Pyrimidine derivative used as TLR7 / 8 agonist or salt thereof as well as pharmaceutical composition and application thereof

Abstract

The pyrimidine derivatives as shown in a formula (I-1), a formula (I-2), a formula (II-1) or a formula (II-2) or stereoisomers, tautomers, isotope derivatives, hydrates, solvates, prodrugs and pharmaceutically acceptable salts thereof can be used as effective TLR7 and / or TLR8 receptor agonists, and have the characteristics of good selectivity, high activity and good safety; meanwhile, the invention provides a preparation method and a pharmaceutical composition of the pyrimidine derivative. The compound or the pharmaceutical composition thereof can be used for preparing drugs for preventing or treating infectious diseases, respiratory diseases, immune-related diseases, viral diseases or tumors.

Description

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

[0001] Cross-references

[0002] This application claims priority to the Chinese patent application with application number "202311048960.0" filed on August 18, 2023, and invention name "Pyrimidine derivatives or salts thereof used as TLR7 / 8 agonists, pharmaceutical compositions and uses thereof", the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present application relates to the technical field of Toll-like receptors (TLRs), and in particular to pyrimidine derivatives or salts thereof used as TLR7 / 8 agonists, pharmaceutical compositions and uses thereof, and methods for preventing or treating 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 Art

[0004] Toll-like receptors are a relatively conservative receptor family in evolution, including at least 13 members, 10 of which (TLR1-10) are found in humans. TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 are expressed on the cell surface and quickly identify the products of bacterial metabolism. TLR3, TLR7, TLR8, and TLR9 are expressed inside the cell and are mainly used to monitor and identify viral nucleic acids. TLR3 recognizes double-stranded RNA, while TLR7 and TLR8 recognize single-stranded RNA. TLR9 recognizes unmethylated CG coenzyme to regulate the response to bacterial DNA and certain viruses.

[0005] TLRs specifically recognize pathogen-associated molecular patterns (PAMPs) and play a crucial role in both innate and adaptive immunity, serving as a bridge between these two pathways. TLR7, upon recognizing virally bound single-stranded RNA or synthetic small purine compounds, recruits specific adaptor proteins, activating a series of signaling cascades and initiating a high-level systemic adaptive immune response that kills virus-infected cells, ultimately eliminating the virus. TLR7 agonists have been clinically used to treat chronic viral infections such as hepatitis B and hepatitis C. Furthermore, TLR7 agonists can induce more rapid and effective immune protection as influenza vaccine adjuvants. TLR7 agonists not only directly stimulate pDCs to secrete IFN-α but also enhance their co-stimulatory and antigen presentation abilities. Activated pDCs promote the proliferation of CD4+ T cells, further activating CD8+ T cells to kill tumor cells. Therefore, the role of TLR7 agonists as immune adjuvants in tumor recognition and killing is gaining increasing attention. cDCs mature and release co-stimulatory factors such as CD80 and CD86, as well as pro-inflammatory cytokines including IL-12, TNF-α, and IL-6, in response to antigen and TLR8 agonist stimulation. cDCs that migrate to dLNs activate T cells, stimulating T cells and NK cells to release IFN-γ, further amplifying the immune cascade.

[0006] TLR7 / 8 agonists mobilize innate and adaptive immune responses through the MyD-NF-κB signaling pathway. As immunomodulators, they can activate and differentiate immune cell development and control the direction of immune responses. Therefore, they have potential applications in respiratory diseases, inflammatory diseases, anti-allergic, anti-viral, anti-tumor, and skin damage. Extensive preclinical and clinical research has been or is underway.

[0007] TLR7 and TLR8 receptors are expressed at different levels on cDCs and pDCs, and also on other somatic and immune cells. The same immune cell expresses different levels of TLR7 (or TLR8) receptors in different organ and tissue locations, and these levels are regulated by the cellular / immune state. TLR signaling regulation is resistant to agonists, and the TLR7 and TLR8 signaling pathways are interconnected. The dose and timing of agonist administration significantly influence clinical outcomes, often demonstrating no clinical effect, severe side effects, or even adverse effects (such as promoting rather than inhibiting tumor progression).

[0008] Currently, there are over 20 core backbones, and among the approximately 1,500 synthetic molecules that combine substitutions and modifications of two major side chains, a large number of small-molecule TLR7 / 8 agonists with varying levels of activity have been produced, many of which have clinically stimulated the immune system (RSC Med. Chem., 2021, 12, 1065-1120). The approved R837 and R848 are limited to topical applications and skin-related diseases, primarily due to severe side effects related to their target or clinical inefficacy.

[0009] While researchers are seeking new small-molecule TLR7 and / or TLR8 agonists, a lot of work is focused on optimizing pharmacokinetics to achieve local accumulation or targeted release and reduce systemic immune responses, including slow release such as hydrosols, nanoparticles (peptides, polymers, cyclodextrins, carrier proteins and others), prodrugs modified with side chains such as long-chain fatty acids or phosphates, or combination with other drugs. These strategies are also used in the development of TLR7 and / or TLR8 as vaccine adjuvants (Advanced Drug Delivery Reviews 175(2021)113803).

[0010] Summary of the Invention

[0011] The present application aims to provide pyrimidine derivatives that can be used as effective TLR7 and / or TLR8 receptor agonists, exhibiting good selectivity, high activity, and good safety. These derivatives can be used to prepare medicaments for the prevention or treatment of infectious diseases, respiratory diseases, immune-related diseases, viral diseases, or tumors. The present application also provides methods for preparing these pyrimidine derivatives and pharmaceutical compositions thereof.

[0012] To achieve the above objectives, in the first aspect, the present application provides a pyrimidine derivative, which is a compound of formula (I-1) or formula (I-2), or a stereoisomer, tautomer, isotope derivative, halogenated derivative, hydrate, solvate, prodrug, and pharmaceutically acceptable salt thereof,

[0013] in,

[0014] represents a single bond or a double bond;

[0015] X1 and X2 are both C-R3, or one of them is C-R3 and the other is N;

[0016] Z is -NH2, -OH, -NH-alkyl, -O-alkyl, -NH-C(O)-alkyl, -OC(O)-alkyl, -NH-C(O)-OH, -OC(O)-OH;

[0017] Y is -O-, -S- or -NR4-, wherein R4 is H or optionally substituted alkyl;

[0018] R1 is alkyl or aryl, optionally selected from oxo, halogen, amino, hydroxyl, nitro, cyano, mercapto, -C(O)-NH2, -C(O)-OH, heteroaryl (optionally substituted by one or more of halogen, amino, hydroxyl, nitro, cyano, mercapto, alkoxy, alkyl), aryl (optionally substituted by one or more of halogen, amino, hydroxyl, nitro, cyano, mercapto, alkoxy, alkyl), heterocycloalkyl (optionally substituted by one or more of halogen, amino, hydroxyl, nitro, cyano, mercapto, alkoxy, alkyl), cycloalkyl (optionally substituted by one or more of halogen, amino, hydroxyl, nitro, cyano, mercapto, alkoxy, alkyl), alkyl, optionally substituted with one or more of: optionally substituted with -C(O)-O-alkyl, optionally substituted with -OC(O)-alkyl, optionally substituted with -C(O)-NH-alkyl, optionally substituted with -NH-C(O)-alkyl, optionally substituted with -S(O)-O-alkyl, optionally substituted with -OS(O)-alkyl, optionally substituted with -S(O)-O-alkyl, optionally substituted with -O-S(O)-alkyl, optionally substituted with -S(O)-NH-alkyl, optionally substituted with -NH-S(O)-alkyl, optionally substituted with -S(O)-NH-alkyl, optionally substituted with -NH-S(O)-alkyl, optionally substituted with -NH-S(O)-alkyl;

[0019] R2 is -L3-R7 can be substituted at the para, meta or ortho position of L2;

[0020] L1, L2, and L3 are a bond or an optionally substituted linear alkylene group, wherein one, two, or more carbon atoms in the linear alkylene group may be replaced by heteroatoms such as 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, and optionally substituted alkylamino;

[0021] R5 is cycloalkyl or heterocycloalkyl, optionally substituted by one or more selected from oxo, halogen, amino, hydroxy, nitro, cyano, mercapto, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamino;

[0022] W and V can be N or CH. When W or V is CH, it can be substituted by R6 or -L3-R7;

[0023] R3 and R6 are each independently H, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamino, halogen, amino, hydroxyl, nitro, cyano, or mercapto;

[0024] 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 ); substituents are selected from one or more of optionally substituted alkyl, optionally substituted alkylamino, and oxo;

[0025] R8 is H or optionally substituted alkyl;

[0026] R9, R 10 Each is independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0027] The substituents in the optionally substituted alkyl group are selected from one or more of halogen, amino, hydroxy, nitro, cyano, thiol, carboxyl, ester, amide, etc.;

[0028] n=0, 1, 2, 3 or 4.

[0029] In one group of embodiments, one of X1 and X2 is C-R3 and the other is N.

[0030] In one group of embodiments, R8 is H or optionally substituted C1-8 alkyl.

[0031] In one group of embodiments, R1 is C1-8 alkyl, optionally substituted by one or more 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, optionally substituted C1-8 alkylsulfonyl; preferably, R1 is C2-6 alkyl, optionally substituted by one or more selected from optionally substituted C1-6 alkyloxy, optionally substituted C1-6 alkylthio, 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, 3-hexyl.

[0032] Further, R1 is n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-hexyl, methoxyethyl, methylthioethyl, methylsulfonylethyl, methoxypropyl, methylthiopropyl, methylsulfonylpropyl,

[0033] Preferably, R1 is n-butyl, Methylthiopropyl, methylsulfonylpropyl,

[0034] In one group of embodiments, W and V are both N, W and V are both C, or one of X and V is N.

[0035] In one group of embodiments, the heterocycloalkyl group is a 3-12 membered monocyclic, bicyclic or polycyclic heterocycloalkyl group. Preferably, the heterocycloalkyl group is a 3-12 membered monocyclic, bicyclic or polycyclic heterocycloalkyl group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S. More preferably, the heteroatoms in the heterocycloalkyl group are connected to L1 or L3. More preferably, the N atom in the heterocycloalkyl group is connected to L1 or L3.

[0036] Furthermore, the heterocycloalkyl group is a 3-7 membered monocyclic heterocycloalkyl group containing 1-2 heteroatoms selected from N, O, and S, or a 7-12 membered cyclic or spirocyclic heterocycloalkyl group containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S; preferably, it is a 4-6 membered monocyclic heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, or a 7-11 membered spirocyclic heterocycloalkyl group containing 2, 3, or 4 heteroatoms selected from N and O.

[0037] Furthermore, the heterocycloalkyl group may be one of the following groups:

[0038] In one group of embodiments, the aryl group is a C6-10 aryl group, preferably a phenyl group.

[0039] In one group of embodiments, L1, L2, and L3 are bonds or optionally substituted straight-chain alkylene groups containing 1-6 chain atoms, 1-2 carbon atoms in the alkylene group may be replaced by heteroatoms such as oxygen, sulfur, and nitrogen, and the substituents are selected from C1-8 alkyl, halogen, amino, hydroxy, nitro, cyano, and mercapto.

[0040] Furthermore, L1 is an optionally substituted straight-chain alkylene group containing 1-4 chain atoms, preferably an optionally substituted straight-chain alkylene group containing 2-3 chain atoms; more preferably -O-propylene- or -CH2CH2CH2-.

[0041] L2 is an optionally substituted straight-chain alkylene group containing 1-4 chain atoms, preferably an optionally substituted straight-chain alkylene group containing 2-3 chain atoms; more preferably -CH2-, -CH2CH2-, -O-, -O-CH2-CH2-, -O-CH2-.

[0042] L3 is a bond, an optionally substituted straight-chain alkylene group containing 1-4 chain atoms, preferably a bond, an optionally substituted straight-chain alkylene group containing 2-3 chain atoms; more preferably a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-CH2-, -O-CH2-, -CH(CH3)CH2-; more preferably

[0043] In one embodiment, R9, R 10 Each is independently H or C1-8 alkyl.

[0044] In one group of embodiments, R7 is -OH, -N(R9R 10 )、-N(R9)NH2、-NO(R9R 10 ), optionally substituted 3-12 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, optionally substituted C6-10 aryl, optionally substituted 3-12 membered heterocycloalkyl-NR9- containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, optionally substituted C6-10 aryl-NR9-; 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 10 Each is independently H or C1-8 alkyl; the heterocycloalkyl is preferably a 4-6 membered monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N and O, or a 7-11 membered spirocyclic heterocycloalkyl containing 2, 3 or 4 heteroatoms selected from N and O; more preferably, the heteroatom in the heterocycloalkyl is connected to L3, and more preferably, the N atom in the heterocycloalkyl is connected to L3.

[0045] In one group of embodiments, R2 is selected from one of the following optionally substituted groups:

[0046] Further, R2 is optionally substituted

[0047] The substituent is selected from one or more of alkyl, alkyloxy, alkylthio, alkylamino, halogen, amino, hydroxyl, nitro, cyano, and mercapto.

[0048] In a preferred embodiment, the compound of formula (I-1) or formula (I-2) has one of the following formulae:

[0049] In a second aspect, the present application provides a pyrimidine derivative, which is a compound of formula (I-1), or a stereoisomer, tautomer, isotope derivative, halogenated derivative, hydrate, solvate, prodrug, and pharmaceutically acceptable salt thereof,

[0050] wherein X1 and X2 are both selected from C-R3;

[0051] Z is -NH2, -OH;

[0052] Y is -O-, -S- or -NR4-, wherein R4 is H or optionally substituted alkyl;

[0053] R1 is alkyl, optionally substituted by 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, optionally substituted alkylsulfonyl;

[0054] R2 is -L3-R7 can be substituted at the para, meta or ortho position of L2;

[0055] L2 and L3 are a bond, an optionally substituted straight-chain alkylene group, wherein one, two or more carbon atoms in the straight-chain alkylene group may be replaced by heteroatoms such as 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 and optionally substituted alkylamino;

[0056] W and V can be N or CH. When W or V is CH, it can be substituted by R6 or -L3-R7;

[0057] R3 and R6 are each independently H, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamino, halogen, amino, hydroxyl, nitro, cyano, or mercapto;

[0058] 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 ); substituents are selected from one or more of optionally substituted alkyl, optionally substituted alkylamino, and oxo;

[0059] R9, R 10 Each is independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0060] The substituents in the optionally substituted alkyl group are selected from one or more of halogen, amino, hydroxy, nitro, cyano, thiol, carboxyl, ester, amide, etc.;

[0061] n=0, 1, 2, 3 or 4.

[0062] In one group of embodiments, R1 is C1-8 alkyl, optionally substituted by one or more selected from optionally substituted C1-8 alkylthio, optionally substituted C1-8 alkylsulfonyl; preferably, R1 is C2-6 alkyl, optionally substituted by one or more selected from optionally substituted C1-6 alkylthio, optionally substituted C1-6 alkylsulfonyl.

[0063] Further, R1 is n-butyl, n-pentyl, 2-pentyl, n-hexyl, 2-hexyl, 3-hexyl, methoxyethyl, methylthioethyl, methylsulfonylethyl, methoxypropyl, methylthiopropyl, methylsulfonylpropyl, Preferably, R1 is n-butyl, Methylthiopropyl, methylsulfonylpropyl,

[0064] In one group of embodiments, W and V are both N, or both W and V are C, or one of W and V is N.

[0065] In one group of embodiments, the heterocycloalkyl group is a 3-12 membered monocyclic, bicyclic or polycyclic heterocycloalkyl group; preferably, the heterocycloalkyl group is a 3-12 membered monocyclic, bicyclic or polycyclic heterocycloalkyl group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S; more preferably, the heteroatoms in the heterocycloalkyl group are connected to L1 or L3; more preferably, the N atom in the heterocycloalkyl group is connected to L1 or L3.

[0066] Further, the heterocycloalkyl group is a 3-7 membered monocyclic heterocycloalkyl group containing 1-2 heteroatoms selected from N, O, and S, or a 7-12 membered cyclic or spirocyclic heterocycloalkyl group containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S; preferably, the heterocycloalkyl group is a 4-6 membered monocyclic heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, or a 7-11 membered spirocyclic heterocycloalkyl group containing 2, 3, or 4 heteroatoms selected from N and O;

[0067] Furthermore, the heterocycloalkyl group is one of the following groups:

[0068] In one group of embodiments, L2 and L3 are a bond or an optionally substituted straight-chain alkylene group containing 1-6 chain atoms, 1-2 carbon atoms in the straight-chain alkylene group may be replaced by heteroatom oxygen, and the substituent is selected from C1-8 alkyl, halogen, amino, hydroxy, nitro, cyano, and mercapto.

[0069] Further, L2 is an optionally substituted straight-chain alkylene group containing 1-4 chain atoms, preferably an optionally substituted straight-chain alkylene group containing 2-3 chain atoms; more preferably -CH2-, -CH2CH2-, -O-, -O-CH2-CH2-, -O-CH2-;

[0070] L3 is a bond, an optionally substituted straight-chain alkylene group containing 1-4 chain atoms, more preferably a bond, an optionally substituted straight-chain alkylene group containing 2-3 chain atoms; preferably a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-CH2-, -O-CH2-, -CH(CH3)CH2-; more preferably

[0071] In one group of embodiments, R7 is -OH, -N(R9R 10 )、-N(R9)NH2、-NO(R9R 10 ), optionally substituted 3-12 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, optionally substituted C6-10 aryl, optionally substituted 3-12 membered heterocycloalkyl-NR9- containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, optionally substituted C6-10 aryl-NR9-; 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 is independently H or C1-8 alkyl; the heterocycloalkyl is preferably a 4-6 membered monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N and O, or a 7-11 membered spirocyclic heterocycloalkyl containing 2, 3 or 4 heteroatoms selected from N and O; more preferably, the heteroatom in the heterocycloalkyl is connected to L3, and more preferably, the N atom in the heterocycloalkyl is connected to L3.

[0072] Further, R7 is -NO(R9R 10 ), an optionally oxo-substituted 3-12 membered heterocycloalkyl group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S.

[0073] In one group of embodiments, R2 is selected from one of the following optionally substituted groups:

[0074] Further, R2 is optionally substituted

[0075] The substituent is selected from one or more of alkyl, alkyloxy, alkylthio, alkylamino, halogen, amino, hydroxyl, nitro, cyano, mercapto, carboxyl, ester, amide and the like.

[0076] In a preferred embodiment, the compound of formula (I-1) has one of the following formulae:

[0077] In a third aspect, the present application provides a pyrimidine derivative, which is a compound of formula (II-1) or formula (II-2), or a stereoisomer, tautomer, isotope derivative, halogenated derivative, hydrate, solvate, prodrug, and pharmaceutically acceptable salt thereof.

