 1-3 R atoms. R' is selected from H, D, halogen, cyano group, hydroxyl group, carboxyl group, NH2, C1-C6 alkyl group, C1-C6 alkoxy group, and C1-C6 alkylamine group, and is preferably H. R, X1, X2, X3, X5, Ring A, R m , R p The definitions of n and n are as described above. In another preferred example, [ka] teeth, [ka] and preferably [Chemical formula] is as follows. In another preferred example, the compound or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate has a structure represented by formula IV. [Chemical formula] (where R1, R2, R3, R4, R5 are each independently H, D, halogen, cyano group, hydroxy group, carboxy group, -S(O) t R m5 , -C(O)R m5 , -C(O)OR m5 , -C(O)NR m6 R m7 , -S(O) t NR m6 R m7 , -C(O)NR m8 S(O) t NR m6 R m7 , -(CH2) q S(O) t R m5 , -(CH2) q C(O)R m5 , -(CH2) q C(O)OR m5 , -(CH2) q C(O)NR m6 [[ID=^3]]R m7 , -(CH2)[[ID=6j]] q (CH2) q S(O) t NR m6 R m7 , -C(O)NR m8 S(O) t NR m6 R m7 , -(CH2) q R m9 It should be noted that there seem to be some unclear or incorrect tags in the original text (such as "R " in multiple places which might be an error in the original tagging). This translation is done based on the best understanding of the provided content.A C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamine group, a C3-C12 cycloalkyl group, a 3-12 membered heterocyclic group, a C6-C10 aryl group, or a 5-12 membered heteroaryl group is selected, where the C1-C6 alkyl group, C1-C6 alkoxy group, C3-C12 cycloalkyl group, 3-12 membered heterocyclic group, or C6-C10 aryl group is optionally substituted with 1 to 3 R atoms. Alternatively, R1 and R2, or R2 and R3, or R3 and R4, or R4 and R5 together with adjacent C atoms constitute a 5-6 membered heterocyclic group, where the 5-6 membered heterocyclic group is optionally substituted with 1-3 R atoms. R' is selected from H, D, halogen, cyano group, hydroxyl group, carboxyl group, NH2, C1-C6 alkyl group, C1-C6 alkoxy group, and C1-C6 alkylamine group, and is preferably H. t, q, R, R m5 , R m6 , R m7 , R m8 , R m9 X1, X2, X3, X5, R p The definitions of n and n are as described above.

[0010] In another preferred example, R1 is H. In another preferred example, R4 is H. In another preferred example, R5 is H. In another preferred example, R1 is H, R4 is H, and R5 is H. In another preferred example, R2 is a C1-C6 alkoxy group (preferably a methoxy group).

[0011] In another preferred example, R3 is a C1-C6 alkoxy group (preferably a methoxy group), C(O)NR m6 R m7 Or S(O)2NR m6 R m7 And here, R m6 and R m7 The definition is as stated above. In another preferred example, R3 is a C1-C6 alkoxy 3-6 member heterocyclic group (preferably an -O-CH2-3-6 member heterocyclic group, an -O-CH2CH2-3-6 member heterocyclic group, etc.), and the C1-C6 alkoxy 3-6 member heterocyclic group may be substituted with 1-4 halogens and C1-C6 alkyl groups.

[0012] In another preferred example, the compound or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate has the structure represented by formula A. [ka] (Here, R6 is selected from H, D, halogen, cyano group, hydroxyl group, carboxyl group, NH2, C1-C6 alkyl group, C1-C6 alkoxy group, and C1-C6 alkylamine group, and is preferably H. R7 is selected from C1-C15 alkyl groups, C1-C15 alkoxy groups, C1-C15 alkylamine groups, C3-C12 cycloalkyl groups, 3-12 member heterocyclic groups, C6-C10 aryl groups, or 5-12 member heteroaryl groups, where the C1-C15 alkyl groups, C1-C15 alkoxy groups, C1-C15 alkylamine groups, C3-C12 cycloalkyl groups, 3-12 member heterocyclic groups, C6-C10 aryl groups, or 5-12 member heteroaryl groups. The reel group is optionally substituted with 1 to 3 groups selected from the group consisting of D, halogen, cyano group, hydroxyl group, carboxyl group, NH2, oxo group (=O), C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 alkylamine group, C(O)OC1-C6 alkyl group, S(O)2C1-C6 alkyl group, C3-C12 cycloalkyl group, 3-12 membered heterocyclic group, C6-C10 aryl group, or 5-12 membered heteroaryl group. The definitions of R1, R2, R3, R4, and R5 are as described above.

[0013] In another preferred example, R2 and R3 together with adjacent C atoms constitute a 5-6 membered heterocyclic group, preferably R2 and R3 together with adjacent C atoms [ka] It constitutes [something].

[0014] In another preferred example, the compound or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs, or solvates have a structure represented by formula B. [ka] (Here, R7 is selected from C1-C15 alkyl groups, C1-C15 alkoxy groups, C1-C15 alkylamine groups, C3-C12 cycloalkyl groups, 3-12 member heterocyclic groups, C6-C10 aryl groups, or 5-12 member heteroaryl groups, where the C1-C15 alkyl groups, C1-C15 alkoxy groups, C1-C15 alkylamine groups, C3-C12 cycloalkyl groups, 3-12 member heterocyclic groups, C6-C10 aryl groups, or 5-12 member heteroaryl groups. The reel group is optionally substituted with 1 to 3 groups selected from the group consisting of D, halogen, cyano group, hydroxyl group, carboxyl group, NH2, oxo group (=O), C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 alkylamine group, C(O)OC1-C6 alkyl group, S(O)2C1-C6 alkyl group, C3-C12 cycloalkyl group, 3-12 membered heterocyclic group, C6-C10 aryl group, or 5-12 membered heteroaryl group. R8 and R9 are independently H, S(O)2NR 11 R 12, selected from C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkylamine groups, C3-C12 cycloalkyl groups, 3-12 membered heterocyclic groups, C6-C10 aryl groups or 5-12 membered heteroaryl groups, or R8 and R9 together with adjacent N atoms constitute a 3-12 membered heterocyclic group (preferably a 5-6 membered heterocyclic group), where the C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C12 cycloalkyl groups, 3-12 membered heterocyclic groups, 5-6 membered heterocyclic groups, C6 - The C10 aryl group or 5-12 membered heteroaryl group is optionally substituted with 1 to 3 groups selected from the group consisting of C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkylamine groups, C(O)OC1-C6 alkyl groups, S(O)2C1-C6 alkyl groups, C3-C12 cycloalkyl groups, C1-C6 alkylC3-C12 cycloalkyl groups, 3-12 membered heterocyclic groups, C1-C6 alkyl3-12 membered heterocyclic groups, C6-C10 aryl groups, or 5-12 membered heteroaryl groups. R 11 and R 12 Each of these is independently selected from H, a C1-6 alkyl group, a C3-C12 cycloalkyl group, a 3-12 membered heterocyclic group, a C6-C10 aryl group, or a 5-12 membered heteroaryl group.

[0015] In another preferred example, [ka] teeth, [ka] They are selected from among them.

[0016] In another preferred example, the compound or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate has a structure represented by formula C. [ka] (Here, R 10It is selected from H, cyano group, and CONH2. R7 is selected from C1-C15 alkyl groups, C1-C15 alkoxy groups, C1-C15 alkylamine groups, C3-C12 cycloalkyl groups, 3-12 membered heterocyclic groups, C6-C10 aryl groups, or 5-12 membered heteroaryl groups, among which the C1-C15 alkyl groups, C1-C15 alkoxy groups, C1-C15 alkylamine groups, C3-C12 cycloalkyl groups, 3-12 membered heterocyclic groups, C6-C10 aryl groups, or 5-12 membered heteroaryl groups. The reel group is optionally substituted with 1 to 3 groups selected from the group consisting of D, halogen, cyano group, hydroxyl group, carboxyl group, NH2, oxo group (=O), C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 alkylamine group, C(O)OC1-C6 alkyl group, S(O)2C1-C6 alkyl group, C3-C12 cycloalkyl group, 3-12 membered heterocyclic group, C6-C10 aryl group, or 5-12 membered heteroaryl group.

[0017] In another preferred example, X1 is N or CH. In another preferred example, X2 is N or CH. In another preferred example, X3 is N, CC(=O)NH2, or C-CN. In another preferred example, X5 is N or CH.

[0018] In another preferred example, [ka] teeth, [ka] That is the case. In another suitable example, L is a combination. In another preferred example, L is NH.

[0019] In another preferred example, ring A is a C6-C10 aryl group or a 3-12 membered heterocyclic group, where the 3-12 membered heterocyclic group is preferably a 5-7 membered heterocyclic group, more preferably a 6 membered heterocyclic group, and the substituent in ring A is defined as the above R m This is similar to (the number of substituents is similar to n).

[0020] In another preferred example, ring A is a benzene ring, [ka] Therefore, the definition of a substituent in ring A (the substituent can be at any position where H is located, including H in -NH-) is as described above in R m This is similar to (the number of substituents is similar to n).

[0021] In another preferred example, ring B is a 5-12 membered heteroaryl group or a C3-C12 cycloalkyl group, preferably a 5-membered heteroaryl group or a 6-membered cycloalkyl group, and the definition of substituents in ring B is the same as for R above.

[0022] In another preferred example, ring B is [ka] Therefore, the definition of substituents in ring B is the same as for R above.

[0023] In another preferred example, R m These are methoxy groups, fluorine, chlorine, cyano groups, hydroxyl groups, carboxyl groups, carboxamide groups, [ka] That is the case.

[0024] In another preferred example, R n teeth, [ka] That is the case.

[0025] In another preferred example, the compound has a structure represented by formula I'. [ka] (Here, X is selected from either O or CH2. X1 is N or CR m1 They are selected from among them. X2 is N or CR m2 They are selected from among them. X3 is N or CR m3 They are selected from among them. X5 is N or CR' m3 They are selected from among them. L stands for bond, -O-, -S, -NR m4 -, -C(O)- or -C(O)NR m4 - will be selected from. Ring A and Ring B are independently selected from a C3-C12 cycloalkyl group, a 3-12 membered heterocyclic group, a C6-C10 aryl group, and a 5-12 membered heteroaryl group, wherein the C3-C12 cycloalkyl group, the 3-12 membered heterocyclic group, the C6-C10 aryl group, and the 5-12 membered heteroaryl group are optionally substituted with 1 to 3 R atoms. Each R m These are independently H, D, halogen, cyano group, hydroxyl group, carboxyl group, and -S(O) t R m5 , -C(O)R m5 , -C(O)OR m5 -C(O)NR m6 R m7 , -S(O) t NR m6 R m7 -C(O)NR m8 S(O) t NR m6 R m7 ,-(CH2) q S(O) t R m5 ,-(CH2) q C(O)R m5 ,-(CH2) q C(O)OR m5 ,-(CH2) qC(O)NR m6 R m7 ,-(CH2) q (CH2) q S(O) t NR m6 R m7 -C(O)NR m8 S(O) t NR m6 R m7 ,-(CH2) q R m9 A C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamine group, a C3-C12 cycloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a 3-12 membered heterocyclic group, a C6-C10 aryl group, or a 5-12 membered heteroaryl group is selected, where the C1-C6 alkyl group, C1-C6 alkoxy group, C3-C12 cycloalkyl group, 3-12 membered heterocyclic group, or C6-C10 aryl group is optionally substituted with 1-3 R atoms. Alternatively, two R atoms in adjacent ring atoms m These atoms, together with adjacent ring atoms, constitute a C3-C12 cycloalkyl group or a 3-12 membered heterocyclic group, where the C3-C12 cycloalkyl group or 3-12 membered heterocyclic group is optionally substituted with 1 to 3 R atoms. R n is H, C1-C15 alkyl group, C2-C15 alkenyl group, C2-C15 alkynyl group, C(O)R p Selected from, here, R p The group is selected from NH2, a C1-C15 alkyl group, a C1-C15 alkoxy group, a C1-C15 alkylamine group, a C2-C15 alkenyl group, a C2-C15 alkynyl group, a C3-C12 cycloalkyl group, a 3-12 membered heterocyclic group, a C6-C10 aryl group, or a 5-12 membered heteroaryl group, where the C1-C15 alkyl group, C1-C15 alkoxy group, C1-C15 alkylamine group, C3-C12 cycloalkyl group, a 3-12 membered heterocyclic group, a C6-C10 aryl group, or a 5-12 membered heteroaryl group is optionally substituted with 1 to 3 R atoms. R m1 , R m2 , R m3 and R' m3Each of these is independently selected from H, a cyano group, a halogen, C(O)NH2, a carboxyl group, S(O)2NH2, a C(O)OC1-C6 alkyl group, or an S(O)2C1-C6 alkyl group. R m4 It is selected from H or C1-C6 alkyl groups. R m5 The group is selected from a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamine group, a C3-C12 cycloalkyl group, a 3-12 membered heterocyclic group, a C6-C10 aryl group, or a 5-12 membered heteroaryl group, where the C1-C6 alkyl group, C1-C6 alkoxy group, C3-C12 cycloalkyl group, a 3-12 membered heterocyclic group, a C6-C10 aryl group, or a 5-12 membered heteroaryl group is optionally substituted with 1 to 3 R atoms. R m6 , R m7 , R m8 and R m9 Each of these is independently selected from H, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkylamine groups, C3-C12 cycloalkyl groups, 3-12 membered heterocyclic groups, C6-C10 aryl groups, or 5-12 membered heteroaryl groups, or R m6 and R m7 These, together with adjacent N atoms, constitute a 3-12 membered heterocyclic group, where the C1-C6 alkyl group, C1-C6 alkoxy group, C3-C12 cycloalkyl group, 3-12 membered heterocyclic group, C6-C10 aryl group, or 5-12 membered heteroaryl group are optionally substituted with 1-3 R atoms. (CH2) q In this case, H is arbitrarily replaced by R. R is selected from H, D, halogen, cyano group, hydroxyl group, carboxyl group, NH2, oxo group (=O), C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 alkylamine group, C(O)OC1-C6 alkyl group, S(O)2C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C12 cycloalkyl group, 3-12 membered heterocyclic group, C6-C10 aryl group, or 5-12 membered heteroaryl group, where the above The C1-C6 alkyl group, C1-C6 alkoxy group, C3-C12 cycloalkyl group, 3-12 membered heterocyclic group, C6-C10 aryl group, or 5-12 membered heteroaryl group is optionally substituted with 1 to 3 groups selected from the group consisting of halogens, cyano groups, hydroxyl groups, carboxyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkylamine groups, C(O)OC1-C6 alkyl groups, and S(O)2C1-C6 alkyl groups. t is 0, 1, or 2. q is 1, 2, 3, 4, 5, or 6. n is 1, 2, 3, 4, 5, or 6.

[0026] In another preferred example, [ka] is OR p And here, R pis a C1-C15 alkyl group (preferably a C1-C6 alkyl group), where the C1-C15 alkyl group (preferably a C1-C6 alkyl group) is optionally substituted with 1, 2, or 3 R groups, where R is a C1-C15 alkylamine group, and the C1-C15 alkylamine group is optionally substituted with 1, 2, or 3 groups selected from the group consisting of halogen, cyano group, hydroxyl group, carboxyl group, C1-C6 alkyl group, C1-C6 haloalkyl group, C6-C10 aryl group substituted with a C1-C6 haloalkyl group, C1-C6 haloalkoxy group, C6-C10 aryl group substituted with a C1-C6 haloalkoxy group, C(O)C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 alkylamine group, C(O)OC1-C6 alkyl group, and S(O)2C1-C6 alkyl group, preferably, [ka] teeth [ka] That is the case.

[0027] In another preferred example, the compound satisfies one or more of the following conditions: (1) X1 is N or CH; (2) X2 is N or CH; (3) X3 is N, CC(=O)NH2 or C-CN; (4) X5 is N or CH; (5) L is a bond or NH; (6) Ring A is a C6-C10 aryl group or a 3-12 membered heterocyclic group, where the 3-12 membered heterocyclic group is preferably a 5-7 membered heterocyclic group, more preferably a 6 membered heterocyclic group, and preferably ring A is a benzene ring, [ka] Therefore, the definition of a substituent in ring A (the substituent can be at any position where H is located, including H in -NH-) is as described above in R m It is similar to (the number of substituents is the same as n); (7) Ring B is a 5-12 member heteroaryl group or a C3-C12 cycloalkyl group, preferably a 5-membered heteroaryl group or a 6-membered cycloalkyl group, preferably ring B is [ka] Therefore, the definition of substituents in ring B is the same as for R above; (8)R m These are methoxy groups, fluorine, chlorine, cyano groups, hydroxyl groups, carboxyl groups, carboxamide groups, [ka] is; (9)R n teeth, [ka] H, acetyl group, isobutyryl group, [ka] Cyclopropyl carbonyl group, cyclobutyl carbonyl group, cyclopentyl carbonyl group, cyclohexyl carbonyl group, phenyl carbonyl group, cyclopropyl methylene carbonyl group, cyclobutyl methylene carbonyl group, cyclopentyl methylene carbonyl group, cyclohexyl methylene carbonyl group or [ka] is; especially, [ka] teeth, [ka] That is the case.

[0028] In another preferred example, X1, X2, X3, X5, ring A, ring B, R m , R p, n, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 represents the corresponding group of each specific compound in the examples.

[0029] In another preferred example, R is selected from C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkylamine groups, C(O)OC1-C6 alkyl groups, S(O)2C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C12 cycloalkyl groups, 3-12 membered heterocyclic groups, C6-C10 aryl groups, or 5-12 membered heteroaryl groups, where C1-C6 alkyl groups, C1-C6 alkoxy groups, C3-C12 cycloalkyl groups, 3-12 membered heterocyclic groups, and C6-C10 aryl groups. The group or 5-12 membered heteroaryl group is optionally substituted with 1-3 groups selected from the group consisting of halogen, cyano, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl-substituted C6-C10 aryl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, C1-C6 haloalkoxy-substituted C6-C10 aryl group, and C(O)C1-C6 alkylC1-C6 alkylamine group, C(O)OC1-C6 alkyl group, and S(O)2C1-C6 alkyl group.

[0030] In another suitable example, Rn is C(O)R p Selected from, here, R p The C1-C15 alkyl group (preferably a C1-C6 alkyl group) is selected from C1-C15 alkyl groups (preferably a C1-C6 alkyl group), where the C1-C15 alkyl group (preferably a C1-C6 alkyl group) is optionally substituted with 1, 2, or 3 R groups, where the R groups are selected from C3-C12 cycloalkyl groups, where the C3-C12 cycloalkyl group is optionally substituted with 1, 2, or 3 groups selected from the group consisting of C1-C6 alkyl groups, C1-C6 haloalkyl groups, C6-C10 aryl groups substituted with C1-C6 haloalkoxy groups, and C(O)C1-C6 alkyl groups.

[0031] In another suitable example, Rn is OR p Selected from, here, R p The group is selected from C1-C15 alkyl groups, where the C1-C15 alkyl group is optionally substituted with 1, 2, or 3 R groups, where R is selected from C1-C15 alkylamine groups, and the C1-C15 alkylamine group is optionally substituted with 1, 2, or 3 groups selected from the group consisting of halogen, cyano group, hydroxyl group, carboxyl group, C1-C6 alkyl group, C1-C6 haloalkyl group, C6-C10 aryl group substituted with a C1-C6 haloalkyl group, C1-C6 haloalkoxy group, C6-C10 aryl group substituted with a C1-C6 haloalkoxy group, C(O)C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 alkylamine group, C(O)OC1-C6 alkyl group, and S(O)2C1-C6 alkyl group.

[0032] In another preferred example, ring A is [ka] The substituents in ring A (the substituents may be at any position where H is located, including H in -NH-) are selected from the above R m This is similar to (the number of substituents is similar to n).

[0033] In another preferred example, [ka] teeth, [ka] Selected from, here, R m The definition is as stated above.

[0034] In another preferred example, ring B is [ka] The substituents are selected from the above, and the definition of substituents in ring B is the same as for R above.

[0035] In another preferred example, R m teeth, [ka] They are selected from among them.

[0036] In another suitable example, Rn is [ka] They are selected from among them. In another suitable example, n is 0.

[0037] In another preferred example, the compound is selected from the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0038] In a second aspect of the present invention, a drug composition is provided comprising a compound described in the first aspect or its stereoisomer or optical isomer, a pharmaceutically acceptable salt, a prodrug or solvate, and a pharmaceutically acceptable carrier.

[0039] In another preferred example, a method for producing a drug composition is provided, comprising the step of forming a drug composition by mixing a pharmaceutically acceptable carrier with a compound or its stereoisomer or optical isomer, a pharmaceutically acceptable salt, a prodrug or solvate described in the first aspect of the present invention.

[0040] In another preferred example, the compound of the present invention may be prepared as a powder, tablet, granule, capsule, solution, emulsion, suspension, etc.

[0041] A third aspect of the present invention provides the use of the compounds described in the first aspect or their stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates or drug compositions described in the second aspect for the manufacture of drugs that treat or prevent diseases related to the activity or expression level of Drak2 kinase, or for the manufacture of drugs that inhibit the activity of Drak2 kinase.

[0042] Preferably, the disease is cancer, an autoimmune disease, or a metabolic disease. Here, the cancers are preferably malignant lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic osteomyelitis, diffuse large B-cell lymphoma, multiple myeloma, non-Hodgkin lymphoma, pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, basal cell carcinoma, breast cancer, brain cancer, adrenal cancer, kidney cancer, nephroblastoma, gastric cancer, gastrointestinal stromal tumor, pituitary adenoma, pancreatic cancer, gallbladder cancer, bile duct cancer, colon cancer, rectal cancer, small intestine cancer, duodenal cancer, retinoblastoma, choroidal melanoma, papillary carcinoma, bladder cancer. Bladder cancer, peritoneal cancer, parathyroid cancer, nasal and paranasal sinus cancer, small cell lung cancer, non-small cell lung cancer (lung adenocarcinoma, lung squamous cell carcinoma), astrocytoma, esophageal cancer, gliocytoma, neuroblastoma, malignant soft tissue tumor, malignant bone tumor, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, penile cancer, oral cancer, lip cancer, pharyngeal cancer, epithelial ovarian cancer, ovarian germ cell carcinoma, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, vaginal cancer, Paget's disease, tonsil cancer, anal cancer, rhabdomyosarcoma, Kaposi's sarcoma, sarcoma, tongue cancer, laryngeal cancer, pleural cancer, thymic cancer, or a combination thereof. The autoimmune disease is preferably selected from inflammatory colitis, Crohn's disease, Behçet's disease, multiple sclerosis, macular degeneration, arthritis, encephalitis, viral meningitis, or a combination thereof. The metabolic disease is preferably selected from diabetes mellitus, and the diabetes mellitus is preferably type 1 diabetes mellitus or type 2 diabetes mellitus, more preferably type 2 diabetes mellitus.

[0043] Of course, within the scope of the present invention, it is understood that the above-mentioned technical features of the present invention and the technical features specifically described below (for example, in the examples) can be combined to form new or preferred technical solutions. Due to space limitations, a detailed explanation will not be provided here. [Modes for carrying out the invention]

[0044] Through extensive and in-depth research, the inventors unexpectedly discovered a novel Drak2 inhibitor with a unique structure, good biological activity, and safety. Based on this, the present invention was completed.

[0045] term In this invention, unless otherwise specifically stated, terms used have the general meanings known to those skilled in the art. When a substituent is described using a standard chemical formula written from left to right, that substituent includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0046] As used herein, when used with specific example numbers, the term “approximately” means that the value may vary by no more than 1% from the example number. For example, as used herein, the expression “approximately 100” includes 99, 101 and all values ​​in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0047] As used herein, the terms “contains” or “includes” may be open, semi-closed, or closed. In other words, the terms also include “basically composed of…” or “composed of…”.

[0048] As used herein, the term “alkyl group” includes linear or branched alkyl groups. For example, a C1-C6 alkyl group represents a linear or branched alkyl group having 1 to 6 carbon atoms, and the alkyl group is preferably C1-C 15 Alkyl alkyl groups, moreover C1-C 10 The alkyl group is, more preferably, a C1-C6 alkyl group, more preferably a C1-C4, and more preferably a C1-C3. The alkyl group includes, but is not limited to, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, and the like. In the present invention, the alkyl group may be optionally substituted or unsubstituted, and the substituted alkyl group includes a haloalkyl group, a benzyl group, and the like.

[0049] As used herein, the term “alkenyl group” includes linear or branched alkenyl groups. For example, a C2-C6 alkenyl group is a linear or branched alkenyl group having 2-6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, and similar groups.

