Quinazolinone-fused five-membered heterocyclic compound, pharmaceutical composition thereof, and use thereof

Abstract

The present invention provides a quinazolinone-fused five-membered heterocyclic derivative with a structure represented by formula (I-A). Experimental results show that the compound provided by the present invention has good inhibitory activity against MAT2A, has inhibitory activity against the proliferation of cancer cells with an MTAP deletion mutation, and can be used for treating and / or preventing MAT2A-related cancer diseases.

Description

A quinazolinone pentane heterocyclic compound, its pharmaceutical composition and uses Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a quinazolinone pentane heterocyclic compound, its pharmaceutical composition, and its uses. Background Technology

[0002] Methionine adenosyltransferase 2A (MAT2A) is an enzyme that synthesizes S-adenosylmethionine (SAM) from methionine (Met) and adenosine triphosphate (ATP). SAM is the major methyl donor in cellular transmethylation (Physiological Reviews, 2012, 92:1515-1542). In organisms, the expression and activity of DNA, RNA, and proteins can be regulated by methylation modifications, thereby controlling cell growth, differentiation, and death. Therefore, intracellular SAM levels are tightly regulated.

[0003] The dysregulation of MAT2A in several cancer types and the observation that MAT2A gene silencing leads to cancer cell death suggest that MAT2A has the potential to be a therapeutic target. Recent studies have shown that MAT1A can be reversed to MAT2A during malignant transformation of the liver. MAT2A has also been found to be overexpressed in human epithelial tumors such as gastric, colon, and liver cancer (Acta Histochemica, 2013, 115:48-55). Research has also found that the X protein of hepatitis B virus (HBx) promotes the binding of NF-κB and CREB to the MAT2A gene promoter, thereby activating MAT2A expression and inhibiting apoptosis in HepG2 liver cancer cells. These studies indicate that MAT2A overexpression promotes cancer cell growth, inhibits cancer cell apoptosis, and accelerates cancer development.

[0004] The loss of MTAP in chr9p21 typically involves the deletion of the CDKN2A tumor suppressor site. Nearly 15% of human cancers exhibit MTAP gene deletion (Journal of Biological Chemistry, 2024, 300:105492), particularly glioblastoma, melanoma, urothelial carcinoma, pancreatic cancer, and non-small cell lung cancer. MTAP is a key enzyme in the methionine reuptake pathway, degrading MTA, a byproduct of polyamine synthesis, into adenine and 5-methylthioadenosine-1-phosphate (MTR-1p). Since MTAP is the only known enzyme catalyzing MTA degradation, its loss leads to MTA accumulation in cancer cells. Increased MTA activity inhibits arginine methyltransferase 5 (PRMT5) activity and increases the susceptibility of cancer cells to further PRMT5 loss (Science, 2016, 351:1208-1213). This susceptibility extends to the upstream metabolic enzyme MAT2A. The synthetic lethality of MAT2A and MTAP was further validated in an MTAP-deficient model. After MAT2A gene knockout, the changes in symmetrical arginine dimethylation markers (SDMA) in the HCT116 isotype differed, with SDMA levels in MTAP-deficient cells significantly lower than in MTAP-wild-type cells. In the metabolically altered and high-MTA environment of MTAP-deficient cells, the reduced intracellular SAM levels regulated by MAT2A inhibited PRMT5 activity, thereby selectively inducing tumor cell death. These studies provide a theoretical basis for the application of MAT2A inhibitors in MTAP-deficient cancers.

[0005] Currently, there are no marketed MAT2A inhibitors domestically or internationally, with three drugs in clinical trials. The small molecule MAT2A inhibitors under development still face several challenges, such as weak activity, poor selectivity for MTAP-deficient mutant cells, and some off-target toxicities. Therefore, MAT2A inhibitors have attracted considerable research interest from pharmaceutical companies, and the development of specific MAT2A inhibitors could become a new therapeutic approach to improve the treatment outcomes of MTAP-deficient cancers. Summary of the Invention

[0006] One object of the present invention is to provide a novel MAT2A inhibitor.

[0007] In a first aspect of the invention, a compound of formula IA is provided, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, hydrate, solvate, or prodrug thereof.

[0008] In the formula,

[0009] Indicates a double bond or a single bond;

[0010] X, Y1, and Y2 are each independently selected from C, CH, CR', O, S, N, NH, or NR';

[0011] R' is selected from: H, deuterium, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy;

[0012] n is selected from 0, 1, 2, 3;

[0013] m is selected from 1, 2, 3, 4, 5, 6;

[0014] L1 is selected from C14, -O-, -NH-, -NR'-, substituted or unsubstituted. 1-6 Alkylene;

[0015] R1 is selected from the following group: halogen, amide, cyano, amino, hydroxyl, amino, oxo (=O), carboxyl, ester, nitro, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-7 membered heterocyclic, 5-7 membered heterocyclic oxygen, halogenated C 3-6 cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyloxy;

[0016] R4 and R5 are each independently selected from the following group of substituent or unsubstituted groups: H, D, amide, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-6 Alkylene-, C 3-10 Cycloalkoxy, 5-10 membered heterocyclic group, 5-10 membered heterocyclic group -C 1-6 alkylene-, 5-10-membered heterocyclic oxy- (5-10-membered heterocyclic -O-), C 3-6 Cycloalkyloxy (C 3-6 cycloalkyl-O-), C 6-10 Aryl, C 6-10 Aryl-C 1-6 alkylene-, 5-10 heteroaryl, 5-10 heteroaryl-C 1-6 Alkylene-, C 3-10 Cycloalkoxy-C1-6 alkylene-;

[0017] Alternatively, R4 and R5, together with the N atom they are connected to, can form substituted or unsubstituted subgroups: 4-9 membered nitrogen-containing heterocyclic groups or 4-9 membered nitrogen-containing heteroaryl groups;

[0018] Ring A is selected from the following group, either substituted or unsubstituted: C6-C 10 Aryl, 5-10 heteroaryl, 3-10 heterocyclic;

[0019] R3 is selected from the following group of substituted or unsubstituted groups: D, halogen, amide, cyano, hydroxyl, amino, amino, oxo (=O), carboxyl, ester, nitro, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 3-6 Cycloalkyl, 5-7 membered heterocyclic, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy;

[0020] R is selected from the following group, whether substituted or unsubstituted: H, deuterium, halogen, hydroxyl, amide, amino, amino, oxo (=O), carboxyl, ester, nitro, cyano, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -NHC(O)OC 1-6 Alkyl, -CONH-C 1-6 Alkyl, -CONH-C 3-6 cycloalkyl, -C 1-6 Alkylene -COOH, -OC 1-6 alkylene-phenyl, -OC 1-6 alkylene-5-6-membered heteroaryl, C 3-6 cycloalkyl, C 3-6 Cycloalkyloxy, 5-7 membered heterocyclic groups, 5-7 membered heterocyclic oxy groups, phenyl, benzyl; or two adjacent or common ring atoms of two R groups forming a 5-7 membered heterocyclic group, C 3-6 cycloalkyl, 5-6 membered heteroaryl, phenyl;

[0021] Unless otherwise specified, substitution refers to the substitution of one or more hydrogen atoms on a group by a group selected from the group consisting of: deuterium, halogen, amino, amine, oxo (=O), carboxyl, amide, hydroxyl, cyano, ester, nitro, phenyl, benzyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-6 cycloalkyl, C 3-6 Cycloalkoxy, 5-7 membered heterocyclic groups, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy group, -NH-C(O)-C 1-6 Alkyl, -NH-C(O)-C 1-6 Alkoxy, sulfonyl, 5-7 membered heterocyclic group -C 1-6 Alkylene-.

[0022] In another preferred embodiment, Selected from the following group:

[0023] In another preferred embodiment, for In another preferred embodiment, for In another preferred embodiment, In another preferred embodiment, for In another preferred embodiment, for In another preferred embodiment, for

[0024] In another preferred embodiment, X is selected from CH, CR', O, S, or N.

[0025] In another preferred embodiment, Y1 and Y2 are each independently selected from CH, CH2, CR', O, S, N, NH or NR'.

[0026] In another preferred embodiment, the compound represented by Formula IA is the compound represented by Formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, hydrate, solvate, or prodrug thereof.