[0078] in,

[0079] X3 is N or CH, X4 is CH, N or NO, when X3 or X4 is CH, it may be substituted by R3;

[0080] Z is -NH2, -OH, -NH-alkyl, -O-alkyl, -NH-C(O)-alkyl, -OC(O)-alkyl, -NH-C(O)-OH, -OC(O)-OH;

[0081] Y is -O-, -S- or -NR4-, wherein R4 is H or optionally substituted alkyl;

[0082] R1 is alkyl or aryl, optionally selected from oxo, halogen, amino, hydroxy, nitro, cyano, mercapto, -C(O)-NH2, -C(O)-OH, heteroaryl (optionally substituted by one or more of halogen, amino, hydroxy, nitro, cyano, mercapto, alkoxy, alkyl), aryl (optionally substituted by one or more of halogen, amino, hydroxy, nitro, cyano, mercapto, alkoxy, alkyl), heterocycloalkyl (optionally substituted by one or more of halogen, amino, hydroxy, nitro, cyano, mercapto, alkoxy, alkyl), cycloalkyl (optionally substituted by one or more of halogen, amino, hydroxy, nitro, cyano, mercapto, alkoxy, alkyl), optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted with one or more of 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;

[0083] R2 is -L3-R7 can be substituted at the para, meta or ortho position of L2;

[0084] L1, L2, and L3 are a bond or an optionally substituted linear alkylene group, wherein one, two, or more carbon atoms in the linear alkylene group may be replaced by heteroatoms such as 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, and optionally substituted alkylamino;

[0085] R5 is cycloalkyl or heterocycloalkyl, optionally substituted by one or more selected from oxo, halogen, amino, hydroxy, nitro, cyano, mercapto, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamino;

[0086] W and V can be N or CH. When W or V is CH, it can be substituted by R6 or -L3-R7;

[0087] 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;

[0088] 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 ); substituents are selected from one or more of optionally substituted alkyl, optionally substituted alkylamino, and oxo;

[0089] R9, R 10 Each is independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0090] The substituents in the optionally substituted alkyl group are selected from one or more of halogen, amino, hydroxy, nitro, cyano, thiol, carboxyl, ester, amide, etc.;

[0091] m=0, 1, 2 or 3, n=0, 1, 2, 3 or 4.

[0092] In one group of embodiments, R1 is C1-8 alkyl, optionally substituted by one or more 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, optionally substituted C1-8 alkylsulfonyl; preferably, R1 is C2-6 alkyl, optionally substituted by one or more selected from optionally substituted C1-6 alkyloxy, optionally substituted C1-6 alkylthio, optionally substituted C1-6 alkylsulfonyl.

[0093] Further, R1 is optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, 2-hexyl, 3-hexyl;

[0094] Preferably, R1 is n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-hexyl, methoxyethyl, methylthioethyl, methylsulfonylethyl, methoxypropyl, methylthiopropyl, methylsulfonylpropyl,

[0095] More preferably, R1 is n-butyl, Methylthiopropyl, methylsulfonylpropyl,

[0096] In one group of embodiments, W and V are both N, W and V are both C, or one of X and V is N.

[0097] In one group of embodiments, the heterocycloalkyl group is a 3-12 membered monocyclic, bicyclic or polycyclic heterocycloalkyl group; preferably, the heterocycloalkyl group is a 3-12 membered monocyclic, bicyclic or polycyclic heterocycloalkyl group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S; preferably, the heteroatoms in the heterocycloalkyl group are connected to L1 or L3, and more preferably, the N atom in the heterocycloalkyl group is connected to L1 or L3.

[0098] Furthermore, the heterocycloalkyl group is a 3-7 membered monocyclic heterocycloalkyl group containing 1-2 heteroatoms selected from N, O, and S, or a 7-12 membered cyclic or spirocyclic heterocycloalkyl group containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S; preferably, it is a 4-6 membered monocyclic heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, or a 7-11 membered spirocyclic heterocycloalkyl group containing 2, 3, or 4 heteroatoms selected from N and O.

[0099] Furthermore, the heterocycloalkyl group may be one of the following groups:

[0100] In one group of embodiments, the aryl group is a C6-10 aryl group, preferably a phenyl group.

[0101] In one group of embodiments, L1, L2, and L3 are bonds or optionally substituted straight-chain alkylene groups containing 1-6 chain atoms, 1-2 carbon atoms in the alkylene group may be replaced by heteroatoms oxygen and sulfur, and the substituents are selected from C1-8 alkyl, halogen, amino, hydroxy, nitro, cyano, and mercapto.

[0102] Furthermore, L1 is an optionally substituted straight-chain alkylene group containing 1-4 chain atoms, preferably an optionally substituted straight-chain alkylene group containing 2-3 chain atoms; more preferably -O-propylene- or -CH2CH2CH2-.

[0103] L2 is an optionally substituted straight-chain alkylene group containing 1 to 4 chain atoms, preferably an optionally substituted straight-chain alkylene group containing 2 to 3 chain atoms; more preferably -CH2-, -CH2CH2-, -O-, -O-CH2-CH2-, -O-CH2-;

[0104] L3 is a bond, an optionally substituted straight-chain alkylene group containing 1-4 chain atoms, preferably a bond, an optionally substituted straight-chain alkylene group containing 2-3 chain atoms; more preferably -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-CH2-, -O-CH2-, -CH(CH3)CH2-; more preferably

[0105] In one group of embodiments, R7 is OH, -N(R9R 10 )、-N(R9)NH2、-NO(R9R 10 ), optionally substituted 3-12 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, optionally substituted C6-10 aryl, optionally substituted 3-12 membered heterocycloalkyl-NR9- containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, optionally substituted C6-10 aryl-NR9-; 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 10 Each independently represents H or C1-8 alkyl. The heterocycloalkyl group is preferably a 4-6 membered monocyclic heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, or a 7-11 membered spirocyclic heterocycloalkyl group containing 2, 3 or 4 heteroatoms selected from N and O; more preferably, the heteroatom in the heterocycloalkyl group is connected to L3, and more preferably, the N atom in the heterocycloalkyl group is connected to L3.

[0106] In one group of embodiments, R2 is selected from one of the following optionally substituted groups:

[0107] Further, R2 is optionally substituted

[0108] The substituent is selected from one or more of alkyl, alkyloxy, alkylthio, alkylamino, halogen, amino, hydroxyl, nitro, cyano, mercapto, carboxyl, ester, amide and the like.

[0109] In a preferred embodiment, the compound of formula (II-1) or formula (II-2) may have the following formula:

[0110] For the sake of simplicity, the "Formula (I-1)", "Formula (I-2)", "Formula (II-1)", "Formula (II-2)", "compounds of the present application", and "compounds of the present application" mentioned below also include their stereoisomers, tautomers, isotope derivatives, halogenated derivatives, hydrates, solvates, prodrugs and pharmaceutically acceptable salts.

[0111] The present application also provides a preparation method of the compound of formula (I-1), which can be prepared by one of the following routes:

[0112] Route 1:

[0113] Route 2:

[0114] Route 3:

[0115] Route 4:

[0116] The other groups are as defined above.

[0117] The present application also provides a preparation method of the compound of formula (II-1), which can be prepared by one of the following routes:

[0118] Route 5:

[0119] Route 6:

[0120] Other groups are as defined above.

[0121] In one embodiment, the linking group between L1 or L2 and the ring where X3 is located is -O-.

[0122] The present application also provides a preparation method of the compound of formula (II-2), which can be prepared by the following route:

[0123] Route 7:

[0124] Other groups are as defined above.

[0125] In one embodiment, the linking group between L1 or L2 and the ring where X4 is located is -O-.

[0126] The present application also provides a preparation method of the compound of formula (II-2), which can be prepared by the following route:

[0127] Route 8:

[0128] Other groups are as defined above.

[0129] The present application also provides a pharmaceutical composition, which contains the compound of the present application as an active ingredient and a pharmaceutically acceptable excipient; the pharmaceutical composition further contains a pharmaceutically acceptable carrier or excipient.

[0130] Routes of administration of the compounds of the present application or their pharmaceutical compositions include, but are not limited to, oral, rectal, transmucosal, topical, transdermal, inhalation, parenteral, sublingual, vaginal, intranasal, intramuscular, subcutaneous, and intravenous administration. The dosage is 0.1-0.2 mg / kg, preferably 0.1 mg / kg, once daily. Furthermore, the concentration of the compounds of the present application in the composition is 0.1-0.2 mg / kg, preferably 0.1 mg / kg.

[0131] The pharmaceutical composition further comprises at least one other therapeutic agent selected from chemotherapeutic agents, immunotherapeutic agents, anti-angiogenic agents, cytokines, hormones, polynucleotides, antibodies, and immunologically active fragments. When the pharmaceutical composition comprises multiple active ingredients, each active ingredient can be administered simultaneously, sequentially, or separately at the discretion of the physician.

[0132] The antibodies are Her2 and / or PD-1 and / or PD-L1 and / or TIM-3 antibodies, preferably, the antibodies are PD-L1 antibodies and Her2 antibodies.

[0133] The compounds of the present application or their pharmaceutical compositions can be used as TLRs receptor agonists for the preparation of medicaments for preventing or treating diseases or conditions associated with TLRs activity. "Diseases or conditions associated with TLRs activity" refers to any disease state associated with toll-like receptors. Preferably, they are used as TLR7 and / or TLR8 receptor agonists, preferably in mammals.

[0134] The present application also provides the use of the compound of the present application or its pharmaceutical composition for preparing a drug for preventing or treating infectious diseases, respiratory diseases, immune-related diseases, viral diseases or cell proliferative diseases.

[0135] The above diseases are preferably asthma, tumors, HIV, and HBV.

[0136] 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, Sjogren's syndrome, Wegener's granulomatosis, sarcoidosis, Reiter syndrome, Behçet's syndrome, rheumatoid arthritis, inflammatory bowel disease, polymyositis, vasculitis, ankylosing spondylitis, and psoriasis.

[0137] Such viral diseases include, but are not limited to, Ebola virus disease, anthrax, genital warts, simple warts, plantar warts, respiratory syncytial virus, hepatitis B, hepatitis C, dengue virus, herpes simplex virus (e.g., HSV-1, HSV-11), molluscum contagiosum, gangrene, smallpox, lentiviruses, human immunodeficiency virus (HIV), human papillomavirus (HPV), cytomegalovirus, herpes zoster virus, rhinovirus, enterovirus, adenovirus, influenza, parainfluenza, mumps virus, measles virus, papovavirus, flavivirus, retrovirus, arenavirus (e.g., LCM, Junin virus, Machupo virus, Guanarito virus, and Lassa fever), and filovirus (e.g., Ebola virus or Marburg virus).

[0138] The cell proliferative disease is a tumor, including but not limited to human sarcomas and carcinomas, such as lymphoma, osteosarcoma, fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, uterine tumor, neuron tumor, gastrointestinal cancer, colon cancer, rectal cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, papillary carcinoma, medullary carcinoma, Bronchogenic carcinoma, hepatocellular carcinoma, liver cancer, bile duct cancer, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, ovarian cancer, testicular tumor, renal cancer, lung cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, polycythemia vera, multiple myeloma and heavy chain disease. The adenocarcinoma can be thyroid cancer, pancreatic cancer, sweat gland cancer, sebaceous gland cancer, breast cancer, nipple adenocarcinoma, cystadenocarcinoma, prostate cancer, and the lung cancer can be small cell lung cancer. The leukemia is acute lymphocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythrocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia. The lymphoma is Hodgkin's disease or non-Hodgkin's disease.

[0139] Preferably, the tumor is a cold tumor, more preferably, the tumor is colon cancer, bladder cancer, melanoma, meningioma, lung cancer, liver cancer or pancreatic cancer.

[0140] The present application also provides the use of the compound of the present application or its pharmaceutical composition in the preparation of a drug for preventing tumor recurrence, which can preferably induce long-lasting systemic immune memory to prevent recurrence.

[0141] The present application also provides the use of the compound or pharmaceutical composition of the present application in preparing a payload of Conjugate (ADC) and in preparing a payload of Conjugate (SMDC).

[0142] The present application also provides the use of the compound or pharmaceutical composition of the present application in the preparation of a pharmaceutical preparation; preferably, the pharmaceutical preparation increases the number of genes in each pathway that are beneficial to immunotherapy, such as inflammation and cytokine-mediated pathways, T cell activation / apoptosis signaling pathways, and B cell activation pathways. More preferably, the pharmaceutical preparation increases the number of genes in the above-mentioned pathways that are beneficial to tumor immunotherapy. Further, the pharmaceutical preparation increases the number of CD8+ T cells; further, the pharmaceutical preparation increases the ratio of CD8+ T cells to Treg cells; further, the pharmaceutical preparation increases PDL-1 expression. Further, the pharmaceutical preparation increases the level of interleukin-2 and / or increases the level of interferon-γ and / or reduces the level of interleukin-10.

[0143] The present application also provides the use of the compound of the present application or its pharmaceutical composition in the preparation of a preparation for downregulating the Wnt signaling pathway. Preferably, the preparation downregulates the expression level of S-catenin protein.

[0144] The present application also provides the use of the compound of the present application or its pharmaceutical composition in the preparation of a pharmaceutical preparation that affects the secretion level of various cytokines in macrophages, preferably, affecting the expression level of mRNA of genes such as Illb, 116, 1112b, Tnf, Ifnbl, Cxcll, Cxcll0 and 1110.

[0145] The present application also provides a method for enhancing the body's positive immune response, comprising: administering a therapeutically effective amount of the compound of the present application or a pharmaceutical composition thereof to a system or individual in need, thereby regulating TLR7 and / or TLR8.

[0146] The present application also provides a method for enhancing the effect of chemotherapy, comprising administering a therapeutically effective amount of a chemotherapy drug to a system or individual in need thereof, and simultaneously or subsequently administering a therapeutically effective amount of a compound of the present application or a pharmaceutical composition thereof.

[0147] The present application also provides a method for improving immunotherapy, comprising: administering a therapeutically effective amount of a compound of the present application or a pharmaceutical composition thereof to a system or individual in need thereof, and simultaneously or subsequently introducing chimeric antigen receptor T cells (CAR-T) into the system or individual.

[0148] The present application also provides the use of the compound or pharmaceutical composition of the present application for preparing a vaccine adjuvant.

[0149] This application has the following beneficial effects:

[0150] 1. The compounds of the present application have excellent TLR7 and / or TLR8 receptor agonist activity and can be used to prepare drugs for preventing or treating infectious diseases, respiratory diseases, immune-related diseases, viral diseases or cell proliferative diseases.

[0151] 2. The compounds of the present application have a high ability to stimulate the immune response of peripheral blood mononuclear cells (PBMCs). The levels of interferon-γ and various other pro-inflammatory cytokines and chemokines secreted by these cells are significantly higher than those of the control compounds D18 and R848. The compounds of the present application demonstrate a strong ability to activate PBMCs to kill cancer cells.

[0152] 3. The compounds of the present application have a short half-life, which can reduce the risk of the compounds inducing systemic immune responses in the body. The compounds of the present application have high concentrations in liver tissue.

[0153] 4. The compounds of the present application are relatively safer and have better tumor inhibition effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0154] FIG1 shows the effects of the compounds of the present application on the cytokine secretion levels of human peripheral blood mononuclear cells.

[0155] FIG2 is a pharmacokinetic diagram of the compound of the present application in mice.

[0156] FIG3 is a graph showing the inhibitory effect of the compounds of the present application on mouse CT26 tumors. DETAILED DESCRIPTION

[0157] The following is a detailed description of the specific embodiments of the present application. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present application and are not intended to limit the present application.

[0158] The endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0159] Before describing this application in detail, it should be understood that the terminology used herein is intended only to describe specific embodiments and is not intended to limit the scope of this application, which is defined solely by the appended claims. In order to more fully understand the present application described herein, the following terms are used and their definitions are as follows. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as understood by one of ordinary skill in the art to which this application belongs.

[0160] definition

[0161] Unless otherwise specified, the following terms used in this application have the following definitions.

[0162] In this application, in the specific compound number, "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.

[0163] In this application, the ring group It means that there can be m R3 and n R6 connected to any possible position on the ring group.

[0164] In this application, some substituents Indicates the connection site.

[0165] Unless otherwise specified, the term "optionally substituted" refers to a hydrogen atom on the substituted group that is not replaced or one or more substitutable positions of the substituent group are independently replaced by a substituent, the substituent being independently selected from one or more of deuterium, oxo, halogen, amino, hydroxyl, nitro, cyano, mercapto, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamino, and optionally substituted dialkylamino; a substituent on the alkyl group is selected from one or more of oxo, deuterium, halogen, amino, hydroxyl, nitro, cyano, and mercapto; and a substituent selected from "oxo" refers to a situation where two hydrogen atoms on the carbon atom at the same substitution position are replaced by an oxygen atom, or a heteroatom is linked to the oxygen atom, such as nitrogen oxide linked to nitrogen, or a sulfinyl or sulfonyl group linked to sulfur. "Optionally oxo" refers to a hydrogen atom on the substituted group that is not replaced or two hydrogen atoms on the carbon atom at the same substitution position are replaced by an oxygen atom, or a heteroatom is linked to the oxygen atom, such as nitrogen oxide linked to nitrogen, or a sulfinyl or sulfonyl group linked to sulfur. The term "independently" means that when there are more than one substituent, these substituents may be the same or different.

[0166] The term "aryl" refers to a monocyclic or bicyclic aromatic carbon ring system containing 6 to 10 carbon atoms. Examples of aryl groups include phenyl and naphthyl.

[0167] The term "heteroaryl" refers to an aromatic monocyclic or polycyclic ring system having a 5-10 membered structure, or preferably a 5-8 membered structure, more preferably a 5-6 membered structure, wherein 1, 2, 3, 4 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2, 3 or 4. The heteroaryl group may be a 5-6 membered aromatic monocyclic ring containing 1-2 atoms selected from N or S, or a 5-6 membered aromatic monocyclic ring containing 1-2 N atoms. Examples of heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzopyridinyl, benzopyrimidinyl, benzo pyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, etc.

[0168] The term "cycloalkyl" refers to a saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms, wherein the monocyclic, bicyclic or tricyclic ring does not contain an aromatic ring, including a bridged ring group, a spirocyclic group, and a cyclocyclic group. A bridged ring group refers to any two rings sharing two ring atoms that are not directly connected. Preferably, it contains 3-10 carbon atoms (C3-10 cycloalkyl), further preferably 3-8 carbon atoms (C3-8 cycloalkyl), 3-6 carbon atoms (C3-6 cycloalkyl), 4-6 carbon atoms (C4-6 cycloalkyl), 5-6 carbon atoms (C5-6 cycloalkyl). Examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, etc.

[0169] The term "heterocycloalkyl" refers to a saturated monocyclic, bicyclic, or tricyclic ring system containing heteroatoms, wherein the monocyclic, bicyclic, or tricyclic ring does not contain an aromatic ring, and includes bridged, spirocyclic, and paracyclic rings. A bridged ring refers to any two rings sharing two ring atoms that are not directly connected. Heterocycloalkyl groups contain 3-12 ring atoms, of which 1, 2, 3, 4, or more are selected from N, O, or S, and the remaining ring atoms are C. Preferably, the heterocycloalkyl group contains 3-8 ring atoms (3-8 membered heterocycloalkyl), 3-7 ring atoms (3-7 membered heterocycloalkyl), 3-6 ring atoms (3-6 membered heterocycloalkyl), 4-6 ring atoms (4-6 membered heterocycloalkyl), or 5-6 ring atoms (5-6 membered heterocycloalkyl). Heterocycloalkyl groups can be 7-12 membered paracyclic, spirocyclic, or 7-9 membered spirocyclic heterocycloalkyls. The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2, or 3). The heterocycloalkyl group may be a 4-6 membered monocyclic heterocycloalkyl group containing 1-2 N or O groups, preferably a 4-, 5-, or 6-membered monocyclic heterocycloalkyl group containing 1-2 N groups, a 4-, 5-, or 6-membered monocyclic heterocycloalkyl group containing 1-2 O groups, a 4-, 5-, or 6-membered monocyclic heterocycloalkyl group containing 1 N and 1 O group, or a 7-, 8-, 9-, 10-, or 11-membered spirocycloalkyl group containing 1, 2, 3, or 4 N or O groups. Examples of heterocycloalkyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, pyranyl, aziridine, oxirane, thiirane, azetidinyl, oxetanyl, thietanyl, oxanyl, morpholinyl, thiomorpholinyl, dioxanyl, dithioxanyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolinyl, wait.