[0050] As used herein, the term “alkynyl group” includes linear or branched alkynyl groups. For example, a C2-C6 alkynyl group is a linear or branched alkynyl group having 2-6 carbon atoms, such as ethynyl, propagyl, butynyl, and similar groups.

[0051] As used herein, the term "cycloalkyl group" refers to a cyclic alkyl group containing a specific number of carbon atoms. For example, "C3-C10 cycloalkyl group" refers to a cycloalkyl group having 3 to 10 (preferably 3, 4, 5, 6, 7, or 8) carbon atoms. Monocyclic groups are also possible, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and similar groups. Bicyclic groups are also possible, such as bridging rings and spiro rings. In this invention, "cycloalkyl group" includes substituted cycloalkyl groups.

[0052] As used herein, the term "C1-C6 alkoxy group" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms and having the formula C1-C6 alkyl-O-, such as a methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, t-butoxy group, etc.

[0053] As used herein, the term "cycloalkyl group" refers to a cyclic alkyl group containing a specific number of carbon atoms. For example, "C3-C12 cycloalkyl group" refers to a cycloalkyl group having 3 to 12 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12). Monocyclic groups may also exist, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. Bicyclic groups may also exist, such as bridging rings or spiro-rings. The cycloalkyl group may be fused to an aryl, heteroaryl, or heterocyclic ring, where the ring linked to the parent structure is a cycloalkyl group, for example, [ka] And so on. In this specification, cycloalkyl includes substituted cycloalkyl groups.

[0054] As used herein, “heterocyclyl” means a saturated or partially saturated cyclic group having heteroatoms selected from N, S, and O. For example, a “3-12 membered heterocyclyl” is a saturated or partially saturated cyclic group having 3-12 atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) of which 1-3 atoms (e.g., 1, 2, or 3) are heteroatoms selected from the group consisting of N, S, and O. It may be monocyclic or bicyclic, such as a bridging ring or a spiro ring. A 3-12 membered heterocyclyl is preferably a 3-8 membered heterocyclyl, more preferably a 3-6 membered or 6-8 membered heterocyclyl. Specific examples may include oxetane, azetidine, tetrahydro-2H-pyranyl group, piperidyl group, piperadyl group, tetrahydrofuryl group, morpholyl group, and pyrrolidyl group. The heterocyclic group may be condensed with a heteroaryl group, aryl group, or cycloalkyl group, where the ring linked to the parent structure is a heterocyclic group, for example, [ka] And so on.

[0055] As used herein, an "aryl group" refers to an aromatic ring group that does not contain a heteroatom, and a "C6-C10 aryl group" refers to an aromatic ring group having 6-10 carbon atoms that does not contain a heteroatom. The aryl group may be fused to a heteroaryl group, a heterocyclic group, or a cycloalkyl ring, where the ring linked to the parent structure is the ring of the aryl group. Examples include a phenyl group (i.e., a 6-membered aromatic ring) and a naphthyl group. Here, a 6-membered aryl group also includes 6-membered aryl condensed 5-6 membered cycloalkyl groups and 6-membered aryl condensed 5-6 membered heterocycloalkyl groups. The aryl group may be optionally substituted or unsubstituted.

[0056] As used herein, a "heteroaryl group" is a cyclic aromatic group having 1-3 (e.g., 1, 2, or 3) heteroatoms selected from the group consisting of N, S, and O, and a "5-10 membered heteroaryl group" is a cyclic aromatic group having 5-12 (e.g., 5, 6, 7, 8, 9, 10, 11, or 12) atoms, of which 1-3 (e.g., 1, 2, or 3) are heteroatoms selected from the group consisting of N, S, and O. It may be a monocyclic or fused ring. Specific examples include pyridyl group, pyridazyl group, pyrimidinyl group, pyrazinyl group, triazyl group, pyrrolyl group, pyrazolyl group, imidazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group, furyl group, thienyl group, isoxazolyl group, thiazolyl group, oxazolyl group, etc. The heteroaryl ring may be condensed with an aryl group, a heterocyclic group, or a cycloalkyl ring, but the ring linked to the parent structure is a heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from alkyl groups, deuterated alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, alkenyl groups, alkynyl groups, alkylthio groups, alkylamino groups, halogens, amino groups, nitro groups, hydroxyl groups, mercapto groups, cyano groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, cycloalkylthio groups, oxo groups, amide groups, sulfonamide groups, formyl groups, carboxamide groups, carboxyl groups, and carboxylic acid ester groups.

[0057] As used herein, “halogen” or “halogen atom” refers to F, Cl, Br, and I. The halogen or halogen atom is preferably selected from F, Cl, and Br. In this specification, "amino group" refers to -NH2. In this specification, "carboxyl group" refers to -COOH.

[0058] In this specification, the term "amide group" means a group having the structure -CONRR', where R and R' may independently represent hydrogen, an alkyl group, a cycloalkyl group, an aryl group, or a heterocyclic group, as defined above. R and R' may be the same or different in the dialkylamine fragment.

[0059] In this specification, the term "sulfonamide group" means a group having the structure -SO2NRR', where R and R' may independently represent hydrogen, an alkyl group, a cycloalkyl group, an aryl group, or a heterocyclic group, as defined above. R and R' may be the same or different in the dialkylamine fragment. In this invention, the term "formyl group" refers to a group containing -CHO.

[0060] In this specification, the term "carboxamide group" means: [ka] The group containing the carboxamide group also means that the carboxamide group contains a substituted carboxamide group, and the formula [ka] The following is a representation of the following: where R and R' independently represent hydrogen, alkyl group, cycloalkyl group, cycloalkenyl group, aryl group, heteroaryl group, and heterocyclic group, respectively, as defined above. Each R may be the same or different.

[0061] In this specification, "alkylamine group" refers to a group having the structure -N(R)(R') or -alkyl-N(R)(R'), where R and R' independently represent hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups, respectively, as defined above. "C1-C6 alkylamine group" includes, but is not limited to, NHCH3, N(CH3)2, NHCH2CH3, N(CH2CH3)2, N(CH3)(CH2CH3), CH2NHCH3, CH2CH2NHCH3, CH2CH2CH2NHCH3, CH2N(CH3)2, CH2CH2N(CH3)2, CH2CH2CH2N(CH3)2, CH2N(CH3)(CH2CH3), CH2CH2N(CH3)(CH2CH3), and CH2CH2CH2N(CH3)(CH2CH3).

[0062] In this specification, a "sulfoxide group" is a group having -S(O)-R, where R independently represents hydrogen, an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, or a heterocyclic group, as defined above. In this specification, "sulfone group" refers to a group having -S(O)2-R, where R independently represents hydrogen, alkyl group, cycloalkyl group, aryl group, heteroaryl group, or heterocyclic group, as defined above.

[0063] In this specification, "ester group" means a group having the structure -C(O)-OR or RC(O)-O-, where R independently represents hydrogen, alkyl group, cycloalkyl group, aryl group, heteroaryl group, or heterocyclic group, as defined above. In this specification, "C3-C12 cycloalkyl C1-C6 alkyl" means -C3-C12 cycloalkyl C1-C6 alkyl or C3-C12 cycloalkyl C1-C6 alkyl-, and "3-12 membered heterocyclic group C1-C6 alkyl" has a similar meaning.

[0064] In this specification, “optionally” means that it is possible, but not necessarily, by the matters or circumstances described below, and such description includes cases where the aforementioned matters or circumstances occur, and cases where they do not occur.

[0065] In the present invention, the term "substitution" means that one or more hydrogen atoms in a particular group are substituted with a particular substituent. The particular substituent is the corresponding substituent described above, or the substituent described in each example. Unless otherwise specified, the substituted group may have one substituent selected from a particular group at any of its substitutable sites, and the substituent may be the same or different at each position. As will be apparent to those skilled in the art, the substituent combinations envisioned in the present invention are stable combinations or chemically feasible combinations.

[0066] Unless otherwise specifically described as "substituted or unsubstituted," any of the groups described in the present invention may be substituted with substituents selected from the group consisting of deuterium, halogens, cyano groups, nitro groups, hydroxyl groups, amino groups, C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C1-C6 alkoxy groups, 3-10 membered heterocycloalkyl groups, C3-C10 cycloalkyl groups, 5-12 membered heteroaryl groups, and C6-C12 aryl groups. In this invention, the term "multiple items" independently refers to 2, 3, 4, or 5 items.

[0067] Unless otherwise specified, the structural formulas described in this invention mean that all isomeric forms (e.g., enantiomers, non-enantiomers, and geometric isomers (or conformosomers)), such as R and S configurations with a chiral center, and (Z) and (E) isomers with a double bond. Therefore, any single stereoisomer of the compound of this invention or a mixture of its enantiomers, non-enantiomers, or geometric isomers (or conformosomers) are included within the scope of this invention.

[0068] As used herein, the term “tautomer” means that structural isomers with different energies can transform into each other over a low energy barrier. For example, proton tautomers (i.e., prototropies) are those that transform by proton transfer, such as 1H-indazole and 2H-indazole. Valence tautomers are those that transform by rearranging some of the bonding electrons. As used herein, the term "solvate" refers to a complex formed by the coordination of the compound of the present invention with a solvent molecule in a specific ratio.

[0069] active ingredient As used herein, “compound of the present invention” means a compound represented by formula I, and also includes stereoisomers, pharmaceutically acceptable salts, prodrugs, or solvates of the compound represented by formula I.

[0070] The compounds of the present invention contain one or more chiral carbon atoms, thereby resulting in enantiomers, non-enantiomers, and other stereoisomers. Each chiral carbon atom is defined as (R)- or (S)- based on stereochemistry. The present invention includes all possible isomers, their racemic mixtures, and optically single forms. The preparation of the compounds of the present invention may involve selecting a racemic mixture, non-enantiomer, or enantiomer as a starting material or intermediate. Optically active isomers may be prepared with chiral synthesis elements or chiral reagents, or divided by conventional techniques, such as crystallization or chiral chromatography.

[0071] Conventional techniques for preparing / separating single optical isomers (i.e., enantiomers and non-enantiomers) include chiral synthesis using a suitable optically single precursor, or separation of racemates (or racemates of salts or derivatives) by, for example, high-performance liquid chromatography of chiral compounds, e.g., Gerald Gubitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; AM Stalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3:341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. See 1990, 23, 128.

[0072] Furthermore, the present invention includes isotope-labeled compounds (i.e., isotope derivatives), which are equivalent to the original compounds being disclosed herein. In practice, it is common for one or more atoms to be replaced by atoms with different atomic weights or mass numbers. Examples of isotopes in the isotope derivatives of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Contains Cl. All isotopic derivatives of the compounds of the present invention are within the scope of protection of the present invention. In this specification, 3 H-labeled compounds and14 Compounds labeled with 1C are useful in drug and substrate tissue distribution experiments. Tritium (i.e., 3 H) and carbon-14 (i.e., 14 Compounds labeled with C) are relatively easy to prepare and detect, and are optimal for isotopes. Furthermore, substitution with heavier isotopes, such as deuterium, is also possible. 2 Due to its superior metabolic stability, H is preferred in some therapies, for example, because it increases half-life in the body or reduces the dosage, and may be considered preferable in some cases. Isotope-labeled compounds can be prepared by conventional methods, using readily available isotope-labeling reagents instead of non-isotope reagents, in the exemplary schemes disclosed.

[0073] In this specification, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0074] A "pharmaceutically acceptable acid addition salt" is a salt formed with an inorganic or organic acid that retains the biological efficacy of the free base and has no other side effects. Inorganic acid salts include, but are not limited to, hydrochloride salts, hydrobromide salts, sulfate salts, nitrate salts, and phosphate salts. Organic salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, caproate, caprylate, caprine, undecylenate, glycolate, gluconate, lactate, sebacinate, adipine, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, and naphthalenedisulfonate. These salts can be produced by methods known in the art.

[0075] A "pharmaceutically acceptable base addition salt" is a salt formed with an inorganic or organic base that retains the biological efficacy of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts, and magnesium salts. Salts derived from inorganic bases include, but are not limited to, salts of primary amines, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as salts of ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-methylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

[0076] When designing the synthesis of a specific enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or by induction with a chiral auxiliary, the resulting non-enantiomer can be separated, and the chiral auxiliary can be removed to obtain a single enantiomer. Alternatively, if the molecule contains a single basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a non-enantiomer can be formed with a suitable optically active acid or base, and then the single enantiomer can be obtained by separation using conventional means such as fractional crystallization or chromatography.

[0077] As described herein, the compounds of the present invention can be substituted with any number of substituents or functional groups to expand their coverage. Generally, the term “substitution” refers to replacing a hydrogen radical with a substituent in a given structure. When multiple positions in a particular structure are substituted with multiple specific substituents, the positions of the substituents may be identical or different. As used herein, the term “substitution” includes substitutions of all permissible organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched, unbranched, carbocyclic and heterocyclic, and aromatic and non-aromatic organic compounds. In this specification, for example, the nitrogen of a heteroatom can have its valence state replaced by a hydrogen substituent or any of the above permissible organic compounds. Furthermore, the present invention does not attempt to limit the organic compounds that are permissible to be substituted in any way. In the present invention, the existence of a combination of substituents and variable groups in the form of a stable compound is advantageous in the treatment of diseases. Here, the term "stable" means that a stable compound is detectable over a sufficiently long period of time, possesses sufficient integrity to maintain the structure of the compound, and is preferably effective over a sufficiently long period of time, and is used herein for the purposes described above.

[0078] The compounds represented by formula I and their pharmaceutically acceptable salts, as well as prodrugs that are converted in the body to the compounds represented by formula I and their pharmaceutically acceptable salts, are also included within the scope of protection of the present invention.

[0079] Method for producing compounds The following describes a method for producing the compound represented by formula I. The order of steps in the reaction scheme may be altered to accelerate the reaction or avoid unwanted by-products. Furthermore, the compounds of the present invention can be conveniently produced by any combination of the various synthetic methods described herein or known in the art, such combinations being readily apparent to those skilled in the art.

[0080] Typically, during manufacturing, each reaction is carried out in an inert solvent at room temperature to reflux temperature (e.g., 0°C-150°C, preferably 10°C-100°C). The reaction time is usually 0.1 hours to 60 hours, preferably 0.5 to 48 hours.

[0081] Preferably, the compounds of the present invention can be produced by the following method. Method 1 Method A: [ka] S1) Under appropriate basic conditions (such as potassium acetate, but not limited to these), a suitable solvent is selected (such as dioxane, but not limited to these), at an appropriate temperature (such as 80°C, but not limited to these), and catalyzed by a suitable coupling catalyst (such as Pd(dppf)2, but not limited to these), compound (A-1) is reacted with the corresponding borate ester or borate compound (A-1a) (such as bis(pinacolato)diborone, but not limited to these) to obtain compound (A-2); S2) Under appropriate basic conditions (such as potassium carbonate, but not limited to these), with a suitable solvent selected (such as a mixed solvent of dioxane and water, but not limited to these), at an appropriate temperature (such as 80°C, but not limited to these), and catalyzed by a suitable coupling catalyst (such as tetrakis(triphenylphosphine)palladium, but not limited to these), compound (A-2) is reacted with the corresponding aryl halide compound (A-2a) (such as 2,6-dibromopyrazine, but not limited to these) to obtain compound (A-3); S3) Under appropriate basic conditions (such as potassium carbonate, but not limited to these), a suitable solvent (such as dioxane, but not limited to these), at an appropriate temperature (such as 60°C, but not limited to these), and catalyzed by a suitable coupling catalyst (such as tetrakis(triphenylphosphine)palladium, but not limited to these), compound (A-3) is reacted with the corresponding boric acid or boric acid ester compound (A-3a) to obtain compound (A-4); S4) Under appropriate basic conditions (such as cesium carbonate, but not limited to these), with a suitable solvent selected (such as toluene, but not limited to these), at an appropriate temperature (such as 110°C, but not limited to these), with a suitable ligand selected (such as BINAP, but not limited to these), and catalyzed by a suitable coupling catalyst (such as Pd2(dba)3, but not limited to these), compound (A-4) is reacted with the corresponding nitrogen-containing compound (A-4a) to obtain compound (A-5-1); S5) Select a suitable solvent (such as tetrahydrofuran, but not limited to these), select a suitable acid (such as 1M hydrochloric acid, but not limited to these), and deprotect compound (A-5-1) to obtain compound (A-5); S6) Select a suitable solvent (such as dichloromethane, but not limited thereto), select a suitable base (such as triethylamine, but not limited thereto), and react compound (A-5) with the corresponding acyl chloride (A-5a) to obtain compound (A).

[0082] Method B: [ka] S1) Under appropriate basic conditions (such as potassium acetate, but not limited to these), a suitable solvent is selected (such as dioxane, but not limited to these), at an appropriate temperature (such as 80°C, but not limited to these), and catalyzed by a suitable coupling catalyst (such as Pd(dppf)2, but not limited to these), compound (A-1) is reacted with the corresponding borate ester or borate compound (A-1a) (such as bis(pinacolato)diborone, but not limited to these) to obtain compound (A-2); S2) Under appropriate basic conditions (such as potassium carbonate, but not limited to these), with a suitable solvent selected (such as a mixed solvent of dioxane and water, but not limited to these), at an appropriate temperature (such as 80°C, but not limited to these), and catalyzed by a suitable coupling catalyst (such as tetrakis(triphenylphosphine)palladium, but not limited to these), compound (A-2) is reacted with the corresponding aryl halide compound (A-2a) (such as 2,6-dibromopiperazine, but not limited to these) to obtain compound (A-3); S3) Under appropriate basic conditions (such as potassium carbonate, but not limited to these), a suitable solvent (such as dioxane, but not limited to these), at an appropriate temperature (such as 60°C, but not limited to these), and catalyzed by a suitable coupling catalyst (such as tetrakis(triphenylphosphine)palladium, but not limited to these), compound (A-3) is reacted with the corresponding boric acid or boric acid ester compound (A-3a) to obtain compound (A-4); S4) Under appropriate basic conditions (such as potassium carbonate, but not limited thereto), select an appropriate solvent (such as DMSO, but not limited thereto), at an appropriate temperature (such as 110 °C, but not limited thereto), select an appropriate ligand (such as L-proline, but not limited thereto), and under the catalysis of an appropriate coupling catalyst (such as cuprous iodide, but not limited thereto), react compound (A-4) with aqueous ammonia of the corresponding nitrogen-containing compound under sealed tube conditions to obtain compound (A-5); S5) Select an appropriate solvent (such as dichloromethane, but not limited thereto), select an appropriate base (such as triethylamine, but not limited thereto), react compound (A-5) with the corresponding acyl chloride (A-5a) to obtain compound (A).

[0083] Method 2

Chemical formula

[0084] Method 3 [ka] S1) Under appropriate basic conditions (such as potassium carbonate, but not limited to these), with a suitable solvent selected (such as a mixed solvent of dioxane and water, but not limited to these), at an appropriate temperature (such as 80°C, but not limited to these), and catalyzed by a suitable coupling catalyst (such as tetrakis(triphenylphosphine)palladium, but not limited to these), compound (C-1) is reacted with the corresponding aryl halide compound (C-1a) to obtain compound (C-2); S2) Under appropriate basic conditions (such as potassium carbonate, but not limited to these), with a suitable solvent selected (such as a mixed solvent of dioxane and water, but not limited to these), at an appropriate temperature (such as 60°C, but not limited to these), and catalyzed by a suitable coupling catalyst (such as tetrakis(triphenylphosphine)palladium, but not limited to these), compound (C-2) is reacted with the corresponding boric acid or boric acid ester compound (C-2a) to obtain compound (C-3); S3) Under appropriate basic conditions (such as cesium carbonate, but not limited to these), with a suitable solvent selected (such as toluene, but not limited to these), at an appropriate temperature (such as 110°C, but not limited to these), with a suitable ligand selected (such as BINAP, but not limited to these), and catalyzed by a suitable coupling catalyst (such as Pd2(dba)3, but not limited to these), compound (C-3) is reacted with the corresponding nitrogen-containing compound (C-3a) to obtain compound (C-4); S4) Select a suitable solvent (such as tetrahydrofuran, but not limited to these), select a suitable acid (such as 1M hydrochloric acid, but not limited to these), and deprotect compound (C-4) to obtain compound (C-5); S5) Select a suitable solvent (such as dichloromethane, but not limited thereto), select a suitable base (such as triethylamine, but not limited thereto), and react compound (C-5) with the corresponding acyl chloride (C-5a) to obtain compound (C-6); S6) Select a suitable solvent (such as t-butanol, but not limited thereto), select a suitable base (such as sodium t-butoxide, but not limited thereto), and hydrolyze the compound (C-6) to obtain the amide compound (C-7).

[0085] Drug composition and method of administration Because the compounds of the present invention have excellent inhibitory activity against Drak2 kinase, drug compositions containing the compounds of the present invention as the main active ingredient are useful for the prevention and / or treatment (stabilization, alleviation, or cure) of diseases related to Drak2 kinase.

[0086] The drug composition of the present invention comprises the compound of the present invention in a safe effective amount and a pharmaceutically acceptable excipient or carrier. Here, "safe effective amount" means an amount of the compound that is sufficient for a significant improvement in the disease condition without causing severe side effects. Typically, the drug composition contains the compound of the present invention in an amount of 1-2000 mg / formulation, preferably 10-200 mg / formulation. Preferably, the "formulation" is a capsule or a tablet.

[0087] A "pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers or gel substances that are applicable to humans and must be of sufficient purity and sufficiently low toxicity. "Compatible" means that each component in a drug composition can be compounded with the compounds of the present invention and with each other without significantly reducing the effect of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., twinol). R These include humectants (e.g., sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, and distilled water from which pyrogenic substances have been removed.

[0088] The mode of administration of the compound or drug composition of the present invention is not particularly limited, but typical modes of administration include, but are not limited to, oral administration and extra-gastrointestinal (intravenous, intramuscular, or subcutaneous) administration.

[0089] Solid dosage forms used for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the compounds of the present invention are mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) a filler or phase solvent, such as starch, lactose, sucrose, glucose, mannitol, or silicic acid; (b) a binder, such as hydromethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, or gum arabic; (c) a humectant, such as glycerin; or (d) a disintegrant, such as agar or carbonate. It is mixed with ingredients such as calcium, potato starch or tapioca starch, alginic acid, certain complex silicates or sodium carbonate, (e) solution retarders, such as paraffin, (f) absorption enhancers, such as ammonium compounds, (g) wetting agents, such as cetanol or glycerin monostearate, (h) adsorbents, such as kaolin, and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may include a buffer.

[0090] Solid dosage forms, such as tablets, pills, capsules, rounds, and granules, can be manufactured with coatings or shells, such as venous coatings and other materials known in the art. Opticants may also be included, and in such drug compositions, the release of the compound of the present invention may be delayed and released in a portion of the gastrointestinal tract. Examples of usable embedding components include polymers and waxy substances. If necessary, the compound of the present invention may be formed in the form of microcapsules with one or more of the above excipients.

[0091] Liquid dosage forms used for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the compounds of the present invention, liquid dosage forms may also include inert diluents commonly used in the art, such as water or other solvents, phase solvents, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame oil, or mixtures thereof.

[0092] In addition to these inert diluents, the drug composition may also contain auxiliary agents, such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, and fragrances. In addition to the compounds of the present invention, the suspension may also contain suspending agents such as ethoxylated isooctadecanol, polyoxyethylene sorbitol or sorbitan ester, microcrystalline cellulose, methoxyaluminum or agar, or mixtures thereof.

[0093] Drug compositions for extra-gastrointestinal injection include physiologically acceptable sterile water-containing or water-free solutions, dispersions, suspensions, and emulsions, as well as sterile powders for redissolution into sterile injectable solutions or dispersions. Suitable water-containing or water-non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyhydric alcohols, and suitable mixtures thereof. The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., EGFR inhibitors).

[0094] When administered in combination, the drug composition further comprises one or more (two, three, four, or more) other pharmaceutically acceptable compounds (e.g., Drak2 inhibitors). One or more (two, three, four, or more) of these other pharmaceutically acceptable compounds (e.g., Drak2 inhibitors) may be used simultaneously, separately, or sequentially with the compounds of the present invention for the prevention and / or treatment of diseases related to the activity or expression level of Drak2 kinase.

[0095] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is used in mammals (such as humans) that require treatment. The dosage during use is a dosage that is considered to be pharmaceutically effective. In the case of a 60 kg human, the daily dosage is usually 1 - 2000 mg, preferably 20 - 500 mg. Of course, the specific dosage should further consider factors such as the mode of administration and the health status of the patient, and all are within the scope of the skills of a skilled doctor.