[0027] In the formula,

[0028] X is selected from O, S, NH, NR'; R' is selected from: H, deuterium, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy;

[0029] R4 and R5 are each independently selected from the following group of substituent or unsubstituted groups: H, D, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkyl-(C 1-6 alkylene)-, C 3-10 Cycloalkoxy, 5-10 membered heterocyclic group, 5-10 membered heterocyclic group-(C 1-6 alkylene group (-), 5-10 heterocyclic oxy group (5-10 heterocyclic group -O-), C 3-6 Cycloalkyloxy (C 3-6 cycloalkyl-O-), C 6-10 Aryl, C 6-10 Aryl-(C 1-6 alkylene)-, 5-10 heteroaryl, 5-10 heteroaryl-(C 1-6 alkylene)-, C 3-10 Cycloalkoxy-(C 1-6 alkylene);

[0030] Alternatively, R4 and R5, together with the N atom they are connected to, can form substituted or unsubstituted subgroups: 4-9 membered nitrogen-containing heterocyclic groups or 4-9 membered nitrogen-containing heteroaryl groups;

[0031] n, m, L1, R1, ring A, R3, R are as described in the first aspect of the present invention.

[0032] In another preferred embodiment, the compound has the structure shown in formula (II):

[0033] Wherein, R1, R4, R5, L1, R, m and ring A are as described in the first aspect of the present invention.

[0034] In another preferred embodiment, L1 is selected from C that is either bonded, substituted, or unsubstituted. 1-3 Alkylene.

[0035] In another preferred embodiment, ring A is selected from the group consisting of substituted or unsubstituted groups: C6-C 10 Aryl, 5-10 heteroaryl, 4-7 heterocyclic;

[0036] Wherein, substitution refers to substitution by one or more groups selected from the group consisting of: halogen, amino, amine, nitro, hydroxyl, cyano, carboxyl, C 1-6 Alkyl, Halogenated C 1-6 alkyl and carboxyl substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy group, -NH-C(O)-C 1-6Alkyl, -NH-C(O)-C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne group.

[0037] In another preferred embodiment, ring A is selected from the following group of substituted or unsubstituted groups: phenyl, pyridinyl, imidazolyl, pyridinyl, pyrimidinyl, thiazolyl, benzopyrazolyl, benzothiazolyl, thiophene; preferably, ring A is selected from substituted or unsubstituted phenyl, pyridinyl, benzopyrazolyl.

[0038] Wherein, substitution refers to substitution by one or more groups selected from the group consisting of: halogen, amino, amine, nitro, hydroxyl, cyano, carboxyl, C 1-6 Alkyl, Halogenated C 1-6 alkyl and carboxyl substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy group, -NH-C(O)-C 1-6 Alkyl, -NH-C(O)-C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group;

[0039] More preferably, ring A is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, pyridazinyl, pyrimidinyl, ...

[0040] In another preferred embodiment, R4 is selected from the following group: H, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl groups; and / or

[0041] R5 is selected from the following group of groups, substituted or unsubstituted: H, amide, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-9 cycloalkyl, C 3-7 Cycloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, phenyl-C 1-6 Alkylene-, 5-7 membered heterocyclic group, 5-7 membered heterocyclic group-C 1-6 alkylene-, benzyl, 5-9-membered heteroaryl, 5-9-membered heteroaryl-C 1-6 Alkylene-, C 3-7 Cycloalkoxy-C 1-6Alkylene; preferably H, amide, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-9 cycloalkyl, C 3-7 Cycloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, phenyl-(C 1-6 alkylene group, 5-7 membered heterocyclic group, 5-7 membered heterocyclic group (C 1-6 alkylene), benzyl, 5-9 heteroaryl, 5-9 heteroaryl-(C 1-6 alkylene)-, C 3-7 Cycloalkoxy-(C 1-6 alkylene);

[0042] Alternatively, when R4 and R5 are linked to form a ring, R4 and R5, along with the N atom they are connected to, together form a substituted or unsubstituted 4-7 membered nitrogen-containing heterocyclic group or a 4-7 membered nitrogen-containing heteroaryl group. The substitution refers to substitution by one or more groups selected from the group consisting of: deuterium, halogen, amino, oxo (=O), carboxyl, amide, hydroxyl, cyano, ester, nitro, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 5-7 membered heterocyclic groups, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 5-7 membered heterocyclic group (C 1-6 (alkylene).

[0043] In another preferred embodiment, R4 is selected from the following group: H, C 1-6 Alkyl, deuterated C 1-6 Alkyl group; preferably H or CD3.

[0044] In another preferred embodiment, R5 is selected from the group consisting of substituted or unsubstituted groups: H, amide, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-9 cycloalkyl, C 3-7 Cycloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, phenyl-C 1-6 Alkylene-, 5-7 membered heterocyclic group, 5-7 membered heterocyclic group-C 1-6 alkylene-, benzyl, 5-9-membered heteroaryl, 5-9-membered heteroaryl-C 1-6 Alkylene-, C3-7 Cycloalkoxy-C 1-6 Alkylene; preferably H, methyl, ethyl, propyl, trifluoroethyl, difluoroethyl, cyclobutoxymethylene, or oxodihydropyridylmethylene. Benzyl pyrazolyl -methylene-,oxodihydropyridyl Pyridylmethylene, cyclopropyl, pyridyl, phenyl, benzyl, pyrazolyl, imidazolyl, trideuterylmethyl, hydroxypropyl, cycloheptyl Acetamide group Methylpyrazolylmethylene Ethynyl, Morpholinyl Ethyl The substituted benzopyrazolyl, propynyl, methoxy-substituted benzyl, methoxy-substituted phenyl, deuterated methyl; preferably H, methyl, ethyl, propyl, trifluoroethyl, difluoroethyl, cyclobutoxymethylene, pyridylmethylene, cyclopropyl, phenyl, benzyl, pyridyl, benzomethylpyrazolylmethylene, pyrazolyl, imidazolyl, oxodihydropyridyl, oxodihydropyridylmethylene, trideuterated methyl, hydroxypropyl, methoxy-substituted phenyl, methoxy-substituted benzyl, cycloheptyl (spirocyclic), acetamyl, methylpyrazolylmethylene, aceynyl, morpholine ethyl-substituted benzopyrazol.

[0045] In another preferred embodiment, R1 is selected from the group consisting of: halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-7 membered heterocyclic groups, halogenated C 3-6 cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl groups; preferably halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkyl group.

[0046] In another preferred embodiment, R1 is selected from the group consisting of: chlorine, fluorine, trifluoromethyl, methyl, bromine, iodine, cyclopropyl, methoxy, difluoromethyl, trifluoromethoxy, and ethyl; more preferably, R1 is selected from the group consisting of: chlorine, fluorine, trifluoromethyl, bromine, iodine, cyclopropyl, methoxy, difluoromethyl, trifluoromethoxy, and ethyl; more preferably, R1 is selected from the group consisting of: chlorine, bromine, trifluoromethyl, cyclopropyl, methoxy, and methyl; even more preferably, it is chlorine, bromine, trifluoromethyl, and cyclopropyl.

[0047] In another preferred embodiment, R3 is selected from the group consisting of: halogen, cyano, nitro, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl; preferably methyl, chlorine, or fluorine.

[0048] In another preferred embodiment, R is selected from the group consisting of: H, halogen, nitro, amino, amide, hydroxyl, cyano, C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 3-6 cycloalkyl, -NHC(O)OC 1-6 Alkyl, -C(O)-NH-C 1-6 Alkyl, C 2-6 alkynyl group, -OC 1-6 alkylene-phenyl, -C 1-6 Alkylene-COOH; preferably H, halogen, nitro, amino, amide, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, -NHC(O)OC 1-6 Alkyl, C 2-6 alkynyl group, -OC 1-6 alkylene-phenyl, -C 1-6 Alkylene-COOH.

[0049] In another preferred embodiment, the compound has the structure shown in formula (III):

[0050] In the formula,

[0051] X1, X2, X3, X4 and X5 are each independently CH or N;

[0052] The definitions of m, L1, R1, R4, R5 and R are as described in the first aspect of this invention.

[0053] In another preferred embodiment, at most two of X1, X2, X3, X4 and X5 are N; more preferably, one of X1, X2, X3, X4 and X5 is N.

[0054] In another preferred embodiment, at most two of X1, X2, X3, X4 and X5 are N, and the rest are CH; more preferably, one of X1, X2, X3, X4 and X5 is N, and the rest are CH.

[0055] In another preferred embodiment, in formula III, L1 is a bond, X2 is N, and X1, X3, X4 and X5 are each independently CH.

[0056] In another preferred embodiment, R is located between and / or adjacent to the position.

