Heterocyclic compounds with antitumor activity and their use

Abstract

The present invention provides a series of compounds, and their stereoisomers, optical isomers, pharmaceutical salts, prodrugs, solvates (e.g., hydrates) or isotopic derivatives. The compounds of the present invention have a triheterocyclic structure (e.g., the structure shown in formula (A)), which is a novel structure and provides a new direction for the development of SOS1 inhibitors. In vitro enzyme activity inhibition studies have shown that these compounds have strong inhibitory effects on SOS1, and are promising compounds for preventing and / or treating SOS1-mediated diseases. Moreover, these compounds show obvious inhibitory activity against NCI-H358 cell proliferation. The present invention also provides a specific synthesis method, which is simple in process, easy to operate, and conducive to large-scale industrial production and use. [Formula 1] TIFF2024545236000154.tif54161

Description

[Technical Field]

[0001] The present invention claims priority to the patent application filed in China on December 17, 2021, titled "Heterocyclic Compounds Having Antitumor Activity and Uses Thereof," application number 202111561282.9, and the patent application filed in China on June 7, 2022, titled "Heterocyclic Compounds Having Antitumor Activity and Uses Thereof," application number 202210634934.5, and incorporates these patent applications as a whole by reference.

[0002] This invention relates to the field of medical technology, and more specifically to compounds as SOS1 inhibitors, as well as compositions, methods of production, and uses of said compounds. [Background technology]

[0003] Currently, three genes are known in the RAS family: KRAS (Kirsten rat sarcoma virus oncogene homolog), NRAS (neuroblastoma RAS virus oncogene homolog), and HRAS (Harvey rat sarcoma virus oncogene). RAS family proteins are low molecular weight GTPases and were the first oncogenes identified in human tumors. RAS family proteins have weak intrinsic GTPase activity and slow nucleotide exchange rates. For example, binding of NF1 to GTPase-activating protein (GAP) increases the GTPase activity of RAS family proteins.

[0004] Mutations in the RAS protein are closely related to tumor development, and the type of RAS mutation varies depending on the tumor type. In human tumors, KRAS mutations (e.g., amino acids G12, G13, Q61, A146) are the most common, accounting for approximately 85%, while NRAS (e.g., amino acids G12, G13, Q61, A146) and HRAS (e.g., amino acids G12, G13, Q61) account for 12% and 3%, respectively. Changes in RAS family proteins (e.g., mutations, overexpression, gene amplification) have been described as mechanisms of resistance to the anticancer drugs EGFR antibodies cetuximab and panitumumab, and the EGFR tyrosine kinase inhibitor osimertinib. In oncogenic RAS variants, GAP activity is weakened or significantly reduced, leading to persistent activation, which underlies oncogenic RAS signaling. Direct inhibition of RAS is already proven to be very difficult and unpromising due to the picomolar affinity of GTP to its binding site, the lack of other clearly defined pockets, and the extended, flat protein-protein interactions of RAS with GEF, GAP, and effectors. Therefore, targeting the upstream guanine nucleotide exchange factor, the SOS protein, to inhibit RAS activation is considered promising.

[0005] There are two human isotypes of SOS, SOS1 and SOS2, but the vast majority of research focuses on SOS1. Human SOS1 contains 1333 amino acids (15kDa) and its components include an N-terminal histone-like domain, a Dbl homolog (DH) domain, a pleckstrin homolog (PH) domain, a helical linker (HL), a Ras exchange motif (Rem) domain, a Cdc25 domain, and a C-terminal region. Of these, PH, Rem, and Cdc25 are SOS cat It is a component of the core catalytic domain.

[0006] Over the past few decades, RAS family protein-SOS1 protein interactions have been recognized. Recently, research has also been conducted on screening and identifying small molecular weight inhibitors of SOS1—that is, compounds that bind to SOS1 and inhibit protein-protein interactions with RAS family proteins—by combining rational design and screening platforms. For example, WO2021105960A1 describes various fused-ring SOS1 inhibitors.

[0007] Although several SOS1 small molecule inhibitors have been disclosed, none of the SOS1 inhibitors currently under development have reached the market. Therefore, it remains an urgent task to develop new compounds that have commercial potential and possess better efficacy and pharmacokinetic properties. [Overview of the project] [Problems that the invention aims to solve]

[0008] The object of the present invention is to provide a compound as an SOS1 inhibitor having a novel structure, a composition thereof, a method for producing it, and its use for treating SOS1-mediated diseases. [Means for solving the problem]

[0009] A first aspect of the present invention relates to a compound represented by the following formula (A), or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or We provide isotopic derivatives, [ka] During the ceremony, [ka] This represents a single bond or a double bond. Y and Z are both selected from C or N, and when Y is N, Z is C, and when Y is C, Z is N. Y and Z together with the atoms to which they are attached form ring A, and ring A is selected from a 5- to 12-membered heterocyclyl group or a 5- to 12-membered heteroaryl group. R 2 is one, two or three, and when it appears, each is independently hydrogen, halogen, hydroxy group, cyano group, amino group, nitro group, formyl group, oxo group, C 1~6 alkyl group, C 1~6 alkoxy group, -C 1~6 alkyl-NH(C 1~6 alkyl), -C 1~6 alkyl-N(C 1~6 alkyl)2, C 2~6 alkenyl group, C 2~6 alkynyl group, C 3~10 cycloalkyl group, C 6~10 aryl group, a 3- to 10-membered heterocyclyl group or a 5- to 10-membered heteroaryl group, where the C 1~6 alkyl group, C 1~6 alkoxy group, -C 1~6 alkyl-NH(C 1~6 alkyl), -C 1~6 alkyl-N(C 1~6 alkyl)2, C 2~6 alkenyl group, C 2~6 alkynyl group, C 3~10 cycloalkyl group, C 6~10 aryl group, a 3- to 10-membered heterocyclyl group and a 5- to 10-membered heteroaryl group may each be optionally substituted by one or more cyano groups, hydroxy groups or halogens. R 3 is hydrogen, halogen, hydroxy group, amino group, cyano group, C 1~6 alkyl group, C 1~6 alkoxy group, C 3~6 cycloalkyl group or a 3- to 6-membered heterocyclyl group, where the C 1~6 alkyl group, C 1~6 alkoxy group, C 3~6 cycloalkyl group and a 3- to 6-membered heterocyclyl group may each be optionally substituted by one or more hydroxy groups or halogens. Ring B is C 4~12Cycloalkyl groups, C 4~12 Cycloalkenyl group, 4-12 membered heterocyclyl group, C 6~12 Aryl group, 5-12 membered heteroaryl group, C 6~12 Aryl condensation C 4~12 Cycloalkyl groups, C 6~12 Aryl condensed 4-12 member heterocyclyl group or C 6~12 Aryl condensation C 4~12 Selected from cycloalkenyl groups, Each R 4 If present, each independently comprises hydrogen, cyano group, halogen, amino group, hydroxyl group, oxo group, nitro group, and C. 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 1~6 Haloalkyl group, C 1~6 Hydroxyalkyl group, C 1~6 Alkoxy group, -C 0~6 Alkyl-NH-C 1~6 Alkyl alkyl group, -C 0~6 Alkyl-N(C 1~6 Alkyl)(C 1~6 Alkyl), C 3~6 Cycloalkyl groups, C 3~6 Selected from a halocycloalkyl group or a 3-6 membered heterocyclyl group, where the C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 1~6 Haloalkyl group, C 1~6 Hydroxyalkyl group, C 1~6 Alkoxy group, -C 0~6 Alkyl-NH-C 1~6 Alkyl alkyl group, -C 0~6 Alkyl-N(C 1~6 Alkyl)(C 1~6 Alkyl), C 3~6 Cycloalkyl groups, C 3~6 The halocycloalkyl group and the 3-6 membered heterocycline group may optionally be a halogen, hydroxyl group, amino group, or -SO2-C 1~4 It may be substituted with one or more substituents that are alkyl groups or oxo groups, where w is 0, 1, 2, 3 or 4. [Chemical formula] When it is a double bond, X is selected from C, and the R connected thereto 1 is -O-R A , -N(R D )R B or R C selected from, R 1 is -O-R A In the case of, R A is C 1~6 alkyl group, C 2~6 alkenyl group, C 2~6 alkynyl group, C 3~10 cycloalkyl group, C 6~10 aryl group, 3- to 10-membered heterocyclyl group or 5- to 10-membered heteroaryl group, where the C 1~6 alkyl group, C 2~6 alkenyl group, C 2~6 alkynyl group, C 3~10 cycloalkyl group, C 6~10 aryl group, 3- to 10-membered heterocyclyl group and 5- to 10-membered heteroaryl group may each be optionally substituted by 1 to 3 same or different R a1 , Each R a1 , when present, is each independently halogen, hydroxy group, cyano group, amino group, nitro group, oxo group, formyl group, C 1~6 alkyl group, C 2~6 alkenyl group, C 2~6 alkynyl group, -OC 1~6 [[ID=·58]]alkyl group, -SC 1~6 alkyl group, -COC [[ID=6l]] 1~6 alkyl group, -CH2COC <00000·92>alkyl group, -CH2CON(C 1~6 alkyl)2, -CH2CONHC 1~6 alkyl group, -NHC 1~6 alkyl group, -N(C 1~6 alkyl)2, C 3~10 cycloalkyl group, C 6~10 aryl group, 3- to 10-membered heterocyclyl group or 5- to 10-membered heteroaryl group, R 1 ga-N(R D )R B If that is the case, R B C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10 The aryl group, 3-10 membered heterocyclyl group, and 5-10 membered heteroaryl group can each have 1-3 identical or different R groups. b1 It may be replaced by, Each R b1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, nitro group, oxo group, formyl group, and C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group, -COC 1~6 Alkyl group, -CH2COC 1~6 Alkyl, -CH2CON(C 1~6 Alkyl)2,-CH2CONHC 1~6 Alkyl alkyl, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, C 3~10 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, R D C is a group of hydrogen, halogen, hydroxyl group, cyano group, amino group, nitro group, oxo group, formyl group, C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -OC 1~6 Alkyl, -SC 1~6Alkyl group, -COC 1~6 Alkyl group, -CH2COC 1~6 Alkyl, -CH2CON(C 1~6 Alkyl)2,-CH2CONHC 1~6 Alkyl alkyl, -NHC 1~6 Alkyl or -N(C) 1~6 Selected from alkyl)2, R 1 R C If that is the case, R C C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10 The aryl group, 3-10 membered heterocyclyl group, and 5-10 membered heteroaryl group can each have 1-4 identical or different R groups. c1 It may be replaced by, Each R c1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, nitro group, oxo group, formyl group, methanesulfonyl group, and C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group, -COC 1~6 Alkyl group, -COC 3~6 Cycloalkyl groups, -CH2COC 1~6 Alkyl, -CH2CON(C 1~6 Alkyl)2,-CH2CONHC 1~6 Alkyl alkyl, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, C 3~10 Cycloalkyl groups, C 6~10Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group, -COC 1~6 Alkyl group, -COC 3~6 Cycloalkyl groups, -CH2COC 1~6 Alkyl, -CH2CON(C 1~6 Alkyl)2,-CH2CONHC 1~6 Alkyl alkyl, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, C 3~10 Cycloalkyl groups, C 6~10 The aryl group, 3-10 membered heterocyclyl group, and 5-10 membered heteroaryl group can all optionally contain deuterium, a hydroxyl group, a cyano group, or C. 1~3 Alkyl alkyl group, C 1~3 It may be substituted with one or more substituents selected from alkoxy groups or halogens. [ka] When it is a single bond, X is chosen from N and connected to R 1 C 3~10 Cycloalkyl groups, C 3~10 Cycloalkenyl group, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 3~10 Cycloalkyl groups, C 3~10 Cycloalkenyl group, C 6~10 The aryl group, 3-10 membered heterocyclyl group, and 5-10 membered heteroaryl group may each be one or more of the same or different R groups. a4 and / or R b4 It may be replaced by, Each R a4 If they exist, each is independent of C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C3~10 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10 The aryl group, 3-10 membered heterocyclyl group, and 5-10 membered heteroaryl group may each be one or more of the same or different R groups. b4 and / or R c4 It may be replaced by, Each R b4 If present, each is independent of -OR c4 , -NR c4 R c4 , halogen, -CN, -C(O)R c4 , -C(O)OR c4 -C(O)NR c4 R c4 ,-OC(O)R c4 -S(O)2R c4 -S(O)2NR c4 R c4 ,-NHC(O)R c4 , -N(C 1~4 Alkyl)C(O)R c4 ,-NHC(O)OR c4 Alternatively, a divalent substituent =O or =NH may be selected, and =O and =NH may be substituents in a non-aromatic ring system. Each R c4 If present, hydrogen and C are independent of each other. 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10The aryl group, 3-10 membered heterocyclyl group, and 5-10 membered heteroaryl group may each be one or more of the same or different R groups. d4 and / or R e4 It may be replaced by, Each R d4 If present, each is independent of -OR e4 , -NR e4 R e4 , halogen, -CN, -C(O)R e4 , -C(O)OR e4 -C(O)NR e4 R e4 -S(O)2R e4 -S(O)2NR e4 R e4 ,-NHC(O)R e4 , -N(C 1~4 Alkyl)C(O)R e4 Alternatively, a divalent substituent =O may be selected, and =O may be any substituent in a non-aromatic ring system. Each R e4 If present, hydrogen and C are independent of each other. 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10 The aryl group, the 3-10 membered heterocyclyl group, and the 5-10 membered heteroaryl group may each be optionally substituted with one or more hydrogen atoms, cyano groups, hydroxyl groups, or halogens. Here, Z and Y are included in the atoms or number of atoms of ring A.

[0010] Unless otherwise specified, the heteroatoms in the heteroaryl and heterocyclyl groups described above are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4.

[0011] Preferably, the present invention relates to a compound having the structure represented by formula (A'), or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or We provide isotopic derivatives, [ka] Each substituent in formula (A') is defined as described in formula (A).

[0012] The present invention also relates to a compound represented by the following formula (I), a compound, or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or We provide isotopic derivatives, [ka] During the ceremony, [ka] This represents a single bond or a double bond. Y and Z are both selected from C or N, and when Y is N, Z is C, and when Y is C, Z is N. Y and Z, together with the atoms attached to them, form ring A, and ring A is selected from a 5-12 membered heterocyclyl group or a 5-12 membered heteroaryl group. R 2 There are one, two, or three of them, and when they appear, each independently represents hydrogen, halogen, hydroxyl group, cyano group, amino group, nitro group, formyl group, oxo group, and C. 1~6 Alkyl alkyl group, C 1~6 Alkoxy group, -C 1~6 Alkyl-NH(C 1~6 Alkyl), -C 1~6 Alkyl-N(C 1~6 Alkyl)2, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 1~6 Alkyl alkyl group, C 1~6 Alkoxy group, -C 1~6 Alkyl-NH(C 1~6 Alkyl), -C 1~6 Alkyl-N(C 1~6 Alkyl)2, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10 The aryl group, the 3-10 membered heterocyclyl group, and the 5-10 membered heteroaryl group may each be optionally substituted with one or more cyano groups, hydroxyl groups, or halogens. R 3 These are hydrogen, halogen, hydroxyl group, amino group, cyano group, and C 1~6 Alkyl alkyl group, C 1~6 Alkoxy group, C 3~6 Selected from a cycloalkyl group or a 3-6 membered heterocyclyl group, where the C 1~6 Alkyl alkyl group, C 1~6 Alkoxy group, C 3~6 The cycloalkyl group and the 3-6 membered heterocyclyl group may each be optionally substituted with one or more hydroxyl groups or halogens. Ring B is C 4~12 Cycloalkyl groups, C 4~12 Cycloalkenyl group, C 4~12 Heterocyclyl group, C 6~12 Aryl group, C 5~12 Heteroaryl group, C 6~12 Aryl condensation C 4~12 Cycloalkyl groups, C 6~12 Aryl condensation C 4~12 Heterocyclyl group or C 6~12 Aryl condensation C 4~12 Selected from cycloalkenyl groups, Each R 4 If present, each independently comprises hydrogen, cyano group, halogen, amino group, hydroxyl group, oxo group, nitro group, and C. 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6Alkynyl group, C 1~6 Haloalkyl group, C 1~6 Hydroxyalkyl group, C 1~6 Alkoxy group, -C 0~6 Alkyl-NH-C 1~6 Alkyl alkyl group, -C 0~6 Alkyl-N(C 1~6 Alkyl)(C 1~6 Alkyl), C 3~6 Cycloalkyl groups, C 3~6 Selected from a halocycloalkyl group or a 3-6 membered heterocyclyl group, where the C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 1~6 Haloalkyl group, C 1~6 Hydroxyalkyl group, C 1~6 Alkoxy group, -C 0~6 Alkyl-NH-C 1~6 Alkyl alkyl group, -C 0~6 Alkyl-N(C 1~6 Alkyl)(C 1~6 Alkyl), C 3~6 Cycloalkyl groups, C 3~6 The halocycloalkyl group and the 3-6 membered heterocycline group may optionally be a halogen, hydroxyl group, amino group, or -SO2-C 1~4 It may be substituted with one or more substituents that are alkyl groups or oxo groups, where w is 0, 1, 2, 3 or 4. [ka] When it is a double bond, X is chosen from C and connected to R 1 is -OR A , -N(R D )R B or R C Selected from, R 1 ga-OR A If that is the case, R A C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10 The aryl group, 3-10 membered heterocyclyl group, and 5-10 membered heteroaryl group can each have 1-3 identical or different R groups. a1 It may be replaced by, Each R a1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, nitro group, oxo group, formyl group, and C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group, -COC 1~6 Alkyl group, -CH2COC 1~6 Alkyl, -CH2CON(C 1~6 Alkyl)2,-CH2CONHC 1~6 Alkyl alkyl, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, C 3~10 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, R 1 ga-N(R D )R B If that is the case, R B C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10The aryl group, 3-10 membered heterocyclyl group, and 5-10 membered heteroaryl group can each have 1-3 identical or different R groups. b1 It may be replaced by, Each R b1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, nitro group, oxo group, formyl group, and C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group, -COC 1~6 Alkyl group, -CH2COC 1~6 Alkyl, -CH2CON(C 1~6 Alkyl)2,-CH2CONHC 1~6 Alkyl alkyl, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, C 3~10 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, R D C is a group of hydrogen, halogen, hydroxyl group, cyano group, amino group, nitro group, oxo group, formyl group, C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group, -COC 1~6 Alkyl group, -CH2COC 1~6 Alkyl, -CH2CON(C 1~6 Alkyl)2,-CH2CONHC 1~6 Alkyl alkyl, -NHC 1~6 Alkyl or -N(C) 1~6 Selected from alkyl)2, R 1 R C If that is the case, R C C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10 The aryl group, 3-10 membered heterocyclyl group, and 5-10 membered heteroaryl group can each have 1-3 identical or different R groups. c1 It may be replaced by, Each R c1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, nitro group, oxo group, formyl group, and C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group, -COC 1~6 Alkyl group, -CH2COC 1~6 Alkyl, -CH2CON(C 1~6 Alkyl)2,-CH2CONHC 1~6 Alkyl alkyl, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, C 3~10 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group, -COC 1~6 Alkyl group, -CH2COC 1~6 Alkyl, -CH2CON(C 1~6 Alkyl)2,-CH2CONHC 1~6 Alkyl alkyl, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, C 3~10 Cycloalkyl groups, C 6~10 The aryl group, the 3-10 membered heterocyclyl group, and the 5-10 membered heteroaryl group can all optionally be a hydroxyl group, C1~3 Alkyl alkyl group, C 1~3 It may be substituted with one or more substituents selected from alkoxy groups or halogens. [ka] When it is a single bond, X is chosen from N and connected to R 1 C 3~10 Cycloalkyl groups, C 3~10 Cycloalkenyl group, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 3~10 Cycloalkyl groups, C 3~10 Cycloalkenyl group, C 6~10 The aryl group, 3-10 membered heterocyclyl group, and 5-10 membered heteroaryl group may each be one or more of the same or different R groups. a4 and / or R b4 It may be replaced by, Each R a4 If they exist, each is independent of C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10 The aryl group, 3-10 membered heterocyclyl group, and 5-10 membered heteroaryl group may each be one or more of the same or different R groups. b4 and / or R c4 It may be replaced by, Each R b4 If present, each is independent of -OR c4 , -NR c4 R c4 , halogen, -CN, -C(O)R c4 , -C(O)OR c4 -C(O)NRc4 R c4 ,-OC(O)R c4 -S(O)2R c4 -S(O)2NR c4 R c4 ,-NHC(O)R c4 , -N(C 1~4 Alkyl)C(O)R c4 ,-NHC(O)OR c4 Alternatively, a divalent substituent =O or =NH may be selected, and =O and =NH may be substituents in a non-aromatic ring system. Each R c4 If present, hydrogen and C are independent of each other. 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10 The aryl group, 3-10 membered heterocyclyl group, and 5-10 membered heteroaryl group may each be one or more of the same or different R groups. d4 and / or R e4 It may be replaced by, Each R d4 If present, each is independent of -OR e4 , -NR e4 R e4 , halogen, -CN, -C(O)R e4 , -C(O)OR e4 -C(O)NR e4 R e4 -S(O)2R e4 -S(O)2NR e4 R e4 ,-NHC(O)R e4 , -N(C 1~4 Alkyl)C(O)R e4 Alternatively, a divalent substituent =O may be selected, and =O may be any substituent in a non-aromatic ring system. Each Re4 If present, hydrogen and C are independent of each other. 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10 The aryl group, the 3-10 membered heterocyclyl group, and the 5-10 membered heteroaryl group may each be optionally substituted with one or more hydrogen atoms, cyano groups, hydroxyl groups, or halogens. Here, Z and Y are included in the atoms or number of atoms of ring A.