[0096] The main advantages of the present invention are as follows. 1. The compound of the present invention has a novel structure and excellent Drak2 kinase inhibitory activity. 2. The compound of the present invention has good pharmacokinetic and pharmacodynamic properties.

[0097] Specific embodiments Hereinafter, the present invention will be further described by specific examples. It should be understood that these examples are only used to illustrate the present invention and do not limit the scope of the present invention. In the following examples, experimental methods for which specific conditions are not described were usually carried out under normal conditions or the conditions recommended by the manufacturer. Unless otherwise specified, % and parts are calculated by weight.

[0098] Examples In this specification, unless otherwise explained, all temperatures are in °C. In this specification, all percentages regarding the yield are mass percentages. In this specification, unless otherwise explained, all parts are volume parts and all percentages are volume percentages.

[0099] In this specification, the preparation of PTLC or TLC (thin layer chromatography) was carried out on a 20×20 cm plate (silica gel with a thickness of 500 μm), and a Biotage flash chromatography system was used for silica gel chromatography.

[0100] In this specification, 1¹H NMR (hydrogen spectrum) was performed using a Bruker Ascend™400 spectrometer at 400 MHz and 298°K, and the chemical shifts (ppm) of residual protons in the deuterating reagents are shown for reference: δ (chemical shift) of CDCl3 is 7.26 ppm, δ of CD3OD is 3.31 ppm, and δ of DMSO-d6 is 2.50 ppm.

[0101] In this specification, LCMS (liquid chromatography-mass spectrometry) measurements were performed using Agilent Technologies' 1200 series or 6120 quadrupole chromatograph for liquid chromatography. For liquid chromatography, the mobile phase was acetonitrile (A) and water (B) with 0.01% formic acid, and the eluent gradients were 6.0 min 5-95% A, 5.0 min 60-95% A, 5.0 min 80-100% A, and 10 min 85-100% A, using an SBC 1850 mm × 4.6 mm × 2.7 μm capillary column. Mass spectrometry (MS) was performed by electrospray ionization (ESI).

[0102] In this specification, the analytical conditions for high-performance liquid chromatography (HPLC)-mass spectrometry (MS) are as follows: LC1 column: SB-C18 50 mm × 4.6 mm × 2.7 μm; Temperature: 50℃; Eluent: 5:95 to 95:5 acetonitrile / water (the above ratios are by volume) + 0.01% formic acid, 6 min; Flow rate: 1.5 mL / min, injection 5 μL; Detection: PDA detector, 200-600 nm; MS: Mass range 150-750 amu; Cation electrospray ionization. LC2 column: SB-C18 50 mm × 4.6 mm × 2.7 μm; Temperature: 50℃; Eluent: Acetonitrile / water in a ratio of 5:95 to 95:5 (above ratios are by volume) + 0.05% TFA (trifluoroacetic acid) gradient, over 3.00 min; Flow rate: 1.5 mL / min, injection 5 μL; Detection: PDA detector, 200-600 nm; MS: Mass range 150-750 amu; Cation electrospray ionization. LC3 column: SB-C18 50 mm × 4.6 mm × 2.7 μm; Temperature: 50℃; Eluent: Acetonitrile / water in a ratio of 10:90 to 98:2 (above ratios are by volume) + 0.05% TFA gradient, over 3.75 min; Flow rate: 1.0 mL / min, injection 10 μL; Detection: PDA detector, 200-600 nm; MS: Mass range 150-750 amu; Cation electrospray ionization.

[0103] In this specification, the meanings of each abbreviation are as follows: AcOH = acetic acid; Alk = alkyl group; AR = aryl group; Boc = t-butoxycarbonyl group; CH2Cl2 = dichloromethane; DBU = 1,8-diazabicyclo[5.4.0]-7-undecene; DCM = dichloromethane; DEAD = diethyl azodicarboxylic acid; DMF = N,N-dimethylformamide; DMSO = dimethyl sulfoxide; EA = ethyl acetate; Et = ethyl group; Depositphotos = ethyl acetate; EtOH = ethanol; HOAc = acetic acid; LiOH = lithium hydroxide; Me = methyl group; MeCN = acetonitrile; MeOH = methanol; MgSO4 = magnesium sulfate; NaCl = sodium chloride; NaOH = sodium hydroxide; Na2SO4 = sodium sulfate; PE = petroleum ether; Ph = phenyl group; PG = protecting group; TFA = trifluoroacetic acid; THF = tetrahydrofuran; Ts = p-toluenesulfonyl group; rt = room temperature; h = hours; min = minutes; bs = broad singlet; s = singlet; d =Broad singlet;dd =Broad singlet;t =Broad singlet;m =Broad singlet.

[0104] Common method Method 1 Method A: [ka] S1) Under appropriate basic conditions (such as potassium acetate, but not limited to these), a suitable solvent is selected (such as dioxane, but not limited to these), at an appropriate temperature (such as 80°C, but not limited to these), and catalyzed by a suitable coupling catalyst (such as Pd(dppf)2, but not limited to these), compound (A-1) is reacted with the corresponding borate ester or borate compound (A-1a) (such as bis(pinacolato)diborone, but not limited to these) to obtain compound (A-2); S2) Under appropriate basic conditions (such as potassium carbonate, but not limited to these), with a suitable solvent selected (such as a mixed solvent of dioxane and water, but not limited to these), at an appropriate temperature (such as 80°C, but not limited to these), and catalyzed by a suitable coupling catalyst (such as tetrakis(triphenylphosphine)palladium, but not limited to these), compound (A-2) is reacted with the corresponding aryl halide compound (A-2a) (such as 2,6-dibromopyrazine, but not limited to these) to obtain compound (A-3); S3) Under appropriate basic conditions (such as potassium carbonate, but not limited to these), a suitable solvent (such as dioxane, but not limited to these), at an appropriate temperature (such as 60°C, but not limited to these), and catalyzed by a suitable coupling catalyst (such as tetrakis(triphenylphosphine)palladium, but not limited to these), compound (A-3) is reacted with the corresponding boric acid or boric acid ester compound (A-3a) to obtain compound (A-4); S4) Under appropriate basic conditions (such as cesium carbonate, but not limited to these), with a suitable solvent selected (such as toluene, but not limited to these), at an appropriate temperature (such as 110°C, but not limited to these), with a suitable ligand selected (such as BINAP, but not limited to these), and catalyzed by a suitable coupling catalyst (such as Pd2(dba)3, but not limited to these), compound (A-4) is reacted with the corresponding nitrogen-containing compound (A-4a) to obtain compound (A-5-1); S5) Select a suitable solvent (such as tetrahydrofuran, but not limited to these), select a suitable acid (such as 1M hydrochloric acid, but not limited to these), and deprotect compound (A-5-1) to obtain compound (A-5); S6) Select a suitable solvent (such as dichloromethane, but not limited thereto), select a suitable base (such as triethylamine, but not limited thereto), and react compound (A-5) with the corresponding acyl chloride (A-5a) to obtain compound (A).

[0105] Method B: [ka] S1) Under appropriate basic conditions (such as potassium acetate, but not limited to these), a suitable solvent is selected (such as dioxane, but not limited to these), at an appropriate temperature (such as 80°C, but not limited to these), and catalyzed by a suitable coupling catalyst (such as Pd(dppf)2, but not limited to these), compound (A-1) is reacted with the corresponding borate ester or borate compound (A-1a) (such as bis(pinacolato)diborone, but not limited to these) to obtain compound (A-2); S2) Under appropriate basic conditions (such as potassium carbonate, but not limited to these), with a suitable solvent selected (such as a mixed solvent of dioxane and water, but not limited to these), at an appropriate temperature (such as 80°C, but not limited to these), and catalyzed by a suitable coupling catalyst (such as tetrakis(triphenylphosphine)palladium, but not limited to these), compound (A-2) is reacted with the corresponding aryl halide compound (A-2a) (such as 2,6-dibromopyrazine, but not limited to these) to obtain compound (A-3); S3) Under appropriate basic conditions (such as potassium carbonate, but not limited to these), a suitable solvent (such as dioxane, but not limited to these), at an appropriate temperature (such as 60°C, but not limited to these), and catalyzed by a suitable coupling catalyst (such as tetrakis(triphenylphosphine)palladium, but not limited to these), compound (A-3) is reacted with the corresponding boric acid or boric acid ester compound (A-3a) to obtain compound (A-4); S4) Under appropriate basic conditions (such as potassium carbonate, but not limited to these), a suitable solvent (such as DMSO, but not limited to these), at an appropriate temperature (such as 110°C, but not limited to these), a suitable ligand (such as L-proline, but not limited to these), and catalyzed by a suitable coupling catalyst (such as cuprous iodide, but not limited to these), compound (A-4) is reacted with aqueous ammonia, a corresponding nitrogen-containing compound, under sealed tube conditions to obtain compound (A-5); S5) Select a suitable solvent (such as dichloromethane, but not limited thereto), select a suitable base (such as triethylamine, but not limited thereto), and react compound (A-5) with the corresponding acyl chloride (A-5a) to obtain compound (A).

[0106] Method 2 [ka] S1) Under appropriate basic conditions (such as potassium acetate, but not limited thereto), select an appropriate solvent (such as dioxane, but not limited thereto), and at an appropriate temperature (such as 80°C, but not limited thereto), react compound (B-1) with a corresponding borate ester or borate compound (B-1a) (such as bis(pinacolato)diborone, but not limited thereto) using a suitable coupling catalyst (such as Pd(dppf)2, but not limited thereto) to obtain compound (B-2); S2) Under appropriate basic conditions (such as potassium carbonate, but not limited to these), a suitable solvent is selected (such as a mixed solvent of dioxane and water, but not limited to these), at an appropriate temperature (such as 80°C, but not limited to these), and catalyzed by a suitable coupling catalyst (such as tetrakis(triphenylphosphine)palladium, but not limited to these), compound (B-2) is reacted with the corresponding aryl halide compound (B-2a) to obtain compound (B-3); S3) Under appropriate basic conditions (such as potassium carbonate, but not limited to these), with a suitable solvent selected (such as a mixed solvent of dioxane and water, but not limited to these), at an appropriate temperature (such as 60°C, but not limited to these), and catalyzed by a suitable coupling catalyst (such as tetrakis(triphenylphosphine)palladium, but not limited to these), compound (B-3) is reacted with the corresponding boric acid or boric acid ester compound (B-3a) to obtain compound (B-4); S4) Under appropriate basic conditions (such as potassium carbonate, but not limited to these), a suitable solvent (such as DMSO, but not limited to these), at an appropriate temperature (such as 110°C, but not limited to these), a suitable ligand (such as L-proline, but not limited to these), and catalyzed by a suitable coupling catalyst (such as cuprous iodide, but not limited to these), compound (B-4) is reacted with aqueous ammonia, a corresponding nitrogen-containing compound, under sealed tube conditions to obtain compound (B-5); S5) Select a suitable solvent (such as dichloromethane, but not limited thereto), select a suitable base (such as triethylamine, but not limited thereto), react compound (B-5) with the corresponding acyl chloride (B-5a) to obtain compound (B-6); S6) Select a suitable solvent (such as a mixed solvent of tetrahydrofuran and water, but not limited to these), select a suitable base (such as lithium hydroxide, but not limited to these), and hydrolyze compound (B-6) to obtain carboxyl compound (B-7); S7) Select a suitable solvent (such as DMF, but not limited to these), and under suitable basic conditions (such as DIEA, but not limited to these), select a suitable condensation reagent (such as EDCI + HOBT, but not limited to these), and react compound (B-7) with the corresponding amine (B-7a) to obtain compound (B-8).

[0107] Method 3 [ka] S1) Under appropriate basic conditions (such as potassium carbonate, but not limited to these), with a suitable solvent selected (such as a mixed solvent of dioxane and water, but not limited to these), at an appropriate temperature (such as 80°C, but not limited to these), and catalyzed by a suitable coupling catalyst (such as tetrakis(triphenylphosphine)palladium, but not limited to these), compound (C-1) is reacted with the corresponding aryl halide compound (C-1a) to obtain compound (C-2); S2) Under appropriate basic conditions (such as potassium carbonate, but not limited to these), with a suitable solvent selected (such as a mixed solvent of dioxane and water, but not limited to these), at an appropriate temperature (such as 60°C, but not limited to these), and catalyzed by a suitable coupling catalyst (such as tetrakis(triphenylphosphine)palladium, but not limited to these), compound (C-2) is reacted with the corresponding boric acid or boric acid ester compound (C-2a) to obtain compound (C-3); S3) Under appropriate basic conditions (such as cesium carbonate, but not limited to these), with a suitable solvent selected (such as toluene, but not limited to these), at an appropriate temperature (such as 110°C, but not limited to these), with a suitable ligand selected (such as BINAP, but not limited to these), and catalyzed by a suitable coupling catalyst (such as Pd2(dba)3, but not limited to these), compound (C-3) is reacted with the corresponding nitrogen-containing compound (C-3a) to obtain compound (C-4); S4) Select a suitable solvent (such as tetrahydrofuran, but not limited to these), select a suitable acid (such as 1M hydrochloric acid, but not limited to these), and deprotect compound (C-4) to obtain compound (C-5); S5) Select a suitable solvent (such as dichloromethane, but not limited thereto), select a suitable base (such as triethylamine, but not limited thereto), and react compound (C-5) with the corresponding acyl chloride (C-5a) to obtain compound (C-6); S6) Select a suitable solvent (such as t-butanol, but not limited thereto), select a suitable base (such as sodium t-butoxide, but not limited thereto), and hydrolyze the compound (C-6) to obtain the amide compound (C-7).

[0108] Example 1: Preparation of N-(5-(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)thiophen-3-yl)pentanamide (A1) (Method A) [ka]

[0109] Step 1: 3,4-Dimethoxyphenylboronic acid pinacol ester (A1-1) 3,4-Dimethoxybromobenzene (910 mg, 4.20 mmol), potassium acetate (1.03 g, 10.50 mmol), [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (154 mg, 0.21 mmol), bis(pinacolato)diborone (1.28 g, 5.00 mmol), and 1,4-dioxane (40 mL) were sequentially placed in a reaction bottle and reacted at 80°C for 5 hours under the protection of nitrogen gas. The completion of the reaction was monitored by TLC. The reaction mixture was filtered, the cake was washed with ethyl acetate, the reaction mixture and washing solution were combined, and the mixture was rotary-dried to obtain 3,4-dimethoxyphenylboronic acid pinacol ester (A1-1, crude product, 4.20 mmol), which was used directly in the next step of the reaction without any purification.

[0110] Second step: 2-bromo-6-(3,4-dimethoxyphenyl)pyrazine (A1-2) 2,6-dibromopyrazine (1.0 g, 4.2 mmol), 3,4-dimethoxyphenylboronic acid pinacol ester (A1-1, crude product, 4.20 mmol), potassium carbonate (1.38 g, 10.00 mmol), tetrakis(triphenylphosphine)palladium (243 mg, 0.21 mmol), 1,4-dioxane (40 mL), and water (10 mL) were sequentially placed in a reaction bottle. The mixture was reacted at 80°C for 5 hours under the protection of nitrogen gas, and the completion of the reaction was monitored by TLC. Most of the 1,4-dioxane was removed by rotary evaporation, and the mixture was redissolved in ethyl acetate (50 mL). The organic phase was sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate, rotated dry, and purified by column chromatography to obtain 2-bromo-6-(3,4-dimethoxyphenyl)pyrazine (A1-2,900 mg, 72.6%). 1HNMR(400 MHz, CDCl3) δ 8.92 (s, 1H), 8.55 (s, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.60 (dd, J = 8.4, 2.1 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 4.02 (s, 3H), 3.98 (s, 3H).

[0111] Third step: 2-(4-bromothiophen-2-yl)-6-(3,4-dimethoxyphenyl)pyrazine (A1-3) 2-Bromo-6-(3,4-dimethoxyphenyl)pyrazine (A1 - 2,488 mg, 1.65 mmol), (4-bromothiophen-2-yl)boronic acid (377 mg, 1.82 mmol), tetrakis(triphenylphosphine)palladium (38 mg, 0.033 mmol), potassium carbonate (524 mg, 3.79 mmol), 1,4-dioxane (16 mL), and water (4 mL) were sequentially placed in a reaction bottle. The mixture was reacted at 80°C for 4 hours under the protection of nitrogen gas, and the completion of the reaction was monitored by TLC. After removing most of the 1,4-dioxane by rotary evaporation of the reaction mixture, dichloromethane (30 mL) and water (10 mL) were added, and the mixture was separated. The aqueous phase was extracted with dichloromethane (20 mL x 2), the organic phase was added, the organic phase was washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, rotated-dried, and purified by column chromatography to obtain 2-(4-bromothiophen-2-yl)-6-(3,4-dimethoxyphenyl)pyrazine (A1-3,463 mg, 74.4%). 1 H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.78 (s, 1H), 7.74 (d, J = 1.9 Hz, 1H), 7.67 (dd, J = 8.4, 2.0 Hz, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.40 (d, J = 1.1 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 4.04 (s, 3H), 3.99 (s, 3H).

[0112] Step 4: N-(5-(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)thiophen-3-yl)-1,1-diphenylmethanymine (A1-4) 2-(4-bromothiophen-2-yl)-6-(3,4-dimethoxyphenyl)pyrazine (A1-3,106 mg, 0.28 mmol), benzophenone imine (76.4 mg, 0.42 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (17.4 mg, 0.028 mmol), tris(dibenzylideneacetone)dipalladium (12.8 mg, 0.014 mmol), cesium carbonate (136.8 mg, 0.42 mmol), and toluene (10 mL) were sequentially placed in a reaction bottle and reacted at 110°C for 16 hours under the protection of nitrogen gas. The completion of the reaction was monitored by TLC. The reaction mixture was rotated dry and purified by column chromatography to obtain N-(5-(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)thiophen-3-yl)-1,1-diphenylmethanymine (A1-4, 59 mg, 43.9%). 1 H NMR (400 MHz, CDCl3) δ 8.82 (d, J = 9.7 Hz, 1H), 8.56 (s, 1H), 7.82 (d, J = 7.3 Hz, 2H), 7.74 (d, J = 1.8 Hz, 1H), 7.65 (dd, J = 8.4, 1.9 Hz, 1H), 7.57-7.49 (m, 1H), 7.43 (dt, J = 9.2, 5.8 Hz, 5H), 7.29 (m, 3H), 7.20 (d, J = 1.3 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 4.03 (s, 3H), 3.98 (s, 3H).

[0113] Step 5: 5-(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)thiophene-3-amine hydrochloride (A1-5) N-(5-(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)thiophen-3-yl)-1,1-diphenylmethaneimine (A1-4, 59 mg, 0.12 mmol) was dissolved in tetrahydrofuran (10 mL), 1 M hydrochloric acid (0.5 mL) was added dropwise to the reaction mixture, and the mixture was reacted at room temperature for 4 hours. A white solid precipitated, which was collected by filtration and dried by heating to obtain 5-(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)thiophen-3-amine hydrochloride (A1-5, 34 mg, 78.5%). 1H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 8.74 (s, 1H), 7.77 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.33 (s, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.38 (s, 1H), 4.05 (s, 3H), 3.99 (s, 3H).

[0114] Step 6: N-(5-(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)thiophen-3-yl)pentanamide (A1) 5-(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)thiophene-3-amine hydrochloride (A1-5, 32 mg, 0.09 mmol) was dissolved in dichloromethane (5 mL), cooled in an ice bath, and triethylamine (18.5 mg, 0.183 mmol) was added. Separately, pentanoic acid chloride (14.9 mg, 0.123 mmol) was dissolved in dichloromethane (0.5 mL) and added dropwise to the above system. Once the addition was complete, the system was returned to room temperature and reacted for 16 hours, and the completion of the reaction was monitored by TLC. The reaction mixture was rotated dry and purified by column chromatography to obtain N-(5-(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)thiophene-3-yl)pentanamide (A1, 19 mg, 53.1%). 1H NMR (400 MHz, DMSO) δ 10.39 (s, 1H), 9.13 (s, 1H), 8.97 (s, 1H), 7.86 (d, J = 1.2 Hz, 1H), 7.80 (dd, J = 8.4, 1.9 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.71 (d, J = 1.2 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 3.90 (s, 3H), 3.83 (d, J = 19.3 Hz, 3H), 2.32 (t, J = 7.4 Hz, 2H), 1.69-1.51 (m, 2H), 1.41-1.29 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H).

[0115] Compounds A2-A34 in Examples 2-34 were obtained by experimental procedures similar to those in Example 1, and compounds A1-A34 are summarized in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0116] Example 35: Preparation of N-(5-(6-(4-(3-hydroxyoxetan-3-yl)-3-methoxyphenyl)pyrazine-2-yl)thiophen-3-yl)pentanamide (A35) (Method B) [ka]

[0117] Step 1: 3-(2-methoxy-4-pinacolvoranyl-phenyl)oxetan-3-ol (A35-1) 3-(4-bromo-2-methoxyphenyl)oxetan-3-ol (400 mg, 1.54 mmol), potassium acetate (379 mg, 3.86 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (57 mg, 0.08 mmol), and bis(pinacolato)diborone (471 mg, 1.85 mmol) were added to 1,4-dioxane (15 mL) and reacted at 80°C for 5 hours under the protection of nitrogen gas. The completion of the reaction was monitored by TLC. The reaction mixture was filtered, the cake was washed with ethyl acetate, the reaction mixture and washing solution were combined, and the mixture was rotary-dried to obtain 3-(2-methoxy-4-pinacolvoranyl-phenyl)oxetan-3-ol (A35-1, crude product, 1.54 mmol (theoretical value)). This product was used directly in the next step of the reaction without any purification.

[0118] Step 2: 3-(4-(6-bromopyrazine-2-yl)-2-methoxyphenyl)oxetan-3-ol(A35-2) 3-(2-methoxy-4-pinacolvoranylphenyl)oxetan-3-ol (A35-1, crude product, 1.54 mmol), potassium carbonate (512 mg, 3.70 mmol), 2,6-dibromopyrazine (551 mg, 2.32 mmol), and tetrakis(triphenylphosphine)palladium (89 mg, 0.08 mmol) were added to 1,4-dioxane / water (4:1, 15 mL) and reacted at 80°C for 5 hours under the protection of nitrogen gas. The completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, 45 mL of water was added, and extraction was performed with EA (20 mL x 3). The organic phase was combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, rotated-dried, and purified by column chromatography to obtain 3-(4-(6-bromopyrazine-2-yl)-2-methoxyphenyl)oxetan-3-ol (A35-2,310 mg, 59.6%). MS (ESI) m / z: Calculated value 337.01 (M+H + ), measured value 337.00.

[0119] Third step: 3-(4-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)-2-methoxyphenyl)oxetan-3-ol(A35-3) 3-(4-(6-bromopyrazine-2-yl)-2-methoxyphenyl)oxetane-3-ol (A35 - 2,310 mg, 0.92 mmol), (4-bromothiophen-2-yl)boronic acid (191 mg, 0.93 mmol), tetrakis(triphenylphosphine)palladium (55 mg, 0.05 mmol), and potassium carbonate (305 mg, 2.21 mmol) were added to 1,4-dioxane / water (4:1, 15 mL) and reacted at 60°C for 0.5 hours under the protection of nitrogen gas. The completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, 45 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, and rotated dry. Purification by column chromatography yielded 3-(4-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)-2-methoxyphenyl)oxetan-3-ol (A35-3, 160 mg, 41.6%). MS (ESI) m / z: Calculated value 419.29 (M+H), Measured value 419.00

[0120] Step 4: 3-(4-(6-(4-aminothiophen-2-yl)pyrazine-2-yl)-2-methoxyphenyl)oxetan-3-ol(A35-4) 3-(4-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)-2-methoxyphenyl)oxetan-3-ol (A35-3, 160 mg, 0.38 mmol), cuprous iodide (15 mg, 0.08 mmol), L-proline (35 mg, 0.31 mmol), dimethyl sulfoxide (3 mL), and aqueous ammonia (25% wt, 360 mg, 2.57 mmol) were sequentially placed in a sealed tube, sealed at 80°C, and allowed to react for 10 hours. The completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, 20 mL of water was added, and it was extracted with ethyl acetate (10 mL x 3). The organic phase was combined, washed with saturated ammonium chloride (10 mL x 2), dried over anhydrous sodium sulfate, and rotated to obtain 3-(4-(6-(4-aminothiophen-2-yl)pyrazine-2-yl)-2-methoxyphenyl)oxetan-3-ol (A35-4, crude product, theoretical value 0.38 mmol). This product was used directly in the next step of the reaction without any purification.