[0170] The term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, preferably a straight or branched chain group containing 1 to 10 carbon atoms (C1-10 alkyl) (the number of carbon atoms is between 1 and 10, specifically 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10), more preferably a C1-8 alkyl group containing 1 to 8 carbon atoms (i.e., a C1-8 alkyl group containing 1 to 8 carbon atoms, specifically 1, 2, 3, 4, 5, 6, 7 or 8), or a C1-6 alkyl group containing 1 to 6 carbon atoms (i.e., a C1-6 alkyl group containing 1 to 6 carbon atoms, 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, 2-pentyl, and the like.

[0171] 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. "-N(O)alkyl" refers to the nitrogen oxide of alkylamino, and the alkyl group is as defined above. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy and the like; methylthio, ethylthio, propylthio, isopropylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio, tert-butylthio and the like; methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino, methylsulfonyl and dimethyl-N(O)-.

[0172] The term "straight-chain alkylene" refers to a divalent saturated straight-chain aliphatic hydrocarbon group, wherein one, two or more carbon atoms in the straight-chain alkylene group may be replaced by heteroatoms such as oxygen, sulfur or nitrogen, and preferably contains 1 to 10 chain atoms, with the number being between 1 and 10, specifically 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, more preferably contains 1 to 8 chain atoms (i.e., the number of chain atoms is between 1 and 8, specifically 1, 2, 3, 4, 5, 6, 7 or 8), and contains 1 to 6 chain atoms (i.e., the number of chain atoms is between 1 and 6, specifically 1, 2, 3, 4, 5 or 6). One or more carbon atoms in the straight-chain alkylene group may be replaced by heteroatoms such as oxygen, sulfur or nitrogen. Examples include, but are not limited to, -O-, -CH2-, -O-CH2-, -CH2-O-, -NH-CH2-, -CH2-NH-, -O-CH2CH2-, -CH2CH2-O-, -NH-CH2CH2-, -CH2CH2-NH-, -CH2CH2CH2-, -CH2CH2-, -OCH2CH2CH2-, -CH2CH2CH2-O-, -NHCH2CH2CH2-, -CH2CH2CH2-NH-, -CH(CH3)CH2-, and the like.

[0173] The term "halogen" refers to F, Cl, Br, I.

[0174] As used herein, numerical ranges related to the number of substituents, carbon atoms, or ring atoms represent a complete enumeration of all integers within the range, and ranges are intended merely as a simplified notation. For example, "1-4 substituents" means 1, 2, 3, or 4 substituents; "3-8 ring atoms" means 3, 4, 5, 6, 7, or 8 ring atoms. Therefore, numerical ranges related to the number of substituents, carbon atoms, or ring atoms also encompass any subranges thereof, and each subrange is considered disclosed herein.

[0175] The active compounds described herein are interpreted to include the compounds of the present invention and their stereoisomers, tautomers, isotopic derivatives, halogenated derivatives, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts. Stereoisomers, tautomers, isotopic derivatives, hydrates, solvates, prodrugs, isotopic derivatives, or pharmaceutically acceptable salts thereof are obtained by conventional techniques in the art and exhibit the same or similar effects in vivo and in vitro through substantially the same mechanism of action as the compounds described herein.

[0176] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including configurational isomers and conformational isomers, wherein configurational isomers further include geometric isomers (or cis-trans isomers) and optical isomers (including enantiomers and diastereomers). Geometric isomers may exist in the present compound. Optical isomers refer to substances with identical molecular structures, similar physicochemical properties, but different optical rotations. The compounds of the present application may contain asymmetrically substituted carbon atoms in the R or S configuration, wherein the terms "R" and "S" are defined as IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10. Compounds with asymmetrically substituted carbon atoms (having equal numbers of R and S configurations) are racemic at those carbon atoms. Atoms having an excess of one configuration (relative to the other) result in that configuration being present in a higher number, 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, the present application includes racemic mixtures, relative and absolute optical isomers, and mixtures of relative and absolute optical isomers.

[0177] The term "tautomer" refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur through the reorganization of some of the bonding electrons.

[0178] The term "isotopic derivative" means that the compounds of the present invention may exist in an isotopically traced or enriched form, containing one or more atoms whose atomic mass or mass number differs from the atomic mass or mass number of the largest atom found in nature. Isotopes may be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to:2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl and 125 I. Compounds containing other isotopes of these and / or other atoms are within the scope of this application. Isotope-labeled compounds of this application can be prepared using general methods well known to those of ordinary skill in the art.

[0179] The term "hydrate" refers to an association formed by one or more water molecules and a compound of the present application.

[0180] The term "solvate" refers to an association formed between one or more solvent molecules and a compound of the present application.

[0181] The term "prodrug" is a derivative of an active drug that is designed to improve some defined, undesirable physical or biological property. Physical properties are usually related to solubility (too high or insufficient lipid or water solubility) or stability, while problematic biological properties include rapid metabolism or poor bioavailability, which themselves may be related to physicochemical properties.

[0182] The term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with mammalian tissues, particularly human tissues, without excessive toxicity, irritation, or allergic reaction, and are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. If the compound is basic, pharmaceutically acceptable salts include salts prepared from inorganic acids and also include salts prepared from organic acids. If the compound is acidic, pharmaceutically acceptable salts include salts prepared from inorganic bases and / or organic bases.

[0183] The terms "pharmaceutically acceptable excipient", "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, disintegrant approved by the relevant governmental regulatory authorities as acceptable for human or veterinary use.

[0184] The pharmaceutical composition of the present application can be prepared into tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, and gels.

[0185] As used herein, the term "treatment" refers to any administration of a therapeutic agent according to a therapeutic regimen that achieves the desired effect, i.e., partially or completely alleviates, improves, alleviates, inhibits, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more symptoms or characteristics of a particular disease, disorder, and / or condition; in some embodiments, the administration of a therapeutic agent according to a therapeutic regimen is associated with the achievement of the desired effect. Such treatment may be directed to subjects who do not exhibit the relevant disease, disorder, and / or condition and / or to subjects who only exhibit early signs of the disease, disorder, and / or condition. Alternatively or in addition, such treatment may be directed to subjects who exhibit one or more determined signs of the relevant disease, disorder, and / or condition. In some embodiments, treatment may be directed to subjects who have been diagnosed with the relevant disease, disorder, and / or condition. In some embodiments, treatment may be directed to subjects who are known to have one or more susceptibility factors that are statistically associated with an increased risk of developing the relevant disease, disorder, and / or condition.

[0186] The compounds of the present application can be synthesized using a variety of methods familiar to those skilled in the art of organic synthesis. The following specific examples provide exemplary methods for synthesizing specific compounds. Obviously, by referring to the exemplary schemes in this application, those skilled in the art can readily design synthetic routes for other related compounds by appropriately adjusting the reactants, reaction conditions, and protecting groups.

[0187] The present application is further illustrated below with reference to examples; however, these examples do not limit the scope of this application. Unless otherwise stated, all reactants used in the examples were obtained from commercial sources; and the instruments and equipment used in the synthesis experiments and product analysis and testing were conventional instruments and equipment commonly used in organic synthesis.

[0188] Preparation of intermediate 30092-6

[0189] Step 1: General method for the preparation of compound 30092-3

[0190] 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) was stirred and added triethylamine (3.34 g, 33 mmol) at room temperature under nitrogen. 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). The organic phase was concentrated under reduced pressure and directly purified on a flash silica gel column (MeOH / DCM = 0-5%) to afford compound 30092-3 (2.6 g, 60% yield) as a brown solid.

[0191] Step 2: General method for preparing compound 30092-4

[0192] To a 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 (30 mL) was added TfO (3.13 g, 11 mmol) with stirring at room temperature under nitrogen. 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). The organic phase was concentrated under reduced pressure and directly purified on a flash silica gel column (MeOH / DCM = 0-10%) to afford compound 30092-4 (2.6 g, 64% yield) as a yellow oil.

[0193] Step 3: General method for preparing compound 30092-5

[0194] At room temperature under nitrogen atmosphere, 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 and extracted with EA (30 mL x 2). The organic phase was concentrated under reduced pressure and directly purified on a flash silica gel column (MeOH / DCM = 0-10%) to give compound 30092-5 (1.2 g, 69.2% yield) as a yellow oil.

[0195] Step 4: General method for preparing compound 30092-6

[0196] To a solution of compound 30092-5 (1.2 g, 5 mmol) in THF (50 mL) was added dropwise with stirring LiAlH (0.93 g, 2.5 mmol) at room temperature under nitrogen. The reaction mixture was stirred at 50°C for 2 hours. HO was added to quench the mixture, filtered, and the filtrate was concentrated under reduced pressure to afford the crude product 30092-6 (0.9 g, 67.4% yield) as a yellow oil.

[0197] Preparation of intermediate 30124-2

[0198] To a solution of compound 30124-1 (320 mg, 1.7 mmol) in THF (10 mL) was added dropwise with stirring LiAlH (323 mg, 8.5 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 25°C for 3 hours. H₂O (10 mL) was added to quench the mixture, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on a reverse phase (C₁₈) silica gel column (ACN / H₂O = 1-10%) to afford compound 30124-2 (300 mg, 1.68 mmol, 99% yield) as a white solid.

[0199] The preparation method of intermediates 30125-INT and 30126-INT is the same as that of 30092-6

[0200] Preparation of intermediate 30144-3

[0201] Step 1: General method for preparing compound 30144-2

[0202] To a solution of compound 30144-1 (1.0 g, 5.6 mmol) in DMF (8 mL) was added NaH (0.34 g, 16.8 mmol) with stirring at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 25°C for half an hour. 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 aqueous NH4Cl (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (20 mL × 3) and dried over anhydrous Na2SO4 to obtain crude compound 30144-2 (1 g, 88% yield), which was used directly in the next step. [M+H] + 195.1.

[0203] Step 2: General method for preparing compound 30144-3

[0204] To a solution of LiAlH4 (7.4 mL, 1 M) at 40°C under nitrogen was added a solution of 30144-2 (0.36 g, 1.86 mmol) in THF (10 mL) dropwise. The reaction mixture was stirred at 40°C for 3 hours. The mixture was quenched by addition of Na2SO4.10H2O, filtered, and the filtrate was concentrated under reduced pressure to afford the 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.

[0205] Preparation of intermediate 30145-3

[0206] Step 1: General method for preparing compound 30145-2

[0207] To a solution of compound 30145-1 (1.0 g, 7.4 mmol) in DMF (10 mL) was added 2 (0.66 g, 7.4 mmol) and NaOH (0.59 g, 14.8 mmol) at room temperature under nitrogen. The reaction mixture was stirred at 25°C for 12 hours. The mixture was quenched with water (30 mL) at zero degrees Celsius and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 30145-2 (0.8 g, 50% yield) as a yellow oil, which was used directly in the next step. [M+H] + 205.2.

[0208] Step 2: General method for preparing compound 30145-3

[0209] To a solution of LiAlH4 (4.9 mL, 1 M) in THF (5 mL) was added a solution of 30145-2 (0.5 g, 2.44 mmol) in THF (5 mL) dropwise at 40°C under nitrogen. The reaction mixture was stirred at 40°C and cooled to room temperature before being quenched by the addition of Na2SO4.10H2O. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford the crude product 30145-3 (0.5 g, 93% yield) as a yellow oil. This was used directly in the next step. [M+H] + 209.2.

[0210] Preparation of intermediate 30146-3, refer to the preparation of intermediate 30145-3

[0211] Preparation of intermediate 30147-2

[0212] Step 1: General method for preparing compound 30147-2

[0213] To a solution of LiAlH4 (6.2 mL, 1 M) at 40°C under nitrogen was added a solution of 30147-1 (0.5 g, 3.10 mmol) in THF (10 mL) dropwise. The reaction mixture was stirred at 40°C for 2 hours. The mixture was quenched by addition of Na2SO4.10H2O, filtered, and the filtrate was concentrated under reduced pressure to afford the crude product. 30147-2 (0.15 g, 28.8% yield) was isolated using a reverse phase column (0-30% ACN / H2O (0.1% NH3.H2O)) as a white solid. [M+H] + 152.1.

[0214] Preparation of intermediate 30148-3, refer to the preparation of intermediate 30145-3

[0215] Preparation of intermediate 30149-4

[0216] Step 1: General method for preparing compound 30149-2

[0217] To a solution of compound 30149-1 (1.5 g, 6.8 mmol) in DMF (15 mL) was added DIEA (2.64 g, 20.4 mmol) and 2 (2.92 g, 8.16 mmol) with stirring at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched with 30 mL of water and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL x 3) and concentrated under reduced pressure. The organic phase was directly purified on a flash silica gel column (THF / PE = 0-1%) to afford compound 30149-2 (2 g, 84% yield) as a yellow oil.

[0218] Step 2: General method for preparing compound 30149-3

[0219] To a solution of 30149-2 (0.5 g, 1.4 mmol) in DMF (2 mL) was added 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) at room temperature under nitrogen. The reaction mixture was stirred at 120°C for 12 hours. The mixture was quenched with 10 mL of water and extracted with ethyl acetate (15 mL x 3). The organic phase was washed with saturated brine (15 mL x 3) and concentrated under reduced pressure. The crude product was directly purified on a flash silica gel column (THF / PE = 0-5%) to afford compound 30149-3 (150 mg, 44% yield) as a white solid. [M+H] + 230.1.

[0220] Step 3: General method for preparing compound 30149-4

[0221] Under nitrogen atmosphere, 30149-3 (100 mg, 0.4345 mmol) was dissolved in BH3 (2M in THF, 5 mL). The reaction mixture was stirred at 60°C for 12 hours. The mixture was concentrated under reduced pressure to give the crude product 30144-3 (90 mg, 95% yield) as a yellow oil. This was used directly in the next step. [M+H] + 206.1.

[0222] Preparation of intermediate INT-I and intermediate INT-II

[0223] Reference J. Med. Chem 2021, 64, 7507-7532, prepared according to the following scheme.

[0224] Example 1: Preparation of Compound 30066

[0225] Step 1: General method for preparing compound 30066-2

[0226] Compound 30066-1 (10 g, 0.041 mol), n A 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 stirred and heated 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 using a flash silica gel column (PE / EA = 9 / 1) to obtain compound 30066-2 (10 g, 86.17%) as a yellow oil.

[0227] Step 2: General method for preparing compound 30066-3

[0228] A solution of compound 30066-2 (10 g, 0.035 mol) and N,N-dimethylformamide dimethyl acetal (DMF-DMA, 21.03 g, 0.177 mol) in DMF (100 mL) was stirred and heated at 130° C. for 12 hours. The solution was directly evaporated to obtain a brown solid, compound 30066-3 (10 g crude product).

[0229] Step 3: General method for preparing compound 30066-5

[0230] A solution of compound 30066-3 (1 g, 0.003 mol) and compound 30066-4 (0.99 g, 0.006 mol) in toluene (20 mL) was stirred and heated at 60° C. for 6 hours. The solution was evaporated under reduced pressure and directly purified by flash silica gel column (PE / EA=9 / 1) to give compound 30066-5 (1 g, 63.49%) as a yellow oil.

[0231] Step 4: General method for preparing compound 30066-6

[0232] A solution of compound 30066-5 (250 mg, 0.739 mmol) in EtOH (5 mL) was stirred and heated at 90° C. for 5 hours. The solvent was removed under reduced pressure and directly purified by flash silica gel column (DCM / MeOH=10 / 1) to give compound 30066-6 (200 mg, 64.99%) as a yellow oil.

[0233] Step 5: General method for preparing compound 30066-7

[0234] 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 afford compound 30066-7 (160 mg, crude) as a yellow oil.

[0235] Step 6: General method for preparing compound 30066-8

[0236] 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×3). The organic layer was washed with brine (20 mL×5), dried over Na2SO4, and concentrated to give 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 at 110°C in a sealed tube for 3 hours. The reaction was quenched with H2O (200 mL) and extracted with EA (100 mL×3). The crude product was evaporated and directly purified on a flash silica gel column (DCM / MeOH=10 / 1) to give crude 30066-8 (200 mg, 53.85%) as a yellow solid. The crude product was further purified by preparative 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 minutes) to give compound 30066-8 (10 mg, 0.027 mmol) as a white solid.

[0237] LCMS: [M+H] + =354.2; Rt=0.956min.

[0238] 1 H NMR: (400 MHz, d6-DMSO)

[0239] δ9.457-9.431(t,J=10.4Hz,1H), δ7.691(s,1H),7.265-7.217(m,4H),6.696(s,2H),6.102-6.084(d,J=7.2Hz,1H),5.145(s,1 H), 5.032 (s, 2H), 4.458-4.449 (d, J = 3.6Hz, 2H), 3.440-3.391 (m, 2H), 2.497 (m, 2H), 1.376-1.302 (m, 2H), 0.929-0.892 (m, 3H).

[0240] Step 7: General method for preparing compound 30066-9

[0241] 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 give a yellow solid, compound 30066-9 (180 mg, 85.53%).

[0242] Step 8: General method for the preparation of compound 30066

[0243] 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) was added DIEA (36 mg, 0.282 mmol), and the mixture was stirred at 60° C. for 6 hours. The solution was filtered and directly purified by preparative HPLC (column: Phenomenex luna C18, 250 mm×100 mm×10 μm; mobile phase: [A: H 2 O (0.1% formic acid), B: acetonitrile]; B%: 40%-80%, 40 minutes) to give compound 30066 (10 mg, 22.95%) as a white solid.

[0244] LCMS: [M+H] + =450.50; Rt=1.557min.

[0245] 1H NMR: (400MHz, d6-DMSO) δ9.403-9.376 (t, J=10.8Hz, 1H), 8.235 (s, 1H), 7.260-7.193 (m, 4H), 6.61 6(s,2H),6.084-6.066(d,J=7.2Hz,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=14.4Hz,3H).

[0246] The following compounds were prepared by the preparation method of reference compound 30066:

[0247] Example 2: Preparation of Compound 30018

[0248] Step 1: General method for preparing compound 30018-2

[0249] To a solution of compound 30066-3 (200 mg, 0.591 mmol) in THF (5 mL) was added dropwise HCl (1.6 mL, 1 M) at room temperature under nitrogen. 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 in vacuo to afford compound 30018-2 (200 mg, crude) as a yellow oil.

[0250] Step 2: General method for preparing compound 30018-4

[0251] A solution 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) was stirred at room temperature for 2 hours. The mixture was extracted with EA (10 mL × 3), washed with water (10 mL × 3), dried over Na2SO4, and evaporated in vacuo to obtain crude compound 30018-4. A solution of crude 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 compound 30018-4 (270 mg, 85% purity, 22.39% yield) as a yellow oil.