[0013] Unless otherwise specified, the heteroatoms in the heteroaryl and heterocyclyl groups described above are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4.

[0014] Preferably, the present invention relates to a compound having the structure represented by formula (II), or Its stereoisomers, optical isomers, pharmaceutical salts, and prodrugs. or Provides a solvate, [ka] Each substituent in formula (II) is defined as described in formula (I).

[0015] Preferably, the present invention relates to a compound having the structure represented by formula (III), or Its stereoisomers, optical isomers, pharmaceutical salts, and prodrugs. or Provides a solvate, [ka] Each substituent in formula (III) is defined as described in formula (I).

[0016] Preferably, the present invention relates to a compound having the structure represented by formula (IV), or Its stereoisomers, optical isomers, pharmaceutical salts, and prodrugs. or Provides a solvate, [ka] Each substituent in formula (IV) is defined as described in formula (I).

[0017] In one preferred embodiment of the present invention, [ka] This is a double bond, where X is chosen from C and R is connected to it. 1 is -OR A That is the case.

[0018] Preferably, R A C 1~6 Alkyl alkyl group, C 3~10 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 1~6 Alkyl alkyl group, C 3~10 Cycloalkyl groups, C 6~10 The aryl group, 3-10 membered heterocyclyl group, and 5-10 membered heteroaryl group can each have 1-3 identical or different R groups. a1 It may be replaced by, Each R a1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, nitro group, oxo group, formyl group, and C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group, -COC 1~6 Alkyl group, -CH2COC 1~6 Alkyl, -CH2CON(C 1~6 Alkyl)2,-CH2CONHC 1~6Alkyl alkyl, -NHC 1~6 Alkyl or -N(C) 1~6 Selected from alkyl(2).

[0019] More preferably, R A C 3~6 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-6 membered heterocyclyl group, or a 5-6 membered heteroaryl group, where the C 3~6 Cycloalkyl groups, C 6~10 The aryl group, 3-6 membered heterocyclyl group, and 5-6 membered heteroaryl group can each have 1-3 identical or different R groups. a1 It may be replaced by, Each R a1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, oxo group, formyl group, and C 1~6 alkyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group or -COC 1~6 Selected from alkyl groups.

[0020] More preferably, R A The group is selected from a 5-6 membered heterocyclyl group or a 5-6 membered heteroaryl group, where the 5-6 membered heterocyclyl group and the 5-6 membered heteroaryl group are each arbitrarily selected from 1 to 3 identical or different R groups. a1 It may be replaced by, Each R a1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, oxo group, formyl group, and C 1~4 alkyl group, -OC 1~4 Alkyl, -SC 1~4 Alkyl group or -COC 1~4 Selected from alkyl groups.

[0021] More preferably, R A R is selected from a 5-6 membered heterocyclyl group, where the 5-6 membered heterocyclyl group is optionally 1-2 of the same or different R a1 It may be replaced by, Each R a1 If present, each of these groups is independently selected from halogen, oxo group, formyl group, acetyl group, methyl group, ethyl group, n-propyl group, isopropyl group, or methoxy group.

[0022] More preferably, R A R is selected from a 5-6 member monocyclic heterocyclyl group, where the 5-6 member monocyclic heterocyclyl group is optionally 1-2 of the same or different R groups. a1 It may be substituted by, and each heteroatom in the 5-6 membered monocyclic heterocyclyl group is independently selected from O, N, or S, and the number of heteroatoms is 1. Each R a1 If present, each of these groups is independently selected from halogen, oxo group, formyl group, acetyl group, methyl group, ethyl group, n-propyl group, isopropyl group, or methoxy group.

[0023] More preferably, R A The group is selected from a tetrahydrofuryl group, a tetrahydrothienyl group, a pyrrolidinyl group, a piperidinyl group, a tetrahydropyranyl group, or a tetrahydrothiopyranyl group, and each of the tetrahydrofuryl group, tetrahydrothienyl group, pyrrolidinyl group, piperidinyl group, tetrahydropyranyl group, and tetrahydrothiopyranyl group can be any one to two of the same or different R groups. a1 It may be replaced by, Each R a1 If present, each of these groups is independently selected from halogen, oxo group, formyl group, acetyl group, methyl group, ethyl group, n-propyl group, isopropyl group, or methoxy group.

[0024] More preferably, R A The following functional groups: [ka] They are selected from among them.

[0025] In one preferred embodiment of the present invention, [ka] This is a double bond, where X is chosen from C and R is connected to it. 1 is -N(R D )R B That is the case.

[0026] Preferably, R B C 1~6 Alkyl alkyl group, C 3~10 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 1~6 Alkyl alkyl group, C 3~10 Cycloalkyl groups, C 6~10 The aryl group, 3-10 membered heterocyclyl group, and 5-10 membered heteroaryl group can each have 1-3 identical or different R groups. b1 It may be replaced by, Each R b1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, nitro group, oxo group, formyl group, and C 1~6 alkyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group or -COC 1~6 Selected from alkyl groups.

[0027] More preferably, R B C 1~6 Selected from alkyl groups, 3-10 membered heterocyclyl groups, or 5-10 membered heteroaryl groups, where the C 1~6 Alkyl groups, 3-10 membered heterocyclyl groups, and 5-10 membered heteroaryl groups may each have 1-3 identical or different R groups. b1 It may be replaced by, Each R b1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, nitro group, oxo group, formyl group, and C 1~6 alkyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group or -COC 1~6 Selected from alkyl groups.

[0028] More preferably, R B C 1~6 Selected from alkyl groups or 5-6 membered monocyclic heterocyclyl groups, where the C 1~6 The alkyl group and the 5-6 membered monocyclic heterocyclyl group may each have 1-2 identical or different R groups. b1 It may be substituted by, and each heteroatom in the 5-6 membered monocyclic heterocyclyl group is independently selected from O, N, or S, and the number of heteroatoms is 1. Each R b1 If present, each is independently a halogen, an oxo group, a formyl group, and C 1~4 alkyl group, -OC 1~4 Alkyl group or -COC 1~4 Selected from alkyl groups.

[0029] More preferably, R B R is selected from methyl group, ethyl group, n-propyl group, isopropyl group, oxetanyl group, tetrahydrofuryl group, tetrahydrothienyl group, pyrrolidinyl group, piperidinyl group, tetrahydropyranyl group, or tetrahydrothiopyranyl group, where each of the methyl group, ethyl group, n-propyl group, isopropyl group, oxetanyl group, tetrahydrofuryl group, tetrahydrothienyl group, pyrrolidinyl group, piperidinyl group, tetrahydropyranyl group, and tetrahydrothiopyranyl group can be any one to two of the same or different R b1 It may be replaced by, Each R b1 If present, each of these groups is independently selected from an oxo group, a formyl group, an acetyl group, a methyl group, an ethyl group, a methoxy group, or an ethoxy group.

[0030] More preferably, R B The following functional groups: [ka] They are selected from among them.

[0031] Preferably, R D is hydrogen, C 1~6 Alkyl alkyl group or -OC 1~6 Selected from alkyl groups, more preferably R D is hydrogen or C 1~3 Selected from alkyl groups, more preferably R D is selected from hydrogen or a methyl group, most preferably R D It is selected from hydrogen.

[0032] In one preferred embodiment of the present invention, [ka] This is a double bond, where X is chosen from C and R is connected to it. 1 R C That is the case.

[0033] Preferably, R C C 1~6 Alkyl alkyl group, C 3~10 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 1~6 Alkyl alkyl group, C 3~10 Cycloalkyl groups, C 6~10 The aryl group, 3-10 membered heterocyclyl group, and 5-10 membered heteroaryl group can each have 1-3 identical or different R groups. c1 It may be replaced by, Each R c1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, nitro group, oxo group, formyl group, and C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group, -COC 1~6 Alkyl group, -CH2COC 1~6 Alkyl, -CH2CON(C 1~6 Alkyl)2,-CH2CONHC 1~6 Alkyl alkyl, -NHC 1~6Alkyl, -N(C 1~6 Alkyl)2, C 3~10 Selected from a cycloalkyl group or a 3-10 membered heterocyclyl group, where the C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group, -COC 1~6 Alkyl group, -CH2COC 1~6 Alkyl, -CH2CON(C 1~6 Alkyl)2,-CH2CONHC 1~6 Alkyl alkyl, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, C 3~10 The cycloalkyl group and the 3-10 membered heterocyclyl group may optionally include a hydroxyl group and a C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with one or more substituents selected from alkoxy groups or halogens.

[0034] More preferably, R C C 1~6 Alkyl alkyl group, C 3~10 Selected from a cycloalkyl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 1~6 Alkyl alkyl group, C 3~10 Cycloalkyl groups, 3-10 membered heterocyclyl groups, and 5-10 membered heteroaryl groups may each have 1-3 identical or different R groups. c1 It may be replaced by, Each R c1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, nitro group, oxo group, formyl group, and C 1~4 alkyl group, -OC 1~4 Alkyl, -SC 1~4 Alkyl group, -COC 1~4 Alkyl, -CH2CON(C 1~4 Alkyl)2,-CH2CONHC 1~4 Selected from alkyl groups or 3-6 membered heterocyclyl groups, where the C 1~4alkyl group, -OC 1~4 Alkyl, -SC 1~4 Alkyl group, -COC 1~4 Alkyl, -CH2CON(C 1~4 Alkyl)2,-CH2CONHC 1~4 The alkyl group and the 3-6 membered heterocyclyl group may each be optionally substituted with one or more substituents selected from a hydroxyl group, a methyl group, a methoxy group, or a halogen.

[0035] More preferably, R C The group is selected from a 3-10 membered heterocyclyl group or a 5-10 membered heteroaryl group, where the 3-10 membered heterocyclyl group and the 5-10 membered heteroaryl group each have 1 to 3 identical or different R groups. c1 It may be replaced by, Each R c1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, oxo group, formyl group, and C 1~4 alkyl group, -OC 1~4 Alkyl group, -COC 1~4 Alkyl, -CH2CON(C 1~4 Selected from alkyl) 2 or 3-6 member heterocyclyl groups, where the C 1~4 alkyl group, -OC 1~4 Alkyl group, -COC 1~4 Alkyl, -CH2CON(C 1~4 The alkyl)2 and 3-6 membered heterocyclyl groups may each be optionally substituted with one or more substituents selected from hydroxyl, methyl, methoxy, or halogen groups.

[0036] More preferably, R C The group is selected from a 5-6 member monocyclic heterocyclyl group, a 6-10 member spiroheterocyclyl group, a 6-8 member bridged heterocyclyl group, or a 5-6 member monocyclic heteroaryl group, where the 5-6 member monocyclic heterocyclyl group, the 6-10 member spiroheterocyclyl group, the 6-8 member bridged heterocyclyl group, and the 5-6 member monocyclic heteroaryl group are each arbitrarily selected from 1 to 3 identical or different R groups. c1It may be replaced by, Each R c1 If present, each of these groups is independently selected from halogen, hydroxyl group, cyano group, amino group, oxo group, formyl group, acetyl group, propionyl group, methoxy group, ethoxy group, methyl group, ethyl group, n-propyl group, isopropyl group, -CH2CON(CH3)2, or a 6-membered heterocyclyl group, where the acetyl group, propionyl group, methoxy group, ethoxy group, methyl group, ethyl group, n-propyl group, isopropyl group, -CH2CON(CH3)2, and 6-membered heterocyclyl group may be optionally substituted with one or more substituents selected from hydroxyl group, methyl group, methoxy group, or halogen.

[0037] More preferably, R C The group is selected from a 6-membered monocyclic heterocyclyl group, a 4 / 6 spiroheterocyclyl group, a 4 / 4 spiroheterocyclyl group, a 7-membered bridged heterocyclyl group, or a 6-membered monocyclic heteroaryl group, where the 6-membered monocyclic heterocyclyl group, the 4 / 6 spiroheterocyclyl group, the 4 / 4 spiroheterocyclyl group, the 7-membered bridged heterocyclyl group, and the 6-membered monocyclic heteroaryl group are each arbitrarily selected from 1 to 3 identical or different R groups. c1 It may be replaced by, Each R c1 If present, each is independently selected from halogen, hydroxyl group, cyano group, amino group, oxo group, formyl group, acetyl group, -COCH2CH3, -COCH2OH, hydroxymethyl group, hydroxyethyl group, -CH2OCH3, methoxy group, ethoxy group, methyl group, ethyl group, n-propyl group, isopropyl group, -CH2CON(CH3)2, or 6-membered heterocyclyl group.

[0038] More preferably, R C teeth, [ka] Selected from, the R C Each of these can be any one or two identical or different R c1 It may be replaced by, Each R c1 If present, each of these groups is independently selected from F, Cl, Br, hydroxyl group, cyano group, amino group, oxo group, acetyl group, -COCH2CH3, -COCH2OH, hydroxymethyl group, hydroxyethyl group, -CH2OCH3, methoxy group, methyl group, ethyl group, isopropyl group, -CH2CON(CH3)2, or morpholinyl group.

[0039] More preferably, optionally R c1 R may be substituted by C The following functional groups: [ka] They are selected from among them.

[0040] In one preferred embodiment of the present invention, ring A is selected from a 5-10 membered heterocyclyl group or a 5-10 membered heteroaryl group, where the heteroatoms in the 5-10 membered heterocyclyl group and the 5-10 membered heteroaryl group are independently selected from O or N, and the number of heteroatoms is 1 to 4.

[0041] More preferably, ring A is selected from a 5-membered monocyclic heterocyclyl group, a 6-membered monocyclic heterocyclyl group, a 5-membered monocyclic heteroaryl group, a 6-membered monocyclic heteroaryl group, a 5 / 5-membered condensed heterocyclyl group, a 5 / 4-membered condensed heterocyclyl group, a 5 / 6-membered condensed heterocyclyl group, a 6 / 5-membered condensed heterocyclyl group, a 6 / 4-membered condensed heterocyclyl group, a 6 / 6-membered condensed heterocyclyl group, a 5 / 3-membered spiroheterocyclyl group, a 5 / 5-membered spiroheterocyclyl group, a 5 / 4-membered spiroheterocyclyl group, a 5 / 6-membered spiroheterocyclyl group, a 6 / 3-membered spiroheterocyclyl group, a 6 / 5-membered spiroheterocyclyl group, a 6 / 4-membered spiroheterocyclyl group, or a 6 / 6-membered spiroheterocyclyl group, where the 5-membered monocyclic heterocyclyl group is selected from the above. The heteroatoms in the krill group, 6-membered monocyclic heterocyclyl group, 5-membered monocyclic heteroaryl group, 6-membered monocyclic heteroaryl group, 5 / 5-membered condensed heterocyclyl group, 5 / 4-membered condensed heterocyclyl group, 5 / 6-membered condensed heterocyclyl group, 6 / 5-membered condensed heterocyclyl group, 6 / 4-membered condensed heterocyclyl group, 6 / 6-membered condensed heterocyclyl group, 5 / 3-membered spiroheterocyclyl group, 5 / 5-membered spiroheterocyclyl group, 5 / 4-membered spiroheterocyclyl group, 5 / 6-membered spiroheterocyclyl group, 6 / 3-membered spiroheterocyclyl group, 6 / 5-membered spiroheterocyclyl group, 6 / 4-membered spiroheterocyclyl group, and 6 / 6-membered spiroheterocyclyl group are each independently selected from N, and the number of heteroatoms is 1 to 4.

[0042] More preferably, ring A is selected from a 5-membered monocyclic heterocyclyl group, a 6-membered monocyclic heterocyclyl group, a 5-membered monocyclic heteroaryl group, a 6-membered monocyclic heteroaryl group, a 5 / 5-membered condensed heterocyclyl group, a 5 / 6-membered condensed heterocyclyl group, or a 5 / 3-membered spiroheterocyclyl group, where the heteroatoms in the 5-membered monocyclic heterocyclyl group, 6-membered monocyclic heterocyclyl group, 5-membered monocyclic heteroaryl group, 6-membered monocyclic heteroaryl group, 5 / 5-membered condensed heterocyclyl group, 5 / 6-membered condensed heterocyclyl group, and 5 / 3-membered spiroheterocyclyl group are each independently selected from N, and the number of heteroatoms is 1 to 3.