[0121] Step 5: N-(5-(6-(4-(3-hydroxyoxetan-3-yl)-3-methoxyphenyl)pyrazine-2-yl)thiophen-3-yl)pentanamide (A35) 3-(4-(6-(4-aminothiophen-2-yl)pyrazine-2-yl)-2-methoxyphenyl)oxetan-3-ol (A35-4, crude product, 0.38 mmol) was dissolved in dichloromethane (10 mL), cooled in an ice bath, triethylamine (117 mg, 1.16 mmol) was added, and pentanoic acid chloride (93 mg, 0.77 mol) dissolved in dichloromethane (0.5 mL) was slowly added dropwise to the system. Once the addition was complete, the reaction was continued in an ice bath for 1 hour, and the completion of the reaction was monitored by TLC. The reaction solution was then rotated dry and purified by column chromatography to obtain N-(5-(6-(4-(3-hydroxyoxetan-3-yl)-3-methoxyphenyl)pyrazine-2-yl)thiophen-3-yl)pentanamide (A35, 32 mg, 19.1%). MS (ESI) m / z: calcd 440.16 (M+H +), found 440.10. 1 H NMR (400 MHz, DMSO) δ 10.39 (s, 1H), 9.19 (s, 1H), 9.06 (s, 1H), 7.89 (d, J = 1.4 Hz, 1H), 7.76 (dd, J = 13.5, 7.3 Hz, 2H), 7.72 (d, J = 1.3 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 5.97 (s, 1H), 5.02 (d, J = 6.9 Hz, 2H), 4.67 (d, J = 6.9 Hz, 2H), 3.94 (d, J = 6.9 Hz, 3H), 2.36-2.29 (m, 2H), 1.64-1.56 (m, 2H), 1.38-1.30 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H).

[0122] Compounds A36-A45 in Examples 36-45 were produced using experimental procedures similar to those in Example 35, and compounds A36-A45 are summarized in Table 2. [Table 2-1] [Table 2-2] [Table 2-3]

[0123] Example 46: Preparation of 2-Methoxy-4-(6-(4-pentanamidethiophen-2-yl)pyrazine-2-yl)-N-(1H-tetrazole-5-yl)benzamide (B4) [ka]

[0124] Step 1: 3-Methoxy-4-methoxycarbonylphenylboronic acid pinacol ester (B4-1) Methyl 4-bromo-2-methoxybenzoate (10 g, 40.8 mmol), potassium acetate (10.1 g, 103 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.51 g, 2.06 mmol), bis(pinacolato)diborone (12.44 g, 49.0 mmol), and 1,4-dioxane (100 mL) were sequentially placed in a reaction bottle and reacted at 80°C for 5 hours under the protection of nitrogen gas. The completion of the reaction was monitored by TLC. The reaction mixture was rotated dry and purified by column chromatography. Pinacol 3-methoxy-4-methoxycarbonylphenylboronic acid (B4-1, 11.0 g, 92.3%) was obtained. 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.40 (s, 1H), 3.97 (s, 3H), 3.91 (s, 3H), 1.37 (s, 12H).

[0125] Step 2: 2-Methoxy-4-(6-bromopyrazine-2-yl)methyl benzoate (B4-2) 2,6-Dibromopyrazine (11.6 g, 48.8 mmol), 3-Methoxy-4-methoxycarbonylphenylboronic acid pinacol ester (B4-1, 11.0 g, 37.6 mmol), potassium carbonate (13.52 g, 98.0 mmol), tetrakis(triphenylphosphine)palladium (2.37 g, 2.05 mmol), 1,4-Dioxane (120 mL), and water (30 mL) were sequentially added to a reaction bottle. The mixture was reacted at 100°C for 5 hours under the protection of nitrogen gas, and the completion of the reaction was monitored by TLC. Most of the 1,4-dioxane was removed by rotary evaporation, water (50 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was then combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, rotated-dried, and purified by column chromatography to obtain methyl 2-methoxy-4-(6-bromopyrazine-2-yl)benzoate (B4-2, 6.67 g, 54.7%). MS (ESI) m / z: Calculated value 323.00 (M+H + ), measured value 322.90; 1 H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.68 (s, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 1.4 Hz, 1H), 7.59 (dd, J = 8.1, 1.6 Hz, 1H), 4.05 (s, 3H), 3.95 (s, 3H).

[0126] Third step: 2-Methoxy-4-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)methyl benzoate (B4-3) Methyl 2-methoxy-4-(6-bromopyrazine-2-yl)benzoate (B4-2, 6.67 g, 20.6 mmol), (4-bromothiophen-2-yl)boronic acid (4.30 g, 20.8 mmol), tetrakis(triphenylphosphine)palladium (1.3 g, 0.86 mmol), potassium carbonate (10.25 g, 74.3 mmol), 1,4-dioxane (120 mL), and water (30 mL) were sequentially placed in a reaction bottle. The mixture was reacted at 60°C for 0.5 hours under the protection of nitrogen gas, and the completion of the reaction was monitored by TLC. After removing most of the 1,4-dioxane by rotary evaporation of the reaction mixture, dichloromethane (60 mL) and water (30 mL) were added, and the mixture was separated. The aqueous phase was extracted with dichloromethane (30 mL x 2), the organic phase was combined, the organic phase was washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, rotated-dried, and purified by column chromatography to obtain 2-methoxy-4-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)methyl benzoate (B4-3, 3.96 g, 47.3%). MS (ESI) m / z: Calculated value 404.98 (M+H + ), measured value 404.90; 1 H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 8.90 (s, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.82 (s, 1H), 7.68 (d, J = 6.5 Hz, 1H), 7.44 (s, 1H), 6.98 (s, 1H), 4.08 (s, 3H), 3.96 (s, 3H).

[0127] Step four: 2-Methoxy-4-(6-(4-aminothiophen-2-yl)pyrazine-2-yl)methyl benzoate (B4-4) 2-Methoxy-4-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)methyl benzoate (B4-3, 400 mg, 0.99 mmol), cuprous iodide (47 mg, 0.25 mmol), L-proline (57 mg, 0.50 mmol), dimethyl sulfoxide (25 mL), and aqueous ammonia (25% wt, 1.0 g, 5.92 mmol) were sequentially placed in a sealed tube, sealed at 80°C, and allowed to react for 10 hours. The completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (40 mL x 3). The organic phase was combined, washed with saturated ammonium chloride (40 mL x 2), dried over anhydrous sodium sulfate, and rotated to obtain 2-methoxy-4-(6-(4-aminothiophen-2-yl)pyrazine-2-yl)methyl benzoate (B4-4, 450 mg crude product, 0.99 mmol (theoretical value)). This product was used directly in the next step of the reaction without any purification. MS (ESI) m / z: Calculated value 342.08 (M+H + ), measured value 342.10.

[0128] Step 5: 2-Methoxy-4-(6-(4-pentanamidothiophen-2-yl)pyrazine-2-yl)methyl benzoate (B1) 2-Methoxy-4-(6-(4-aminothiophen-2-yl)pyrazine-2-yl)methyl benzoate (B4-4, 450 mg crude product, 0.99 mmol (theoretical value)) was dissolved in dichloromethane (5 mL), cooled in an ice bath, and triethylamine (666 mg, 6.59 mmol) was added. Separately, pentanoic acid chloride (318 mg, 2.64 mmol) was dissolved in dichloromethane (1 mL) and added dropwise to the above system. After the addition was complete, the system was returned to room temperature and reacted for 0.5 hours, and the complete reaction was measured by TLC. The reaction solution was rotated dry and purified by column chromatography to obtain 2-Methoxy-4-(6-(4-pentanamidothiophen-2-yl)pyrazine-2-yl)methyl benzoate (B1, 295 mg, 70.0%). MS (ESI) m / z: Calculated value 426.14 (M+H +), measured value 426.10. 1 H NMR (400 MHz, DMSO) δ 10.42 (s, 1H), 9.27 (s, 1H), 9.13 (s, 1H), 7.91 (d, J = 3.2 Hz, 2H), 7.85 (s, 2H), 7.74 (s, 1H), 3.98 (s, 3H), 3.84 (s, 3H), 2.32 (t, J = 7.4Hz, 2H), 1.67-1.54 (m, 2H), 1.39-1.30(m, 2H), 0.92 (t, J = 7.3 Hz, 3H).

[0129] Step 6: 2-Methoxy-4-(6-(4-pentanamidothiophen-2-yl)pyrazine-2-yl)benzoic acid (B2) 2-Methoxy-4-(6-(4-pentanamidothiophen-2-yl)pyrazine-2-yl)methyl benzoate (B1, 295 mg, 0.69 mmol), lithium hydroxide monohydrate (146 mg, 3.48 mmol), tetrahydrofuran (6 mL), and water (2 mL) were sequentially added to a reaction bottle and reacted at room temperature for 16 hours, with the completion of the reaction monitored by TLC. Tetrahydrofuran was removed by rotary evaporation, diluted with 5 mL of water, acidified with 1 M hydrochloric acid to pH=3-4, extracted with ethyl acetate (10 mL × 3), and the organic phase was combined. The organic phase was sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate, rotated-dried, and purified by column chromatography to obtain 2-methoxy-4-(6-(4-pentanamidothiophen-2-yl)pyrazine-2-yl)benzoic acid (B2, 258 mg, 90.4%). MS (ESI) m / z: Calculated value 412.13 (M+H + ), measured value 412.10.

[0130] Step 7: 2-Methoxy-4-(6-(4-pentanamidothiophen-2-yl)pyrazine-2-yl)-N-(1H-tetrazole-5-yl)benzamide(B4) 2-Methoxy-4-(6-(4-pentanamidothiophen-2-yl)pyrazine-2-yl)benzoic acid (B4-6, 258 mg, 0.63 mmol), 5-aminotetrazole (56 mg, 0.66 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (241 mg, 1.26 mmol), 1-hydroxybenzotriazole (170 mg, 1.26 mmol), N,N-diisopropylethylamine (324 mg, 2.51 mmol), and N,N-dimethylformamide (5 mL) were sequentially placed in a reaction bottle and allowed to react at room temperature for 16 hours. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (20 mL x 3), and the ethyl acetate phase was combined. The organic phase was then washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, rotated dry, and purified by column chromatography to obtain 2-methoxy-4-(6-(4-pentanamidethiophen-2-yl)pyrazine-2-yl)-N-(1H-tetrazole-5-yl)benzamide (B4, 115 mg, 38.3%). MS (ESI) m / z: Calculated value 477.15 (MH) + ), measured value 477.10; 1 H NMR (400 MHz, DMSO) δ 10.40 (s, 1H), 9.29 (s, 1H), 9.13 (s, 1H), 8.05-7.82 (m, 3H), 7.73 (d, J = 1.3 Hz, 1H), 4.05 (s, 3H), 2.36-2.26 (m, 2H), 1.64-1.57(m, 2H), 1.44-1.28 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H).

[0131] Example 47-121 (compounds B1-B78) was prepared by an experimental procedure similar to that of Example 46, and compounds B1-B78 are summarized in Table 3. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14] [Table 3-15] [Table 3-16]

[0132] Example 122: Preparation of 3-(4-(cyclobutancarboxamide)thiophen-2-yl)-5-(3,4-dimethoxyphenyl)isonicotinamide (C1) [ka]

[0133] Step 1: 3-Bromo-5-(3,4-dimethoxyphenyl)isonicotinonitrile (C1-1) 3,5-Dibromo-4-cyanopyridine (1.5 g, 5.73 mmol), 3,4-Dimethoxyphenylboronic acid (1.15 g, 6.30 mmol), tetrakis(triphenylphosphine)palladium (132 mg, 0.12 mmol), potassium carbonate (1.82 g, 13.17 mmol), 1,4-Dioxane (20 mL), and water (4 mL) were placed in a reaction bottle and reacted at 80°C for 14 hours under the protection of nitrogen gas. The completion of the reaction was monitored by TLC. Most of the 1,4-dioxane was removed by rotary evaporation, the solution was diluted with 25 mL of water, extracted with dichloromethane (15 mL x 2), the organic phase was combined, the organic phase was washed with saturated saline (15 mL x 1), dried over anhydrous sodium sulfate, and after rotary drying, the solution was purified by column chromatography to obtain 3-bromo-5-(3,4-dimethoxyphenyl)isonicotinonitrile (C1-1,676 mg, 37.0%). 1 H NMR (400 MHz, DMSO) δ 9.01 (s, 1H), 8.89 (s, 1H), 7.34 (d, J = 2.0 Hz, 1H), 7.26 (dd, J = 8.3, 2.0 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H).

[0134] Step 2: 3-(4-bromothiophen-2-yl)-5-(3,4-dimethoxy)isonicotinonitrile (C1-2) 3-Bromo-5-(3,4-dimethoxyphenyl)isonicotinonitrile (C1 - 1,470 mg, 1.47 mmol), (4-bromothiophen-2-yl)boronic acid (335.1 mg, 1.62 mmol), tetrakis(triphenylphosphine)palladium (34 mg, 0.029 mmol), potassium carbonate (610 mg, 4.42 mmol), 1,4-dioxane (10 mL), and water (2.5 mL) were placed in a reaction bottle and reacted at 80°C for 14 hours under the protection of nitrogen gas. The completion of the reaction was monitored by TLC. Most of the 1,4-dioxane was removed by rotary evaporation, diluted with water (15 mL), extracted with dichloromethane (10 mL x 3), the organic phase was combined, the organic phase was washed with saturated saline (5 mL x 1), dried over anhydrous sodium sulfate, and after rotary drying, it was purified by column chromatography to obtain 3-(4-bromothiophen-2-yl)-5-(3,4-dimethoxyphenyl)isonicotinonitrile (C1-2, 190.5 mg, 30.8%). 1 H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.90 (s, 1H), 8.02 (d, J = 1.3 Hz, 1H), 7.77 (d, J = 1.4 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.29 (dd, J = 8.3, 2.0 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H).

[0135] Third step: 3-(3,4-dimethoxyphenyl)-5-(4-((diphenylmethylene)amino)thiophen-2-yl)isonicotinonitrile(C1-3) 3-(4-bromothiophen-2-yl)-5-(3,4-dimethoxy)isonicotinonitrile (C1-2,100 mg, 0.238 mmol), benzophenone imine (64.83 mg, 0.358 mmol), 2,2'-bis(diphenylphosphin)-1,1'-binaphthyl (29.70 mg, 0.048 mmol), tris(dibenzylideneacetone)dipalladium (21.84 mg, 0.024 mmol), sodium t-butoxide (68.76 mg, 0.715 mmol), and toluene (5 mL) were sequentially placed in a reaction bottle and reacted at 100°C for 16 hours under the protection of nitrogen gas. The completion of the reaction was monitored by TLC. The reaction mixture was rotated dry and purified by column chromatography to obtain 3-(3,4-dimethoxyphenyl)-5-(4-((diphenylmethylene)amino)thiophen-2-yl)isonicotinonitrile (C1-3, 110 mg, 92.1%). 1 H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.69 (s, 1H), 7.82 (d, J = 6.2 Hz, 2H), 7.47-7.40 (m, 10H), 6.82 (d, J = 3.5 Hz, 1H), 6.77 (s, 1H), 6.65 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H).

[0136] Step 4: 3-(4-aminothiophen-2-yl)-5-(3,4-dimethoxyphenyl)isonicotinonitrile hydrochloride (C1-4) 3-(3,4-dimethoxyphenyl)-5-(4-((diphenylmethylene)amino)thiophen-2-yl)isonicotinonitrile (C1-3, 110 mg, 0.219 mmol) was dissolved in dichloromethane, two drops of concentrated hydrochloric acid were added dropwise, and the mixture was reacted at room temperature for 4 hours. A white solid precipitated, which was collected by filtration and heated to obtain 3-(4-aminothiophen-2-yl)-5-(3,4-dimethoxyphenyl)isonicotinonitrile hydrochloride (C1-4, 47 mg, 57.4%). MS (ESI) m / z: Calculated value 338.09 (M+H +), measured value 338.10.

[0137] Step 5: N-(5-(4-cyano-5-(3,4-dimethoxyphenyl)pyridine-3-yl)thiophen-3-yl)cyclobutanecarboxamide (C2) 3-(4-aminothiophen-2-yl)-5-(3,4-dimethoxyphenyl)isonicotinonitrile hydrochloride (C1-4, 30 mg, 0.08 mmol) was dissolved in 3 mL of dichloromethane, cooled in an ice bath, and triethylamine (40.4 mg, 0.40 mmol) was added to the reaction system. Separately, cyclobutanecarboxylate chloride (11.61 mg, 0.098 mmol) was dissolved in dichloromethane (0.5 mL) and slowly added dropwise to the reaction system. Once the addition was complete, the mixture was allowed to return to room temperature and reacted for 3 hours, and the completion of the reaction was monitored by TLC. The reaction mixture was rotated dry and purified by column chromatography to obtain N-(5-(4-cyano-5-(3,4-dimethoxyphenyl)pyridine-3-yl)thiophen-3-yl)cyclobutanecarboxamide (C2, 32 mg, 95%). 1 H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.75 (s, 1H), 7.91 (s, 1H), 7.61 (s, 1H), 7.48 (s, 1H), 7.19 (dd, J = 8.3, 2.0 Hz, 1H), 7.14 (d, J = 1.9 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 3.99 (s, 6H), 3.25-3.13 (m, 1H), 2.51-2.37 (m, 2H), 2.31-2.25 (m, 2H).

[0138] Step 6: 3-(4-(cyclobutanecarboxamide)thiophen-2-yl)-5-(3,4-dimethoxyphenyl)isonicotinamide (C1) N-(5-(4-cyano-5-(3,4-dimethoxyphenyl)pyridine-3-yl)thiophen-3-yl)cyclobutanecarboxamide (C2, 2 mg, 0.0048 mmol), sodium t-butoxide (1.68 mg, 0.015 mmol), and t-butanol (3 mL) were placed in a reaction bottle, the temperature was raised to 50°C, and the reaction was allowed to proceed for 2 hours. The completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, the reaction was quenched with ice water (10 mL), extracted with ethyl acetate (5 mL x 3), the organic phase was combined, the organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and rotated to obtain 3-(4-(cyclobutanecarboxamide)thiophen-2-yl)-5-(3,4-dimethoxyphenyl)isonicotinamide (C1, 1.8 mg). 1 H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.64 (s, 1H), 7.78 (s, 1H), 7.60 (s, 1H), 7.12 (d, J = 1.5 Hz, 1H), 7.09 (dd, J = 8.0, 1.7 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.20-3.12 (m, 1H), 2.44-2.36 (m, 2H), 2.28-2.20 (m, 2H).

[0139] Examples 123-124 were prepared using experimental procedures similar to those of Example 122, and compounds C1-C4 are summarized in Table 4. [Table 4-1] [Table 4-2]

[0140] Example 125: Preparation of N-(4-((6-(3,4-dimethoxyphenyl)pyrazine-2-yl)amino)cyclohexyl)cyclobutanecarboxamide (D2) [ka]

[0141] First step:N 1 -(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)cyclohexane-1,4-diamine(D1) 2-Bromo-6-(3,4-dimethoxyphenyl)pyrazine (A1 - 2.50 mg, 0.17 mmol), 1,4-cyclohexanediamine (97 mg, 0.85 mmol), sodium t-butoxide (33 mg, 0.34 mmol), 2,2'-bis(diphenylphosphin)-1,1'-binaphthyl (10.6 mg, 0.017 mmol), tris(dibenzylideneacetone)dipalladium (7.3 mg, 0.008 mmol), and toluene (10 mL) were sequentially placed in a reaction bottle and reacted at 110°C for 4 hours under the protection of nitrogen gas. The completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, the solvent was removed by rotational evaporation, and then purified by column chromatography. 1 -(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)cyclohexane-1,4-diamine (D1, 25 mg, 45.0%) was obtained. 1 H NMR (400 MHz, DMSO) δ 8.23 ​​(s, 1H), 7.78 (s, 1H), 7.64 (s, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 7.0 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.04 (dt, J = 13.9, 7.0 Hz, 2H), 2.05 (s, 2H), 1.87 (s, 2H), 1.26 (s, 4H).

[0142] Second step: N-(4-((6-(3,4-dimethoxyphenyl)pyrazine-2-yl)amino)cyclohexyl)cyclobutanecarboxamide (D2) N 1-(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)cyclohexane-1,4-diamine (D1, 14 mg, 0.043 mmol) was dissolved in dichloromethane (5 mL), cyclobutanecarboxylate chloride (6.1 mg, 0.051 mmol) was added, and the mixture was allowed to react at room temperature for 2 hours. The completion of the reaction was monitored by TLC. Water (10 mL) was added to the reaction system to quench the reaction, and the reaction was separated. The aqueous phase was extracted with dichloromethane (5 mL), and the organic phase was combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, rotated dry, and purified by column chromatography to obtain N-(4-((6-(3,4-dimethoxyphenyl)pyrazine-2-yl)amino)cyclohexyl)cyclobutanecarboxamide (D2, 8 mg, 45.3%). MS (ESI) m / z: Calculated value 411.23 (M+H + ), measured value 411.57; 1 H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.80 (s, 1H), 7.60 (d, J = 1.8 Hz, 1H), 7.55 (dd, J = 8.3, 1.9 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 5.20 (d, J = 7.6 Hz, 1H), 4.70 (s, 1H), 4.00 (s, 3H), 3.96 (s, 3H), 3.37-3.26 (m, 1H), 3.03-2.94 (m, 1H), 2.34-2.31 (m, 4H), 2.21-2.07 (m, 4H), 1.93-1.86 (m, 1H), 1.35-1.22 (m, 4H), 0.96-0.77 (m, 2H).

[0143] Example 126: Preparation of 3-(2-(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)thiazole-4-yl)-1,1-diethylurea (D4) [ka]

[0144] Step 1: 6-(3,4-dimethoxyphenyl)pyrazine-2-carbonitrile (D4-1) 2-Bromo-6-(3,4-dimethoxyphenyl)pyrazine (A1-2, 520 mg, 1.76 mmol), cuprous cyanide (189 mg, 2.11 mmol), and N-methylpyrrolidone (14 mL) were sequentially added to a reaction bottle and reacted at 180°C for 1 hour. The completion of the reaction was monitored by TLC. The reaction solution was cooled to room temperature, diluted with water (70 mL), extracted with ethyl acetate (30 mL x 3), and the organic phase was combined. The organic phase was sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate, and 6-(3,4-dimethoxyphenyl)pyrazine-2-carbonitrile (D4-1,268 mg, 63.1%) was obtained. 1 H NMR (400 MHz, DMSO) δ 9.58 (s, 1H), 9.09 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.73 (s, 1H), 7.16 (d, J = 8.5 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H).

[0145] Step 2: 6-(3,4-dimethoxyphenyl)pyrazine-2-carboxamide (D4-2) 6-(3,4-dimethoxyphenyl)pyrazine-2-carbonitrile (D4-1, 268 mg, 1.11 mmol) was dissolved in trifluoroacetic acid / concentrated sulfuric acid (4 / 1, 10 mL), and the reaction was carried out at 50°C for 3 hours. The completion of the reaction was monitored by TLC. The reaction mixture was cooled in an ice bath, and the pH was reduced to 8-11 with 2 M sodium hydroxide solution. The solid precipitated, was filtered, and the solid was collected. It was then heated and dried to obtain 6-(3,4-dimethoxyphenyl)pyrazine-2-carboxamide (D4-2, 201 mg, 69.8%). 1 H NMR (400 MHz, DMSO) δ 9.44 (s, 1H), 9.04 (s, 1H), 8.48 (s, 1H), 8.07-7.87 (m, 3H), 7.12 (d, J = 8.4 Hz, 1H), 3.92 (s, 3H), 3.86 (s, 3H).

[0146] Third step: 6-(3,4-dimethoxyphenyl)pyrazine-2-thiocarboxamide (D4-3) 6-(3,4-dimethoxyphenyl)pyrazine-2-carboxamide (D4-2, 201 mg, 0.775 mmol), Lawson's reagent (188 mg, 0.465 mmol), and acetonitrile (10 mL) were placed in a reaction bottle and reacted at 80°C for 16 hours. The completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, rotated dry, and purified by column chromatography to obtain 6-(3,4-dimethoxyphenyl)pyrazine-2-thiocarboxamide (D4-3, 157 mg, 73.5%). 1 H NMR (400 MHz, DMSO) δ 10.41 (s, 1H), 10.18 (s, 1H), 9.44 (d, J = 6.2 Hz, 2H), 8.09-7.83 (m, 2H), 7.11 (d, J = 8.5 Hz, 1H), 3.92 (s, 3H), 3.86 (s, 3H).

