Pyrimidine derivatives or salts thereof used as TLR7 / 8 agonists, and their pharmaceutical compositions and uses

Abstract

This application relates to pyrimidine derivatives described in formula (I-1), formula (I-2), formula (II-1), or formula (II-2), or their stereoisomers, tautomers, isotopic derivatives, hydrates, solvates, prodrugs, and pharmaceutically acceptable salts, which can be used as effective TLR7 and / or TLR8 receptor agonists and are characterized by good selectivity, high activity, and excellent safety. This application also provides a method for preparing the pyrimidine derivatives and a pharmaceutical composition thereof. The compounds of this application or their pharmaceutical compositions can be used in the preparation of pharmaceuticals for the prevention or treatment of infectious diseases, respiratory diseases, immune-related diseases, viral diseases, or tumors. TIFF2026528992000173.tif3891

Description

[Technical Field]

[0001] [Cross-reference of related applications] This application claims priority to a Chinese patent application filed on August 18, 2023, with application number "202311048960.0" and invention title "Pyrimidine derivatives or salts thereof used as TLR7 / 8 agonists, and pharmaceutical compositions thereof and uses," and incorporates all of its contents by reference.

[0002] [Technical field] This application relates to the technical field of Toll-like receptors (TLRs), and more particularly to pyrimidine derivatives or salts thereof used as TLR7 / 8 agonists, and pharmaceutical compositions thereof and their uses, as well as methods for the prevention or treatment of infectious diseases, respiratory diseases, immune-related diseases, viral diseases or tumors using pyrimidine derivatives or salts thereof used as TLR7 and / or TLR8 agonists. [Background technology]

[0003] Toll-like receptors are a relatively conserved family of receptors in evolution, comprising at least 13 members. In humans, 10 types (TLR1-10) have been discovered. TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 are expressed on the cell surface and rapidly recognize bacterial metabolites, while TLR3, TLR7, TLR8, and TLR9 are expressed intracellularly and primarily monitor and recognize viral nucleic acids. TLR3 recognizes double-stranded RNA, TLR7 and TLR8 recognize single-stranded RNA, and TLR9 recognizes unmethylated CG coenzymes, regulating responses to bacterial DNA and certain viruses.

[0004] TLRs can specifically recognize pathogen-associated molecular patterns (PAMPs) and play a crucial role in both innate and adaptive immunity, acting as a bridge between the two. Here, TLR7 recognizes single-stranded RNA or artificially synthesized small purine compounds bound to the virus, then recruits specific linker proteins, activating a series of signaling cascade reactions that initiate a high-level systemic adaptive immune response, killing virus-infected cells and thereby completely eliminating the virus. Clinically, TLR7 agonists are already being used to treat chronic viral infections such as hepatitis B and C. Furthermore, TLR7 agonists can induce more rapid and effective immunoprotection as adjuvants for influenza vaccines. TLR7 agonists can not only directly stimulate pDCs to secrete IFN-α, but they can also enhance the co-stimulatory and antigen-presenting capabilities of pDCs. Activated pDCs promote the proliferation of CD4+ T cells and further activate CD8+ T cells to kill tumor cells. Therefore, TLR7 agonists are increasingly attracting attention for their role as immune adjuvants in the tumor recognition and killing processes in the body. cDCs mature under stimulation of antigens and TLR8 agonists, releasing co-stimulatory factors such as CD80 and CD86, as well as pro-inflammatory cytokines such as IL-12, TNF-α, and IL-6. cDCs that migrate to dLNs activate T cells and stimulate T cells and NK cells to release IFN-γ, further expanding the immune cascade response.

[0005] TLR7 / 8 agonists induce innate and adaptive immune responses through the MyD-NF-κB signaling pathway. As immunomodulators, they can activate and differentiate immune cells, thereby controlling the direction of immune responses. They can exert effects in areas such as respiratory diseases, inflammatory diseases, anti-allergic, antiviral, antitumor, and skin injury, and have already or are currently undergoing numerous studies in preclinical and clinical trials.

[0006] TLR7 and TLR8 receptors exhibit different expression levels in cDCs and pDCs, and also show different expression levels in other somatic and immune cells. Even within the same immune cell, TLR7 (or TLR8) receptor expression levels differ depending on the organ or tissue location, and are regulated by the cell / immune state. TLR signaling regulation is agonist-resistant, and the TLR7 and TLR8 signaling pathways are interrelated. The dose and timing of agonist administration have a significant impact on clinical efficacy, and clinically, they are often ineffective or accompanied by serious side effects or adverse effects (e.g., promoting rather than inhibiting tumor progression).

[0007] Currently, numerous small molecule TLR7 / 8 agonists with different activity levels have been created from approximately 1500 artificially synthesized molecules, each possessing more than 20 nuclear skeletons and combining substitutions and modifications of two main different branched chains. Many of these molecules have clinically stimulating effects on the immune system (RSC Med.Chem., 2021, 12, 1065-1120). The approved R837 and R848 are limited to topical use and skin-related diseases, mainly due to serious target-related side effects and a lack of clinical efficacy.

[0008] While researchers are searching for novel small molecule TLR7 and / or TLR8 agonists, much of the research is focused on optimizing pharmacokinetics, aiming to achieve local accumulation or targeted release and reduce systemic immune responses. This includes sustained-release forms such as hydrosols, nanoparticles (polypeptides, polymers, cyclodextrins, carrier proteins, etc.), branched-chain modified prodrugs such as long-chain fatty acids and phosphates, or combinations with other drugs. These strategies are also being used in research to develop TLR7 and / or TLR8 as vaccine adjuvants (Advanced Drug Delivery Reviews 175(2021)113803). [Overview of the project] [Problems that the invention aims to solve]

[0009] This application aims to provide a pyrimidine derivative that can be used as an effective TLR7 and / or TLR8 receptor agonist, possessing good selectivity, high activity, and excellent safety, and that can be used in the preparation of pharmaceuticals for the prevention or treatment of infectious diseases, respiratory diseases, immune-related diseases, viral diseases, or tumors. This application also provides a method for preparing the pyrimidine derivative and a pharmaceutical composition thereof. [Means for solving the problem]

[0010] To achieve the above objective, in a first aspect, this application provides pyrimidine derivatives which are compounds of formula (I-1) or formula (I-2), or their stereoisomers, tautomers, isotopic derivatives, halogenated derivatives, hydrates, solvates, prodrugs and pharmaceutically acceptable salts, TIFF2026528992000002.tif3680 Here, TIFF2026528992000003.tif810 represents a single bond or a double bond. X1 and X2 are either both C-R3, or one is C-R3 and the other is N. Z is -NH2, -OH, -NH-alkyl, -O-alkyl, -NH-C(O)-alkyl, -OC(O)-alkyl, -NH-C(O)-OH, -OC(O)-OH, Y is -O-, -S-, or -NR4-, where R4 is H or an optionally substituted alkyl group. R1 is alkyl or aryl, and can be oxo, halogen, amino, hydroxy, nitro, cyano, mercapto, -C(O)-NH2, -C(O)-OH, heteroaryl (optionally substituted with one or more of halogen, amino, hydroxy, nitro, cyano, mercapto, alkoxy, or alkyl), aryl (optionally substituted with one or more of halogen, amino, hydroxy, nitro, cyano, mercapto, alkoxy, or alkyl), heterocycloalkyl (optionally substituted with one or more of halogen, amino, hydroxy, nitro, cyano, mercapto, alkoxy, or alkyl), cycloalkyl (optionally substituted with one or more of halogen, amino, hydroxy, nitro, cyano, mercapto, alkoxy, or alkyl), optionally substituted alkyl, optionally substituted alkyl Optionally substituted with one or more selected from oxy, optionally substituted alkylthio, optionally substituted alkylamino, optionally substituted alkylacyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, optionally substituted -C(O)-O-alkyl, optionally substituted -OC(O)-alkyl, optionally substituted -C(O)-NH-alkyl, optionally substituted -NH-C(O)-alkyl, optionally substituted -S(O)-O-alkyl, optionally substituted -OS(O)-alkyl, optionally substituted -S(O)2-O-alkyl, optionally substituted -OS(O)2-alkyl, optionally substituted -S(O)-NH-alkyl, optionally substituted -NH-S(O)-alkyl, optionally substituted -S(O)2-NH-alkyl, optionally substituted -NH-S(O)2-alkyl, R2 is TIFF2026528992000004.tif1120 or The file is TIFF2026528992000005.tif1636, and -L3-R7 can be substituted at the para, meta, or ortho position of L2. L1, L2, and L3 are bonded, optionally substituted linear alkylenes, where one, two, or more carbon atoms in the linear alkylene may be substituted with heteroatoms oxygen, sulfur, or nitrogen, and the substituents are selected from one or more of optionally substituted alkyl, halogen, amino, hydroxy, nitro, cyano, mercapto, optionally substituted alkyloxy, optionally substituted alkylthio, or optionally substituted alkylamino. R5 is a cycloalkyl or heterocycloalkyl, and is optionally substituted with one or more selected from oxo, halogen, amino, hydroxy, nitro, cyano, mercapto, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, and optionally substituted alkylamino. W and V may be N or CH, and if W or V is CH, it may be substituted with R6 or -L3-R7. R3 and R6 are independently H, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamino, halogen, amino, hydroxy, nitro, cyano, and mercapto. R7 is H, -OH, -N(R9R 10 ), -N(R9)NH2, -NO(R9R 10 ), optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl-NR9-, optionally substituted cycloalkyl-NR9-, optionally substituted aryl-NR9-, optionally substituted heteroaryl-NR9-, -OC(O)-R9, -C(O)O-R9, -N(R9)-C(O)-R 10 ,-C(O)-N(R9R 10 ) and the substituent is selected from one or more of optionally substituted alkyl, optionally substituted alkylamino, and oxo. R8 is H or an optionally substituted alkyl group. R9, R 10These are, independently, H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl. The substituents in the optionally substituted alkyl group are selected from one or more of the following: halogen, amino, hydroxy, nitro, cyano, mercapto, carboxyl, ester, amide groups, etc. n is 0, 1, 2, 3, or 4.

[0011] In one embodiment, X1 and X2 are, in one case, C-R3 and in the other case, N.

[0012] In one embodiment, R8 is H or an optionally substituted C1-8 alkyl group.

[0013] In one embodiment, R1 is a C1-8 alkyl group, optionally substituted with one or more groups selected from optionally substituted C1-8 alkyloxy, optionally substituted C1-8 alkylthio, optionally substituted C1-8 alkylamino, optionally substituted C1-8 alkylacyl, optionally substituted C1-8 alkylsulfinyl, or optionally substituted C1-8 alkylsulfonyl, preferably R1 is a C2-6 alkyl group, optionally substituted with a group selected from optionally substituted C1-6 alkyloxy, optionally substituted C1-6 alkylthio, or optionally substituted C1-6 alkylsulfonyl, preferably R1 is optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, 2-hexyl, or 3-hexyl.

[0014] Furthermore, R1 is n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-hexyl, methoxyethyl, methylthioethyl, methylsulfonylethyl, methoxypropyl, methylthiopropyl, methylsulfonylpropyl, The filename is TIFF2026528992000006.tif2145. Preferably, R1 is n-butyl, TIFF2026528992000007.tif1927 Methylthiopropyl, Methylsulfonylpropyl, The filename is TIFF2026528992000008.tif2145.

[0015] In one embodiment, both W and V are N, and both W and V are C, or either X or V is N.

[0016] In one embodiment, the heterocycloalkyl is a 3- to 12-membered monocyclic, bicyclic, or polycyclic heterocycloalkyl, preferably a 3- to 12-membered monocyclic, bicyclic, or polycyclic heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, more preferably the heteroatoms in the heterocycloalkyl are linked to L1 or L3, and even more preferably the N atoms in the heterocycloalkyl are linked to L1 or L3.

[0017] Furthermore, the heterocycloalkyl is a 3-7 member monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N, O, and S, or a 7-12 member fused ring or spiro-ring heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, preferably a 4-6 member monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N and O, or a 7-11 member spiro-ring heterocycloalkyl containing 2, 3, or 4 heteroatoms selected from N and O.

[0018] Furthermore, heterocycloalkyls are It may also be any of the following: TIFF2026528992000009.tif15155.

[0019] In one embodiment, the aryl is a C6-10 aryl, preferably a phenyl.

[0020] In one embodiment, L1, L2, and L3 are linear alkylenes containing 1 to 6 bonded or optionally substituted chain atoms, where 1 to 2 carbon atoms in the alkylene may be substituted with heteroatoms oxygen, sulfur, or nitrogen, and the substituents are selected from C1-8 alkyl, halogen, amino, hydroxy, nitro, cyano, and mercapto.

[0021] Furthermore, L1 is a linear alkylene containing 1 to 4 optionally substituted chain atoms, preferably a linear alkylene containing 2 to 3 optionally substituted chain atoms, and more preferably an -O-propylene group- or -CH2CH2CH2-.

[0022] L2 is a linear alkylene containing 1 to 4 optionally substituted chain atoms, preferably a linear alkylene containing 2 to 3 optionally substituted chain atoms, and more preferably -CH2-, -CH2CH2-, -O-, -O-CH2-CH2-, -O-CH2-.

[0023] L3 is a linear alkylene containing 1 to 4 chain atoms bonded and optionally substituted, preferably a linear alkylene containing 2 to 3 chain atoms bonded and optionally substituted, more preferably bonded to -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-CH2-, -O-CH2-, -CH(CH3)CH2-, and even more preferably The filename is TIFF2026528992000010.tif1031.

[0024] In one set of mounting devices, R9, R 10 Each of these is independently either H or C1-8 alkyl.

[0025] In one embodiment, R7 is -OH, -N(R9R 10 ), -N(R9)NH2, -NO(R9R 10)、3- to 12-membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms selected from optionally substituted N, O, S; optionally substituted C6-10 aryl; 3- to 12-membered heterocycloalkyl-NR9- containing 1, 2, 3 or 4 heteroatoms selected from optionally substituted N, O, S; optionally substituted C6-10 aryl-NR9-, wherein the substituents are selected from one or more of optionally substituted C1-8 alkyl, optionally substituted C1-8 alkylamino, optionally substituted di(C1-8)alkylamino, oxo, and R9, R 10 are each independently H or C1-8 alkyl, and the heterocycloalkyl is preferably a 4- to 6-membered monocyclic heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O, or a 7- to 11-membered spirocyclic heterocycloalkyl containing 2, 3, 4 heteroatoms selected from N, O, more preferably, the heteroatoms in the heterocycloalkyl are linked to L3, and even more preferably, the N atom in the heterocycloalkyl is linked to L3.

[0026] In one set of embodiments, R2 is optionally substituted TIFF202652899,2000011.tif, 227,155 TIFF202652899,2000012.tif, 224,151 selected from any of TIFF202652899,2000013.tif, 234,153, and further, R2 is optionally substituted TIFF202652899,2000014.tif, 181,23 TIFF202652899,2000015.tif, 50,150, and the substituents are selected from one or more of alkyl, alkyloxy, alkylthio, alkylamino, halogen, amino, hydroxy, nitro, cyano, mercapto.

[0027] In one set of preferred embodiments, the compound of formula (I-1) or formula (I-2) is particularly TIFF202652899,2000016.tif, 150,151 TIFF2026528992000017.tif240151 TIFF2026528992000018.tif234151 It has one of the following: TIFF2026528992000019.tif202151.

[0028] In a second aspect, the present application provides pyrimidine derivatives which are compounds of formula (I-1), or stereoisomers, tautomers, isotopic derivatives, halogenated derivatives, hydrates, solvates, prodrugs and pharmaceutically acceptable salts thereof. TIFF2026528992000020.tif2934 Here, both X1 and X2 are selected from C-R3. Z is -NH2, -OH, Y is -O-, -S-, or -NR4-, where R4 is H or an optionally substituted alkyl group. R1 is alkyl and is optionally substituted with one or more selected from oxo, halogen, amino, hydroxy, nitro, cyano, mercapto, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamino, optionally substituted alkylacyl, optionally substituted alkylsulfinyl, and optionally substituted alkylsulfonyl. R2 is The file is TIFF2026528992000021.tif1636, and -L3-R7 can be substituted at the para, meta, or ortho position of L2. L2 and L3 are bonded, optionally substituted linear alkylenes, where one, two, or more carbon atoms in the linear alkylene may be substituted with heteroatoms oxygen, sulfur, or nitrogen, and the substituents are selected from one or more of optionally substituted alkyl, halogen, amino, hydroxy, nitro, cyano, mercapto, optionally substituted alkyloxy, optionally substituted alkylthio, or optionally substituted alkylamino. W and V may be N or CH, and if W or V is CH, it may be substituted with R6 or -L3-R7. R3 and R6 are independently H, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamino, halogen, amino, hydroxy, nitro, cyano, and mercapto. R7 is H, -OH, -N(R9R 10 ), -N(R9)NH2, -NO(R9R 10 ), optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl-NR9-, optionally substituted cycloalkyl-NR9-, optionally substituted aryl-NR9-, optionally substituted heteroaryl-NR9-, -OC(O)-R9, -C(O)O-R9, -N(R9)-C(O)-R 10 ,-C(O)-N(R9R 10 ) and the substituent is selected from one or more of optionally substituted alkyl, optionally substituted alkylamino, and oxo. R9, R 10 These are, independently, H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl. The substituents in the optionally substituted alkyl group are selected from one or more of the following: halogen, amino, hydroxy, nitro, cyano, mercapto, carboxyl, ester, amide groups, etc. n is 0, 1, 2, 3, or 4.

[0029] In one embodiment, R1 is a C1-8 alkyl group, optionally substituted with one or more optionally substituted C1-8 alkylthio groups or optionally substituted C1-8 alkylsulfonyl groups, preferably R1 is a C2-6 alkyl group, optionally substituted with groups selected from optionally substituted C1-6 alkylthio groups or optionally substituted C1-6 alkylsulfonyl groups.

[0030] Furthermore, R1 is n-butyl, n-pentyl, 2-pentyl, n-hexyl, 2-hexyl, 3-hexyl, methoxyethyl, methylthioethyl, methylsulfonylethyl, methoxypropyl, methylthiopropyl, methylsulfonylpropyl, The filename is TIFF2026528992000022.tif2145, and preferably R1 is n-butyl. TIFF2026528992000023.tif1931 Methylthiopropyl, Methylsulfonylpropyl, The filename is TIFF2026528992000024.tif2145.

[0031] In one embodiment, W and V are both N, or W and V are both C, or one of W and V is N.

[0032] In one embodiment, the heterocycloalkyl is a 3- to 12-membered monocyclic, bicyclic, or polycyclic heterocycloalkyl, preferably a 3- to 12-membered monocyclic, bicyclic, or polycyclic heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, more preferably the heteroatoms in the heterocycloalkyl are linked to L1 or L3, and even more preferably the N atoms in the heterocycloalkyl are linked to L1 or L3.

[0033] Furthermore, the heterocycloalkyl is a 3-7 member monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N, O, and S, or a 7-12 member fused ring or spiro-ring heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, preferably a 4-6 member monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N and O, or a 7-11 member spiro-ring heterocycloalkyl containing 2, 3, or 4 heteroatoms selected from N and O. Furthermore, heterocycloalkyls are It is one of the following: TIFF2026528992000025.tif30134.

[0034] In one embodiment, L2 and L3 are linear alkylenes containing 1 to 6 bonded or optionally substituted chain atoms, where 1 to 2 carbon atoms in the linear alkylene may be substituted with heteroatoms, oxygen, and the substituents are selected from C1-8 alkyl, halogen, amino, hydroxy, nitro, cyano, and mercapto.

[0035] Furthermore, L2 is a linear alkylene containing 1 to 4 optionally substituted chain atoms, preferably a linear alkylene containing 2 to 3 optionally substituted chain atoms, and more preferably -CH2-, -CH2CH2-, -O-, -O-CH2-CH2-, -O-CH2- L3 is a linear alkylene containing 1 to 4 chain atoms bonded and optionally substituted, more preferably a linear alkylene containing 2 to 3 chain atoms bonded and optionally substituted, preferably bonded to -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-CH2-, -O-CH2-, -CH(CH3)CH2-, more preferably The filename is TIFF2026528992000026.tif1031.

[0036] In one embodiment, R7 is -OH, -N(R9R 10 ), -N(R9)NH2, -NO(R9R 10 ), a 3-12 member heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms selected from optionally substituted N, O, S, optionally substituted C6-10 aryl, a 3-12 member heterocycloalkyl-NR9- containing 1, 2, 3 or 4 heteroatoms selected from optionally substituted N, O, S, optionally substituted C6-10 aryl-NR9-, wherein the substituents are selected from one or more of optionally substituted C1-8 alkyl, optionally substituted C1-8 alkylamino, optionally substituted di(C1-8)alkylamino, and oxo, R9, R 10Each of these is independently H or C1-8 alkyl, and the heterocycloalkyl is preferably a 4-6 member monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N and O, or a 7-11 member spirocyclic heterocycloalkyl containing 2, 3, or 4 heteroatoms selected from N and O, more preferably the heteroatoms in the heterocycloalkyl are linked to L3, and even more preferably the N atoms in the heterocycloalkyl are linked to L3.

[0037] Furthermore, R7 is -NO(R9R 10 ), is a 3- to 12-membered heterocycloalkyl group containing 1, 2, 3, or 4 heteroatoms optionally selected from oxosubstituted N, O, and S.

[0038] In one embodiment, R2 is optionally replaced TIFF2026528992000027.tif147154 TIFF2026528992000028.tif239153 TIFF2026528992000029.tif236152 Select from one of the following: TIFF2026528992000030.tif38152 Furthermore, R2 is arbitrarily substituted The filename is TIFF2026528992000031.tif52156. The substituent is selected from one or more of the following: alkyl, alkyloxy, alkylthio, alkylamino, halogen, amino, hydroxy, nitro, cyano, mercapto, carboxyl, ester group, amide group, etc.

[0039] In one preferred embodiment, the compound of formula (I-1) is particularly TIFF2026528992000032.tif83120 It has one of the following: TIFF2026528992000033.tif249132.

[0040] In a third aspect, the present application provides pyrimidine derivatives which are compounds of formula (II-1) or formula (II-2), or their stereoisomers, tautomers, isotopic derivatives, halogenated derivatives, hydrates, solvates, prodrugs and pharmaceutically acceptable salts, TIFF2026528992000034.tif3178 Here, X3 is N or CH, and X4 is CH, N, or NO. If X3 or X4 is CH, it can be substituted with R3. Z is -NH2, -OH, -NH-alkyl, -O-alkyl, -NH-C(O)-alkyl, -OC(O)-alkyl, -NH-C(O)-OH, -OC(O)-OH, Y is -O-, -S-, or -NR4-, where R4 is H or an optionally substituted alkyl group. R1 is alkyl or aryl, and can be oxo, halogen, amino, hydroxy, nitro, cyano, mercapto, -C(O)-NH2, -C(O)-OH, heteroaryl (optionally substituted with one or more of halogen, amino, hydroxy, nitro, cyano, mercapto, alkoxy, or alkyl), aryl (optionally substituted with one or more of halogen, amino, hydroxy, nitro, cyano, mercapto, alkoxy, or alkyl), heterocycloalkyl (optionally substituted with one or more of halogen, amino, hydroxy, nitro, cyano, mercapto, alkoxy, or alkyl), cycloalkyl (optionally substituted with one or more of halogen, amino, hydroxy, nitro, cyano, mercapto, alkoxy, or alkyl), optionally substituted alkyl, optionally substituted alkyl Optionally substituted with one or more selected from oxy, optionally substituted alkylthio, optionally substituted alkylamino, optionally substituted alkylacyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, optionally substituted -C(O)-O-alkyl, optionally substituted -OC(O)-alkyl, optionally substituted -C(O)-NH-alkyl, optionally substituted -NH-C(O)-alkyl, optionally substituted -S(O)-O-alkyl, optionally substituted -OS(O)-alkyl, optionally substituted -S(O)2-O-alkyl, optionally substituted -OS(O)2-alkyl, optionally substituted -S(O)-NH-alkyl, optionally substituted -NH-S(O)-alkyl, optionally substituted -S(O)2-NH-alkyl, optionally substituted -NH-S(O)2-alkyl, R2 is TIFF2026528992000035.tif1119 or The file is TIFF2026528992000036.tif1632, and -L3-R7 can be substituted at the para, meta, or ortho position of L2. L1, L2, and L3 are bonded, optionally substituted linear alkylenes, where one, two, or more carbon atoms in the linear alkylene may be substituted with heteroatoms oxygen, sulfur, or nitrogen, and the substituents are selected from one or more of optionally substituted alkyl, halogen, amino, hydroxy, nitro, cyano, mercapto, optionally substituted alkyloxy, optionally substituted alkylthio, or optionally substituted alkylamino. R5 is a cycloalkyl or heterocycloalkyl, and is optionally substituted with one or more selected from oxo, halogen, amino, hydroxy, nitro, cyano, mercapto, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, and optionally substituted alkylamino. W and V may be N or CH, and if W or V is CH, it may be substituted with R6 or -L3-R7. R3 and R6 are independently H, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamino, halogen, amino, hydroxy, nitro, cyano, or mercapto. R7 is H, -OH, -N(R9R 10 ), -N(R9)NH2, -NO(R9R 10 ), optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl-NR9-, optionally substituted cycloalkyl-NR9-, optionally substituted aryl-NR9-, optionally substituted heteroaryl-NR9-, -OC(O)-R9, -C(O)O-R9, -N(R9)-C(O)-R 10 ,-C(O)-N(R9R 10 ) and the substituent is selected from one or more of optionally substituted alkyl, optionally substituted alkylamino, and oxo. R9, R 10These are, independently, H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl. The substituents in the optionally substituted alkyl group are selected from one or more of the following: halogen, amino, hydroxy, nitro, cyano, mercapto, carboxyl, ester, amide groups, etc. m is 0, 1, 2, or 3, and n is 0, 1, 2, 3, or 4.