[0043] More preferably, ring A is selected from a 5-membered monocyclic heterocyclyl group or a 5-membered monocyclic heteroaryl group, and the heteroatoms in the 5-membered monocyclic heterocyclyl group and the 5-membered monocyclic heteroaryl group are selected from N, with the number of heteroatoms being 1 to 3.

[0044] More preferably, ring A has the following functional group: [ka] They are selected from among them.

[0045] More preferably, ring A has the following functional group: [ka] They are selected from among them.

[0046] In one preferred embodiment of the present invention, R 2 There are one, two, or three of them, and when they appear, each independently represents hydrogen, halogen, hydroxyl group, cyano group, amino group, nitro group, formyl group, oxo group, and C. 1~3 Alkyl alkyl group, C 1~3 Alkoxy group, -C 1~3 Alkyl-NH(C 1~3 Alkyl) or -C 1~3 Alkyl-N(C 1~3 Selected from alkyl)2, where the C 1~3 Alkyl alkyl group, C 1~3 Alkoxy group, -C 1~3 Alkyl-NH(C 1~3 Alkyl) and -C 1~3 Alkyl-N(C 1~3 Alkyl)2 may be optionally substituted with one or more hydroxyl groups or halogens. More preferably, R 2 There are one, two, or three of them, and when they appear, each is independently selected from hydrogen, halogen, hydroxyl group, cyano group, amino group, nitro group, formyl group, oxo group, methoxy group, methyl group, ethyl group, n-propyl group, or isopropyl group. More preferably, R 2 There are one or two of them, and when they appear, each is independently selected from hydrogen, halogen, hydroxyl group, cyano group, amino group, nitro group, methoxy group, or methyl group. More preferably, R 2 There are one or two of them, and when they appear, each is independently chosen from either a hydrogen or a methyl group.

[0047] In one preferred embodiment of the present invention, R 3 These are hydrogen, halogen, hydroxyl group, amino group, cyano group, and C 1~4 Alkyl alkyl group, C 1~4 Alkoxy group or C 3~6 Selected from cycloalkyl groups, where the C 1~4 Alkyl alkyl group, C 1~4 Alkoxy groups and C 3~6 Each cycloalkyl group may be optionally substituted with one or more hydroxyl groups or halogens. More preferably, R 3 This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, or methoxy group. More preferably, R 3 This is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, or cyclopropyl group. More preferably, R 3 The group is selected from hydrogen, F, Cl, Br, an amino group, a methyl group, an ethyl group, or a cyclopropyl group.

[0048] In one preferred embodiment of the present invention, ring B is C 4~12 Cycloalkenyl group, C 4~12 Heterocyclyl group, C 6~12 Aryl group, C 6~8 Aryl condensation C 4~6 Cycloalkyl groups, C 6~8 Aryl condensation C 4~6 Heterocyclyl group or C5~12 Selected from heteroaryl groups.

[0049] More preferably, ring B is C 6~10 Aryl group or C 5~10 Selected from heteroaryl groups.

[0050] More preferably, ring B is selected from a phenyl group or a pyridinyl group.

[0051] One preferred embodiment of the present invention, each R 4 If present, each independently comprises hydrogen, cyano group, halogen, amino group, nitro group, and C. 1~4 Alkyl alkyl group, C 1~4 Haloalkyl group, C 1~4 Hydroxyalkyl group, C 3~6 Cycloalkyl groups, C 3~6 Selected from a halocycloalkyl group or a 3-6 membered heterocyclyl group, where the C 1~4 Alkyl alkyl group, C 1~4 Haloalkyl group, C 1~4 Hydroxyalkyl group, C 3~6 Cycloalkyl groups, C 3~6 The halocycloalkyl group and the 3-6 membered heterocycline group may optionally be a halogen, hydroxyl group, amino group, or -SO2-C 1~4 w may be substituted with one or more substituents that are alkyl groups or oxo groups, where w is 0, 1, 2, or 3.

[0052] More preferably, each R 4 Each of these independently consists of hydrogen, a cyano group, a halogen, an amino group, a nitro group, and C. 1~4 Alkyl alkyl group, C 1~4 Haloalkyl group or C 1~4 Selected from hydroxyalkyl groups, where the C 1~4 Alkyl alkyl group, C 1~4 Haloalkyl and C 1~4 Each hydroxyalkyl group may be optionally substituted with one or more substituents that are halogens, hydroxyl groups, or amino groups, and w is 1, 2, or 3.

[0053] More preferably, each R 4 Each of these is independently selected from hydrogen, a cyano group, a halogen, an amino group, a nitro group, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group, where the methyl group, ethyl group, n-propyl group, and isopropyl group may each be optionally substituted with one or more substituents that are halogens or hydroxyl groups, and w is 1, 2, or 3.

[0054] More preferably, each R 4 Each of these is independently selected from hydrogen, halogen, amino group, methyl group, ethyl group, or isopropyl group, where the methyl group, ethyl group, and isopropyl group may each be optionally substituted with one or more substituents that are halogen or hydroxyl groups, and w is 1, 2, or 3.

[0055] More preferably, each R 4 Each of these is independently selected from hydrogen, halogen, amino group, methyl group, trifluoromethyl group, difluoromethyl group, monofluoromethyl group, -CF2CH2OH, -C(CH3)2OH, or -CF2CH3, and w is 1, 2, or 3.

[0056] The present invention also relates to a compound having the structure represented by formula (B), or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or We provide isotopic derivatives, [ka] In the formula, R 1 is -OR A , -N(R D )R B or R C Selected from, R 1 ga-OR A If that is the case, R A C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10 The aryl group, 3-10 membered heterocyclyl group, and 5-10 membered heteroaryl group can each have 1-3 identical or different R groups. a1 It may be replaced by, Each R a1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, nitro group, oxo group, formyl group, and C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group, -COC 1~6 Alkyl group, -CH2COC 1~6 Alkyl, -CH2CON(C 1~6 Alkyl)2,-CH2CONHC 1~6 Alkyl alkyl, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, C 3~10 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, R 1 ga-N(R D )R B If that is the case, R B C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C3~10 Cycloalkyl groups, C 6~10 The aryl group, 3-10 membered heterocyclyl group, and 5-10 membered heteroaryl group can each have 1-3 identical or different R groups. b1 It may be replaced by, Each R b1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, nitro group, oxo group, formyl group, and C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group, -COC 1~6 Alkyl group, -CH2COC 1~6 Alkyl, -CH2CON(C 1~6 Alkyl)2,-CH2CONHC 1~6 Alkyl alkyl, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, C 3~10 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, R D C is a group of hydrogen, halogen, hydroxyl group, cyano group, amino group, nitro group, oxo group, formyl group, C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group, -COC 1~6 Alkyl group, -CH2COC 1~6 Alkyl, -CH2CON(C 1~6 Alkyl)2,-CH2CONHC 1~6 Alkyl alkyl, -NHC 1~6 Alkyl or -N(C) 1~6 Selected from alkyl)2, R 1 R C If that is the case, R C C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C3~10 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~10 Cycloalkyl groups, C 6~10 The aryl group, 3-10 membered heterocyclyl group, and 5-10 membered heteroaryl group can each have 1-4 identical or different R groups. c1 It may be replaced by, Each R c1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, nitro group, oxo group, formyl group, methanesulfonyl group, and C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group, -COC 1~6 Alkyl group, -COC 3~6 Cycloalkyl groups, -CH2COC 1~6 Alkyl, -CH2CON(C 1~6 Alkyl)2,-CH2CONHC 1~6 Alkyl alkyl, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, C 3~10 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group, -COC 1~6 Alkyl group, -COC 3~6 Cycloalkyl groups, -CH2COC 1~6 Alkyl, -CH2CON(C 1~6 Alkyl)2,-CH2CONHC 1~6 Alkyl alkyl, -NHC 1~6 Alkyl, -N(C 1~6Alkyl)2, C 3~10 Cycloalkyl groups, C 6~10 The aryl group, 3-10 membered heterocyclyl group, and 5-10 membered heteroaryl group can all optionally contain deuterium, a hydroxyl group, a cyano group, or C. 1~3 Alkyl alkyl group, C 1~3 It may be substituted with one or more substituents selected from alkoxy groups or halogens. R 2 There are one or two of them, and when they appear, each independently represents hydrogen, halogen, hydroxyl group, cyano group, amino group, nitro group, formyl group, oxo group, and C. 1~6 Alkyl alkyl group, C 1~6 Alkoxy group, Halo C 1~6 Alkyl or halo C 1~6 Selected from alkoxy groups, R 3 These are hydrogen, halogen, hydroxyl group, amino group, cyano group, and C 1~6 Alkyl alkyl group, C 1~6 Alkoxy group, C 3~6 Selected from a cycloalkyl group or a 3-6 membered heterocyclyl group, where the C 1~6 Alkyl alkyl group, C 1~6 Alkoxy group, C 3~6 The cycloalkyl group and the 3-6 membered heterocyclyl group may each be optionally substituted with one or more hydroxyl groups or halogens. Ring B is C 4~12 Cycloalkyl groups, C 4~12 Cycloalkenyl group, C 4~12 Heterocyclyl group, C 6~12 Aryl group, C 5~12 Heteroaryl group, C 6~12 Aryl condensation C 4~12 Cycloalkyl groups, C 6~12 Aryl condensation C 4~12 Heterocyclyl group or C 6~12 Aryl condensation C 4~12 Selected from cycloalkenyl groups, Each R 4 If present, each independently comprises hydrogen, cyano group, halogen, amino group, hydroxyl group, oxo group, nitro group, and C. 1~6 Alkyl alkyl group, C2~6 An alkenyl group, C 2~6 An alkynyl group, C 1~6 A haloalkyl group, C 1~6 A hydroxyalkyl group, C 1~6 An alkoxy group, -C 0~6 An alkyl-NH-C 1~6 An alkyl group, -C 0~6 An alkyl-N(C 1~6 An alkyl)(C 1~6 An alkyl), C 3~6 A cycloalkyl group, C 3~6 Selected from a halocycloalkyl group or a 3- to 6-membered heterocyclyl group, wherein the C 1~6 An alkyl group, C 2~6 An alkenyl group, C 2~6 An alkynyl group, C 1~6 A haloalkyl group, C 1~6 A hydroxyalkyl group, C 1~6 An alkoxy group, -C 0~6 An alkyl-NH-C 1~6 An alkyl group, -C 0~6 An alkyl-N(C 1~6 An alkyl)(C 1~6 An alkyl), C 3~6 A cycloalkyl group, C 3~6 The halocycloalkyl group and the 3- to 6-membered heterocyclyl group may each optionally be substituted by one or more of the substituents that are a halogen, a hydroxy group, an amino group, a -SO2-C 1~4 An alkyl group or an oxo group, w is 0, 1, 2, 3 or 4, Unless otherwise specified, the heteroatoms in the above heteroaryl group and heterocyclyl group are each independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0057] In one preferred embodiment of the present invention, R 1 Is -O-R A And R A Is, C 1~6 An alkyl group, C 3~10 A cycloalkyl group, C 6~10 Selected from an aryl group, a 3- to 10-membered heterocyclyl group or a 5- to 10-membered heteroaryl group, wherein the C1~6 Alkyl alkyl group, C 3~10 Cycloalkyl groups, C 6~10 The aryl group, 3-10 membered heterocyclyl group, and 5-10 membered heteroaryl group can each have 1-3 identical or different R groups. a1 It may be replaced by, Each R a1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, nitro group, oxo group, formyl group, and C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group, -COC 1~6 Alkyl group, -CH2COC 1~6 Alkyl, -CH2CON(C 1~6 Alkyl)2,-CH2CONHC 1~6 Alkyl alkyl, -NHC 1~6 Alkyl or -N(C) 1~6 Selected from alkyl(2).

[0058] More preferably, R A C 3~6 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-6 membered heterocyclyl group, or a 5-6 membered heteroaryl group, where the C 3~6 Cycloalkyl groups, C 6~10 The aryl group, 3-6 membered heterocyclyl group, and 5-6 membered heteroaryl group can each have 1-3 identical or different R groups. a1 It may be replaced by, Each R a1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, oxo group, formyl group, and C 1~6 alkyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group or -COC 1~6 Selected from alkyl groups.

[0059] More preferably, R AThe group is selected from a 5-6 membered heterocyclyl group or a 5-6 membered heteroaryl group, where the 5-6 membered heterocyclyl group and the 5-6 membered heteroaryl group are each arbitrarily selected from 1 to 3 identical or different R groups. a1 It may be replaced by, Each R a1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, oxo group, formyl group, and C 1~4 alkyl group, -OC 1~4 Alkyl, -SC 1~4 Alkyl group or -COC 1~4 Selected from alkyl groups.

[0060] More preferably, R A R is selected from a 5-6 membered heterocyclyl group, where the 5-6 membered heterocyclyl group is optionally 1-2 of the same or different R a1 It may be replaced by, Each R a1 If present, each of these groups is independently selected from halogen, oxo group, formyl group, acetyl group, methyl group, ethyl group, n-propyl group, isopropyl group, or methoxy group.

[0061] More preferably, R A R is selected from a 5-6 member monocyclic heterocyclyl group, where the 5-6 member monocyclic heterocyclyl group is optionally 1-2 of the same or different R groups. a1 It may be substituted by, and each heteroatom in the 5-6 membered monocyclic heterocyclyl group is independently selected from O, N, or S, and the number of heteroatoms is 1. Each R a1 If present, each of these groups is independently selected from halogen, oxo group, formyl group, acetyl group, methyl group, ethyl group, n-propyl group, isopropyl group, or methoxy group.

[0062] More preferably, R Ais selected from a tetrahydrofuryl group, a tetrahydrothienyl group, a pyrrolidinyl group, a piperidinyl group, a tetrahydropyranyl group or a tetrahydrothiopyranyl group, and the tetrahydrofuryl group, the tetrahydrothienyl group, the pyrrolidinyl group, the piperidinyl group, the tetrahydropyranyl group and the tetrahydrothiopyranyl group are each optionally substituted by one or two same or different R a1 and may be substituted by each R a1 , when present, is independently selected from halogen, an oxo group, a formyl group, an acetyl group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group or a methoxy group.

[0063] More preferably, R A is the following functional group:

Chemical formula

[0064] In one preferred embodiment of the present invention, R 1 is -N(R D )R B , R B is selected from a C 1~6 alkyl group, a C 3~10 cycloalkyl group, a C 6~10 aryl group, a 3- to 10-membered heterocyclyl group or a 5- to 10-membered heteroaryl group, wherein the C 1~6 alkyl group, the C 3~10 cycloalkyl group, the C 6~10 aryl group, the 3- to 10-membered heterocyclyl group and the 5- to 10-membered heteroaryl group may each be optionally substituted by one to three same or different R b1 and each R b1 , when present, is independently selected from halogen, a hydroxy group, a cyano group, an amino group, a nitro group, an oxo group, a formyl group, a C 1~6 alkyl group, -OC 1~6 alkyl group, -SC 1~6 alkyl group or -COC 1~6 alkyl group.

[0065] More preferably, R B C 1~6 Selected from alkyl groups, 3-10 membered heterocyclyl groups, or 5-10 membered heteroaryl groups, where the C 1~6 Alkyl groups, 3-10 membered heterocyclyl groups, and 5-10 membered heteroaryl groups may each have 1-3 identical or different R groups. b1 It may be replaced by, Each R b1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, nitro group, oxo group, formyl group, and C 1~6 alkyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group or -COC 1~6 Selected from alkyl groups.

[0066] More preferably, R B C 1~6 Selected from alkyl groups or 5-6 membered monocyclic heterocyclyl groups, where the C 1~6 The alkyl group and the 5-6 membered monocyclic heterocyclyl group may each have 1-2 identical or different R groups. b1 It may be substituted by, and each heteroatom in the 5-6 membered monocyclic heterocyclyl group is independently selected from O, N, or S, and the number of heteroatoms is 1. Each R b1 If present, each is independently a halogen, an oxo group, a formyl group, and C 1~4 alkyl group, -OC 1~4 Alkyl group or -COC 1~4 Selected from alkyl groups.

[0067] More preferably, R BR is selected from methyl group, ethyl group, n-propyl group, isopropyl group, oxetanyl group, tetrahydrofuryl group, tetrahydrothienyl group, pyrrolidinyl group, piperidinyl group, tetrahydropyranyl group, or tetrahydrothiopyranyl group, where the methyl group, ethyl group, n-propyl group, isopropyl group, oxetanyl group, tetrahydrofuryl group, tetrahydrothienyl group, pyrrolidinyl group, piperidinyl group, tetrahydropyranyl group, and tetrahydrothiopyranyl group are each arbitrarily selected from 1 to 2 of the same or different R b1 It may be replaced by, Each R b1 If present, each of these groups is independently selected from an oxo group, a formyl group, an acetyl group, a methyl group, an ethyl group, a methoxy group, or an ethoxy group.

[0068] More preferably, R B The following functional groups: [ka] They are selected from among them.

[0069] R D is hydrogen, C 1~6 Alkyl alkyl group or -OC 1~6 Selected from alkyl groups, more preferably R D is hydrogen or C 1~3 Selected from alkyl groups, more preferably R D is selected from hydrogen or a methyl group, most preferably R D It is selected from hydrogen.

[0070] In one preferred embodiment of the present invention, R 1 R C And R C C 3~10 Cycloalkyl groups, C 6~10 Selected from an aryl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 3~10 Cycloalkyl groups, C 6~10The aryl group, 3-10 membered heterocyclyl group, and 5-10 membered heteroaryl group can each have 1-4 identical or different R groups. c1 It may be replaced by, Each R c1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, nitro group, oxo group, formyl group, methanesulfonyl group, and C 1~6 alkyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group, -COC 1~6 Alkyl group, -COC 3~6 Cycloalkyl groups, -CH2COC 1~6 Alkyl, -CH2CON(C 1~6 Alkyl)2,-CH2CONHC 1~6 Alkyl alkyl, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, C 3~10 Selected from a cycloalkyl group or a 3-10 membered heterocyclyl group, where the C 1~6 alkyl group, -OC 1~6 Alkyl, -SC 1~6 Alkyl group, -COC 1~6 Alkyl group, -COC 3~6 Cycloalkyl groups, -CH2COC 1~6 Alkyl, -CH2CON(C 1~6 Alkyl)2,-CH2CONHC 1~6 Alkyl alkyl, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, C 3~10 The cycloalkyl group and the 3-10 membered heterocyclyl group may optionally be deuterium, a hydroxyl group, a cyano group, or C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with one or more substituents selected from alkoxy groups or halogens.