[0252] Step 3: General method for preparing compound 30018-5

[0253] A mixture of compound 30018-4 (350 mg, 0.84 mmol) and DIBAL-H (240 mg, 1.69 mmol) in THF (5 mL) was stirred at room temperature for 2 hours. The mixture was diluted with water (10 mL), extracted with EA (10 mL×3), washed with saturated brine (50 mL), dried over NaSO, and evaporated in vacuo. The crude product was purified by flash column chromatography (PE / EA=1 / 1) to give compound 30018-5 (175 g, 85% purity, 45.59% yield) as a yellow oil.

[0254] The other steps refer to the synthesis method of compound 30066 to prepare compound 30018,

[0255] [M+H] + =409.2; Rt=0.756min. 1 H NMR: (400MHz, d6-DMSO) δ9.034 (t, J=5.6Hz, 1H), 8.193 (s, 0.1H), 7.215 (ddd, J= 24.4,15.6,7.6Hz,4H),6.627(s,2H),4.575(s,2H),3.556(s,2H),3.421–3.195( m,4H),2.643(t,J=6.8Hz,2H),2.414(s,4H),1.678(dt,J=6.4,3.2Hz,4H),1.51 2(dt,J=14.8,7.2Hz,2H), 1.343(dq,J=14.4,7.2Hz,2H), 0.908(t,J=7.4Hz,3H).

[0256] Example 3: Preparation of Compound 30042

[0257] Step 1: General method for preparing compound 30042-3

[0258] 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 stirred and heated at 85° C. for 5 hours. The reaction was quenched with H O (200 mL) and extracted with ethyl acetate (100 mL×3). The mixture was evaporated in vacuo to give compound 30042-3 (360 mg, crude product) as a brown oil.

[0259] Step 2: General method for preparing compound 30042-4

[0260] 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×2), and evaporated in vacuo to give compound 30042-4 (280 mg, crude product) as a brown oil.

[0261] Step 3: General method for the preparation of compound 30042

[0262] 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 saturated Na₂SO₃ solution (2 mL) was added. The resulting mixture was stirred vigorously for 1 hour, after which the organic phase was separated, evaporated, and purified by preparative 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% to 50% over 40 minutes) to afford 30042 as a white solid (12.35 mg, 6% yield).

[0263] LCMS: [M+H] + =411.1; Rt=0.886min.

[0264] 1H NMR: (400MHz, CDCl3)δ9.797(br s,1H),7.293(d,J=7.6Hz,1H),7.212(d,J=8.4Hz,2H),6.899(d,J=8.4Hz,2H),6.314(d,J=7.6Hz ,1H),5.026(s,2H),4.189(t,J=5.2Hz,2H),3.516(dd,J=12.8,7.2Hz,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=7.2Hz,3H).

[0265] The following compounds were prepared by referring to the synthesis method of compound 30042: Compound 30019 was obtained by reducing compound 30027 (Pd(OH)2 / C, H2, Dioanxe, EtOH, rt, 15 hr).

[0266] The following compounds were prepared by the synthetic method of reference compound 30042

[0267] Example 4: Preparation of Compound 30043

[0268] Step 1: General method for preparing compound 30043-1

[0269] 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 by flash silica gel column (DCM / MeOH=95 / 5) to give compound 30043-1 (80 mg, 91% yield) as a yellow oil.

[0270] Step 2: General method for the preparation of compound 30043

[0271] To a solution of compound 30043-1 (50 mg, 0.14 mmol), tetrahydropyrrole (12 mg, 0.16 mmol), and AcOH (12 mg, 0.21 mmol) in isopropanol (2 mL) was added sodium triacetylborohydride (43 mg, 0.21 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The solution was filtered and directly purified by preparative HPLC (column: Phenomenex luna C18, 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% formic acid), B: acetonitrile]; B%: 10%-50% over 40 minutes) to afford compound 30043 (7.16 mg, 15% yield) as a white solid.

[0272] LCMS: [M+H] + =421.1; Rt=0.878min.

[0273] 1 H NMR: (400MHz, CD3OD) δ7.562(d,J=7.6Hz,1H),7.289–7.221(m,4H),6.171(d,J=7.6Hz,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=7.2Hz,3H).

[0274] The following compounds were synthesized by referring to the synthetic method of compound 30043.

[0275] Example 5: Preparation of Compounds 30058, 30089 and 30090

[0276] Step 1: General method for preparing compound 30058-3

[0277] To a solution of compound 30058-1 (500 mg, 2.027 mmol) in THF (15 mL) was added dropwise N,N-diisopropylethylamine (DIEA, 786 mg, 6.080 mmol) and compound 30058-2 (212 mg, 2.432 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was heated and stirred at 70°C for 4 hours. The solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (MeOH / DCM = 2%) to obtain compound 30058-3 (440 mg, 1.479 mmol, 72.96% yield) as a yellow solid.

[0278] Step 2: General method for preparing compound 30058-4

[0279] To a solution of compound 30058-3 (240 mg, 0.807 mmol) in DMF (5 mL) was added dropwise N,N-dimethylformamide dimethyl acetal (DMF-DMA, 384.65 mg, 3.228 mmol) at room temperature under a nitrogen atmosphere. 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, filtered, and concentrated. 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.

[0280] Step 3: General method for preparing compound 30058-6

[0281] To a solution of compound 30058-4 (218 mg, 0.618 mmol) in EtOH (5 mL) was added compound 30058-5 (177 mg, 1.288 mmol) at room temperature under nitrogen. The reaction mixture was stirred and heated at 90°C for 5 hours. The solvent was removed under reduced pressure to obtain a 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.

[0282] Step 4: General method for preparing compound 30058-7

[0283] 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 × 3). The organic layer was collected, washed with water (20 mL × 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.

[0284] Step 5: General method for preparing compound 58-8

[0285] A solution of compound 30058-7 (150 mg, 0.362 mmol) in 1,4-dioxane / NH₃·H₂O = 1:2 (5 mL) 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 afford compound 30058-8 (100 mg, 0.272 mmol, 75.14% yield) as a yellow solid.

[0286] Step 6: General method for preparing compound 30058-9

[0287] To a solution of compound 30058-8 (100 mg, 0.272 mmol) in DCM (5 mL) was added dropwise SOCl2 (49 mg, 0.408 mmol) at room temperature under nitrogen. 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 afford compound 30058-9 (70 mg, 0.181 mmol, 66.54% yield) as a yellow solid.

[0288] Step 7: General method for the preparation of compound 30058

[0289] A mixture of compound 30058-9 (70 mg, 0.181 mmol), MeNH (41 mg, 0.907 mmol), and KCO (75 mg, 0.544 mmol) in THF (5 mL) was stirred at room temperature under a nitrogen atmosphere for 3 hours. The solvent was removed under reduced pressure. The crude product was then purified by preparative HPLC (column: Phenomenex luna C18 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% trifluoroacetic acid), B: acetonitrile]; B%: 40%-80% over 40 minutes) to afford compound 30058 (25 mg, 0.062 mmol, 34.23% yield) as a white solid.

[0290] LCMS: [M+H] + =395.45; Rt=1.655min.

[0291] 1 H NMR: (400MHz, MeOD) δ8.420 (s, 1H), 7.748–7.729 (d, J = 7.6Hz, 1H), 7.480-7.420 (d d,J=8.4,15.6Hz,4H),6.278-6.259(d,J=7.6Hz,1H),5.221-5.124(dd,J=15.2,23 .6Hz,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=6.4Hz,3H),0.962-0.926(t,J=7.2Hz,3H).

[0292] Step 8: General method for preparing compounds 30089 and 30090

[0293] Compound 30058 was separated using supercritical fluid chromatography (SFC) to obtain compounds 30089 and 30090.

[0294] Column: DAICEL IG 4.6mm I.D.*250mm L 5μm

[0295] Mobile phase: CO2 / MeOH [0.1% NH3 (7M Solution in MeOH)]

[0296] Column temperature: 4°C

[0297] Flow rate: 2.5 mL / min

[0298] Equipment: SHIMADZU LC-30AD SFC

[0299] SFC: Compound 30089, Rt=5.929 min.

[0300] LCMS: [M+H] + =395.55; Rt=1.659min.

[0301] 1H NMR: (400MHz, MeOD) δ8.420(s,1H),7.708(s,1H),7.455-7.416(t,J=15.6Hz,4H),6.267-6.248(d,J=7.6Hz,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),1.42 5-1.392(m,2H),1.239-1.223(m,3H),0.962-0.926(t,J=14.4Hz,3H).

[0302] SFC: Compound 30090, Rt=6.597 min.

[0303] LCMS: [M+H] + =395.90; Rt=1.668min.

[0304] 1 H NMR: (400MHz, MeOD) δ8.452(s,1H),7.7689(s,1H),7.450-7.409(t,J=16.4Hz,4H),6.257-6.238(d,J=7.6Hz,1H),5.173-5.113(m,2H),4.34 4-4.311(m,1H),4.165(s,2H),2.739(s,6H),1.586-1.533(m,2H),1.4 25-1.392(m,2H),1.239-1.223(m,3H),0.962-0.926(t,J=14.4Hz,3H).

[0305] Compound 30056 was prepared by referring to the preparation method of compound 30058.

[0306] Example 6: Preparation of Compound 30089

[0307] The synthesis method was the same as that in Example 5, using chiral amine reagent 30089-2. The product was purified by preparative 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: 10% B to 25% B over 30 minutes to obtain compound 30089 (20 mg, 0.05 mmol, 40.12% yield) as a white solid.

[0308] LCMS: [M+H]+ =395.4; Rt=1.655min.

[0309] 1 H NMR: (400MHz, MeOD) δ8.415(s,1H),7.666(s,1H),7.444-7.408(t,J=14.4Hz,4H),6.243-6.224(d,J=7.6Hz,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),1.44 4-1.359(m,2H),1.235-1.219(m,3H),0.962-0.925(t,J=14.8Hz,3H).

[0310] The following compound was prepared by referring to the preparation method of compound 30089 in Example 6

[0311] The following compound was prepared from intermediate 30144-3 by referring to the preparation method of compound 30089 in Example 6:

[0312] The following compound was prepared from intermediate 30147-2 by referring to the preparation method of compound 30089 in Example 6:

[0313] The following compound was prepared from intermediate 30149-4 by referring to the preparation method of compound 30089 in Example 6:

[0314] Example 7: Preparation of Compound 30102

[0315] Step 1: General method for preparing compound 30102-2

[0316] 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 under nitrogen for 8 hours. The mixture was diluted with water (20 mL), extracted with DCM (20 mL x 3), and evaporated in vacuo. The crude product was purified by flash column chromatography (MeOH / DCM = 0-5%) to afford compound 30102-2 (1 g, 49.3% yield) as a yellow oil.

[0317] Step 2: General method for preparing compound 30102-4

[0318] At 0°C under a nitrogen atmosphere, oxalyl chloride (510 mg, 4.02 mmol) was added dropwise to a solution of compound 102-3 (800 mg, 3.35 mmol) in DCM / DMF = 100 / 1 (15 mL), and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to obtain a yellow solid. TEA (966 mg, 9.54 mmol) was added dropwise to a solution of the obtained yellow solid and compound 30102-2 (800 mg, 3.18 mmol) in DCM (20 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (20 mL), extracted with EA (20 mL × 3), and evaporated in vacuo. 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.

[0319] Step 3: General method for preparing compound 30102-5

[0320] A solution of compound 30102-4 (800 mg, 3.18 mmol), NH3 in MeOH (0.7 mL, 5 mmol), and EA (0.39 g, 4 mmol) in DMF (15 mL) was stirred at room temperature under nitrogen for 4 hours. The mixture was diluted with water (20 mL), extracted with EA (20 mL x 3), and evaporated in vacuo to afford the crude product 30102-5 (1 g, 56.3% yield) as a yellow oil.

[0321] Step 4: General method for preparing compound 30102-7

[0322] 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 at room temperature under nitrogen atmosphere. The mixture was evaporated in vacuo to give the crude product 30102-7 (800 mg, 63.6% yield) as a yellow oil.

[0323] Step 5: General method for preparing compound 30102-8

[0324] To a solution of compound 30102-7 (0.8 g, 2 mmol) and 1-butylamine (150 mg, 2 mmol) in DMF (10 mL) was added DIEA (330 mg, 3 mmol) at room temperature under nitrogen. The reaction mixture was stirred at 80°C for 1 hour. Extraction was performed with EA (20 mL x 2) and the mixture was evaporated in vacuo. The crude product was purified by flash column chromatography (EA / PE = 0-25%) to afford compound 30102-8 (0.65 g, 70.6% yield) as a white solid.

[0325] Step 6: General method for preparing compound 30102-9

[0326] 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 and evaporated in vacuo to give the crude product 30102-9 (700 mg, 75.2% yield).

[0327] Step 7: General method for preparing compound 30102-10

[0328] The 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 at 110°C in a sealed tube for 1 hour. Evaporation in vacuo gave the crude product 30102-10 (450 mg, 62% yield) as a white solid.

[0329] Step 7: General method for preparing compound 30102-11

[0330] To a solution of compound 30102-10 (100 mg, 0.21 mmol) in THF (3 mL) was added dropwise 1 M TBAF in THF (0.5 mL, 0.21 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 hour. DCM (10 mL) was added, filtered, and the solvent was removed under reduced pressure to give the crude product 30102-11 (40 mg, 85% yield) as a yellow solid.

[0331] The other steps were carried out by referring to the preparation method of compound 30093 to prepare compound 30102.

[0332] LCMS: [M+H] + =408.4; Rt=1.619min.

[0333] 1 H NMR: (400MHz, CD3OD) δ8.419(s,1H),7.396(s,4H),5.125(s,2H),3.883(s,2H),3.505(t,J=7.2Hz,2H),2.81 1(s,4H),1.891(s,4H),1.611(dd,J=14.8,7.2Hz,2H),1.425(dd,J=15.2,7.2Hz,2H),0.969(t,J=7.2Hz,3H).

[0334] Example 8: Preparation of Compound 30085

[0335] Step 1: General method for the preparation of compound 30085-3

[0336] 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 stirred and heated at 45° C. for 1 hour. The reaction was quenched with H O (50 mL) and extracted with ethyl acetate (50 mL×2). The mixture was evaporated in vacuo to afford compound 30085-3 (4.3 g, 93.04%) as a white solid.

[0337] Step 2: General method for preparing compound 30085-4

[0338] To a solution of compound 30085-3 (4.3 g, 15.09 mmol) in DCM (45 mL) was added TBSCl (2.73 g, 18.11 mmol) and imidazole (2.06 g, 30.18 mmol) at room temperature under nitrogen. 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 in vacuo. The crude product was purified by flash column chromatography (EtOH / PE = 0-20%) to afford compound 30085-4 (4.5 g, 74.74% yield) as a yellow solid.

[0339] Step 3: General method for preparing compound 30085-5

[0340] A solution of compound 30085-4 (4.5 g, 11.28 mmol) and N,N-dimethylformamide dimethyl acetal (DMF·DMA, 6.72 g, 56.39 mmol) in DMF (50 mL) was stirred and heated at 130° C. for 15 hours. The solution was directly evaporated to give compound 30085-5 as a yellow solid (80% yield, 4.5 g crude product).

[0341] Step 4: General method for preparing compound 30085-7

[0342] 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 stirred and heated at 80° C. for 2 hours. The solution was evaporated under reduced pressure and directly purified by flash silica gel column (EA / PE=0-25%) to give compound 30085-7 (4.5 g, 86.18% yield) as a yellow solid.

[0343] Step 5: General method for preparing compound 30085-8

[0344] 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 concentrated by evaporation under reduced pressure to give a 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 concentrated by evaporation under reduced pressure, quenched by addition of H2O (50 mL), and extracted with EA (50 mL×2). The crude product was evaporated and directly purified by flash silica gel column (MeOH / DCM=0-5%) to give 30085-8 (3.0 g, 70.89% yield) as a yellow solid.

[0345] Step 6: General method for preparing compound 30085-9

[0346] To a solution of compound 30085-8 (3.0 g, 6.03 mmol) in THF (20 mL) was added dropwise TBAF (15 mL) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 hour. H O (50 mL) was added to quench the mixture, and the mixture was extracted with EA (50 mL x 2). The solvent was removed under reduced pressure to afford the crude product 30085-9 (2.0 g, 86.59% yield) as a yellow solid.

[0347] Step 7: General method for the preparation of compound 30085-10

[0348] To a solution of compound 30085-9 (1.5 g, 3.91 mmol) in SOCl2 / THF = 1 / 4 (20 mL) was added dropwise TBAC (21.74 g, 78.2 mmol) at room temperature under nitrogen. 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 give the crude product 30085-10 (1.3 g, 82.89% yield) as a yellow solid.

[0349] Step 8: General method for the preparation of compound 30085-11

[0350] To a solution of compound 30085-10 (1.3 g, 3.24 mmol) in DMF (20 mL) was added MeSNa (340 mg, 4.86 mmol) at room temperature under nitrogen. The reaction mixture was stirred at 80°C for 1 hour. H2O (30 mL) was added to quench the mixture, followed by extraction with EA (30 mL x 3). The solvent was removed under reduced pressure to afford the crude product 30085-11 (800 mg, 59.76%) as a yellow solid.

[0351] Step 9: General method for the preparation of compound 30085-12

[0352] To a solution of compound 30085-11 (600 mg, 1.45 mmol) in THF (10 mL) was added BH3·SMe2 (551 mg, 7.25 mmol) at 0°C under nitrogen. The reaction mixture was stirred at 0°C for 2 hours. HO (20 mL) was added to quench the mixture, followed by extraction with EA (30 mL x 2). The solvent was removed under reduced pressure to afford the crude product, which was directly purified on a flash silica gel column (MeOH / DCM = 0-5%) to afford 30085-12 (350 mg, 62.69% yield) as a yellow solid.

[0353] Step 10: General method for the preparation of compound 30085-13

[0354] A solution of compound 30085-12 (100 mg, 0.26 mmol) and SOCl2 (2 mL) in DCM (2 mL) was stirred at room temperature for 1 hour. The solution was concentrated by evaporation under reduced pressure to give the crude product 30085-13 (80 mg, 76.35% yield).

[0355] Step 11: General method for the preparation of compound 30085

[0356] 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. HO (5 mL) was added to quench the mixture, and the mixture was extracted with EA (5 mL×2). The mixture was concentrated by evaporation under reduced pressure and purified by preparative HPLC (column: Phenomenex luna C18, 250 mm×100 mm×10 μm; mobile phase: [A: HO (0.1% trifluoroacetic acid), B: acetonitrile]; B%: 40%-80%, 40 minutes) to give compound M030085 (5.84 mg, 0.013 mmol, 19.04% yield) as a white solid.

[0357] LCMS: [M+H] + =439.40; Rt=1.627min.

[0358] 1H NMR: (400MHz, MeOD) δ7.569(d,J=7.6Hz,1H),7.359(d,J=8.0Hz,2H),7.315(d,J=8.0Hz,2H),6.185(d,J=7.6Hz,1H),5.110(s,2H),3.775(s,2H), 3.611(t,J=6.8Hz,2H),2.698(s,4H),2.569(t,J=7.2Hz,2H),2.090(s,3H),1.969–1.934(m,2H),1.852(s,4H).