[0147] Step 4: 2-(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)thiazole-4-carboxylate methyl ester (D4-4) 6-(3,4-dimethoxyphenyl)pyrazine-2-thiocarboxamide (D4-3, 142 mg, 0.52 mmol), methyl bromopyruvate (140 mg, 0.62 mmol), and methanol (15 mL) were sequentially added to a reaction bottle and reacted at 70°C for 16 hours. The completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, a solid precipitated, and the solid was collected by filtration. The solid was heated and dried to obtain 2-(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)thiazole-4-carboxylate methyl ester (D4-4, 82 mg, 44.1%). 1H NMR (400 MHz, DMSO) δ 9.42 (s, 1H), 9.20 (s, 1H), 8.80 (s, 1H), 7.87 (dd, J = 8.5, 1.9 Hz, 1H), 7.82 (d, J = 1.9 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 3.92 (s, 6H), 3.87 (s, 3H).

[0148] Step 5: 2-(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)thiazole-4-carboxylic acid (D4-5) 2-(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)thiazole-4-carboxylic acid methyl ester (D4-4, 80 mg, 0.224 mmol), lithium hydroxide monohydrate (47 mg, 1.12 mmol), and tetrahydrofuran / water (3 / 1, 4 mL) were sequentially added to a reaction bottle and reacted at 40°C for 2 hours. The completion of the reaction was monitored by TLC. The reaction mixture was cooled in an ice bath, acidified with 2 M hydrochloric acid to adjust the pH to 3-4, and a solid precipitated. The mixture was filtered, the solid was collected, and it was heated and dried to obtain 2-(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)thiazole-4-carboxylic acid (D4-5, 75.0 mg, 97.5%). 1 H NMR (400 MHz, DMSO) δ 9.41 (s, 1H), 9.19 (s, 1H), 8.70 (s, 1H), 7.87 (dd, J = 8.4, 1.9 Hz, 1H), 7.82 (d, J = 1.9 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 3.92 (s, 3H), 3.87 (s, 3H).

[0149] Step 6: (2-(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)thiazole-4-yl)carbamate t-butyl ester (D3) 2-(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)thiazole-4-carboxylic acid (D4-5, 50.0 mg, 0.146 mmol), triethylamine (44.3 mg, 0.438 mmol), and t-butanol (5 mL) were sequentially added to a reaction bottle. Diphenyl phosphate azide (80.1 mg, 0.292 mmol, diluted with 0.5 mL of t-butanol) was added dropwise, and after addition was complete, the temperature was raised to 85°C and the reaction was allowed to proceed for 16 hours. The completion of the reaction was monitored by TLC. The reaction mixture was rotated dry and purified by column chromatography to obtain (2-(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)thiazole-4-yl)carbamate t-butyl ester (D3, 25 mg, 41.3%). 1 H NMR (400 MHz, CDCl3) δ 9.20 (s, 1H), 9.02 (s, 1H), 7.77 (d, J = 1.9 Hz, 1H), 7.73-7.61 (m, 2H), 7.47 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 4.06 (s, 3H), 4.00 (s, 3H), 1.59 (s, 9H).

[0150] Step 7: 3-(2-(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)thiazole-4-yl)-1,1-diethylurea(D4) (2-(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)thiazole-4-yl)carbamate t-butyl ester (D3, 18 mg, 0.043 mmol) and ethyl acetate solution of hydrogen chloride (3 M, 5 mL) were sequentially added to a reaction bottle and reacted at room temperature for 1 hour until a solid precipitated. The solid was collected by filtration and transferred to a reaction bottle. It was dissolved in dichloromethane (2 mL) and triethylamine (27.3 mg, 0.27 mmol). Separately, N,N-diethyl chlorocarboxamide (14.9 mg, 0.11 mmol) was dissolved in dichloromethane (0.5 mL) and added dropwise to the system. Once the dropwise addition was complete, the mixture was allowed to react at room temperature for 2 hours, and the completion of the reaction was monitored by TLC. The reaction mixture was rotate-dried and purified by column chromatography to obtain 3-(2-(6-(3,4-dimethoxyphenyl)pyrazine-2-yl)thiazole-4-yl)-1,1-diethylurea (D4, 0.8 mg, 4.5%). MS (ESI) m / z: Calculated value 414.15 (M+H + ), measured value 414.10; 1 H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 9.01 (s, 1H), 7.77 (d, J = 1.9 Hz, 1H), 7.70 (dd, J = 8.3, 1.9 Hz, 1H), 7.64 (s, 1H), 7.44 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 4.06 (s, 3H), 4.00 (s, 3H), 3.46 (q, J = 7.2 Hz, 4H), 1.31 (t, J = 7.2 Hz, 6H).

[0151] Example 127: Preparation of 2-Methoxy-4-(4-(4-pentanamidethiophene)pyrimidine-2-yl)-N-methyl-N-(1-methylpiperidine-4-yl)benzamide (D5) [ka]

[0152] First step: 2-bromo-4-(4-bromothiophen-2-yl)pyrimidine (D5-1) 2,4-Dibromopyrimidine (100 mg, 0.42 mmol), (4-bromothiophen-2-yl)boronic acid (87 mg, 0.42 mmol), tetrakis(triphenylphosphine)palladium (24 mg, 0.021 mmol), potassium carbonate (87 mg, 0.63 mmol), 1,4-dioxane (1.6 mL), and water (0.4 mL) were reacted at 80°C for 4 hours under the protection of nitrogen gas, and the completion of the reaction was monitored by TLC. After rotational drying of the reaction mixture, it was purified by column chromatography to obtain 2-bromo-4-(4-bromothiophen-2-yl)pyrimidine (D5-1, 90 mg, 67.0%). MS (ESI) m / z: Calculated value 318.85 (M+H + ), measured value 318.90.

[0153] Step 2: 4-(4-(4-bromothiophen-2-yl)pyrimidine-2-yl)-2-methoxybenzoate methyl ester (D5-2) 2-bromo-4-(4-bromothiophen-2-yl)pyrimidine (D5 - 1.90 mg, 0.28 mmol), 3-methoxy-4-methoxycarbonylphenylboronic acid pinacol ester (B4 - 1.98 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium (32 mg, 0.028 mmol), potassium carbonate (58 mg, 0.42 mmol), 1,4-dioxane (2 mL), and water (0.5 mL) were reacted at 80°C for 2 hours under the protection of nitrogen gas, and the completion of the reaction was monitored by TLC. The reaction mixture was rotated dry and then purified by column chromatography to obtain 4-(4-(4-bromothiophen-2-yl)pyrimidine-2-yl)-2-methoxybenzoate methyl ester (D5-2, 101 mg, 88.9%). 1H NMR (400 MHz, DMSO) δ 9.00 (d, J = 5.3 Hz, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 8.08 (d, J = 8.1 Hz, 1H), 8.04 (d, J = 6.7 Hz, 2H), 7.84 (d, J = 8.0 Hz, 1H), 3.96 (s, 3H), 3.84 (s, 3H).

[0154] Third step: 4-(4-(4-aminothiophen-2-yl)pyrimidine-2-yl)-2-methoxybenzoate methyl ester (D5-3) 4-(4-(4-bromothiophen-2-yl)pyrimidine-2-yl)-2-methoxybenzoate methyl ester (D5-2, 100 mg, 0.247 mmol), cuprous iodide (9.4 mg, 0.049 mmol), L-proline (11.4 mg, 0.10 mmol), dimethyl sulfoxide (2 mL), and aqueous ammonia (25% wt, 200 mg, 1.48 mmol) were sequentially placed in a sealed tube, sealed at 80°C, and allowed to react for 16 hours. The completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phase was combined, washed with saturated ammonium chloride (5 mL x 4), dried over anhydrous sodium sulfate, and rotated-dried to obtain 4-(4-(4-aminothiophen-2-yl)pyrimidine-2-yl)-2-methoxybenzoate methyl ester (D5-3, 105 mg crude product, 0.247 mmol (theoretical value)). This product was used directly in the next step of the reaction without any purification. MS (ESI) m / z: Calculated value 342.08 (M+H + ), measured value 342.10.

[0155] Step 4: 2-Methoxy-4-(4-(4-pentanamidothiophen-2-yl)pyrimidine-2-yl)methyl benzoate (D5-4) 4-(4-(4-aminothiophen-2-yl)pyrimidine-2-yl)-2-methoxybenzoate methyl ester (D5-3, 105 mg crude product, 0.247 mmol (theoretical value)) was dissolved in dichloromethane (5 mL), cooled in an ice bath, and triethylamine (31 mg, 0.31 mmol) was added. Separately, pentanoic acid chloride (56 mg, 0.46 mmol) was dissolved in dichloromethane (1 mL) and added dropwise to the above system. After the addition was complete, the system was returned to room temperature and reacted for 0.5 hours, and the complete reaction was measured by TLC. The reaction solution was rotated dry and purified by column chromatography to obtain 2-methoxy-4-(4-(4-pentanamidethiophen-2-yl)pyrimidine-2-yl)benzoate methyl ester (D5-4, 67 mg, 63.8%). MS (ESI) m / z: Calculated value 426.14 (M+H + ), measured value 426.10.

[0156] Step 5: 2-Methoxy-4-(4-(4-pentanamidethiophen-2-yl)pyrimidine-2-yl)benzoic acid (D5-5) 2-Methoxy-4-(4-(4-pentanamidothiophen-2-yl)pyrimidine-2-yl)methyl benzoate (D5-4, 67 mg, 0.158 mmol), lithium hydroxide monohydrate (33 mg, 0.786 mmol), tetrahydrofuran (4 mL), and water (1 mL) were sequentially added to a reaction bottle and reacted at room temperature for 16 hours, with the completion of the reaction monitored by TLC. Tetrahydrofuran was removed by rotary evaporation, diluted with water (5 mL), acidified with saturated citric acid to pH=3-4, extracted with ethyl acetate (10 mL × 3), the organic phase was combined, the organic phase was sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate, rotated-dried, and purified by column chromatography to obtain 2-methoxy-4-(4-(4-pentanamidothiophen-2-yl)pyrimidine-2-yl)benzoic acid (D5-5, 56 mg, 86.1%). MS (ESI) m / z: Calculated value 412.13 (M+H + ), measured value 412.10.

[0157] Step 6: 2-Methoxy-4-(4-(4-pentanamidethiophene)pyrimidine-2-yl)-N-methyl-N-(1-methylpiperidine-4-yl)benzamide (D5) 2-Methoxy-4-(4-(4-pentanamidothiophen-2-yl)pyrimidine-2-yl)benzoic acid (D5-5, 10 mg, 0.024 mmol), 1-methyl-4-(methylamino)piperidine (4.7 mg, 0.036 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.3 mg, 0.048 mmol), 1-hydroxybenzotriazole (6.6 mg, 0.048 mmol), N,N-diisopropylethylamine (9.4 mg, 0.073 mmol), and N,N-dimethylformamide (1 mL) were sequentially placed in a reaction bottle and reacted at room temperature for 5 hours. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (5 mL x 3), and the organic phase was combined. The organic phase was then washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, rotated-dried, and purified by column chromatography to obtain 2-methoxy-4-(4-(4-pentanamidethiophene)pyrimidine-2-yl)-N-methyl-N-(1-methylpiperidine-4-yl)benzamide (D5, 5 mg, 39.4%). MS (ESI) m / z: Calculated value 522.25 (M+H + ), measured value 522.40; 1H NMR (400 MHz, DMSO) δ 10.42 (s, 1H), 8.92 (dd, J = 5.3, 2.2 Hz, 1H), 8.16 - 8.06 (m, 2H), 8.01 (dd, J = 5.6, 1.4 Hz, 1H), 7.84 (dd, J = 5.3, 2.6 Hz, 1H), 7.78 (dd, J = 3.2, 1.3 Hz, 1H), 7.38 (dd, J = 10.3, 8.2 Hz, 1H), 3.93 (s, 3H), 3.52 (d, J = 8.0 Hz, 2H), 3.19 (d, J = 12.6 Hz, 2H), 2.99 (s, 1H), 2.92-2.79 (m, 3H), 2.66 (d, J = 7.1 Hz, 3H), 2.32 (t, J = 7.4 Hz, 2H), 2.08-1.77 (m, 4H), 1.60 (dt, J = 15.0, 7.5 Hz, 2H), 1.34 (dq, J = 14.5, 7.3 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H).

[0158] Example 128: Preparation of N-(5-(6-(4-(methylsulfonyl)piperazine-1-yl)pyrazine-2-yl)thiophen-3-yl)pentanamide (D6) [ka]

[0159] Step 1: 4-(6-bromopyrazine-2-yl)piperazine-1-carboxylate t-butyl ester (D6-1) Piperazine-1-carboxylate t-butyl ester (300 mg, 1.61 mmol), 2,6-dibromopyrazine (460 mg, 1.93 mmol), potassium carbonate (445 mg, 3.22 mmol), and dimethyl sulfoxide (9 mL) were reacted at 120°C for 5 hours under the protection of nitrogen gas, and the completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was combined and washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, and rotated to obtain 4-(6-bromopyrazine-2-yl)piperazine-1-carboxylate t-butyl ester (D6-1,250 mg, 45.2%). MS (ESI) m / z: Calculated value 343.07 (M+H), measured value 343.10.

[0160] Step 2: 4-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)piperazine-1-carboxylate t-butyl ester (D6-2) 4-(6-bromopyrazine-2-yl)piperazine-1-carboxylate t-butyl ester (250 mg, 0.73 mmol), (4-bromothiophen-2-yl)boronic acid (200 mg, 0.97 mmol), tetrakis(triphenylphosphine)palladium (42 mg, 0.036 mmol), potassium carbonate (242 mg, 1.75 mmol), and 1,4-dioxane / water (4:1, 15 mL) were sequentially placed in a reaction bottle and reacted at 60°C for 0.5 hours under the protection of nitrogen gas. The completion of the reaction was monitored by TLC. Water (25 mL) was added to the reaction mixture, extracted with ethyl acetate (20 mL x 3), and the organic phase was combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotated-dried. The compound was purified by column chromatography to obtain 4-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)piperazine-1-carboxylic acid t-butyl ester (D6-2, 105 mg, 33.8%). ¹H NMR (400 MHz, DMSO) δ values ​​were 8.46 (s, 1H), 8.26 (s, 1H), 7.91 (d, J = 1.3 Hz, 1H), 7.81 (d, J = 1.3 Hz, 1H), 3.64-3.60 (m, 4H), 3.48-3.45 (m, 4H), 1.44 (s, 9H).

[0161] Third step: 4-(6-(4-aminothiophen-2-yl)pyrazine-2-yl)piperazine-1-carboxylate t-butyl ester (D6-3) 4-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)piperazine-1-carboxylate t-butyl ester (105 mg, 0.25 mmol), cuprous iodide (10 mg, 0.052 mmol), L-proline (23 mg, 0.2 mmol), dimethyl sulfoxide (2 mL), and aqueous ammonia (25% wt, 59 mg, 1.69 mmol) were sequentially placed in a sealed tube, sealed at 80°C, and reacted for 16 hours. The completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phase was combined, washed with saturated ammonium chloride (5 mL x 2), dried over anhydrous sodium sulfate, and rotated-dried to obtain 4-(6-(4-aminothiophen-2-yl)pyrazine-2-yl)piperazine-1-carboxylic acid t-butyl ester (D6-3, 90 mg, 0.25 mmol (theoretical value)). This ester was used directly in the next step of the reaction without any purification. MS (ESI) m / z: Calculated value 362.16 (M+H), measured value 362.10.

[0162] Step 4: 4-(6-(4-pentanamidemothiophen-2-yl)pyrazine-2-yl)piperazine-1-carboxylate t-butyl ester (D6-4) 4-(6-(4-aminothiophen-2-yl)pyrazine-2-yl)piperazine-1-carboxylate t-butyl ester (D6-3, 90 mg, 0.25 mmol (theoretical value)) was dissolved in dichloromethane (5 mL), cooled in an ice bath, and triethylamine (76 mg, 0.75 mmol) was added. Separately, pentanoic acid chloride (60 mg, 0.498 mmol) was dissolved in dichloromethane (0.5 mL) and slowly added dropwise to the above reaction system. The reaction was allowed to proceed in an ice bath for 1 hour, the completion of the reaction was monitored by TLC, and the product was purified by column chromatography to obtain 4-(6-(4-pentanamidethiophen-2-yl)pyrazine-2-yl)piperazine-1-carboxylate t-butyl ester (D6-4, 65 mg, 58.3%). MS (ESI) m / z: Calculated value 446.21 (M+H + ), measured value 446.30.

[0163] Step 5: N-(5-(6-(piperazine-1-yl)pyrazine-2-yl)thiophen-3-yl)pentanamide(D6-5) 4-(6-(4-pentanamidethiophen-2-yl)pyrazine-2-yl)piperazine-1-carboxylic acid t-butyl ester (65 mg, 0.146 mmol) was dissolved in methanol (1 mL), and then a methanol solution of hydrogen chloride (3 M, 1 mL) was added to the system. The reaction was allowed to proceed at room temperature for 16 hours. The completion of the reaction was monitored by TLC, and the reaction mixture was rotated dry without any further treatment. The reaction was then continued to obtain N-(5-(6-(piperazine-1-yl)pyrazine-2-yl)thiophen-3-yl)pentanamide (D6-5, 0.146 mmol (theoretical value)). MS (ESI) m / z: Calculated value 346.21 (M+H + ), measured value 346.30.

[0164] Step 6: N-(5-(6-(4-(methylsulfonyl)piperazine-1-yl)pyrazine-2-yl)thiophen-3-yl)pentanamide (D6) N-(5-(6-(piperazin-1-yl)pyrazine-2-yl)thiophen-3-yl)pentanamide (D6-5, 0.146 mmol (theoretical value)) was dissolved in dichloromethane (5 mL), cooled in an ice bath, and triethylamine (73 mg, 0.72 mmol) was added. Separately, methanesulfonyl chloride (25 mg, 0.22 mmol) was dissolved in dichloromethane (0.5 mL) and slowly added dropwise to the system. Once the addition was complete, the mixture was allowed to return to room temperature and reacted for 0.5 hours. The completion of the reaction was monitored by TLC, and the reaction solution was rotated dry and then purified by column chromatography to obtain N-(5-(6-(4-(methylsulfonyl)piperazin-1-yl)pyrazine-2-yl)thiophen-3-yl)pentanamide (D6, 21 mg, 34.0%). MS (ESI) m / z: Calculated value 423.55 (M+H +), Actual value 424.30;1H NMR (400 MHz, DMSO) δ 10.31 (s, 1H), 8.31 (s, 1H), 8.27 (s, 1H), 7.69 (d, J = 1.4 Hz, 1H), 7.62 (s, 1H), 3.77 (s, 4H), 3.26 (d, J = 4.9 Hz, 4H), 2.92 (s, 3H), 2.31 - 2.27 (m, 2H), 1.58 (d, J = 7.4 Hz, 2H), 1.35-1.30 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H).

[0165] Example 129: Preparation of N-(5-(6-(1-(methylsulfonyl)piperidine-4-yl)pyrazine-2-yl)thiophene-3-yl)pentanamide (D7) [ka]

[0166] Step 1: 4-(6-bromopyrazine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate t-butyl ester (D7-1) N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (500 mg, 1.62 mmol), 2,6-dibromopyrazine (385 mg, 1.62 mmol), sodium carbonate (429 mg, 4.05 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (60 mg, 0.082 mmol), and 1,4-dioxane / water (5:1, 12 mL) were sequentially placed in a reaction bottle and reacted at 100°C for 5 hours under the protection of nitrogen gas. The completion of the reaction was monitored by TLC. After rotational drying of the reaction mixture, it was purified by column chromatography to obtain 4-(6-bromopyrazine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate t-butyl ester (D7-1, 310 mg, 56.3%). 1H NMR (400 MHz, DMSO) δ 8.88 (s, 1H), 8.72 (s, 1H), 6.88 (s, 1H), 4.10 (d, J = 2.3 Hz, 2H), 3.60-3.49 (m, 2H), 2.54 (d, J = 1.7 Hz, 2H), 1.43 (s, 9H).

[0167] Step 2: 4-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate t-butyl ester (D7-2) 4-(6-bromopyrazine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate t-butyl ester (D7-1, 220 mg, 0.647 mmol), (4-bromothiophen-2-yl)boronic acid (134 mg, 0.647 mmol), tetrakis(triphenylphosphine)palladium (75 mg, 0.065 mmol), potassium carbonate (214 mg, 1.75 mmol), and 1,4-dioxane / water (5:1, 6 mL) were sequentially placed in a reaction bottle and reacted at 60°C for 0.5 hours under the protection of nitrogen gas. The completion of the reaction was monitored by TLC. Water (25 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, rotated-dried, and purified by column chromatography to obtain 4-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate t-butyl ester (D7-2, 158 mg, 57.8%). 1 H NMR (400 MHz, DMSO) δ 9.12 (s, 1H), 8.78 (s, 1H), 8.07 (d, J = 1.4 Hz, 1H), 7.89 (d, J = 1.4 Hz, 1H), 6.90 (s, 1H), 4.12 (s, 2H), 3.66-3.52 (m, 3H), 2.62 (s, 2H), 1.44 (s, 9H).

[0168] Third step: 4-(6-(4-aminothiophen-2-yl)pyrazine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate t-butyl(D7-3) 4-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate t-butyl ester (D7-2, 158 mg, 0.375 mmol), cuprous iodide (14 mg, 0.074 mmol), L-proline (17 mg, 0.148 mmol), dimethyl sulfoxide (2 mL), and aqueous ammonia (25% wt, 315 mg, 2.25 mmol) were sequentially placed in a sealed tube, sealed at 80°C, and reacted for 16 hours. The completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phase was combined, washed with saturated ammonium chloride (5 mL x 2), dried over anhydrous sodium sulfate, and rotated to obtain 4-(6-(4-aminothiophen-2-yl)pyrazine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate t-butyl (D7-3, 0.375 mmol (theoretical value)). This was used directly in the next step of the reaction without any purification. MS (ESI) m / z: Calculated value 359.15 (M+H + ), measured value 359.10.

[0169] Step 4: 4-(6-(4-pentanamidethiophen-2-yl)pyrazine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate t-butyl ester (D7-4) 4-(6-(4-aminothiophen-2-yl)pyrazine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate t-butyl (D7-3, 0.375 mmol (theoretical value)) was dissolved in dichloromethane (5 mL), cooled in an ice bath, and triethylamine (73 mg, 0.72 mmol) was added. Separately, pentanoic acid chloride (134 mg, 1.11 mmol) was dissolved in dichloromethane (0.5 mL) and slowly added dropwise to the above system. Once the addition was complete, the system was returned to room temperature and reacted for 0.5 hours. The completion of the reaction was monitored by TLC, and the reaction mixture was rotated dry and purified by column chromatography to obtain 4-(6-(4-pentanamidethiophen-2-yl)pyrazine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate t-butyl ester (D7-4, 35 mg, 21.1%). MS (ESI) m / z: Calculated value 443.20 (M+H + ), measured value 443.10.

[0170] Step 5: 4-(6-(4-pentanamidethiophen-2-yl)pyrazine-2-yl)piperidine-1-carboxylate t-butyl ester (D7-5) 4-(6-(4-pentanamidethiophen-2-yl)pyrazine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate t-butyl ester (D7-4, 35 mg, 0.079 mmol) was dissolved in methanol (2 mL), palladium carbon (35 mg) was added, and the reaction was carried out at room temperature for 16 hours in a hydrogen gas (1 atm) atmosphere, and the completion of the reaction was monitored by TLC. Palladium carbon was removed by filtration, and the mixture was rotated dry to obtain 4-(6-(4-pentanamidethiophen-2-yl)pyrazine-2-yl)piperidine-1-carboxylate t-butyl ester (D7-5, 35 mg, 100%). MS (ESI) m / z: Calculated value 445.22 (M+H + ), measured value 445.20.

[0171] Step 6: N-(5-(6-(piperidine-4-yl)pyrazine-2-yl)thiophene-3-yl)pentanamide hydrochloride (D7-6) 4-(6-(4-pentanamidethiophen-2-yl)pyrazine-2-yl)piperidine-1-carboxylate t-butyl ester (D7-5, 35 mg, 0.079 mmol) was dissolved in methanol (4 mL), a methanol solution of hydrogen chloride (3 M, 4 mL) was added, and the mixture was reacted at room temperature for 1 hour. The completion of the reaction was monitored by LC-MS, and the mixture was rotated dry and used directly in the next step to obtain N-(5-(6-(piperidine-4-yl)pyrazine-2-yl)thiophen-3-yl)pentanamide hydrochloride (D7-6, 30 mg, 100%). MS (ESI) m / z: Calculated value 345.17 (M+H + ), measured value 345.10.