[0071] More preferably, R C C 3~10 Selected from a cycloalkyl group, a 3-10 membered heterocyclyl group, or a 5-10 membered heteroaryl group, where the C 3~10The cycloalkyl group, 3-10 membered heterocyclyl group, and 5-10 membered heteroaryl group may each have 1-4 identical or different R groups. c1 It may be replaced by, Each R c1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, nitro group, oxo group, formyl group, methanesulfonyl group, and C 1~4 alkyl group, -OC 1~4 Alkyl, -SC 1~4 Alkyl group, -COC 1~4 Alkyl group, -COC 3~6 Cycloalkyl groups, -CH2COC 1~4 Alkyl, -CH2CON(C 1~4 Alkyl)2,-CH2CONHC 1~4 Alkyl alkyl group, C 3~6 Selected from a cycloalkyl group or a 3-6 membered heterocyclyl group, where the C 1~4 alkyl group, -OC 1~4 Alkyl, -SC 1~4 Alkyl group, -COC 1~4 Alkyl group, -COC 3~6 Cycloalkyl groups, -CH2COC 1~4 Alkyl, -CH2CON(C 1~4 Alkyl)2,-CH2CONHC 1~4 Alkyl alkyl group, C 3~6 The cycloalkyl group and the 3-6 membered heterocyclyl group may optionally contain deuterium, a hydroxyl group, a cyano group, or C 1~3 Alkyl alkyl group, C 1~3 It may be substituted with one or more substituents selected from alkoxy groups or halogens.

[0072] More preferably, R C The group is selected from a 3-10 membered heterocyclyl group or a 5-10 membered heteroaryl group, where the 3-10 membered heterocyclyl group and the 5-10 membered heteroaryl group each have 1 to 4 identical or different R groups. c1 It may be replaced by, Each R c1If present, each is independently a halogen, hydroxyl group, cyano group, amino group, oxo group, formyl group, methanesulfonyl group, and C 1~4 alkyl group, -OC 1~4 Alkyl group, -COC 1~4 Alkyl group, -COC 3~6 Cycloalkyl groups, -CH2CON(C 1~4 Selected from alkyl) 2 or 3-6 member heterocyclyl groups, where the C 1~4 alkyl group, -OC 1~4 Alkyl group, -COC 1~4 Alkyl group, -COC 3~6 Cycloalkyl groups, -CH2CON(C 1~4 The alkyl)2 and 3-6 membered heterocyclyl groups may each be optionally substituted with one or more substituents selected from deuterium, hydroxyl, cyano, methyl, methoxy, or halogen.

[0073] More preferably, R C The group is selected from a 5-6 member monocyclic heterocyclyl group, a 6-10 member spiroheterocyclyl group, a 6-8 member bridged heterocyclyl group, an 8-10 member condensed heterocyclyl group, or a 5-6 member monocyclic heteroaryl group, where the 5-6 member monocyclic heterocyclyl group, the 6-10 member spiroheterocyclyl group, the 6-8 member bridged heterocyclyl group, the 8-10 member condensed heterocyclyl group, and the 5-6 member monocyclic heteroaryl group are each arbitrarily selected from 1 to 4 identical or different R groups. c1 It may be replaced by, Each R c1If present, each of these groups is independently selected from halogen, hydroxyl group, cyano group, amino group, oxo group, formyl group, acetyl group, propionyl group, methanesulfonyl group, methoxy group, ethoxy group, methyl group, ethyl group, n-propyl group, isopropyl group, -CH2CON(CH3)2, -CO-cyclopropyl group, -CO-cyclobutyl group, 4-membered heterocyclyl group, 5-membered heterocyclyl group, or 6-membered heterocyclyl group, where the acetyl group, propionyl group, methanesulfonyl group, methoxy group, ethoxy group, methyl group, ethyl group, n-propyl group, isopropyl group, -CH2CON(CH3)2, -CO-cyclopropyl group, -CO-cyclobutyl group, 4-membered heterocyclyl group, 5-membered heterocyclyl group, and 6-membered heterocyclyl group may be optionally substituted with one or more substituents selected from deuterium, hydroxyl group, cyano group, methyl group, methoxy group, or halogen.

[0074] More preferably, R C The group is selected from a 6-membered monocyclic heterocyclyl group, a 4-membered / 6-membered spiroheterocyclyl group, a 4-membered / 4-membered spiroheterocyclyl group, a 6-membered / 5-membered condensed heterocyclyl group, a 7-membered bridged heterocyclyl group, or a 6-membered monocyclic heteroaryl group, where the 6-membered monocyclic heterocyclyl group, the 4-membered / 6-membered spiroheterocyclyl group, the 4-membered / 4-membered spiroheterocyclyl group, the 6-membered / 4-membered condensed heterocyclyl group, the 7-membered bridged heterocyclyl group, and the 6-membered monocyclic heteroaryl group are each arbitrarily selected from 1 to 4 identical or different R groups. c1 It may be replaced by, Each R c1If present, each of these groups is independently selected from halogen, hydroxyl group, cyano group, amino group, oxo group, formyl group, acetyl group, propionyl group, methanesulfonyl group, methoxy group, ethoxy group, methyl group, ethyl group, n-propyl group, isopropyl group, -CH2CON(CH3)2, -CO-cyclopropyl group, 4-membered heterocyclyl group, 5-membered heterocyclyl group, or 6-membered heterocyclyl group, where the acetyl group, propionyl group, methanesulfonyl group, methoxy group, ethoxy group, methyl group, ethyl group, n-propyl group, isopropyl group, -CH2CON(CH3)2, -CO-cyclopropyl group, 4-membered heterocyclyl group, 5-membered heterocyclyl group, and 6-membered heterocyclyl group may be optionally substituted with one or more substituents selected from deuterium, hydroxyl group, cyano group, methyl group, methoxy group, or halogen.

[0075] More preferably, R C teeth, [ka] Selected from, the R C Each of these can be any 1 to 4 identical or different R c1 It may be replaced by, Each R c1 If present, each independently includes F, Cl, Br, hydroxyl group, cyano group, amino group, oxo group, methanesulfonyl group, acetyl group, -COCH2CH3, -COCH2OH, -COCH2CN, -CH(OH)(CH3)2, hydroxymethyl group, hydroxyethyl group, -CH2OCH3, -CH2CH2OCH3, methoxy group, methyl group, CD3, ethyl group, isopropyl group, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, monofluoroethyl group, difluoroethyl group, trifluoroethyl group, [ka] Selected from -CH2CON(CH3)2 or a morpholinyl group.

[0076] More preferably, optionally Rc1 R may be substituted by C The following functional groups: [ka] They are selected from among them.

[0077] In one preferred embodiment of the present invention, R 2 There are one or two of these groups, and when they appear, each is independently selected from hydrogen, halogen, hydroxyl group, cyano group, amino group, nitro group, formyl group, oxo group, methoxy group, methyl group, ethyl group, n-propyl group, or isopropyl group.

[0078] More preferably, R 2 There are one or two of them, and when they appear, each is independently selected from hydrogen, halogen, hydroxyl group, cyano group, amino group, nitro group, methoxy group, or methyl group.

[0079] More preferably, R 2 There are one or two of them, and when they appear, each is independently chosen from either a hydrogen or a methyl group.

[0080] More preferably, R 2 It is hydrogen.

[0081] In one preferred embodiment of the present invention, R 3 The group is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, or methoxy group.

[0082] More preferably, R 3 The group is selected from hydrogen, halogen, hydroxyl group, amino group, cyano group, methyl group, ethyl group, n-propyl group, isopropyl group, or cyclopropyl group.

[0083] More preferably, R 3The group is selected from hydrogen, F, Cl, Br, an amino group, a methyl group, an ethyl group, or a cyclopropyl group.

[0084] In one preferred embodiment of the present invention, ring B is C 4~12 Cycloalkenyl group, 4-12 membered heterocyclyl group, C 6~12 Aryl group, C 6~8 Aryl condensation C 4~6 Cycloalkyl groups, C 6~8 Selected from aryl condensed 4-6 membered heterocyclyl groups or 5-12 membered heteroaryl groups.

[0085] More preferably, ring B is C 6~10 Aryl group, 5-10 membered heteroaryl group, or C 6~8 Selected from aryl condensed 4-6 member heterocyclyl groups.

[0086] More preferably, ring B is selected from a phenyl group, a pyridinyl group, or a benzotetrahydrofuryl group.

[0087] One preferred embodiment of the present invention, each R 4 If present, each independently comprises hydrogen, cyano group, halogen, amino group, nitro group, and C. 1~4 Alkyl alkyl group, C 1~4 Haloalkyl group, C 1~4 Hydroxyalkyl group, C 3~6 Cycloalkyl groups, C 3~6 Selected from a halocycloalkyl group or a 3-6 membered heterocyclyl group, where the C 1~4 Alkyl alkyl group, C 1~4 Haloalkyl group, C 1~4 Hydroxyalkyl group, C 3~6 Cycloalkyl groups, C 3~6 The halocycloalkyl group and the 3-6 membered heterocycline group may optionally be a halogen, hydroxyl group, amino group, or -SO2-C 1~4 w may be substituted with one or more substituents that are alkyl groups or oxo groups, where w is 0, 1, 2, or 3.

[0088] More preferably, each R 4 Each of these independently consists of hydrogen, a cyano group, a halogen, an amino group, a nitro group, and C. 1~4 Alkyl alkyl group, C 1~4 Haloalkyl group or C 1~4 Selected from hydroxyalkyl groups, where the C 1~4 Alkyl alkyl group, C 1~4 Haloalkyl and C 1~4 Each hydroxyalkyl group may be optionally substituted with one or more substituents that are halogens, hydroxyl groups, or amino groups, and w is 1, 2, or 3.

[0089] More preferably, each R 4 Each of these is independently selected from hydrogen, a cyano group, a halogen, an amino group, a nitro group, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group, where the methyl group, ethyl group, n-propyl group, and isopropyl group may each be optionally substituted with one or more substituents that are halogens or hydroxyl groups, and w is 1, 2, or 3.

[0090] More preferably, each R 4 Each of these is independently selected from hydrogen, halogen, amino group, cyano group, methyl group, ethyl group, or isopropyl group, where the methyl group, ethyl group, and isopropyl group may each be optionally substituted with one or more substituents that are halogen or hydroxyl groups, and w is 1, 2, or 3.

[0091] More preferably, each R 4 Each of these is independently selected from hydrogen, fluorine, amino group, cyano group, methyl group, trifluoromethyl group, difluoromethyl group, monofluoromethyl group, -CF2CH2OH, -C(CH3)2OH, -CF2CH3, or -CH2CHF2, and w is 1, 2, or 3.

[0092] The present invention relates to a compound having the structure represented by formula (C), or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates orWe provide isotopic derivatives, [ka] Each substituent in formula (C) is defined as described in formula (B).

[0093] The present invention also relates to a compound having the structure represented by formula (D), or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or We provide isotopic derivatives, [ka] In the formula, R 1 , R 4 w is defined as described in formulas (A), (A'), (I), (II), (III), (IV), (B), or (C).

[0094] Preferably, each R 4 If present, each independently comprises a cyano group, halogen, amino group, and C 1~6 Alkyl alkyl group or C 1~6 Selected from haloalkyl groups, where C 1~6 Alkyl and C 1~6 Each haloalkyl group may be optionally substituted with one or more hydroxyl groups, and w is 1 or 2. R 1 is -OR A , -N(R D )R B or R C Selected from, R 1 ga-OR A If that is the case, R A R is selected from 3-10 membered heterocyclyl groups, where the 3-10 membered heterocyclyl groups are optionally 1-3 of the same or different R groups. a1 It may be replaced by, Each R a1 If they exist, each is independent of C 1~6 Alkyl group or -COC 1~6 Selected from alkyl groups, R1 ga-N(R D )R B If that is the case, R B C 1~6 Selected from alkyl groups or 3-10 membered heterocyclyl groups, where the C 1~6 The alkyl group and the 3-10 membered heterocyclyl group may each have 1-3 identical or different R groups. b1 It may be replaced by, Each R b1 If present, each is independently of -OC 1~6 Selected from alkyl groups, R D It was selected from hydrogen, R 1 R C If that is the case, R C The group is selected from a 3-10 membered heterocyclyl group or a 5-10 membered heteroaryl group, where the 3-10 membered heterocyclyl group and the 5-10 membered heteroaryl group each have 1 to 4 identical or different R groups. c1 It may be replaced by, Each R c1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, methanesulfonyl group, and C 1~6 alkyl group, -OC 1~6 Alkyl group, -COC 1~6 Alkyl group, -COC 3~6 Cycloalkyl groups, -CH2CON(C 1~6 A group selected from an alkyl 2 or 3-10 member heterocyclyl group, where the C 1~6 alkyl group, -OC 1~6 Alkyl group, -COC 1~6 Alkyl group, -COC 3~6 Cycloalkyl groups, -CH2CON(C 1~6 The alkyl) 2 and 3-10 member heterocyclyl groups can optionally contain deuterium, a hydroxyl group, a cyano group, or C 1~3 It may be substituted with one or more substituents selected from alkoxy groups or halogens.

[0095] Unless otherwise specified, the heteroatoms in the heteroaryl and heterocyclyl groups described above are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4.

[0096] In one preferred embodiment of the present invention, R 1 is -OR A And R A The group is selected from 3-6 membered heterocyclyl groups, where the 3-6 membered heterocyclyl groups are optionally 1-3 identical or different R groups. a1 It may be replaced by, Each R a1 If they exist, each is independent of C 1~6 Alkyl group or -COC 1~6 Selected from alkyl groups.

[0097] More preferably, R A R is selected from a 5-6 membered heterocyclyl group, where the 5-6 membered heterocyclyl group is optionally 1-2 of the same or different R a1 It may be replaced by, Each R a1 If present, each of these groups is independently selected from acetyl, methyl, ethyl, n-propyl, or isopropyl groups.

[0098] More preferably, R A R is selected from a 5-6 member monocyclic heterocyclyl group, where the 5-6 member monocyclic heterocyclyl group is optionally 1-2 of the same or different R groups. a1 It may be substituted by, and each heteroatom in the 5-6 membered monocyclic heterocyclyl group is independently selected from O, N, or S, and the number of heteroatoms is 1. Each R a1 If present, each of these groups is independently selected from an acetyl group, a methyl group, or an ethyl group.

[0099] More preferably, R AThe group is selected from a tetrahydrofuryl group, a tetrahydrothienyl group, a pyrrolidinyl group, a piperidinyl group, a tetrahydropyranyl group, or a tetrahydrothiopyranyl group, and each of the tetrahydrofuryl group, tetrahydrothienyl group, pyrrolidinyl group, piperidinyl group, tetrahydropyranyl group, and tetrahydrothiopyranyl group can be any one to two of the same or different R groups. a1 It may be replaced by, Each R a1 If present, each of these groups is independently selected from an acetyl group, a methyl group, or an ethyl group.

[0100] More preferably, R A The following functional groups: [ka] They are selected from among them.

[0101] In one preferred embodiment of the present invention, R 1 is -N(R D )R B And R B C 1~6 Selected from alkyl groups or 3-6 membered monocyclic heterocyclyl groups, where the C 1~6 The alkyl group and the 3-6 membered monocyclic heterocyclyl group may each have 1-2 identical or different R groups. b1 It may be substituted by, and each heteroatom in the 3-6 membered monocyclic heterocyclyl group is independently selected from O, N, or S, and the number of heteroatoms is 1. Each R b1 If present, each is independently of -OC 1~4 Selected from alkyl groups.

[0102] More preferably, R BR is selected from methyl group, ethyl group, n-propyl group, isopropyl group, oxetanyl group, tetrahydrofuryl group, tetrahydrothienyl group, pyrrolidinyl group, piperidinyl group, tetrahydropyranyl group, or tetrahydrothiopyranyl group, where the methyl group, ethyl group, n-propyl group, isopropyl group, oxetanyl group, tetrahydrofuryl group, tetrahydrothienyl group, pyrrolidinyl group, piperidinyl group, tetrahydropyranyl group, and tetrahydrothiopyranyl group are each arbitrarily selected from 1 to 2 of the same or different R b1 It may be replaced by, Each R b1 If present, each is independently selected from either a methoxy group or an ethoxy group.

[0103] More preferably, R B The following functional groups: [ka] They are selected from among them.

[0104] In one preferred embodiment of the present invention, R 1 R C And R C The group is selected from a 3-10 membered heterocyclyl group or a 5-10 membered heteroaryl group, where the 3-10 membered heterocyclyl group and the 5-10 membered heteroaryl group each have 1 to 4 identical or different R groups. c1 It may be replaced by, Each R c1 If present, each is independently a halogen, hydroxyl group, cyano group, amino group, methanesulfonyl group, and C 1~4 alkyl group, -OC 1~4 Alkyl group, -COC 1~4 Alkyl group, -COC 3~6 Cycloalkyl groups, -CH2CON(C 1~4 Selected from alkyl) 2 or 3-6 member heterocyclyl groups, where the C 1~4 alkyl group, -OC 1~4 Alkyl group, -COC 1~4 Alkyl group, -COC 3~6Cycloalkyl groups, -CH2CON(C 1~4 The alkyl)2 and 3-6 membered heterocyclyl groups may each be optionally substituted with one or more substituents selected from deuterium, hydroxyl, cyano, methoxy, or halogen.

[0105] More preferably, R C The group is selected from a 5-6 member monocyclic heterocyclyl group, a 6-10 member spiroheterocyclyl group, a 6-8 member bridged heterocyclyl group, an 8-10 member condensed heterocyclyl group, or a 5-6 member monocyclic heteroaryl group, where the 5-6 member monocyclic heterocyclyl group, the 6-10 member spiroheterocyclyl group, the 6-8 member bridged heterocyclyl group, the 8-10 member condensed heterocyclyl group, and the 5-6 member monocyclic heteroaryl group are each arbitrarily selected from 1 to 4 identical or different R groups. c1 It may be replaced by, Each R c1 If present, each of these groups is independently selected from halogen, hydroxyl group, cyano group, amino group, methanesulfonyl group, methyl group, ethyl group, n-propyl group, isopropyl group, methoxy group, ethoxy group, acetyl group, propionyl group, -CO-cyclopropyl group, -CO-cyclobutyl group, -CH2CON(CH3)2, 4-membered heterocyclyl group, 5-membered heterocyclyl group, or 6-membered heterocyclyl group, where the methanesulfonyl group, methyl group, ethyl group, n-propyl group, isopropyl group, methoxy group, ethoxy group, acetyl group, propionyl group, -CO-cyclopropyl group, -CO-cyclobutyl group, -CH2CON(CH3)2, 4-membered heterocyclyl group, 5-membered heterocyclyl group, and 6-membered heterocyclyl group may be optionally substituted with one or more substituents selected from deuterium, hydroxyl group, cyano group, methoxy group, or halogen.