[0359] Compound 30087 was prepared by referring to the preparation method of compound 30085.

[0360] [M+H] + =481.40; Rt=1.895min. 1 H NMR: (400MHz, MeOD) δ7.567(d,J=7.6Hz,1H),7.312(d,J=13.6Hz,4H),6.189(d,J=7.6Hz,1H),5.104(s,2H),3.673(s,2H),2.54 3(dd,J=18.0,9.6Hz,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).

[0361] Example 9: Preparation of Compound 30086

[0362] Step 1: General method for the preparation of compound 30086-2

[0363] To a solution of compound 30085-12 (100 mg, 0.26 mmol) in MeOH / THF / H₂O = 1:1:1 (6 mL) was added oxone (191 mg, 0.31 mmol) with stirring at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated by evaporation under reduced pressure and purified by preparative HPLC (column: Phenomenex luna C₁₈, 250 mm × 100 mm × 10 μm; mobile phase: [A: H₂O (0.1% trifluoroacetic acid), B: acetonitrile]; B%: 10%-50% over 40 minutes) to afford compound 30086-2 (50 mg, 43.87% yield) as a white solid.

[0364] Step 2: General method for preparing compound 30086-3

[0365] To a solution of compound 30086-2 (40 mg, 0.10 mmol) in DMF (5 mL) was added Dess-Martin periodinane (203 mg, 0.48 mmol) with stirring under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated by evaporation under reduced pressure and purified by preparative HPLC (column: Phenomenex luna C18, 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% trifluoroacetic acid), B: acetonitrile]; B%: 10%-50% over 40 minutes) to afford compound 30086-3 (30 mg, 67.85% yield) as a white solid.

[0366] Step 3: General method for the preparation of compound 30086

[0367] To a solution of compound 30086-3 (30 mg, 0.072 mmol) in DCM / iPrOH = 1:1 (4 mL) at 0°C under a nitrogen atmosphere, pyrrolidine (16 mg, 0.22 mmol) and NaBH(OAc) (31 mg, 0.14 mmol) were added with stirring. The reaction mixture was stirred at 0°C for 4 hours. The product was concentrated by evaporation under reduced pressure and purified by preparative HPLC (column: Phenomenex luna C18, 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% trifluoroacetic acid), B: acetonitrile]; B%: 10%-30% over 30 minutes) to afford compound M030086 (12 mg, 34.63% yield) as a white solid.

[0368] LCMS: [M+H] + =471.40; Rt=1.342min.

[0369] 1 H NMR: (400MHz, MeOD) δ7.649(d,J=7.2Hz,1H),7.485(d,J=8.0Hz,2H),7.432(d,J=8.0Hz,2H),6.227(d,J=7.6Hz,1H),5.150( s,2H),4.291(s,2H),3.704(t,J=13.6Hz,2H),3.306-3.185(m,6H),2.970(s,3H),2.172-2.116(m,2H),2.066-2.001(m,4H).

[0370] Example 10: Preparation of Compound 30088

[0371] Step 1: General method for the preparation of compound 30088-7-3

[0372] To a solution of compound 30088-7-1 (1000 mg, 5.10 mmol) in ACN (30 mL) was added KCO (1548 mg, 15.30 mmol) and pyrrolidine (726 mg, 10.20 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 24 hours. The product was concentrated by evaporation under reduced pressure and directly purified on a flash silica gel column (MeOH / DCM = 0-8%) to afford 30088-7-3 (800 mg, 4.30 mmol, 84.31% yield) as a white solid.

[0373] Step 2: General method for preparing compound 30088-7

[0374] To a solution of compound 30088-7-3 (800 mg, 4.30 mmol) in THF (20 mL) was added LAH (489 mg, 12.90 mmol) at 0°C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. HO (10 mL) was added to quench the mixture, diluted with EA (100 mL), washed with water and saturated brine, dried over NaSO, and concentrated. The crude product was purified by flash column chromatography (MeOH / DCM = 0-30%) to afford compound 30088-7 (850 mg, 4.47 mmol, 93.60% yield) as a white solid.

[0375] Step 3: General method for preparing compound 30088-3

[0376] A solution of compound 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) was stirred and heated 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.

[0377] Step 4: General method for preparing compound 30088-4

[0378] To a solution of compound 30088-3 (500 mg, 1.53 mmol) in DCM (15 mL) was added dropwise with stirring at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to afford the crude product 30088-4 (500 mg, 1.45 mmol, 94.77% yield) as a yellow oil.

[0379] Step 5: General method for preparing compound 30088-5

[0380] To a solution of compound 30088-4 (500 mg, 1.45 mmol) in DMF (15 mL) was added DIEA (561 mg, 4.34 mmol) and MeSNa (203 mg, 2.89 mmol) at room temperature under nitrogen. The reaction mixture was stirred at 80°C for 2 hours. The solvent was removed under reduced pressure to afford the crude product. The crude product was directly purified using a flash silica gel column (EA / PE = 0-15%) to afford compound 30088-5 (250 mg, 0.70 mmol, 49.30% yield) as a yellow oil.

[0381] Step 6: General method for preparing compound 30088-6

[0382] A solution of compound 30088-5 (50 mg, 0.14 mmol) and N,N-dimethylformamide dimethyl acetal (DMF-DMA, 50 mg, 0.42 mmol) in DMF (3 mL) was stirred and heated at 130° C. for 16 hours. The solution was directly evaporated, and the crude product was directly purified by flash silica gel column (EA / PE=0-20%) to give compound 30088-6 (50 mg, 0.12 mmol, 85.71% yield) as a yellow oil.

[0383] Step 7: General method for the preparation of compound 30088-8

[0384] 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 stirred and heated 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 give compound 30088-8 (30 mg, 0.06 mmol, 48.29% yield) as a yellow solid.

[0385] Step 8: General method for preparing compound 30088-9

[0386] To a solution of compound 30088-8 (30 mg, 0.06 mmol) in DMF (3 mL) was added m-CPBA (81 mg, 0.48 mmol) with stirring at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated by evaporation under reduced pressure and purified by preparative HPLC (column: Phenomenex luna C18, 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% trifluoroacetic acid), B: acetonitrile]; B%: 10%-40% over 30 minutes) to afford compound 30088-9 (15 mg, 0.024 mmol, 41.13% yield) as a white solid.

[0387] Step 9: General method for the preparation of compound 30088-10

[0388] A solution of compound 30088-9 (15 mg, 0.024 mmol) in 1,4-dioxane / NH3·H2O = 1:2 (3 mL) was stirred and heated under reflux at 100°C for 2 hours. The mixture was concentrated by evaporation under reduced pressure and purified by preparative 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 afford compound 30088-10 (10 mg, 0.018 mmol, 71.15% yield) as a white solid.

[0389] Step 10: General method for preparing compound M030088

[0390] To a solution of compound 30088-10 (10 mg, 0.018 mmol) and pinacol diboronate (B2Pin2, 6 mg, 0.023 mmol) in ACN (3 mL) was added 30088-11 (23 mg, 0.36 mmol) with stirring at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by preparative HPLC (column: Phenomenex luna C18, 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% FA), B: acetonitrile]; B%: 5%-30% over 30 minutes) to afford compound M030088 (3.5 mg, 0.007 mmol, 34.92% yield) as a white solid.

[0391] LCMS: [M+H] + =513.50; Rt=1.574min.

[0392] 1H NMR: (400MHz, MeOD) δ7.634-7.615(d,J=7.6Hz,1H),7.475-7.403(m,4H),6.222(d,J=7.6Hz,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=14.8Hz,3H).

[0393] Example 11: Preparation of Compound 30081

[0394] Step 1: General method for intermediate 30081-2

[0395] A solution of compound 30081-1 (3 g, 18.6 mmol) in EtOH (20 mL) was added with concentrated sulfuric acid (180 mg, 1.8 mmol), followed by stirring and heating under reflux at 80° C. for 2 hours. The mixture was concentrated by evaporation under reduced pressure to afford compound 30081-2 (3.2 g, 16.9 mmol, 91% yield, 90% purity) as a yellow solid. 1 HNMR: (400MHz, CDCl3) δ7.632 (d, J = 8.4Hz, 2H), 7.414 (d, J = 8.4Hz, 2H), 4.171 (q, J = 7.2Hz, 2H), 3.685 (s, 2H), 1.262 (t, J = 7.2Hz, 3H).

[0396] Step 2: General procedure for intermediate 30081-3

[0397] To a solution of compound 30081-2 (3.2 g, 16.9 mmol) in toluene (30 mL) were added paraformaldehyde (3.04 g, 33.8 mmol), KCO (4.67 g, 33.8 mmol), and TBAI (2.50 g, 6.7 mmol), followed by stirring and heating under reflux at 80° C. for 6 hours. The mixture was concentrated by evaporation under reduced pressure, and the crude product was purified by flash column chromatography (EtAc / PE=0-30%) to give compound 30081-3 (0.8 g, 4.0 mmol, 24% yield, 90% purity) as a white solid. 1H NMR: (400MHz, CDCl3) δ7.656 (d, J = 8.4Hz, 2H), 7.543 (d, J = 8.4Hz, 2H), 6.502 (s, 1H), 5.984 (s, 1H), 4.301 (q, J = 7.2Hz, 2H), 1.344 (t, J = 7.2Hz, 3H).

[0398] Step 3: General procedure for intermediate 30081-4

[0399] A mixture of compound 30081-3 (600 mg, 2.98 mmol) in MeOH (10 mL) and Pd / C (318 mg, 2.98 mmol) was stirred at 25°C under a hydrogen atmosphere for 4 hours. After filtration, the mixture was concentrated by evaporation under reduced pressure. The crude product was purified by flash chromatography on a reverse-phase C18 silica gel column (10-40% acetonitrile in water, 0.1% HCl) to afford 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.

[0400] Compound 30081 was prepared using 30081-4 as the starting material according to the preparation method of compound 30043.

[0401] [M+H] + ,435.45;Rt=1.790min.

[0402] 1 H NMR(400MHz,CD3OD)δ8.534(s,1H),7.582(d,J=7.6Hz,1H),7.366–7.242(m,4H ),6.183(d,J=7.6Hz,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=14.8,7.2Hz,2H), 1.456(dd,J=15.2,7.2Hz,2H), 1.285(d,J=6.4Hz,4H), 0.987(t,J=7.2Hz,3H).

[0403] Example 12: Preparation of Compounds 30129, 30130, 30138, and 30139

[0404] Referring to the preparation method of compound 30081, the intermediate was prepared according to the following scheme

[0405] Compounds 30129, 30130, 30138, and 30139 were prepared by referring to the preparation method of compound 30042.

[0406] [M+H] + =449.25; Rt=0.874min.

[0407] 1 H NMR: (400MHz, CD3OD) δ8.054(d,J=7.6Hz,1H),7.395(q,J=8.0Hz,4H),6.398(d,J=7.6Hz,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=13.2,6.0Hz,2H),3.219(dd,J=16.4,6.8 Hz,2H),3.168–3.120(m,1H),3.023(d,J=8.0Hz,1H),2.222–2.034(m,2H),1.941(ddd,J=15.2,9.6,6.8Hz,2H),1 .676–1.566(m,2H),1.467–1.389(m,2H),1.321(d,J=6.8Hz,3H),1.283(d,J=6.8Hz,3H),0.965(t,J=7.2Hz,3H).

[0408] [M+H] + =449.2; Rt=0.906 min.

[0409] 1H NMR:(400MHz,MeOD)δ8.057-8.038(d,J=7.6Hz,1H),7.418-7.353(m,4H),6.424-6.406(d,J=7.2Hz,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=7.2Hz,3H),1.283-1.267(d,J=6.4Hz,3H),0.975-0.939(t,J=14.4Hz,3H).

[0410] [M+H] + =425.65;Rt=1.320 min.

[0411] 1 H NMR:(400MHz,CD3OD)δ7.567(d,J=7.2Hz,1H),7.310-7.263(m,4H),6.183(d,J=7.6Hz,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=6.4Hz,3H),0.965(t,J=14.4Hz,3H).

[0412] [M+H] + =451.55;Rt=1.353min.

[0413] 1H NMR: (400MHz, CD3OD) δ7.567-7.549(d,J=7.2Hz,1H),7.313-7.262(m,4H),6.182-6.163(d,J=7.6Hz,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=6.4Hz,3H),0.965-0.929(t,J=14.4Hz,3H).

[0414] Example 13: Preparation of Compound 30012

[0415] Step 1: General method for preparing compound 30012-2

[0416] Under 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×3), and evaporated in vacuo. The crude product was purified by flash column chromatography (PE / EA=2 / 1) to give compound 30012-2 (3 g, 54.85% yield) as a white oil.

[0417] Step 2: General method for preparing compound 30012-3

[0418] Under 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 yellow solid was collected by filtration to give the crude product compound 30012-3 (1.2 g, 37.35% yield).

[0419] Step 3: General method for preparing compound 30012-4

[0420] To a solution of compound 30012-3 (1.2 g, 0.006 mol) in DMF (10 mL) was added DBU (2.88 g, 0.019 mol), benzotriazole-1-oxytris(dimethylamino)phosphine hexafluorophosphate (BOP, 3.34 g, 0.008 mol), and n-butylamine (1.38 g, 0.019 mol) at room temperature under nitrogen. 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), and evaporated in vacuo. The crude product was purified by flash column chromatography (MeOH / DCM = 1 / 20) to afford compound 30012-4 (1 g, 63.49% yield) as a yellow oil.

[0421] Step 4: General method for preparing compound 30012-5

[0422] 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 pyridine (10 mL) was stirred at 120° C. for 8 hours. The mixture was evaporated in vacuo, and the crude product was purified by a C18 reverse phase silica gel column (ACN-H2O=35%) to give compound 30012-5 (0.8 g, 82.93% yield) as a yellow solid.

[0423] Step 5: General method for preparing compound 30012-7

[0424] Under 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×3), and evaporated in vacuo to give the crude product, compound 30012-7 (120 mg), as a yellow oil.

[0425] Step 6: General method for the preparation of compound 30012

[0426] 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 solvent was removed by filtration under reduced pressure. The crude product was then 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 M030012 (20 mg, 20.06% yield) as a white solid.

[0427] LCMS: [M+H] + =406.3; Rt=0.814min.

[0428] 1 H NMR: (400MHz, d6-DMSO) δ8.225 (s, 1H), 7.815 (s, 1H), 7.505-7.485 (dd, J = 8.0Hz, 2H) ,7.425-7.375(m,3H),6.815(d,J=8.0Hz,1H),6.725(d,J=10.0Hz,1H),6.351(s,1H), 5.215(s,2H),3.615(s,2H),3.355-3.305(dd,J=8.4Hz,2H),2.445(s,4H),1.705(d, J=8.0Hz,4H),1.123(t,J=7.6Hz,2H),1.085(t,J=6.4Hz,2H),0.758(t,J=6.4Hz,3H).

[0429] Compounds 30013, 30044, 30047 and 30048 were prepared by referring to the preparation method of compound 30012.

[0430] Example 14: Preparation of Compound 30014

[0431] Step 1: General method for preparing compound 30014-2

[0432] A reaction mixture of compound 30014-1 (200 mg, 1.379 mmol), PPh (387 mg, 1.517 mmol), and CBr (490 mg, 1.517 mmol) in THF (50 mL) was stirred at room temperature under a nitrogen atmosphere for 12 hours. The mixture was diluted with H2O / Et2O = 1 / 3 (20 mL) and 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 give the crude product, compound 30014-2 (200 mg), as a white oil.

[0433] Step 1: General method for the preparation of compound 30014

[0434] Under a nitrogen atmosphere, a mixture of compound 30014-2 (99 mg, 0.474 mmol), compound 30012-5 (100 mg, 0.431 mmol), and CsCO (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. The crude product was then purified by preparative HPLC (column: Phenomenex luna C18 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% FA), B: acetonitrile]; B%: 5%-30%, 20 minutes) to afford compound M030014 (20 mg, 12.01% yield) as a white solid.

[0435] LCMS: [M+H] + =360.3.

[0436] 1 H NMR: (400MHz, d6-DMSO) δ8.305 (s, 1H), 7.995-7.981 (d, J = 8.0Hz, 1H), 7.415-7.395 (dd, J = 8.0Hz, 1H), 6.835-6 .815(dd,J=8.0Hz,1H),6.735(s,1H),6.665-6.645(dd,J=8.0Hz,1H),4.225-4.195(dd,J=8.0Hz,2H),3.596(s, 4H),3.475(s,2H),2.505-2.385(m,6H),1.995(d,J=8.4Hz,2H),1.585(d,J=8.4Hz,2H),1.415(d,J=8.4Hz,2H)0.965-0.925(t,J=7.6Hz,3H).

[0437] Example 15: Preparation of Compound 30016

[0438] Step 1: General method for preparing compound 30016-3

[0439] To a solution of compound 30016-1 (2 g, 0.016 mol) in DCM (15 mL) at 0°C under nitrogen was added compound 30016-2 (1.28 g, 0.018 mol) dropwise, followed by the addition of NaBH(OAc) (5.21 g, 0.025 mol). 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 NaSO, and concentrated. The crude product 30016-3 (1 g, 0.005 mmol, 31.10% yield) was obtained as a white solid.

[0440] Step 2: General method for preparing compound 30016-5

[0441] Under nitrogen atmosphere, a solution of compound 30016-4 (1 g, 0.006 mol), K CO (2.65 g, 0.019 mol) and 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) and extracted with EA (50 mL×3). The organic layer was collected, washed with saturated brine (50 mL×5), dried over Na SO and concentrated. The crude product was purified by flash column chromatography (PE / EA=2 / 1) to give compound 30016-5 (1 g, 82.81% yield) as a yellow oil.

[0442] Step 3: General method for preparing compound 30016-7

[0443] Under 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 white solid was collected by filtration to give the crude product compound 30016-7 (0.5 g, 43.75% yield).

[0444] Step 4: General method for preparing compound 30016-8

[0445] Refer to step 3 of the preparation of compound 30012.

[0446] Step 5: General method for the preparation of compound 16

[0447] Under nitrogen atmosphere, a mixture of compound 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 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 give compound M030016 (1.05 mg, 0.003 mmol, 1.3% yield) as a white solid.

[0448] LCMS: [M+H] + =392.1; Rt = 0.852 min.

[0449] 1 H NMR:,(400MHz,MeOD)δ7.440(d,J=8.0Hz,1H),7.380(d,J=8.0Hz,1H),7.25 0(d,J=7.6Hz,1H),7.152(s,1H),7.070(dd,J=8.0,2.0Hz,1H),7.020(d,J=8 .4Hz,1H),6.414(d,J=8.0Hz,1H),3.675(s,2H),3.567(s,2H),2.574(s,4H ),1.813(t,J=3.2Hz,4H),1.600(s,2H),1.368(s,2H),0.915–0.889(m,3H).

[0450] Example 16: Preparation of Compound 30046

[0451] Step 1: General method for preparing compound 30046-2

[0452] To a solution of compound 30046-1 (500 mg, 2.183 mmol) in THF (20 mL) was added dropwise BH3·SMe2 (497 mg, 6.548 mmol) at 0°C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (10 mL), filtered, and concentrated to afford the crude product 30046-2 (350 mg) as a white solid.