[0041] In one embodiment, R1 is a C1-8 alkyl group, optionally substituted with one or more groups selected from optionally substituted C1-8 alkyloxy, optionally substituted C1-8 alkylthio, optionally substituted C1-8 alkylamino, optionally substituted C1-8 alkylacyl, optionally substituted C1-8 alkylsulfinyl, and optionally substituted C1-8 alkylsulfonyl groups, preferably R1 is a C2-6 alkyl group, optionally substituted with groups selected from optionally substituted C1-6 alkyloxy, optionally substituted C1-6 alkylthio, and optionally substituted C1-6 alkylsulfonyl groups.

[0042] Furthermore, R1 is optionally substituted with methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, 2-hexyl, or 3-hexyl. Preferably, R1 is n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-hexyl, methoxyethyl, methylthioethyl, methylsulfonylethyl, methoxypropyl, methylthiopropyl, methylsulfonylpropyl, The filename is TIFF2026528992000037.tif2145. More preferably, R1 is n-butyl, TIFF2026528992000038.tif1927 Methylthiopropyl, Methylsulfonylpropyl, The filename is TIFF2026528992000039.tif2145.

[0043] In one embodiment, both W and V are N, and both W and V are C, or either X or V is N.

[0044] In one embodiment, the heterocycloalkyl is a 3- to 12-membered monocyclic, bicyclic, or polycyclic heterocycloalkyl, preferably a 3- to 12-membered monocyclic, bicyclic, or polycyclic heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, preferably the heteroatoms in the heterocycloalkyl are linked to L1 or L3, and more preferably the N atoms in the heterocycloalkyl are linked to L1 or L3.

[0045] Furthermore, the heterocycloalkyl is a 3-7 member monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N, O, and S, or a 7-12 member fused ring or spiro-ring heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, preferably a 4-6 member monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N and O, or a 7-11 member spiro-ring heterocycloalkyl containing 2, 3, or 4 heteroatoms selected from N and O.

[0046] Furthermore, heterocycloalkyls are It may also be any of the TIFF2026528992000040.tif15155 files.

[0047] In one embodiment, the aryl is a C6-10 aryl, preferably a phenyl.

[0048] In one embodiment, L1, L2, and L3 are linear alkylenes containing 1 to 6 bonded or optionally substituted chain atoms, where 1 to 2 carbon atoms in the alkylene may be substituted with heteroatoms oxygen and sulfur, and the substituents are selected from C1-8 alkyl, halogen, amino, hydroxy, nitro, cyano, and mercapto.

[0049] Furthermore, L1 is a linear alkylene containing 1 to 4 optionally substituted chain atoms, preferably a linear alkylene containing 2 to 3 optionally substituted chain atoms, and more preferably an -O-propylene group- or -CH2CH2CH2-.

[0050] L2 is a linear alkylene containing 1 to 4 optionally substituted chain atoms, preferably a linear alkylene containing 2 to 3 optionally substituted chain atoms, and more preferably -CH2-, -CH2CH2-, -O-, -O-CH2-CH2-, -O-CH2- L3 is a linear alkylene containing 1 to 4 bonded and optionally substituted chain atoms, preferably a linear alkylene containing 2 to 3 bonded and optionally substituted chain atoms, more preferably -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-CH2-, -O-CH2-, -CH(CH3)CH2-, and even more preferably The filename is TIFF2026528992000041.tif1031.

[0051] In one embodiment, R7 is OH, -N(R9R 10 ), -N(R9)NH2, -NO(R9R 10 ), a 3-12 member heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms selected from optionally substituted N, O, S, optionally substituted C6-10 aryl, a 3-12 member heterocycloalkyl-NR9- containing 1, 2, 3 or 4 heteroatoms selected from optionally substituted N, O, S, optionally substituted C6-10 aryl-NR9-, wherein the substituents are selected from one or more of optionally substituted C1-8 alkyl, optionally substituted C1-8 alkylamino, optionally substituted di(C1-8)alkylamino, and oxo, R9, R 10Each of these is independently H or C1-8 alkyl. The heterocycloalkyl is preferably a 4-6 member monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N and O, or a 7-11 member spirocyclic heterocycloalkyl containing 2, 3, or 4 heteroatoms selected from N and O, more preferably the heteroatoms in the heterocycloalkyl are linked to L3, and even more preferably the N atoms in the heterocycloalkyl are linked to L3.

[0052] In one embodiment, R2 is optionally replaced TIFF2026528992000042.tif199152 TIFF2026528992000043.tif228154 TIFF2026528992000044.tif219153 Select from one of the following: TIFF2026528992000045.tif38152 Furthermore, R2 is arbitrarily substituted The filename is TIFF2026528992000046.tif52157. The substituent is selected from one or more of the following: alkyl, alkyloxy, alkylthio, alkylamino, halogen, amino, hydroxy, nitro, cyano, mercapto, carboxyl, ester group, amide group, etc.

[0053] In one preferred embodiment, the compound of formula (II-1) or formula (II-2) is particularly TIFF2026528992000047.tif123150 It is possible to have TIFF2026528992000048.tif231151.

[0054] For brevity, the terms "Formula (I-1)", "Formula (I-2)", "Formula (II-1)", "Formula (II-2)", "Compound of this Application", and "Compound of this Application" described below also include their stereoisomers, tautomers, isotopic derivatives, halogenated derivatives, hydrates, solvates, prodrugs, and pharmaceutically acceptable salts.

[0055] This application further provides a method for preparing formula (I-1), which can be prepared by any of the following routes. Route 1: JPEG2026528992000049.jpg89147

[0056] Route 2: JPEG2026528992000050.jpg85147

[0057] Route 3: JPEG2026528992000051.jpg94147

[0058] Route 4: The definitions of the other elements in JPEG2026528992000052.jpg84134 are all as described above.

[0059] This application further provides a method for preparing formula (II-1), which can be prepared by any of the following routes.

[0060] Route 5: JPEG2026528992000053.jpg63147

[0061] Route 6: The definitions of other elements are as described above.

[0062] In one embodiment, the linking group between L1 or L2 and the ring containing X3 is -O-.

[0063] This application further provides a method for preparing formula (II-2), which can be prepared by the following route.

[0064] Route 7: The definitions of other elements in JPEG2026528992000055.jpg49147 are as described above.

[0065] In one embodiment, the linking group between L1 or L2 and the ring containing X4 is -O-.

[0066] This application further provides a method for preparing formula (II-2), which can be prepared by the following route.

[0067] Route 8: The definitions of other elements in JPEG2026528992000056.jpg33147 are as described above.

[0068] This application further provides a pharmaceutical composition comprising the compound of this application as an active ingredient and further comprising a pharmaceutically acceptable adjuvant, the pharmaceutical composition further comprising a pharmaceutically acceptable carrier or excipient.

[0069] The administration routes of the compound or pharmaceutical composition thereof of this application include, but are not limited to, oral, rectal, mucosal permeation, topical, transdermal, inhalation, parenteral, sublingual, vaginal, nasal, intramuscular, subcutaneous, and intravenous administration. The dosage is 0.1 to 0.2 mg / kg, preferably 0.1 mg / kg once daily. Furthermore, the concentration of the compound in the composition is 0.1 to 0.2 mg / kg, with a preferred concentration of 0.1 mg / kg.

[0070] The pharmaceutical composition further comprises at least one other therapeutic agent, the therapeutic agent being selected from chemotherapeutic agents, immunotherapeutic agents, anti-angiogenic agents, cytokines, hormones, polynucleotides, antibodies, and immunoactive fragments. If the pharmaceutical composition contains multiple active ingredients, each active ingredient may be administered simultaneously, sequentially, or separately at the discretion of the physician.

[0071] The antibodies are Her2 and / or PD-1 and / or PD-L1 and / or TIM-3 antibodies, and preferably the antibodies are PD-L1 antibody and Her2 antibody.

[0072] The compounds or pharmaceutical compositions thereof of this application can be used as TLRs receptor agonists to prepare pharmaceuticals for the prevention or treatment of diseases or conditions related to TLRs activity, where “diseases or conditions related to TLRs activity” refers to any pathological condition related to Toll-like receptors. Preferably, they are used as TLR7 and / or TLR8 receptor agonists and preferably for use in mammals.

[0073] This application further provides uses for the compounds or pharmaceutical compositions thereof in the preparation of pharmaceuticals for the prevention or treatment of infectious diseases, respiratory diseases, immune-related diseases, viral diseases, or proliferative disorders.

[0074] The above-mentioned diseases are preferably asthma, tumors, HIV, and HBV.

[0075] The respiratory diseases include, but are not limited to, asthma, chronic obstructive pulmonary disease, and adult respiratory distress syndrome. The immune-related diseases include, but are not limited to, systemic lupus erythematosus, Sjögren's syndrome, Wegener's granulomatosis, sarcoidosis, Reiter's syndrome, Behçet's disease, rheumatoid arthritis, inflammatory bowel disease, polymyositis, vasculitis, ankylosing spondylitis, and psoriatic arthritis.

[0076] The aforementioned viral diseases include, but are not limited to, Ebola virus disease, anthrax infection, genital warts, common warts, plantar warts, respiratory syncytial virus, hepatitis B, hepatitis C, dengue virus, herpes simplex virus (e.g., HSV-I, HSV-11), molluscum contagiosum, emphysema, smallpox, lentivirus, human immunodeficiency virus (HIV), human papillomavirus (HPV), cytomegalovirus, varicella-zoster virus, nasal viruses, enteric viruses, adenovirus, influenza, parainfluenza, mumps virus, measles virus, papovavirus, flavivirus, retrovirus, sand virus (e.g., LCM, uninvirus, machupovirus, guanalitovirus, and Lassa fever) and filovirus (e.g., Ebola virus or marbovirus).

[0077] The aforementioned cell proliferative disorders are tumors, including but not limited to human sarcomas and carcinomas, such as lymphoma, osteosarcoma, fibrosarcoma, myasarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endosarcoma, lymphangiosarcoma, lymphangiosarcoma, synoviomas, mesothelioma, Euin sarcoma, leiomyosarcoma, rhabdomyosarcoma, uterine sarcoma, neuroma, gastrointestinal cancer, colon cancer, rectal cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, and papillary carcinoma. Examples include medullary carcinoma, bronchial carcinoma, hepatocellular carcinoma, liver carcinoma, cholangiocarcinoma, choriocarcinoma, spermatogonia, germ cell tumor, nephroblastoma, cervical carcinoma, ovarian carcinoma, testicular carcinoma, kidney carcinoma, lung carcinoma, epithelial carcinoma, glioblastoma, astrocytoma, medulloblastoma, craniopharyngocytic canal, ependymoma, pineal glandoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, polycythemia vera, multiple myeloma, and heavy chain disease. The aforementioned adenocarcinoma may also be thyroid carcinoma, pancreatic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, breast carcinoma, papillary carcinoma, cystic carcinoma, or prostate carcinoma, and the aforementioned lung carcinoma may be small cell lung carcinoma. The aforementioned leukemias are acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, and chronic granulocytic leukemia. The aforementioned lymphomas are Hodgkin's disease and non-Hodgkin's disease.

[0078] Preferably, the tumor is a cold tumor, and more preferably, the tumor is colon cancer, bladder cancer, melanoma, meningioma, lung cancer, liver cancer, or pancreatic cancer.

[0079] This application further provides uses of the compounds or pharmaceutical compositions thereof in the preparation of pharmaceuticals for preventing tumor recurrence, preferably by inducing persistent systemic immune memory.

[0080] This application further provides uses of the compound or pharmaceutical composition of this application in the preparation of a Conjugate (ADC) payload and in the preparation of a Conjugate (SMDC) payload.

[0081] This application further provides uses of the compounds or pharmaceutical compositions of this application in the preparation of pharmaceutical formulations, preferably the pharmaceutical formulations upregulating the number of genes favorable for immunotherapy in various pathways, such as inflammation and cytokine-mediated pathways, T cell activation / apoptotic signaling pathways, and B cell activation pathways. More preferably the pharmaceutical formulations upregulating the number of genes favorable for tumor immunotherapy in the above pathways. Furthermore, the pharmaceutical formulations increase the number of CD8+ T cells, further improve the CD8+ T cell / Treg cell ratio, and further increase the expression of PDL-1. Furthermore, the pharmaceutical formulations increase the level of interleukin-2 and / or interferon-Y and / or decrease the level of interleukin-10.

[0082] This application further provides uses of the compound or the pharmaceutical composition thereof in the preparation of formulations that downregulate the Wnt signaling pathway. Preferably, the expression level of the S-catenin protein is downregulated.

[0083] This application further provides uses of the compounds or pharmaceutical compositions thereof in the preparation of pharmaceutical formulations that affect the secretion levels of various cytokines in macrophages, preferably affecting the mRNA level expression of genes such as Illb, 116, 1112b, Tnf, Ifnbl, Cxcll, Cxcll0, and 1110.

[0084] This application further provides a method for improving a positive immune response in a living organism, comprising regulating TLR7 and / or TLR8 by administering a therapeutically effective amount of the compound or a pharmaceutical composition thereof to a system or individual in need.

[0085] This application further provides a method for enhancing the effects of chemotherapy, comprising administering a therapeutically effective amount of a chemotherapeutic agent to a system or individual in need, and simultaneously with, or subsequently, administering a therapeutically effective amount of the compound of this application or a pharmaceutical composition thereof.

[0086] This application further provides a method for enhancing immunotherapy, comprising administering a therapeutically effective amount of the compound or its pharmaceutical composition to a system or individual as needed, and simultaneously, or subsequently, introducing chimeric antigen receptor T cells (CAR-T) into the system or individual.

[0087] This application further provides uses for the compounds or pharmaceutical compositions of this application in the preparation of vaccine adjuvants.

[0088] This application has the following beneficial effects. 1. The compounds of this application have excellent TLR7 and / or TLR8 receptor agonist activity and can be used in the preparation of pharmaceuticals for the prevention or treatment of infectious diseases, respiratory diseases, immune-related diseases, viral diseases, or cell proliferation disorders. 2. The compounds of this application exhibit extremely high immune response stimulating activity against peripheral blood mononuclear cells in the immune system. The levels of interferon-γ and various other pro-inflammatory cytokines and chemokines secreted by human peripheral blood mononuclear cells are far higher than those of the control substances D18 and R848. The compounds of this application can potently activate the cancer cell-killing ability of human peripheral blood mononuclear cells. 3. The compounds of this application have a short half-life, and a short half-life can reduce the risk of the compounds causing a systemic immune response in the body. The compounds of this application have a high distribution concentration in liver tissue. 4. The compounds of this application have higher relative safety and superior tumor-suppressing effects. [Brief explanation of the drawing]

[0089] [Figure 1] This figure shows the effect of the compound of this application on the cytokine secretion level of human peripheral blood mononuclear cells. [Figure 2] This figure shows the pharmacokinetics of the compound of this application in mice. [Figure 3] This figure shows the inhibitory effect of the compound in this application on mouse CT26 tumors. [Modes for carrying out the invention]

[0090] [Specific implementation details] The specific embodiments of this application will be described in detail below. It should be understood that the specific embodiments described herein are for illustrative and interpretive purposes only and are not intended to limit this application.

[0091] The endpoints and any values ​​of the ranges disclosed herein are not limited to such exact ranges or values, and these ranges or values ​​should be understood to include values ​​that approximate these ranges or values. For numerical ranges, one or more new numerical ranges can be obtained by combining the endpoint values ​​of each range, the endpoint values ​​of each range with individual point values, and the endpoint values ​​of individual points with each other, and these numerical ranges should be considered as specifically disclosed herein.

[0092] Before describing this application in detail, it should be understood that the terms used herein are for the sole purpose of describing specific embodiments and are not intended to limit the scope of this application, which is limited only by the appended claims. For a more complete understanding of this application as described herein, the following terms are adopted, and their definitions are set forth below. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those understood by those skilled in the art to which this application belongs.

[0093] definition Unless otherwise specified, the following terms in this application have the following definitions.

[0094] In this application, in specific compound numbers, "M030xxx", "030xxx", "M30xxx", and "30xxx" can all be abbreviated as "xxx" and represent the same compound as "xxx". "M0300xx", "0300xx", "M300xx", and "300xx" can all be abbreviated as "xx" and represent the same compound as "xx". "M03000x", "03000x", "M3000x", and "3000x" can all be abbreviated as "x" and represent the same compound as "x". For example, M030012 and 12 refer to the same compound, i.e., compound 12; 30102 and 102 refer to the same compound, i.e., compound 102; and M30004 and 4 refer to the same compound, i.e., compound 4.

[0095] In this application, on the ring group TIFF2026528992000057.tif921 represents that m R3s and n R6s can be connected at any possible position on the ring base.

[0096] In this application, at some substituents TIFF2026528992000058.tif1011 represents a connection point.

[0097] Unless otherwise specified, "optionally substituted" means that the hydrogen on the substituent is not substituted, or that one or more substituted sites of the substituent are independently substituted with a substituent, and the substituent is independently selected from one or more of deuterium, oxo, halogen, amino, hydroxy, nitro, cyano, mercapto, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamino, and optionally substituted dialkylamino, and the substituent on the alkyl is selected from one or more of oxo, deuterium, halogen, amino, hydroxy, nitro, cyano, and mercapto, and when the substituent is selected from "oxo", it means that two hydrogen atoms on the carbon at the same substitution position are substituted with oxygen atoms, or a heteroatom is bonded to oxygen, for example, nitrogen oxides with nitrogen and oxygen bonded, and sulfinyl or sulfonyl groups with sulfur and oxygen bonded. "Arbitrarily oxosubstituted" means that the hydrogen atoms on the substituent are not substituted, or two hydrogen atoms on the carbon at the same substitution position are substituted with oxygen atoms, or a heteroatom is bonded to oxygen. Examples include nitrogen oxides where nitrogen and oxygen are bonded, and sulfinyl or sulfonyl groups where sulfur and oxygen are bonded. The term "independently" means that if there is more than one substituent, these substituents may be the same or different.

[0098] The term "aryl" refers to a monocyclic or bicyclic aromatic carbocyclic system containing 6 to 10 carbon atoms. Examples of aryl groups include phenyl and naphthyl.

[0099] The term "heteroaryl" refers to an aromatic monocyclic or polycyclic system containing a 5-10 membered structure, preferably a 5-8 membered structure, more preferably a 5-6 membered structure, where one, two, three, four or more ring atoms are heteroatoms, the remaining atoms are carbon, the heteroatoms are independently selected from O, N, or S, and the number of heteroatoms is preferably one, two, three, or four. A heteroaryl may be an aromatic monocyclic containing one or two 5-6 membered structures selected from N or S, or an aromatic monocyclic with a 5-6 membered structure containing one or two N atoms. Examples of heteroaryls include furanil, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, thiadiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranil, benzothienyl, benzopyridyl, ben Examples include, but are not limited to, zopyrimidinil, benzopyradinil, benzofuranil, benzophthalazinil, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinil, imidazo[1,2-b]pyridazinil, [1,2,4]triazolo[4,3-b]pyridazinil, [1,2,4]triazolo[1,5-a]pyrimidinil, and [1,2,4]triazolo[1,5-a]pyridyl.

[0100] The term "cycloalkyl" refers to a saturated monocyclic, dicyclic, or tricyclic system containing 3 to 12 carbon atoms, where the monocyclic, dicyclic, or tricyclic systems do not include aromatic rings and include bridging groups, spirocyclic groups, fused ring groups, etc. A bridging group refers to any two rings sharing two ring atoms that are not directly linked. Preferably, it contains 3 to 10 carbon atoms (C3-10 cycloalkyl), and more preferably 3 to 8 carbon atoms (C3-8 cycloalkyl), 3 to 6 carbon atoms (C3-6 cycloalkyl), 4 to 6 carbon atoms (C4-6 cycloalkyl), or 5 to 6 carbon atoms (C5-6 cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, and dimethylcyclobutyl.

[0101] The term "heterocycloalkyl" refers to a saturated monocyclic, dicyclic, or tricyclic system containing heteroatoms, where the monocyclic, dicyclic, or tricyclic elements do not include aromatic rings, but include bridging groups, spirocyclic groups, fused ring groups, etc. A bridging group refers to any two rings sharing two ring atoms that are not directly linked. Heterocycloalkyls contain 3 to 12 ring atoms, where 1, 2, 3, 4 or more ring atoms are selected from N, O, or S, and the remaining ring atoms are C. Preferably, they contain 3 to 8 ring atoms (3-8 membered heterocycloalkyl), 3 to 7 ring atoms (3-7 membered heterocycloalkyl), or 3 to 6 ring atoms (3-6 membered heterocycloalkyl), or 4 to 6 ring atoms (4-6 membered heterocycloalkyl), or 5 to 6 ring atoms (5-6 membered heterocycloalkyl). The heterocycloalkyl may be a 7-12 member fused ring or spiro ring heterocycloalkyl, or a 7-9 member spiro ring heterocycloalkyl. The heteroatoms are preferably 1-4, more preferably 1-3 (i.e., 1, 2, or 3). The heterocycloalkyl may also be a 4-6 member monocyclic heterocycloalkyl containing 1-2 N or O atoms, preferably a 4, 5, or 6 member monocyclic heterocycloalkyl containing 1-2 N atoms, a 4, 5, or 6 member monocyclic heterocycloalkyl containing 1-2 O atoms, a 4, 5, or 6 member monocyclic heterocycloalkyl containing 1 N and 1 O atom, or a 7, 8, 9, 10, or 11 member spiral cycloalkyl containing 1, 2, 3, or 4 N or O atoms. Examples of heterocycloalkyls include pyrrolidinyl, imidazolidinyl, tetrahydrofuranil, piperidinyl, piperazinyl, pyranil, azilidinyl, oxyranil, thiranil, azetidinyl, oxetanil, thietanil, oxanil, morpholinil, thiomorpholinil, dioxanil, dithiacyclohexyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, Examples include TIFF2026528992000059.tif1240.

[0102] The term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, preferably a linear or branched group containing 1 to 10 carbon atoms (C1-10 alkyl) (the number of carbon atoms being between 1 and 10, specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), more preferably a group containing 1 to 8 carbon atoms (i.e., C1-8 alkyl, the number of carbon atoms being between 1 and 8, specifically 1, 2, 3, 4, 5, 6, 7, or 8), or a group containing 1 to 6 carbon atoms (i.e., C1-6 alkyl, the number of carbon atoms being between 1 and 6, specifically 1, 2, 3, 4, 5, or 6). Examples 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, n-octyl, 3-hexyl, and 2-pentyl.

[0103] The terms "alkyloxy," "alkylthio," "alkylacyl," "alkylsulfonyl," and "alkylsulfinyl" refer to -O-alkyl, -S-alkyl, -C(O)-alkyl, -S(O)2-alkyl, or -S(O)alkyl, respectively. "Alkylamino" refers to -NH-alkyl or -N-dialkyl, and "-N(O)alkyl" refers to the nitrogen oxide of alkylamino. The definitions of alkyl are as described above. Typical examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio, tert-butylthio, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino, methylsulfonyl, and dimethyl-N(O)-.

[0104] The term "linear alkylene" refers to a divalent saturated linear aliphatic hydrocarbon group, where one, two, or more carbon atoms may be substituted with heteroatoms of oxygen, sulfur, or nitrogen, preferably containing 1 to 10 chain atoms (the number being between 1 and 10, specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), more preferably containing 1 to 8 chain atoms (i.e., the number of chain atoms being between 1 and 8, specifically 1, 2, 3, 4, 5, 6, 7, or 8), or containing 1 to 6 chain atoms (i.e., the number of chain atoms being between 1 and 6, specifically 1, 2, 3, 4, 5, or 6). Here, one or more carbon atoms in the linear alkylene may be substituted with heteroatoms of oxygen, sulfur, or nitrogen. Ultimately, examples include -O-, -CH2-, -O-CH2-, -CH2-O-, -NH-CH2-, -CH2-NH-, -O-CH2CH2-, -CH2CH2-O-, -NH-CH2CH2-, -CH2CH2-NH-, -CH2CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2-O-, -NHCH2CH2CH2-, -CH2CH2CH2-NH-, -CH(CH3)CH2-, etc., but are not limited to these.