[0057] In another preferred embodiment, the compound forms a dimer structure as shown in formula (IV): Da-W-Db (IV)

[0058] In the formula,

[0059] Da and Db are each independently selected from compounds represented by formula (I'-A):

[0060] Wherein, Y1, Y2, ring A, n, m, X, L1, R1, R, R3, R4, and R5 are as described in the first aspect of the present invention;

[0061] W is a divalent linker, having the structure shown below: -Wa-L-Wb-;

[0062] Among them, Wa and Wb are each independently selected from the following groups: none, -O-, -S-, -NR. a -, -CO-, -COO-, -SO-, -SO2-, -CO-NR a -、-NR a -CO-, -SO-N(R) a )-、-N(R a -SO-, -NR a -COO-、-COO-NR a -、C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group;

[0063] L is selected from the following group: -O-, -S-, -NR a -, -CO-, -COO-, -SO-, -SO2-, -CO-NR a -、-NR a -CO-, -SO-N(R) a )-、-N(R a -SO-, -NR a -COO-、-COO-NR a -、C 1-6 Alkylene, C 2-6 alkenyl, C6 arylene, 4-7 membered heterocyclic, C 3-9 Cycloalkylene;

[0064] R a Each is independently selected from the following groups: H, deuterium, cyano, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, or substituted or unsubstituted C4 groups 3-6 Cycloalkyl groups (preferably substituted with C) 1-6 Alkyl substitution and / or halogen substitution).

[0065] In another preferred embodiment, Da and Db are each independently selected from the compounds represented by formula I': Rings A, n, m, X, L1, R1, R, R3, R4, and R5 are as described in the first aspect of this invention.

[0066] In another preferred embodiment, Da and Db are each independently the structure shown in Equation I'-B: Preferably, Da and Db are each independently the structure shown in Equation I'. in, Indicates the connection site between Da or Db and W; R1, R4, R5 are as described in the first aspect of the present invention.

[0067] In another preferred embodiment, the linking site of the divalent group of the compound of formula (I') is located at the meta, para, or ortho position of the linking site a; preferably at the meta position.

[0068] In another preferred example, Da and Db are the same or different.

[0069] In another preferred embodiment, Da and Db are the same. In another preferred embodiment, Da and Db are different.

[0070] In another preferred embodiment, Wa and Wb are each independently selected from the following group: none, -O-, -S-, -NR. a -, -CO-, -COO-, -SO-, -SO2-, -CO-NR a -、-NR a -CO-、-NR a -COO-、-COO-NR a -、C 1-6 Alkylene.

[0071] In another preferred embodiment, L is selected from the group consisting of: -O-, -S-, -NR. a -, -CO-, -COO-, -SO-, -CO-NR a -、-NR a -CO-、-NR a -COO-、-COO-NR a -、C 1-6 Alkylene, 4-7 membered heterocyclic group, C 3-9 Cycloalkylene.

[0072] In another preferred embodiment, W is ethylene, -NH-C(O)-,

[0073] In another preferred embodiment, the compound is selected from the compounds shown in Table 1:

[0074] Table 1

[0075] In another preferred embodiment, the compound is the compound prepared in the examples.

[0076] In another preferred embodiment, each group is the corresponding group in the compound prepared in the examples.

[0077] In a second aspect of the invention, a pharmaceutical composition is provided, the pharmaceutical composition comprising:

[0078] (i) a compound as described in the first aspect of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated product, hydrate, solvate, or prodrug thereof; and

[0079] (ii) Pharmaceutically acceptable carriers.

[0080] In another preferred embodiment, the dosage form of the pharmaceutical composition is selected from the group consisting of pills, tablets, capsules, powders, and injections.

[0081] In a third aspect of the invention, a use is provided for the compound described in the first aspect of the invention for preparing (i) a MAT2A enzyme inhibitor, and / or (ii) a medicament for the prevention and treatment of MAT2A-related cancers.

[0082] In another preferred embodiment, the cancer associated with MAT2A is an MTAP-deficient cancer.

[0083] In another preferred embodiment, the cancer associated with MAT2A is a cancer with an MTAP deletion mutation.

[0084] In another preferred embodiment, the MTAP deficiency refers to a reduction in MTAP protein levels or function.

[0085] In another preferred embodiment, the MTAP deficiency refers to the deletion or mutation of the MTAP gene.

[0086] In another preferred embodiment, the MAT2A-related cancer is caused by enhanced MAT2A function.

[0087] In another preferred embodiment, the cancer is selected from solid tumors and liquid tumors; more preferably, it is selected from the group consisting of glioblastoma, melanoma, urothelial carcinoma, pancreatic cancer, non-small cell lung cancer, colorectal cancer, ovarian cancer, lung cancer, breast cancer, leukemia, liver cancer, thyroid cancer, stomach cancer, bladder cancer, lymphoma, gallbladder cancer, brain cancer, or combinations thereof.

[0088] In a fourth aspect of the invention, a method for treating cancer associated with MAT2A is provided, comprising the steps of administering to a subject in need a therapeutically effective amount of the compound of the first aspect of the invention, or the pharmaceutical composition of the second aspect of the invention.

[0089] In another preferred embodiment, the object is MTAP-deficient cancer cells; more preferably, it is MTAP-deleted mutant cancer cells.

[0090] In a fifth aspect of the invention, a method for inhibiting MAT2A enzyme activity is provided, wherein a compound described in the first aspect of the invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or a pharmaceutical composition as described in the second aspect of the invention, is contacted with a protein or cell to inhibit MAT2A enzyme activity.

[0091] In another preferred embodiment, the method is non-diagnostic and non-therapeutic.

[0092] In another preferred embodiment, the method is performed in vitro.

[0093] In another preferred embodiment, the object is a mammal, such as a human.

[0094] In another preferred embodiment, the object is a cell.

[0095] In another preferred embodiment, the object is an MTAP-deficient mutant cancer cell.

[0096] In another preferred embodiment, the cells are derived from rodents (such as mice or rats) or primates (such as humans).

[0097] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0098] Figure 1 shows the in vivo antitumor activity of some compounds. Detailed Implementation

[0099] Through extensive and in-depth research, the inventors have, for the first time, provided a novel MAT2A inhibitor with the structure shown in Formula IA. The compound of this invention exhibits excellent MAT2A inhibitory activity. Based on this, the inventors completed this invention.

[0100] the term

[0101] Unless otherwise stated, the keys indicated by wavy lines in each structure represent the locations where they connect to other parts.

[0102] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0103] The term "alkyl" refers to a straight-chain or branched alkane group or a cyclic hydrocarbon group (including hydrocarbon groups connected to other parts via a carbon atom on a ring or a non-cyclic atom), preferably a straight-chain or branched alkane group, containing 1-10 carbon atoms, more preferably 1-10 carbon atoms (C1-C10), and more preferably 1-6 carbon atoms (C1-C6). Typical "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, etc. Amyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, etc. In this invention, alkyl also includes substituted alkyl groups. "Substituted alkyl" means that one or more positions in an alkyl group are substituted, particularly 1-4 substituents, which can be substituted at any position.

[0104] The term "alkylene" refers to a group formed by removing a hydrogen atom from an alkyl or substituted alkyl group, such as methylene (e.g., Or -CH2-), ethylene (e.g.) ), propylidene (e.g.) ), isopropylidene (e.g.) ), butylide (such as) ), pentylene (e.g.) ), hexyl (such as) ), subheptagen (such as ), Etc. In this invention, the alkylene group also includes substituted alkylene groups, and the substituents can be halogenated (e.g., ...). -CHF- or -CF2-), hydroxyl, cyano, nitro, etc.

[0105] Term "C" 3-10 cycloalkyl (C 1-6 "alkylene" is a divalent alkylene group with a cycloalkyl group attached to one end. Preferably, it is a C1-C6 alkylene or a C3-C6 cycloalkylene.

[0106] In this invention, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing one or more double bonds and typically having a length of 2 to 10 carbon atoms. Alkenyl groups are preferably C2-C6 alkenyl groups, more preferably C2-C4 alkenyl groups. Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc. In this invention, alkenyl groups include substituted alkenyl groups. In this invention, alkenyl groups also include substituted alkenyl groups, and the substituents can be halogenated, hydroxylated, cyano, nitro, etc.

[0107] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing one or more triple bonds and typically having a length of 2 to 10 carbon atoms. The alkynyl group is preferably C2-C6 alkynyl, more preferably C2-C4 alkynyl. The alkynyl group includes, but is not limited to, ethynyl, propynyl, or similar groups. In this invention, the alkynyl group also includes substituted alkynyl groups, which can be halogenated, hydroxyl, cyano, nitro, etc.