[0106] More preferably, R CThe group is selected from a 6-membered monocyclic heterocyclyl group, a 4-membered / 6-membered spiroheterocyclyl group, a 4-membered / 4-membered spiroheterocyclyl group, a 7-membered bridged heterocyclyl group, a 6-membered / 5-membered condensed heterocyclyl group, or a 6-membered monocyclic heteroaryl group, where the 6-membered monocyclic heterocyclyl group, the 4-membered / 6-membered spiroheterocyclyl group, the 4-membered / 4-membered spiroheterocyclyl group, the 7-membered bridged heterocyclyl group, the 6-membered / 4-membered condensed heterocyclyl group, and the 6-membered monocyclic heteroaryl group are each arbitrarily selected from 1 to 4 identical or different R groups. c1 It may be replaced by, Each R c1 If present, each of these groups is independently selected from halogen, hydroxyl group, cyano group, amino group, methanesulfonyl group, methyl group, ethyl group, n-propyl group, isopropyl group, methoxy group, ethoxy group, acetyl group, propionyl group, -CO-cyclopropyl group, -CH2CON(CH3)2, 4-membered heterocyclyl group, 5-membered heterocyclyl group, or 6-membered heterocyclyl group, where the methanesulfonyl group, methyl group, ethyl group, n-propyl group, isopropyl group, methoxy group, ethoxy group, acetyl group, propionyl group, -CO-cyclopropyl group, 4-membered heterocyclyl group, 5-membered heterocyclyl group, and 6-membered heterocyclyl group may be optionally substituted with one or more substituents selected from deuterium, hydroxyl group, cyano group, methoxy group, or halogen.

[0107] More preferably, R C teeth, [ka] Selected from, the R C Each of these can be any 1 to 4 identical or different R c1 It may be replaced by, Each R c1If present, each independently includes F, Cl, Br, hydroxyl group, cyano group, amino group, methanesulfonyl group, methyl group, ethyl group, isopropyl group, CD3, hydroxymethyl group, hydroxyethyl group (e.g., 2-hydroxyethyl group), -CH(OH)(CH3)2, -CH2OCH3, -CH2CH2OCH3, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, monofluoroethyl group (e.g., 2-fluoroethyl group), difluoroethyl group (e.g., 2,2-difluoroethyl group), trifluoroethyl group (e.g., 2,2,2-trifluoroethyl group), methoxy group, acetyl group, -COCH2CH3, -COCH2OH, -COCH2CN, [ka] -CH2CON(CH3)2, oxetanyl group (for example, [ka] ) or selected from a morpholinyl group (e.g., morpholin-4-yl).

[0108] More preferably, optionally R c1 R may be substituted by C The following functional groups: [ka] They are selected from among them.

[0109] One preferred embodiment of the present invention, each R 4 If present, each independently comprises a cyano group, halogen, amino group, and C 1~4 Alkyl alkyl group or C 1~4 Selected from haloalkyl groups, where C 1~4 Alkyl and C 1~4 Each haloalkyl group may be optionally substituted with one or more hydroxyl groups, and w is 1 or 2.

[0110] More preferably, each R 4Each of the following groups is independently selected from cyano group, fluorine, amino group, methyl group, trifluoromethyl group, difluoromethyl group, monofluoromethyl group, -CF2CH2OH, -CF2C(CH3)2OH, -CF2CH3, or -CH2CHF2, and w is either 1 or 2.

[0111] The present invention relates to a compound having the structure represented by formula (E), or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or We provide isotopic derivatives, [ka] Each substituent in formula (E) is defined as described in formula (D).

[0112] The present invention also relates to compounds having a structure represented by formula (F) or formula (F'), or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or We provide isotopic derivatives, [ka] In the formula, R c1 , R 4 w is defined as described in formula (D) or formula (E), and v is 0 or 1, and if v is 1, R c1 It is preferable that it is bonded to the N atom.

[0113] Preferably, R c1 This includes methyl group, ethyl group, isopropyl group, CD3, hydroxymethyl group, hydroxyethyl group (e.g., 2-hydroxyethyl group), monofluoromethyl group, difluoromethyl group, trifluoromethyl group, monofluoroethyl group (e.g., 2-fluoroethyl group), difluoroethyl group (e.g., 2,2-difluoroethyl group), trifluoroethyl group (e.g., 2,2,2-trifluoroethyl group), -CH2CON(CH3)2 or oxetanyl group (e.g., [ka] ) will be selected from.

[0114] more, [ka] The following functional groups: [ka] They are selected from among them.

[0115] The present invention relates to a compound having a structure represented by formula (G) or formula (G'), or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or We provide isotopic derivatives, [ka] In the formula, R c1 , R 4 w is defined as described in formula (D) or formula (E), and v is 0 or 1, and if v is 1, R c1 It is preferable that it is bonded to the N atom.

[0116] Preferably, R c1 The group is selected from methyl group, ethyl group, isopropyl group, hydroxymethyl group, hydroxyethyl group (e.g., 2-hydroxyethyl group), -CH2OCH3, -CH2CH2OCH3, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, monofluoroethyl group (e.g., 2-fluoroethyl group), difluoroethyl group (e.g., 2,2-difluoroethyl group), trifluoroethyl group (e.g., 2,2,2-trifluoroethyl group), or -CH2CON(CH3)2.

[0117] more, [ka] The following functional groups: [ka] They are selected from among them.

[0118] Preferably, the present invention relates to a compound having the following structure, or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or We provide isotopic derivatives. [ka] [ka] [ka] [ka] [ka]

[0119] Preferably, the present invention relates to a compound having the following structure, or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or We provide isotopic derivatives. [ka] [ka] [ka] [ka] [ka] [ka]

[0120] The object of the present invention is also the compound of the present invention, orIts stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or The invention includes providing a method for producing an intermediate of an isotopic derivative, wherein the intermediate is represented by formula (V), [ka] In the formula, R 2 , R 3 The rings A, X, Y, and Z are defined as described in formula (A), formula (I), or formula (II), R 5 The group is selected from halogen, hydroxyl group, -O-methanesulfonyl group, -Op-toluenesulfonyl group, or -O-trifluoromethanesulfonyl group, and is preferably chlorine or a hydroxyl group.

[0121] R 6 The halogen is selected from halogens, preferably bromine or iodine.

[0122] The object of the present invention is also the compound of the present invention, or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or The invention includes providing a method for producing an intermediate of an isotopic derivative, wherein the intermediate is as shown in formula (VI), [ka] In the formula, R 2 , R 3 , R 4 , w, ring A, X, Y, Z are defined as described in formula (A) or formula (I), R 6 The halogen is selected from halogens, preferably bromine or iodine.

[0123] Furthermore, the compound of the present invention, or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or The isotopic derivative has the structure shown in formula (VII), [ka] In the formula, R 2 , R 3 , R 4 The rings w, A, X, Y, and Z are defined as shown in equation (II), R 6 The halogen is selected from halogens, preferably bromine or iodine.

[0124] Furthermore, the compound of the present invention, or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or The isotopic derivative has the structure shown in formula (VIII), [ka] In the formula, R 2 , R 3 , R 4 w, rings A, Y, and Z are defined as shown in equation (III), R 6 The halogen is selected from halogens, preferably bromine or iodine.

[0125] Furthermore, the compound of the present invention, or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or The isotopic derivative has the structure shown in formula (IX), [ka] In the formula, R 2 , R 3 , R 4 w, rings A, Y, and Z are defined as shown in equation (IV), R 6 The halogen is selected from halogens, preferably bromine or iodine.

[0126] The present invention also relates to the compounds of the present invention. or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or The present invention provides a pharmaceutical composition comprising an isotopic derivative.

[0127] The present invention also relates to the compounds of the present invention. orIts stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or The present invention provides a pharmaceutical composition comprising an isotopic derivative and a pharmaceutically acceptable additive.

[0128] The object of the present invention is also to provide the compound of the present invention used as a drug. or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or Isotope derivatives or The present invention includes providing a pharmaceutical composition.

[0129] The object of the present invention is also to provide compounds of the present invention for the prevention and / or treatment of SOS1-mediated diseases. or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or Isotope derivatives or The present invention includes providing a pharmaceutical composition.

[0130] The object of the present invention is also to provide compounds of the present invention for the prevention and / or treatment of diseases caused by RAS mutations. or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or Isotope derivatives or The present invention includes providing a pharmaceutical composition.

[0131] The object of the present invention is also to develop the compounds of the present invention in the manufacture of drugs for preventing and / or treating SOS1-mediated diseases. or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or Isotope derivatives or The present invention includes providing information on the use of the pharmaceutical composition.

[0132] In some embodiments, the SOS1-mediated disease is cancer or tumor and related diseases.

[0133] In some embodiments, the SOS1-mediated disease is lung cancer (e.g., non-small cell lung cancer (NSCLC)) and related diseases.

[0134] The object of the present invention is also to provide compounds of the present invention in the manufacture of drugs for preventing and / or treating diseases caused by RAS mutations. or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or Isotope derivatives or The present invention includes providing information on the use of the pharmaceutical composition.

[0135] In some embodiments, the disease caused by the RAS mutation is cancer or tumor, and related diseases.

[0136] In some embodiments, the diseases caused by the RAS mutation are lung cancer (e.g., non-small cell lung cancer (NSCLC)) and related diseases.

[0137] The object of the present invention is also to provide patients with an effective dose of the compound of the present invention for prevention and / or treatment. or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or Isotope derivatives or The present invention provides a method for preventing and / or treating SOS1-mediated diseases, comprising administering a pharmaceutical composition of the present invention.

[0138] The object of the present invention is also to provide patients with an effective dose of the compound of the present invention for prevention and / or treatment. or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or Isotope derivatives or The present invention provides a method for preventing and / or treating diseases caused by RAS mutations, comprising administering a pharmaceutical composition of the present invention.

[0139] The object of the present invention is also the compound of the present invention, or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or Isotope derivatives orThe present invention provides a non-diagnostic and non-therapeutic use of a pharmaceutical composition for inhibiting the activity of guanine nucleotide exchange factors (GEFs) in vitro, wherein the guanine nucleotide exchange factors are selected from SOS1.

[0140] The object of the present invention is also to provide subjects with an effective inhibitory dose of the compound of the present invention. or Its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates or Isotope derivatives or The present invention provides a non-diagnostic and non-therapeutic method for inhibiting the activity of a guanine nucleotide exchange factor in vitro, comprising administering a pharmaceutical composition of the present invention, wherein the guanine nucleotide exchange factor is selected from SOS1. [Effects of the Invention]

[0141] The beneficial effects of this invention are as follows: This invention designs a series of compounds with novel structures, offering a new direction in the development of SOS1 inhibitors. In vitro enzyme activity inhibition studies have shown that these compounds exhibit strong inhibitory effects against SOS1 and are promising as compounds for the prevention and / or treatment of SOS1-mediated diseases. Moreover, these compounds show clear inhibitory activity against NCI-H358 cell proliferation. Furthermore, this invention explores a specific synthesis method that is simple, easy to operate, and suitable for large-scale industrial production and use. [Modes for carrying out the invention]

[0142] (Definition of terms) The terms "optional," "at will," "at will," or "may be at will" mean that the event or situation described thereafter may occur, but is not necessarily guaranteed to occur, and the description includes both cases where the event or situation occurs and cases where it does not.

[0143] Unless otherwise specified, the term "alkyl group" means a linear or branched monovalent saturated aliphatic hydrocarbon functional group that generally comprises 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms (i.e., C 1~10 Alkyl), more preferably comprising 1 to 8 carbon atoms (i.e., C 1~8 Alkyl), more preferably comprising 1 to 6 carbon atoms (i.e., C 1~6 It refers to alkyl groups. For example, "C 1~6 An alkyl group refers to a functional group that is an alkyl group and has 1 to 6 carbon atoms on its carbon chain (specifically, 1, 2, 3, 4, 5, or 6). Non-exclusive examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, and n-octyl groups.

[0144] Unless otherwise specified, the term "alkenyl group" means a monovalent unsaturated aliphatic hydrocarbon functional group, either linear or branched, having at least one double bond, generally comprising 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2~10 Alkenyl group), more preferably comprising 2 to 8 carbon atoms (i.e., C 2~8 Alkenyl group), more preferably comprising 2 to 6 carbon atoms (i.e., C 2~6 This refers to an alkenyl group. For example, "C 2~6 An "alkenyl group" refers to a functional group that is an alkenyl group and has 2 to 6 carbon atoms on its carbon chain (specifically, 2, 3, 4, 5, or 6 carbon atoms). Non-exclusive examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl groups.

[0145] Unless otherwise specified, the term "alkynyl group" means a monovalent unsaturated aliphatic hydrocarbon functional group, either linear or branched, having at least one triple bond, generally comprising 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2~10 Alkynyl group), more preferably comprising 2 to 8 carbon atoms (i.e., C 2~8 Alkynyl group), more preferably comprising 2 to 6 carbon atoms (i.e., C 2~6 This refers to an alkynyl group. For example, "C 2~6 An "alkynyl group" refers to a functional group that is an alkynyl group and has 2 to 6 carbon atoms on its carbon chain (specifically, 2, 3, 4, 5, or 6 carbon atoms). Non-exclusive examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl groups.

[0146] Unless otherwise specified, the term "cycloalkyl group" means a monocyclic or polycyclic (e.g., fused ring, bridging ring, or spiro ring) monovalent aliphatic hydrocarbon functional group that does not contain unsaturated bonds and generally comprises 3 to 12 carbon atoms (i.e., C 3~12 Cycloalkyl), more preferably comprising 3 to 10 carbon atoms (i.e., C 3~10 Cycloalkyl), more preferably 3 to 6 carbon atoms (i.e., C 3~6 Cycloalkyl), 4-6 carbon atoms (i.e., C 4~6 Cycloalkyl), 5-6 carbon atoms (i.e., C 5~6 This refers to cycloalkyl groups. Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethylcyclopentyl, and dimethylcyclobutyl groups. Non-limiting examples of condensed ring cycloalkyl groups include, but are not limited to, decahydronaphthyl, octahydroindenyl, and octahydropentarenyl groups. Non-limiting examples of crosslinked ring cycloalkyl groups are, [ka] These include, but are not limited to, spirocyclic cycloalkyl groups. [ka] These include, but are not limited to, those listed above.

[0147] Unless otherwise specified, the term "cycloalkenyl group" means a monocyclic or polycyclic monovalent aliphatic hydrocarbon functional group having at least one double bond and generally comprising 3 to 12 carbon atoms (i.e., C 3~12 Cycloalkenyl group), more preferably 4 to 12 carbon atoms (i.e., C 4~12 A cycloalkenyl group, or 3 to 10 carbon atoms (i.e., C 3~10 It comprises a cycloalkenyl group, and more preferably 3 to 6 carbon atoms (i.e., C 3~6 Cycloalkenyl group), 4-6 carbon atoms (i.e., C 4~6 Cycloalkenyl group), 5-6 carbon atoms (i.e., C 5~6 This refers to groups that are cycloalkenyl groups. Non-restrictive examples of monocyclic cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclopentadienyl, cyclohexadienyl, cycloheptatrienyl, and cyclooctotrienyl groups.

[0148] Unless otherwise specified, the term "alkoxy group" refers to a functional group called "-O-alkyl group," and the definition of alkyl group is the same as above, namely, a group comprising 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6). Typical examples include, but are not limited to, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, 1-methylpropoxy group, 2-methylpropoxy group, tert-butoxy group, pentyloxy group, 1-methylbutoxy group, 2-methylbutoxy group, 3-methylbutoxy group, 1,1-dimethylpropoxy group, 1,2-dimethylpropoxy group, 2,2-dimethylpropoxy group, and 1-ethylpropoxy group.

[0149] Unless otherwise specified, the terms "halogen" or "halo" refer to F, Cl, Br, and I. The term "haloalkyl group" refers to an alkyl group defined above in which one, two, or more hydrogen atoms, or all of the hydrogen atoms, are substituted with a halogen. Typical examples of haloalkyl groups include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, and CF2CF3. Different notation methods may be used for haloalkyl groups, for example, "C 1~6 "Haloalkyl" is "Halo C 1~6 It may also be written as "alkyl group". The term "haloalkoxy group" refers to an alkoxy group defined above in which one, two, or more hydrogen atoms, or all hydrogen atoms, are substituted with halogens. Typical examples of haloalkoxy groups include OCl3, OCF3, OCHCl2, OCH2Cl, OCH2Br, OCH2I, OCH2CF3, and OCF2CF3. Different notation methods may be used for haloalkoxy groups, for example, "C 1~6 "Haloalkoxy group" is "Halo C 1~6 It may also be written as "alkoxy group". The term "halocycloalkyl group" refers to a cycloalkyl group defined above in which one, two, or more hydrogen atoms, or all of the hydrogen atoms, are substituted with halogens.

[0150] Unless otherwise specified, the term "heterocyclyl group" refers to the following: a saturated or partially unsaturated monocyclic or polycyclic (e.g., fused, bridging, or spirocyclic) monovalent aliphatic ring system, which is entirely non-aromatic, and generally comprises 3 to 20 ring atoms, of which 1, 2, 3 or more ring atoms are selected from N, O, or S, and the remaining ring atoms are C, preferably comprising 3 to 12 ring atoms, more preferably 4 to 12 ring atoms, or 5 to 12 ring atoms, or 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 4 to 6 ring atoms, or 5 to 6 ring atoms. The heteroatoms are preferably 1 to 4 in number, and more preferably 1 to 3 (i.e., 1, 2, or 3). Non-limiting examples of monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, 2,5-dihydrofuryl, and pyridonyl groups. Polycyclic heterocyclyl groups include spirocyclic, fused, and bridging heterocyclyl groups. Non-limiting examples of fused heterocyclyl groups include, but are not limited to, decahydroquinolinyl and octahydroindolyl groups. Non-limiting examples of bridging heterocyclyl groups are, [ka] These include, but are not limited to, spirocyclic heterocyclyl groups. [ka] These include, but are not limited to, those listed above.

[0151] Unless otherwise specified, the term "aryl group" refers to a monovalent aromatic ring system, either monocyclic or polycyclic (e.g., fused ring), generally comprising 6 to 16 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms, preferably 6 to 10 carbon atoms. The term "aryl group" may be substituted for the term "aromatic ring." Non-exclusive examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, or pyrenyl groups.