[0105] The term "halogen" refers to F, Cl, Br, and I.

[0106] In this specification, ranges of numbers relating to the number of substituents, carbon atoms, or ring atoms represent a list of all integers within that range, and the range notation is merely a simplified expression. For example, "1 to 4 substituents" refers to one, two, three, or four substituents, and "3 to 8 ring atoms" refers to three, four, five, six, seven, or eight ring atoms. Thus, ranges of numbers relating to the number of substituents, carbon atoms, or ring atoms include any subranges thereof, and each subrange is also deemed to be disclosed herein.

[0107] The active compounds described in this application are interpreted to include the compounds of this application and their stereoisomers, tautomers, isotopic derivatives, halogenated derivatives, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof. The stereoisomers, tautomers, isotopic derivatives, hydrates, solvates, prodrugs, isotopic derivatives, or pharmaceutically acceptable salts thereof of the compounds of this application are obtained by ordinary technical means in the art and exert the same or similar effects in vivo and extracellularly through essentially the same mechanism of action as the compounds.

[0108] The term "stereoisomer" refers to an isomer resulting from the spatially different arrangement of atoms within a molecule, and includes configurational isomers and conformational isomers, where configurational isomers include geometric isomers (or cis-trans isomers) and optical isomers (including enantiomers and non-enantiomers). Geometric isomers may be present in the present compound. Optical isomers refer to substances that have exactly the same molecular structure and similar physicochemical properties but different optical activity. The compounds of this application may contain asymmetrically substituted carbon atoms in the R or S configuration, where the terms "R" and "S" are as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10. Compounds having asymmetrically substituted carbon atoms (having an equal number of R and S configurations) are racemic at those carbon atoms. Atoms in which one configuration is present in excess (relative to the other) are more abundant in that configuration, preferably in an excess of about 85% to 90%, more preferably in an excess of about 95% to 99%, and even more preferably in an excess of about 99%. Accordingly, this application includes racemic mixtures, relative and absolute optical isomers, and mixtures of relative and absolute optical isomers.

[0109] The term "tautomer" refers to structural isomers that have different energies and can be converted to each other across low energy barriers. When tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (also called proton transfer tautomers) include interconversions by proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence bond tautomers include interconversions by rearrangement of some bond electrons.

[0110] The term "isotope derivative" refers to a compound of this application that may exist in the form of an isotope tracer or enrichment, containing one or more atoms whose atomic weight or mass number differs from that of the most abundant atom in nature. The isotopes may be radioactive or non-radioactive. For example, isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine are: 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl and 125 This includes, but is not limited to, I. Compounds containing these atoms and / or other isotopes of other atoms are included within the scope of this application. The isotope-labeled compounds of this application can be prepared by general methods well known to those skilled in the art.

[0111] The term "hydrate" refers to a compound formed by one or more water molecules with the compound of this application.

[0112] The term "solvate" refers to a compound formed by one or more solvent molecules with the compound of this application.

[0113] The term "prodrug" refers to a drug designed as a derivative of an active pharmaceutical product to improve certain undesirable physical or biological properties. Physical properties are typically related to solubility (excessive or insufficient lipid or water solubility) or stability, while biological properties in question include excessive metabolism or low bioavailability, which may themselves be related to physicochemical properties.

[0114] The term "pharmaceutically acceptable salt" refers to a salt that, within the bounds of reasonable medical judgment, is applicable to contact with mammalian tissues, particularly human tissues, is free from excessive toxicity, irritation, or allergic reactions, and has a reasonable benefit-to-risk ratio. If the compound is basic, a pharmaceutically acceptable salt includes salts prepared from inorganic acids and also salts prepared from organic acids. If the compound is acidic, a pharmaceutically acceptable salt includes salts prepared from inorganic bases and / or organic bases.

[0115] The terms “pharmaceutically acceptable adjuvants,” “pharmaceutically acceptable carriers,” or “pharmaceutically acceptable excipients” include, but are not limited to, adjuvants, carriers, excipients, flow enhancers, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, emulsifiers, and disintegrants that have been authorized by the relevant government regulatory body to be permitted for use in humans or livestock.

[0116] The pharmaceutical composition of this application can be prepared as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, or gelling agents.

[0117] As used herein, “treatment” means any administration of a therapeutic reagent based on a regimen, and the achievement of the desired effect of such regimen means partial or complete reduction, improvement, mitigation, suppression, delay of onset, reduction of severity, and / or reduction of incidence of one or more symptoms or characteristics of a particular disease, disorder, and / or condition, and in some embodiments, the administration of a therapeutic reagent based on a regimen is related to the achievement of the desired effect. This treatment may be intended for subjects who do not exhibit the relevant disease, disorder, and / or condition, and / or subjects who exhibit only the initial signs of the disease, disorder, and / or condition. Alternatively or additionally, this treatment may be intended for subjects who exhibit one or more identified signs of the relevant disease, disorder, and / or condition. In some embodiments, the treatment may be intended for subjects who have been diagnosed with the relevant disease, disorder, and / or condition. In some embodiments, the treatment may be intended for subjects who are known to have one or more susceptibility factors statistically associated with an increased risk of developing the relevant disease, disorder, and / or condition.

[0118] The compounds of this application can be synthesized by technicians in the field of organic synthesis using a variety of well-known methods. The following specific examples illustrate methods for synthesizing some exemplary specific compounds. Clearly, by referring to the exemplary schemes of this application, those skilled in the art can easily design synthetic routes for other related compounds by appropriately adjusting the reactants, reaction conditions, and protecting groups.

[0119] The present application will be further described below with reference to examples. However, these examples are not intended to limit the scope of this application. Unless otherwise specified, all reactants used in each example are commercially available, and the instruments and apparatus used in the synthesis experiments and the analysis and detection of the products are all common instruments and apparatus normally used in organic synthesis.

[0120] Preparation of intermediate 30092-6 TIFF2026528992000060.tif64146

[0121] Step 1: General method for preparing compound 30092-3 Under a nitrogen atmosphere at room temperature, triethylamine (3.34 g, 33 mmol) was added with stirring to a solution of compound 30092-1 (3 g, 17 mmol), EDCI (4.74 g, 25 mmol), HOBt (3.34 g, 25 mmol), and pyrrolidine (1.41 g, 20 mmol) in DMF (30 mL). The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure and extracted with ethyl acetate (30 mL x 2). After concentrating the organic phase under reduced pressure, it was directly purified using a flash silica gel column (MeOH / DCM = 0-5%) to obtain compound 30092-3 (2.6 g, 60% yield) as a brown solid.

[0122] Step 2: General method for preparing compound 30092-4 Under a nitrogen atmosphere at room temperature, Tf2O (3.13 g, 11 mmol) was added while stirring to a 30 mL solution of compound 30092-3 (2.6 g, 11 mmol), TEA (1.35 g, 13 mmol), and DMAP (0.14 g, 1 mmol) in DCM. The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure and extracted with DCM (30 mL x 2). After concentrating the organic phase under reduced pressure, it was directly purified using a flash silica gel column (MeOH / DCM = 0-10%) to obtain compound 30092-4 (2.6 g, 64% yield) as a yellow oily substance.

[0123] Step 3: General method for preparing compound 30092-5 Under a nitrogen atmosphere at room temperature, a mixture of compound 30092-4 (2.6 g, 7.1 mmol), Zn(CN)2 (0.50 g, 4 mmol), and Pd(PPh3)4 (0.82 g, 1 mmol) in DMF (15 mL) was stirred at 80°C for 8 hours. The mixture was concentrated under reduced pressure, extracted with EA (30 mL x 2), and the organic phase was concentrated under reduced pressure. After direct purification using a flash silica gel column (MeOH / DCM = 0-10%), compound 30092-5 (1.2 g, 69.2% yield) was obtained as a yellow oil.

[0124] Step 4: General method for preparing compound 30092-6 Under a nitrogen atmosphere at room temperature, LiAlH4 (0.93 g, 2.5 mmol) was added dropwise to a solution of compound 30092-5 (1.2 g, 5 mmol) in THF (50 mL) while stirring. The reaction mixture was stirred at 50°C for 2 hours. H2O was added to quench the mixture, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 30092-6 (0.9 g, 67.4% yield) as a yellow oily substance.

[0125] Preparation of intermediate 30124-2 TIFF2026528992000061.tif28106

[0126] Under a nitrogen atmosphere at room temperature, LiAlH4 (323 mg, 8.5 mmol) was added dropwise to a solution of compound 30124-1 (320 mg, 1.7 mmol) in THF (10 mL) with stirring. The reaction mixture was stirred at 25°C for 3 hours. H2O (10 mL) was added to quench the mixture, and the solution was filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by flash reverse-phase (C18) silica gel column (ACN / H2O = 1-10%) to obtain compound 30124-2 (300 mg, 1.68 mmol, 99% yield) as a white solid.

[0127] The preparation method for intermediates 30125-INT and 30126-INT is the same as for 30092-6. JPEG2026528992000062.jpg3397

[0128] Preparation of intermediate 30144-3 TIFF2026528992000063.tif29132

[0129] Step 1: General method for preparing compound 30144-2 Under a nitrogen atmosphere at room temperature, NaH (0.34 g, 16.8 mmol) was added to a solution of compound 30144-1 (1.0 g, 5.6 mmol) in DMF (8 mL) with stirring. The reaction mixture was stirred at 25°C for 30 minutes. A solution of ICD3 (2.44 g, 16.8 mmol) in DMF (2 mL) was added dropwise, and the reaction mixture was stirred at 25°C for 1 hour. The mixture was quenched with saturated NH4Cl aqueous solution (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was washed with saturated brine (20 mL x 3), and dried over anhydrous Na2SO4 to obtain the crude product compound 30144-2 (1 g, 88% yield). This was used directly in the next step. [M+H] + 195.1.

[0130] Step 2: General method for preparing compound 30144-3 Under a nitrogen atmosphere at 40°C, a solution of 30144-2 (0.36 g, 1.86 mmol) in THF (10 mL) was added dropwise to a solution of LiAlH4 (7.4 mL, 1 M). The reaction mixture was stirred at 40°C for 3 hours. Na2SO4·10H2O was added to quench the mixture, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 30144-3 (0.3 g, 76% yield) as a colorless oil. This was used directly in the next step. [M+H] + 171.1.

[0131] Preparation of intermediate 30145-3 TIFF2026528992000064.tif19149

[0132] Step 1: General method for preparing compound 30145-2 Under a nitrogen atmosphere at room temperature, compound 30145-1 (1.0 g, 7.4 mmol) was dissolved in DMF (10 mL), to which compound 2 (0.66 g, 7.4 mmol) and NaOH (0.59 g, 14.8 mmol) were added with stirring. The reaction mixture was stirred at 25 °C for 12 hours. At 0 °C, the mixture was quenched with water (30 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product compound 30145-2 (0.8 g, 50% yield), a yellowish oily substance. This was used directly in the next step. [M+H] + 205.2.

[0133] Step 2: General method for preparing compound 30145-3 Under a nitrogen atmosphere at 40°C, a solution of 30145-2 (0.5 g, 2.44 mmol) in THF (5 mL) was added dropwise to a solution of LiAlH4 (4.9 mL, 1 M) in THF (5 mL). The reaction mixture was stirred at 40°C, cooled to room temperature, and then quenched by adding Na2SO4·10H2O. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 30145-3 (0.5 g, 93% yield) as a yellow oily substance. This was used directly in the next step. [M+H] + 209.2.

[0134] The preparation of intermediate 30146-3 followed the procedure for preparing intermediate 30145-3. TIFF2026528992000065.tif21155

[0135] Preparation of intermediate 30147-2 TIFF2026528992000066.tif29101

[0136] Step 1: General method for preparing compound 30147-2 Under a nitrogen atmosphere at 40°C, a solution of 30147-1 (0.5 g, 3.10 mmol) in THF (10 mL) was added dropwise to a solution of LiAlH4 (6.2 mL, 1 M). The reaction mixture was stirred at 40°C for 2 hours. Na2SO4·10H2O was added to quench the mixture, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was separated by reverse-phase column chromatography (0-30% ACN / H2O (0.1% NH3.H2O)) to obtain 30147-2 (0.15 g, 28.8% yield) as a white solid. [M+H] + 152.1.

[0137] The preparation of intermediate 30148-3 followed the procedure for preparing intermediate 30145-3. TIFF2026528992000067.tif21151

[0138] Preparation of intermediate 30149-4 TIFF2026528992000068.tif27151

[0139] Step 1: General method for preparing compound 30149-2 Under a nitrogen atmosphere at room temperature, compound 30149-1 (1.5 g, 6.8 mmol) was dissolved in DMF (15 mL) and DIEA (2.64 g, 20.4 mmol) and DIEA (2.92 g, 8.16 mmol) were added while stirring. The reaction mixture was stirred at room temperature for 1 hour. 30 mL of water was added to quench the mixture, and it was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated saline solution (50 mL x 3), concentrated under reduced pressure, and the resulting mixture was directly purified using a flash silica gel column (THF / PE = 0-1%) to obtain compound 30149-2 (2 g, 84% yield) as a yellow oily substance.

[0140] Step 2: General method for preparing compound 30149-3 Under a nitrogen atmosphere at room temperature, TEA (0.43 g, 4.25 mmol), Zn(CN)2 (199.46 mg, 1.69872 mmol), and PdCl2(dppf) (103.58 mg, 0.14156 mmol) were added to a solution of 30149-2 (0.5 g, 1.4 mmol) in DMF (2 mL) with stirring. The reaction mixture was stirred at 120 °C for 12 hours. 10 mL of water was added to quench the mixture, and it was extracted with ethyl acetate (15 mL x 3). The organic phase was washed with saturated brine (15 mL x 3), concentrated under reduced pressure, and the crude product was directly purified by flash silica gel column (THF / PE = 0-5%) to obtain compound 30149-3 (150 mg, 44% yield) as a white solid. [M+H] + 230.1.

[0141] Step 3: General method for preparing compound 30149-4 Under a nitrogen atmosphere, 30149-3 (100 mg, 0.4345 mmol) was dissolved in BH3 (2 M THF solution, 5 mL). The reaction mixture was stirred at 60°C for 12 hours. The mixture was concentrated under reduced pressure to obtain crude product 30144-3 (90 mg, 95% yield) as a yellow oily substance. This was used directly in the next step. [M+H] + 206.1.

[0142] Preparation of intermediates INT-I and INT-II Refer to reference J. Med. Chem 2021, 64, 7507-7532 and prepare according to the following scheme. TIFF2026528992000069.tif98147

[0143] Example 1: Preparation of Compound 30066 TIFF2026528992000070.tif124151

[0144] Step 1: General method for preparing compound 30066-2 Compound 30066-1 (10g, 0.041mol), nA solution of BuNH2 (4.44 g, 0.061 mol) and N,N-diisopropylethylamine (DIEA, 15.7 g, 0.122 mol) in DMF (100 mL) was heated with stirring at 70 °C for 4 hours. The reaction was quenched with H2O (200 mL) and extracted with ethyl acetate (100 mL x 3). The solvent was removed under reduced pressure to obtain the crude product. The crude product was directly purified by flash silica gel column (PE / EA = 9 / 1) to obtain compound 30066-2 (10 g, 86.17%) as a yellow oily substance.

[0145] Step 2: General method for preparing compound 30066-3 A solution of compound 30066-2 (10 g, 0.035 mol) and N,N-dimethylformamide dimethylacetal (DMF-DMA, 21.03 g, 0.177 mol) in DMF (100 mL) was heated with stirring at 130 °C for 12 hours. The solution was directly evaporated to obtain compound 30066-3 (10 g, crude product) as a brown solid.

[0146] Step 3: General method for preparing compound 30066-5 A toluene (20 mL) solution of compound 30066-3 (1 g, 0.003 mol) and compound 30066-4 (0.99 g, 0.006 mol) was heated with stirring at 60°C for 6 hours. The solution was evaporated under reduced pressure and directly purified using a flash silica gel column (PE / EA=9 / 1) to obtain compound 30066-5 (1 g, 63.49%) as a yellow oily substance.

[0147] Step 4: General method for preparing compound 30066-6 A solution of compound 30066-5 (250 mg, 0.739 mmol) in EtOH (5 mL) was heated with stirring at 90°C for 5 hours. The solvent was removed under reduced pressure, and the compound was directly purified using a flash silica gel column (DCM / MeOH = 10 / 1) to obtain compound 30066-6 (200 mg, 64.99%) as a yellow oily substance.

[0148] Step 5: General method for preparing compound 30066-7 A mixture of compound 30066-6 (200 mg, 0.485 mmol) and LiAlH4 (55 mg, 1.454 mmol) in THF (5 mL) was stirred at room temperature for 2 hours. The reaction was quenched with H2O (10 mL) and extracted with EA (15 mL x 3). The solution was evaporated to obtain compound 30066-7 (160 mg, crude product) as a yellow oily substance.

[0149] Step 6: General method for preparing compound 30066-8 A solution of compound 30066-7 (400 mg, 1.040 mmol) and m-CPBA (413 mg, 2.393 mmol) in DMF (4 mL) was stirred at room temperature for 2 hours. The reaction was quenched with H₂O (20 mL) and extracted with EA (20 mL x 3). The organic layer was washed with saline solution (20 mL x 5), dried over Na₂SO₄, and then concentrated to obtain the crude product. The crude product was redissolved in dioxane (10 mL), and then NH₄OH (365 mg, 10.403 mmol) was added. The resulting solution was stirred and heated in a sealed tube at 110°C for 3 hours. The reaction was quenched with H₂O (200 mL) and extracted with EA (100 mL x 3). The crude product was evaporated and directly purified using a flash silica gel column (DCM / MeOH=10 / 1) to obtain crude product 30066-8 (200 mg, 53.85%) as a yellow solid. The crude product was further purified by preparation HPLC (column: Phenomenex luna C18, 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% trifluoroacetic acid), B: acetonitrile]; B%: 20%~60%, 30 min) to obtain white solid compound 30066-8 (10 mg, 0.027 mmol). LCMS:[M+H] + =354.2; Rt=0.956min. 1 1H NMR: (400 MHz, d6-DMSO) δ9.457 - 9.431 (t, J = 10.4 Hz, 1H), δ 7.691 (s, 1H), 7.265 - 7.217 (m, 4H), 6.696 (s, 2H), 6.102 - 6.084 (d, J = 7.2 Hz, 1H), 5.145 (s, 1H), 5.032 (s, 2H), 4.458 - 4.449 (d, J = 3.6 Hz, 2H), 3.440 - 3.391 (m, 2H), 2.497 (m, 2H), 1.376 - 1.302 (m, 2H), 0.929 - 0.892 (m, 3H).

[0150] Step 7: General method for preparing compound 30066-9 A solution of compound 30066-8 (170 mg, 0.481 mmol) and SOCl2 (114 mg, 0.962 mmol) in DCM (2 mL) was stirred at room temperature for 15 hours. The reaction was quenched with H2O (200 mL) and extracted with EA (100 mL x 3). The solvent was removed under reduced pressure to obtain compound 30066-9 (180 mg, 85.53%) as a yellow solid.

[0151] Step 8: General method for preparing compound 30066 To a solution of compound 30066-9 (35 mg, 0.094 mmol) and compound 30066-10 (16 mg, 0.141 mmol) in DMF (3 mL), DIEA (36 mg, 0.282 mmol) was added and the mixture was stirred at 60°C for 6 hours. After filtering the solution, compound 30066 (10 mg, 22.95%) was directly purified by prepared HPLC (column: Phenomenex luna C18, 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% formic acid), B: acetonitrile]; B%: 40%~80%, 40 min) to obtain compound 30066 (10 mg, 22.95%) as a white solid. LCMS:[M+H] + =450.50; Rt=1.557min. 1H NMR: (400 MHz, d6-DMSO) δ 9.403 - 9.376 (t, J = 10.8 Hz, 1H), 8.235 (s, 1H), 7.260 - 7.193 (m, 4H), 6.616 (s, 2H), 6.084 - 6.066 (d, J = 7.2 Hz, 1H), 5.024 (s, 2H), 3.559 - 3.437 (m, 4H), 2.735 - 2.666 (m, 1H), 2.636 - 2.596 (m, 1H), 2.557 - 2.536 (m, 1H), 2.422 - 2.329 (m, 1H), 2.248 - 2.209 (m, 1H), 2.077 (s, 6H), 1.834 - 1.780 (m, 1H), 1.605 - 1.501 (m, 3H), 1.356 - 1.301 (m, 2H), 0.927 - 0.891 (t, J = 14.4 Hz, 3H).

[0152] The following compounds were prepared by referring to the preparation method for compound 30066.

[0153] TIFF2026528992000071.tif243164 TIFF2026528992000072.tif228164 TIFF2026528992000073.tif234164 TIFF2026528992000074.tif92164

[0154] Example 2: Preparation of Compound 30018 TIFF2026528992000075.tif88148

[0155] Step 1: General method for preparing compound 30018-2 Under a nitrogen atmosphere at room temperature, HCl (1.6 mL, 1 M) was added dropwise to a solution of compound 30066-3 (200 mg, 0.591 mmol) in THF (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (20 mL), extracted with EA (20 mL x 3), and evaporated under vacuum to obtain compound 30018-2 (200 mg, crude product) as a yellow oily substance.

[0156] Step 2: General method for preparing compound 30018-4 Solutions of compound 30018-2 (770 mg, 2.47 mmol), compound 30018-3 (490 mg, 2.97 mmol), and NaBH3CN (311 mg, 4.95 mmol) in DCE (10 mL) were stirred at room temperature for 2 hours. The mixture was extracted with EA (10 mL x 3), washed with water (10 mL x 3), dried over Na2SO4, and then evaporated under vacuum to obtain the crude product of compound 30018-4. A solution of the crude product of compound 30018-4 in EtOH (20 mL) was heated and stirred at 90°C for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (PE / EA = 3 / 1) to obtain a yellow, oily compound 30018-4 (270 mg, 85% purity, 22.39% yield).

[0157] Step 3: General method for preparing compound 30018-5 A mixture of compound 30018-4 (350 mg, 0.84 mmol) and a THF (5 mL) solution of DIBAL-H (240 mg, 1.69 mmol) was stirred at room temperature for 2 hours. The mixture was diluted with water (10 mL), extracted with EA (10 mL x 3), washed with saturated saline (50 mL), dried over Na2SO4, and then evaporated under vacuum. The crude product was purified by flash column chromatography (PE / EA = 1 / 1) to obtain the yellow oily compound 30018-5 (175 g, 85% purity, 45.59% yield).

[0158] The other steps were followed to prepare compound 30018, referring to the synthesis method for compound 30066. [M+H] + = 409.2; Rt = 0.756 min. 1H NMR: (400 MHz, d6-DMSO) δ 9.034 (t, J = 5.6 Hz, 1H), 8.193 (s, 0.1H), 7.215 (ddd, J = 24.4, 15.6, 7.6 Hz, 4H), 6.627 (s, 2H), 4.575 (s, 2H), 3.556 (s, 2H), 3.421 - 3.195 (m, 4H), 2.643 (t, J = 6.8 Hz, 2H), 2.414 (s, 4H), 1.678 (dt, J = 6.4, 3.2 Hz, 4H), 1.512 (dt, J = 14.8, 7.2 Hz, 2H), 1.343 (dq, J = 14.4, 7.2 Hz, 2H), 0.908 (t, J = 7.4 Hz, 3H).

[0159] Example 3: Preparation of Compound 30042 TIFF2026528992000076.tif59146

[0160] Step 1: General method for preparing compound 30042-3 A mixture of compound 30025-3 (300 mg, 0.89 mmol) and compound 30042-2 (207 mg, 1.06 mmol) in EtOH (6 mL) was heated with stirring at 85 °C for 5 hours. The reaction was quenched with H2O (200 mL) and extracted with ethyl acetate (100 mL x 3). The mixture was evaporated under vacuum to obtain compound 30042-3 (360 mg, crude product) as a brown oily substance.

[0161] Step 2: General method for preparing compound 30042-4 A mixture of compound 30042-3 (360 mg, 0.82 mmol) and m-CPBA (414 mg, 2.04 mmol, 85%) in DMF (3 mL) was stirred at room temperature for 16 hours. The mixture was diluted with water (20 mL), extracted with EA (1 mL x 2), and evaporated under vacuum to obtain compound 30042-4 (280 mg, crude product) as a brown oily substance.