[0108] In this invention, the term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon compound group comprising 1-3 rings, each ring containing 3-8 carbon atoms. The term "C3-C..." 10 "" refers to a cycloalkyl group containing 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The cycloalkyl group is preferably C3-C. 10 Cycloalkyl groups, more preferably C3-C6 monocyclic cycloalkyl groups, C7-C 10 Bicyclic or tricyclic cycloalkyl groups. "Substituted cycloalkyl" refers to a cycloalkyl group in which one or more positions are substituted, particularly 1-4 substituents, which can be substituted at any position. Examples of cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, etc.

[0109] The term "C3-C9 cycloalkylene" refers to the group formed by removing two hydrogen atoms from a cycloalkyl group, such as:

[0110] wait.

[0111] In this invention, the term "heterocyclic group" refers to a fully saturated or partially unsaturated cyclic group (including, but not limited to, 3-7 membered monocyclic, 4-7 membered monocyclic, or 6-11 membered bicyclic groups), wherein at least one heteroatom is present in a ring with at least one carbon atom. The term "5-12 membered heterocyclic group" refers to a heterocyclic group containing 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms. "Heterocyclic group" is preferably a 4-10 membered heterocyclic group, such as a 4-6 membered monocyclic heterocyclic group or a 7-10 membered bicyclic group, more preferably a 4-8 membered heterocyclic group, and even more preferably a 4-6 membered heterocyclic group. Each heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms, each of which is independently selected from nitrogen, oxygen, or sulfur atoms, wherein the nitrogen or sulfur atom may be oxidized or quaternized. Heterocyclic groups can be attached to any heteroatom or carbon atom residue in a ring or cyclic molecule, preferably to an N or C atom in a ring or cyclic molecule. Typical monocyclic heterocycles include, but are not limited to, azazolinyl, pyrrolidinyl, oxazolinyl, imidazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, hexahydroacoxaneyl, 4-piperidinoneyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinosulfoxide, thiomorpholinosulfone, 1,3-dioxane, and tetrahydro-1,1-dioxothiophene, etc. Polycyclic heterocyclic groups refer to heterocyclic groups including spirocyclic, fused-ring, and bridged-ring groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring; the "heterocyclic group" can be substituted or unsubstituted, and when substituted, one or more positions of the heterocyclic group are substituted, especially 1-4 substituents, which can be substituted at any position.

[0112] The term "4-7 membered subheterocyclic group" refers to a group formed by removing two hydrogen atoms from a heterocyclic group, such as:

[0113] wait.

[0114] In this invention, the term "aryl" refers to an aromatic cyclic hydrocarbon group, particularly monocyclic and bicyclic groups. Specifically, "C6-C..." 10 "Aryl" refers to an aromatic cyclic hydrocarbon compound group containing 6, 7, 8, 9, or 10 ring carbon atoms. Aryl groups include phenyl, biphenyl, or naphthyl. The aryl group can be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring. Examples include phenyl (i.e., a six-membered aromatic ring), naphthyl, etc., where six-membered aryl groups are also intended to include six-membered aryl 5-6-membered cycloalkyl and six-membered aryl 5-6-membered heterocyclic alkyl groups. C6-C 12Aryl C6-C is preferred 10 Aryl. "Substituted aryl" means that one or more positions of the aryl group are substituted, especially 1-3 substituents, which can be substituted at any position.

[0115] The term "heteroaryl" refers to an aromatic cyclic hydrocarbon group containing 1-4 heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur. "5-10-membered heteroaryl" refers to a heteroaromatic system containing 1-4 heteroatoms and 5-10 ring atoms. Heteroaryl groups are preferably 5- to 9-membered rings, more preferably 5, 6, or 7-membered, and non-limiting examples of heteroaryl groups include pyridinyl, pyrazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, terpineyl, phthalazinyl, benzotriazinyl, purine, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzoisoxazoleyl, isobenzofuryl, and isoindole. The heteroaryl group includes alkyl, indene, benzotriazinyl, thienopyridyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuranyl, benzothiaphenyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazoleyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrroleyl, thiazolyl, furanyl, thiopheneyl, isothiazolyl, furanyl, triazinyl, triazolyl, and tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. "Hyperaryl" can be substituted or unsubstituted; when substituted, one or more positions of the heteroaryl group are substituted, particularly 1-4 substituents, which can be substituted at any position.

[0116] In this invention, the term "alkoxy" refers to an alkoxy group having a straight or branched chain, including alkyl-O- and alkyl-O-alkyl groups, wherein "C1-C 10 "Alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 10 carbon atoms, including C1-C2. 10 Alkyl-O-, -C1-C6 alkyl-O-C1-C6 alkyl, including, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy. Preferably, it is C1-C8 alkoxy, more preferably C1-C6 alkoxy.

[0117] In this invention, the term "cycloalkyloxy" refers to cycloalkyl-O-, wherein "C3-C 10 "Cycloalkyloxy" refers to C3-C 10 cycloalkyl-O-, wherein, C3-C 10 The definition of cycloalkyl is as described above.

[0118] In this invention, the term "heterocyclic oxy group" refers to a heterocyclic group -O-, for example, "5-7-membered heterocyclic oxy group" refers to a 5-7-membered heterocyclic group -O-, wherein the definition of a 5-7-membered heterocyclic group is as described above.

[0119] In this invention, the term "halogen" or "halogen" refers to chlorine, bromine, fluorine, and iodine.

[0120] In this invention, the term "halogenated" refers to being replaced by a halogen.

[0121] In this invention, the term "deuterium substitution" refers to being replaced by deuterium.

[0122] In this invention, the term "hydroxyl group" refers to a group with the structure OH.

[0123] In this invention, the term "nitro" refers to a group containing the structure NO2.

[0124] In this invention, the term "cyano" refers to a group containing the structure CN.

[0125] In this invention, the term "ester group" refers to a group with the structure -COOR, where R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic. The ester group is preferably -COO C1-C6 alkyl.

[0126] The term "amino group" refers to a group with the structure -NR'R", where R' and R" can independently represent hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic groups, as defined above. In one embodiment, R' or R" is each independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and 4-7 membered heterocyclic groups. R' and R" can be the same or different in the dialkylamine segment. The amino group is preferably NH2, NHC1-C6 alkyl, or N(C1-C6 alkyl)2.

[0127] The term "amide" refers to a group with the structure -CONR'R", where R' and R" can independently represent hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic groups, as defined above. R' and R" can be the same or different in the dialkylamine segment. The amide group is preferably -CONH2, -NHCO (C1-C6 alkyl), or -NHCO (C3-C6 cycloalkyl).

[0128] In this invention, the term "substitution" refers to the substitution of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible. Such substituents include (but are not limited to): deuterium, halogen, amino, amine, oxo (=O), carboxyl, amide, hydroxyl, cyano, ester, nitro, phenyl, benzyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 5-7 membered heterocyclic groups, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy group, -NH-C(O)-C 1-6 Alkyl, -NH-C(O)-C 1-6 Alkoxy, sulfonyl, 5-7 membered heterocyclic group (C 1-6 (alkylene).

[0129] Unless otherwise stated, it is assumed that any heteroatom in a suboptimal valence state has enough hydrogen atoms to compensate for its valence state.

[0130] When the substituent is a non-terminal substituent, it is a subunit of the corresponding group. For example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclic corresponds to heterocyclic, alkoxy corresponds to alkoxy, etc.

[0131] In this invention, "multiple" refers to 2, 3, 4, and 5.

[0132] For the compounds presented herein, a bond from a substituent (typically an R group) to the center of an aromatic ring (e.g., benzene, pyridine, etc.) will be understood as a bond that provides a connection at any available vertex of the aromatic ring. In some embodiments, this description also includes connections on rings fused to the aromatic ring. For example, a bond drawn to the center of a quinazoline would represent a bond connected to any available vertex of the benzene ring or pyrimidine moiety of the quinazoline.

[0133] Unless otherwise specified, the structural formulas described in this invention are intended to include all isomers (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers with double bonds, etc. Therefore, any single stereochemical isomer of the compounds of this invention, or a mixture of its enantiomers, diastereomers, or geometric isomers (or conformational isomers), is within the scope of this invention.