[0152] Unless otherwise specified, the term "heteroaryl group" refers to the following: a monocyclic or polycyclic (e.g., fused ring) monovalent aromatic ring system that generally contains a 5-12 member structure, preferably a 5-10 member structure, a 5-8 member structure, and more preferably a 5-6 member structure, where one, two, three or more ring atoms are heteroatoms and the remaining atoms are carbon, with each heteroatom independently selected from O, N, or S, and preferably the number of heteroatoms being one, two, or three. The term "heteroaryl group" may be substituted for the term "heteroaromatic ring". Non-exclusive examples of heteroaryl groups include furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, thiadiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, prinyl, indolyl, isoindolyl, indazolyl, benzofuryl, benzothienyl, and benzopy These include, but are not limited to, lydinyl groups, benzopyrimidinyl groups, benzopyradinyl groups, benzimidazolyl groups, benzophthalazinyl groups, pyrrolo[2,3-b]pyridinyl groups, imidazo[1,2-a]pyridinyl groups, pyrazolo[1,5-a]pyridinyl groups, pyrazolo[1,5-a]pyridinyl groups, imidazo[1,2-b]pyridadinyl groups, [1,2,4]triazolo[4,3-b]pyridadinyl groups, [1,2,4]triazolo[1,5-a]pyridinyl groups, and [1,2,4]triazolo[1,5-a]pyridinyl groups.

[0153] Unless otherwise specified, the term "hydroxyl group" refers to the "-OH" functional group.

[0154] Unless otherwise specified, the term "cyano group" refers to the "-CN" functional group.

[0155] Unless otherwise specified, the term "amino group" refers to the "-NH2" functional group. In some cases, the term "amino group" also refers to a group in which one or two hydrogen atoms are alkyl groups (e.g., C 1~6 Alkyl alkyl group, preferably C 1~4 This refers to a functional group that is substituted with an alkyl group.

[0156] Unless otherwise specified, the term "nitro group" refers to the "-NO2" functional group.

[0157] Unless otherwise specified, the terms "formyl group" or "aldehyde group" refer to the "-C(=O)H" functional group.

[0158] Unless otherwise specified, the term "oxo group" refers to an "=O" functional group linked to a carbon atom, and the term "oxygen group" refers to an "=O" functional group linked to a heteroatom (for example, a sulfur atom).

[0159] Unless otherwise specified, the terms “medicinal salt,” “medicinal salt,” or “salt usable for pharmaceutical purposes” refer to a salt that is suitable for contact with mammalian tissue, particularly human tissue, within the bounds of reasonable medical judgment, and that does not cause excessive toxicity, irritation, or allergic reactions, and whose benefits-risks are reasonable. During the final separation and purification of the compounds of the present invention, the salt may be produced in situ, or it may be produced by reacting a free base or free acid alone with a suitable reagent. For example, a free base may be reacted with a suitable acid.

[0160] Unless otherwise specified, the term “solvate” or “solvide” refers to a compound of the present invention that is physically associated with one or more solvent molecules (whether organic or inorganic). Such physical association includes hydrogen bonding. In some cases, for example, if one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. The solvent molecules in the solvate may exist in regular and / or irregular arrangements. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. “Solvate” covers both the solution phase and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanol hydrates, methanol hydrates, and isopropanol hydrates. Methods of solvation are well known in the art.

[0161] Unless otherwise specified, the compounds of the present invention include their "isotope derivatives" (such as deuterides), and the term "isotope derivative" refers to compounds of the present invention that may exist in an isotopically traceable or enriched form, containing one or more atoms, and whose atomic weights or mass numbers differ from those of the most abundant atom occurring in nature. The isotopes may be radioactive or non-radioactive. Generally, isotopes used for isotopic labeling are hydrogen isotopes. 2 H(D) and 3 H(T), carbon isotope 13 C and 14 C, chlorine isotope 35 Cl and 37 Cl, fluorine isotope 18 F, an iodine isotope 123 I and 125 I, Nitrogen isotopes 13 N and 15 N, oxygen isotope 15 O, 17 O and 18 O, and sulfur isotopes 35 This is S. Compounds labeled with these isotopes can be used to study the distribution of pharmaceutical molecules in tissues. In particular 3 H and 13C is widely used because it is easy to label and detect. Some heavy isotopes, such as deuterium ( 2 Substitution with H) offers therapeutic advantages by increasing metabolic stability and extending the half-life, thereby achieving the goal of dose reduction. Isotope-labeled compounds are generally synthesized from labeled starting materials using conventional synthetic techniques, similar to unisotopically labeled compounds.

[0162] Unless otherwise specified, the term "prodrug" refers to a drug that is converted to a parent drug in vivo. Prodrugs are generally useful because, in some cases, they are easier to administer than their parent drugs. For example, they may be utilized by the organism when administered orally, whereas the parent drug may not be. Compared to the parent drug, prodrugs have improved solubility in pharmaceutical compositions.

[0163] Unless otherwise specified, the term "optical isomer" refers to substances that have exactly the same molecular structure and similar physicochemical properties, but differ in optical activity.

[0164] Unless otherwise specified, the term "stereoisomer" refers to a compound that has the same chemical structure but differs in the spatial arrangement of its atoms or functional groups. Stereoiomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), and atrop isomers. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, or diastereomers based on the differences in the physicochemical properties of their components, for example, by chromatography and / or fractional crystallization.

[0165] Unless otherwise specified, the structural formulas described in this invention include all isomeric forms (enantiomers, diastereomers, geometric isomers (or conformosomers), etc.), such as the R, S configuration containing a chiral center, the (Z), (E) isomer due to a double bond, and the (Z), (E) conformosomer. Therefore, any single stereochemical isomer of a compound of the present invention, or a mixture thereof of its enantiomers, diastereomers, or geometric isomers (or conformosomers), all fall within the scope of this invention.

[0166] Unless otherwise specified, the terms “optional substitution,” “may be optionally substituted by…,” and “optionally substituted by…” mean that the hydrogen atoms of the substituted sites of the functional group are either not substituted or are substituted by one or more substituents, and such substituents include halogens, hydroxyl groups, mercapto groups, cyano groups, nitro groups, amino groups, azide groups, oxo groups, carboxyl groups, and C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 1~6 Alkyl alkyl group, C 1~6 Alkoxy group, C 3~10 Cycloalkyl group, 3-10 membered heterocyclyl group, C 6~14 A substituent is preferredly selected from the group consisting of an aryl group or a 5-10 membered heteroaromatic ring group, among which the C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 1~6 Alkyl alkyl group, C 1~6 Alkoxy group, C 3~10 Cycloalkyl group, 3-10 membered heterocyclyl group, C 6~14 Aryl groups and 5-10 membered heteroaromatic ring groups are all halogens, hydroxyl groups, amino groups, cyano groups, and C 1~6 Alkyl alkyl group or C 1~6 The group may be optionally substituted with one or more substituents selected from the alkoxy group. [Examples]

[0167] The present invention will be further described below in conjunction with specific examples. These examples are not intended to limit the scope of the present invention, but merely to illustrate it. Test methods in the following examples that do not specify concrete conditions are performed under normal conditions or conditions recommended by the manufacturer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those well known to those skilled in the art. Furthermore, any method and material similar to or equivalent to those described may be used in the methods of the present invention. The preferred methods and materials shown herein are illustrative only.

[0168] The structure of the compounds of the present invention is determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or high-performance liquid chromatography (HPLC). The instrument used for NMR measurements is a Bruker AVANCE III 600 MHz, the instrument used for LC-MS is a WATERS ACQUITY UPLC H-Class PLUS and / or SQD2, and the instrument used for HPLC is a WATERS e2695_2998 and / or Agilent 1100.

[0169] In the embodiments of the present invention, the starting materials may be existing materials purchased from the market or synthesized by conventional methods in the art.

[0170] Manufacturing Example 1: Synthesis of Intermediate A [ka] Synthesis of intermediate A-2: 1-(3-nitro-5-trifluoromethylphenyl)-ethanone (10.00 g, 43.0 mmol) was dissolved in ethanol (200 mL), followed by the addition of iron powder (7.22 g, 129.0 mmol) and concentrated hydrochloric acid (50 mL). The system was reacted at 80°C for 2 hours. After monitoring by LC-MS and confirming that no starting materials remained, the mixture was cooled and filtered. The filtrate was evaporated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (dichloromethane:methanol = 50:1~20:1) to obtain A-2 (8.12 g, 40.0 mmol, 92%). ESI-MS: m / z 204.12 [M+H] + .

[0171] Synthesis of intermediate A-3: A-2 (27.02 g, 133.0 mmol) was dissolved in tetrahydrofuran (50 mL), followed by the addition of (R)-(+)-2-methyl-2-propanesulfinamide (24.24 g, 200.0 mmol) and Ti(OEt)4 (91.02 g, 399 mmol). The system was reacted at 80°C for 2 hours, and no starting materials remained after monitoring by LC-MS. The reaction mixture was quenched with ice water, and the precipitate was dissolved in ethyl acetate and filtered. The filtrate was evaporated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (dichloromethane:methanol = 50:1~20:1) to obtain product A-3 (34.65 g, 113.1 mmol, 85%). ESI-MS: m / z 307.12 [M+H] + .

[0172] Synthesis of intermediate A-4: A-3 (34.65 g, 113.1 mmol) was dissolved in tetrahydrofuran (50 mL), and sodium borohydride (6.42 g, 169.7 mmol) was added at -78°C. The reaction system temperature was slowly raised to room temperature and monitored by LC-MS to ensure no starting materials remained. The reaction mixture was quenched with ice water, extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated brine (100 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 50:1~20:1) to obtain A-4 (28.43 g, 92.2 mmol, 82%). ESI-MS: m / z 309.10 [M+H] + .

[0173] Synthesis of intermediate A: Dissolve A-4 (28.43 g, 92.2 mmol) in hydrochloric acid-dioxane solution (50 mL), react the system at room temperature for 2 hours, and monitor by LC-MS. Once no starting material remains, evaporate under reduced pressure to remove the solvent and obtain intermediate A. The reaction in the hydrochloride salt form was carried out directly in the next step. ESI-MS: m / z 205.22 [M+H] + .

[0174] The following intermediates may be obtained by referring to the synthesis method of intermediate A or the related synthesis method of CN110167928A. If necessary, the crude product is purified by chromatography. [Table 1]

[0175] Example 1: Synthesis of Compound 1 [ka] Synthesis of intermediate 1-1: 2-amino-6-chloronicotinic acid (5.00 g, 29.0 mmol) was dissolved in 80 mL of methanol, the system was cooled to 0°C, and then 16 mL of concentrated sulfuric acid was added. The system was reacted at 80°C for 5 hours, and no starting material remained after monitoring by LC-MS. 100 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1~1:1) to obtain 1-1 (5.03 g, yield 93%). ESI-MS: m / z 187.02 [M+H] + .

[0176] Synthesis of intermediates 1-2: 1-1 (5.03 g, 26.9 mmol) was dissolved in acetonitrile (80 mL), followed by the addition of N-bromosuccinimide (7.17 g, 40.3 mmol). The reaction was allowed to proceed at room temperature for 1.5 hours, and no starting material remained after monitoring by LC-MS. The reaction mixture was quenched with ice water, extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated brine (100 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1~1:3) to obtain 1-2 (6.85 g, yield 96%). ESI-MS: m / z 265.10 / 267.13 [M+H] + .

[0177] Synthesis of intermediates 1-3: Dissolve 1-2 (6.85 g, 25.8 mmol) in 80 mL of acetonitrile, then add 15 mL of methanesulfonic acid. React the system at 130°C for 8 hours, monitoring by LC-MS until no starting materials remain. Quench the reaction mixture with ice water, extract with ethyl acetate (100 mL x 3), combine the organic phases, wash with saturated brine (100 mL x 2), and dry over anhydrous sodium sulfate. Remove the solvent by evaporation under reduced pressure, and purify the residue by column chromatography (petroleum ether:ethyl acetate = 5:1~1:3) to obtain 1-3 (1.51 g, yield 21%). ESI-MS: m / z 274.02 / 275.98 [M+H] + .

[0178] Synthesis of intermediates 1-4: Dissolve 1-3 (1.51 g, 5.50 mmol) in 50 mL of ethanol, then add hydrazine monohydrate (1.76 g, 55.0 mmol). React at 80°C for 2 hours, and monitoring by LC-MS confirmed no residue remained. The solvent was removed by evaporation under reduced pressure, and the residue was directly used for the next step. ESI-MS: m / z 270.01 / 272.03 [M+H] + .

[0179] Synthesis of intermediates 1-5: Dissolve 1-4 in 30 mL of chloroform, then add 10 mL of triethyl orthoformate. React at 80°C for 2 hours, and monitor by LC-MS to ensure no starting materials remain. Quench the reaction mixture with ice water, extract with ethyl acetate (100 mL x 3), combine the organic phases, wash with saturated brine (100 mL x 2), and dry over anhydrous sodium sulfate. Remove the solvent by evaporation under reduced pressure, and purify the residue by column chromatography (petroleum ether:ethyl acetate = 5:1~1:3) to obtain 1-5 (1.00 g, two-step yield 65%). ESI-MS: m / z 280.00 / 282.02 [M+H] + .

[0180] Synthesis of intermediates 1-6: 1-5 (1.00 g, 3.60 mmol) was dissolved in 50 mL of toluene, followed by the addition of diisopropylethylamine (464 mg, 3.60 mmol) and phosphoryl chloride (2.76 g, 18.0 mmol). The system was reacted at 100°C for 2 hours, and no starting materials remained after monitoring by LC-MS. The reaction mixture was quenched with ice water, extracted with ethyl acetate (100 mL x 3), combined the organic phases, washed with saturated brine (100 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1~1:1) to obtain 1-6 (800 mg, yield 75%). ESI-MS: m / z 298.03 / 300.02 [M+H] + .

[0181] Synthesis of intermediates 1-7: 1-6 (800 mg, 2.68 mmol) was dissolved in 30 mL of N,N-dimethylformamide, followed by the addition of diisopropylethylamine (697 mg, 5.40 mmol) and intermediate B (612 mg, 3.24 mmol). The system was reacted at 120°C for 2 hours, and LC-MS monitoring ensured no starting materials remained. The reaction mixture was quenched with ice water, extracted with ethyl acetate (100 mL x 3), combined the organic phases, washed with saturated brine (100 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1~1:2) to obtain 1-7 (798 mg, yield 66%). ESI-MS: m / z 451.02 / 453.07 [M+H] + .

[0182] Synthesis of intermediates 1-8: Dissolve 1-7 (100 mg, 0.22 mmol) in dioxane (40 mL) and water (10 mL), then add potassium hydroxide (25 mg, 0.44 mmol), tris(dibenzylideneacetone)dipalladium (0) (18 mg, 0.02 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (10 mg, 0.02 mmol). Stir the entire system at 100 °C and react for 3 hours. Monitor by TLC and if no starting materials remain, add 50 mL of water to the reaction solution, extract with ethyl acetate (30 mL x 3), combine the organic phases, wash with saturated brine (50 mL x 2), dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and purify by column chromatography (dichloromethane:methanol = 60:1~20:1) to obtain 1-8 (40 mg, yield 47%). ESI-MS: m / z 389.15[M+H] + .

[0183] Synthesis of compound 1: Dissolve 1-8 (40 mg, 0.10 mmol) in N,N-dimethylformamide (15 mL), then add (R)-3-(p-toluenesulfonyl)oxytetrahydrofuran (30 mg, 0.12 mmol) and cesium carbonate (65 mg, 0.20 mmol). Stir the entire system at 80°C and react for 3 hours. Monitor by TLC until no starting materials remain. Add 30 mL of water to the reaction mixture, extract with ethyl acetate (30 mL x 3), combine the organic phases, wash with saturated brine (50 mL x 2), dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and purify by column chromatography (dichloromethane:methanol = 60:1~20:1) to obtain compound 1 (30 mg, yield 65%). ESI-MS: m / z 459.25 [M+H] + . 1H NMR(600MHz,DMSO-d6):δ 9.59(s,1H),8.40(d,J=7.2Hz,1H),7.82(s,1H),7.77(d,J=7.2Hz,1H),7.63-7.58(m,2H),7.46(s,1H),5.71-5.64(m,1H),5.4 7-5.45(m,1H),4.05-4.03(m,1H),3.98-3.94(m,2H),3.88-3.84(m,1H),2.46(s,3H),2.42-2.37(m,2H),1.66(d,J=7.2Hz,3H).

[0184] Example 2: Synthesis of Compound 2 [ka] Synthesis of intermediate 2-1: Dissolve 1-7 (100 mg, 0.22 mmol) in dioxane (30 mL), then add N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (84 mg, 0.27 mmol), tetrakis(triphenylphosphine)palladium (0) (23 mg, 0.02 mmol), and cesium carbonate (143 mg, 0.44 mmol). Stir the entire system at 100°C and react for 3 hours. Monitor by TLC and if no starting materials remain, add 50 mL of water to the reaction mixture, extract with ethyl acetate (30 mL x 3), combine the organic phases, wash with saturated brine (50 mL x 2), dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and purify by column chromatography (dichloromethane:methanol = 60:1~20:1) to obtain 2-1 (100 mg, yield 82%). ESI-MS: m / z 554.19[M+H] + .

[0185] Synthesis of intermediate 2-2: Dissolve 2-1 (100 mg, 0.18 mmol) in 4 M hydrochloric acid / ethyl acetate solution (10 mL), stir at room temperature, and react for 2 hours. After monitoring by TLC and confirming no starting material remained, remove the solvent under reduced pressure to obtain residue 2-2. The reaction was then carried out directly in the next step. ESI-MS: m / z 454.16 [M+H] + .

[0186] Synthesis of compound 2: Compound 2-2 was dissolved in dichloromethane (10 mL), followed by the addition of triethylamine (36 mg, 0.36 mmol) and acetic anhydride (22 mg, 0.22 mmol). The mixture was stirred at room temperature and reacted for 2 hours. After monitoring by TLC and confirming that no starting materials remained, water was added to the reaction mixture to quench it. The mixture was extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the compound was purified by column chromatography (dichloromethane:methanol = 60:1~15:1) to obtain compound 2 (50 mg, yield 56%). ESI-MS: m / z 496.17 [M+H] + . 1 H NMR(600MHz,DMSO-d6):δ 9.59(d,J=3.6Hz,1H),8.75(dd,J=7.8Hz,J=7.8Hz,1H),8.03(d,J=5.4Hz,1H),7.83(s,1H),7.78(d,J=7.2Hz,1H),7.63-7.58(m,2H),7.49-7. 47(m,1H),5.72-5.68(m,1H),4.33-4.26(m,2H),3.77-3.73(m,2H),2. 87-2.63(m,2H),2.48(s,3H),2.13-2.08(m,3H),1.66(d,J=7.2Hz,3H).