[0162] Step 3: General method for preparing compound 30042 A mixture of compound 30042-4 (250 mg, 0.53 mmol) and NH4OH (2 mL) in 1,4-dioxane (1 mL) was heated with stirring at 100 °C for 1 hour. The mixture was extracted with ethyl acetate (5 mL x 2) and evaporated under vacuum. The residue was dissolved in EA (2 mL), and then saturated Na2SO3 solution (2 mL) was added. The resulting mixture was vigorously stirred for 1 hour, then the organic phase was separated and evaporated, and the mixture was purified by prepared HPLC (column: Phenomenex luna C18, 250 mm x 100 mm x 10 μm, mobile phase: [A: H2O (0.1% trifluoroacetic acid), B: acetonitrile]; B%: 10%~50%, 40 min) to obtain a white solid 30042 (12.35 mg, 6% yield). LCMS: [M+H] + = 411.1; Rt = 0.886 min 1 H NMR: (400 MHz, CDCl3) δ 9.797 (br s, 1H), 7.293 (d, J = 7.6 Hz, 1H), 7.212 (d, J = 8.4 Hz, 2H), 6.899 (d, J = 8.4 Hz, 2H), 6.314 (d, J = 7.6 Hz, 1H), 5.026 (s, 2H), 4.189 (t, J = 5.2 Hz, 2H), 3.516 (dd, J = 12.8, 7.2 Hz, 2H), 2.982 - 2.901 (m, 2H), 2.507 (s, 6H), 1.678 - 1.613 (m, 2H), 1.456 - 1.404 (m, 2H), 0.965 (t, J = 7.2 Hz, 3H).

[0163] The following compounds were prepared by referring to the synthesis method of compound 30042. Here, compound 30019 was obtained by reducing compound 30027 (Pd(OH)2 / C, H2, dioxane, EtOH, rt, 15hr).

[0164] TIFF2026528992000077.tif168157 TIFF2026528992000078.tif245157

[0165] The following compounds were prepared by referring to the synthesis method of compound 30042.

[0166] TIFF2026528992000079.tif163157

[0167] Example 4: Preparation of Compound 30043 TIFF2026528992000080.tif61152

[0168] Step 1: General method for preparing compound 30043-1 A solution of compound 30039 (80 mg, 0.22 mmol) and compound DMP (185 mg, 0.44 mmol) in DCM (3 mL) was stirred at room temperature for 1 hour. The solution was evaporated under reduced pressure and directly purified using a flash silica gel column (DCM / MeOH = 95 / 5) to obtain compound 30043-1 (80 mg, 91% yield) as a yellow oily substance.

[0169] Step 2: General method for preparing compound 30043 Compound 30043-1 (50 mg, 0.14 mmol), tetrahydropyrrole (12 mg, 0.16 mmol), and AcOH (12 mg, 0.21 mmol) were dissolved in isopropanol (2 mL), to which sodium triacetoxyborohydride (43 mg, 0.21 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours. After filtering the solution, it was directly purified by prepared HPLC (column: Phenomenex luna C18, 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% formic acid), B: acetonitrile]; B%: 10%~50%, 40 min) to obtain compound 30043 (7.16 mg, 15% yield) as a white solid. LCMS:[M+H] + =421.1; Rt=0.878min. 1H NMR: (400 MHz, CD3OD) δ 7.562 (d, J = 7.6 Hz, 1H), 7.289 - 7.221 (m, 4H), 6.171 (d, J = 7.6 Hz, 1H), 5.077 (s, 2H), 3.522 - 3.467 (m, 2H), 3.001 - 2.931 (m, 2H), 2.93 - 2.84 (m, 6H), 1.954 - 1.883 (m, 4H), 1.656 - 1.597 (m, 2H), 1.480 - 1.412 (m, 2H), 0.978 (t, J = 7.2 Hz, 3H).

[0170] The following compounds were synthesized by referring to the synthesis method for compound 30043.

[0171] TIFF2026528992000081.tif226164 TIFF2026528992000082.tif58164

[0172] Example 5: Preparation of compounds 30058, 30089, and 30090 TIFF2026528992000083.tif118154

[0173] Step 1: General method for preparing compound 30058-3 Under a nitrogen atmosphere at room temperature, N,N-diisopropylethylamine (DIEA, 786 mg, 6.080 mmol) and compound 30058-2 (212 mg, 2.432 mmol) were added dropwise to a solution of compound 30058-1 (500 mg, 2.027 mmol) in THF (15 mL). The reaction mixture was heated and stirred at 70 °C for 4 hours. The solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by flash chromatography (MeOH / DCM = 2%) to obtain compound 30058-3 (440 mg, 1.479 mmol, 72.96% yield) as a yellow solid.

[0174] Step 2: General method for preparing compound 30058-4 Under a nitrogen atmosphere at room temperature, N,N-dimethylformamide dimethylacetal (DMF-DMA, 384.65 mg, 3.228 mmol) was added dropwise to a solution of compound 30058-3 (240 mg, 0.807 mmol) in DMF (5 mL). The reaction mixture was heated and stirred at 130 °C for 16 hours. The reaction was quenched with H₂O (2 mL), diluted with DCM (100 mL), and washed with water and brine. The organic layer was collected, dried over Na₂SO₄, and concentrated by filtration. The crude product was purified by flash column chromatography (MeOH / DCM = 3%) to obtain compound 30058-4 (218 mg, 0.618 mmol, 76.58% yield) as a yellow solid.

[0175] Step 3: General method for preparing compound 30058-6 Under a nitrogen atmosphere at room temperature, compound 30058-5 (177 mg, 1.288 mmol) was added to a solution of compound 30058-4 (218 mg, 0.618 mmol) in EtOH (5 mL). The reaction mixture was heated and stirred at 90 °C for 5 hours. The solvent was removed under reduced pressure to obtain the residue. The crude product was purified by flash column chromatography (MeOH / DCM = 10%) to obtain compound 30058-6 (200 mg, 0.502 mmol, 81.23% yield) as a yellow solid.

[0176] Step 4: General method for preparing compound 30058-7 A solution of compound 30058-6 (200 mg, 0.502 mmol) and m-CPBA (260 mg, 1.506 mmol) in DMF (4 mL) was stirred at room temperature for 2 hours. The reaction solution was quenched with water (20 mL) and extracted with EA (20 mL x 3). The organic layer was collected, washed with water (20 mL x 5), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (MeOH / DCM = 6%) to obtain compound 30058-7 (150 mg, 0.362 mmol, 72.11% yield) as a yellow solid.

[0177] Step 5: General method for preparing compound 58-8 A 1,4-dioxane / NH3·H2O=1:2 (5 mL) solution of compound 30058-7 (150 mg, 0.362 mmol) was heated and stirred at 110°C for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (MeOH / DCM=10%) to obtain compound 30058-8 (100 mg, 0.272 mmol, 75.14% yield) as a yellow solid.

[0178] Step 6: General method for preparing compound 30058-9 Under a nitrogen atmosphere at room temperature, SOCl2 (49 mg, 0.408 mmol) was added dropwise to a solution of compound 30058-8 (100 mg, 0.272 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (MeOH / DCM = 3%) to obtain compound 30058-9 (70 mg, 0.181 mmol, 66.54% yield) as a yellow solid.

[0179] Step 7: General method for preparing compound 30058 A mixture of compound 30058-9 (70 mg, 0.181 mmol), Me2NH (41 mg, 0.907 mmol), and K2CO3 (75 mg, 0.544 mmol) in THF (5 mL) was stirred for 3 hours under a nitrogen atmosphere at room temperature. The solvent was removed under reduced pressure. The crude product was then purified by preparatory HPLC (column: Phenomenex luna C18 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% trifluoroacetic acid), B: acetonitrile]; B%: 40%~80%, 40 min) to obtain compound 30058 (25 mg, 0.062 mmol, 34.23% yield) as a white solid. LCMS:[M+H] + =395.45; Rt=1.655min. 11H NMR: (400 MHz, MeOD) δ 8.420 (s, 1H), 7.748 - 7.729 (d, J = 7.6 Hz, 1H), 7.480 - 7.420 (dd, J = 8.4, 15.6 Hz, 4H), 6.278 - 6.259 (d, J = 7.6 Hz, 1H), 5.221 - 5.124 (dd, J = 15.2, 23.6 Hz, 2H), 4.353 - 4.317 (m, 1H), 4.200 (s, 2H), 2.764 (s, 6H), 1.606 - 1.516 (m, 2H), 1.443 - 1.374 (m, 2H), 1.241 - 1.225 (d, J = 6.4 Hz, 3H), 0.962 - 0.926 (t, J = 7.2 Hz, 3H).

[0180] Step 8: General method for preparing compounds 30089 and 30090 Using supercritical fluid chromatography (SFC), compound 30058 was separated to obtain compounds 30089 and 30090. Column: DAICEL IG 4.6mm I.D.*250mm L 5μm Mobile phase: CO2 / MeOH [0.1% NH3 (7M solution, in MeOH)] Column temperature: 4°C Flow rate: 2.5 mL / min Apparatus: SHIMADZU LC-30AD SFC SFC: Compound 30089, Rt = 5.929 min. LCMS: [M+H] + = 395.55; Rt = 1.659 min. 1H NMR: (400 MHz, MeOD)δ 8.420 (s, 1H), 7.708 (s, 1H), 7.455-7.416 (t, J = 15.6 Hz, 4H), 6.267-6.248 (d, J = 7.6 Hz, 1H), 5.157-5.119 (m, 2H), 4.347- 4.316 (m, 1H), 4.187 (s, 2H), 2.755 (s, 6H), 1.586-1.533 (m, 2H), 1.425-1.392 (m, 2H), 1.239-1.223 (m, 3H), 0.962-0.926 (t, J = 14.4 Hz, 3H). SFC: Compound 30090, Rt=6.597min. LCMS:[M+H] + =395.90; Rt=1.668min. 1 H NMR: (400 MHz, MeOD) δ 8.452 (s, 1H), 7.7689 (s, 1H), 7.450-7.409 (t, J = 16.4 Hz, 4H), 6.257-6.238 (d, J = 7.6 Hz, 1H), 5.173-5.113 (m, 2H), 4.344-4.311 (m, 1H), 4.165 (s, 2H), 2.739(s, 6H), 1.586-1.533 (m, 2H), 1.425-1.392 (m, 2H), 1.239-1.223 (m, 3H), 0.962-0.926 (t, J = 14.4 Hz, 3H).

[0181] The preparation method of compound 30058 is as follows, and the preparation method of compound 30056 is as follows.

[0182] TIFF2026528992000084.tif42164

[0183] Example 6: Preparation of compound 30089 TIFF2026528992000085.tif117148

[0184] The synthesis method was the same as in Example 5, using chiral amine reagent 30089-2. The final product was purified by preparation HPLC under the following conditions: Column: Phenomenex luna C18 250 mm × 100 mm × 10 μm; Mobile phase A: H2O (0.1% FA); Mobile phase B: ACN; Gradient: From 10% B to 25% B within 30 minutes. Compound 30089 (20 mg, 0.05 mmol, 40.12% yield) was obtained as a white solid. LCMS: [M+H] + = 395.4; Rt = 1.655 min. 1 H NMR: (400 MHz, MeOD) δ 8.415 (s, 1H), 7.666 (s, 1H), 7.444-7.408 (t, J = 14.4 Hz, 4H), 6.243-6.224 (d, J = 7.6 Hz, 1H), 5.147-5.110 (m, 2H), 4.357-4.288 (m, 1H), 4.158 (s, 2H), 2.737 (s, 6H), 1.601-1.511 (m, 2H), 1.444-1.359 (m, 2H), 1.235-1.219 (m, 3H), 0.962-0.925 (t, J = 14.8 Hz, 3H).

[0185] The following compounds were prepared by referring to the preparation method for compound 30089 in Example 6.

[0186] TIFF2026528992000086.tif164164

[0187] Referring to the preparation method for compound 30089 in Example 6, the following compounds were prepared from intermediate 30144-3.

[0188] TIFF2026528992000087.tif47164

[0189] Referring to the preparation method for compound 30089 in Example 6, the following compounds were prepared from intermediate 30147-2.

[0190] TIFF2026528992000088.tif53164

[0191] Referring to the preparation method for compound 30089 in Example 6, the following compounds were prepared from intermediate 30149-4.

[0192] TIFF2026528992000089.tif47164

[0193] Example 7: Preparation of Compound 30102 TIFF2026528992000090.tif138150

[0194] Step 1: General method for preparing compound 30102-2 Under a nitrogen atmosphere at room temperature, a solution of compound 30102-1 (1 g, 7 mmol), imidazole (0.74 g, 11 mmol), and compound TBSCl (1.32 g, 9 mmol) in DCM (20 mL) was stirred at room temperature for 8 hours. The mixture was diluted with water (20 mL), extracted with DCM (20 mL x 3), evaporated under vacuum, and the crude product was purified by flash column chromatography (MeOH / DCM = 0-5%) to obtain compound 30102-2 (1 g, 49.3% yield) as a yellow oil.

[0195] Step 2: General method for preparing compound 30102-4 To a 15 mL solution of compound 102-3 (800 mg, 3.35 mmol) in DCM / DMF = 100 / 1, dichloride oxalate (510 mg, 4.02 mmol) was added dropwise under a nitrogen atmosphere at 0°C, and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to obtain a yellow solid. Under a nitrogen atmosphere at room temperature, TEA (966 mg, 9.54 mmol) was added dropwise to a 20 mL solution of the obtained yellow solid and compound 30102-2 (800 mg, 3.18 mmol) in DCM. The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (20 mL), extracted with EA (20 mL x 3), evaporated under vacuum, and the crude product was purified by flash column chromatography (MeOH / DCM = 0-5%) to obtain compound 30102-4 (0.8 g, 47.9% yield) as a yellow solid.

[0196] Step 3: General method for preparing compound 30102-5 Under a nitrogen atmosphere at room temperature, a solution of compound 30102-4 (800 mg, 3.18 mmol) in MeOH (0.7 mL, 5 mmol) containing NH3 and a solution of EA (0.39 g, 4 mmol) in DMF (15 mL) were stirred at room temperature for 4 hours. The mixture was diluted with water (20 mL) and extracted with EA (20 mL × 3), and then evaporated in vacuo to obtain a crude product 30102-5 (1 g, 56.3% yield) as a yellow oil.

[0197] Step 4: General method for preparing compound 30102-7 Under a nitrogen atmosphere at room temperature, a reaction mixture of compound 30102-5 (1 g, 2.2 mmol), TsOH·H2O (0.04 g, 0.2 mol) and triethyl orthoformate (10 mL) was stirred at 110 °C for 1 hour. The mixture was evaporated in vacuo to obtain a crude product 30102-7 (800 mg, 63.6% yield) as a yellow oil.

[0198] Step 5: General method for preparing compound 30102-8 Under a nitrogen atmosphere at room temperature, DIEA (330 mg, 3 mmol) was added to a solution of compound 30102-7 (0.8 g, 2 mmol) and 1-butylamine (150 mg, 2 mmol) in DMF (10 mL). The reaction mixture was stirred at 80 °C for 1 hour. It was extracted with EA (20 mL × 2) and evaporated in vacuo, and the crude product was purified by flash column chromatography (EA / PE = 0~25%) to obtain compound 30102-8 (0.65 g, 70.6% yield) as a white solid.

[0199] Step 6: General method for preparing compound 30102-9 A solution of compound 30102-8 (700 mg, 1.40 mmol) and m-CPBA (363 mg, 2.10 mmol) in DCM (15 mL) was stirred at 25 °C for 2 hours. It was evaporated in vacuo to obtain a crude product 30102-9 (700 mg, 75.2% yield).

[0200] Step 7: General method for preparing compound 30102-10 Crude product 30102-9 (700 mg) was redissolved in dioxane (2 mL), and then NH4OH (4 mL) was added. The resulting solution was stirred and heated in a sealed tube at 110°C for 1 hour. By vacuum evaporation, crude product 30102-10 (450 mg, 62% yield) was obtained as a white solid.

[0201] Step 7: General method for preparing compound 30102-11 Under a nitrogen atmosphere at room temperature, a solution of compound 30102-10 (100 mg, 0.21 mmol) in THF (3 mL) was added dropwise to a solution of 1 M TBAF in THF (0.5 mL, 0.21 mmol). The reaction mixture was stirred at room temperature for 1 hour. DCM (10 mL) was added, the mixture was filtered, and the solvent was removed under reduced pressure to obtain crude product 30102-11 (40 mg, 85% yield) as a yellow solid.

[0202] The other steps were followed to prepare compound 30102, referring to the preparation method for compound 30093. LCMS: [M+H] + = 408.4; Rt = 1.619 min. 1 H NMR: (400 MHz, CD3OD) δ 8.419 (s, 1H), 7.396 (s, 4H), 5.125 (s, 2H), 3.883 (s, 2H), 3.505 (t, J = 7.2 Hz, 2H), 2.811 (s, 4H), 1.891 (s, 4H), 1.611 (dd, J = 14.8, 7.2 Hz, 2H), 1.425 (dd, J = 15.2, 7.2 Hz, 2H), 0.969 (t, J = 7.2 Hz, 3H).

[0203] Example 8: Preparation of Compound 30085 TIFF2026528992000091.tif173152

[0204] Step 1: General method for preparing compound 30085-3 A mixture of compound 30085-1 (4 g, 16.21 mmol), TEA (1.64 g, 16.21 mmol), and compound 30085-2 (1.22 g, 16.21 mmol) in DMF (40 mL) was heated with stirring at 45 °C for 1 hour. The reaction was quenched with H₂O (50 mL) and extracted with ethyl acetate (50 mL x 2). The mixture was evaporated under vacuum to obtain compound 30085-3 (4.3 g, 93.04%) as a white solid.

[0205] Step 2: General method for preparing compound 30085-4 Under a nitrogen atmosphere at room temperature, TBSCl (2.73 g, 18.11 mmol) and imidazole (2.06 g, 30.18 mmol) were added to a 45 mL solution of compound 30085-3 (4.3 g, 15.09 mmol) in distilled water (DCM). The reaction mixture was stirred at room temperature for 12 hours. The mixture was diluted with water (50 mL), extracted with DCM (50 mL x 2), and evaporated under vacuum. The crude product was purified by flash column chromatography (EtOH / PE = 0-20%) to obtain compound 30085-4 (4.5 g, 74.74% yield) as a yellow solid.

[0206] Step 3: General method for preparing compound 30085-5 A solution of compound 30085-4 (4.5 g, 11.28 mmol) and N,N-dimethylformamide dimethylacetal (DMF·DMA, 6.72 g, 56.39 mmol) in DMF (50 mL) was heated with stirring at 130 °C for 15 hours. The solution was directly evaporated to obtain the yellow solid compound 30085-5 (80% yield, 4.5 g crude product).

[0207] Step 4: General method for preparing compound 30085-7 A solution of compound 30085-5 (4.5 g, 9.89 mmol) and compound 30085-6 (2.0 g, 9.89 mmol) in EtOH (50 mL) was heated with stirring at 80°C for 2 hours. The solution was evaporated under reduced pressure and directly purified using a flash silica gel column (EA / PE = 0-25%) to obtain compound 30085-7 (4.5 g, 86.18% yield) as a yellow solid.

[0208] Step 5: General method for preparing compound 30085-8 A solution of compound 30085-7 (4.5 g, 8.51 mmol) and m-CPBA (4.32 g, 21.28 mmol) in DMF (50 mL) was stirred at room temperature for 10 hours. The solution was evaporated under reduced pressure and concentrated to obtain the crude product. The crude product was redissolved in dioxane (40 mL), and then NH4OH (20 mL) was added. The resulting solution was stirred and heated at 100°C for 1 hour. The solution was evaporated under reduced pressure and concentrated, quenched with H2O (50 mL), and extracted with EA (50 mL × 2). The crude product was evaporated and directly purified using a flash silica gel column (MeOH / DCM = 0~5%) to obtain 30085-8 (3.0 g, 70.89% yield) as a yellow solid.

[0209] Step 6: General method for preparing compound 30085-9 Under a nitrogen atmosphere at room temperature, TBAF (15 mL) was added dropwise to a solution of compound 30085-8 (3.0 g, 6.03 mmol) in THF (20 mL). The reaction mixture was stirred at room temperature for 1 hour. H2O (50 mL) was added to quench the mixture, and it was extracted with EA (50 mL x 2). The solvent was removed under reduced pressure to obtain crude product 30085-9 (2.0 g, 86.59% yield) as a yellow solid.

[0210] Step 7: General method for preparing compound 30085-10 Under a nitrogen atmosphere at room temperature, TBAC (21.74 g, 78.2 mmol) was added dropwise to a 20 mL solution of compound 30085-9 (1.5 g, 3.91 mmol) in SOCl2 / THF = 1 / 4. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, quenched with H2O (80 mL), and extracted with EA (80 mL x 3). The solvent was removed under reduced pressure to obtain crude product 30085-10 (1.3 g, 82.89% yield) as a yellow solid.

[0211] Step 8: General method for preparing compound 30085-11 Under a nitrogen atmosphere at room temperature, MeSNa (340 mg, 4.86 mmol) was added to a solution of compound 30085-10 (1.3 g, 3.24 mmol) in DMF (20 mL). The reaction mixture was stirred at 80 °C for 1 hour. The mixture was quenched with H2O (30 mL), extracted with EA (30 mL x 3), and the solvent was removed under reduced pressure to obtain the crude product 30085-11 (800 mg, 59.76%) as a yellow solid.

[0212] Step 9: General method for preparing compound 30085-12 Under a nitrogen atmosphere at 0°C, BH3·SMe2 (551 mg, 7.25 mmol) was added to a solution of compound 30085-11 (600 mg, 1.45 mmol) in THF (10 mL). The reaction mixture was stirred at 0°C for 2 hours. The mixture was quenched with H2O (20 mL), extracted with EA (30 mL x 2), and the solvent was removed under reduced pressure to obtain the crude product. This was directly purified using a flash silica gel column (MeOH / DCM = 0-5%) to obtain 30085-12 (350 mg, 62.69% yield) as a yellow solid.

[0213] Step 10: General method for preparing compound 30085-13 Compound 30085-12 (100 mg, 0.26 mmol) and a solution of SOCl2 (2 mL) in DCM (2 mL) were stirred at room temperature for 1 hour. The solution was evaporated under reduced pressure and concentrated to obtain crude product 30085-13 (80 mg, 76.35% yield).

[0214] Step 11: General method for preparing compound 30085 A solution of compound 30085-13 (30 mg, 0.07 mmol), compound 30085-14 (14 mg, 0.18 mmol), and DIPEA (23 mg, 0.18 mmol) in DMF (2 mL) was stirred at 60°C for 1 hour. H2O (5 mL) was added to quench the solution, and it was extracted with EA (5 mL x 2). The solution was evaporated under reduced pressure and concentrated. This was purified by a prepared HPLC (column: Phenomenex luna C18, 250 mm x 100 mm x 10 μm; mobile phase: [A: H2O (0.1% trifluoroacetic acid), B: acetonitrile]; B%: 40%~80%, 40 min) to obtain compound M030085 (5.84 mg, 0.013 mmol, 19.04% yield) as a white solid. LCMS: [M+H] + = 439.40; Rt = 1.627 min. 1 H NMR: (400 MHz, MeOD) δ 7.569 (d, J = 7.6 Hz, 1H), 7.359 (d, J = 8.0 Hz, 2H), 7.315 (d, J = 8.0 Hz, 2H), 6.185 (d, J = 7.6 Hz, 1H), 5.110 (s, 2H), 3.775 (s, 2H), 3.611 (t, J = 6.8 Hz, 2H), 2.698 (s, 4H), 2.569 (t, J = 7.2 Hz, 2H), 2.090 (s, 3H), 1.969 - 1.934 (m, 2H), 1.852 (s, 4H).

[0215] Compound 30087 was prepared by referring to the preparation method for compound 30085. TIFF2026528992000092.tif4063[M+H] + = 481.40; Rt = 1.895 min. 1H NMR: (400 MHz, MeOD) δ 7.567 (d, J = 7.6 Hz, 1H), 7.312 (d, J = 13.6 Hz, 4H), 6.189 (d, J = 7.6 Hz, 1H), 5.104 (s, 2H), 3.673 (s, 2H), 2.543 (dd, J = 18.0, 9.6 Hz, 7H), 2.065 (s, 3H), 1.813 - 1.793 (m, 6H), 1.613 - 1.515 (m, 2H), 1.441 - 1.367 (m, 2H), 0.942 (t, J = 7.2Hz, 3H).

[0216] Example 9: Preparation of Compound 30086 TIFF2026528992000093.tif53149

[0217] Step 1: General method for preparing compound 30086-2 Under a nitrogen atmosphere at room temperature, 191 mg of Oxon (0.31 mmol) was added to a 6 mL MeOH / THF / H2O = 1:1:1 solution of compound 30085-12 (100 mg, 0.26 mmol) while stirring. The reaction mixture was stirred at room temperature for 2 hours. The mixture was evaporated under reduced pressure, concentrated, and purified by a prepared HPLC (column: Phenomenex luna C18, 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% trifluoroacetic acid), B: acetonitrile]; B%: 10%~50%, 40 min) to obtain compound 30086-2 (50 mg, 43.87% yield) as a white solid.