[0172] Step 7: N-(5-(6-(1-(methylsulfonyl)piperidine-4-yl)pyrazine-2-yl)thiophene-3-yl)pentanamide (D7) N-(5-(6-(piperidine-4-yl)pyrazine-2-yl)thiophen-3-yl)pentanamide hydrochloride (D7-6, 30 mg, 0.079 mmol) was dissolved in dichloromethane (5 mL), triethylamine (24 mg, 0.238 mmol) was added, and the mixture was cooled in an ice bath. Separately, methanesulfonyl chloride (13.6 mg, 0.119 mmol) was dissolved in dichloromethane (2 mL) and added dropwise to the above system. Once the addition was complete, the mixture was returned to room temperature and reacted for 0.5 hours, and the completion of the reaction was monitored by LC-MS. The reaction mixture was rotated dry and then purified by column chromatography to obtain N-(5-(6-(1-(methylsulfonyl)piperidine-4-yl)pyrazine-2-yl)thiophen-3-yl)pentanamide (D7, 1.6 mg, 4.8%). MS (ESI) m / z: Calculated value 423.14 (M+H + ), measured value 423.10; 1H NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 8.94 (s, 1H), 8.51 (d, J = 3.7 Hz, 1H), 7.81 (d, J = 1.4 Hz, 1H), 7.66 (d, J = 1.3 Hz, 1H), 3.70 (d, J = 11.9 Hz, 2H), 3.01-2.83 (m, 5H), 2.34-2.28 (m, 2H), 2.08-2.01 (m, 2H), 1.88-1.77 (m, 2H), 1.63-1.55 (m, 2H), 1.38-1.30 (m, 2H), 1.24 (s, 1H), 0.91 (t, J = 7.3 Hz, 3H).

[0173] Example 130 was prepared by an experimental procedure similar to that of Examples 123-129, and compounds D1-D8 are summarized in Table 5. [Table 5-1] [Table 5-2]

[0174] Examples 131-152 (compound B79-100) were prepared by an experimental procedure similar to that of Example 46, and compound B79-100 is summarized in Table 6. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9] [Table 6-10]

[0175] Example 155: Preparation of 2-Cyclopropyl-N-(5-(6-(3-Methoxy-4-(N-Methyl-N-(1-methylpiperidine-4-yl)sulfamoyl)phenyl)pyrazine-2-yl)thiophen-3-yl)acetamide (B103) [ka]

[0176] Step 1: 4-Bromo-2-methoxybenzenesulfonyl chloride (B103-1) Cuprous chloride (20 mg, 0.20 mmol) was dissolved in water (30 mL), the reaction system was cooled to 0-10°C in an ice bath, thionyl chloride (8.0 g, 67.24 mmol) was slowly added dropwise to the reaction system, allowed to return to room temperature naturally, and then reacted for 16 hours to form stable system A. 2-methoxy-4-bromoaniline (3.0 g, 14.85 mmol) was dissolved in acetic acid (15 mL), the system was cooled to about 10°C in an ice bath, sodium nitrite (1.12 g, 16.23 mmol) was separately dissolved in water (5 mL), and this was added dropwise to the reaction system. After the addition was complete, the reaction was continued at 0°C for 1 hour to form stable system B. Stable system A was cooled to 0-10°C, stable system B was slowly added dropwise to A, and after the addition was complete, the mixture was allowed to return to room temperature naturally and then reacted for 16 hours. Completion of the reaction was detected by TLC. The reaction system was extracted with ethyl acetate (50 mL x 3), the organic phase was combined, the organic phase was washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, and rotated-dried. Purification by column chromatography yielded 4-bromo-2-methoxybenzenesulfonyl chloride (B103 - 1,671 mg, 15.8%). 1 H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.4 Hz, 1H), 7.30-7.27 (m, 2H), 4.09 (s, 3H).

[0177] Step 2: 4-Bromo-2-methoxy-N-methyl-N-(1-methylpiperidine-4-yl)benzenesulfonamide (B103-2) 4-Bromo-2-methoxybenzenesulfonyl chloride (B103-1, 200 mg, 0.7 mmol) was dissolved in dichloromethane (8 mL), and 1-methyl-4-(methylamino)piperidine (99 mg, 0.77 mmol) and triethylamine (142 mg, 1.40 mmol) were sequentially added to the reaction system. The reaction was allowed to proceed at room temperature for 14 hours, and completion of the reaction was detected by TLC. After rotational drying of the reaction mixture, it was purified by column chromatography to obtain 4-bromo-2-methoxy-N-methyl-N-(1-methylpiperidine-4-yl)benzenesulfonamide (B103-2, 264 mg, 100%). MS (ESI) m / z: Calculated value 377.05 (M+H + ), measured value 377.40.

[0178] Third step: (3-Methoxy-4-(N-methyl-N-(1-methylpiperidine-4-yl)aminosulfonyl)phenyl)boronic acid (B103-3) 4-Bromo-2-methoxy-N-methyl-N-(1-methylpiperidine-4-yl)benzenesulfonamide (B103-2, 264 mg, 0.70 mmol) and triisopropyl borate (396 mg, 2.10 mmol) were placed in tetrahydrofuran (20 mL), cooled to -78°C, and lithium-n-butoxide (0.84 mL, 2.10 mmol, 2.5 M THF solution) was slowly added dropwise. After the addition was complete, the mixture was allowed to return to room temperature naturally and then reacted for 14 hours. Completion of the reaction was detected by LC-MS. An appropriate amount of water (1 mL) was added to the system to quench the reaction, most of the inorganic salts were removed by filtration, and after rotary drying, the mixture was used directly in the next step without any purification. MS (ESI) m / z: Calculated value 343.14 (M+H + ), measured value 343.60.

[0179] Step 4: 4-(6-bromopyrazine-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidine-4-yl)benzenesulfonamide (B103-4) (3-Methoxy-4-(N-methyl-N-(1-methylpiperidine-4-yl)aminosulfonyl)phenyl)boronic acid (B103-3, crude product, theoretical value 0.70 mmol), 2,6-dibromopyrazine (200 mg, 0.84 mmol), and tetrakis(triphenylphosphine)palladium (40 mg, 0.035 mmol) were placed in 1,4-dioxane / water (4:1, 10 mL) and reacted at 80°C for 5 hours under the protection of nitrogen gas. The completion of the reaction was monitored by LC-MS. After rotational drying of the reaction mixture, it was purified by column chromatography to obtain 4-(6-bromopyrazine-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidine-4-yl)benzenesulfonamide (B103-4, 216 mg, 47.9%). MS (ESI) m / z: Calculated value 455.07 (M+H + ), measured value 454.90.

[0180] Step 5: 4-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidine-4-yl)benzenesulfonamide (B103-5) 4-(6-bromopyrazine-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidine-4-yl)benzenesulfonamide (B103-4, 216 mg, 0.48 mmol), (4-bromothiophen-2-yl)boronic acid (98.5 mg, 0.48 mmol), tetrakis(triphenylphosphine)palladium (27 mg, 0.023 mmol), and potassium carbonate (158 mg, 1.14 mmol) were added to 1,4-dioxane / water (4:1, 10 mL) and reacted at 60°C for 0.5 hours under the protection of nitrogen gas. The completion of the reaction was monitored by TLC. The reaction mixture was rotated-dried and then purified by column chromatography to obtain 4-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidine-4-yl)benzenesulfonamide (B103-5, 182 mg, 71.4%). MS (ESI) m / z: Calculated value 537.06 (M+H), measured value 536.90.

[0181] Step 6: 4-(6-(4-aminothiophen-2-yl)pyrazine-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidine-4-yl)benzenesulfonamide (B103-6) 4-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidine-4-yl)benzenesulfonamide (B103-5, 182 mg, 0.34 mmol), cuprous iodide (13 mg, 0.07 mmol), L-proline (16 mg, 0.14 mmol), dimethyl sulfoxide (2 mL), and aqueous ammonia (25% wt, 286 mg, 2.04 mmol) were sequentially placed in a sealed tube, sealed at 80°C, and allowed to react for 10 hours. The completion of the reaction was monitored by LC-MS. The reaction mixture was cooled to room temperature, 20 mL of water was added, and it was extracted with ethyl acetate (10 mL ×), the organic phase was combined, the organic phase was washed with saturated ammonium chloride (10 mL × 2), dried over anhydrous sodium sulfate, and rotated-dried to obtain 4-(6-(4-aminothiophen-2-yl)pyrazine-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidine-4-yl)benzenesulfonamide (B103-6, crude product, theoretical value 0.34 mmol). This product was used directly in the next step of the reaction without any purification. MS (ESI) m / z: calculated value 474.16 (M+H), measured value 474.10.

[0182] Step 7: 2-Cyclopropyl-N-(5-(6-(3-Methoxy-4-(N-Methyl-N-(1-Methylpiperidine-4-yl)sulfamoyl)phenyl)pyrazine-2-yl)thiophen-3-yl)acetamide (B103) 4-(6-(4-aminothiophen-2-yl)pyrazine-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidine-4-yl)benzenesulfonamide (B103-6, crude product, theoretical value 0.17 mmol) was added to DMF (3 mL), and cyclopropylacetic acid (25.4 mg, 0.25 mmol), L-proline (65 mg, 0.34 mmol), HOBT (46 mg, 0.34 mmol), and DIEA (109 mg, 0.84 mmol) were sequentially added to the reaction bottle. The mixture was allowed to react at room temperature for 14 hours, and completion of the reaction was detected by LC-MS. The reaction mixture was diluted with sufficient water, extracted with ethyl acetate (20 mL x 3), the ethyl acetate phase was combined, the organic phase was washed with saturated ammonium chloride (10 mL x 2), dried over anhydrous sodium sulfate, and rotated dry. Purification by column chromatography yielded 2-cyclopropyl-N-(5-(6-(3-methoxy-4-(N-methyl-N-(1-methylpiperidine-4-yl)sulfamoyl)phenyl)pyrazine-2-yl)thiophen-3-yl)acetamide (B103, 25 mg, 26.4%). MS (ESI) m / z: Calculated value 556.20 (M+H + ), measured value 556.00. 1 H NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 9.27 (s, 1H), 9.15 (s, 1H), 8.01-7.86 (m, 4H), 7.75 (t, J = 2.4 Hz, 1H), 4.03 (s, 3H), 3.64-3.57 (m, 1H), 2.85-2.74 (m, 5H), 2.22 (d, J = 7.0 Hz, 2H), 2.12 (s, 3H), 1.89 (t, J = 11.0 Hz, 2H), 1.76-1.66 (m, 2H), 1.36 (d, J = 13.0 Hz, 2H), 1.29-1.20 (m, 1H), 0.55-0.46 (m, 2H), 0.26-0.17 (m, 2H).

[0183] Examples 153-157 (compounds B101-105) were prepared by experimental procedures similar to those of Example 155, and compounds B101-105 are summarized in Table 7. [Table 7-1] [Table 7-2] [Table 7-3]

[0184] Example 158: Preparation of 2-cyclopropyl-N-(5-(6-(4-(1-methylpiperidine-4-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyrazine-2-yl)thiophen-3-yl)acetamide (E2) [ka]

[0185] Step 1: 7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (E2-1) 2-amino-5-bromophenol (500 mg, 2.66 mmol), 1,2-dibromoethane (1 g, 5.32 mmol), potassium carbonate (735 mg, 5.32 mmol), and acetonitrile (35 mL) were sequentially added to a reaction bottle and reacted at 80°C for 16 hours. The completion of the reaction was monitored by LC-MS. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The aqueous phase was extracted again. The organic phase was combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was concentrated and purified by column chromatography. 7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (E2-1,190 mg, 33.4%) was obtained. MS (ESI) m / z: Calculated value 216.1 (M+H), Measured value 216.10.

[0186] Step 2: 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (E2-2) 7-Bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (E2-1, 190 mg, 0.89 mmol), bis(pinacolato)diborone (271 mg, 1.07 mmol), potassium acetate (218 mg, 2.22 mmol), Pd(dppf)2Cl2 (33 mg, 0.05 mmol), and 1,4-dioxane (10 mL) were sequentially placed in a reaction bottle and reacted at 80°C for 6 hours under the protection of nitrogen gas. The completion of the reaction was monitored by LC-MS, the reaction mixture was filtered, the solid was washed with ethyl acetate, and the filtrate was collected and concentrated. The solution was purified by column chromatography. 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (E2-2, 243 mg, 100%) was obtained. MS (ESI) m / z: Calculated value 262.15, (M+H), measured value 262.10.

[0187] Third step: 7-(6-bromopyrazine-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (E2-3) 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (E2-2, 243 mg, 0.93 mmol), 2,6-dibromopyrazine (266 mg, 1.12 mmol), potassium carbonate (309 mg, 2.24 mmol), Pd(PPh3)4 (54 mg, 0.05 mmol), and 1,4-dioxane:water = 4:1 (15 mL) were sequentially placed in a reaction bottle and reacted at 80°C for 6 hours under the protection of nitrogen gas. The completion of the reaction was monitored by LC-MS. The reaction mixture was diluted with water, extracted with EA, the aqueous phase was extracted again, the organic phase was combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was concentrated and purified by column chromatography. 7-(6-bromopyrazine-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (E2-3, 120 mg, 44.12%) was obtained. MS (ESI) m / z: Calculated value 292.00 (M+H), measured value 293.90.

[0188] Step 4: 7-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (E2-4) 7-(6-bromopyrazine-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (E2-3, 120 mg, 0.41 mmol), (4-bromothiophen-2-yl)boronic acid (85 mg, 0.41 mmol), potassium carbonate (136 mg, 0.98 mmol), Pd(PPh3)4 (24 mg, 0.02 mmol), and 1,4-dioxane:water = 4:1 (10 mL) were sequentially added to a reaction bottle and reacted at 60°C for 40 min under the protection of nitrogen gas. The completion of the reaction was monitored by LC-MS, water was added and extracted with EA, the aqueous phase was extracted again, the organic phase was combined, washed with saturated brine and dried over anhydrous sodium sulfate. The solution was concentrated and purified by column chromatography. 7-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (E2-4, 85 mg, 55.19%) was obtained. MS (ESI) m / z: Calculated value 373.99 (M+H), measured value 376.00.

[0189] Step 5: 1-Methylpiperidine-4-carbonyl chloride (E2-5) 1-Methylpiperidine-4-carboxylic acid (150 mg, 1.05 mmol) was placed in a bottle, dichloromethane (10 mL) was added, and oxalyl chloride (266 mg, 2.10 mmol) was slowly added dropwise. After completion, N,N-dimethylformamide (0.5 mL) was added dropwise, and the reaction was allowed to proceed at room temperature for 3 hours. The reaction solution was then rotated dry to obtain 1-methylpiperidine-4-carbonyl chloride (E2-5, 167 mg, 99.82%).

[0190] Step 6: (7-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(1-methylpiperidine-4-yl)ketone(E2-6) 7-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (E2-4, 85 mg, 0.23 mmol), 1-methylpiperidine-4-carbonyl chloride (E2-5, 55 mg, 0.34 mmol), and 1,2-dichloroethane (8 mL) were sequentially added to a reaction bottle and reacted at 85°C for 2 hours. The completion of the reaction was monitored by LC-MS. The mixture was diluted with water, extracted with DCM, the aqueous phase was extracted again, the organic phase was combined, washed with saturated saline, and dried over anhydrous sodium sulfate. The product was concentrated to obtain (7-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(1-methylpiperidine-4-yl)ketone (E2-6, 60 mg, 53.1%) as the crude product. MS (ESI) m / z: Calculated value 499.07 (M+H), measured value 501.20.

[0191] Step 7: (7-(6-(4-aminothiophen-2-yl)pyrazine-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(1-methylpiperidine-4-yl)ketone(E2-7) (7-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(1-methylpiperidine-4-yl)ketone (E2-6, 60 mg, 0.12 mmol), cuprous iodide (5 mg, 0.03 mmol), L-proline (6 mg, 0.06 mmol), potassium carbonate (25 mg, 0.18 mmol), dimethyl sulfoxide (4 mL), and aqueous ammonia (42 mg, 1.2 mmol) were sequentially placed in a sealed tube and reacted at 80°C for 10 hours. The completion of the reaction was monitored by LC-MS. Water was added to the reaction mixture, extracted with EA, the aqueous phase was extracted again, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. (7-(6-(4-aminothiophen-2-yl)pyrazine-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(1-methylpiperidine-4-yl)ketone (E2-7, 20 mg, 38.5%) was obtained as the crude product. MS (ESI) m / z: Calculated value 436.17 (M+H), measured value 436.30.

[0192] Step 8: 2-Cyclopropyl-N-(5-(6-(4-(1-methylpiperidine-4-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyrazine-2-yl)thiophen-3-yl)acetamide(E2) 1-Cyclopropylacetic acid (7 mg, 0.07 mmol), EDCI (18 mg, 0.09 mmol), HOBT (12 mg, 0.09 mmol), and N,N-dimethylformamide (5 mL) were placed in a reaction bottle and reacted at room temperature for 5 minutes. Then, N,N-diisopropylethylamine (30 mg, 0.23 mmol) and (7-(6-(4-aminothiophen-2-yl)pyrazine-2-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)(1-methylpiperidine-4-yl)ketone (E2-7, 20 mg, 0.05 mmol) were added and the mixture was reacted at room temperature overnight. The completion of the reaction was monitored by MS, water was added to the reaction mixture, extracted with EA, the aqueous phase was extracted again, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 2-cyclopropyl-N-(5-(6-(4-(1-methylpiperidine-4-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyrazine-2-yl)thiophen-3-yl)acetamide (E2, 5.18 mg, 21.7%). MS (ESI) m / z: calculated value 518.21 (M+H), measured value 518.50;1H NMR (400 MHz, DMSO) δ 10.33 (s, 1H), 9.12 (s, 1H), 9.02 (s, 1H), 7.89 (d, J = 1.4 Hz, 1H), 7.79-7.71 (m, 3H), 4.38-4.31 (m, 2H), 4.01-3.93 (m, 2H), 2.92-2.79 (m, 3H), 2.22 (d, J = 7.1 Hz, 2H), 2.20 (s, 2H), 2.12 (d, J = 7.0 Hz, 1H), 2.02-1.92 (m, 2H), 1.82-1.65 (m, 4H), 1.11-1.05 (m, 1H), 0.52-0.43 (m, 2H), 0.23-0.19 (m, 1H), 0.14-0.08 (m, 1H).

[0193] In Example 159, compound E1 was produced by an experimental procedure similar to that of Example 158; see Table 8. [Table 8]

[0194] Example 160: Preparation of 4-(6-(4-(3-cyclobutylureido)thiophen-2-yl)pyrazine-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidine-4-yl)benzamide (F1) [ka]

[0195] Step 1: 4-(6-(4-aminothiophen-2-yl)pyrazine-2-yl-2-methoxybenzoate methyl ester (F1-1) 4-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)-2-methoxybenzoate methyl ester (B4-3, 200 mg, 0.49 mmol), cuprous iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol), and potassium carbonate (102 mg, 0.74 mmol) were placed in dimethyl sulfoxide (4 mL), ammonia water (1.0 mL) was added, the tube was sealed, and the mixture was heated to 80°C and stirred for 8 hours. After confirming the completion of the reaction by TLC, the mixture was poured into water, extracted with ethyl acetate, the organic phase was washed three times with deionized water, dried over anhydrous sodium sulfate, and the ethyl acetate was concentrated to obtain methyl 4-(6-(4-aminothiophen-2-yl)pyrazine-2-yl-2-methoxybenzoate (F1-1, 150 mg, 89%). MS (ESI) m / z: calculated value 342.08 (M+H), measured value 342.1.

[0196] Step 2: 4-(6-(4-(3-cyclobutylureido)thiophen-2-yl)pyrazine-2-yl)-2-methoxybenzoate methyl ester (F1-2) 4-(6-(4-aminothiophen-2-yl)pyrazine-2-yl-2-methoxybenzoate methyl ester (F1-1, 148 mg, 0.43 mmol) was added to dichloromethane (10 mL), triethylamine (53 mg, 0.52 mmol) and phenyl chloroformate (75 mg, 0.48 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The completion of the reaction was monitored by LC-MS. The reaction mixture was washed three times with water, the organic phase was dried over anhydrous sodium sulfate, and concentrated. The product and cyclobutylamine (34 mg, 0.48 mmol) were added to N,N-dimethylformamide (8 mL), N,N-diisopropylethylamine (181 mg, 1.4 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The mixture was stirred. The completion of the reaction was monitored by LC-MS. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic phase was washed three times with deionized water. The mixture was dried over anhydrous sodium sulfate, and the ethyl acetate was concentrated. Purification by column chromatography yielded 4-(6-(4-(3-cyclobutylureido)thiophen-2-yl)pyrazine-2-yl)-2-methoxybenzoate methyl ester (F1-2, 75 mg, 39.5%). MS (ESI) m / z: Calculated value 439.14 (M+H), measured value 349.3.

[0197] Third step: 4-(6-(4-(3-cyclobutylureido)thiophen-2-yl)pyrazine-2-yl)-2-methoxybenzoic acid (F1-3) 4-(6-(4-(3-cyclobutylureido)thiophen-2-yl)pyrazine-2-yl)-2-methoxybenzoic acid methyl ester (F1-2, 75 mg, 0.17 mmol) was added to a mixed solvent of tetrahydrofuran and water (8 mL, 2 mL), lithium hydroxide (29 mg, 0.69 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The completion of the reaction was monitored by LC-MS. The reaction mixture was adjusted to weak acidity with 2 M hydrochloric acid, extracted three times with ethyl acetate, and the organic phase was combined. The organic phase was dried over anhydrous sodium sulfate and concentrated. 4-(6-(4-(3-cyclobutylureido)thiophen-2-yl)pyrazine-2-yl)-2-methoxybenzoic acid (F1-3, 40 mg, 55.3%) was obtained. MS (ESI) m / z: Calculated value 425.12, (M+H), Measured value 452.2.

[0198] Step 4: 4-(6-(4-(3-cyclobutylureido)thiophen-2-yl)pyrazine-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidine-4-yl)benzamide(F1-4) 4-(6-(4-(3-cyclobutylureido)thiophen-2-yl)pyrazine-2-yl)-2-methoxybenzoic acid (F1-3, 40 mg, 0.094 mmol), 1-methyl-4-(methylamino)piperidine (15 mg, 0.12 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (72 mg, 0.19 mmol) were added to dichloromethane, and N,N-diisopropylethylamine (49 mg, 0.38 mmol) was added. The mixture was stirred at room temperature for 1 hour. The completion of the reaction was monitored by TLC. The reaction mixture was washed with water, the organic phase was dried over anhydrous sodium sulfate, and the mixture was concentrated. The compound was purified by column chromatography to obtain 4-(6-(4-(3-cyclobutylureido)thiophen-2-yl)pyrazine-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidine-4-yl)benzamide (F1, 25 mg, 49.8%). MS (ESI) m / z: Calculated value 535.24, (M+H), Measured value 535.4. 1H NMR (400 MHz, DMSO) δ 9.21 (d, J = 10.7 Hz, 1H), 9.10 (d, J = 2.6 Hz, 1H), 8.69 (s, 1H), 7.84 (d, J = 8.2 Hz, 3H), 7.40 (s, 1H), 7.34 (t, J = 7.3 Hz, 1H), 6.51 (d, J = 7.8 Hz, 1H), 4.21-4.07 (m, 1H), 3.93 (d, J = 2.7 Hz, 3H), 3.16 (s, 1H), 2.95-2.61 (m, 6H), 2.22-2.17 (m, 2H), 2.09-1.94 (m, 4H), 1.92-1.75 (m, 4H), 1.69-1.54 (m, 4H).

[0199] Example 161: Preparation of (S)-4-(6-(4-(4-amino-3-methylbutoxy)thiophen-2-yl)pyrazine-2-yl)-2-methoxy-N-methyl-N-(1-methylpiperidine-4-yl)benzamide (G1) [ka]

[0200] Step 1: 2-Methoxy-4-(6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboronic acid-2-yl)thiophen-2-yl)pyrazine-2-yl)methyl benzoate (G1-1) 4-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)-2-methoxybenzoate methyl ester (B4-3, 200 mg, 0.49 mmol), bis(pinacolato)diborone (150 mg, 0.59 mmol), Pd(dppf)2Cl2 (18 mg, 0.02 mmol), potassium acetate (121 mg, 1.23 mmol), and 1,4-dioxane (10 mL) were sequentially placed in a reaction bottle and reacted at 80°C for 14 hours under the protection of nitrogen gas. The completion of the reaction was monitored by MS, and the reaction mixture was filtered. The solid was washed with ethyl acetate, the filtrate was concentrated, and purified by column chromatography to obtain 2-methoxy-4-(6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboronic acid-2-yl)thiophen-2-yl)pyrazine-2-yl)methyl benzoate (G1-1,197 mg, 89.8%). MS (ESI) m / z: calculated value 453.16 (M+H), measured value 453.50.