[0134] The term "pharmaceutically acceptable salt" is intended to include salts prepared from active compounds with relatively non-toxic acids or bases, depending on the specific substituents on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds in their neutral form with a sufficient amount of the desired base (solvent-free or in a suitable inert solvent). Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese sulfide, potassium, sodium, zinc, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, etc., such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, heparin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, aminobutanetriol, etc. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds in neutral form with a sufficient amount of the desired acid (solvent-free or in a suitable inert solvent). Pharmaceutically acceptable examples of acid addition salts include those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid, etc.; and salts derived from relatively non-toxic organic acids, such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids, such as arginine salts, and salts of organic acids, such as glucuronic acid or galactunoric acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, thereby enabling the conversion of the compound into a basic addition salt or an acid addition salt.

[0135] The neutral form of a compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in some physical properties (e.g., solubility in polar solvents), but otherwise, for the purposes of this invention, those salts are equivalent to the parent form of the compound.

[0136] In addition to salt forms, the present invention provides compounds in prodrug form. The prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Furthermore, prodrugs can be converted into the compounds of the present invention in an in vitro environment by chemical or biochemical methods. For example, when placed in a transdermal patch reservoir containing suitable enzymes or chemical reagents, the prodrug can be slowly converted into the compounds of the present invention.

[0137] Some compounds of the present invention may exist in both solvated and hydrated forms, including hydrated forms. The hydrated forms are generally equivalent to the hydrated forms and should be included within the scope of the present invention. Some compounds of the present invention may exist in polymorphic or amorphous forms. Generally, all physical forms are equivalent for the applications contemplated by the present invention and should be included within the scope of the present invention.

[0138] Some compounds of this invention possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., isolated enantiomers) should all be included within the scope of this invention. When the compounds provided herein have a defined stereochemistry (denoted as R or S, or indicated by dashed or wedge-shaped bonds), it will be understood by those skilled in the art that those compounds are substantially free of other isomers (e.g., at least 80%, 90%, 95%, 98%, 99%, and at most 100% free of other isomers).

[0139] The term "stereoisomer" refers to compounds that have the same chemical structure but differ in the spatial arrangement of their atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and inhibited isomers. Any mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0140] The term "transisomer" refers to a conformational stereoisomer that occurs when rotation around a single bond in a molecule is blocked or significantly slowed due to spatial interactions with other parts of the molecule. The compounds of this invention include all transisomers as a single transisomer, or as a nonspecific mixture of each. If the rotational barrier around the single bond is high enough, and the interconversion between conformations is slow enough, then the separation and differentiation of isomer species as different compounds can be allowed. For example, groups such as, but not limited to, the following groups...

[0141] It may exhibit restricted transformation. For example, compounds S128 and S129 in this invention are transisomers, including...

[0142] Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called proton transfer tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

[0143] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or its enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers), is within the scope of this invention.

[0144] The compounds of the present invention may also contain non-natural proportions of atomic isotopes at one or more isotopic atoms constituting such compounds. A non-natural proportion of an isotope can be defined as ranging from the amount of the atom in question that is naturally found to 100% of that atom. For example, the compounds may be doped with radioactive isotopes, such as tritium (…). 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C), or non-radioactive isotopes, such as deuterium (C), 2 H) or carbon-13 ( 13C). In addition to the uses described in this application, such isotopic variants may provide additional uses. For example, isotopic variants of the compounds of the present invention may have additional uses, including but not limited to, as diagnostic and / or imaging agents, or as cytotoxic / radiotoxic therapeutic agents. Furthermore, isotopic variants of the compounds of the present invention may have altered pharmacokinetic and pharmacodynamic characteristics, thereby contributing to increased safety, tolerability, or efficacy during treatment. All isotopic variants of the compounds of the present invention, regardless of radioactivity, should be included within the scope of this invention.

[0145] Active ingredients

[0146] As used herein, the term "compound of the invention" refers to a compound as defined in the first aspect (e.g., a compound represented by formula I, II, III or IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, hydrate, solvate or prodrug thereof. The term also includes various crystal forms of compounds of formula I, or pharmaceutically acceptable salts thereof.

[0147] Preparation method

[0148] The present invention also provides a method for preparing compounds of formula (I) of the present invention. Typically, the preparation of compounds of general formula (I) of the present invention can be accomplished by the following exemplary methods and examples, but these methods and examples should not be considered in any way as limiting the scope of the invention. The compounds of the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or by a combination of synthetic methods known in the art and the methods described herein. The products obtained from each reaction step are obtained using separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc. The starting materials and chemical reagents required for synthesis can be conventionally synthesized according to literature (such as those provided by Scifinder) or purchased.

[0149] Method 1:

[0150] Step 1: Compound 1 reacts with iodomethane to produce compound 2;

[0151] The organic solvent used in the reaction is not particularly limited, but it is preferably carried out in a suitable organic solvent. The organic solvent can be selected from amide solvents, nitrile solvents, ether solvents, etc.; preferably selected from DMF, acetonitrile, tetrahydrofuran, etc., and more preferably from DMF. The reaction is carried out under alkaline conditions, and the base used is not particularly limited, but it is preferably carried out under suitable alkaline conditions. The base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, TEA, DIPEA, or cesium carbonate; preferably, the base is selected from cesium carbonate. The reaction temperature is not particularly limited, but room temperature is preferred. The reaction time is not particularly limited, for example, 1-24 hours.

[0152] Step 2: Compound 2 and 2,2-ethoxyethanol are nucleophilically substituted to give compound 3;

[0153] The organic solvent used in the reaction is not particularly limited, but is preferably carried out in a suitable organic solvent. The organic solvent is preferably an anhydrous solvent, such as an ether solvent (e.g., tetrahydrofuran). The reaction is carried out under alkaline conditions, and the base used is not particularly limited, but is preferably selected from sodium hydroxide. The reaction temperature is not particularly limited, but is preferably cooled to room temperature in an ice bath. The reaction time is not particularly limited, for example, 1-24 hours.

[0154] Step 3: Compound 3 undergoes a ring-closing reaction to give compound 4;

[0155] The organic solvent used in the reaction is not particularly limited, but is preferably carried out in a suitable organic solvent. The organic solvent is preferably an aromatic solvent, such as toluene. The reaction is preferably carried out under acidic conditions, and the acid is not particularly limited, but preferably selected from polyphosphoric acid. The reaction temperature is not particularly limited, but is preferably 50-80°C, more preferably 60-65°C. The reaction time is not particularly limited, for example, 1-24 hours.

[0156] Step 4: Compound 4 undergoes ammonolysis with ammonia-methanol to produce compound 5;

[0157] The preferred reagent is 7M ammonia-methanol. The reaction temperature is not particularly limited, but is preferably 80-100°C, more preferably 60-65°C. The reaction time is not particularly limited, for example, 12-24 hours.

[0158] Step 5: In the presence of oxalyl chloride, use formula R 2 The amine-treated compound 5, represented by NH2, yields the acylurea compound 6.

[0159] The organic solvent used in the reaction is not particularly limited, but it is preferably carried out in a suitable organic solvent. The organic solvent is preferably an anhydrous solvent, such as 1,2-dichloroethane. The reaction temperature is not particularly limited, but is preferably 50-85°C, more preferably 80-85°C. The reaction time is not particularly limited, for example, 1-3 hours.

[0160] Step 6: Compound 6 is cyclized by dehydrogenation in the presence of a base to obtain compound 7;

[0161] The organic solvent used in the reaction is not particularly limited, but is preferably carried out in a suitable organic solvent. The organic solvent is preferably an anhydrous solvent, such as tetrahydrofuran. The reaction is carried out under alkaline conditions, and the base used is not particularly limited, but is preferably selected from KHMDS. The reaction temperature is not particularly limited, but is preferably -78 to 0°C, more preferably -78°C. The reaction time is not particularly limited, for example, 4 to 24 hours.

[0162] Step 7: Under the action of a base such as triethylamine, the lactam is chlorinated with phosphorus oxychloride to obtain compound 8;

[0163] The organic solvent used in the reaction is not particularly limited, but it is preferably carried out in a suitable organic solvent. The organic solvent is preferably an anhydrous solvent, such as acetonitrile. The reaction is carried out under alkaline conditions, and the base used is not particularly limited, but preferably selected from TEA. The reaction temperature is not particularly limited, but it is preferably 70-80°C, more preferably 80°C. The reaction time is not particularly limited, for example, 1-4 hours.

[0164] Step 8: Compound 5 and NHR 4 R 5 Nucleophilic substitution yielded compound 9.