[0218] Step 2: General method for preparing compound 30086-3 Under a nitrogen atmosphere at room temperature, Dess-Martin periodinane (203 mg, 0.48 mmol) was added to a solution of compound 30086-2 (40 mg, 0.10 mmol) in DMF (5 mL) with stirring. The reaction mixture was stirred at room temperature for 2 hours. The mixture was evaporated under reduced pressure, concentrated, and purified by prepared HPLC (column: Phenomenex luna C18, 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% trifluoroacetic acid), B: acetonitrile]; B%: 10%~50%, 40 min) to obtain compound 30086-3 (30 mg, 67.85% yield) as a white solid.

[0219] Step 3: General method for preparing compound 30086 Under a nitrogen atmosphere at 0°C, compound 30086-3 (30 mg, 0.072 mmol) was added to a DCM / iPrOH = 1:1 (4 mL) solution with compound 30086-4 pyrrolidine (16 mg, 0.22 mmol) and NaBH(OAc)3 (31 mg, 0.14 mmol) while stirring. The reaction mixture was stirred at 0°C for 4 hours. The mixture was evaporated under reduced pressure, concentrated, and purified by prepared HPLC (column: Phenomenex luna C18, 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% trifluoroacetic acid), B: acetonitrile]; B%: 10%~30%, 30 min) to obtain compound M030086 (12 mg, 34.63% yield) as a white solid. LCMS:[M+H] + =471.40; Rt=1.342min. 1 H NMR: (400 MHz, MeOD) δ 7.649 (d, J = 7.2 Hz, 1H), 7.485 (d, J = 8.0 Hz, 2H), 7.432 (d, J = 8.0 Hz, 2H), 6.227 (d, J = 7.6 Hz, 1H), 5.150 (s, 2H), 4.291 (s, 2H), 3.704 (t, J = 13.6 Hz, 2H), 3.306-3.185 (m, 6H), 2.970 (s, 3H), 2.172-2.116 (m, 2H), 2.066-2.001 (m, 4H).

[0220] Example 10: Preparation of Compound 30088 TIFF2026528992000094.tif134148

[0221] Step 1: General method for preparing compound 30088-7-3 Under a nitrogen atmosphere at room temperature, K2CO3 (1548 mg, 15.30 mmol) and pyrrolidine (726 mg, 10.20 mmol) were added to a 30 mL ACN solution of compound 30088-7-1 (1000 mg, 5.10 mmol) with stirring. The reaction mixture was stirred at room temperature for 24 hours. The mixture was evaporated under reduced pressure, concentrated, and directly purified using a flash silica gel column (MeOH / DCM = 0-8%) to obtain 30088-7-3 (800 mg, 4.30 mmol, 84.31% yield) as a white solid.

[0222] Step 2: General method for preparing compound 30088-7 Under a nitrogen atmosphere at 0°C, LAH (489 mg, 12.90 mmol) was added to a solution of compound 30088-7-3 (800 mg, 4.30 mmol) in THF (20 mL). The reaction mixture was stirred at room temperature for 2 hours. H2O (10 mL) was added to quench the mixture, it was diluted with EA (100 mL), washed with water and saturated brine, dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (MeOH / DCM = 0-30%) to obtain compound 30088-7 (850 mg, 4.47 mmol, 93.60% yield) as a white solid.

[0223] Step 3: General method for preparing compound 30088-3 Solutions of compounds 30088-1 (1 g, 4.1 mmol), 30088-2 (0.96 g, 8.2 mmol), and TEA (1.24 g, 12.3 mmol) in DMF (15 mL) were heated with stirring at 50 °C for 2 hours. The solvent was removed under reduced pressure to obtain the crude product. The crude product was directly purified using a flash silica gel column (EA / PE = 0-15%) to obtain compound 30088-3 (1.1 g, 3.4 mmol, 81.93% yield) as a yellow solid.

[0224] Step 4: General method for preparing compound 30088-4 Under a nitrogen atmosphere at room temperature, SOCl2 (273 mg, 2.29 mmol) was added dropwise to a 15 mL solution of compound 30088-3 (500 mg, 1.53 mmol) in DCM while stirring. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain crude product 30088-4 (500 mg, 1.45 mmol, 94.77% yield) as a yellow oily substance.

[0225] Step 5: General method for preparing compound 30088-5 Under a nitrogen atmosphere at room temperature, DIEA (561 mg, 4.34 mmol) and MeSNa (203 mg, 2.89 mmol) were added to a 15 mL solution of compound 30088-4 (500 mg, 1.45 mmol) in DMF. The reaction mixture was stirred at 80°C for 2 hours. The solvent was removed under reduced pressure to obtain the crude product. The crude product was directly purified using a flash silica gel column (EA / PE = 0-15%) to obtain compound 30088-5 (250 mg, 0.70 mmol, 49.30% yield) as a yellow oily substance.

[0226] Step 6: General method for preparing compound 30088-6 A solution of compound 30088-5 (50 mg, 0.14 mmol) and N,N-dimethylformamide dimethylacetal (DMF-DMA, 50 mg, 0.42 mmol) in DMF (3 mL) was heated with stirring at 130°C for 16 hours. The solution was directly evaporated, and the crude product was directly purified using a flash silica gel column (EA / PE = 0-20%) to obtain compound 30088-6 (50 mg, 0.12 mmol, 85.71% yield) as a yellow oily substance.

[0227] Step 7: General method for preparing compound 30088-8 A mixture of compound 30088-6 (50 mg, 0.12 mmol) and compound 30088-7 (72 mg, 0.39 mmol) in EtOH (3 mL) was heated with stirring at 90°C for 2 hours. The solution was directly evaporated, and the crude product was purified by flash column chromatography (MeOH / DCM = 0-5%) to obtain compound 30088-8 (30 mg, 0.06 mmol, 48.29% yield) as a yellow solid.

[0228] Step 8: General method for preparing compound 30088-9 Under a nitrogen atmosphere at room temperature, m-CPBA (81 mg, 0.48 mmol) was added to a solution of compound 30088-8 (30 mg, 0.06 mmol) in DMF (3 mL) with stirring. The reaction mixture was stirred at room temperature for 3 hours. The mixture was evaporated under reduced pressure, concentrated, and purified by a prepared HPLC (column: Phenomenex luna C18, 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% trifluoroacetic acid), B: acetonitrile]; B%: 10%~40%, 30 min) to obtain compound 30088-9 (15 mg, 0.024 mmol, 41.13% yield) as a white solid.

[0229] Step 9: General method for preparing compound 30088-10 A 1,4-dioxane / NH3·H2O=1:2 (3 mL) solution of compound 30088-9 (15 mg, 0.024 mmol) was heated and stirred at 100°C for 2 hours. The solution was evaporated under reduced pressure, concentrated, and purified by prepared HPLC (column: Phenomenex luna C18, 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% FA), B: acetonitrile]; B%: 5%~25%, 30 min) to obtain compound 30088-10 (10 mg, 0.018 mmol, 71.15% yield) as a white solid.

[0230] Step 10: General method for preparing compound M030088 Under a nitrogen atmosphere at room temperature, compound 30088-11 (23 mg, 0.36 mmol) was added to a 3 mL ACN solution of compound 30088-10 (10 mg, 0.018 mmol) and bis(pinacorato)diborone (B2Pin2, 6 mg, 0.023 mmol) while stirring. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated by evaporation under reduced pressure and purified by a prepared HPLC (column: Phenomenex luna C18, 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% FA), B: acetonitrile]; B%: 5%~30%, 30 min) to obtain compound M030088 (3.5 mg, 0.007 mmol, 34.92% yield) as a white solid. LCMS: [M+H] + = 513.50; Rt = 1.574 min. 1 H NMR: (400 MHz, MeOD) δ 7.634-7.615 (d, J = 7.6 Hz, 1H), 7.475-7.403 (m, 4H), 6.222 (d, J = 7.6 Hz, 1H), 5.198-5.085 (m 2H), 4.453 (s, 1H), 4.232 (s, 1H), 3.204-3.180 (m, 6H), 2.943 (s, 3H), 2.188-2.114 (m, 1H), 2.027-1.975 (m, 5H), 1.663-1.568 (m, 2H), 4.423-1.366 (m, 2H), 0.969 (t, J = 14.8 Hz, 3H).

[0231] Example 11: Preparation of compound 30081 TIFF2026528992000095.tif48144

[0232] Step 1: General method for preparing intermediate 30081-2 To a solution of compound 30081-1 (3 g, 18.6 mmol) in EtOH (20 mL), concentrated sulfuric acid (180 mg, 1.8 mmol) was added, and the mixture was heated and stirred at 80°C for 2 hours. The solution was evaporated under reduced pressure and concentrated to obtain compound 30081-2 (3.2 g, 16.9 mmol, 91% yield, 90% purity) as a yellow solid. 1 H NMR: (400 MHz, CDCl3) δ 7.632 (d, J = 8.4 Hz, 2H), 7.414 (d, J = 8.4 Hz, 2H), 4.171 (q, J = 7.2 Hz, 2H), 3.685 (s, 2H), 1.262 (t, J = 7.2 Hz, 3H).

[0233] Step 2: General method for preparing intermediate 30081-3 To a solution of compound 30081-2 (3.2 g, 16.9 mmol) in toluene (30 mL), paraformaldehyde (3.04 g, 33.8 mmol), K2CO3 (4.67 g, 33.8 mmol), and TBAI (2.50 g, 6.7 mmol) were added, and the mixture was heated and stirred at 80°C for 6 hours. The solution was evaporated under reduced pressure, concentrated, and the crude product was purified by flash column chromatography (EtAc / PE = 0-30%) to obtain compound 30081-3 (0.8 g, 4.0 mmol, 24% yield, 90% purity) as a white solid. 1 H NMR: (400 MHz, CDCl3) δ 7.656 (d, J = 8.4 Hz, 2H), 7.543 (d, J = 8.4 Hz, 2H), 6.502 (s, 1H), 5.984 (s, 1H), 4.301 (q, J = 7.2 Hz, 2H), 1.344 (t, J = 7.2 Hz, 3H).

[0234] Step 3: General method for preparing intermediate 30081-4 Compound 30081-3 (600 mg, 2.98 mmol) was mixed with MeOH (10 mL)Pd / C (318 mg, 2.98 mmol) and stirred for 4 hours under a hydrogen atmosphere at 25°C. After filtration, the mixture was evaporated under reduced pressure, concentrated, and the crude product was purified by flash reverse-phase C18 silica gel column chromatography (acetonitrile aqueous solution = 10-40%, 0.1% HCl) to obtain compound 30081-4 (500 mg, 2.41 mmol, 81% yield, 90% purity) as a white solid. LC-MS: (M+H) + ,208.25;Rt=1.343min.

[0235] Compound 30081 was prepared using 30081-4 as a raw material, following the preparation method for compound 30043. TIFF2026528992000096.tif38107[M+H] + , 435.45; Rt = 1.790 min. 1 H NMR (400 MHz, CD3OD) δ 8.534 (s, 1H), 7.582 (d, J = 7.6 Hz, 1H), 7.366 - 7.242 (m, 4H), 6.183 (d, J = 7.6 Hz, 1H), 5.094 (s, 2H), 4.592 (s, 1H), 3.544 - 3.470 (m, 2H), 3.168 - 2.992 (m, 3H), 2.901 (s, 3H), 1.876 (s, 4H), 1.623 (dd, J = 14.8, 7.2 Hz, 2H), 1.456 (dd, J = 15.2, 7.2Hz, 2H), 1.285 (d, J = 6.4 Hz, 4H), 0.987 (t, J = 7.2 Hz, 3H).

[0236] Example 12: Preparation of compounds 30129, 30130, 30138, and 30139 The intermediate was prepared according to the following scheme, referring to the preparation method for compound 30081. TIFF2026528992000097.tif21127 JPEG2026528992000098.jpg59150

[0237] The preparation method of compound 30042 is as follows, and the preparation method of compounds 30129, 30130, 30138, and 30139 is as follows.

[0238] TIFF2026528992000099.tif4160[M+H] + = 449.25; Rt = 0.874 min. 1 H NMR: (400 MHz, CD3OD) δ 8.054 (d, J = 7.6 Hz, 1H), 7.395 (q, J = 8.0 Hz, 4H), 6.398 (d, J = 7.6 Hz, 1H), 5.310 - 5.162 (m, 2H), 4.464 - 4.352 (m, 1H), 3.616 (s, 1H), 3.525 - 3.474 (m, 1H), 3.401 (dd, J = 13.2, 6.0 Hz, 2H), 3.219 (dd, J = 16.4, 6.8 Hz, 2H), 3.168 - 3.120 (m, 1H), 3.023 (d, J = 8.0 Hz, 1H), 2.222 - 2.034 (m, 2H), 1.941 (ddd, J = 15.2, 9.6, 6.8 Hz, 2H), 1.676 - 1.566 (m, 2H), 1.467 - 1.389 (m, 2H), 1.321 (d, J = 6.8 Hz, 3H), 1.283 (d, J = 6.8 Hz, 3H), 0.965 (t, J = 7.2 Hz, 3H).

[0239] TIFF2026528992000100.tif4059[M+H] + = 449.2; Rt = 0.906 min. 1H NMR: (400 MHz, MeOD) δ 8.057-8.038 (d, J = 7.6 Hz, 1H), 7.418-7.353 (m, 4H), 6.424-6.406 (d, J = 7.2 Hz, 1H), 5.248-5.156 (m, 2H), 4.435-4.381 (m, 1H), 3.611-3.583 (m, 1H), 3.542-3.474 (m, 1H), 3.453-3.379 (m, 2H), 2.091-2.061 (m, 2H), 1.950-1.917 (m, 2H), 1.633-1.581(m, 2H), 1.427-1.383 (m, 2H), 1.329-1.311 (d, J = 7.2 Hz, 3H), 1.283-1.267 (d, J = 6.4 Hz, 3H), 0.975-0.939 (t, J = 14.4 Hz, 3H).

[0240] TIFF2026528992000101.tif4360[M+H] + = 425.65; Rt = 1.320 min. 1 H NMR: (400 MHz, CD3OD) δ 7.567 (d, J = 7.2 Hz, 1H), 7.310-7.263 (m, 4H), 6.183 (d, J = 7.6 Hz, 1H), 5.124-5.027 (m, 2H), 4.336-4.268 (m, 1H), 3.486-3.444 (m, 2H), 3.198 (s, 6H), 3.180-3.129 (m, 2H), 1.603-1.494 (m, 2H), 1.452-1.381 (m, 2H), 1.233 (d, J = 6.4 Hz, 3H), 0.965 (t, J = 14.4 (Hz, 3H).

[0241] TIFF2026528992000102.tif4464[M+H] + = 451.55; Rt = 1.353 min. 1H NMR: (400 MHz, CD3OD) δ 7.567-7.549 (d, J = 7.2 Hz, 1H), 7.313-7.262 (m, 4H), 6.182-6.163 (d, J = 7.6 Hz, 1H), 5.123-5.027 (m 2H), 4.336-4.284 (m, 1H), 4.232 (s, 1H), 3.546-3.504 (m, 2H), 3.413-3.392 (m, 4H), 3.247-3.206 (m, 2H), 2.336-2.319 (d, J = 6.8 Hz, 5H), 2.047s, 2H), 1.603-1.526 (m, 2H), 1.417-1.382 (m, 2H), 1.233-1.217 (d, J = 6.4 Hz, 3H), 0.965-0.929 (t, J = 14.4 Hz, 3H).

[0242] Example 13: Preparation of Compound 30012 TIFF2026528992000103.tif93150

[0243] Step 1: General method for preparing compound 30012-2 Under a nitrogen atmosphere, a solution of compound 30012-1 (5 g, 0.030 mol), K2CO3 (12.40 g, 0.090 mol), and dimethyl sulfate (4.53 g, 0.036 mol) in DMF (50 mL) was stirred at 0°C for 2 hours. The mixture was diluted with water (100 mL), extracted with EA (50 mL x 3), and evaporated under vacuum. The crude product was purified by flash column chromatography (PE / EA = 2 / 1) to obtain compound 30012-2 (3 g, 54.85% yield) as a white oil.

[0244] Step 2: General method for preparing compound 30012-3 Under a nitrogen atmosphere, a solution of compound 30012-2 (3 g, 0.017 mol), cyanamide (1.39 g, 0.033 mol), and concentrated hydrochloric acid (4.14 mL) in EtOH (30 mL) was stirred at 80°C for 12 hours. The mixture was filtered, and the yellow solid was collected to obtain the crude product compound 30012-3 (1.2 g, 37.35% yield).

[0245] Step 3: General method for preparing compound 30012-4 Under a nitrogen atmosphere at room temperature, compound 30012-3 (1.2 g, 0.006 mol) was dissolved in DMF (10 mL) and DBU (2.88 g, 0.019 mol), benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 3.34 g, 0.008 mol), and n-butylamine (1.38 g, 0.019 mol) were added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with water (20 mL), extracted with EA (10 mL x 3), evaporated under vacuum, and the crude product was purified by flash column chromatography (MeOH / DCM = 1 / 20) to obtain compound 30012-4 (1 g, 63.49% yield) as a yellow oil.

[0246] Step 4: General method for preparing compound 30012-5 Under a nitrogen atmosphere, a mixture of compound 30012-4 (1 g, 0.004 mol) and pyridine hydrochloride (2.84 g, 0.025 mol) in a pyridine solution (10 mL) was stirred at 120°C for 8 hours. The mixture was evaporated under vacuum, and the crude product was purified using a C18 reversed-phase silica gel column (ACN-H2O=35%) to obtain compound 30012-5 (0.8 g, 82.93% yield) as a yellow solid.

[0247] Step 5: General method for preparing compound 30012-7 Under a nitrogen atmosphere, a mixture of compound 30012-5 (200 mg, 0.861 mmol), Cs2CO3 (842 mg, 2.583 mmol), and compound 30012-6 (250 mg, 0.947 mmol) in DMF (5 mL) was stirred at room temperature for 2 hours. The mixture was diluted with water (10 mL), extracted with EA (5 mL x 3), and evaporated under vacuum to obtain the crude product compound 30012-7 (120 mg) as a yellow oily substance.

[0248] Step 6: General method for preparing compound 30012 Under a nitrogen atmosphere, a mixture of compound 30012-7 (100 mg, 0.241 mmol) and compound 30012-8 pyrrolidine (51 mg, 0.722 mmol) in DMF (2 mL) was stirred at room temperature for 2 hours. The mixture was filtered, and the solvent was removed under reduced pressure. The crude product was then purified by preparation HPLC (column: Phenomenex luna C18 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% FA), B: acetonitrile]; B%: 10%~50%, 40 min) to obtain compound M030012 (20 mg, 20.06% yield) as a white solid. LCMS: [M+H] + = 406.3; Rt = 0.814 min. 1 H NMR: (400 MHz, d6-DMSO) δ 8.225 (s, 1H), 7.815 (s, 1H), 7.505 - 7.485 (dd, J = 8.0 Hz, 2H), 7.425 - 7.375 (m, 3H), 6.815 (d, J = 8.0 Hz, 1H), 6.725 (d, J = 10.0 Hz, 1H), 6.351 (s, 1H), 5.215 (s, 2H), 3.615 (s, 2H), 3.355 - 3.305 (dd, J = 8.4 Hz, 2H), 2.445 (s, 4H), 1.705 (d, J = 8.0 Hz, 4H), 1.123 (t, J = 7.6 Hz, 2H), 1.085 (t, J = 6.4 Hz, 2H), 0.758 (t, J = 6.4 Hz, 3H).

[0249] Compounds 30013, 30044, 30047, and 30048 were prepared by referring to the preparation method for compound 30012. TIFF2026528992000104.tif162164

[0250] Example 14: Preparation of Compound 30014 TIFF2026528992000105.tif33153

[0251] Step 1: General method for preparing compound 30014-2 Under a nitrogen atmosphere at room temperature, a THF (50 mL) reaction mixture of compound 30014-1 (200 mg, 1.379 mmol), PPh3 (387 mg, 1.517 mmol), and CBr4 (490 mg, 1.517 mmol) was stirred at room temperature for 12 hours. The mixture was diluted with H2O / Et2O = 1 / 3 (20 mL), extracted with 1M HCl (20 mL), the aqueous phase was adjusted to pH 10 with 4M NaOH, extracted with EA (20 mL × 3), and evaporated in vacuo to obtain the crude product compound 30014-2 (200 mg) as a white oil.

[0252] Step 1: General method for preparing compound 30014 Under a nitrogen atmosphere, a mixture of compound 30014-2 (99 mg, 0.474 mmol), compound 30012-5 (100 mg, 0.431 mmol), and Cs2CO3 (421 mg, 1.292 mmol) in DMF (2 mL) was stirred at room temperature for 2 hours. The mixture was filtered and the solvent was removed under reduced pressure. Subsequently, the crude product was purified by preparative HPLC (column: Phenomenex luna C18 250 mm × 100 mm × l0 μm; mobile phase: [A: H2O (0.1% FA), B: acetonitrile]; B%: 5% - 30%, 20 minutes) to obtain compound M030014 (20 mg, 12.01% yield) as a white solid. LCMS: [M+H] + = 360.3. 1H NMR: (400 MHz, d6-DMSO) δ 8.305 (s, 1H), 7.995 - 7.981 (d, J = 8.0 Hz, 1H), 7.415 - 7.395 (dd, J = 8.0 Hz, 1H), 6.835 - 6.815 (dd, J = 8.0 Hz, 1H), 6.735 (s, 1H), 6.665 - 6.645 (dd, J = 8.0 Hz, 1H), 4.225 - 4.195 (dd, J = 8.0 Hz, 2H), 3.596(s, 4H), 3.475 (s, 2H), 2.505 - 2.385 (m, 6H), 1.995 (d, 1.585 (d, J = 8.4 Hz, 2H), 1.415 (d, J = 8.4 Hz, 2H) 0.965 - 0.925 (t, J = 7.6 Hz, 3H).

[0253] Example 15: Preparation of Compound 30016 TIFF2026528992000106.tif99146

[0254] Step 1: General method for preparing compound 30016-3 Under a nitrogen atmosphere at 0°C, compound 30016-2 pyrrolidine (1.28 g, 0.018 mol) was added dropwise to a solution of compound 30016-1 (2 g, 0.016 mol) in DCM (15 mL), and NaBH(OAc)3 (5.21 g, 0.025 mol) was further added. The reaction mixture was stirred at room temperature for 12 hours. The mixture was diluted with water (30 mL), extracted with DCM (30 mL x 3), dried over Na2SO4, and concentrated. Crude product 30016-3 (1 g, 0.005 mmol, 31.10% yield) was obtained as a white solid.

[0255] Step 2: General method for preparing compound 30016-5 Under a nitrogen atmosphere, a solution of compound 30016-4 (1 g, 0.006 mol), K2CO3 (2.65 g, 0.019 mol), and compound dimethyl sulfate (0.97 g, 0.008 mol) in DMF (10 mL) was stirred at 0°C for 3 hours. The mixture was diluted with water (50 mL), extracted with EA (50 mL x 3), the organic layer was recovered, washed with saturated brine (50 mL x 5), dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (PE / EA = 2 / 1) to obtain compound 30016-5 (1 g, 82.81% yield) as a yellow oil.

[0256] Step 3: General method for preparing compound 30016-7 Under a nitrogen atmosphere, a solution of compound 30016-5 (1 g, 0.006 mol), cyanamide (0.4 g, 0.010 mmol), and concentrated hydrochloric acid (1 mL) in EtOH (30 mL) was stirred at 100°C for 12 hours. The mixture was filtered to collect a white solid, and the crude product compound 30016-7 (0.5 g, 43.75% yield) was obtained.

[0257] Step 4: General method for preparing compound 30016-8 Refer to step 3 for preparing compound 30012.

[0258] Step 5: General method for preparing compound 16 Under a nitrogen atmosphere, a mixture of compounds 30016-3 (45 mg, 0.256 mmol), Cs2CO3 (83 mg, 0.256 mmol), and 30016-8 (50 mg, 0.213 mmol) in DMF (1 mL) was stirred at 160°C for 3 hours. The mixture was diluted with MeOH (5 mL) and then purified by a prepared HPLC (column: Phenomenex luna C18 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% FA), B: acetonitrile]; B%: 10%~50%, 40 min) to obtain compound M030016 (1.05 mg, 0.003 mmol, 1.3% yield) as a white solid. LCMS: [M+H] + = 392.1; Rt = 0.852 min. 1 H NMR:, (400 MHz, MeOD) δ 7.440 (d, J = 8.0 Hz, 1H), 7.380 (d, J = 8.0 Hz, 1H), 7.250 (d, J = 7.6 Hz, 1H), 7.152 (s, 1H), 7.070 (dd, J = 8.0, 2.0 Hz, 1H), 7.020 (d, J = 8.4 Hz, 1H), 6.414 (d, J = 8.0 Hz, 1H), 3.675 (s, 2H), 3.567 (s, 2H), 2.574 (s, 4H), 1.813 (t, J = 3.2 Hz, 4H), 1.600 (s, 2H), 1.368 (s, 2H), 0.915 - 0.889 (m, 3H).