[0201] Second step: (5-(6-(3-methoxy-4-(methoxycarbonyl)phenyl)pyrazine-2-yl)thiophen-3-yl)boronic acid (G1-2) 2-Methoxy-4-(6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboronic acid-2-yl)thiophene-2-yl)pyrazine-2-yl)methyl benzoate (G1-1, 197 mg, 0.44 mmol), sodium periodate (189 mg, 0.88 mmol), sodium acetate (171 mg, 2.21 mmol), and tetrahydrofuran:water = 3:1 (10 mL) were sequentially placed in a reaction bottle and reacted at room temperature for 14 hours. The completion of the reaction was monitored by LC-MS, the reaction mixture was filtered, the solid was collected, washed with water, and heated and dried to obtain yellow (5-(6-(3-methoxy-4-(methoxycarbonyl)phenyl)pyrazine-2-yl)thiophene-3-yl)boronic acid (G1-2, 110 mg, 67.6%). MS (ESI) m / z: Calculated value 371.08 (M+H), measured value 371.30.

[0202] Third step: 4-(6-(4-hydroxythiophen-2-yl)pyrazine-2-yl)-2-methoxybenzoate methyl ester (G1-3) (5-(6-(3-methoxy-4-(methoxycarbonyl)phenyl)pyrazine-2-yl)thiophene-3-yl)boronic acid (G1-2, 110 mg, 0.30 mmol) was placed in a bottle, tetrahydrofuran (10 mL) was added, and the mixture was reacted in an ice bath. Water peroxide (35%, 230 mg, 2.37 mmol) was slowly added dropwise, followed by the addition of 2 mol / L hydroxide solution (5 mg). After the addition was complete, the ice bath was removed, and the mixture was allowed to react at room temperature for 14 hours. The completion of the reaction was monitored by LC-MS. The reaction mixture was filtered, the solid was collected, washed with water, and heated and dried to obtain 4-(6-(4-hydroxythiophene-2-yl)pyrazine-2-yl)-2-methoxybenzoate methyl ester (G1-3, 54 mg, 48.9%). MS (ESI) m / z: Calculated value 342.07 (M+H), measured value 343.30.

[0203] Step 4: (R)-4-((t-butoxycarbonyl)amino)-3-methylmethanesulfonate butyl ester (G1-4) (R)-(4-hydroxy-2-methylbutyl)carbamate (100 mg, 0.49 mmol) was placed in a bottle, dichloromethane (10 mL) was added, and the mixture was reacted in an ice bath. Triethylamine (149 mg, 1.47 mmol) was added, followed by the slow addition of methanesulfonyl chloride (68 mg, 0.59 mmol). After the addition was complete, the ice bath was removed, and the mixture was allowed to react at room temperature for 30 minutes. The completion of the reaction was monitored by LC-MS. The reaction was quenched with water, extracted with dichloromethane, the aqueous phase was extracted again, the organic phase was combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was concentrated to obtain (R)-4-((t-butoxycarbonyl)amino)-3-methylmethanesulfonate butyl ester (G1-4, 131 mg, 94.93%) as the crude product. MS (ESI) m / z: Calculated value 282.13, Measured value 282.40.

[0204] Step 5: (S)-4-(6-(4-(4-(t-butoxycarbonyl)amino)-3-methylbutoxy)thiophen-2-yl)pyrazine-2-yl-2-methoxybenzoate methyl ester (G1-5) 4-(6-(4-hydroxythiophen-2-yl)pyrazine-2-yl)-2-methoxybenzoate methyl ester (G1-3, 54 mg, 0.16 mmol), (R)-4-((t-butoxycarbonyl)amino)-3-methylmethanesulfonate butyl ester (G1-4, 53 mg, 0.19 mmol), cesium carbonate (103 mg, 0.32 mmol), and N,N-dimethylformamide (10 mL) were sequentially placed in a bottle and reacted at 100°C for 14 hours. The completion of the reaction was monitored by MS. Water was added to the reaction mixture and extracted with ethyl acetate, and the aqueous phase was extracted again. The organic phase was combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was concentrated and purified by column chromatography to obtain (S)-4-(6-(4-(4-(t-butoxycarbonyl)amino)-3-methylbutoxy)thiophen-2-yl)pyrazine-2-yl-2-methoxybenzoate methyl ester (G1-5, 40 mg, 48.2%). MS (ESI) m / z: Calculated value 528.21 (M+H), measured value 528.40.

[0205] Step 6: (S)-4-(6-(4-(4-((t-butoxycarbonyl)amino)-3-methylbutoxy)thiophen-2-yl)pyrazine-2-yl)-2-methoxybenzoic acid (A1-06) (S)-4-(6-(4-(4-(t-butoxycarbonyl)amino)-3-methylbutoxy)thiophen-2-yl)pyrazine-2-yl-2-methoxybenzoate methyl ester (G1-5, 40 mg, 0.08 mmol), lithium hydroxide (13 mg, 0.31 mmol), and tetrahydrofuran:water = 4:1 (10 mL) were sequentially added to a reaction bottle and allowed to react at room temperature for 14 hours. Completion of the reaction was monitored by MS. The reaction solution was adjusted to a pH of approximately 6 with citric acid, water was added, and the mixture was extracted with ethyl acetate. The aqueous phase was extracted again, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain (S)-4-(6-(4-(4-((t-butoxycarbonyl)amino)-3-methylbutoxy)thiophen-2-yl)pyrazine-2-yl)-2-methoxybenzoic acid (G1-6, 45 mg) as the crude product. MS (ESI) m / z: Calculated value 514.19 (M+H), measured value 514.40.

[0206] Step 7: (S)-(4-(5-(6-(3-methoxy-4-(methyl(1-methylpiperidine-4-ylcarbamoyl)phenyl)pyrazine-2-yl)thiophene-3-yloxy)-2-methylbutyl)carbamate t-butyl ester (G1-7) (S)-4-(6-(4-(4-((t-butoxycarbonyl)amino)-3-methylbutoxy)thiophen-2-yl)pyrazine-2-yl)-2-methoxybenzoic acid (G1-6, 45 mg, 0.09 mmol) was mixed with 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (67 mg, 0.18 mmol) and dichloromethane (10 mL), and reacted at room temperature for 5 minutes. Then, 1-methyl-4-(methylamino)piperidine (14 mg, 0.11 mmol) and N,N-diisopropylethylamine (45 mg, 0.35 mmol) were added, and the mixture was reacted at room temperature for 2 hours. The reaction was monitored by LC-MS, water was added, and the mixture was extracted with DCM. The aqueous phase was extracted again, the organic phase was combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was concentrated and purified by column chromatography to obtain (S)-(4-(5-(6-(3-methoxy-4-(methyl(1-methylpiperidine-4-ylcarbamoyl)phenyl)pyrazine-2-yl)thiophen-3-yloxy)-2-methylbutyl)carbamate t-butyl ester (G1-7, 21 mg, 38.2%). MS (ESI) m / z: Calculated value 624.31, (M+H), Measured value 624.50.

[0207] Step 8: (S)-4-(6-(4-(4-amino-3-methylbutoxy)thiophen-2-yl)pyrazine-2-yl]-2-methoxy-N-methyl-N-(1-methylpiperidine-4-yl)benzamide (G1) (S)-(4-(5-(6-(3-methoxy-4-(methyl(1-methylpiperidine-4-ylcarbamoyl)phenyl)pyrazine-2-yl)thiophen-3-yloxy)-2-methylbutyl)carbamate t-butyl ester (G1-7, 21 mg, 0.03 mmol) was mixed with ethyl acetate hydrochloride solution (3 mol / L, 3 mL) and ethyl acetate (1 mL). The reaction was allowed to proceed at room temperature for 30 minutes, and the completion of the reaction was monitored by LC-MS. The reaction mixture was then rotated and dried as is. The product obtained as a yellow solid was (S)-4-(6-(4-(4-amino-3-methylbutoxy)thiophen-2-yl)pyrazine-2-yl]-2-methoxy-N-methyl-N-(1-methylpiperidine-4-yl)benzamide hydrochloride (G1, 12 mg, 66.67%). MS (ESI) m / z: Calculated value 524.26 (M+H), measured value 524.50; 1 H NMR (400 MHz, DMSO) δ 9.21 (dd, J = 15.2, 7.4 Hz, 2H), 8.10 (s, 3H), 7.95-7.74 (m, 3H), 7.46-7.33 (m, 1H), 6.96-6.88 (m, 1H), 4.12-4.06 (m, 1H), 3.94 (s, 3H), 3.65-3.53 (m, 2H), 3.47 (d, J = 11.2 Hz, 1H), 3.41-3.23 (m, 2H), 3.23-3.07 (m, 2H), 2.91-2.81 (m, 3H), 2.74-2.67 (m, 3H), 2.59 (d, J = 4.6 Hz, 2H), 2.38-2.17 (m, 2H), 2.08-1.96 (m, 1H), 1.95-1.87 (m, 1H), 1.80 (t, J = 12.1 Hz, 1H), 1.70-1.56 (m, 2H), 1.02 (d, J = 6.7 Hz, 3H).

[0208] Examples 162-164 (compounds A46-A48) were prepared by an experimental procedure similar to that of Example 35, and compounds A46-A48 are summarized in Table 9. [Table 9]

[0209] Example 166: Preparation of 2-Cyclobutyl-N-(5-(6-(2-(1-methylpiperidine-4-yl)methyl)-2H-indazole-6-yl)pyrazine-2-yl)thiophene-3-yl)acetamide (A50) [ka]

[0210] Step 1: 4-(6-bromo-2H-indazole-2-yl)methyl)piperidine-1-carboxylate t-butyl (A50-1) 6-bromo-1H-indazole (600 mg, 3.04 mmol), 4-(hydroxymethyl)piperidine-1-carboxylate t-butyl ester (1.0 g, 3.6 mmol), and cesium carbonate (1.98 g, 6.08 mmol) were placed in N,N-dimethylformamide (10 ml) and heated to 60°C, stirring for 3 hours. After confirming the completion of the reaction by LC-MS and TLC, the mixture was poured into water, extracted with ethyl acetate, the organic phase was washed three times with water, dried over anhydrous sodium sulfate, and the ethyl acetate was concentrated. Purification by column chromatography yielded 4-(6-bromo-2H-indazole-2-yl)methyl)piperidine-1-carboxylate t-butyl (A50- 1,630 mg, 52.3%). MS (ESI) m / z: Calculated value 394.11 (M+H), measured value 338.2.

[0211] Second step: 4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-2-ylmethyl)piperidine-1-carboxylate t-butyl ester (A50-2) 4-(6-bromo-2H-indazole-2-yl)methyl)piperidine-1-carboxylate t-butyl ester (A50-1, 630 mg, 1.59 mmol), bis(pinacolato)diborone (487 mg, 1.90 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (58 mg, 0.08 mmol), and potassium acetate (392 mg, 3.98 mmol) were placed in dioxane (10 mL) and heated to 80°C under the protection of nitrogen gas, and stirred for 14 hours. After confirming the completion of the reaction by LC-MS and TLC, the crude product was used directly for the next step. 4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-2-ylmethyl)piperidine-1-carboxylate t-butyl ester (A50-2, 705 mg crude product, theoretical value 1.59 mmol) was obtained. MS (ESI) m / z: calculated value 442.28 (M+H), measured value 442.5.

[0212] Third step: 4-((6-(6-bromopyrazine-2-yl)-2H-indazole-2-yl)methyl)piperidine-1-carboxylate t-butyl ester (A50-3) 4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-2-ylmethyl)piperidine-1-carboxylate t-butyl ester (A50-2, 705 mg crude product, theoretical value 1.59 mmol), 2,6-dibromopyrazine (456 mg, 1.90 mmol), tetrakis(triphenylphosphine)palladium (92 mg, 0.08 mmol), and potassium carbonate (530 mg, 3.80 mmol) were placed in a mixed solvent of dioxane / water (12 mL / 3 mL) and heated to 80°C under the protection of nitrogen gas. The mixture was stirred. After confirming the completion of the reaction by LC-MS and TLC, the mixture was poured into water and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the ethyl acetate was concentrated. Purification by column chromatography yielded 4-((6-(6-bromopyrazine-2-yl)-2H-indazole-2-yl)methyl)piperidine-1-carboxylate t-butyl ester (A50-3,280 mg, 37.1%). MS (ESI) m / z: Calculated value 472.13 (M+H), measured value 374.2.

[0213] Fourth step: 4-(6-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)-2H-indazole-2-yl))methylpiperidine-1-carboxylate t-butyl ester (A50-4) 4-((6-(6-bromopyrazine-2-yl)-2H-indazole-2-yl)methyl)piperidine-1-carboxylate t-butyl ester (A50-3, 280 mg, 0.59 mmol), (4-bromothiophen-2-yl)boronic acid (122 mg, 0.59 mmol), tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol), and potassium carbonate (197 mg, 1.44 mmol) were placed in a mixed solvent of dioxane / water (12 mL / 3 mL) and heated to 60°C under the protection of nitrogen gas, stirring for 0.5 hours. After confirming completion of the reaction by MS and TLC, the mixture was poured into water, extracted three times with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the ethyl acetate was concentrated. The compound was purified by column chromatography to obtain 4-(6-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)-2H-indazole-2-yl))methylpiperidine-1-carboxylate t-butyl ester (A50-4, 240 mg, 83.0%). MS (ESI) m / z: Calculated value 554.11 (M+H), measured value 456.2.

[0214] Step 5: 4-(6-(6-(4-aminothiophen-2-yl)pyrazine-2-yl)-2H-indazole-2-yl))methylpipette)lysine-1-carboxylate t-butyl ester (A50-5) 4-(6-(6-(4-bromothiophen-2-yl)pyrazine-2-yl)-2H-indazole-2-yl))methylpiperidine-1-carboxylate t-butyl ester (A50-4, 240 mg, 0.49 mmol), cuprous iodide (16 mg, 0.10 mmol), L-proline (19 mg, 0.20 mmol), and potassium carbonate (85 mg, 1.18 mmol) were placed in dimethyl sulfoxide (4 mL), water ammonia (1 mL) was added, the tube was sealed, and the mixture was heated to 80°C and stirred for 8 hours. After confirming the completion of the reaction by TLC, the mixture was poured into water, extracted with ethyl acetate, the organic phase was washed three times with water, dried over anhydrous sodium sulfate, the ethyl acetate was concentrated, and the crude product was directly added to the next step. 4-(6-(6-(4-aminothiophen-2-yl)pyrazine-2-yl)-2H-indazole-2-yl))methylpipette)lysine-1-carboxylate t-butyl ester (A50-5, 220 mg crude product, 0.49 mmol theoretical value) was obtained. MS (ESI) m / z: Calculated value 491.22 (M+H), measured value 491.6.

[0215] Step 6: 4-(6-(6-(4-(2-cyclobutylacetamide)thiophen-2-yl)pyrazine-2-yl)-2H-indazole-2-yl))methylpiperidine-1-carboxylate t-butyl ester (A50-6) 4-(6-(6-(4-aminothiophen-2-yl)pyrazine-2-yl)-2H-indazole-2-yl))methylpipe)lysine-1-carboxylate t-butyl ester (A50-5, 220 mg crude product, 0.49 mmol theoretical value), 2-cyclobutylacetic acid (62 mg, 0.54 mmol), 1-hydroxybenzotriazole (122 mg, 0.90 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (172 mg, 0.90 mmol) were added to dichloromethane (12 mL), N,N-diisopropylethylamine (232 mg, 1.80 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After confirming the completion of the reaction by LC-MS and TLC, the mixture was poured into water, extracted with ethyl acetate, the organic phase was washed three times with water, dried over anhydrous sodium sulfate, and the ethyl acetate was concentrated. The compound was purified by column chromatography to obtain 4-(6-(6-(4-(2-cyclobutylacetamido)thiophen-2-yl)pyrazine-2-yl)-2H-indazole-2-yl))methylpiperidine-1-carboxylate t-butyl ester (A50-6, 70 mg, 20.4%). MS (ESI) m / z: Calculated value 586.27 (M+H), measured value 487.6.

[0216] Step 7: 2-Cyclobutyl-N-(5-(6-(2-(2-(piperidine-4-ylmethyl)-2H-indazole-6-yl)pyrazine-2-yl)thiophen-3-yl)acetamide (A50-7) 4-(6-(6-(4-(2-cyclobutylacetamido)thiophen-2-yl)pyrazine-2-yl)-2H-indazole-2-yl))methylpiperidine-1-carboxylate t-butyl ester (A50-6, 70 mg, 0.1 mmol) was dissolved in 2 mL of ethyl acetate, and 4 mL of ethyl acetate solution with 3 M hydrogen chloride was added. The mixture was stirred at room temperature for 10 hours. The completion of the reaction was monitored by TLC. The solvent was removed by rotary drying, and the crude product was directly added to the next step. 2-Cyclobutyl-N-(5-(6-(2-(2-(piperidine-4-ylmethyl)-2H-indazole-6-yl)pyrazine-2-yl)thiophene-3-yl)acetamide (A50-7, 90 mg crude product, 0.1 mmol (theoretical value)). MS (ESI) m / z: Calculated value 486.22 (M+H), Measured value 487.5.

[0217] Step 8: 2-Cyclobutyl-N-(5-(6-(2-(1-methylpiperidine-4-yl)methyl)-2H-indazole-6-yl)pyrazine-2-yl)thiophen-3-yl)acetamide (A50) 2-Cyclobutyl-N-(5-(6-(2-(2-(piperidine-4-ylmethyl)-2H-indazole-6-yl)pyrazine-2-yl)thiophene-3-yl)acetamide (A50-7, 90 mg crude product, 0.1 mmol (theoretical value)), formaldehyde (55 mg, 1.90 mmol), and acetic acid (34.2 mg, 0.57 mmol) were added to methanol (12 mL), stirred at room temperature for 0.5 hours, then sodium triacetoxyborohydride (196 mg, 0.93 mmol) was added, and the mixture was stirred at room temperature for 14 hours. The mixture was stirred. After confirming the completion of the reaction by LC-MS and TLC, the solvent was removed by rotary drying. Water and ethyl acetate were added for extraction, the organic phase was dried over anhydrous sodium sulfate, and the ethyl acetate was concentrated. Purification by column chromatography yielded 2-cyclobutyl-N-(5-(6-(2-(1-methylpiperidine-4-yl)methyl)-2H-indazole-6-yl)pyrazine-2-yl)thiophen-3-yl)acetamide (A50, 20 mg, 39.9%). MS (ESI) m / z: Calculated value 501.24 (M+H), measured value 501.40. 1 H NMR (400 MHz, DMSO) δ 10.40 (s, 1H), 9.23 (s, 1H), 9.03 (s, 1H), 8.50 (s, 1H), 8.45 (s, 1H), 7.90 (dd, J = 5.0, 1.1 Hz, 3H), 7.71 (d, J = 1.2 Hz, 1H), 4.37 (d, J = 7.2 Hz, 2H), 2.79-2.69 (m, 2H), 2.69-2.65 (m, 1H), 2.44 (d, J = 7.6 Hz, 2H), 2.13 (s, 2H), 2.10-2.05 (m, 1H), 2.02-1.93 (m, 1H), 1.91-1.82 (m, 2H), 1.80 (s, 3H), 1.78-1.69 (m, 2H), 1.45 (d, J = 10.8 Hz, 2H), 1.35-1.26 (m, 3H).

[0218] Examples 165-168 (compounds A49-A52) were prepared by an experimental procedure similar to that of Example A50, and compounds A49-A52 are summarized in Table 10. [Table 10-1] [Table 10-2]

[0219] Example of effect 1 Drak2 activity testing method The activity of Drak2 was detected using Promega's ADP-Glo ​​kinase detection kit. The reaction was carried out in a 384-white shallow-well plate, with a total reaction system volume of 5 μL. Specifically, it contained 1 μL of the test compound (2% DMSO), 2 μL of Drak2, and 2 μL of ATP, with a reaction buffer system of 50 mM Na3PO4, 0.02% NaN 3, The reaction was incubated at room temperature for 2 hours in a buffer system of 0.1 mM Na3VO4, 5 mM MgCl2, 0.01% (w / v) BSA, and 50 mM HEPES at pH 7.0 (the above reaction buffer system was used to dilute Drak2 and ATP, and the above concentrations are for a total reaction system volume of 5 μL). Then, 5 μL of ADP-Glo ​​stop buffer (reagent in the kit) was added to stop the kinase reaction, and the remaining ATP was consumed. After reacting for 1 hour, the kinase detection reagent (reagent in the kit) was added and incubated for half an hour to convert ADP to ATP. At the same time, the newly synthesized ATP was detected by reacting it with the coupling luciferase / fluorothane (reagent in the kit), and the effect of the test compound on Drak2 kinase activity was detected by reading the numerical values ​​with an Envision multi-label plate reader. The Envision parameter was set to Aperure, specifically 384 plate US Lminescence aperture-In. In the reaction, a background well without Drak2 and a Drak2 total enzyme activity well without the compound were prepared.

[0220] IC2 inhibits the Drak2 kinase activity of compounds. 50 The values ​​were calculated using Graphpad Prism 7.00 software and the formula: Y = 100 / (1 + 10^((LogIC50 - X) * HillSlope)). The activity ranges are: A: <10 nM; B: 10 -100 nM; C: 101 - 1000 nM; D: 1001 - 10000 nM; E: >10000 nM. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5]

[0221] From the activity data in the table above, it can be seen that the compound of the present invention has Drak2 kinase inhibitory activity.

[0222] All documents relating to the present invention are cited herein by reference, so that each document may be cited independently. Furthermore, after reading the above, those skilled in the art will understand that various variations and modifications of the present invention may be made, and that equivalent forms thereof are included within the scope of the claims of the present invention.