[0165] The organic solvent used in the reaction is not particularly limited, but is preferably carried out in a suitable organic solvent. The organic solvent is preferably an anhydrous solvent, such as acetonitrile. The reaction is carried out under alkaline conditions, and the base used is not particularly limited, but is preferably selected from DIPEA. The reaction temperature is not particularly limited, but is preferably 50-70°C, more preferably 60°C. The reaction time is not particularly limited, for example, 0.5-4 hours.

[0166] Among them, R 2 For L1-ring A, R 1 R 4 R 5 L1 and ring A are defined as in the first aspect of this invention.

[0167] Pharmaceutical Compositions and Administration

[0168] Because the compounds of this invention possess excellent MAT2A enzyme inhibitory activity, the compounds of this invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of this invention as the main active ingredient can be used to treat and prevent diseases related to MAT2A expression or MTAP deletion-mutant cancers. According to the prior art, the compounds of this invention can be used to treat the following diseases: cancer, etc.

[0169] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects.

[0170] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0171] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0172] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in the dosage forms of capsules, tablets, and pills.

[0173] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0174] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0175] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0176] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0177] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0178] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0179] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0180] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment, wherein the dose administered is the pharmaceutically considered effective dose. Because the compound of the present invention has excellent inhibitory effects on MAT2A enzyme activity, only low doses are needed to achieve therapeutic or preventative effects against MAT2A-related tumors. Generally, for a person weighing 60 kg, the daily dose is typically 0.01–10 mg / kg (based on the portion of the compound of the present invention in the compound, pharmaceutical composition, or prodrug), preferably 0.05–5 mg / kg, more preferably 0.1–1 mg / kg. Of course, the specific dosage should also consider factors such as the route of administration and the patient's health condition, which are all within the scope of a skilled physician's expertise.

[0181] Compared with the prior art, the main advantages of the present invention include:

[0182] (a) The compounds of the present invention have novel structures and good MAT2A inhibitory activity.

[0183] (b) The compounds of the present invention have good pharmacokinetic properties and bioavailability.

[0184] (c) The compounds of the present invention have good in vivo antitumor activity.

[0185] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0186] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0187] General Synthesis Method

[0188] The compounds of the present invention can be prepared, isolated, or obtained by any method obvious to those skilled in the art. The compounds of the present invention can also be prepared according to the exemplary preparation methods provided below (such as the methods in the examples). Reaction conditions, steps, and reactants not provided in the exemplary preparation methods are obvious and known to those skilled in the art. As used herein, the symbols and conventions used in these processes, methods, and examples, whether or not specific abbreviations are specifically defined, have meanings well known to those skilled in the art. Specifically, but not limited to, the following abbreviations may be used in the examples and throughout the specification: g (gram); mg (milligram); mL (milliliter); μL (microliter); millimeter (millimolar); μM (micromolar); MHz (hertz); MHz (megahertz); mmol (millimolar); hr or hrs (hour); min (minute); MS (mass spectrometry); ESI (electrospray ionization); TLC (thin-layer chromatography); HPLC (high-performance liquid chromatography); THF (tetrahydrofuran); CDCl3 (deuterated chloroform); AcOH (acetic acid); DCM (dichloromethane); DMSO (dimethyl sulfoxide); EtOAc (ethyl acetate); MeOH (methanol); DIPEA (N,N-diisopropylethylamine); KHMDS (bis(trimethylsilyl)aminopotassium); TEA (triethylamine); and BOC (tert-butyloxycarbonyl), etc.

[0189] Unless otherwise stated, the raw materials used in the examples may be obtained commercially available or synthesized in a manner known to those skilled in the art or by similar methods described in the examples.

[0190] Example 1: Synthesis of 4-chloro-9-(methylamino)-6-phenylfurano[2,3-f]quinazolin-7(6H)-one (S1)

[0191] Synthesis of S1-2: Cesium carbonate (1.86 g, 5.70 mmol) and methyl iodide (370 μL, 5.97 mmol) were added sequentially to a DMF (10 mL) solution of compound S1-1 (1 g, 5.19 mmol). The mixture was stirred overnight, extracted with water and ethyl acetate, and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound S1-2 (1.03 g) as a brown oil. 1 HNMR (600MHz, CDCl3) δ7.00 (d, J = 7.8Hz, 2H), 3.94 (s, 3H).

[0192] Synthesis of S1-3: Under ice bath conditions, sodium hydroxide (60%, 219 mg, 5.48 mmol) was added dropwise to an anhydrous tetrahydrofuran (12.5 mL) solution of 2,2-ethoxyethanol (702 mg, 5.233 mmol), and the reaction mixture was stirred at 10 °C for 1 hour. Then, a tetrahydrofuran solution (2.5 mL) of S1-2 (1.03 g, 4.98 mol) was slowly added dropwise to the above reaction mixture. After stirring the reaction system at room temperature for 3 hours, the reaction was quenched with ice water (20 mL), the aqueous phase was extracted with ethyl acetate, the organic phase was separated and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography to obtain intermediate S1-3 as a colorless oil (959 mg). 1 H NMR (600MHz, CDCl3) δ6.78-6.77(m,2H),4.78(t,J=5.4Hz,1H),4.02(d,J=5.4Hz ,2H),3.89(s,3H),3.78-3.73(m,2H),3.63-3.58(m,2H),1.23(t,J=6.6Hz,6H).

[0193] Synthesis of S1-4: A suspension of polyphosphoric acid (2.6 g, 7.67 mmol) in toluene (18 mL) was stirred at 60 °C for 30 minutes. Then, a toluene solution (4.5 mL) of intermediate S1-3 (815 mg, 2.54 mmol) was added to the above suspension. The reaction system was stirred at 60 °C for 2 hours and concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the organic phase was washed with water and saturated sodium bicarbonate aqueous solution, respectively. The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography to give intermediate S1-4 (385 mg) as a yellow solid. 1 H NMR (600MHz, CDCl3) δ7.76 (d, J = 2.4Hz, 1H), 7.15 (d, J = 10.8Hz, 1H), 6.88 (d, J = 1.8Hz, 1H), 4.01 (s, 3H).

[0194] Synthesis of S1-5: A solution of intermediate S1-4 (385 mg, 1.80 mmol) in ammonia-methanol (7 M, 5 mL) was heated to 100 °C and stirred for 24 h in a sealed tube. The reaction solution was concentrated under reduced pressure, and the residue was slurried with a mixture of petroleum ether and ethyl acetate to obtain intermediate S1-5 (225 mg) as a pale yellow solid. 1 H NMR (400MHz, MeOD-d4) δ7.95 (d, J = 2.4Hz, 1H), 7.27 (d, J = 10.4Hz, 1H), 6.99 (d, J = 2.4Hz, 1H).

[0195] Synthesis of S1-6: Oxaloyl chloride (36 mg, 0.28 mmol) was added dropwise to a 1,2-dichloroethane (2 mL) solution of intermediate S1-5 (50 mg, 0.23 mmol) under ice bath conditions. The reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was then cooled in an ice-water bath, and a 1,2-dichloroethane (0.5 mL) solution of aniline (44 mg, 0.47 mmol) was slowly added dropwise to the above reaction mixture. The reaction mixture was stirred at room temperature for 2 hours, and the reaction was quenched with ice water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography to give intermediate S1-6 (48 mg) as a white solid. 1 H NMR (400MHz, CDCl3) δ10.59(s,1H),8.79(s,1H),7.85(d,J=2.0Hz,1H),7.59(d,J=2.0Hz,2H) ,7.37(t,J=7.6Hz,2H),7.25(d,J=11.6Hz,1H),7.15(t,J=7.2Hz,1H),6.98(d,J=2.8Hz,1H).

[0196] Synthesis of S1-7: At -78℃, KHMDS (0.4M toluene solution, 2.26 mL) was slowly added dropwise to an anhydrous tetrahydrofuran (2.5 mL) solution of intermediate S1-6 (50 mg, 0.15 mmol). The resulting mixture was slowly heated to room temperature and stirred for 4 hours. The reaction was then quenched with saturated ammonium chloride aqueous solution. The aqueous phase was extracted with ethyl acetate. The organic phase was separated, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with a mixture of petroleum ether and ethyl acetate, filtered, and the filter cake was dried under vacuum to obtain intermediate S1-7 (30 mg) as a white solid. 1 H NMR (600MHz, DMSO-d6) δ11.84(s,1H),8.25(s,1H),7.66-7.63(m,2H),7.60-7.57(m,1H),7.47(d,J=7.8Hz,2H),7.09(s,1H),6.27(s,1H).