[0453] Step 2: General method for preparing compound 30046-4

[0454] Under a nitrogen atmosphere, a solution of compound 30046-2 (350 mg, 1.627 mmol), Cs CO (1591 mg, 4.882 mmol) and compound 30012-5 (378 mg, 1.627 mmol) in DMF (10 mL) was stirred at room temperature for 4 hours. The mixture was diluted with water (2 mL) and extracted with DCM (100 mL). The organic layer was collected, washed with water and saturated brine, dried over Na SO and concentrated. The crude product was purified by flash column chromatography (MeOH / DCM = 10%) to give compound 30046-4 (280 mg, 0.76 mmol, 46.96% yield) as a yellow solid.

[0455] Step 3: General method for preparing compound 30046-5

[0456] To a solution of compound 30046-4 (50 mg, 0.14 mmol) in DCM (1 mL) was added Dess-Martin periodinane (116 mg, 0.27 mmol) with stirring at room temperature under nitrogen. 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 afford compound 30046-5 (30 mg, 50% yield) as a brown solid.

[0457] Step 4: General method for the preparation of compound 30046

[0458] To a solution of compound 30046-5 (30 mg, 0.08 mmol), dimethylamine (0.05 mL, 0.10 mmol, 2 M in THF), and AcOH (7 mg, 0.12 mmol) in iPrOH (1 mL) was stirred at 0°C under a nitrogen atmosphere. NaBH(OAc) (26 mg, 0.12 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and 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% over 40 minutes) to afford compound M030046 (1.60 mg, 4% yield) as a white solid.

[0459] LCMS: [M+H] + =394.4; Rt=1.761min.

[0460] 1H NMR: (400MHz, CD3OD) δ7.646(t,J=8.4Hz,1H),7.508(d,J=8.0Hz,2H),7.370(d,J=8.0Hz,2H),7.067(d,J=8.4Hz,1H),6.963(d,J=8.4Hz,1H) ,5.308(s,2H),3.512(t,J=6.8Hz,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=7.2Hz,3H).

[0461] Compound 50 was prepared by the same preparation method as compound 30046.

[0462] LC-MS: [M+H] + =420.2; Rt=0.871min.

[0463] 1 H NMR: (400MHz, d6-DMSO) δ8.330(s,1H),7.763(s,1H),7.443(m,2H),7.359(m,1H),7.315-7.29 5(d,J=8.0Hz,2H),6.813-6.792(d,J=8.4Hz,1H),6.720-6.700(d,J=8.0Hz,1H),6.242(s,2H), 5.186(s,2H),3.340-3.294(m,6H),2.793-2.756(t,J=14.8Hz,2H),2.660-2.622(t,J=15.2Hz ,2H),1.682(s,4H),1.301-1.264(m,2H),1.127-1.071(m,2H),0.783-0.746(t,J=14.8Hz,3H).

[0464] Example 17: Preparation of Compound 30049

[0465] Step 1: General method for preparing compound 30049-2

[0466] 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 TsOH·H2O (80 mg, 0.40 mmol) in THF (25 mL) was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was extracted with EA (20 mL x 2), filtered, and concentrated to afford the crude product 30049-2 (9.0 g) as a brown oil.

[0467] Step 2: General method for preparing compound 30049-4

[0468] To a solution of compound 30049-2 (3000 mg, 14.40 mmol) and sodium hydroxide (1152 mg, 28.80 mmol) in water (12 mL) was added compound 30049-3 (2076 mg, 14.40 mmol) with stirring at 80° C. under a nitrogen atmosphere. The reaction mixture was stirred at 80° C. for 10 minutes. The mixture was extracted with EA (10 mL×2), filtered, and concentrated. The crude product was purified by flash column chromatography (MeOH / DCM=3-5%) to give compound 30049-4 (800 mg, 18% yield) as a colorless oil.

[0469] Step 3: General method for preparing compound 30049-5

[0470] The reaction mixture of compound 30049-4 (115 mg, 0.41 mmol) and TsOH·H 2 O (78 mg, 0.41 mmol) in MeOH (3 mL) was stirred at room temperature under nitrogen atmosphere for 3 hours. The mixture was diluted with saturated NaHCO 3 water and extracted with EA (5 mL×2). The organic layer was concentrated to give the crude product 30049-5 (80 mg) as a colorless oil.

[0471] Step 4: General method for the preparation of compound 30049

[0472] 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 give a crude product, which was then 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 give compound M030049 (1.66 mg, 2% yield) as a white solid.

[0473] LCMS: [M+H] + =410.2; Rt=0.843min.

[0474] 1 H NMR: (400MHz, CD3OD) δ7.547(t,J=8.4Hz,1H),7.480(d,J=8.4Hz,2H),7.052(d,J=8.8Hz,2H),6.932(dd,J=8.0,4.8Hz,2H),5.182(s,2H),4.149( t,J=5.2Hz,2H),3.419(t,J=6.8Hz,2H),2.817(t,J=5.2Hz,2H),2.370(s ,6H),1.378–1.301(m,2H),1.152–1.067(m,2H),0.806(t,J=7.2Hz,3H).

[0475] Example 18: Preparation of Compound 30059

[0476] Step 1: General method for the preparation of compound 30059-2-3

[0477] Under a nitrogen atmosphere, a reaction mixture of 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-methylphenyl)phosphine (0.99 g, 0.003 mol), and TEA (5.46 g, 0.054 mol) in DMF (20 mL) was stirred at 90°C for 1 hour. The mixture was concentrated, diluted with water (20 mL), and extracted with EA (20 mL x 5). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and evaporated in vacuo. The crude product was purified by flash column chromatography (EA / PE = 50%) to give compound 30059-2-3 (2.6 g, 0.0126 mol, 46.67% yield) as a white solid.

[0478] Step 2: General method for preparing compound 30059-2-4

[0479] To a solution of compound 30059-2-3 (2.6 g, 0.0126 mol) in THF / MeOH = 3:1 (10 mL) was added NaBH4 (0.71 g, 0.019 mol) with stirring at 0°C under a nitrogen atmosphere. The reaction mixture was stirred at 0°C for 1 hour. The mixture was concentrated, diluted with water (10 mL), and extracted with EA (10 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and evaporated in vacuo. The crude product was purified by flash column chromatography (DCM / MeOH = 10 / 1) to afford compound 30059-2-4 (1.9 g, 0.009 mol, 71.43% yield) as a white solid.

[0480] Step 3: General method for preparing compound 30059-2

[0481] Under a nitrogen atmosphere, a reaction mixture of compound 30059-2-4 (1.9 g, 0.009 mol) and PBr (3.69 g, 0.0134 mol) in EtO (10 mL) was stirred at 0°C for 1 hour. The mixture was concentrated, diluted with water (10 mL), and extracted with EA (10 mL×3). The organic phase was washed with saturated brine, dried over anhydrous NaSO, and evaporated in vacuo. The crude product was purified by flash column chromatography (EA / PE=50%) to give compound 30059-2 (1.3 g, 0.004 mol, 47.25% yield) as a white solid.

[0482] Step 4: General method for preparing compound 30059-3

[0483] Under a nitrogen atmosphere, a solution of compound 30059-2 (700 mg, 2.583 mmol), Cs CO (2104 mg, 6.458 mmol) and compound 30012-5 (500 mg, 2.153 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The mixture was concentrated, diluted with water (30 mL), extracted with EA (30 mL×3), and the organic layer was collected, washed with water and saturated brine, dried over Na SO and concentrated. The crude product was purified by flash column chromatography (MeOH / DCM=1 / 10) to give compound 30059-3 (600 mg, 1.278 mmol, 59.37% yield) as a white solid.

[0484] Step 5: General method for preparing compound 30059-4

[0485] To a solution of LiAlH4 (108 mg, 2.840 mmol) in THF (5 mL) was added dropwise with stirring a solution of compound 30059-3 (600 mg, 1.420 mmol) in THF (5 mL) at 0°C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated, diluted with water (10 mL), and extracted with EA (10 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and evaporated in vacuo. The crude product was purified by flash column chromatography (DCM / MeOH = 10 / 1) to afford compound 30059-4 (340 mg, 0.804 mmol, 56.63% yield) as a white solid.

[0486] Step 6: General method for preparing compound 30059-5

[0487] Refer to Step 3 of the preparation of compound 30046.

[0488] Step 7: General method for the preparation of compound 59

[0489] Refer to step 4 of the preparation of compound 30046.

[0490] LCMS: [M+H] + =408.1; Rt=0.835min.

[0491] 1 H NMR(400MHz,d4-MeOD)δ8.536(s,1H),7.601(t,J=8.4Hz,1H),7.469(s,2H),7.3 37(d,J=8.0Hz,2H),6.975(dd,J=25.8,8.4Hz,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=1 5.8,8.0Hz,2H),1.414–1.342(m,2H),1.191-1.117(m,2H),0.839–0.764(m,3H).

[0492] Example 19: Preparation of Compound 30004

[0493] Step 1: General method for preparing compound 30004-3

[0494] Under nitrogen atmosphere, a solution of compound 30004-1 (500 mg, 4.20 mmol) and 30004-2 (806 mg, 9.25 mmol) in DCM (5 mL) was stirred at room temperature for 4 hours. The mixture was concentrated and extracted with DCM (10 mL×2). The organic layer was collected, washed with saturated brine, dried over Na2SO4, and concentrated to give the crude product, compound 30004-3 (300 mg), as a colorless oil.

[0495] Step 2: General method for preparing compound 30004-5

[0496] 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(PPh 3 ) 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×2), the organic phase was evaporated in vacuo, and the crude product was purified by flash column chromatography (DCM / MeOH=20 / 1) to give compound 30004-5 (40 mg, 90% yield) as a brown solid.

[0497] Step 3: General method for the preparation of compound 30004

[0498] 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, and the organic layer was concentrated and then purified using preparative HPLC (column: Phenomenex luna C18 250 mm × 100 mm × 10 μm; mobile phase: (A: H2O (0.1% FA), B: acetonitrile); B%: 15%-55%, 40 minutes) to afford compound M030004 (8.2 mg, 20% yield) as a white solid.

[0499] LC-MS: [M+H] + =345.3; Rt=0.631min.

[0500] 1H NMR: (400MHz, CDCl3) δ8.044(br s,1H),7.835(d,J=8.4Hz,1H),7.438(d,J=8.4Hz,1H),5.971(br s,2H),3.825(t,J=4.8Hz,4H),3.660(dd,J=13.6,6.8Hz,2H),2.912(t,J=7.2Hz,2H),2.671(s,4H),2.60 7–2.550(m,2H),2.201–2.102(m,2H),1.759–1.681(m,2H),1.510–1.401(m,2H),0.996(t,J=7.2Hz,3H).

[0501] Example 20: Preparation of Compound 30005

[0502] Step 1: General method for preparing compound 30005-3

[0503] To a solution of pyrrolidine (707 mg, 9.947 mmol) in THF (10 mL) was added a solution of compound 30005-1 (500 mg, 2.487 mmol) in THF (5 mL) at 0°C under nitrogen. The reaction mixture was stirred at room temperature for 2 hours. It was concentrated under reduced pressure and dissolved in 1M HCl (25 mL). The product was washed with Et2O (×2), cooled with ice water, and then NaOH (2 g, 50 mmol) was added. The product was extracted with EA, the organic layer was collected, dried over Na2SO4, and concentrated to give the crude product, compound 30005-3 (440 mg), as a yellow oil.

[0504] Step 2: General method for the preparation of compound 30005

[0505] A solution of compound 30005-4, INT-I (41 mg, 0.214 mmol) and NaH (10 mg, 0.255 mmol) in DMF (1 mL) was stirred at 0°C under a nitrogen atmosphere for 0.5 hours. A solution of compound 30005-3 (30 mg, 0.102 mmol) in DMF (1 mL) was then added dropwise. The reaction mixture was stirred at 100°C for 2 hours. The mixture was diluted with MeOH, and the organic layer was concentrated and then purified by preparative HPLC (column: Phenomenex luna C18 250 mm × 100 mm × 10 μm; mobile phase: (A: H2O (0.1% FA), B: acetonitrile); B%: 5%-50% over 35 minutes) to afford compound 30005 (7.66 mg, 0.02 mmol, 17% yield) as a white solid.

[0506] LCMS: [M+H] + =407.2; Rt=0.911min.

[0507] 1 H NMR: (400MHz, CDCl3) δ7.750(d,J=9.2Hz,1H),7.418(s,4H),7.117(d,J=9.2Hz,1H),6.825(s,1H),6.234(s,2H),5.368(s,2H),3.752(s,2 H),3.598(dd,J=13.6,6.8Hz,2H),2.668(s,4H),1.855(s,4H),1.732–1.659(m,2H),1.460(dd,J=15.2,7.4Hz,2H),1.003(t,J=7.2Hz,3H).

[0508] Example 21: Preparation of Compound 30006

[0509] Step 1: General method for preparing compound 30006-2

[0510] Under a nitrogen atmosphere, a solution of compound 30006-1 (500 mg, 2.183 mmol) in toluene (5 mL) was added dropwise with stirring at 0°C to DIBAL-H (621 mg, 4.365 mmol). The reaction mixture was stirred at 0°C for 2 hours. The mixture was concentrated and extracted with EA, and the organic layer was collected, dried over Na2SO4, and concentrated to give the crude product, compound 30006-2 (350 mg), as a yellow oil.

[0511] The remaining steps were carried out by referring to the preparation method of compound 30005 to prepare compound 30006.

[0512] LCMS: [M+H] + =407.2.

[0513] 1 H NMR: 400MHz, CDCl3) δ7.850(d,J=9.2Hz,1H),7.694(s,1H),7.440–7.382(m,3H),7.250–7.212(m,1H),7.167(d,J=9.2Hz,1H),5.410(s,2H) ),3.984(s,2H),3.644(d,J=6.4Hz,2H),2.950(s,4H),1.987(s,4H),1.706(t,J=7.2Hz,2H),1.478–1.440(m,2H),1.000(t,J=7.2Hz,3H).

[0514] Example 22: Preparation of Compound 30007

[0515] Step 1: General method for preparing compound 30007-3

[0516] Under a nitrogen atmosphere, the reaction mixture of a solution 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), and extracted with EA (30 mL×3). The organic layer was collected, washed with saturated brine (40 mL×5), dried over Na 2 SO 4 and concentrated. The crude product was purified by flash column chromatography (EA / PE=1 / 5) to give the crude product, compound 30007-3 (230 mg, 34.5% yield), as a colorless oil.

[0517] Step 2: General method for preparing compound 30007-4

[0518] Under a nitrogen atmosphere, the reaction mixture of a solution of compound 30007-3 (50 mg, 0.228 mmol) and LiAlH 4 (17 mg, 0.456 mmol) in THF (1 mL) was stirred at 25° C. for 2 hours. The mixture was concentrated and extracted with EA (30 mL×3), and the organic layer was collected, dried over Na 2 SO 4 and concentrated to give the crude product, compound 30007-4 (19 mg, 0.09 mmol, 38.55% yield), as a yellow oil.

[0519] The remaining steps were carried out by referring to the preparation method of compound 30005 to prepare compound 30007.

[0520] LCMS: [M+H] + =421.1.

[0521] 1 H NMR: (400MHz, CDCl3) δ7.850(d,J=9.2Hz,1H),7.410(d,J=8.0Hz,2H),7.287(s,2H),7.140(d,J=9.2Hz,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=14.8,7.2Hz,2H),1.010(t,J=7.2Hz,3H).

[0522] Example 23: Preparation of Compound 30008

[0523] Compound 30008 was prepared by referring to the preparation method of compound 30007.

[0524] LCMS: [M+H] + =361.3;

[0525] 1 H NMR: (400MHz, CDCl3) δ7.874(d,J=9.2Hz,1H),7.479(s,1H),7.080(d,J=9.2Hz,1H),4.440(t,J=4.4Hz,2H),3.844(s,4H),3.664–3.6 12(m,2H),2.741(s,6H),2.136(d,J=5.2Hz,2H),1.700(dd,J=14.8,7.6Hz,2H),1.443(dt,J=14.8,7.6Hz,2H),1.000(t,J=7.6Hz,3H).

[0526] Example 24: Preparation of Compound 30009

[0527] Step 1: General method for preparing compound 30009-3

[0528] To a solution of compound 30009-1 (500 mg, 3.673 mmol) and pyrrolidine (287 mg, 4.040 mmol) in DCM (5 mL) at room temperature under a nitrogen atmosphere was added NaBH(OAc) (1168 mg, 5.509 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. The mixture was extracted with EA, and the organic layer was collected, dried over NaSO, and concentrated to give the crude product, compound 30009-3 (400 mg), as a yellow solid.

[0529] Step 2: General method for the preparation of compound 30009

[0530] Under nitrogen atmosphere, a 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 (1 mL) was stirred at 150° C. for 2 hours. The mixture was then diluted with MeOH and 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%-40%, 25 minutes) to afford compound M030009 (3.85 mg, 0.01 mmol, 5.1% yield) as a white solid.

[0531] LCMS: [M+H] + =393.3;

[0532] 1 H NMR: (400MHz, CDCl3) δ7.950(d,J=8.8Hz,1H),7.605(d,J=8.0Hz,2H),7.248(s,1H),7.180(d,J=8.4Hz,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=14.8,7.2Hz,2H),0.935(t,J=7.2Hz,3H).

[0533] Example 25: Preparation of Compound 30010

[0534] Compound 30010 was prepared by referring to the preparation method of compound 30009.

[0535] LCMS: [M+H] + =393.3

[0536] 1H NMR: (400MHz, CDCl3) δ7.710(d,J=8.8Hz,1H),7.349(t,J=7.6Hz,1H),7.204(d,J =7.6Hz,1H),7.159–7.123(m,2H),7.065(d,J=8.0Hz,1H),6.468(s,1H),4.819(s, 2H),3.655(s,2H),3.467(dd,J=13.2,6.8Hz,2H),2.551(s,4H),1.800(s,4H),1.5 69(dd,J=14.8,7.2Hz,2H), 1.372(dd,J=15.2,7.2Hz,2H), 0.931(t,J=7.2Hz,3H).

[0537] Example 26: Preparation of Compound 30011

[0538] Step 1: General method for preparing compound 30011-2

[0539] At room temperature under nitrogen atmosphere, 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 and extracted with MTBE (30 mL×2). The organic layer was collected and concentrated to give the crude product, compound 30011-2 (2.2 g, 92%), as a brown oil.

[0540] Step 2: General method for preparing compound 30011-4

[0541] 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 give compound 30011-4 (500 mg, 40% yield) as a brown solid.

[0542] Step 3: General method for the preparation of compound 30011

[0543] Compound 30011 was prepared by referring to step 2 of the preparation of compound 30009.

[0544] LCMS: [M+H] + =407.2.

[0545] 1H NMR: (400MHz, CDCl3)δ10.888(br s,2H),7.888(d,J=8.8Hz,1H),7.301–7.269(m,2H),7.203(d,J=8.8Hz,1H),7.092(d,J=8.4Hz,2H),7.047(t,J=5.6Hz,1H),3.510(d d,J=13.2,6.8Hz,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=7.2Hz,3H).