Claims

1. A compound represented by formula I, or its stereoisomer or optical isomer, a pharmaceutically acceptable salt, or a solvate thereof. 【Chemistry 1】 (Here, 【Chemistry 2】 teeth, 【Transformation 3】 and; L represents bonding. Ring B is, 【Chemistry 4】 and the above 【Transformation 5】 It is optionally substituted with H, D, halogen, cyano group, hydroxyl group, NH2, or C1-C3 alkyl group. 【Transformation 6】 teeth, 【Transformation 7】 Selected from, here Each R ｍ is independently H, D, halogen, cyano group, hydroxy group, carboxy group, -S(O) ｔ R ｍ５ , -C(O)R ｍ５ , -C(O)OR ｍ５ , -C(O)NR ｍ６ R ｍ７ , -S(O) ｔ NR ｍ６ R ｍ７ , -C(O)NRS(O) ｍ８ S(O) ｔ NR ｍ６ R ｍ７ , -(CH ２ ) ), -S(O) ｑ R ｔ R ｍ５ , -(CH ２ ), -C(O)R ｑ C(O)R ｍ５ , -(CH ２ ), -C(O)OR ｑ C(O)OR ｍ５ , -(CH ２ ), -C(O)NR ｑ C(O)NR ｍ６ R ｍ７ , -(CH ２ ), -(CH ｑ (CH ２ ), -S(O) ｑ NR ｔ NR ｍ６ R ｍ７ , -(CH ２ ), -R ｑ R ｍ９ , -C1-C6 alkyl group, -C1-C6 alkoxy group, -C1-C6 alkylamine group, C3-C7 cycloalkyl group, 4-7 membered heterocyclic group, C6-C10 aryl group or 5-7 membered heteroaryl group, where the C1-C6 alkyl group, C1-C6 alkoxy group, C3-C7 cycloalkyl group, 4-7 membered heterocyclic group, C6-C10 aryl group, or 5-7 membered heteroaryl group is optionally substituted with 1-3 R's, or Alternatively, two R atoms in adjacent ring atoms ｍ These atoms, together with adjacent ring atoms, constitute a 5-6 membered heterocyclic group, where the 5-6 membered heterocyclic group is optionally substituted with 1-3 R atoms. or, 【Transformation 8】 teeth, 【Chemistry 9】 Selected from, here, R m is -S(O) t R m5, -C(O) R m5, -C(O) OR m5, -C(O) NR m6 R m7, or -S(O) t NR m6 R m7, R ｎ These are H, C1-C15 alkyl groups, and C(O)R ｐ Selected from, here, R ｐ NH ２ , selected from C1-C15 alkyl groups, C1-C15 alkoxy groups, C1-C15 alkylamine groups, C3-C7 cycloalkyl groups, 4-7 membered heterocyclic groups, C6-C10 aryl groups, or 5-7 membered heteroaryl groups, where the C1-C15 alkyl groups, C1-C15 alkoxy groups, C1-C15 alkylamine groups, C3-C7 cycloalkyl groups, 4-7 membered heterocyclic groups, C6-C10 aryl groups, or 5-7 membered heteroaryl groups are optionally substituted with 1-3 R groups, where R is H, D, halogen, cyano group, hydroxyl group, carboxyl group, NH₂, oxo group (=O), C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 alkylamine group, C(O)OC1-C6 alkyl group, S(O)₂ A C1-C6 alkyl group, a C3-C7 cycloalkyl group, a 4-7 membered heterocyclic group, a C6-C10 aryl group, and a 5-7 membered heteroaryl group are selected, where the C3-C7 cycloalkyl group, the 4-7 membered heterocyclic group, the C6-C10 aryl group, or the 5-7 membered heteroaryl group is optionally substituted with 1-3 groups selected from the group consisting of halogens, cyano groups, hydroxyl groups, carboxyl groups, C1-C6 alkyl groups, and C1-C6 alkoxy groups. Alternatively, R ｐ The C1-C6 alkyl group is selected from C1-C6 alkyl groups, where the C1-C6 alkyl group is substituted with a C3-C7 cycloalkyl group, where the C3-C7 cycloalkyl group is substituted with one, two, or three groups selected from the group consisting of C1-C6 alkyl groups, C1-C6 haloalkyl groups, C6-C10 aryl groups substituted with C1-C6 haloalkyl groups, and C(O)OC1-C6 alkyl groups. R ｍ５ The group is selected from a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamine group, a C3-C7 cycloalkyl group, or a 4-7 membered heterocyclic group, where the C1-C6 alkyl group, C1-C6 alkoxy group, C3-C7 cycloalkyl group, or 4-7 membered heterocyclic group is optionally substituted with 1-3 R atoms. R ｍ８ This is selected from H, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a C1-C6 alkylamine group, where the C1-C6 alkyl group or C1-C6 alkoxy group is optionally substituted with 1 to 3 R atoms. R ｍ６ , R ｍ７ , and R ｍ９ Each of these is independently selected from H, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkylamine groups, C3-C7 cycloalkyl groups, 4-7 membered heterocyclic groups, C6-C10 aryl groups, or 5-7 membered heteroaryl groups, or R ｍ６ and R ｍ７ These, together with adjacent N atoms, constitute a 4-7 membered heterocyclic group, where the C1-C6 alkyl group, C1-C6 alkoxy group, C3-C7 cycloalkyl group, 4-7 membered heterocyclic group, C6-C10 aryl group, or 5-7 membered heteroaryl group are optionally substituted with 1-3 R atoms. R is H, D, halogen, cyano group, hydroxyl group, carboxyl group, NH ２ , oxo group (=O), C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 alkylamine group, C(O)OC1-C6 alkyl group, S(O) ２ Selected from C1-C6 alkyl groups, C3-C7 cycloalkyl groups, 4-7 membered heterocyclic groups, C6-C10 aryl groups, or 5-7 membered heteroaryl groups, where the C1-C6 alkyl group, C1-C6 alkoxy group, C3-C7 cycloalkyl group, 4-7 membered heterocyclic group, C6-C10 aryl group, or 5-7 membered heteroaryl group may optionally be a halogen, cyano group, hydroxyl group, carboxyl group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 alkylamine group, C(O)OC1-C6 alkyl group, and S(O) ２ It is substituted with 1 to 3 groups selected from the group consisting of C1-C6 alkyl groups. t is either 1 or 2. q is 1, 2, 3, or 4. n is 1, 2, 3, 4, or 5.

2. The compound according to claim 1, characterized by having a structure represented by formula II, its stereoisomer or optical isomer, a pharmaceutically acceptable salt, or a solvate thereof. 【Chemistry 10】 Here, 【Chemistry 11】 teeth, 【Chemistry 12】 Selected from, where each R m is independently H, D, halogen, cyano group, hydroxyl group, carboxyl group, -S(O)t R m5, -C(O)R m5, -C(O)OR m5, -C(O)NR m6 R m7, -S(O)t NR m6 R m7, -C(O)NR m8 S(O)t NR m6 R m7, -(CH2)q S(O)t R m5, -(CH2)q C(O)R m5, -(CH2)q C(O)OR m5, -(CH2)q C(O)NR m6 R m7, -(CH2)q (CH2)q S(O) t NR m6 R m7, -(CH2) q R m9, selected from -C1-C6 alkyl group, -C1-C6 alkoxy group, -C1-C6 alkylamine group, C3-C7 cycloalkyl group, 4-7 membered heterocyclic group, C6-C10 aryl group and 5-7 membered heteroaryl group, where the C1-C6 alkyl group, C1-C6 alkoxy group, C3-C7 cycloalkyl group, 4-7 membered heterocyclic group, C6-C10 aryl group, or 5-7 membered heteroaryl group is optionally substituted with 1-3 Rs, Alternatively, two R m atoms on adjacent ring atoms, together with their adjacent ring atoms, constitute a 5-6 membered heterocyclic group, where the 5-6 membered heterocyclic group is optionally substituted with 1-3 R atoms. Ring B is, 【Chemistry 13】 and the above 【Chemistry 14】 This is arbitrarily replaced with H or D. Here, 【Chemistry 15】 R m5 , R m6 , R m7 , R m8 , R m9 , R, R ｐ The definitions of t, q, and n are as described in claim 1.

3. The compound described in Claim 1 or its stereoisomer or optical isomer, pharmaceutically acceptable salt, or solvate. Here, ring A is, 【Chemistry 16】 And, Here, each R m is as defined in claim 1.

4. A compound according to claim 1, characterized by having a structure represented by formula IV, or a stereoisomer or optical isomer thereof, a pharmaceutically acceptable salt, or a solvate thereof. 【Chemistry 17】 (Here, [Chemistry 18] teeth, 【Chemistry 19】 And, R １ 、R ２ 、R ３ 、R ４ 、R ５ are each independently H, D, halogen, cyano group, hydroxy group, carboxy group, -S(O) ｔ R ｍ５ 、 -C(O)R ｍ５ 、 -C(O)OR ｍ５ 、 -C(O)NR ｍ６ R ｍ７ 、 -S(O) ｔ NR ｍ６ R ｍ７ 、 -C(O)NR ｍ８ S(O) ｔ NR ｍ６ R ｍ７ 、 -(CH ２ ) ｑ S(O) ｔ R ｍ５ 、 -(CH ２ ) ｑ C(O)R ｍ５ 、 -(CH ２ ) ｑ C(O)OR ｍ５ 、 -(CH ２ ) ｑ C(O)NR ｍ６ R ｍ７ 、 -(CH ２ ) ｑ (CH ２ ) ｑ S(O) ｔ NR ｍ６ R ｍ７ 、 -(CH ２ ) ｑ R ｍ９ 、 a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylamine group, a C3-C7 cycloalkyl group, a 4-7 membered heterocyclic group, a C6-C10 aryl group or a 5-7 membered heteroaryl group, wherein the C1-C6 alkyl group, C1-C6 alkoxy group, C3-C7 cycloalkyl group, 4-7 membered heterocyclic group, C6-C10 aryl group or 5-7 membered heteroaryl group is optionally substituted with 1-3 R's, or Alternatively, R １ and R ２ , or R ２ and R ３ , or R ３ and R ４ , or R ４ and R ５ These atoms, together with adjacent C atoms, constitute a 5-6 membered heterocyclic group, where the 5-6 membered heterocyclic group is optionally substituted with 1-3 R atoms. R' is either H or D. t, q, R, R ｍ５ , R ｍ６ , R ｍ７ , R ｍ８ , R m9 and R ｐ The definition is as described in claim 1.

5. A compound according to claim 1, characterized by having a structure represented by formula A, or a stereoisomer or optical isomer thereof, a pharmaceutically acceptable salt, or a solvate thereof. 【Chemistry 20】 (Here, R ６ H, D, halogen, cyano group, hydroxyl group, NH ２ or selected from C1-C3 alkyl groups. R ７ The group is selected from C1-C15 alkyl groups, C1-C15 alkoxy groups, C1-C15 alkylamine groups, C3-C7 cycloalkyl groups, 4-7 membered heterocyclic groups, C6-C10 aryl groups, or 5-7 membered heteroaryl groups, where the C1-C15 alkyl groups, C1-C15 alkoxy groups, C1-C15 alkylamine groups, C3-C7 cycloalkyl groups, 4-7 membered heterocyclic groups, C6-C10 aryl groups, or 5-7 membered heteroaryl groups may optionally be D, halogen, cyano group, hydroxyl group, carboxyl group, or NH ２ , oxo group (=O), C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 alkylamine group, C(O)OC1-C6 alkyl group, S(O) ２ It is substituted with 1 to 3 groups selected from the group consisting of C1-C6 alkyl groups, C3-C7 cycloalkyl groups, 4-7 membered heterocyclic groups, C6-C10 aryl groups, or 5-7 membered heteroaryl groups. R １ , R ２ , R ３ , R ４ , R ５ These are, independently, H, D, halogen, cyano group, hydroxyl group, carboxyl group, and -S(O). ｔ R ｍ５ , -C(O)R ｍ５ , -C(O)OR ｍ５ , -C(O)NR ｍ６ R ｍ７ , -S(O) ｔ NR ｍ６ R ｍ７ , -C(O)NR ｍ８ S(O) ｔ NR ｍ６ R ｍ７ ,-(CH ２ ) ｑ S(O) ｔ R ｍ５ ,-(CH ２ ) ｑ C(O)R ｍ５ ,-(CH ２ ) ｑ C(O)OR ｍ５ ,-(CH ２ ) ｑ C(O)NR ｍ６ R ｍ７ ,-(CH ２ ) ｑ (CH ２ ) ｑ S(O) ｔ NR ｍ６ R ｍ７ ,-(CH ２ ) ｑ R ｍ９ , selected from -C1-C6 alkyl groups, -C1-C6 alkoxy groups, -C1-C6 alkylamine groups, C3-C7 cycloalkyl groups, 4-7 membered heterocyclic groups, C6-C10 aryl groups, or 5-7 membered heteroaryl groups, where the C1-C6 alkyl group, C1-C6 alkoxy group, C3-C7 cycloalkyl group, 4-7 membered heterocyclic group, C6-C10 aryl group, or 5-7 membered heteroaryl group is optionally substituted with 1-3 R groups, Alternatively, R １ and R ２ , or R ２ and R ３ , or R ３ and R ４ , or R ４ and R ５ These atoms, together with adjacent C atoms, constitute a 5-6 membered heterocyclic group, where the 5-6 membered heterocyclic group is optionally substituted with 1-3 R atoms. t, q, R, R ｍ５ , R ｍ６ , R ｍ７ , R ｍ８ and R ｍ９ The definition is as described in claim 1.

6. The compound according to claim 1, characterized by having a structure represented by formula B, or its stereoisomer or optical isomer, pharmaceutically acceptable salt, or solvate. 【Chemistry 21】 (Here, X １ It is either N or CH. X ２ It is CH. R ７ The group is selected from C1-C15 alkyl groups, C1-C15 alkoxy groups, C1-C15 alkylamine groups, C3-C7 cycloalkyl groups, 4-7 membered heterocyclic groups, C6-C10 aryl groups, or 5-7 membered heteroaryl groups, where the C1-C15 alkyl groups, C1-C15 alkoxy groups, C1-C15 alkylamine groups, C3-C7 cycloalkyl groups, 4-7 membered heterocyclic groups, C6-C10 aryl groups, or 5-7 membered heteroaryl groups may optionally be D, halogen, cyano group, hydroxyl group, carboxyl group, or NH ２ , oxo group (=O), C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 alkylamine group, C(O)OC1-C6 alkyl group, S(O) ２ It is substituted with 1 to 3 groups selected from the group consisting of C1-C6 alkyl groups, C3-C7 cycloalkyl groups, 4-7 membered heterocyclic groups, C6-C10 aryl groups, or 5-7 membered heteroaryl groups. R ８ and R ９ These are H and S(O) respectively, independently. ２ NR １１ R １２ , selected from C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkylamine groups, C3-C7 cycloalkyl groups, 4-7 membered heterocyclic groups, C6-C10 aryl groups or 5-7 membered heteroaryl groups, or R ８ and R ９ These, together with adjacent N atoms, constitute a 5-6 membered heterocyclic group, where the C1-C6 alkyl group, C1-C6 alkoxy group, C3-C7 cycloalkyl group, 4-7 membered heterocyclic group, 5-6 membered heterocyclic group, C6-C10 aryl group, or 5-7 membered heteroaryl group may optionally be a C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 alkylamine group, C(O)OC1-C6 alkyl group, or S(O) ２ It is substituted with 1 to 3 groups selected from the group consisting of C1-C6 alkyl groups, C3-C7 cycloalkyl groups, C1-C6 alkylC3-C7 cycloalkyl groups, 4-7 membered heterocyclic groups, C1-C6 alkyl 4-7 membered heterocyclic groups, C6-C10 aryl groups, or 5-7 membered heteroaryl groups. R １１ and R １２ Each of these is independently selected from H, a C1-6 alkyl group, a C3-C7 cycloalkyl group, a 4-7 membered heterocyclic group, a C6-C10 aryl group, or a 5-7 membered heteroaryl group.

7. The compound according to claim 1, characterized by having a structure represented by formula C, or its stereoisomer or optical isomer, pharmaceutically acceptable salt, or solvate. 【Chemistry 22】 (Here, R １０ H, cyano group, CONH ２ They are selected from among them. R ７ The group is selected from C1-C15 alkyl groups, C1-C15 alkoxy groups, C1-C15 alkylamine groups, C3-C7 cycloalkyl groups, 4-7 membered heterocyclic groups, C6-C10 aryl groups, or 5-7 membered heteroaryl groups, where the C1-C15 alkyl groups, C1-C15 alkoxy groups, C1-C15 alkylamine groups, C3-C7 cycloalkyl groups, 4-7 membered heterocyclic groups, C6-C10 aryl groups, or 5-7 membered heteroaryl groups may optionally be D, halogen, cyano group, hydroxyl group, carboxyl group, or NH ２ , oxo group (=O), C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 alkylamine group, C(O)OC1-C6 alkyl group, S(O) ２ It is substituted with 1 to 3 groups selected from the group consisting of C1-C6 alkyl groups, C3-C7 cycloalkyl groups, 4-7 membered heterocyclic groups, C6-C10 aryl groups, or 5-7 membered heteroaryl groups.

8. The compound described in claim 1 is characterized by satisfying one or more of the following conditions: (1) R ｍ These include methoxy groups, fluorine, chlorine, cyano groups, hydroxyl groups, carboxyl groups, and carboxamide groups. 【Chemistry 23】 It is; (2) R ｎ teeth, 【Chemistry 24】 Acetyl group, isobutyryl group, 【Chemistry 25】 Cyclopropyl carbonyl group, cyclobutyl carbonyl group, cyclopentyl carbonyl group, cyclohexyl carbonyl group, phenyl carbonyl group, cyclopropyl methylene carbonyl group, cyclobutyl methylene carbonyl group, cyclopentyl methylene carbonyl group, cyclohexyl methylene carbonyl group, or 【Chemistry 26】 is or, R ｎ is H; and （３） 【Chemistry 27】 teeth, 【Chemistry 28】 That is the case. 【Request Item 9】 【Chemistry 29】 teeth, 【Transformation 30】 Selected from, Alternatively, Rm is, 【Chemistry 31】 To be selected from, Alternatively, Rn is, 【Chemistry 32】 To be selected from, Alternatively, n is 0. A compound according to claim 1, characterized by the stereoisomer or optical isomer thereof, a pharmaceutically acceptable salt, or a solvate thereof.

10. A compound represented by formula I', or its stereoisomer or optical isomer, a pharmaceutically acceptable salt, or a solvate thereof. 【Transformation 33】 (Here, X is O or CH ２ They are selected from among them. 【Transformation 34】 teeth, 【Chemistry 35】 And, L represents bonding. Ring B is, 【Transformation 36】 and the above 【Chemistry 37】 The elements are optionally H, D, halogen, cyano group, hydroxyl group, and NH. ２ , or substituted with a C1-C3 alkyl group. 【Transformation 38】 teeth, 【Chemistry 39】 Selected from, Each R ｍ These are independently H, D, halogen, cyano group, hydroxyl group, carboxyl group, and -S(O). ｔ R ｍ５ , -C(O)R ｍ５ , -C(O)OR ｍ５ , -C(O)NR ｍ６ R ｍ７ , -S(O) ｔ NR ｍ６ R ｍ７ , -C(O)NR ｍ８ S(O) ｔ NR ｍ６ R ｍ７ ,-(CH ２ ) ｑ S(O) ｔ R ｍ５ ,-(CH ２ ) ｑ C(O)R ｍ５ ,-(CH ２ ) ｑ C(O)OR ｍ５ ,-(CH ２ ) ｑ C(O)NR ｍ６ R ｍ７ ,-(CH ２ ) ｑ (CH ２ ) ｑ S(O) ｔ NR ｍ６ R ｍ７ ,-(CH ２ ) ｑ R ｍ９ , selected from -C1-C6 alkyl groups, -C1-C6 alkoxy groups, -C1-C6 alkylamine groups, C3-C7 cycloalkyl groups, 4-7 membered heterocyclic groups, C6-C10 aryl groups, and 5-7 membered heteroaryl groups, where the C1-C6 alkyl group, C1-C6 alkoxy group, C3-C7 cycloalkyl group, 4-7 membered heterocyclic group, C6-C10 aryl group, or 5-7 membered heteroaryl group is optionally substituted with 1-3 R groups, Alternatively, two R atoms in adjacent ring atoms ｍ However, together with the adjacent ring atoms, they form a 5-6 membered heterocyclic group, where the 5-6 membered heterocyclic group is optionally substituted with 1-3 R atoms. or, 【Chemistry 40】 teeth, 【Chemistry 41】 Selected from, where R m is -S(O) t R m5, -C(O) R m5, -C(O) OR m5, -C(O) NR m6 R m7, or -S(O) t NR m6 R m7, R ｎ These are H, C1-C15 alkyl groups, and C(O)R ｐ Selected from, here, R ｐ NH ２ , selected from C1-C15 alkyl groups, C1-C15 alkoxy groups, C1-C15 alkylamine groups, C3-C7 cycloalkyl groups, 4-7 membered heterocyclic groups, C6-C10 aryl groups, or 5-7 membered heteroaryl groups, where the C1-C15 alkyl groups, C1-C15 alkoxy groups, C1-C15 alkylamine groups, C3-C7 cycloalkyl groups, 4-7 membered heterocyclic groups, C6-C10 aryl groups, or 5-7 membered heteroaryl groups are optionally substituted with 1-3 R groups, where R is H, D, halogen, cyano group, hydroxyl group, carboxyl group, NH₂, oxo group (=O), C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 alkylamine group, C(O)OC1-C6 alkyl group, S(O)₂ The group is selected from C1-C6 alkyl groups, C3-C7 cycloalkyl groups, 4-7 membered heterocyclic groups, C6-C10 aryl groups, and 5-7 membered heteroaryl groups, where the C3-C7 cycloalkyl group, 4-7 membered heterocyclic group, C6-C10 aryl group, or 5-7 membered heteroaryl group is optionally substituted with 1-3 groups selected from the group consisting of halogens, cyano groups, hydroxyl groups, carboxyl groups, C1-C6 alkyl groups, and C1-C6 alkoxy groups. Alternatively, Rp is selected from C1-C6 alkyl groups, where the C1-C6 alkyl group is substituted with a C3-C7 cycloalkyl group, where the C3-C7 cycloalkyl group is substituted with one, two, or three groups selected from the group consisting of C1-C6 alkyl groups, C1-C6 haloalkyl groups, C6-C10 aryl groups substituted with C1-C6 haloalkyl groups, and C(O)OC1-C6 alkyl groups. R ｍ５ The group is selected from C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkylamine groups, C3-C7 cycloalkyl groups, and 4-7 membered heterocyclic groups, where the C1-C6 alkyl group, C1-C6 alkoxy group, C3-C7 cycloalkyl group, or 4-7 membered heterocyclic group is optionally substituted with 1-3 R atoms. R m8 is selected from H, C1-C6 alkyl groups, C1-C6 alkoxy groups, and C1-C6 alkylamine groups, where the C1-C6 alkyl group or C1-C6 alkoxy group is optionally substituted with 1 to 3 R groups. R ｍ６ , R ｍ７ , and R ｍ９ Each of these is independently selected from H, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkylamine groups, C3-C7 cycloalkyl groups, 4-7 membered heterocyclic groups, C6-C10 aryl groups, or 5-7 membered heteroaryl groups, or R ｍ６ and R ｍ７ These, together with adjacent N atoms, constitute a 4-7 membered heterocyclic group, where the C1-C6 alkyl group, C1-C6 alkoxy group, C3-C7 cycloalkyl group, 4-7 membered heterocyclic group, C6-C10 aryl group, or 5-7 membered heteroaryl group are optionally substituted with 1-3 R atoms. R is H, D, halogen, cyano group, hydroxyl group, carboxyl group, NH ２ , oxo group (=O), C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 alkylamine group, C(O)OC1-C6 alkyl group, S(O) ２ Selected from C1-C6 alkyl groups, C3-C7 cycloalkyl groups, 4-7 membered heterocyclic groups, C6-C10 aryl groups, or 5-7 membered heteroaryl groups, where the C1-C6 alkyl group, C1-C6 alkoxy group, C3-C7 cycloalkyl group, 4-7 membered heterocyclic group, C6-C10 aryl group, or 5-7 membered heteroaryl group may optionally be a halogen, cyano group, hydroxyl group, carboxyl group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 alkylamine group, C(O)OC1-C6 alkyl group, and S(O) ２ It is substituted with 1 to 3 groups selected from the group consisting of C1-C6 alkyl groups. t is either 1 or 2. q is 1, 2, 3, or 4. n is 1, 2, 3, 4, or 5.

11. below: 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 【Chemistry 52】 A compound selected from the above, or its stereoisomer or optical isomer, a pharmaceutically acceptable salt, or a solvate.

12. A drug composition comprising a compound according to any one of claims 1 to 11 or a stereoisomer or optical isomer thereof, a pharmaceutically acceptable salt, or a solvate thereof, and a pharmaceutically acceptable carrier.

13. The use of a compound according to any one of claims 1 to 11, or its stereoisomer or optical isomer, a pharmaceutically acceptable salt, or a solvate thereof, The use described above is for the manufacture of a drug that treats or prevents a disease related to the activity or expression level of Drak2 kinase, or for the manufacture of a drug that inhibits the activity of Drak2 kinase.

14. The aforementioned diseases are cancer, autoimmune diseases, or metabolic diseases. Here, the cancers mentioned above include malignant lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic osteomyelitis, diffuse large B-cell lymphoma, multiple myeloma, non-Hodgkin lymphoma, pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, basal cell carcinoma, breast cancer, brain cancer, adrenal cancer, kidney cancer, nephroblastoma, gastric cancer, gastrointestinal stromal tumor, pituitary adenoma, pancreatic cancer, gallbladder cancer, bile duct cancer, colon cancer, rectal cancer, small intestine cancer, duodenal cancer, retinoblastoma, choroidal melanoma, papillary cancer, bladder cancer, peritoneal cancer, parathyroid cancer. Adenocarcinoma, nasal and paranasal sinus cancer, small cell lung cancer, non-small cell lung cancer, astrocytoma, esophageal cancer, gliocytoma, neuroblastoma, malignant soft tissue tumor, malignant bone tumor, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, penile cancer, oral cancer, lip cancer, pharyngeal cancer, epithelial ovarian cancer, ovarian germ cell carcinoma, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, vaginal cancer, Paget's disease, tonsil cancer, anal cancer, rhabdomyosarcoma, Kaposi's sarcoma, sarcoma, tongue cancer, laryngeal cancer, pleural cancer, thymic cancer, or a combination thereof, where non-small cell lung cancer is lung adenocarcinoma or lung squamous cell carcinoma. The aforementioned autoimmune diseases are selected from inflammatory colitis, Crohn's disease, Behçet's disease, multiple sclerosis, macular degeneration, arthritis, encephalitis, viral meningitis, or a combination thereof, and The use according to claim 13, characterized in that the metabolic disease is selected from diabetes, and the diabetes is type 1 diabetes or type 2 diabetes.

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