[0197] Synthesis of S1: Triethylamine (53.4 μL, 0.384 mmol) and phosphorus oxychloride (35 μL, 0.384 mmol) were added sequentially to an anhydrous acetonitrile (2 mL) solution of intermediate S1-7 (20 mg, 0.064 mmol). The reaction mixture was stirred at 80 °C for 2 hours. The reaction was monitored by TCL until complete. DIPEA (267 μL, 1.53 mmol) and methylamine hydrochloride (21.6 mg, 0.32 mmol) were added sequentially. The reaction mixture was stirred at 60 °C for 2 hours, concentrated under reduced pressure, and purified by reverse-phase preparative HPLC to give compound S1 as a white solid. 1 H NMR(600MHz,MeOD-d4)δ8.09(d,J=2.4Hz,1H),7.67(t,J=7.8Hz,2H),7.64-7.58(m,1H),7.37 (d,J=7.2Hz,2H),7.11(d,J=2.4Hz,1H),6.49(s,1H),3.30(s,3H).ESI-MS(m / z):326.1[M+H] + .

[0198] Example 2: Synthesis of 4-chloro-9-(dimethylamino)-6-phenylfurano[2,3-f]quinazolin-7(6H)-one (S2)

[0199] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(600MHz,MeOD-d4)δ8.06(d,J=2.0Hz,1H),7.68(t,J=7.6Hz,2H),7.65-7.60(m,1H),7. 41-7.37(m,2H),7.09(d,J=2.0Hz,1H),6.53(s,1H),3.40(s,6H).ESI-MS(m / z):340.2[M+H] + .

[0200] Example 3: Synthesis of 4-chloro-9-(ethylamino)-6-phenylfurano[2,3-f]quinazolin-7(6H)-one (S3)

[0201] The preparation was carried out according to the preparation method of Example 1. 1 H NMR (400MHz, MeOD-d4) δ8.07 (d, J=2.0Hz, 1H), 7.70-7.55 (m, 3H), 7.37-7.31 (m, 2H), 7.08 (d, J= 2.0Hz,1H),6.46(s,1H),3.79(q,J=7.2Hz,2H),1.39(t,J=7.2Hz,3H).ESI-MS(m / z):340.2[M+H] +.

[0202] Example 4: Synthesis of 4-chloro-6-phenyl-9-(propylamino)furano[2,3-f]quinazolin-7(6H)-one (S4)

[0203] The preparation was carried out according to the preparation method of Example 1. 1 H NMR (600MHz, MeOD-d4) δ8.10(d,J=2.4Hz,1H),7.67(t,J=7.8Hz,2H),7.61(t,J=7.8Hz,1H),7.37(d,J=7.8Hz,2H),7.11(d ,J=1.8Hz,1H),6.49(s,1H),3.74(t,J=7.2Hz,2H),1.85(q,J=7.8Hz,2H),1.09(t,J=7.8Hz,3H).ESI-MS(m / z):354.2[M+H] + .

[0204] Example 5: Synthesis of 9-amino-4-chloro-6-phenylfurano[2,3-f]quinazolin-7(6H)-one (S5)

[0205] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(600MHz,MeOD-d4)δ8.17(s,1H),7.73-7.63(m,3H),7.45(d,J=7.2Hz,2H),7.18(s,1H),6.55(s,1H).ESI-MS(m / z):312.1[M+H] + .

[0206] Example 6: Synthesis of 4-chloro-6-phenyl-9-((2,2,2-trifluoroethyl)amino)furano[2,3-f]quinazolin-7(6H)-one (S6)

[0207] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(400MHz,MeOD-d4)δ8.11(d,J=1.6Hz,1H),7.71-7.56(m,3H),7.37(d,J=7.6Hz,2H ),7.12(d,J=1.6Hz,1H),6.51(s,1H),4.59(q,J=9.2Hz,2H).ESI-MS(m / z):394.1[M+H] +

[0208] Example 7: Synthesis of 4-chloro-9-((2,2-difluoroethyl)amino)-6-phenylfurano[2,3-f]quinazolin-7(6H)-one (S7)

[0209] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(600MHz,MeOD-d4)δ8.09(d,J=2.4Hz,1H),7.68-7.64(m,2H),7.60(t,J=7.2Hz,1H),7.36(d,J=7.2Hz,2H),7.11 (d,J=2.4Hz,1H),6.49(s,1H),6.29(tt,J=56.4,4.2Hz,1H),4.15(td,J=14.4,4.2Hz,2H).ESI-MS(m / z):376.1[M+H] + .

[0210] Example 8: Synthesis of 4-chloro-9-((oxetane-3-ylmethyl)amino)-6-phenylfurano[2,3-f]quinazolin-7(6H)-one (S8)

[0211] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(600MHz,MeOD-d4)δ8.22(d,J=2.4Hz,1H),7.74-7.67(m,3H),7.46-7.44(m,2H),7.23(d,J=2.4Hz,1H),6.57(s,1H),4.58-4.54(m,1H),4.0 5-4.01(m,1H),3.82(dd,J=13.8,9.6Hz,1H),3.80(d,J=5.4Hz,2H),3.69(dd,J=14.1,9.0Hz,1H),2.54-2.50(m,1H).ESI-MS(m / z):382.2[M+H] + .

[0212] Example 9: Synthesis of 4-chloro-6-phenyl-9-((pyridin-3-ylmethyl)amino)furano[2,3-f]quinazolin-7(6H)-one (S9)

[0213] The preparation was carried out according to the preparation method of Example 1. 1H NMR(600MHz,MeOD-d4)δ9.05(s,1H),8.75-8.70(m,2H),8.11(d,J=1.8Hz,1H),8.00(t,J=7.2Hz,1H),7.65(t,J=7.8Hz,2H ),7.60(t,J=7.8Hz,1H),7.32(d,J=6.6Hz,2H),7.12(d,J=1.8Hz,1H),6.48(s,1H),5.10(s,2H).ESI-MS(m / z):403.2[M+H] + .

[0214] Example 10: Synthesis of 4-chloro-9-(cyclopropylamino)-6-phenylfurano[2,3-f]quinazolin-7(6H)-one (S10)

[0215] The preparation was carried out according to the preparation method of Example 1. 1 H NMR (600MHz, MeOD-d4) δ8.09(d,J=2.4Hz,1H),7.68(t,J=7.8Hz,2H),7.63(t,J=7.8Hz,1H),7.39(d,J=7.8Hz,2H),7. 12(d,J=1.8Hz,1H),6.51(s,1H),3.17-3.13(m,1H),1.12-1.08(m,2H),0.96-0.93(m,2H).ESI-MS(m / z):352.2[M+H] + .

[0216] Example 11: Synthesis of 4-chloro-6-phenyl-9-(phenylamino)furan[2,3-f]quinazolin-7(6H)-one (S11)

[0217] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(400MHz,MeOD-d4)δ8.17(d,J=2.4Hz,1H),7.94-7.91(m,2H),7.70-7.65(m,2H),7.64-7.59(m,1H),7.50-7.4 6(m,2H),7.41-7.38(m,2H),7.29(t,J=7.6Hz,1H),7.16(d,J=2.4Hz,1H),6.55(s,1H).ESI-MS(m / z):388.2[M+H] + .

[0218] Example 12: Synthesis of 9-(benzylamino)-4-chloro-6-phenylfurano[2,3-f]quinazolin-7(6H)-one (S12)

[0219] The preparation was carried out according to the preparation method of Example 1. 1 H NMR (600MHz, DMSO-d6) δ8.44(t,J=6.0Hz,1H),8.26(d,J=2.4Hz,1H),7.61(t,J=7.8Hz,2H),7.54(t,J=7.8Hz,1H),7.45(d,J=7.2H z,2H),7.38-7.33(m,4H),7.29-7.26(m,1H),7.17(d,J=2.4Hz,1H),6.29(s,1H),4.89(d,J=6.0Hz,2H).ESI-MS(m / z):402.2[M+H] + .

[0220] Example 13: Synthesis of 4-chloro-6-phenyl-9-(pyridin-3-ylamino)furano[2,3-f]quinazolin-7(6H)-one (S13)

[0221] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(600MHz,MeOD-d4)δ9.60(s,1H),8.82(d,J=7.8Hz,1H),8.59(s,1H),8.18(s,1H),7.95(m,1H),7.69(t,J= 7.5Hz,2H),7.63(t,J=7.6Hz,1H),7.40(d,J=7.7Hz,2H),7.18(s,1H),6.58(s,1H).ESI-MS(m / z):389.1[M+H] + .