[0259] Example 16: Preparation of Compound 30046 TIFF2026528992000107.tif62151

[0260] Step 1: General method for preparing compound 30046-2 Under a nitrogen atmosphere at 0°C, BH3·SMe2 (497 mg, 6.548 mmol) was added dropwise to a solution of compound 30046-1 (500 mg, 2.183 mmol) in THF (20 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (10 mL), filtered and concentrated to obtain crude product 30046-2 (350 mg) as a white solid.

[0261] Step 2: General method for preparing compound 30046-4 Under a nitrogen atmosphere, a 10 mL solution of compound 30046-2 (350 mg, 1.627 mmol), Cs2CO3 (1591 mg, 4.882 mmol), and compound 30012-5 (378 mg, 1.627 mmol) in DMF was stirred at room temperature for 4 hours. The mixture was diluted with water (2 mL), extracted with DCM (100 mL), and the organic layer was recovered. It was washed with water and saturated brine, dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (MeOH / DCM = 10%) to obtain compound 30046-4 (280 mg, 0.76 mmol, 46.96% yield) as a yellow solid.

[0262] Step 3: General method for preparing compound 30046-5 Under a nitrogen atmosphere at room temperature, Dess-Martin periodinane (116 mg, 0.27 mmol) was added to a 1 mL solution of compound 30046-4 (50 mg, 0.14 mmol) in DCM while stirring. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was purified by flash column chromatography (MeOH / DCM = 5%) to obtain compound 30046-5 (30 mg, 50% yield) as a brown solid.

[0263] Step 4: General method for preparing compound 30046 Under a nitrogen atmosphere at 0°C, compound 30046-5 (30 mg, 0.08 mmol), dimethylamine (0.05 mL, 0.10 mmol, 2 M THF solution), and AcOH (7 mg, 0.12 mmol) were added to a solution of iPrOH (1 mL) with stirring. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by a prepared HPLC (column: Phenomenex luna C18, 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% FA), B: acetonitrile]; B%: 10%~50%, 40 min) to obtain compound M030046 (1.60 mg, 4% yield) as a white solid. LCMS: [M+H] + = 394.4; Rt = 1.761 min. 1 H NMR: (400 MHz, CD3OD) δ 7.646 (t, J = 8.4 Hz, 1H), 7.508 (d, J = 8.0 Hz, 2H), 7.370 (d, J = 8.0 Hz, 2H), 7.067 (d, J = 8.4 Hz, 1H), 6.963 (d, J = 8.4 Hz, 1H), 5.308 (s, 2H), 3.512 (t, J = 6.8 Hz, 2H), 2.967 - 2.867 (m, 4H), 2.562 (s, 6H), 1.434 - 1.362 (m, 2H), 1.211 - 1.131 (m, 2H), 0.834 (t, J = 7.2 Hz, 3H).

[0264] The preparation method of compound 30046 is the same as that of the preparation method, and the preparation method of compound 50 is the same. TIFF2026528992000108.tif4155LC-MS:[M+H] + = 420.2; Rt = 0.871 min. 1 H NMR: (400 MHz, d6-DMSO) δ 8.330 (s, 1H), 7.763 (s, 1H), 7.443 (m, 2H), 7.359 (m, 1H), 7.315 - 7.295 (d, J = 8.0 Hz, 2H), 6.813 - 6.792 (d, J = 8.4 Hz, 1H), 6.720 - 6.700 (d, J = 8.0 Hz, 1H), 6.242 (s, 2H), 5.186 (s, 2H), 3.340 - 3.294 (m, 6H), 2.793 - 2.756 (t, J = 14.8 Hz, 2H), 2.660 - 2.622 (t, J = 15.2 Hz, 2H), 1.682 (s, 4H), 1.301 - 1.264 (m, 2H), 1.127 - 1.071 (m, 2H), 0.783 - 0.746 (t, J = 14.8 Hz, 3H).

[0265] Example 17: Preparation of compound 30049 TIFF2026528992000109.tif62154

[0266] Step 1: General method for preparing compound 30049-2 Under a nitrogen atmosphere at 0°C, the reaction mixture of compound 30049-1 (5.0 g, 40.30 mmol), 3,4-dihydro-2H-pyran (4.07 g, 48.30 mmol), and a THF solution (25 mL) of TsOH·H2O (80 mg, 0.40 mmol) was stirred at room temperature for 16 hours. The mixture was extracted with EA (20 mL x 2) and concentrated by filtration to obtain crude product 30049-2 (9.0 g) as a brown oily substance.

[0267] Step 2: General method for preparing compound 30049-4 Under a nitrogen atmosphere at 80°C, compound 30049-3 (2076 mg, 14.40 mmol) was added with stirring to a solution of compound 30049-2 (3000 mg, 14.40 mmol) and sodium hydroxide (1152 mg, 28.80 mmol) in 12 mL of water. The reaction mixture was stirred at 80°C for 10 minutes. The mixture was extracted with EA (10 mL x 2), filtered and concentrated, and the crude product was purified by flash column chromatography (MeOH / DCM = 3-5%) to obtain compound 30049-4 (800 mg, 18% yield) as a colorless oil.

[0268] Step 3: General method for preparing compound 30049-5 Under a nitrogen atmosphere at room temperature, the reaction mixture of compound 30049-4 (115 mg, 0.41 mmol) and TsOH·H2O (78 mg, 0.41 mmol) in MeOH (3 mL) was stirred at room temperature for 3 hours. The mixture was diluted with saturated NaHCO3 aqueous solution, extracted with EA (5 mL x 2), and the organic layer was concentrated to obtain crude product 30049-5 (80 mg) as a colorless oil.

[0269] Step 4: General method for preparing compound 30049 Under a nitrogen atmosphere, a mixture of Compound 30049-5 (40 mg, 0.20 mmol), Cs2CO3 (67 mg, 0.20 mmol), and Compound 30016-8 (40 mg, 0.17 mmol) in DMF (1 mL) was stirred at 155 °C for 1.5 hours. The mixture was extracted with EA (5 mL × 2), and the organic layer was concentrated to obtain a crude product. Subsequently, it was purified by preparative HPLC (column: Phenomenex luna C18 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% FA), B: acetonitrile]; B%: 10% - 50%, 40 minutes) to obtain Compound M030049 (1.66 mg, 2% yield) as a white solid. LCMS: [M+H] + = 410.2; Rt = 0.843 min. 1 1H NMR: (400 MHz, CD3OD) δ 7.547 (t, J = 8.4 Hz, 1H), 7.480 (d, J = 8.4 Hz, 2H), 7.052 (d, J = 8.8 Hz, 2H), 6.932 (dd, J = 8.0, 4.8 Hz, 2H), 5.182 (s, 2H), 4.149 (t, J = 5.2 Hz, 2H), 3.419 (t, J = 6.8 Hz, 2H), 2.817 (t, J = 5.2 Hz, 2H), 2.370 (s, 6H), 1.378 - 1.301 (m, 2H), 1.152 - 1.067 (m, 2H), 0.806 (t, J = 7.2 Hz, 3H).

[0270] Example 18: Preparation of Compound 30059 TIFF2026528992000110.tif111155

[0271] Step 1: General method for preparing Compound 30059-2-3 Under a nitrogen atmosphere, the reaction mixture in DMF (20 mL) containing compound 30059-2-1 (5 g, 0.027 mol), compound 30059-2-2 (10.54 g, 0.081 mol), palladium acetate (0.18 g, 0.001 mol), tri-o-tolylphosphine (0.99 g, 0.003 mol), and TEA (5.46 g, 0.054 mol) was stirred at 90°C for 1 hour. The mixture was concentrated, diluted with water (20 mL), extracted with EA (20 mL x 5), the organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and then evaporated under vacuum. The crude product was purified by flash column chromatography (EA / PE = 50%) to obtain compound 30059-2-3 (2.6 g, 0.0126 mol, 46.67% yield) as a white solid.

[0272] Step 2: General method for preparing compound 30059-2-4 Under a nitrogen atmosphere at 0°C, NaBH4 (0.71 g, 0.019 mol) was added with stirring to a THF / MeOH=3:1 (10 mL) solution of compound 30059-2-3 (2.6 g, 0.0126 mol). The reaction mixture was stirred at 0°C for 1 hour. The mixture was concentrated, diluted with water (10 mL), extracted with EA (10 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and then evaporated under vacuum. The crude product was purified by flash column chromatography (DCM / MeOH=10 / 1) to obtain compound 30059-2-4 (1.9 g, 0.009 mol, 71.43% yield) as a white solid.

[0273] Step 3: General method for preparing compound 30059-2 Under a nitrogen atmosphere, the reaction mixture of compound 30059-2-4 (1.9 g, 0.009 mol) and PBr3 (3.69 g, 0.0134 mol) in Et2O (10 mL) was stirred at 0°C for 1 hour. The mixture was concentrated, diluted with water (10 mL), extracted with EA (10 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and then evaporated under vacuum. The crude product was purified by flash column chromatography (EA / PE = 50%) to obtain compound 30059-2 (1.3 g, 0.004 mol, 47.25% yield) as a white solid.

[0274] Step 4: General method for preparing compound 30059-3 Under a nitrogen atmosphere, a 5 mL solution of compound 30059-2 (700 mg, 2.583 mmol), Cs2CO3 (2104 mg, 6.458 mmol), and compound 30012-5 (500 mg, 2.153 mmol) in DMF was stirred at room temperature for 16 hours. The mixture was concentrated, diluted with water (30 mL), extracted with EA (30 mL x 3), and the organic layer was recovered. It was washed with water and saturated brine, dried over Na2SO4, and concentrated. The crude product was purified by flash column chromatography (MeOH / DCM = 1 / 10) to obtain compound 30059-3 (600 mg, 1.278 mmol, 59.37% yield) as a white solid.

[0275] Step 5: General method for preparing compound 30059-4 Under a nitrogen atmosphere at 0°C, a solution of compound 30059-3 (600 mg, 1,420 mmol) in THF (5 mL) was added dropwise to a solution of LiAlH4 (108 mg, 2,840 mmol) in THF (5 mL) with stirring. The reaction mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated, diluted with water (10 mL), extracted with EA (10 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and then evaporated under vacuum. The crude product was purified by flash column chromatography (DCM / MeOH = 10 / 1) to obtain compound 30059-4 (340 mg, 0.804 mmol, 56.63% yield) as a white solid.

[0276] Step 6: General method for preparing compound 30059-5 Refer to step 3 for preparing compound 30046.

[0277] Step 7: General method for preparing compound 59 Refer to step 4 for preparing compound 30046. LCMS: [M+H] + = 408.1; Rt = 0.835 min. 1 H NMR (400 MHz, d4-MeOD) δ 8.536 (s, 1H), 7.601 (t, J = 8.4 Hz, 1H), 7.469 (s, 2H), 7.337 (d, J = 8.0 Hz, 2H), 6.975 (dd, J = 25.8, 8.4 Hz, 2H), 5.266 (s, 2H), 3.457 (t, J = 6.8 Hz, 2H), 2.723 - 2.685 (m, 2H), 2.610 - 2.571 (m, 2H), 2.422 (s, 6H), 1.895 (dt, J = 15.8, 8.0 Hz, 2H), 1.414 - 1.342 (m, 2H), 1.191 - 1.117 (m, 2H), 0.839 - 0.764 (m, 3H).

[0278] Example 19: Preparation of Compound 30004 TIFF2026528992000111.tif69150

[0279] Step 1: General method for preparing compound 30004-3 Under a nitrogen atmosphere, solutions of compounds 30004-1 (500 mg, 4.20 mmol) and 30004-2 (806 mg, 9.25 mmol) in DCM (5 mL) were stirred at room temperature for 4 hours. The mixture was concentrated, extracted with DCM (10 mL x 2), the organic layer was recovered, washed with saturated brine, dried over Na2SO4, and concentrated to obtain crude product compound 30004-3 (300 mg) as a colorless oil.

[0280] Step 2: General method for preparing compound 30004-5 Under a nitrogen atmosphere, the reaction mixture of compound 30004-4, i.e., INT-II (30 mg, 0.12 mmol), compound 30004-3 (18 mg, 0.14 mmol), Pd(PPh3)4 (21 mg, 0.02 mmol), cuprous iodide (3 mg, 0.02 mmol), and triethylamine (36 mg, 0.36 mmol) in DMF (0.5 mL) was stirred at 90°C for 1 hour. The mixture was extracted with EA (10 mL x 2), the organic phase was evaporated under vacuum, and the crude product was purified by flash column chromatography (DCM / MeOH = 20 / 1) to obtain compound 30004-5 (40 mg, 90% yield) as a brown solid.

[0281] Step 3: General method for preparing compound 30004 Under a hydrogen atmosphere, a solution of compound 30004-5 (40 mg, 0.12 mmol) and Pd / C (10 mg) in EA (3 mL) was stirred at room temperature for 16 hours. The mixture was filtered, the organic layer was concentrated, and then purified by a prepared HPLC (column: Phenomenex luna C18 250 mm × 100 mm × 10 μm; mobile phase: (A: H2O (0.1% FA), B: acetonitrile); B%: 15%~55%, 40 min) to obtain compound M030004 (8.2 mg, 20% yield) as a white solid. LC-MS: [M+H] + = 345.3; Rt = 0.631 min. 1H NMR: (400 MHz, CDCl3) δ 8.044 (br s, 1H), 7.835 (d, J = 8.4 Hz, 1H), 7.438 (d, J = 8.4 Hz, 1H), 5.971 (br s, 2H), 3.825 (t, J = 4.8 Hz, 4H), 3.660 (dd, J = 13.6, 6.8 Hz, 2H), 2.912 (t, J = 7.2 Hz, 2H), 2.671 (s, 4H), 2.607 - 2.550 (m, 2H), 2.201 - 2.102 (m, 2H), 1.759 - 1.681 (m, 2H), 1.510 - 1.401 (m, 2H), 0.996 (t, J = 7.2 Hz, 3H).

[0282] Example 20: Preparation of Compound 30005 TIFF2026528992000112.tif28155

[0283] Step 1: General method for preparing compound 30005-3 Under a nitrogen atmosphere at 0°C, a solution of compound 30005-1 (500 mg, 2.487 mmol) in THF (5 mL) was added dropwise to a solution of pyrrolidine (707 mg, 9.947 mmol) in THF (10 mL) with stirring. The reaction mixture was stirred at room temperature for 2 hours. This was concentrated under reduced pressure and dissolved in 1 M HCl (25 mL). After washing with Et2O (×2) and cooling with ice water, NaOH (2 g, 50 mmol) was added. Extraction with EA was performed, the organic layer was recovered, dried over Na2SO4, and concentrated to obtain the crude product compound 30005-3 (440 mg) as a yellow oil.

[0284] Step 2: General method for preparing compound 30005 Under a nitrogen atmosphere at 0°C, a solution of compound 30005-4, i.e., INT-I (41 mg, 0.214 mmol) and NaH (10 mg, 0.255 mmol) in DMF (1 mL) was stirred for 0.5 hours. Then, a solution of compound 30005-3 (30 mg, 0.102 mmol) in DMF (1 mL) was added dropwise. The reaction mixture was stirred at 100°C for 2 hours. The mixture was diluted with MeOH, the organic layer was concentrated, and then purified by prepared HPLC (column: Phenomenex luna C18 250 mm × 100 mm × 10 μm; mobile phase: (A: H2O (0.1% FA), B: acetonitrile); B%: 5%~50%, 35 min) to obtain compound 30005 (7.66 mg, 0.02 mmol, 17% yield) as a white solid. LCMS: [M+H] + = 407.2; Rt = 0.911 min. 1 H NMR: (400 MHz, CDCl3) δ 7.750 (d, J = 9.2 Hz, 1H), 7.418 (s, 4H), 7.117 (d, J = 9.2 Hz, 1H), 6.825 (s, 1H), 6.234 (s, 2H), 5.368 (s, 2H), 3.752 (s, 2H), 3.598 (dd, J = 13.6, 6.8 Hz, 2H), 2.668 (s, 4H), 1.855 (s, 4H), 1.732 - 1.659 (m, 2H), 1.460 (dd, J = 15.2, 7.4 Hz, 2H), 1.003 (t, J = 7.2 Hz, 3H).

[0285] Example 21: Preparation of Compound 30006 TIFF2026528992000113.tif68157

[0286] Step 1: General method for preparing compound 30006-2 Under a nitrogen atmosphere, a solution of compound 30006-1 (500 mg, 2.183 mmol) in toluene (5 mL) was added dropwise with DIBAL-H (621 mg, 4.365 mmol) while stirring at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The mixture was concentrated, extracted with EA, the organic layer was recovered, dried over Na2SO4, and concentrated to obtain crude product compound 30006-2 (350 mg) as a yellow oily substance.

[0287] The remaining steps were followed to prepare compound 30006, referring to the preparation method for compound 30005. LCMS: [M+H] + = 407.2. 1 H NMR: 400 MHz, CDCl3) δ 7.850 (d, J = 9.2 Hz, 1H), 7.694 (s, 1H), 7.440 - 7.382 (m, 3H), 7.250 - 7.212 (m, 1H), 7.167 (d, J = 9.2 Hz, 1H), 5.410 (s, 2H), 3.984 (s, 2H), 3.644 (d, J = 6.4 Hz, 2H), 2.950 (s, 4H), 1.987 (s, 4H), 1.706 (t, J = 7.2 Hz, 2H), 1.478 - 1.440 (m, 2H), 1.000 (t, J = 7.2 Hz, 3H).

[0288] Example 22: Preparation of Compound 30007 TIFF2026528992000114.tif64152

[0289] Step 1: General method for preparing compound 30007-3 Under a nitrogen atmosphere, the reaction mixture of compound 30007-1 (500 mg, 3.009 mmol), pyrrolidine (235 mg, 3.310 mmol), DCC (683 mg, 3.310 mmol), and HOBT (447 mg, 3.310 mmol) in DMF (5 mL) was stirred at 0°C for 2 hours. The mixture was concentrated, diluted with water (30 mL), extracted with EA (30 mL x 3), the organic layer was recovered, washed with saturated brine (40 mL x 5), dried over Na2SO4, concentrated, and the crude product was purified by flash column chromatography (EA / PE = 1 / 5) to obtain the crude product compound 30007-3 (230 mg, 34.5% yield) as a colorless oil.

[0290] Step 2: General method for preparing compound 30007-4 Under a nitrogen atmosphere, the reaction mixture of compound 30007-3 (50 mg, 0.228 mmol) and LiAlH4 (17 mg, 0.456 mmol) in THF (1 mL) was stirred at 25°C for 2 hours. The mixture was concentrated, extracted with EA (30 mL x 3), the organic layer was recovered, dried over Na2SO4, and concentrated to obtain crude product compound 30007-4 (19 mg, 0.09 mmol, 38.55% yield) as a yellow oil.

[0291] The remaining steps were followed to prepare compound 30007, referring to the preparation method for compound 30005. LCMS: [M+H] + = 421.1. 1 H NMR: (400 MHz, CDCl3) δ 7.850 (d, J = 9.2 Hz, 1H), 7.410 (d, J = 8.0 Hz, 2H), 7.287 (s, 2H), 7.140 (d, J = 9.2 Hz, 1H), 7.046 (s, 1H), 5.349 (s, 2H), 3.646 - 3.595 (m, 2H), 3.180 (s, 8H), 2.099 (s, 4H), 1.724 - 1.687 (m, 2H), 1.460 (dd, J = 14.8, 7.2 Hz, 2H), 1.010 (t, J = 7.2 Hz, 3H).

[0292] Example 23: Preparation of Compound 30008 TIFF2026528992000115.tif41136

[0293] Compound 30008 was prepared by referring to the preparation method for compound 30007. LCMS: [M+H] + = 361.3; 1 H NMR: (400 MHz, CDCl3) δ 7.874 (d, J = 9.2 Hz, 1H), 7.479 (s, 1H), 7.080 (d, J = 9.2 Hz, 1H), 4.440 (t, J = 4.4 Hz, 2H), 3.844 (s, 4H), 3.664 - 3.612 (m, 2H), 2.741 (s, 6H), 2.136 (d, J = 5.2 Hz, 2H), 1.700 (dd, J = 14.8, 7.6 Hz, 2H), 1.443 (dt, J = 14.8, 7.6 Hz, 2H), 1.000 (t, J = 7.6 Hz, 3H).

[0294] Example 24: Preparation of Compound 30009 TIFF2026528992000116.tif34155

[0295] Step 1: General method for preparing compound 30009-3 Under a nitrogen atmosphere at room temperature, NaBH(OAc)3 (1168 mg, 5.509 mmol) was added to a 5 mL DCM solution of compound 30009-1 (500 mg, 3.673 mmol) and pyrrolidine (287 mg, 4.040 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. The mixture was extracted with EA, the organic layer was recovered, dried over Na2SO4, and concentrated to obtain crude product compound 30009-3 (400 mg) as a yellow solid.

[0296] Step 2: General method for preparing compound 30009 Under a nitrogen atmosphere, a 1 mL solution of compound 30009-3 (42 mg, 0.238 mmol), compound 30009-4, i.e., INT-II (50 mg, 0.199 mmol), and Cs2CO3 (78 mg, 0.238 mmol) in DMF was stirred at 150°C for 2 hours. The solution was then diluted with MeOH and purified by a prepared HPLC (column: Phenomenex luna C18 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% FA), B: acetonitrile]; B%: 10%~40%, 25 min) to obtain compound M030009 (3.85 mg, 0.01 mmol, 5.1% yield) as a white solid. LCMS: [M+H] + = 393.3; 1 H NMR: (400 MHz, CDCl3) δ 7.950 (d, J = 8.8 Hz, 1H), 7.605 (d, J = 8.0 Hz, 2H), 7.248 (s, 1H), 7.180 (d, J = 8.4 Hz, 2H), 7.101 (s, 1H), 4.091 (s, 2H), 3.556 - 3.505 (m, 2H), 3.126 (s, 4H), 2.075 (s, 4H), 1.606 - 1.551 (m, 2H), 1.367 (dd, J = 14.8, 7.2 Hz, 2H), 0.935 (t, J = 7.2 Hz, 3H).

[0297] Example 25: Preparation of Compound 30010 Compound 30010 was prepared by referring to the preparation method for compound 30009 (TIFF2026528992000117.tif37154). LCMS: [M+H] + = 393.3 1H NMR: (400 MHz, CDCl3) δ 7.710 (d, J = 8.8 Hz, 1H), 7.349 (t, J = 7.6 Hz, 1H), 7.204 (d, J = 7.6 Hz, 1H), 7.159 - 7.123 (m, 2H), 7.065 (d, J = 8.0 Hz, 1H), 6.468 (s, 1H), 4.819 (s, 2H), 3.655 (s, 2H), 3.467 (dd, J = 13.2, 6.8 Hz, 2H), 2.551 (s, 4H), 1.800 (s, 4H), 1.569 (dd, J = 14.8, 7.2 Hz, 2H), 1.372 (dd, J = 15.2, 7.2 Hz, 2H), 0.931 (t, J = 7.2 Hz, 3H).

[0298] Example 26: Preparation of Compound 30011 TIFF2026528992000118.tif62151

[0299] Step 1: General method for preparing compound 30011-2 Under a nitrogen atmosphere at room temperature, the reaction mixture of compound 30011-1 (2.0 g, 14.50 mmol) and concentrated hydrochloric acid (15 mL) was stirred at 100 °C for 3 hours. The mixture was quenched with water, extracted with MTBE (30 mL x 2), and the organic layer was recovered and concentrated to obtain the crude product compound 30011-2 (2.2 g, 92%) as a brown oily substance.

[0300] Step 2: General method for preparing compound 30011-4 Under a nitrogen atmosphere, a mixture of compound 30011-2 (1000 mg, 6.39 mmol), pyrrolidine (707 mg, 9.947 mmol), and triethylamine (1938 mg, 19.16 mmol) in acetonitrile (10 mL) was stirred at 80°C for 3 hours. The mixture was concentrated under reduced pressure, and the crude product was purified by flash column chromatography (DCM / MeOH=20 / 1) to obtain compound 30011-4 (500 mg, 40% yield) as a brown solid.

[0301] Step 3: General method for preparing compound 30011 Compound 30011 was prepared by referring to preparation step 2 for preparing compound 30009. LCMS: [M+H] + = 407.2. 1 H NMR: (400 MHz, CDCl3) δ 10.888 (br s, 2H), 7.888 (d, J = 8.8 Hz, 1H), 7.301 - 7.269 (m, 2H), 7.203 (d, J = 8.8 Hz, 1H), 7.092 (d, J = 8.4 Hz, 2H), 7.047 (t, J = 5.6 Hz, 1H), 3.510 (dd, J = 13.2, 6.8 Hz, 2H), 3.170 - 2.981 (m, 8H), 2.062 - 1.970 (m, 4H), 1.628 - 1.537 (m, 2H), 1.409 - 1.301 (m, 2H), 0.938 (t, J = 7.2 Hz, 3H).