[0546] Example 27: Preparation of Compound 30151

[0547] Step 1: General method for preparing compound 30151-2

[0548] To a solution of compound 30151-1 (500 mg, 3.25 mmol) in MeOH (10 mL) was added Raney Ni (191 mg, 3.25 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 25°C under a hydrogen atmosphere for 1 hour. The residue was removed by filtration through Celite and concentrated under reduced pressure to afford crude compound 30151-2 (400 mg, 62% yield) as a white solid. [M+H] + =158.1.

[0549] Step 2: General method for preparing compound 30151-3

[0550] To a solution of compound 3 (300 mg, 0.88 mmol) in EtOH (5 mL) was added compound 30151-2 (209 mg, 1.32 mmol) at room temperature under nitrogen. The reaction mixture was heated and stirred at 100°C for 1 hour. The solvent was removed under reduced pressure to obtain a 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.

[0551] Step 3: General method for preparing compound 30151-4

[0552] 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 give the crude product 30151-4 (150 mg, 62% yield) as a yellow solid. [M+H] + =451.1.

[0553] Step 4: General method for preparing compound 30151-5

[0554] Compound 30151-4 (200 mg, 0.44 mmol) was dissolved in 1,4-dioxane (1 mL), 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.

[0555] Step 5: General method for the preparation of compound 30151

[0556] To a solution of compound 30151-5 (30 mg, 0.07 mmol) in DMF (2 mL) was added 4 (16 mg, 0.15 mmol) and KCO (42 mg, 0.32 mmol). The mixture was stirred at 50° C. under a nitrogen atmosphere for 1 hour. The solvent was removed under reduced pressure. The crude product was then purified by preparative HPLC (column: Phenomenex luna C18 250 mm × 100 mm × 10 μm; mobile phase: [A: H2O (0.1% trifluoroacetic acid), B: acetonitrile]; B%: 0%-80% over 10 minutes) to afford compound 30151 (4 mg, 10% yield) as a white solid.

[0557] LCMS: [M+H] + 459.2; Rt=0.995min. 1H NMR(400MHz, DMSO-d6)δ9.26(d,J=8Hz,1H),8.18(s,1H),7.57(d,J=8Hz,1H),7.04(s,1H),6.93–6.91(m,2H),6.62(s,2H),6.11(d, J=8Hz,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

[0558] Example 28: Preparation of Compound 30155

[0559] Under a nitrogen atmosphere, triethylamine (36 mg, 0.36 mmol) and acetyl chloride (28 mg, 0.36 mmol) were added to a solution of compound 30137 (50 mg, 0.12 mmol) in dichloroethane (1 mL), and the mixture was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure and purified by preparative HPLC (10-80% acetonitrile:water, 10 min) to give compound 30155 (10 mg, 17% yield) as a white solid.

[0560] LCMS: [M+H] + =453.3.

[0561] Test Example 1: Determination of the agonist activity of the present compound on hTLR7 and hTLR8

[0562] Application of HEK-Blue TM hTLR cells were used to test the agonist activity of the compounds of the present application on hTLR7 and hTLR8. R848 was used as a positive control compound, and its structure is as follows:

[0563] 1. Serially dilute the compound to 10 concentration points and add to a 96-well plate. 100 nL DMSO was used instead of the compound as a negative control, and 28.51 μM R848 was used to treat hTLR7 and hTLR8 cells as a positive control.

[0564] 2. HEK-Blue TM hTLR cells were seeded into 96-well plates containing compounds, with 100 μL per well, containing 50,000 cells per well. The concentration of DMSO in the wells was 0.1%.

[0565] 3. The above 96-well plate was incubated overnight at 37°C with 5% CO2.

[0566] 4. After overnight incubation, take 20 μL of supernatant from each well and add it to the plate containing 180 μL of QUANTI-Blue TM The 96-well plate was incubated at 37°C for 1 h.

[0567] 5. After 1 hour of incubation, measure the OD using a microplate reader 650nm optical density.

[0568] 6. Cell viability was determined using CellTiter-Glo according to the manufacturer's instructions. Luminescence signal (RLU) in each well was measured using a microplate reader.

[0569] 7. Analyze OD using GraphPad Prism Software 650nm The EC values ​​of the compounds for hTLR7 and hTLR8 were calculated based on the data. 50 , and draw the fitting curve.

[0570] 8. Analyze cell viability data using GraphPad Prism software and calculate CC of compounds against hTLR7 and hTLR8 50 , and draw the fitting curve.

[0571] Cell viability % = (RLU Compound / RLU DMSOControl)×100%.

[0572] Table 1 Agonistic activity and toxicity data of the compounds of the present application on hTLR7 and hTLR8

[0573] According to the data in Table 1, it can be seen that compared with the clinically approved drug R848 (Resiquimod), the compound of the present application exhibits excellent TLR7 and TLR8 agonist activity, and can be used to prepare drugs for preventing or treating diseases or conditions related to TLRs activity.

[0574] Test Example 2: Testing the effect of the compound of the present application on the cytokine secretion level of human peripheral blood mononuclear cells

[0575] Human peripheral blood mononuclear cells were purchased from iXcells Biotechnologies according to the manufacturer's instructions at a density of 2 × 10 6 cells / mL were inoculated into 96-well plates, and different concentrations of the test compounds were added. After culturing for 14 hours, the culture medium was collected and LEGENDplex TMA human cytokine test kit (Biolegend, Cat#740390) was used to detect cytokine levels in the culture medium (see Figure 1). Figure 1 shows the comparative experimental effects of compound 89 and R848, with the vertical axis representing the mean fluorescence density. The compounds of the present invention, as TLR7 / 8 agonists, stimulated human peripheral blood mononuclear cells to secrete interferon gamma and various other pro-inflammatory cytokines and chemokines (TNF-α, IL-10, IL-1β, and IL-12p70) at a concentration of 1 nM, which was much higher than the control, R848 (Resiquimod). This indicates that the compounds of the present application have a high ability to stimulate the immune response of the peripheral blood mononuclear cell system in the immune system.

[0576] Test Example 3: Testing the effect of the compound of the present application on killing tumor cells by human peripheral blood mononuclear cells in vitro

[0577] H1568 cells were purchased from ATCC (stored at 37°C, 5% CO2 in a storage medium containing 10% fetal bovine serum, 100 units / mL penicillin, and 100 μg / mL streptomycin). RPMI 1640 containing 2 mM L-glutamine, 10 mM HEPES, 1 mM sodium pyruvate, 4500 mg / mL glucose, and 1500 mg / L sodium bicarbonate was used as the culture medium. H1568 cells were seeded at a density of 8,000 cells / well in a 96-well RTCA E-plate (purchased from Agilent, CAS#300601030, real-time cell monitoring electronic plate) and cultured overnight at 37°C. Human peripheral blood mononuclear cells (previously activated with 100 IU / mL IL-2 for 72 hours) purchased from iXcells were suspended in RPMI 1640 containing 10% fetal bovine serum. The suspension was added to a 96-well plate cultured with H1568 cells along with a certain concentration of the test compound, or only a certain concentration of the test compound was added to a 96-well plate cultured with H1568 cells. DMSO was used as a negative control. The cell culture was continuously monitored for 3-5 days using an RTCA detection system. The data read was the cell index, which corresponds to tumor cell viability. The smaller the index, the higher the degree of inhibition or killing of tumor cells. The cell index data for 72 hours were collected and analyzed using GraphPad Prism software at different concentrations of the same compound to calculate the EC50 activity of the compound in killing tumor cells in the presence or absence of human peripheral blood mononuclear cells. 50 (See Table 2).

[0578] The compound of the present application showed a strong ability to activate human peripheral blood mononuclear cells to kill cancer cells (EC 50 between 1-10 nM).

[0579] Table 2

[0580] Test Example 4: Testing the in vitro pharmacokinetic properties of the compounds of the present application

[0581] The in vitro pharmacokinetic properties of the compounds of the present application were commissioned to Kanglong Chemical (Beijing) for testing, and the main tests were the stability evaluation of in vitro cell membrane permeability (MDCK-MDR1) and liver microsome (LM) metabolism.

[0582] In vitro cell membrane permeability (i.e., bidirectional transport in MDCK-MDR1 cell monolayer model): According to the operating procedures, the density of the prepared 6 pcs / mL -1 MDCK-MDR1 cell suspension was inoculated into the filter wells of 96-well HTS Transwell, 50 μL was added to each well, and cultured continuously for 4-8 days in an incubator at 37°C, 5% CO2, and 95% relative humidity, with the medium changed every day; the transmembrane resistance (greater than 42 ohms / cm 2 ) to evaluate the integrity and tightness of the MDCK-MDR1 monolayer model. After the resistance was verified to be qualified, the culture medium at the AP and BL ends was aspirated, and both ends were washed twice with 37°C HBSS (10mM HEPES, pH 7.4) solution. After incubation in a constant temperature shaking incubator (37°C) for 30 minutes, the Ap→Bl absorption transport test was performed: the test solution (1μmol·L -1 , 125 μL) and HBSS (10 mM HEPES, pH 7.4) solution (235 μL) at the BL end. Immediately remove 50 μL from the AP end and place it in a new 96-well plate. Bl→Ap efflux assay: Add the test solution (1 μmol·L) to the AP end of the Transwell chamber and the BL end. -1 , 285 μL). Immediately remove 50 μL from the BL end and place it in a new 96-well plate. After incubating all 96-well plates in a constant temperature shaking incubator (37°C) for 2 hours, remove 50 μL from each of the dosing and receiving ends and place them in a new 96-well plate. Add 200 μL of acetonitrile containing the internal standard to each well of the new 96-well plate, gently vortex for 5 minutes, and then spin centrifuge at 3220g for 40 minutes. Collect the supernatant, add ultrapure water, and analyze the sample concentration using HPLC.

[0583] Metabolic stability of liver microsomes (LM): Liver microsomes (human LM, Corning, Cat#452117; Rat LM, Corning, Cat#452501; Mouse LM, XENOTECH, Cat#M1000) were incubated in a total volume of 400 μL, consisting of 200 μL of 0.2 M phosphate buffer (pH 7.4), 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 (40 μL of ultrapure water was added when NADPH was not included). 4 μL of the 100 μM analyte was added, and the cells were incubated in a 37°C water bath. Each sample was repeated three times. A 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 min), 50 μL of the sample was removed and terminated by the addition of 4 volumes of pre-chilled acetonitrile (containing IS: 3% formic acid, 100 nM alprazolam, 200 nM labetalol, 200 nM caffeine, and 2 μM ketoprofen). The sample was centrifuged at 3220 g for 40 minutes, and 100 μL of the supernatant was mixed with 100 μL of ultrapure water for analysis of the analyte content by LC-MS / MS. Data were analyzed using MS Excel.

[0584] Hepatocyte metabolic stability experiment: After thawing and recovery, hepatocytes were cultured in culture medium at 37℃ until 1.5×10 6 After passing the activity test (>75%), dilute to 0.5×10 6 cells / mL. After pre-warming 198 μL of hepatocytes for 10 minutes, 2 μL of 100 μM test substance or control was added. Metabolic reactions were performed using an incubation method at 37°C. At various time points (0, 15, 30, 60, 90, and 120 minutes), 25 μL of the solution was removed from the system and terminated by the addition of 150 μL of an organic solvent (acetonitrile containing 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 for analysis of the test substance content by LC-MS / MS. All incubations were repeated in duplicate. Data were analyzed using MS Excel.

[0585] The results show (see Table 3 below) that the compound of the present invention has a shorter half-life period compared to R848 (Resiquimod). The shorter half-life of the compound of the present invention can reduce the risk of the compound causing a systemic immune response in the body.

[0586] Table 3

[0587] Test Example 5: Testing the pharmacokinetic properties of the compound of the present application in CD1 mice

[0588] Due to the serious side effects associated with the target, the pharmacokinetic properties of TLR7 / 8 agonists largely determine their drugability. Therefore, the pharmacokinetic evaluation of the compounds of the present application was carried out in mice. The experiment used 6-8 weeks old, ~20-30g male CD1 mice, 3 per group, fasted overnight before administration and fed 4 hours after administration. The test compounds with a molecular weight difference of more than 4 were grouped into 3-5 groups and administered intraperitoneally. The formula was: 0.4mg / mL, 10% SBE-β-CD in 50mM citrate buffer pH 5.0; the dose was 2mpk; at each time point of 5, 15, 30 minutes, 1, 2, 4, 8, and 24 hours after administration, ~0.03mL of blood was collected from the dorsal plantar vein and transferred to a plastic centrifuge tube containing EDTA-K2. The plasma was processed and the residual amount of the test compound was detected by LC-MS; after 24 hours of death by CO2 asphyxiation, liver tissue was obtained and processed, and the residual amount of the drug in the liver tissue was detected by LC-MS.

[0589] After data processing, the half-life T 1 / 2 , maximum concentration C max , and maximum concentration time T max , AUC last ,AUC inf , AUC _％Extrap_obs , and parameters such as tissue / plasma distribution ratios are shown in Table 4 and Figure 2. Consistent with the in vitro pharmacokinetic evaluation, the compounds of the present application, except for 30078, quickly reached a maximum concentration in the mouse circulatory system and then quickly returned to the range of 10-30 ng / mL.

[0590] Table 4

[0591] Test Example 6: Testing the efficacy of the compound of the present application in a female Balb / C mouse subcutaneous syngeneic transplantation model of mouse colon cancer CT-26 cells

[0592] 1. Resuscitate CT-26 cells and culture in RPMI1640+10% FBS to obtain 2.5×10 7 cell.

[0593] 2. After one week of adaptive feeding, 40 6-8 week old female Balb / C mice were weighed and divided into groups.

[0594] 3. Inoculation conditions

[0595] Cell seeding information is as follows:

[0596] 4. After inoculation, tumor volume and body weight were measured once a week. When the average tumor volume reached 79.6 mm 3 At 4 hr, the animals were randomly divided into 6 groups based on tumor volume and body weight, with 4 mice in each group. Dosing was immediately initiated after grouping. The start date of dosing was considered day 0. Dosing and grouping information is as follows:

[0597] Grouping and dosing information are as follows:

[0598] 5. After the start of drug administration, the body weight and tumor volume of the mice were measured three times per week. Drug administration was performed twice during the experimental period, and observations were completed on experimental day 12. At the end of the experiment, tumors were harvested and the residual concentration of the administered drug in the tumor tissue was determined.

[0599] Referring to FIG3 , the results show that the compound of the present application is relatively safe and has a significant tumor inhibition effect.

[0600] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the scope of protection of the present invention.

[0601] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any appropriate manner without contradiction. To avoid unnecessary repetition, the present invention will not further describe various possible combinations. As long as they do not violate the spirit of the present invention, they should also be regarded as the content disclosed by the present invention.

Claims

1. A pyrimidine derivative, which is a compound of formula (I-1) or (I-2), or a stereoisomer, tautomer, isotope derivative, hydrate, solvate, prodrug, or pharmaceutically acceptable salt thereof, in, represents a single bond or a double bond; X1 and X2 are both C-R3, or one of them 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-, wherein R4 is H or optionally substituted alkyl; R1 is alkyl or aryl, optionally selected from oxo, halogen, amino, hydroxyl, nitro, cyano, mercapto, -C(O)-NH2, -C(O)-OH, heteroaryl (optionally substituted with one or more of halogen, amino, hydroxyl, nitro, cyano, mercapto, alkoxy, alkyl), aryl (optionally substituted with one or more of halogen, amino, hydroxyl, nitro, cyano, mercapto, alkoxy, alkyl), heterocycloalkyl (optionally substituted with one or more of halogen, amino, hydroxyl, nitro, cyano, mercapto, alkoxy, alkyl), cycloalkyl (optionally substituted with one or more of halogen, amino, hydroxyl, 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 -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 -L3-R7 can be substituted at the para, meta or ortho position of L2; L1, L2, L3 are a bond, an optionally substituted straight-chain alkylene group, wherein one, two or more carbon atoms in the straight-chain alkylene group may be replaced by heteroatoms oxygen, sulfur, and nitrogen, and the substituent is selected from one or more of an optionally substituted alkyl group, a halogen group, an amino group, a hydroxyl group, a nitro group, a cyano group, a thiol group, an optionally substituted alkyloxy group, an optionally substituted alkylthio group, and an optionally substituted alkylamino group; R5 is cycloalkyl or heterocycloalkyl, optionally substituted by one or more selected from oxo, halogen, amino, hydroxy, nitro, cyano, mercapto, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamino; W and V can be N or CH. When W or V is CH, it can be substituted by R6 or -L3-R7; R3 and R6 are each independently H, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamino, halogen, amino, hydroxyl, nitro, cyano, thiol; 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 ); the substituent is selected from one or more of optionally substituted alkyl, optionally substituted alkylamino, optionally substituted dialkylamino, and oxo; R8 is H or optionally substituted alkyl; R9, R 10 each independently represents H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; The substituent of the optionally substituted group is selected from one or more of halogen, amino, hydroxyl, nitro, cyano, thiol, carboxyl, ester, amide, etc.; n=0, 1, 2, 3 or 4.

2. The pyrimidine derivative according to claim 1, wherein one of X1 and X2 is C-R3, and the other is N.

3. The pyrimidine derivative according to claim 1, wherein R8 is H or C1-8 alkyl.

4. The pyrimidine derivative according to any one of claims 1 to 3, wherein R1 is C1-8 alkyl, optionally substituted by one or more 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, optionally substituted C1-8 alkylsulfonyl; Preferably, R1 is C2-6 alkyl, optionally substituted by an optionally substituted C1-6 alkyloxy, an optionally substituted C1-6 alkylthio, an 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, 3-hexyl; More preferably, R1 is n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-hexyl, methoxyethyl, methylthioethyl, methylsulfonylethyl, methoxypropyl, methylthiopropyl, methylsulfonylpropyl, More preferably, R1 is n-butyl, Methylthiopropyl, methylsulfonylpropyl, 5. The 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 one of W and V is N.

6. The pyrimidine derivative according to any one of claims 1 to 5, wherein The heterocycloalkyl group is a 3-12 membered monocyclic, bicyclic or polycyclic heterocycloalkyl group; preferably, the heterocycloalkyl group is a 3-12 membered monocyclic, bicyclic or polycyclic heterocycloalkyl group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S; more preferably, the heteroatoms in the heterocycloalkyl group are connected to L1 or L3; more preferably, the N atom in the heterocycloalkyl group is connected to L1 or L3.