[0187] Example 3: Synthesis of Compound 3 [ka] Compounds 1-7 (100 mg, 0.22 mmol) were dissolved in N-methylpyrrolidone (30 mL), followed by the addition of N-methylpiperazine (27 mg, 0.27 mmol), tris(dibenzylideneacetone)dipalladium (0) (18 mg, 0.02 mmol), and sodium tert-butoxide (42 mg, 0.44 mmol). The entire system was stirred at 120 °C and reacted for 3 hours. After monitoring by TLC and confirming that no starting materials remained, 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was purified by column chromatography (dichloromethane:methanol = 60:1~20:1) to obtain compound 3 (41 mg, yield 40%). ESI-MS: m / z 471.18 [M+H] + . 1 H NMR(600MHz,DMSO-d6):δ 9.53(s,1H),8.42(d,J=7.8Hz,1H),7.82(s,1H),7.77(d,J=7.2Hz,1H),7.61-7.57(m,2H),7.10(s,1H),5 .68-5.65(m,1H),3.65-3.60(m,4H),2.63-2.59(m,4H),2.43(s,3H),2.30(s,3H),1.65(d,J=7.2Hz,3H).

[0188] Example 4: Synthesis of Compound 4 [ka] Compounds 1-7 (100 mg, 0.22 mmol) were dissolved in N-methylpyrrolidone (30 mL), followed by the addition of morpholine (24 mg, 0.27 mmol), tris(dibenzylideneacetone)dipalladium (0) (18 mg, 0.02 mmol), and sodium tert-butoxide (42 mg, 0.44 mmol). The entire system was stirred at 120 °C and reacted for 3 hours. After monitoring by TLC and confirming that no starting materials remained, 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was purified by column chromatography (dichloromethane:methanol = 60:1~20:1) to obtain compound 4 (50 mg, 50% yield). ESI-MS: m / z 458.16 [M+H] + . 1 H NMR(600MHz,DMSO-d6):δ 9.53(s,1H),8.43(d,J=7.8Hz,1H),7.82(s,1H),7.77(d,J=6.6Hz,1H),7.62-7.58(m,2H),7.13(s ,1H),5.70-5.65(m,1H),3.88-3.87(m,4H),3.61-3.59(m,4H),2.43(s,3H),1.65(d,J=7.2Hz,3H).

[0189] Example 5: Synthesis of Compound 5 [ka] Synthesis of intermediate 5-1: 4,6-Dichloro-2-methylpyrimidine-5-carbaldehyde (2.00 g, 10.47 mmol) was dissolved in tetrahydrofuran (20 mL), followed by the addition of (ethoxycarbonylmethylene)triphenylphosphoran (5.47 g, 15.71 mmol) and triethylamine (2.12 g, 20.94 mmol). The system was reacted at 80°C for 6 hours and monitored by LC-MS to ensure no starting materials remained. The reaction system was purified by direct column chromatography (n-hexane:ethyl acetate = 20:1~10:1) to obtain 5-1 (1.71 g, 6.54 mmol, yield 63%). ESI-MS: m / z 260.85 [M+H]+ .

[0190] Synthesis of intermediate 5-2: Dissolve 5-1 (1.71 g, 6.54 mmol) in N,N-dimethylformamide (20 mL), then add tert-butyl (2-aminoethyl)carbamate (1.26 g, 7.85 mmol) and triethylamine (1.32 g, 13.08 mmol). React the system at room temperature for 12 hours. Monitor by LC-MS until no starting materials remain. Add water (30 mL) to the reaction mixture, extract with ethyl acetate (30 mL x 3), combine the organic phases, wash with saturated brine (30 mL x 2), and dry over anhydrous sodium sulfate. Remove the solvent by evaporation under reduced pressure, and purify the residue by thin-layer chromatography (n-hexane:ethyl acetate = 10:1~3:1) to obtain 5-2 (2.30 g, 5.99 mmol, yield 92%). ESI-MS: m / z 385.15 [M+H] + .

[0191] Synthesis of intermediate 5-3: Dissolve 5-2 (2.30 g, 5.99 mmol) in methanol (30 mL), then add sodium methoxide (3.6 mL, 17.97 mmol, 30% w / w in methanol). React the system at room temperature for 12 hours until a solid precipitated from the reaction mixture. After monitoring with LC-MS and confirming that no starting materials remained, add water (10 mL) to the reaction mixture, filter, and obtain a white solid 5-3 (1.60 g, 4.79 mmol, 80% yield). ESI-MS: m / z 335.07 [M+H] + .

[0192] Synthesis of intermediates 5-4: 5-3 (1.60 g, 4.79 mmol) was dissolved in dichloromethane (30 mL), followed by the addition of bromine (1.15 g, 7.19 mmol). The system was reacted at room temperature for 12 hours, and no starting material remained after monitoring by LC-MS. The reaction system was purified by direct column chromatography (n-hexane:ethyl acetate = 5:1~3:1) to obtain 5-4 (1.80 g, 4.36 mmol, 91% yield). ESI-MS: m / z 412.98 / 415.00 [M+H] + .

[0193] Synthesis of intermediate 5-5: Dissolve 5-4 (1.80 g, 4.36 mmol) in dichloromethane (20 mL), then add 5 mL of trifluoroacetic acid. The system was reacted at room temperature for 4 hours, and LC-MS monitoring ensured no starting material remained. The solvent was removed by evaporation under reduced pressure, and 15 mL of water was added to the residue. The pH was adjusted to 8-9 with saturated sodium carbonate aqueous solution. Extraction was performed with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine (20 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to obtain 5-5 (0.90 g, 2.88 mmol, yield 66%). ESI-MS: m / z 312.92 / 314.91 [M+H] + .

[0194] Synthesis of intermediates 5-6: 5-5 (0.90 g, 2.88 mmol) was dissolved in toluene (20 mL), followed by the slow addition of trimethylaluminum (1.9 mL, 3.75 mmol, 2.0 M in toluene). The system was reacted at 120 °C for 5 hours, and LC-MS monitoring confirmed that no starting materials remained. The reaction mixture was quenched with saturated ammonium chloride aqueous solution, evaporated under reduced pressure to remove toluene, and 15 mL of water was added to the residue. Extraction was performed with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine (20 mL x 2), and dried over anhydrous sodium sulfate. Evaporation under reduced pressure removed the solvent to obtain 5-6 (0.59 g, 2.01 mmol, yield 70%). ESI-MS: m / z 294.87 / 296.83 [M+H] + .

[0195] Synthesis of intermediates 5-7: Dissolve 5-6 (0.59 g, 2.01 mmol) in dichloromethane (10 mL), and slowly add boron tribromide (2.52 g, 10.05 mmol) in an ice bath. Once complete, remove the ice bath and allow the system to react at room temperature for 72 hours. Monitor by LC-MS to ensure no starting materials remain. Slowly add sodium carbonate solution in an ice bath to quench the reaction, and a solid precipitate forms. Filter the mixture to obtain 5-7 (0.46 g, 1.64 mmol, 82% yield). ESI-MS: m / z 280.82 / 282.84 [M+H] + .

[0196] Synthesis of intermediates 5-8: 5-7 (50 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (15 mL), followed by the addition of (R)-1-[3-(trifluoromethyl)phenyl]ethylamine hydrochloride (61 mg, 0.27 mmol), 1H-benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (102 mg, 0.23 mmol), and 1,8-diazabicyclo[5.4.0]-7-undecene (82 mg, 0.54 mmol). The system was reacted at room temperature for 8 hours. After monitoring by LC-MS and confirming that no starting materials remained, water (30 mL) was added to the reaction mixture, extracted with ethyl acetate (30 mL x 3), combined the organic phases, washed with saturated brine (30 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain 5-8 (40 mg, 0.089 mmol, yield 49%). ESI-MS: m / z 451.94 / 453.94 [M+H] + .

[0197] Synthesis of compound 5: 5-8 (40 mg, 0.089 mmol) was dissolved in dioxane (10 mL) and water (2 mL), followed by the addition of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one (31 mg, 0.133 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13 mg, 0.018 mmol), and cesium carbonate (58 mg, 0.178 mmol). The system was reacted at 100 °C for 4 hours and monitored by LC-MS to ensure no starting materials remained. The solvent was removed by evaporation under reduced pressure, and the residue was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol:triethylamine = 100:2:1) to obtain compound 5 (17 mg, 0.035 mmol, 40% yield). ESI-MS: m / z 481.11 [M+H] + . 1 H NMR(600MHz,DMSO-d6):δ 8.37(s,1H),8.32(s,1H),7.78-7.73(m,3H),7.60-7.59(m,2H),7.21(s,1H),6.81(d,J=12.0Hz,1H),5.61- 5.59(m,1H),4.12(t,J=6.0Hz,2H),3.97(t,J=6.0Hz,2H),3.46(s,3H),2.31(s,3H),1.59(d,J=6.0Hz,3H).

[0198] Example 6: Synthesis of Compound 6 [ka] Synthesis of intermediate 6-1: 5-7 (100 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (15 mL), followed by the addition of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)phenylamine (110 mg, 0.54 mmol), 1H-benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (207 mg, 0.47 mmol), and 1,8-diazabicyclo[5.4.0]-7-undecene (164 mg, 1.08 mmol). The system was reacted at room temperature for 8 hours. After monitoring by LC-MS and confirming that no starting materials remained, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain 6-1 (60 mg, yield 36%). ESI-MS: m / z 466.91 / 469.12 [M+H] + .

[0199] Synthesis of compound 6: 6-1 (60 mg, 0.128 mmol) was dissolved in dioxane (10 mL) and water (2 mL), followed by the addition of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one (45 mg, 0.191 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19 mg, 0.026 mmol), and cesium carbonate (84 mg, 0.258 mmol). The system was reacted at 100 °C for 4 hours and monitored by LC-MS to ensure no starting materials remained. The solvent was removed by evaporation under reduced pressure, and the residue was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol:triethylamine = 50:2:1) to obtain compound 6 (20 mg, 31% yield). ESI-MS: m / z 496.08 [M+H] + . 1H NMR(600MHz,DMSO-d6):δ 8.30(s,1H),8.13(d,J=6.0Hz,1H),7.72(d,J=6.0Hz,1H),7.32(s,1H),6.88(d,J=6.0Hz,1H),6.84-6.82(m,2H),6.71(s,1 H),5.57(s,2H),5.50-5.47(m,1H),4.07-4.05(m,2H),3.98-3.95(m,2H),3.45(s,3H),2.31(s,3H),1.52(d,J=6.0Hz,3H).

[0200] Example 7: Synthesis of Compound 7 [ka] Synthesis of intermediate 7-1: 5-7 (100 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (15 mL), followed by the addition of (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine hydrochloride (121 mg, 0.54 mmol), 1H-benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (205 mg, 0.47 mmol), and 1,8-diazabicyclo[5.4.0]-7-undecene (163 mg, 1.08 mmol). The system was reacted at room temperature for 8 hours. After monitoring by LC-MS and confirming that no starting materials remained, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain 7-1 (110 mg, 68% yield). ESI-MS: m / z 451.93 / 453.93 [M+H] + .

[0201] Synthesis of compound 7: 7-1 (110 mg, 0.243 mmol) was dissolved in dioxane (10 mL) and water (2 mL), followed by the addition of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one (86 mg, 0.366 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36 mg, 0.049 mmol), and cesium carbonate (159 mg, 0.488 mmol). The system was reacted at 100 °C for 4 hours and monitored by LC-MS to ensure no starting materials remained. The solvent was removed by evaporation under reduced pressure, and the residue was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol:triethylamine = 100:2:1) to obtain compound 7 (50 mg, 43% yield). ESI-MS: m / z 481.09 [M+H] + . 1 H NMR(600MHz,DMSO-d6):δ 8.33(s,1H),8.18(d,J=6.0Hz,1H),7.72(d,J=6.0Hz,1H),7.66-7.64(m,1H),7.52-7.50(m,1H),7.33-7.32(m,2H),7.24(t ,J=54.0Hz,1H),6.91-6.89(m,1H),5.75-5.70(m,1H),4.02-3.95(m,4H),3.45(s,3H),3.25(s,3H),1.58(d,J=6.0Hz,3H).

[0202] Example 8: Synthesis of Compound 8 [ka] Synthesis of intermediate 8-1: 5-7 (100 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (15 mL), followed by the addition of intermediate G (112 mg, 0.54 mmol), 1H-benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (205 mg, 0.47 mmol), and 1,8-diazabicyclo[5.4.0]-7-undecene (163 mg, 1.08 mmol). The system was reacted at room temperature for 8 hours. After monitoring by LC-MS and confirming that no starting materials remained, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain 8-1 (127 mg, yield 75%). ESI-MS: m / z 470.98 / 472.98[M+H] + .

[0203] Synthesis of compound 8: 8-1 (113 mg, 0.24 mmol) was dissolved in dioxane (10 mL) and water (2 mL), followed by the addition of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one (86 mg, 0.366 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36 mg, 0.049 mmol), and cesium carbonate (159 mg, 0.488 mmol). The system was reacted at 100 °C for 4 hours and monitored by LC-MS to ensure no starting materials remained. The solvent was removed by evaporation under reduced pressure, and the residue was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol:triethylamine = 100:2:1) to obtain compound 8 (55 mg, 46% yield). ESI-MS: m / z 499.11 [M+H] + . 1H NMR(600MHz,DMSO-d6):δ 8.95(s,1H),8.80(s,1H),7.87-7.85(m,2H),7.67(dd,J=6.6Hz,J=6.6Hz,1H),7.39(dd,J=7.8Hz,J=7.8Hz,1H),6.91 (s,1H),6.65(d,J=6.6Hz,1H),5.77-5.71(m,1H),4.41-4.34(m,4H),3.50(s,3H),2.34(s,3H),1.62(d,J=6.0Hz,3H).

[0204] Example 9: Synthesis of Compound 9 [ka] Synthesis of intermediate 9-1: 3-amino-2-chloroisonicotinic acid (5.00 g, 29.0 mmol) was dissolved in methanol (80 mL), the system was cooled to 0°C, and then concentrated sulfuric acid (16 mL) was added. The system was reacted at 80°C for 5 hours, and no starting material remained after monitoring by LC-MS. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1~1:1) to obtain 9-1 (5.00 g, yield 92%). ESI-MS: m / z 187.02 [M+H] + .

[0205] Synthesis of intermediate 9-2: 9-1 (5.00 g, 26.8 mmol) was dissolved in acetonitrile (80 mL), followed by the addition of N-bromosuccinimide (7.17 g, 40.3 mmol). The reaction was allowed to proceed at room temperature for 1.5 hours, and no starting material remained after monitoring by LC-MS. The reaction mixture was quenched with ice water, extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated brine (100 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1~1:3) to obtain 9-2 (6.85 g, yield 96%). ESI-MS: m / z 265.10 / 267.12 [M+H] + .

[0206] Synthesis of intermediate 9-3: Dissolve 9-2 (6.85 g, 25.8 mmol) in acetonitrile (80 mL), then add methanesulfonic acid (15 mL). React at 130°C for 8 hours. Monitor by LC-MS until no starting material remains. Quench the reaction mixture with ice water, extract with ethyl acetate (100 mL x 3), combine the organic phases, wash with saturated brine (100 mL x 2), and dry over anhydrous sodium sulfate. Remove the solvent by evaporation under reduced pressure, and purify the residue by column chromatography (petroleum ether:ethyl acetate = 5:1~1:3) to obtain 9-3 (1.51 g, yield 21%). ESI-MS: m / z 274.02 / 276.11 [M+H] + .

[0207] Synthesis of intermediate 9-4: 9-3 (1.51 g, 5.50 mmol) was dissolved in ethanol (50 mL), followed by the addition of hydrazine monohydrate (1.76 g, 55.0 mmol). The system was reacted at 80°C for 2 hours, and LC-MS monitoring confirmed that no starting materials remained. The solvent was removed by evaporation under reduced pressure, and the residue was directly used for the next step in the reaction. ESI-MS: m / z 270.02 / 271.06 [M+H] + .

[0208] Synthesis of intermediate 9-5: Dissolve 9-4 in chloroform (30 mL), then add triethyl orthoformate (10 mL). React at 80°C for 2 hours, monitoring by LC-MS to ensure no starting materials remained. Quench the reaction mixture with ice water, extract with ethyl acetate (100 mL x 3), combine the organic phases, wash with saturated brine (100 mL x 2), and dry over anhydrous sodium sulfate. Remove the solvent by evaporation under reduced pressure, and purify the residue by column chromatography (petroleum ether:ethyl acetate = 5:1~1:3) to obtain 9-5 (1.00 g, yield 65%). ESI-MS: m / z 280.02 / 282.14 [M+H] + .

[0209] Synthesis of intermediates 9-6: 9-5 (1.00 g, 3.60 mmol) was dissolved in toluene (50 mL), followed by the addition of diisopropylethylamine (465 mg, 3.60 mmol) and phosphoryl chloride (2.76 g, 18.0 mmol). The system was reacted at 100°C for 2 hours, and no starting materials remained after monitoring by LC-MS. The reaction mixture was quenched with ice water, extracted with ethyl acetate (100 mL x 3), combined the organic phases, washed with saturated brine (100 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1~1:1) to obtain 9-6 (800 mg, yield 74%). ESI-MS: m / z 298.02 / 300.20 [M+H] + .

[0210] Synthesis of intermediates 9-7: 9-6 (400 mg, 1.34 mmol) was dissolved in N,N-dimethylformamide (30 mL), followed by the addition of diisopropylethylamine (349 mg, 2.70 mmol) and intermediate D (384 mg, 2.02 mmol). The system was reacted at 120°C for 2 hours, and LC-MS monitoring confirmed that no starting materials remained. The reaction mixture was quenched with ice water, extracted with ethyl acetate (100 mL x 3), combined the organic phases, washed with saturated brine (100 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1~1:2) to obtain 9-7 (397 mg, yield 66%). ESI-MS: m / z 451.02 / 453.09 [M+H] + .

[0211] Synthesis of compound 9: Dissolve 9-7 (397 mg, 0.88 mmol) in dioxane (30 mL), then add 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one (249 mg, 1.06 mmol), tetrakis(triphenylphosphine)palladium(0) (104 mg, 0.09 mmol), and cesium carbonate (574 mg, 1.76 mmol) to the entire system and mix until 10 The reaction was stirred at 0°C for 3 hours. After monitoring by TLC and confirming that no starting materials remained, water (50 mL) was added to the reaction mixture, and extraction was performed with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was purified by column chromatography (dichloromethane:methanol = 60:1~20:1) to obtain compound 9 (253 mg, yield 60%). ESI-MS: m / z 480.11 [M+H] + . 11H NMR (600MHz, DMSO-d6):δ 9.34(s,1H),8.58(d,J=7.2Hz,1H),7.98(d,J=6.6Hz,1H),7.94(s,1H),7.70(dd ,J=7.2Hz,J=7.2Hz,1H),7.53(dd,J=6.6Hz,J=7.2Hz,1H),7.32(dd,J=7.8Hz,J= 7.8Hz,1H),7.26(t,J=54.6Hz,1H),6.87(d,J=1.8Hz,1H),6.66(dd,J=1.8Hz,J= 2.4Hz, 1H), 5.81-5.79 (m, 1H), 3.56 (s, 3H), 2.49 (s, 3H), 1.63 (d, J=6.6Hz, 3H).