[0302] Example 27: Preparation of Compound 30151 TIFF2026528992000119.tif71150

[0303] Step 1: General method for preparing compound 30151-2 Under a nitrogen atmosphere at room temperature, compound Raney Ni (191 mg, 3.25 mmol) was added to a solution of compound 30151-1 (500 mg, 3.25 mmol) in MeOH (10 mL). The reaction mixture was stirred for 1 hour under a hydrogen atmosphere at 25 °C. The residue was removed by filtration through Celite, and the mixture was concentrated under reduced pressure to obtain the crude product compound 30151-2 (400 mg, 62% yield) as a white solid. [M+H] + = 158.1.

[0304] Step 2: General method for preparing compound 30151-3 Under a nitrogen atmosphere at room temperature, compound 30151-2 (209 mg, 1.32 mmol) was added to a solution of compound 3 (300 mg, 0.88 mmol) in EtOH (5 mL). The reaction mixture was heated and stirred at 100 °C for 1 hour. The solvent was removed under reduced pressure to obtain the residue. The crude product was purified by flash column chromatography (0-10% ethyl acetate / PE) to obtain compound 30151-3 (300 mg, 72% yield) as a yellow solid. [M+H] + = 418.8.

[0305] Step 3: General method for preparing compound 30151-4 A solution of compound 30151-3 (200 mg, 0.47 mmol) and m-CPBA (411 mg, 2.38 mmol) in DMF (5 mL) was stirred at room temperature for 1 hour. The reaction solution was quenched with aqueous Na2S2O3 (10 mL) and extracted with EA (40 mL x 2). The organic layer was collected, dried over Na2SO4, and concentrated to obtain crude product 30151-4 (150 mg, 62% yield) as a yellow solid. [M+H] + = 451.1.

[0306] Step 4: General method for preparing compound 30151-5 Compound 30151-4 (200 mg, 0.44 mmol) was dissolved in 1 mL of 1,4-dioxane, and aqueous ammonia (2 mL) was added. The solution was heated and stirred at 90°C for 1 hour. The solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (15 min, 0-10% ethyl acetate / PE) to obtain compound 30151-5 (100 mg, 55% yield) as a yellow solid. [M+H] + = 388.3.

[0307] Step 5: General method for preparing compound 30151 Compound 30151-5 (30 mg, 0.07 mmol) was dissolved in DMF (2 mL), to which compound 4 (16 mg, 0.15 mmol) and K2CO3 (42 mg, 0.32 mmol) were added. The mixture was stirred under a nitrogen atmosphere at 50°C for 1 hour. The solvent was removed under reduced pressure. The crude product was then purified by preparatory HPLC (column: Phenomenex luna C18 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% trifluoroacetic acid), B: acetonitrile]; B%: 0%~80%, 10 min) to obtain compound 30151 (4 mg, 10% yield) as a white solid. LCMS: [M+H] + 459.2; Rt = 0.995 min. 1 H NMR (400 MHz, DMSO-d6) δ 9.26(d, J = 8 Hz, 1H), 8.18 (s, 1H), 7.57 (d, J = 8 Hz, 1H), 7.04 (s, 1H), 6.93 - 6.91 (m, 2H), 6.62 (s, 2H), 6.11 (d, J = 8 Hz, 1H), 5.09 - 4.98 (m, 4H), 4.21 - 4.20 (m, 1H), 4.07 - 4.05 (m, 2H), 2.51 - 2.50 (m, 2H), 2.22 (s, 6H), 1.49 - 1.34 (m, 4H), 1.13 - 1.12

[0308] Example 28: Preparation of Compound 30155 TIFF2026528992000120.tif41150

[0309] Under a nitrogen atmosphere, a solution of compound 30137 (50 mg, 0.12 mmol) in dichloroethane (1 mL) was mixed with triethylamine (36 mg, 0.36 mmol) and acetyl chloride (28 mg, 0.36 mmol). The mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure and purified by preparing HPLC (10-80% acetonitrile:water, 10 min) to obtain compound 30155 (10 mg, 17% yield) as a white solid. LCMS: [M+H] + = 453.3.

[0310] Test Example 1: Measurement of the operative activity of the compound of this application against hTLR7 and hTLR8 The activating activity of the compounds of this application against hTLR7 and hTLR8 was detected using HEK-Blue (trade name) hTLR cells. R848 was a positive control compound, and its structure is The filename is JPEG2026528992000121.jpg2442.

[0311] 1. The compound was progressively diluted to create 10 concentration points, which were then added to a 96-well plate. 100 nL of DMSO was used as a negative control instead of the compound of this application, and 28.51 μM of R848 was used to treat hTLR7 and hTLR8 cells as a positive control. 2. HEK-Blue (trade name) hTLR cells were seeded in a 96-well plate containing the compound, with 100 μL seeded in each well, resulting in 50,000 cells per well. The concentration of DMSO in each well was 0.1%. 3. The above 96-well plates were incubated overnight under conditions of 5% CO2 and 37°C. 4. After incubation overnight, 20 μL of supernatant was taken from each well and added to the wells containing 180 μL of QUANTI-Blue (trade name). The 96-well plate was then incubated at 37°C for 1 hour. 5. After 1 hour of incubation, use a microplate reader to perform OD (Obstruction Spectroscopy). 650nm The optical density was measured. 6. Cell viability was measured using CellTiter-Glo according to the manufacturer's manual. The luminescence signal (RLU) of each well was measured using a microplate reader. 7. Use GraphPad Prism software to perform OD 650nm The data was analyzed to determine the activating activity of the compound against hTLR7 and hTLR8. 50 We calculated the values ​​and created a fitting curve. 8. Using GraphPad Prism software, analyze cell viability data and determine the toxicity of the compound against hTLR7 and hTLR8. 50 We calculated the values ​​and created a fitting curve. Cell viability%=(RLU Compound / RLU DMSO Control ) × 100%.

[0312] [Table 1]

[0313] The data in Table 1 shows that, compared to the clinically approved drug R848 (reciquimod), the compound of this application exhibits superior TLR7 and TLR8 agonistic activity and can be used in the preparation of drugs for the prevention or treatment of diseases or conditions related to TLR activity.

[0314] Test Example 2: Test of the effect of the compound of this application on cytokine secretion levels in human peripheral blood mononuclear cells. Human peripheral blood mononuclear cells were purchased from iXcells Biotechnologies and, according to the manufacturer's instructions, were densified to 2 × 10⁶ cells. 6 Cells / mL were seeded in a 96-well plate, different concentrations of the test compound were added, and after 14 hours of incubation, the culture medium was collected. The cytokine levels in the culture medium were detected using the LEGENDplex (trade name) human cytokine measurement kit (Biolegend, Cat#740390) (see Figure 1). Figure 1 shows the comparative experimental results of compound 89 and R848, with the vertical axis representing the average fluorescence density. When the compound of the present invention stimulated human peripheral blood mononuclear cells at a concentration of 1 nM as a TLR7 / 8 agonist, the secretion levels of interferon-γ and various other pro-inflammatory cytokines and chemokines (TNF-α, IL-10, IL-1β, and IL-12p70) were much higher than those of the control substance R848 (reciquimod). This indicates that the compound of this application has a very high ability to stimulate the immune response in the peripheral blood mononuclear cell lineage of the immune system.

[0315] Test Example 3: In vitro study of the effect of the compound of this application on the ability of human peripheral blood mononuclear cells to kill tumor cells. H1568 cells were purchased from ATCC (stored at 37°C in a 5% CO2 environment, with a storage solution containing 10% fetal bovine serum, 100 units / mL penicillin, and 100 μg / mL streptomycin). The culture medium was RPMI 1640 containing 2 mM L-glutamine, 10 mM HEPES, 1 mM sodium pyruvate, 4500 mg / mL glucose, and 1500 mg / L sodium bicarbonate. H1568 cells were seeded at a density of 8000 cells / well into 96-well RTCA E-plates (purchased from Agilent, CAS# 300601030, electronic well plates for real-time cell monitoring) and cultured overnight at 37°C. Human peripheral blood mononuclear cells (pre-activated with 100 IU / mL IL-2 for 72 hours) purchased from iXcells were suspended in RPMI 1640 culture medium containing 10% fetal bovine serum. This suspension was either added to a 96-well plate containing H1568 cells along with a fixed concentration of the test compound, or added to a 96-well plate containing H1568 cells along with a fixed concentration of the test compound alone. DMSO was used as a negative control. Cell culture was continuously monitored for 3-5 days using an RTCA detection system. The data read were cell indices, corresponding to tumor cell viability; a smaller index indicates a higher degree of tumor cell suppression or killing. Cell index data was obtained after 72 hours, and cell index data at different concentrations of the same compound were analyzed using GraphPad Prism software to determine the activation activity of the compound in killing tumor cells in the presence or absence of human peripheral blood mononuclear cells. 50 The following was calculated (see Table 2).

[0316] The compound of this application has the potent ability to activate human peripheral blood mononuclear cells and kill cancer cells (EC). 50 This indicates a range of 1 to 10 nM.

[0317] [Table 2]

[0318] Test Example 4: Testing of the in vitro pharmacokinetic properties of the compound of this application. The in vitro pharmacokinetic properties of the compound in this application were tested by Kanglong Chemical Co., Ltd. (Beijing), primarily evaluating extracorporeal cell membrane permeability (MDCK-MDR1) and the stability of liver microsome (LM) metabolism. Extracorporeal cell membrane permeability (i.e., bidirectional transport in the MDCK-MDR1 cell monolayer model): According to the operating procedure, density is 1.56 × 10⁻⁶ 6 pieces / mL -1 Prepare an MDCK-MDR1 cell suspension and seed it into the filtered wells of a 96-well HTS Transwell. Add 50 μL to each well and culture continuously for 4-8 days in an incubator at 37°C, 5% CO2, and 95% relative humidity, changing the nutrient solution daily. Transmembrane resistance (42 Ω / cm²) was measured. 2 The integrity and adhesion of the MDCK-MDR1 monolayer model were evaluated by (exceeding) the resistance. After passing the resistance verification, the culture medium was aspirated and removed from the AP and BL ends, and each end was washed twice with HBSS (10 mM HEPES, pH 7.4) solution at 37°C. After incubation in a constant temperature shaking incubator (37°C) for 30 minutes, a p→Bl absorption transport test was performed: test solution (1 μmol·L) was placed at the AP end of the Transwell chamber. -1 125 μL of HBSS (10 mM HEPES, pH 7.4) solution (235 μL) was added to the BL end, and 50 μL was immediately withdrawn from the AP end and transferred to a new 96-well plate. BL→Ap external flow test: 75 μL of HBSS (10 mM HEPES, pH 7.4) solution was added to the AP end of the Transwell chamber, and 1 μmol·L of the test solution was added to the BL end. -1285 μL of each substance was added. Immediately, 50 μL was taken from the BL end and transferred to a new 96-well plate. All 96-well plates were incubated in a constant temperature shaking incubator (37°C) for 2 hours, after which 50 μL was taken from the administration end and 50 μL from the reception end and transferred to a new 96-well plate. 200 μL of acetonitrile containing the internal standard was added to each well of the new 96-well plate, followed by gentle rotation for 5 minutes and then centrifugation at 3220 g for 40 minutes. The supernatant was taken out, treated with ultrapure water, and the sample concentration was detected by HPLC.

[0319] Stability of liver microsome (LM) metabolism: Liver microsomes (human LM, Corning, Cat#452117; rat LM, Corning, Cat#452501; mouse LM, XENOTECH, Cat#M1000) were used. The total volume of each incubation system was 400 μL. Each system contained 200 μL of 0.2 M pH 7.4 phosphate buffer, 106 μL of ultrapure water, 40 μL of 50 mM magnesium chloride, 10 μL of 20 mg / mL LM, and 40 μL of 10 mM NADPH (if NADPH is not present, add 40 μL of ultrapure water). 4 μL of 100 μM of the test substance was added, and the system was incubated in a 37°C water bath. Each sample was tested three times in parallel, and the sample without the NADPH generation system was used as a negative control. At predetermined reaction time points (e.g., 0, 15, 30, 45, and 60 minutes), 50 μL of each sample was taken out, and the reaction was stopped by adding four times the volume of pre-cooled acetonitrile (IS: containing 3% formic acid, 100 nM alprazolam, 200 nM labetalol, 200 nM caffeine, and 2 μM ketoprofen). The samples were centrifuged at 3220 g for 40 minutes, and 100 μL of the supernatant was mixed with 100 μL of ultrapure water. The content of the test substance was then analyzed by LC-MS / MS. Data analysis was performed using MS Excel.

[0320] Liver cell metabolic stability experiment: After thawing and resuscitating liver cells, approximately 1.5 × 10⁶ cells were cultured in a 37°C culture medium. 6 The cells were cultured until the cell count reached 1 / mL. After activity measurement (>75%), 0.5 × 10⁶ cells were obtained. 6The test substance was diluted to cells / mL. 198 μL of hepatocytes were pre-warmed for 10 minutes, after which 2 μL of 100 μM test substance or control substance was added. Using a warming method, the metabolic reaction was carried out at 37°C. At different time points during the reaction (0, 15, 30, 60, 90, and 120 minutes), 25 μL of the solution was taken from the system, and the reaction was stopped by adding 150 μL of organic solvent (containing acetonitrile, 100 nM alprazolam, 200 nM labetalol, 200 nM caffeine, and 2 μM ketoprofen). The sample was centrifuged at 3220 g for 20 minutes, and 100 μL of the supernatant was mixed with 100 μL of ultrapure water. The content of the test substance was then analyzed by LC-MS / MS. All warming metabolic reactions were repeated twice. Data analysis was performed using MS Excel.

[0321] The results (see Table 3) show that the compound of the present invention has a shorter half-life compared to R848 (reciquimod). The short half-life of the compound of the present invention can reduce the risk of the compound causing a systemic immune response in the body.

[0322] [Table 3]

[0323] Test Example 5: Testing of the pharmacokinetic properties of compound CD1 of this application in mice. Due to the serious side effects associated with the target, the pharmacokinetic properties of TLR7 / 8 agonists significantly influence their drug potential. Therefore, we evaluated the pharmacokinetics of the compounds in this application in mice. For the experiments, we used 6-8 week old, approximately 20-30g male CD1 mice, with 3 mice per group. The mice were fasted overnight before administration and fed 4 hours after administration. For test compounds with a molecular weight difference of 4 or more, 3-5 molecules were used per group and administered intraperitoneally. Formula: 0.4 mg / mL, 10% SBE-β-CD in 50 mM citrate buffer, pH 5.0; dose: 2 mpk; approximately 0.03 mL of blood was collected from the dorsal vein of the foot at 5, 15, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration, transferred to a plastic centrifuge tube containing EDTA-K2, and the amount of residual test compound in the plasma after processing was detected by LC-MS. After 24 hours, the mice were euthanized by CO2 asphyxiation, and liver tissue was collected. After processing, the amount of residual drug in the liver tissue was detected by LC-MS.

[0324] After data processing, half-life T 1 / 2 , maximum concentration C max , time to reach maximum concentration T max AUC last AUC inf AUC _%Extrap_obs Parameters such as tissue / plasma distribution ratio were obtained (see Table 4 and Figure 2). Consistent with in vitro pharmacokinetic evaluation, the compounds of this application (except 30078) rapidly reached maximal concentrations in the mouse circulatory system, after which concentrations rapidly decreased to the range of 10–30 ng / mL.

[0325] [Table 4]

[0326] Test Example 6: Efficacy study of the compound of this application in a female Balb / C mouse subcutaneous homologous transplantation model using mouse colon cancer CT-26 cells. 1. CT-26 cells were revived and cultured in vitro in RPMI1640 + 10% FBS, and 2.5 × 10⁶ cells were cultured. 7 We obtained cells. 2. Forty female Balb / C mice, aged 2.6 to 8 weeks, were reared for one week to adapt, then weighed and grouped. 3.Seeding conditions The cell seeding information is as follows:

[0327] TIFF2026528992000126.tif32157

[0328] 4. After seeding, tumor volume and body weight were measured once a week, and the average tumor volume was 79.6 mm². 3 Upon reaching this stage, the animals were randomly divided into six groups of four based on tumor volume and body weight. Administration was initiated immediately after grouping. The day administration began was designated as day 0. The administration and grouping information is as follows: The grouping and administration information are as follows:

[0329] TIFF2026528992000127.tif20150

[0330] 5. After administration began, the body weight and tumor volume of the mice were measured three times a week. A total of two doses were administered during the experimental period. The trial observation was completed on Day 12 of the experiment, and the tumor was collected at the end of the trial. The residual concentration of the administered drug in the tumor tissue was detected.

[0331] Referring to Figure 3, the results show that the compound of this application has high relative safety and remarkable tumor-suppressing effects.

[0332] Although preferred embodiments of the present invention have been described in detail above, the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution means of the present invention within the scope of the technical concept of the present invention, and all of these simple modifications are included within the scope of protection of the present invention.

[0333] Furthermore, each specific technical feature described in the above-described embodiment can be combined in any suitable manner, as long as they do not contradict each other. To avoid unnecessary redundancy, the present invention does not describe various possible combinations in detail. As long as they do not contradict the spirit of the present invention, they should also be considered as part of the disclosures of the present invention.

Claims

1. A pyrimidine derivative which is a compound of formula (I-1) or formula (I-2), or a stereoisomer, tautomer, isotope derivative, hydrate, solvate, prodrug and pharmaceutically acceptable salt thereof, Here, This represents a single bond or a double bond. X 1 , X 2 All of these are CR-R 3 Either one is C-R 3 The other is a program, Z is -NH 2 These are -OH, -NH-alkyl, -O-alkyl, -NH-C(O)-alkyl, -O-C(O)-alkyl, -NH-C(O)-OH, and -O-C(O)-OH. Y is -O-, -S-, or -NR 4 - and here, R 4 is H or optionally substituted alkyl, R 1 is alkyl or aryl and is optionally substituted with one or more of oxo, halogen, amino, hydroxy, nitro, cyano, mercapto, -C(O)-NH 2 , -C(O)-OH, heteroaryl (optionally substituted with one or more of halogen, amino, hydroxy, nitro, cyano, mercapto, alkoxy, alkyl), aryl (optionally substituted with one or more of halogen, amino, hydroxy, nitro, cyano, mercapto, alkoxy, alkyl), heterocycloalkyl (optionally substituted with one or more of halogen, amino, hydroxy, nitro, cyano, mercapto, alkoxy, alkyl), cycloalkyl (optionally substituted with one or more of halogen, amino, hydroxy, nitro, cyano, mercapto, alkoxy, alkyl), optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamino, optionally substituted alkylacyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, optionally substituted -C(O)-O-alkyl, optionally substituted -O-C(O)-alkyl, optionally substituted -C(O)-NH-alkyl, optionally substituted -NH-C(O)-alkyl, optionally substituted -S(O)-O-alkyl, optionally substituted -O-S(O)-alkyl, optionally substituted -S(O) 2 -O-alkyl, optionally substituted -O-S(O) 2 -alkyl, optionally substituted -S(O)-NH-alkyl, optionally substituted -NH-S(O)-alkyl, optionally substituted -S(O) 2 -NH-alkyl, optionally substituted -NH-S(O) 2 -alkyl, and is optionally substituted with one or more selected from R 2 teeth, or And, -L 3 -R 7 is, L 2 It can be substituted at the para, meta, or ortho position. L 1 , L 2 , L 3 This is a bonded, optionally substituted linear alkylene, where one, two, or more carbon atoms in the linear alkylene may be substituted with heteroatoms oxygen, sulfur, or nitrogen, and the substituents are selected from one or more of optionally substituted alkyl, halogen, amino, hydroxy, nitro, cyano, mercapto, optionally substituted alkyloxy, optionally substituted alkylthio, or optionally substituted alkylamino. R 5 is a cycloalkyl or heterocycloalkyl, and is optionally substituted with one or more selected from oxo, halogen, amino, hydroxy, nitro, cyano, mercapto, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, and optionally substituted alkylamino. W and V may be N or CH, and if W or V is CH, then it is R 6 or -L 3 -R 7 It can be replaced by, R 3 , R 6 These are, independently, H, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamino, halogen, amino, hydroxy, nitro, cyano, and mercapto. R 7 H, -OH, -N(R) 9 R 10 ), -N(R 9 ) NH 2 , -NO(R 9 R 10 ), optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl-NR 9 -, optionally substituted cycloalkyl-NR 9 - Arbitrarily substituted aryl-NR 9 -, arbitrarily substituted heteroaryl-NR 9 -, -OC(O)-R 9 , -C(O)O-R 9 , -N(R 9 )-C(O)-R 10 , -C(O)-N(R 9 R 10 ) and the substituent is selected from one or more of optionally substituted alkyl, optionally substituted alkylamino, optionally substituted dialkylamino, and oxo. R 8 is H or optionally substituted alkyl, R 9 , R 10 These are, independently, H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl. The substituents of the optionally substituted group are selected from one or more of the following: halogen, amino, hydroxy, nitro, cyano, mercapto, carboxyl, ester, amide groups, etc. n is a pyrimidine derivative where n is 0, 1, 2, 3, or 4.

2. X 1 , X 2 Either one of them is CR 3 The pyrimidine derivative according to claim 1, wherein the other is N.

3. R 8 The pyrimidine derivative according to claim 1, wherein is H or C1-8 alkyl.

4. R 1 It is a C1-8 alkyl group, and is optionally substituted with one or more of the following: optionally substituted C1-8 alkyloxy, optionally substituted C1-8 alkylthio, optionally substituted C1-8 alkylamino, optionally substituted C1-8 alkylacyl, optionally substituted C1-8 alkylsulfinyl, or optionally substituted C1-8 alkylsulfonyl. Preferably, R 1 It is a C2-6 alkyl group, and is optionally substituted with a group selected from optionally substituted C1-6 alkyloxy, optionally substituted C1-6 alkylthio, or optionally substituted C1-6 alkylsulfonyl groups. Preferably, R 1 These are optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, 2-hexyl, and 3-hexyl. More specifically, R 1 n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-hexyl, methoxyethyl, methylthioethyl, methylsulfonylethyl, methoxypropyl, methylthiopropyl, methylsulfonylpropyl, And, More preferably, R 1 n-butyl, Methylthiopropyl, methylsulfonylpropyl, The pyrimidine derivative according to any one of claims 1 to 3.

5. A pyrimidine derivative according to any one of claims 1 to 4, wherein W and V are both N, or W and V are both C, or either W or V is N.

6. The heterocycloalkyl is a 3- to 12-membered monocyclic, bicyclic, or polycyclic heterocycloalkyl, preferably a 3- to 12-membered monocyclic, bicyclic, or polycyclic heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and more preferably the heteroatoms in the heterocycloalkyl are L 1 or L 3 Linked to, and more preferably, the N atom in the heterocycloalkyl is L 1 or L 3 A pyrimidine derivative according to any one of claims 1 to 5, which is linked to a pyrimidine derivative.

7. The heterocycloalkyl is a 3-7 member monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N, O, and S, or a 7-12 member fused ring or spiro ring heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S. Preferably, the heterocycloalkyl is a 4-6 member monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N and O, or a 7-11 member spirocyclic heterocycloalkyl containing 2, 3, or 4 heteroatoms selected from N and O. More preferably, heterocycloalkyls are The pyrimidine derivative according to claim 6, which is any of the following.

8. The pyrimidine derivative according to any one of claims 1 to 7, wherein the aryl is a C6-10 aryl, preferably a phenyl.

9. L 1 , L 2 , L 3 This is a linear alkylene containing 1 to 6 chain atoms bonded or optionally substituted, where 1 to 2 carbon atoms in the linear alkylene may be substituted with heteroatoms oxygen, sulfur, or nitrogen, and the substituents are selected from C1-8 alkyl, halogen, amino, hydroxy, nitro, cyano, and mercapto. L 1 Preferably, it is a linear alkylene containing 1 to 4 optionally substituted chain atoms, more preferably a linear alkylene containing 2 to 3 optionally substituted chain atoms, and even more preferably an -O-propylene group, -CH 2 CH 2 CH 2 - and L 2 Preferably, it is a linear alkylene containing 1 to 4 optionally substituted chain atoms, more preferably a linear alkylene containing 2 to 3 optionally substituted chain atoms, and even more preferably -CH 2 -ien-CH 2 CH 2 -, -O-, -O-CH 2 -CH 2 -, -O-CH 2 - and L 3 Preferably, it is a linear alkylene containing 1 to 4 chain atoms that are bonded or optionally substituted, more preferably a linear alkylene containing 2 to 3 chain atoms that are bonded or optionally substituted, and even more preferably bonded, -CH 2 -ien-CH 2 CH 2 -ien-CH 2 CH 2 CH 2 -, -O-CH 2 -CH 2 -, -O-CH 2 -, -CH(CH 3 )CH 2 - and more preferably The pyrimidine derivative according to any one of claims 1 to 8.