7. The pyrimidine derivative according to claim 6, wherein the heterocycloalkyl group is a 3-7 membered monocyclic heterocycloalkyl group containing 1-2 heteroatoms selected from N, O, and S, or a 7-12 membered cyclic or spirocyclic heterocycloalkyl group containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S; Preferably, the heterocycloalkyl group is a 4-6 membered monocyclic heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, or a 7-11 membered spirocyclic heterocycloalkyl group containing 2, 3 or 4 heteroatoms selected from N and O; More preferably, the heterocycloalkyl group is one of the following groups:

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

9. The pyrimidine derivative according to any one of claims 1 to 8, wherein L1, L2, and L3 are bonds or optionally substituted straight-chain alkylene groups containing 1 to 6 chain atoms, 1 to 2 carbon atoms in the straight-chain alkylene group may be replaced by heteroatoms such as oxygen, sulfur, and nitrogen, and the substituents are selected from C1-8 alkyl, halogen, amino, hydroxyl, nitro, cyano, and mercapto; L1 is preferably an optionally substituted straight-chain alkylene group containing 1 to 4 chain atoms, more preferably an optionally substituted straight-chain alkylene group containing 2 to 3 chain atoms; more preferably -O-propylene, -CH2CH2CH2-; L2 is preferably an optionally substituted straight-chain alkylene group containing 1 to 4 chain atoms, more preferably an optionally substituted straight-chain alkylene group containing 2 to 3 chain atoms; more preferably -CH2-, -CH2CH2-, -O-, -O-CH2-CH2-, -O-CH2-; L3 is preferably a bond, an optionally substituted straight-chain alkylene group containing 1-4 chain atoms, more preferably a bond, an optionally substituted straight-chain alkylene group containing 2-3 chain atoms; more preferably a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-CH2-, -O-CH2-, -CH(CH3)CH2-; more preferably 10. The pyrimidine derivative according to any one of claims 1 to 9, wherein R9, R 10 Each is independently H or C1-8 alkyl.

11. The pyrimidine derivative according to any one of claims 1 to 10, wherein: R7 is -OH, -N(R9R 10 )、-N(R9)NH2、-NO(R9R 10 ), optionally substituted 3-12 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, optionally substituted C6-10 aryl, optionally substituted 3-12 membered heterocycloalkyl-NR9- containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, optionally substituted C6-10 aryl-NR9-; 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; R9, R 10 Each is independently H or C1-8 alkyl; The heterocycloalkyl group is preferably a 4-6 membered monocyclic heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, or a 7-11 membered spirocyclic heterocycloalkyl group containing 2, 3 or 4 heteroatoms selected from N and O; more preferably, the heteroatom in the heterocycloalkyl group is connected to L3, and more preferably, the N atom in the heterocycloalkyl group is connected to L3.

12. The pyrimidine derivative according to any one of claims 1 to 10, wherein R2 is selected from one of the following optionally substituted groups: Further, R2 is optionally substituted The substituent is selected from one or more of alkyl, alkyloxy, alkylthio, alkylamino, halogen, amino, hydroxyl, nitro, cyano, and mercapto.

13. The pyrimidine derivative according to any one of claims 1 to 12, wherein the compound of formula (I-1) or formula (I-2) has one of the following formulae:

14. The pyrimidine derivative according to claim 1, characterized in that X1 and X2 are both selected from C-R3.

15. The pyrimidine derivative according to claim 14, wherein Z is -NH2, -OH; Y is -O-, -S- or -NR4-, wherein R4 is H or optionally substituted alkyl; R1 is alkyl, optionally selected from oxo, halogen, amino, hydroxy, nitro, cyano, mercapto, substituted by one or more of optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamino, optionally substituted alkylacyl, optionally substituted alkylsulfinyl, and optionally substituted alkylsulfonyl; R2 is -L3-R7 can be substituted at the para, meta or ortho position of L2; L2 and L3 are a bond, an optionally substituted straight-chain alkylene group, wherein one, two or more carbon atoms in the straight-chain alkylene group may be replaced by heteroatoms oxygen, sulfur or nitrogen, and the substituent is selected from one or more of an optionally substituted alkyl group, a halogen group, an amino group, a hydroxyl group, a nitro group, a cyano group, a thiol group, an optionally substituted alkyloxy group, an optionally substituted alkylthio group, and an optionally substituted alkylamino group; W and V can be N or CH. When W or V is CH, it can be substituted by R6 or -L3-R7; R3 and R6 are each independently H, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamino, halogen, amino, hydroxyl, nitro, cyano, thiol; 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 );The substituent is selected from one or more of optionally substituted alkyl, optionally substituted alkylamino, and oxo; R9, R 10 each independently represents H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; The substituents in the optionally substituted alkyl are selected from one or more of halogen, amino, hydroxyl, nitro, cyano, thiol, carboxyl, ester, and amide groups; n=0, 1, 2, 3 or 4.

16. The pyrimidine derivative according to claim 15, wherein R1 is C1-8 alkyl, optionally substituted by one or more selected from optionally substituted C1-8 alkylthio, optionally substituted C1-8 alkylsulfonyl; Preferably, R1 is C2-6 alkyl, optionally substituted by an optionally substituted C1-6 alkylthio, an optionally substituted C1-6 alkylsulfonyl; Preferably, R1 is n-butyl, n-pentyl, 2-pentyl, n-hexyl, 2-hexyl, 3-hexyl, methoxyethyl, methylthioethyl, methylsulfonylethyl, methoxypropyl, methylthiopropyl, methylsulfonylpropyl, More preferably, R1 is n-butyl, Methylthiopropyl, methylsulfonylpropyl, 17. The 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 one of W and V is N.

18. The pyrimidine derivative according to any one of claims 15 to 17, wherein The heterocycloalkyl group is a 3-12 membered monocyclic, bicyclic or polycyclic heterocycloalkyl group; preferably, the heterocycloalkyl group is a 3-12 membered monocyclic, bicyclic or polycyclic heterocycloalkyl group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S; more preferably, the heteroatoms in the heterocycloalkyl group are connected to L1 or L3; more preferably, the N atom in the heterocycloalkyl group is connected to L1 or L3.

19. The pyrimidine derivative according to claim 18, wherein the heterocycloalkyl group is a 3-7 membered monocyclic heterocycloalkyl group containing 1-2 heteroatoms selected from N, O, and S, or a 7-12 membered cyclic or spirocyclic heterocycloalkyl group containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S; Preferably, the heterocycloalkyl group is a 4-6 membered monocyclic heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, or a 7-11 membered spirocyclic heterocycloalkyl group containing 2, 3 or 4 heteroatoms selected from N and O; More preferably, the heterocycloalkyl group is one of the following groups:

20. The pyrimidine derivative according to any one of claims 15 to 19, wherein L2 and L3 are a bond or an optionally substituted straight-chain alkylene group containing 1 to 6 chain atoms, 1 to 2 carbon atoms in the straight-chain alkylene group may be replaced by heteroatom oxygen, and the substituent is selected from C1-8 alkyl, halogen, amino, hydroxyl, nitro, cyano, and mercapto; L2 is preferably an optionally substituted straight-chain alkylene group containing 1 to 4 chain atoms, more preferably an optionally substituted straight-chain alkylene group containing 2 to 3 chain atoms; more preferably -CH2-, -CH2CH2-, -O-, -O-CH2-CH2-, -O-CH2-; L3 is preferably a bond, an optionally substituted straight-chain alkylene group containing 1-4 chain atoms, more preferably a bond, an optionally substituted straight-chain alkylene group containing 2-3 chain atoms; more preferably a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-CH2-, -O-CH2-, -CH(CH3)CH2-; more preferably 21. The pyrimidine derivative according to any one of claims 15 to 20, wherein: R7 is -OH, -N(R9R 10 )、-N(R9)NH2、-NO(R9R 10 ), optionally substituted 3-12 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, optionally substituted C6-10 aryl, optionally substituted 3-12 membered heterocycloalkyl-NR9- containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, optionally substituted C6-10 aryl-NR9-; 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; R9, R 10 Each is independently H or C1-8 alkyl; The heterocycloalkyl group is preferably a 4-6 membered monocyclic heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, or a 7-11 membered spirocyclic heterocycloalkyl group containing 2, 3 or 4 heteroatoms selected from N and O; more preferably, the heteroatom in the heterocycloalkyl group is connected to L3, and more preferably, the N atom in the heterocycloalkyl group is connected to L3.

22. The pyrimidine derivative according to claim 21, wherein R7 is -NO(R9R 10 ), an optionally oxo-substituted 3-12 membered heterocycloalkyl group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S.

23. The pyrimidine derivative according to any one of claims 15 to 22, wherein R2 is selected from one of the following optionally substituted groups: Further, R2 is optionally substituted The substituent is selected from one or more of alkyl, alkyloxy, alkylthio, alkylamino, halogen, amino, hydroxyl, nitro, cyano, and mercapto.

24. The pyrimidine derivative according to any one of claims 15 to 23, wherein the compound of formula (I-1) has one of the following formulae:

25. A pyrimidine derivative, which is a compound of formula (II-1) or formula (II-2), or a stereoisomer, tautomer, isotope derivative, halogenated derivative, hydrate, solvate, prodrug, or pharmaceutically acceptable salt thereof, in, X3 is N or CH, X4 is CH, N or NO, when X3 or X4 is CH, it may be substituted by 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-, wherein R4 is H or optionally substituted alkyl; R1 is alkyl or aryl, optionally selected from oxo, halogen, amino, hydroxyl, nitro, cyano, mercapto, -C(O)-NH2, -C(O)-OH, heteroaryl (optionally substituted by one or more of halogen, amino, hydroxyl, nitro, cyano, mercapto, alkoxy, alkyl), aryl (optionally substituted by one or more of halogen, amino, hydroxyl, nitro, cyano, mercapto, alkoxy, alkyl), heterocycloalkyl (optionally substituted by one or more of halogen, amino, hydroxyl, nitro, cyano, mercapto, alkoxy, alkyl), cycloalkyl (optionally substituted by one or more of halogen, amino, hydroxyl, 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 -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 -L3-R7 can be substituted at the para, meta or ortho position of L2; L1, L2, L3 are a bond, an optionally substituted straight-chain alkylene group, wherein one, two or more carbon atoms in the straight-chain alkylene group may be replaced by heteroatoms oxygen, sulfur, and nitrogen, and the substituent is selected from one or more of an optionally substituted alkyl group, a halogen group, an amino group, a hydroxyl group, a nitro group, a cyano group, a thiol group, an optionally substituted alkyloxy group, an optionally substituted alkylthio group, and an optionally substituted alkylamino group; R5 is cycloalkyl or heterocycloalkyl, optionally substituted by one or more selected from oxo, halogen, amino, hydroxy, nitro, cyano, mercapto, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamino; W and V can be N or CH. When W or V is CH, it can be substituted by R6 or -L3-R7; R3 and R6 are independently H, optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylamino, halogen, amino, hydroxyl, nitro, cyano, thiol; 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 );The substituent is selected from one or more of optionally substituted alkyl, optionally substituted alkylamino, and oxo; R9, R 10 each independently represents H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; The substituents in the optionally substituted groups are selected from one or more of halogen, amino, hydroxyl, nitro, cyano, thiol, carboxyl, ester, and amide groups; m=0, 1, 2 or 3, n=0, 1, 2, 3 or 4.

26. The pyrimidine derivative according to claim 25, wherein R1 is C1-8 alkyl, optionally substituted by one or more 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, optionally substituted C1-8 alkylsulfonyl; Preferably, R1 is C2-6 alkyl, optionally substituted by an optionally substituted C1-6 alkyloxy, an optionally substituted C1-6 alkylthio, an 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, 3-hexyl; More preferably, R1 is n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-hexyl, methoxyethyl, methylthioethyl, methylsulfonylethyl, methoxypropyl, methylthiopropyl, methylsulfonylpropyl, More preferably, R1 is n-butyl, Methylthiopropyl, methylsulfonylpropyl, 27. The 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 one of W and V is N.

28. The pyrimidine derivative according to any one of claims 25 to 27, wherein The heterocycloalkyl group is a 3-12 membered monocyclic, bicyclic or polycyclic heterocycloalkyl group; preferably, the heterocycloalkyl group is a 3-12 membered monocyclic, bicyclic or polycyclic heterocycloalkyl group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S; more preferably, the heteroatoms in the heterocycloalkyl group are connected to L1 or L3; more preferably, the N atom in the heterocycloalkyl group is connected to L1 or L3.

29. The pyrimidine derivative according to claim 28, wherein the heterocycloalkyl group is a 3-7 membered monocyclic heterocycloalkyl group containing 1-2 heteroatoms selected from N, O, and S, or a 7-12 membered cyclic or spirocyclic heterocycloalkyl group containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S; Preferably, the heterocycloalkyl group is a 4-6 membered monocyclic heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, or a 7-11 membered spirocyclic heterocycloalkyl group containing 2, 3 or 4 heteroatoms selected from N and O; More preferably, the heterocycloalkyl group is one of the following groups:

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

31. The pyrimidine derivative according to any one of claims 25 to 30, wherein L1, L2, and L3 are bonds or optionally substituted straight-chain alkylene groups containing 1 to 6 chain atoms, 1 to 2 carbon atoms in the alkylene group may be replaced by heteroatoms oxygen and sulfur, and the substituents are selected from C1-8 alkyl, halogen, amino, hydroxyl, nitro, cyano, and mercapto; L1 is preferably an optionally substituted straight-chain alkylene group containing 1 to 4 chain atoms, more preferably an optionally substituted straight-chain alkylene group containing 2 to 3 chain atoms; more preferably -O-propylene-, -CH2CH2CH2-; L2 is preferably an optionally substituted straight-chain alkylene group containing 1 to 4 chain atoms, more preferably an optionally substituted straight-chain alkylene group containing 2 to 3 chain atoms; more preferably -CH2-, -CH2CH2-, -O-, -O-CH2-CH2-, -O-CH2-; L3 is preferably a bond, an optionally substituted straight-chain alkylene group containing 1-4 chain atoms, more preferably a bond, an optionally substituted straight-chain alkylene group containing 2-3 chain atoms; more preferably a bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -O-CH2-CH2-, -O-CH2-, -CH(CH3)CH2-; more preferably 32. The pyrimidine derivative according to any one of claims 25 to 31, wherein R7 is OH, -N(R9R 10 )、-N(R9)NH2、-NO(R9R 10 ), optionally substituted 3-12 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, optionally substituted C6-10 aryl, optionally substituted 3-12 membered heterocycloalkyl-NR9- containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, optionally substituted C6-10 aryl-NR9-; 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, oxo; R9, R 10 Each is independently H or C1-8 alkyl; The heterocycloalkyl group is preferably a 4-6 membered monocyclic heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, or a 7-11 membered spirocyclic heterocycloalkyl group containing 2, 3 or 4 heteroatoms selected from N and O; more preferably, the heteroatom in the heterocycloalkyl group is connected to L3, and more preferably, the N atom in the heterocycloalkyl group is connected to L3.

33. A pyrimidine derivative according to any one of claims 25 to 32, wherein R2 is selected from one of the following optionally substituted groups: Further, R2 is optionally substituted The substituent is selected from one or more of alkyl, alkyloxy, alkylthio, alkylamino, halogen, amino, hydroxyl, nitro, cyano, and mercapto.

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

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

36. The pharmaceutical composition of claim 35 further comprises at least one other therapeutic agent, preferably, the therapeutic agent is selected from chemotherapeutic agents, immunotherapies, anti-angiogenic agents, cytokines, hormones, polynucleotides, antibodies, and immunologically active fragments; when the drug contains multiple active ingredients, each active ingredient can be administered simultaneously, sequentially or separately according to the judgment of the physician.

37. Use 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 preparing a medicament for preventing or treating a disease or condition associated with TLRs activity.

38. Use 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 preparing a medicament for preventing or treating infectious diseases, respiratory diseases, immune-related diseases, viral diseases or cell proliferative diseases.

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

40. The use according to claim 38, wherein the respiratory disease is asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome; The immune-related diseases are: systemic lupus erythematosus, Sjögren's syndrome, Wegener's granulomatosis, sarcoidosis, Reiter's syndrome, Behcet's syndrome, rheumatoid arthritis, inflammatory bowel disease, polymyositis, vasculitis, ankylosing spondylitis, psoriasis; The viral diseases are: Ebola virus disease, anthrax, condyloma acuminatum, simple warts, plantar warts, respiratory syncytial virus, hepatitis B, hepatitis C, dengue virus, herpes simplex virus (e.g., HSV-1, HSV-11), molluscum contagiosum, anthrax, smallpox, lentivirus, human immunodeficiency virus (HIV), human papillomavirus (HPV), cytomegalovirus, herpes zoster virus, rhinovirus, enterovirus, adenovirus, influenza, parainfluenza, mumps virus, measles virus, papovavirus, flavivirus, retrovirus, arenavirus (e.g., LCM, Junin virus, Machupo virus, Guanarito virus, and Lassa fever) and filovirus (e.g., Ebola virus or Marburg virus); The cell proliferative disease is a tumor, including but not limited to human sarcomas and carcinomas, such as lymphoma, osteosarcoma, fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovial tumor, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, uterine tumor, neuron tumor, gastrointestinal cancer, colon cancer, rectal cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, papillary carcinoma, medullary carcinoma, Bronchogenic carcinoma, hepatoma, liver cancer, bile duct cancer, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, ovarian cancer, testicular tumor, renal cancer, lung cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, polycythemia vera, multiple myeloma and heavy chain disease. The adenocarcinoma can be thyroid cancer, pancreatic cancer, sweat gland cancer, sebaceous gland cancer, breast cancer, nipple adenocarcinoma, cystadenocarcinoma, prostate cancer, and the lung cancer can be small cell lung cancer. The leukemia is acute lymphocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, Acute myelomonocytic leukemia, acute monocytic leukemia, acute erythrocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia. The lymphoma is Hodgkin's disease or non-Hodgkin's disease; Preferably, the tumor is a cold tumor, more preferably, the tumor is colon cancer, bladder cancer, melanoma, meningioma, lung cancer, liver cancer or pancreatic cancer.

41. Use 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 preparing a drug for preventing tumor recurrence; preferably, the drug can induce persistent systemic immune memory to prevent recurrence.

42. Use 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 preparing a charge carrier for coupling a drug.

43. Use of the pyrimidine derivative described in any one of claims 1-34, or the pharmaceutical composition described in any one of claims 35-36, for preparing a pharmaceutical preparation, wherein the pharmaceutical preparation upregulates the number of genes in each of the inflammation and cytokine-mediated pathways, the T cell activation / apoptosis signaling pathway, and the B cell activation pathway that are beneficial to immunotherapy; preferably, the pharmaceutical preparation upregulates the number of genes in the above-mentioned pathways that are beneficial to tumor immunotherapy.

44. According to the use of claim 43, the pharmaceutical preparation increases the number of CD8+T cells, and / or increases the ratio of CD8+T cells / Treg cells, and / or increases PDL-1 expression, and / or increases the level of interleukin 2, and / or increases the level of interferon γ, and / or reduces the level of interleukin 10.

45. Use of the pyrimidine derivative according to any one of claims 1-34, or the pharmaceutical composition according to any one of claims 35-36, for preparing a preparation for down-regulating the Wnt signaling pathway; preferably, down-regulating the expression level of S-catenin protein.

46. ​​Use of the pyrimidine derivative according to any one of claims 1-34, or the pharmaceutical composition according to any one of claims 35-36, for preparing a pharmaceutical preparation that affects the secretion level of each cytokine in macrophages; preferably, affecting the expression level of mRNA of Illb, 116, 1112b, Tnf, Ifnbl, Cxcll, Cxcll0 and 1110 genes.

47. Use 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 preparing a vaccine adjuvant.

48. A method for improving a body's positive immune response, comprising: A therapeutically effective amount 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, is administered to a system or individual in need thereof, thereby regulating TLR7 and / or TLR8.

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

50. A method for improving immunotherapy, comprising: 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, is administered to a system or individual in need thereof, and simultaneously or subsequently chimeric antigen receptor T cells (CAR-T) are introduced into the system or individual.

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