[0212] Example 10: Synthesis of Compound 10 [ka] Synthesis of intermediate 10-1: 9-6 (400 mg, 1.34 mmol) was dissolved in N,N-dimethylformamide (30 mL), followed by the addition of diisopropylethylamine (349 mg, 2.70 mmol) and intermediate G (418 mg, 2.02 mmol). The system was reacted at 120°C for 2 hours, and LC-MS monitoring confirmed that no starting materials remained. The reaction mixture was quenched with ice water, extracted with ethyl acetate (100 mL x 3), combined the organic phases, washed with saturated brine (100 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1~1:2) to obtain 10-1 (415 mg, yield 66%). ESI-MS: m / z 469.02 / 471.09 [M+H] + .

[0213] Synthesis of compound 10: Dissolve 10-1 (415 mg, 0.88 mmol) in dioxane (30 mL), then add 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one (249 mg, 1.06 mmol), tetrakis(triphenylphosphine)palladium(0) (104 mg, 0.09 mmol), and cesium carbonate (574 mg, 1.76 mmol) to the entire system, and 10 The reaction was stirred at 0°C for 3 hours. After monitoring by TLC and confirming that no starting materials remained, water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was purified by column chromatography (dichloromethane:methanol = 60:1~20:1) to obtain compound 10 (250 mg, yield 57%). ESI-MS: m / z 498.11 [M+H] + . 1 H NMR(600MHz,DMSO-d6):δ 9.34(s,1H),8.64(d,J=6.6Hz,1H),7.98(d,J=6.6Hz,1H),7.94(s,1H),7.83(dd,J=7.2Hz,J=7.2Hz,1H),7.67(dd,J=6.6Hz,J=7.2Hz,1H),7.38(dd, J=7.8Hz,J=7.8Hz,1H),6.87(d,J=1.8Hz,1H),6.67(dd,J=1.8Hz,J=1.8Hz ,1H),5.78-5.74(m,1H),3.56(s,3H),2.47(s,3H),1.64(d,J=6.6Hz,3H).

[0214] Example 11: Synthesis of Compound 11 [ka] Synthesis of intermediate 11-1: Intermediate 1-3 (0.68 g, 2.48 mmol) was dissolved in anhydrous ethanol (10 mL), and aminoacetaldehyde diethyl acetal (0.49 g, 3.72 mmol) and N,N-diisopropylethylamine (0.64 g, 4.96 mmol) were added. The mixture was refluxed and reacted for 5 hours, and LC-MS monitoring confirmed that no starting materials remained. The reaction system was cooled, saturated brine was added, and the mixture was extracted with ethyl acetate. It was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent, yielding 11-1 (0.83 g, 90% yield). ESI-MS: m / z 371.58 / 373.32 [M+H] + .

[0215] Synthesis of intermediate 11-2: Intermediate 11-1 (0.83 g, 2.24 mmol) was dissolved in concentrated sulfuric acid and reacted at 65°C for 2 hours. After monitoring by LC-MS and confirming that no starting materials remained, the reaction was slowly quenched by adding the reaction mixture dropwise to saturated sodium bicarbonate solution. Ethyl acetate was added for extraction, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent, yielding 11-2 (0.40 g, 63% yield). ESI-MS: m / z 279.10 / 301.14 [M+H] + .

[0216] Synthesis of intermediate 11-3: Intermediate 11-2 (0.26 g, 0.94 mmol) was dissolved in N,N-dimethylformamide (5 mL), and intermediate B (0.27 g, 1.22 mmol) and 1H-benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate (0.74 g, 1.41 mmol) were added. The mixture was reacted at room temperature for 2 hours. After monitoring by LC-MS and confirming that no starting materials remained, saturated saline solution was added to the reaction system, extracted with ethyl acetate, washed with saturated saline solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent, yielding 11-3 (0.18 g, yield 43%). ESI-MS: m / z 449.90 / 451.91 [M+H] + .

[0217] Synthesis of intermediate 11-4: Dissolve 11-3 (180 mg, 0.40 mmol) in dioxane (40 mL) and water (10 mL), then add potassium hydroxide (67 mg, 1.2 mmol), tris(dibenzylideneacetone)dipalladium (0) (18 mg, 0.02 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (10 mg, 0.02 mmol). Stir the entire system at 100 °C and react for 3 hours. Monitor by TLC and if no starting materials remain, add 50 mL of water to the reaction mixture, extract with ethyl acetate (30 mL x 3), combine the organic phases, wash with saturated brine (50 mL x 2), dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and purify by column chromatography (dichloromethane:methanol = 60:1~20:1) to obtain 11-4 (71 mg, yield 46%). ESI-MS: m / z 388.07[M+H] + .

[0218] Synthesis of compound 11: 11-4 (71 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (15 mL), followed by the addition of (R)-3-(p-toluenesulfonyl)oxytetrahydrofuran (47 mg, 0.19 mmol) and cesium carbonate (104 mg, 0.32 mmol). The entire system was stirred at 80°C and reacted for 3 hours. After monitoring by TLC and confirming that no starting materials remained, 30 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was purified by column chromatography (dichloromethane:methanol = 60:1~20:1) to obtain compound 11 (48 mg, yield 66%). ESI-MS: m / z 458.32 [M+H] + . 1H NMR(600MHz,DMSO-d6):δ 8.29(s,1H),7.87(d,J=4.8Hz,1H),7.82(d,J=6.3Hz,1H),7.67-7.53(m,4H),5.69(p,J=7.2Hz,1H),5.51(d,J=6.5Hz,1H),4 .05(dt,J=10.8,3.6Hz,1H),3.97-3.91(m,2H),3.84(td,J=8.3,4.5Hz,1H),2.45(s,3H),1.68(d,J=7.1Hz,3H),1.23(m,2H).

[0219] Examples 12-30: The compounds in Examples 12 to 30 below may also be obtained by referring to the synthesis methods of Examples 1 to 11. [Table 2-1] [Table 2-2] [Table 2-3]

[0220] Example 31: Synthesis of Compound 31 [ka] Synthesis of compound 31: Intermediate 7-1 (99 mg, 0.22 mmol) from Example 7 was dissolved in dioxane (30 mL), followed by the addition of 1-acetyl-5,6-dihydro-2H-pyridine-4-boronic acid pinacol ester (68 mg, 0.27 mmol), tetrakis(triphenylphosphine)palladium (0) (23 mg, 0.02 mmol), and cesium carbonate (143 mg, 0.44 mmol). The entire system was stirred at 100°C and reacted for 3 hours. After monitoring by TLC and confirming that no starting materials remained, 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The compound was purified by column chromatography (dichloromethane:methanol = 60:1~15:1) to obtain compound 31 (69 mg, 0.14 mmol, yield 64%). ESI-MS: m / z 497.24[M+H] + . 1 1H NMR (600MHz, DMSO-d6):δ 8.23(s,1H),8.00(s,1H),7.64(dd,J=7.2Hz,J=7.2Hz,1H),7.50(dd,J=7.2H z,J=7.2Hz,1H),7.32-7.29(m,1H),7.23(t,J=54.0Hz,1H),6.82(d,J=87.6Hz ,1H),5.75-5.70(m,1H),4.22-4.02(m,4H),3.95-3.92(m,2H),3.67-3.62(m, 2H),2.50(s,3H),2.26(s,3H),2.06(d,J=24.6Hz,2H),1.56(d,J=6.6Hz,3H).

[0221] Examples 32-92: The compounds in Examples 32 to 92 may also be obtained by referring to the synthesis methods of Examples 1 to 11. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7]

[0222] Example 93: Synthesis of Compound 93 [ka] Synthesis of compound 93: Intermediate 5-8 (40 mg, 0.089 mmol) from Example 5 was dissolved in dioxane (10 mL) and water (2 mL). Subsequently, 1-acetyl-5,6-dihydro-2H-pyridine-4-boronic acid pinacol ester (34 mg, 0.133 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13 mg, 0.018 mmol), and cesium carbonate (58 mg, 0.178 mmol) were added. The system was reacted at 100 °C for 4 hours and monitored by LC-MS to ensure no starting materials remained. The solvent was removed by evaporation under reduced pressure, and the residue was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol:triethylamine = 100:2:1) to obtain compound 93 (29 mg, 0.058 mmol, 65% yield). ESI-MS: m / z 497.27 [M+H] + . 1H NMR(600MHz,DMSO-d6):δ 7.97(s,1H),7.76(s,1H),7.72-7.71(m,2H),7.62-7.56(m,2H),7.06(d,J=96.0Hz,1H),5.60-5.55(m,1H),4.16-4. 10(m,2H),4.03-3.90(m,4H),3.66-3.62(m,2H),2.51(s,3H),2.27(s,3H),2.08-2.04(m,2H),1.57(d,J=6.6Hz,3H).

[0223] Examples 94-108: The compounds in Examples 94-108 may also be obtained by referring to the synthesis method in Example 93. [Table 4-1] [Table 4-2] [Table 4-3]

[0224] Example 109: Synthesis of Compound 109 [ka] Intermediate 5-8 (40 mg, 0.089 mmol) from Example 5 was dissolved in dioxane (10 mL) and water (2 mL). Subsequently, 1-(methyl-d3)-pyridine-2-one-4-boronic acid pinacol ester (32 mg, 0.133 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13 mg, 0.018 mmol), and cesium carbonate (58 mg, 0.178 mmol) were added. The system was reacted at 100 °C for 4 hours and monitored by LC-MS to ensure no starting material remained. The solvent was removed by evaporation under reduced pressure, and the residue was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol:triethylamine = 100:2:1) to obtain compound 109 (25 mg, 0.051 mmol, 57% yield). ESI-MS: m / z 484.24 [M+H] + . 1 H NMR(600MHz,DMSO-d6):δ 8.29(s,1H),8.22(d,J=7.2Hz,1H),7.77(s,1H),7.76-7.68(m,2H),7.65-7.54(m,2H),7.28(s,1H) ),6.86(d,J=7.0Hz,1H),5.65-5.53(m,1H),4.22-3.87(m,4H),2.29(s,3H),1.59(d,J=7.0Hz,3H).

[0225] Examples 110-121: The compounds in Examples 110 to 121 may also be obtained by referring to the synthesis method in Example 93. [Table 5-1] [Table 5-2] [Table 5-3]

[0226] Example 122: Synthesis of Compound 122 [ka] Synthesis of intermediate 122-1: Dissolve 7-1 (99 mg, 0.22 mmol) in dioxane (30 mL), then add N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (84 mg, 0.27 mmol), tetrakis(triphenylphosphine)palladium (0) (23 mg, 0.02 mmol), and cesium carbonate (143 mg, 0.44 mmol). Stir the entire system at 100°C and react for 3 hours. Monitor by TLC and if no starting materials remain, add 50 mL of water to the reaction mixture, extract with ethyl acetate (30 mL x 3), combine the organic phases, wash with saturated brine (50 mL x 2), dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and purify by column chromatography (dichloromethane:methanol = 60:1~20:1) to obtain 122-1 (100 mg, yield 82%). ESI-MS: m / z 555.19[M+H] + .

[0227] Synthesis of intermediate 122-2: Dissolve 122-1 (100 mg, 0.18 mmol) in 4 M hydrochloric acid / ethyl acetate solution (10 mL), stir at room temperature, and react for 2 hours. After monitoring by TLC and confirming no starting material remained, remove the solvent under reduced pressure to obtain residue 122-2. The reaction was then carried out directly in the next step. ESI-MS: m / z 455.18 [M+H] + .

[0228] Synthesis of compound 122: Compound 122-2 was dissolved in dichloromethane (10 mL), followed by the addition of triethylamine (36 mg, 0.36 mmol) and methanesulfonyl chloride (25 mg, 0.22 mmol). The mixture was stirred at room temperature and reacted for 2 hours. After monitoring by TLC and confirming that no starting materials remained, water was added to the reaction mixture to quench it. The mixture was extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the compound was purified by column chromatography (dichloromethane:methanol = 60:1~15:1) to obtain compound 122 (50 mg, yield 52%). ESI-MS: m / z 533.20 [M+H] + . 1 H NMR(600MHz,DMSO-d6):δ 8.00(s,1H),7.80(s,1H),7.64(dd,J=7.2Hz,J=7.2Hz,1H),7.50(dd,J=7.2Hz,J=7.2Hz,1H),7.32-7.30(m,1H),7.24(t,J=54.0Hz,1H),7 .11(s,1H),5.75-5.70(m,1H),4.00-3.88(m,6H),3.40-3.37(m,2H),2.95(s,3H),2.72-2.63(m,2H),2.24(s,3H),1.56(d,J=6.6Hz,3H).

[0229] Examples 123, 124: The compounds in Examples 123 and 124 may also be obtained by referring to the synthesis method in Example 93. [Table 6]

[0230] Example 125: Synthesis of Compound 125 [ka] Compound 124 (100 mg, 0.18 mmol) was dissolved in dichloromethane / isopropanol (22 mL, V1:V2=1:10), and phenylsilane (19.5 mg, 0.18 mmol) and tris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III) (7.6 mg, 0.01 mmol) were added in that order at room temperature. The reaction mixture was changed three times under an oxygen atmosphere, and then stirred at room temperature for 16 hours under an oxygen balloon atmosphere. LC-MS showed that the starting materials had reacted completely. The reaction mixture was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 60:1~15:1) to obtain compound 125 (28 mg, yield 28%). ESI-MS: m / z 559.24 [M+H] + . 1 H NMR(400MHz,CD3OD):δ 8.32(d,J=16.0Hz,1H),7.57(t,J=7.2Hz,1H),7.47(t,J=7.2Hz,1H),7.23(t,J=8.0Hz,1H),6.99(t,J=54.8Hz,1H),5.82-5.73(m,1H), 4.56-4.24(m,4H),4.10(t,J=10.0Hz,2H),3.85-3.45(m,2H),2.39(s,3H),2.10-2.06(m,4H),1.64(d,J=7.2Hz,3H),1.28-1.24(m,4H).

[0231] Biological activity measurement test: 1. K-Ras G12D Analysis of the binding of and hSOS1 This assay can investigate the inhibitory effect of compounds on the protein-protein interaction between SOS1 and KRAS G12D. Homogeneous time-resolved fluorescence (HTRF) can be used to analyze the interaction between GST-KRas conjugated with anti-GSK-Europium (FRET donor). G12D Then, the binding of His-labeled hSOS1 (FRET donor) bound to anti-6His-XL665 is detected, and K-Ras G12D The inhibitory effect of the compound on hSOS1 will be measured.

[0232] 1.1 Reagents Buffer solution (5 mM HEPES (pH 7.4), 150 mM NaCl, 10 mM EDTA, 1 mM DTT, 0.05% BAS (pH 7.0), 0.0025% IGEPAR, 100 mM KF) GST-tagged hK-RasG12D (homemade) His-Tagged hSOS1 (Homemade)

[0233] Preparation of Ras mixture: GST-hK-RasG12D 10nM (final concentration) and anti-GSK-Europium 2nM (final concentration) were mixed in a test buffer and left to stand at room temperature in preparation for use.

[0234] Preparation of SOS mixture: His-tagged hSOS1 20 nM (final concentration) and anti-6His-XL665 10 nM (final concentration) were mixed in a test buffer and left to stand at room temperature in preparation for use.

[0235] The test compound was dissolved in DMSO, resulting in a concentration 100 times the test concentration. 50 nL was extracted using a Hummingbird liquid handler or Echo acoustic system and placed in a black detection microplate.

[0236] 1.2 Test Steps All test steps were performed at 20°C. During the test, 2.5 μL of Ras mixture was added to all wells of the detection plate using a multidrop dispenser. After incubation for 2 minutes, 2.5 μL of SOS mixture was added to each of the control wells except for the wells located on the outer periphery, and 2.5 μL of compound control solution was added to the wells located on the outer periphery. After incubation for 60 minutes, the samples were passed through the Pheraster HTRF module (excitation light 337 nm, emission light 1: 620 nm, emission light 2: 665 nm).

[0237] 1.3 Data Calculation IC using a 4-parameter logistic regression model50 The values ​​were calculated and analyzed.

[0238] 1.4 Results of SOS1 inhibitory activity Representative compounds from the examples were tested using the method described above, and the SOS1 inhibitory activity data is shown in the table below. [Table 7]

[0239] Here, A is IC 50 <10nM represents B, where 10nM ≤ IC 50 <50nM represents C, where C is 50nM ≤ IC 50 <100nM represents D, where 100nM ≤ IC 50 This represents <300nM.

[0240] 2. 3D cell proliferation inhibition test Cell proliferation inhibition studies were used to detect in vitro inhibition of the compound at the 3D cell level against the proliferation and growth of tumor cell lines mediated by SOS1, using the CellTiter-Glo® 3D detection assay.

[0241] 2.1 Reagents and Materials NCI-H358: KRAS G12C mutation in non-small cell lung cancer (NSCLC) CellTiter-Glo® 3D Cell Viability Assay, Promega, G9683 RPMI 1640 medium, Gibco, A10491-01 FBS, Gibco, 10099141C

[0242] 2.2 Examination Steps: 2.2.1 Cell culture On day 1, NCI-H358 was subcultured in a T75 cell culture flask. On day 3, the culture medium was removed, the cells were washed once with DPBS, and the cells were digested at room temperature or 37°C with 2 mL of TrypLE® Express Enzyme until the cells were detached. 5 mL of fresh medium was added, and the cells were centrifuged at 1000 rpm for 5 minutes. The supernatant was discarded, and the cells were resuspended with 5 mL of fresh medium. After counting the cells, they were inoculated at 40 μL / well into 3D cell plates (Echo Qualified polypropylene 384-well microplate 2.0, clear, flat-bottom).

[0243] 2.2.2 Inhibition of 3D cell proliferation On day 1, the test compound was dissolved in DMSO to prepare a 10 mM stock solution. After diluting 1000-fold with DMSO solution, a 3-fold gradient dilution was performed to obtain a concentration gradient of 10, with an initial concentration of 10 μM. 200 nL of the compound was added to a culture plate. On day 8, 40 μL / well of 3D CTG reagent was added, and the signal value was detected using Envision.

[0244] 2.3 Data Analysis Using Graphpad Prism 8 nonlinear regression equations for compound IC 50 I substituted the values. Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope)) X: Log of cpd concentration (logarithm of the compound's concentration) Y: Percent inhibition (%inh, inhibition percentage)

[0245] 2.4 Results of NCI-H358 cell proliferation inhibitory activity The compounds in the examples were tested using the method described above, and the NCI-H358 cell proliferation inhibitory activity data is shown in the table below. [Table 8]

[0246] Here, A is IC50 <50nM represents B, where 50nM ≤ IC 50 <100nM represents C, where C is 100nM ≤ IC 50 This represents <500nM.

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