10. R 9 , R 10 The pyrimidine derivative according to any one of claims 1 to 9, wherein each is independently H or C1-8 alkyl.

11. R 7 is -OH, -N(R 9 R 10 ), -N(R 9 )NH 2 , -NO(R 9 R 10 ), a 3- to 12-member heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms selected from optionally substituted N, O, S, an optionally substituted C6-10 aryl, a 3- to 12-member heterocycloalkyl-NR 9 -, an optionally substituted C6-10 aryl-NR 9 -, and the substituents are selected from one or more of an optionally substituted C1-8 alkyl, an optionally substituted C1-8 alkylamino, an optionally substituted di(C1-8)alkylamino, oxo, and R 9 , R 10 are each independently H or C1-8 alkyl, The heterocycloalkyl is preferably a 4-6 member monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N and O, or a 7-11 member spirocyclic heterocycloalkyl containing 2, 3, or 4 heteroatoms selected from N and O, and more preferably the heteroatoms in the heterocycloalkyl are L 3 Linked to, and more preferably, the N atom in the heterocycloalkyl is L 3 A pyrimidine derivative according to any one of claims 1 to 10, which is linked to a pyrimidine derivative.

12. R 2 is arbitrarily replaced Select from one of the following: Furthermore, R 2 is arbitrarily replaced And, The substituent is selected from one or more of alkyl, alkyloxy, alkylthio, alkylamino, halogen, amino, hydroxy, nitro, cyano, and mercapto, and is a pyrimidine derivative according to any one of claims 1 to 10.

13. The compound of formula (I-1) or formula (I-2) is particularly A pyrimidine derivative according to any one of claims 1 to 12, having any of the above.

14. X 1 , X 2 All of these are CR-R 3 A pyrimidine derivative according to claim 1, selected from the following.

15. Z is -NH 2 , -OH, Y is -O-, -S-, or -NR 4 - and here, R 4 is H or optionally substituted alkyl, R 1 is alkyl, and is optionally substituted with one or more selected from oxo, halogen, amino, hydroxy, nitro, cyano, mercapto, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamino, optionally substituted alkylacyl, optionally substituted alkylsulfinyl, and optionally substituted alkylsulfonyl. R 2 teeth, And, -L 3 -R 7 is, L 2 It can be substituted at the para, meta, or ortho position. L 2 , L 3 This is a bonded, optionally substituted linear alkylene, where one, two, or more carbon atoms in the linear alkylene may be substituted with heteroatoms oxygen, sulfur, or nitrogen, and the substituents are selected from one or more of optionally substituted alkyl, halogen, amino, hydroxy, nitro, cyano, mercapto, optionally substituted alkyloxy, optionally substituted alkylthio, or optionally substituted alkylamino. W and V may be N or CH, and if W or V is CH, then it is R 6 or -L 3 -R 7 It can be replaced by, R 3 , R 6 These are, independently, H, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamino, halogen, amino, hydroxy, nitro, cyano, and mercapto. R 7 H, -OH, -N(R) 9 R 10 ), -N(R 9 ) NH 2 , -NO(R 9 R 10 ), optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl-NR 9 -, optionally substituted cycloalkyl-NR 9 - Arbitrarily substituted aryl-NR 9 -, arbitrarily substituted heteroaryl-NR 9 -, -OC(O)-R 9 , -C(O)O-R 9 , -N(R 9 )-C(O)-R 10 , -C(O)-N(R 9 R 10 ) and the substituent is selected from one or more of optionally substituted alkyl, optionally substituted alkylamino, and oxo. R 9 , R 10 These are, independently, H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl. The substituents in the optionally substituted alkyl group are selected from one or more of the following: halogen, amino, hydroxy, nitro, cyano, mercapto, carboxyl, ester, and amide groups. The pyrimidine derivative according to claim 14, wherein n is 0, 1, 2, 3, or 4.

16. R 1 It is a C1-8 alkyl group, and is optionally substituted with one or more optionally substituted C1-8 alkylthio groups and optionally substituted C1-8 alkylsulfonyl groups. Preferably, R 1 It is a C2-6 alkyl group, optionally substituted with a group selected from optionally substituted C1-6 alkylthio groups and optionally substituted C1-6 alkylsulfonyl groups. More specifically, R 1 n-butyl, n-pentyl, 2-pentyl, n-hexyl, 2-hexyl, 3-hexyl, methoxyethyl, methylthioethyl, methylsulfonylethyl, methoxypropyl, methylthiopropyl, methylsulfonylpropyl, And, More preferably, R 1 n-butyl, Methylthiopropyl, methylsulfonylpropyl, The pyrimidine derivative according to claim 15.

17. A pyrimidine derivative according to any one of claims 15 to 16, wherein W and V are both N, or W and V are both C, or either W or V is N.

18. The heterocycloalkyl is a 3- to 12-membered monocyclic, bicyclic, or polycyclic heterocycloalkyl, preferably a 3- to 12-membered monocyclic, bicyclic, or polycyclic heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and more preferably the heteroatoms in the heterocycloalkyl are L 1 or L 3 Linked to, and more preferably, the N atom in the heterocycloalkyl is L 1 or L 3 A pyrimidine derivative according to any one of claims 15 to 17, which is linked to a pyrimidine derivative.

19. The heterocycloalkyl is a 3-7 member monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N, O, and S, or a 7-12 member fused ring or spiro ring heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S. Preferably, the heterocycloalkyl is a 4-6 member monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N and O, or a 7-11 member spirocyclic heterocycloalkyl containing 2, 3, or 4 heteroatoms selected from N and O. More preferably, heterocycloalkyls are The pyrimidine derivative according to claim 18, which is any of the following.

20. L 2 , L 3 This is a linear alkylene containing 1 to 6 chain atoms bonded or optionally substituted, wherein 1 to 2 carbon atoms in the linear alkylene may be substituted with heteroatoms (oxygen), and the substituents are selected from C1-8 alkyl, halogen, amino, hydroxy, nitro, cyano, and mercapto. L 2 Preferably, it is a linear alkylene containing 1 to 4 optionally substituted chain atoms, more preferably a linear alkylene containing 2 to 3 optionally substituted chain atoms, and even more preferably -CH 2 -ien-CH 2 CH 2 -, -O-, -O-CH 2 -CH 2 -, -O-CH 2 - and L 3 Preferably, it is a linear alkylene containing 1 to 4 chain atoms that are bonded or optionally substituted, more preferably a linear alkylene containing 2 to 3 chain atoms that are bonded or optionally substituted, and even more preferably bonded, -CH 2 -ien-CH 2 CH 2 -ien-CH 2 CH 2 CH 2 -, -O-CH 2 -CH 2 -, -O-CH 2 -, -CH(CH 3 )CH 2 - and more preferably The pyrimidine derivative according to any one of claims 15 to 19.

21. R 7 is -OH, -N(R 9 R 10 ), -N(R 9 ) NH 2 , -NO(R 9 R 10 ), 3- to 12-membered heterocycloalkyls containing 1, 2, 3 or 4 heteroatoms selected from optionally substituted N, O, S, optionally substituted C6-10 aryls, 3- to 12-membered heterocycloalkyl-NRs containing 1, 2, 3 or 4 heteroatoms selected from optionally substituted N, O, S 9 -, optionally substituted C6-10 aryl-NR 9 - and the substituent is selected from one or more of optionally substituted C1-8 alkyl, optionally substituted C1-8 alkylamino, optionally substituted di(C1-8)alkylamino, and oxo, R 9 , R 10 Each of these is independently H or C1-8 alkyl, The heterocycloalkyl is preferably a 4-6 member monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N and O, or a 7-11 member spirocyclic heterocycloalkyl containing 2, 3, or 4 heteroatoms selected from N and O, and more preferably the heteroatoms in the heterocycloalkyl are L 3 Linked to, and more preferably, the N atom in the heterocycloalkyl is L 3 A pyrimidine derivative according to any one of claims 15 to 20, which is linked to a pyrimidine derivative.

22. R 7 is -NO(R 9 R 10 The pyrimidine derivative according to claim 21, which is a 3- to 12-membered heterocycloalkyl group comprising 1, 2, 3, or 4 heteroatoms optionally selected from oxosubstituted N, O, and S.

23. R 2 is arbitrarily replaced Select from one of the following: Furthermore, R 2 is arbitrarily replaced And, The pyrimidine derivative according to any one of claims 15 to 22, wherein the substituent is selected from one or more of alkyl, alkyloxy, alkylthio, alkylamino, halogen, amino, hydroxy, nitro, cyano, and mercapto.

24. The compound of formula (I-1) is particularly A pyrimidine derivative according to any one of claims 15 to 23, having any of the above.

25. A pyrimidine derivative which is a compound of formula (II-1) or formula (II-2), or a stereoisomer, tautomer, isotopic derivative, halogenated derivative, hydrate, solvate, prodrug and pharmaceutically acceptable salt thereof, Here, X 3 is N or CH, and X 4 If is CH, N, or NO, and X3 or X4 is CH, then it is R 3 It can be replaced by, Z is -NH 2 These are -OH, -NH-alkyl, -O-alkyl, -NH-C(O)-alkyl, -O-C(O)-alkyl, -NH-C(O)-OH, and -O-C(O)-OH. Y is -O-, -S-, or -NR 4 - and here, R 4 is H or optionally substituted alkyl, R 1 These are alkyl or aryl compounds, including oxo, halogen, amino, hydroxy, nitro, cyano, mercapto, and -C(O)-NH 2 -C(O)-OH, heteroaryl (optionally substituted with one or more of halogens, amino, hydroxy, nitro, cyano, mercapto, alkoxy, or alkyl), aryl (optionally substituted with one or more of halogens, amino, hydroxy, nitro, cyano, mercapto, alkoxy, or alkyl), heterocycloalkyl (optionally substituted with one or more of halogens, amino, hydroxy, nitro, cyano, mercapto, alkoxy, or alkyl), cycloalkyl (optionally substituted with one or more of halogens, amino, hydroxy, nitro, cyano, mercapto, alkoxy, or alkyl) (These are optionally substituted in multiple ways), optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamino, optionally substituted alkylacyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, optionally substituted -C(O)-O-alkyl, optionally substituted -O-C(O)-alkyl, optionally substituted -C(O)-NH-alkyl, optionally substituted -NH-C(O)-alkyl, optionally substituted -S(O)-O-alkyl, optionally substituted -O-S(O)-alkyl, optionally substituted -S(O) 2 -O-alkyl, optionally substituted -O-S(O) 2 -alkyl, optionally substituted -S(O)-NH-alkyl, optionally substituted -NH-S(O)-alkyl, optionally substituted -S(O) 2 -NH-alkyl, optionally substituted -NH-S(O) 2 - Optionally substituted with one or more alkyl groups selected from, R 2 teeth, or And, -L 3 -R 7 is, L 2 It can be substituted at the para, meta, or ortho position. L 1 , L 2 , L 3 This is a bonded, optionally substituted linear alkylene, where one, two, or more carbon atoms in the linear alkylene may be substituted with heteroatoms oxygen, sulfur, or nitrogen, and the substituents are selected from one or more of optionally substituted alkyl, halogen, amino, hydroxy, nitro, cyano, mercapto, optionally substituted alkyloxy, optionally substituted alkylthio, or optionally substituted alkylamino. R 5 is a cycloalkyl or heterocycloalkyl, and is optionally substituted with one or more selected from oxo, halogen, amino, hydroxy, nitro, cyano, mercapto, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, and optionally substituted alkylamino. W and V may be N or CH, and if W or V is CH, then it is R 6 or -L 3 -R 7 It can be replaced by, R 3 , R 6 These are independently H, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamino, halogen, amino, hydroxy, nitro, cyano, and mercapto. R 7 H, -OH, -N(R) 9 R 10 ), -N(R 9 ) NH 2 , -NO(R 9 R 10 ), optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl-NR 9 -, optionally substituted cycloalkyl-NR 9 - Arbitrarily substituted aryl-NR 9 -, arbitrarily substituted heteroaryl-NR 9 -, -OC(O)-R 9 , -C(O)O-R 9 , -N(R 9 )-C(O)-R 10 , -C(O)-N(R 9 R 10 ) and the substituent is selected from one or more of optionally substituted alkyl, optionally substituted alkylamino, and oxo. R 9 , R 10 These are, independently, H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl. The substituents in the optionally substituted group are selected from one or more of halogen, amino, hydroxy, nitro, cyano, mercapto, carboxyl, ester, and amide groups. A pyrimidine derivative in which m is 0, 1, 2, or 3, and n is 0, 1, 2, 3, or 4.

26. R 1 It is a C1-8 alkyl group, and is optionally substituted with one or more of the following: optionally substituted C1-8 alkyloxy, optionally substituted C1-8 alkylthio, optionally substituted C1-8 alkylamino, optionally substituted C1-8 alkylacyl, optionally substituted C1-8 alkylsulfinyl, or optionally substituted C1-8 alkylsulfonyl. Preferably, R 1 It is a C2-6 alkyl group, and is optionally substituted with a group selected from optionally substituted C1-6 alkyloxy, optionally substituted C1-6 alkylthio, or optionally substituted C1-6 alkylsulfonyl groups. Preferably, R 1 These are optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, 2-hexyl, and 3-hexyl. More specifically, R 1 n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-hexyl, methoxyethyl, methylthioethyl, methylsulfonylethyl, methoxypropyl, methylthiopropyl, methylsulfonylpropyl, And, More preferably, R 1 n-butyl, Methylthiopropyl, methylsulfonylpropyl, The pyrimidine derivative according to claim 25.

27. A pyrimidine derivative according to any one of claims 25 to 26, wherein W and V are both N, or W and V are both C, or either W or V is N.

28. The heterocycloalkyl is a 3- to 12-membered monocyclic, bicyclic, or polycyclic heterocycloalkyl, preferably a 3- to 12-membered monocyclic, bicyclic, or polycyclic heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and more preferably the heteroatoms in the heterocycloalkyl are L 1 or L 3 Linked to, and more preferably, the N atom in the heterocycloalkyl is L 1 or L 3 A pyrimidine derivative according to any one of claims 25 to 27, which is linked to a pyrimidine derivative.

29. The heterocycloalkyl is a 3-7 membered monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N, O, and S, or a 7-12 membered fused ring or spiro ring heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S. Preferably, the heterocycloalkyl is a 4-6 member monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N and O, or a 7-11 member spirocyclic heterocycloalkyl containing 2, 3, or 4 heteroatoms selected from N and O. More preferably, heterocycloalkyls are The pyrimidine derivative according to claim 28, which is any of the following.

30. The pyrimidine derivative according to any one of claims 25 to 29, wherein the aryl is a C6-10 aryl, preferably a phenyl.

31. L 1 , L 2 , L 3 This is a linear alkylene containing 1 to 6 chain atoms bonded or optionally substituted, where 1 to 2 carbon atoms in the alkylene may be substituted with heteroatoms oxygen and sulfur, and the substituents are selected from C1-8 alkyl, halogen, amino, hydroxy, nitro, cyano, and mercapto. L 1 Preferably, it is a linear alkylene containing 1 to 4 optionally substituted chain atoms, more preferably a linear alkylene containing 2 to 3 optionally substituted chain atoms, and even more preferably an -O-propylene group-, -CH 2 CH 2 CH 2 - and L 2 Preferably, it is a linear alkylene containing 1 to 4 optionally substituted chain atoms, more preferably a linear alkylene containing 2 to 3 optionally substituted chain atoms, and even more preferably -CH 2 -ien-CH 2 CH 2 -, -O-, -O-CH 2 -CH 2 -, -O-CH 2 - and L 3 Preferably, it is a linear alkylene containing 1 to 4 chain atoms that are bonded or optionally substituted, more preferably a linear alkylene containing 2 to 3 chain atoms that are bonded or optionally substituted, and even more preferably bonded, -CH 2 -ien-CH 2 CH 2 -ien-CH 2 CH 2 CH 2 -, -O-CH 2 -CH 2 -, -O-CH 2 -, -CH(CH 3 )CH 2 - and more preferably The pyrimidine derivative according to any one of claims 25 to 30.

32. R 7 is OH, -N(R 9 R 10 ), -N(R 9 ) NH 2 , -NO(R 9 R 10 ), 3- to 12-membered heterocycloalkyls containing 1, 2, 3 or 4 heteroatoms selected from optionally substituted N, O, S, optionally substituted C6-10 aryls, 3- to 12-membered heterocycloalkyl-NRs containing 1, 2, 3 or 4 heteroatoms selected from optionally substituted N, O, S 9 -, optionally substituted C6-10 aryl-NR 9 - and the substituent is selected from one or more of optionally substituted C1-8 alkyl, optionally substituted C1-8 alkylamino, optionally substituted di(C1-8)alkylamino, and oxo, R 9 , R 10 Each of these is independently H or C1-8 alkyl, The heterocycloalkyl is preferably a 4-6 member monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N and O, or a 7-11 member spirocyclic heterocycloalkyl containing 2, 3, or 4 heteroatoms selected from N and O, and more preferably the heteroatoms in the heterocycloalkyl are L 3 Linked to, and more preferably, the N atom in the heterocycloalkyl is L 3 A pyrimidine derivative according to any one of claims 25 to 31, which is linked to a pyrimidine derivative.

33. R 2 is arbitrarily replaced Select from one of the following: Furthermore, R 2 is arbitrarily replaced And, The pyrimidine derivative according to any one of claims 25 to 32, wherein the substituent is selected from one or more of alkyl, alkyloxy, alkylthio, alkylamino, halogen, amino, hydroxy, nitro, cyano, and mercapto.

34. The compound of formula (II-1) or formula (II-2) is particularly A pyrimidine derivative according to any one of claims 25 to 33, which may have the following characteristics.

35. A pharmaceutical composition comprising a pyrimidine derivative according to any one of claims 1 to 34, and preferably further comprising a pharmaceutically acceptable carrier or excipient.

36. A pharmaceutical composition according to claim 35, further comprising at least one other therapeutic agent, preferably the therapeutic agent being selected from chemotherapeutic agents, immunotherapeutic agents, anti-angiogenic agents, cytokines, hormones, polynucleotides, antibodies, and immunoactive fragments, wherein the pharmaceutical composition comprises multiple active ingredients, and each active ingredient may be administered simultaneously, sequentially, or separately at the discretion of a physician.

37. Uses of the pyrimidine derivative according to any one of claims 1 to 34, or the pharmaceutical composition according to any one of claims 35 to 36, for use in preparing a pharmaceutical for the prevention or treatment of a disease or condition related to TLR activity.

38. Uses of the pyrimidine derivative according to any one of claims 1 to 34, or the pharmaceutical composition according to any one of claims 35 to 36, for use in preparing a pharmaceutical for the prevention or treatment of infectious diseases, respiratory diseases, immune-related diseases, viral diseases, or cell proliferation disorders.

39. The use according to claim 38, wherein the disease is asthma, tumor, HIV, or HBV.

40. The aforementioned respiratory diseases are asthma, chronic obstructive pulmonary disease, and adult respiratory distress syndrome. The aforementioned immune-related diseases include systemic lupus erythematosus, Sjögren's syndrome, Wegener's granulomatosis, sarcoidosis, Reiter's syndrome, Behçet's disease, rheumatoid arthritis, inflammatory bowel disease, polymyositis, vasculitis, ankylosing spondylitis, and psoriatic arthritis. The aforementioned viral diseases include Ebola virus disease, anthrax infection, genital warts, common warts, plantar warts, respiratory syncytial virus, hepatitis B, hepatitis C, dengue virus, herpes simplex virus (e.g., HSV-I, HSV-11), molluscum contagiosum, emphysema, smallpox, lentivirus, human immunodeficiency virus (HIV), human papillomavirus (HPV), cytomegalovirus, varicella-zoster virus, rhinitis virus, enteric viruses, adenovirus, influenza, parainfluenza, mumps virus, measles virus, papovavirus, flavivirus, retrovirus, sand virus (e.g., LCM, uninvirus, machupovirus, guanalitovirus, and Lassa fever) and filovirus (e.g., Ebola virus or marbovirus). The aforementioned cell proliferative disorders are tumors, including but not limited to human sarcomas and carcinomas, for example, lymphoma, osteosarcoma, fibrosarcoma, myasarcoma, liposarcoma, chondrosarcoma, adult osteosarcoma, chordoma, angiosarcoma, endosarcoma, lymphangiosarcoma, lymphangiosarcoma, synoviomas, mesothelioma, Euin sarcoma, leiomyosarcoma, rhabdomyosarcoma, uterine sarcoma, neuroma, gastrointestinal cancer, colon cancer, rectal cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, papillary carcinoma, medullary carcinoma, bronchial cancer, hepatocellular carcinoma, liver cancer, cholangiocarcinoma, choriocarcinoma, spermatogonia, germ cell tumor, nephroblastoma, cervical cancer, ovarian cancer, testicular cancer, kidney cancer, lung cancer, epithelial carcinoma, glioblastoma, astrocytoma, medulloblastoma, craniopharyngotoma, ependymoma, The aforementioned adenocarcinomas are pineal gland tumors, hemangioblastomas, acoustic neuromas, oligodendrogliomas, meningiomas, melanomas, neuroblastomas, retinoblastomas, leukemias, polycythemia vera, multiple myelomas, and heavy chain disease. The aforementioned adenocarcinomas may also be thyroid cancer, pancreatic cancer, sweat gland cancer, sebaceous gland cancer, breast cancer, papillary adenocarcinoma, cystic adenocarcinoma, and prostate cancer. The aforementioned lung cancers may also be small cell lung cancers. The aforementioned leukemias are acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, and chronic granulocytic leukemia. The aforementioned lymphomas are Hodgkin's disease and non-Hodgkin's disease. Preferably, the tumor is a cold tumor, and more preferably, the tumor is colon cancer, bladder cancer, melanoma, meningioma, lung cancer, liver cancer, or pancreatic cancer, as per claim 38.

41. Uses of a pyrimidine derivative according to any one of claims 1 to 34, or a pharmaceutical composition according to any one of claims 35 to 36, which can be used to prepare a pharmacopoeia for the prevention of tumor recurrence, preferably by inducing persistent systemic immune memory to prevent recurrence.

42. Uses of the pyrimidine derivative according to any one of claims 1 to 34, or the pharmaceutical composition according to any one of claims 35 to 36, for use in preparing a payload of a conjugate drug.

43. Uses of a pyrimidine derivative according to any one of claims 1 to 34, or a pharmaceutical composition according to any one of claims 35 to 36, which are used to prepare a pharmaceutical formulation, wherein the pharmaceutical formulation upregulates the number of genes favorable for immunotherapy in each of the following pathways: inflammation and cytokine-mediated pathways, T cell activation / apoptotic signaling pathways, and B cell activation pathways, and preferably, the pharmaceutical formulation upregulates the number of genes favorable for tumor immunotherapy in the above pathways.

44. The use of the pharmaceutical preparation according to claim 43, wherein the pharmaceutical preparation increases the number of CD8+ T cells and / or improves the CD8+ T cell / Treg cell ratio and / or increases the expression of PDL-1 and / or increases the level of interleukin 2 and / or increases the level of interferon Y and / or decreases the level of interleukin 10.

45. Uses of a pyrimidine derivative according to any one of claims 1 to 34, or a pharmaceutical composition according to any one of claims 35 to 36, for preparing a formulation that downregulates the Wnt signaling pathway, preferably for downregulating the expression level of the S-catenin protein.

46. Uses of a pyrimidine derivative according to any one of claims 1 to 34, or a pharmaceutical composition according to any one of claims 35 to 36, for preparing a pharmaceutical formulation that affects the secretion levels of various cytokines in macrophages, preferably affecting the mRNA expression levels of the Illb, 116, 1112b, Tnf, Ifnbl, Cxcl, Cxcl0, and 1110 genes.

47. Uses of the pyrimidine derivative according to any one of claims 1 to 34, or the pharmaceutical composition according to any one of claims 35 to 36, for use in preparing a vaccine adjuvant.

48. A method for improving a positive immune response in a living organism, comprising regulating TLR7 and / or TLR8 by administering a therapeutically effective amount of a pyrimidine derivative according to any one of claims 1 to 34, or a pharmaceutical composition according to any one of claims 35 to 36, to a system or individual in need.

49. A method for enhancing the effect of chemotherapy, comprising administering a therapeutically effective amount of a chemotherapeutic agent to a system or individual in need, and simultaneously, or subsequently, administering a therapeutically effective amount of a pyrimidine derivative according to any one of claims 1 to 34, or a pharmaceutical composition according to any one of claims 35 to 36.

50. A method for improving immunotherapy, comprising administering a therapeutically effective amount of a pyrimidine derivative according to any one of claims 1 to 34, or a pharmaceutical composition according to any one of claims 35 to 36, to a system or individual as needed, and simultaneously, or subsequently, introducing chimeric antigen receptor T cells (CAR-T) into the system or individual.

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