[0222] Example 14: Synthesis of 4-chloro-6-phenyl-9-((pyridin-4-ylmethyl)amino)furano[2,3-f]quinazolin-7(6H)-one (S14)

[0223] The preparation was carried out according to the preparation method of Example 1. 1 H NMR (600MHz, MeOD-d4) δ8.77(d,J=5.4Hz,2H),8.15(d,J=5.4Hz,2H),8.13(s,1H),7.65(t,J=7.2Hz,2H),7. 59(t,J=7.8Hz,1H),7.32(d,J=7.8Hz,2H),7.14(s,1H),6.51(s,1H),5.22(s,2H).ESI-MS(m / z):403.1[M+H] + .

[0224] Example 15: Synthesis of 4-chloro-9-(methylamino)-6-(pyridin-3-yl)furan[2,3-f]quinazolin-7(6H)-one (S15)

[0225] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(600MHz,MeOD-d4)δ8.84(s,1H),8.74(s,1H),8.15-8.08(m,2H),7.86(dd,J=7.2, 4.8Hz,1H),7.14(d,J=2.4Hz,1H),6.57(s,1H),3.32(s,3H).ESI-MS(m / z):327.2[M+H] + .

[0226] Example 16: Synthesis of 4-chloro-6-(3-fluorophenyl)-9-(methylamino)furano[2,3-f]quinazolin-7(6H)-one (S16)

[0227] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(400MHz,MeOD-d4)δ8.13(s,1H),7.76-7.63(m,1H),7.45-7.35(m,1H),7.25( d,J=8.0Hz,2H),7.15(s,1H),6.54(s,1H),3.33(s,3H).ESI-MS(m / z):344.1[M+H] + .

[0228] Example 17: Synthesis of 3-(4-chloro-9-(methylamino)-7-oxofuran[2,3-f]quinazolin-6(7H)-yl)benzonitrile (S17)

[0229] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(600MHz,MeOD-d4)δ8.12(d,J=2.4Hz,1H),7.73-7.67(m,1H),7.42-7.37(m,1H),7.27 -7.23(m,2H),7.14(d,J=2.4Hz,1H),6.54(s,1H),3.32(s,3H).ESI-MS(m / z):351.1[M+H] + .

[0230] Example 18: Synthesis of 6-((1H-imidazol-5-yl)methyl)-4-chloro-9-(methylamino)furan[2,3-f]quinazolin-7(6H)-one (S18)

[0231] Synthesis of S18-2: Under ice bath conditions, sodium hydroxide (60%, 118 mg, 2.96 mmol) was added in portions to an anhydrous tetrahydrofuran (2.5 mL) solution of S18-1 (250 mg, 2.69 mmol), and the mixture was stirred for 2 hours. Then, SEMCl (672 mg, 4.03 mmol) was slowly added dropwise to the above reaction mixture. After stirring the reaction system at room temperature for 1.5 hours, the reaction was quenched with ice water. The aqueous phase was extracted with ethyl acetate, the organic phase was separated and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography to obtain intermediate S18-2 (466 mg). 1 H NMR (400MHz, CDCl3) δ7.63 (s, 1H), 7.59 (s, 1H), 5.31 (s, 2H), 3.50 (t, J = 8.4Hz, 2H), 0.92 (t, J = 8.4Hz, 2H), -0.01 (s, 9H).

[0232] Synthesis of S18-3: Compound S18-2 (150 mg, 0.672 mmol) and THF (2.5 mL) were placed in a vial under nitrogen atmosphere. LAH (38.27 mg, 1.01 mmol) was added, and the reaction mixture was stirred at 70 °C for 2 hours. The reaction mixture was cooled to 0 °C and quenched with wet Na₂SO₄. The reaction mixture was filtered through a diatomaceous earth mat after washing with EtOAc. The filtrate was dried over Na₂SO₄, filtered, and concentrated to give S18-3 (70 mg). 1 H NMR (600MHz, CDCl3) δ7.51(s,1H),6.88(s,1H),5.20(s,2H),3.79(s,2H),3.46(t,J=7.6Hz,2H),1.83(brs,2H),0.89(t,J=7.6Hz,2H),-0.029(s,9H).

[0233] Synthesis of S18-4: Refer to the preparation method in Example 1, except that aniline is replaced with (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)methylamine;

[0234] Synthesis of S18-5: Refer to the preparation method of Example 1, except that S1-6 is replaced with S18-4;

[0235] Synthesis of S18: Triethylamine (74.64 μL, 0.537 mmol) and phosphorus oxychloride (49 μL, 0.547 mmol) were added sequentially to an anhydrous acetonitrile (4 mL) solution of intermediate S18-5 (40 mg, 0.089 mmol). The reaction mixture was stirred at 80 °C for 2 h, and the reaction was monitored by TCL until complete. DIPEA (371 μL, 2.14 mmol) and methylamine hydrochloride (30 mg, 0.445 mmol) were added sequentially. The reaction mixture was stirred at 60 °C for 2 h, concentrated directly under reduced pressure, washed with saturated ammonium chloride solution and extracted with DCM. After drying with anhydrous sodium sulfate, the solution was directly evaporated to dryness without further purification and directly added to the next step. The obtained compound was dissolved in 1 mL of trifluoroacetic acid, stirred at room temperature for 2 h, concentrated directly under reduced pressure, and purified by reversed-phase preparative HPLC to obtain compound S18 as a white solid. 1 H NMR (600MHz, MeOD-d4) δ 8.82 (s, 1H), 8.07 (s, 1H), 7.55 (d, J = 8.3Hz, 2H), 7.12 (s, 1H), 5.54 (s, 2H), 3.22 (s, 3H). ESI-MS(m / z):330.1[M+H] + .

[0236] Example 19: Synthesis of 4-chloro-6-(2-fluorophenyl)-9-(methylamino)furan[2,3-f]quinazolin-7(6H)-one (S19)

[0237] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(400MHz,MeOD-d4)δ8.11(d,J=2.4Hz,1H),7.69-7.63(m,1H),7.50-7.43(m,3H), 7.13(d,J=2.4Hz,1H),6.54(d,J=1.2Hz,1H),3.30(s,3H).ESI-MS(m / z):344.2[M+H] + .

[0238] Example 20: Synthesis of 4-chloro-9-(methylamino)-6-(2-methylpyridin-3-yl)furano[2,3-f]quinazolin-7(6H)-one (S20)

[0239] The preparation was carried out according to the preparation method of Example 1. 1H NMR(600MHz,MeOD-d4)δ8.82(d,J=5.4Hz,1H),8.30(d,J=8.4Hz,1H),8.13(s,1H),7.90(t,J =7.2Hz,1H),7.14(s,1H),6.61(s,1H),3.30(s,3H),2.48(s,3H).ESI-MS(m / z):341.1[M+H] + .

[0240] Example 21: Synthesis of 9-(methylamino)-6-phenyl-4-(trifluoromethyl)furan[2,3-f]quinazolin-7(6H)-one (S21)

[0241] Synthesis of S21-3: Refer to the synthesis of S1-4.

[0242] Synthesis of S21-4: Under a nitrogen atmosphere, compound S21-3 (50 mg, 0.183 mmol), CH3O2CCF2SO2F (176 mg, 0.915 mmol), and CuI (70 mg, 0.366 mmol) were added sequentially to a 250 μL solution of DMF. The reaction was carried out at 100 °C for 20 hours. The reaction solution was extracted with water and EtOAc, and the organic phase was dried over anhydrous sodium sulfate. The intermediate S21-4 was purified by Flash column chromatography. 1 H NMR (400MHz, CDCl3) δ7.84 (s, 1H), 7.39 (d, J = 10.4Hz, 1H), 6.98 (s, 1H), 4.05 (s, 3H).

[0243] Synthesis of S21: Prepared according to the method of Example 1, replacing S1-4 with S21-4. 1 H NMR(600MHz,MeOD-d4)δ8.19(d,J=2.4Hz,1H),7.68(t,J=7.8Hz,2H),7.62(t,J=7.8Hz,1H ),7.40(d,J=7.2Hz,2H),7.16(s,1H),6.75(s,1H),3.32(s,3H).ESI-MS(m / z):360.2[M+H] + .

[0244] Example 22: Synthesis of 9-(methylamino)-6-(pyridin-3-yl)-4-(trifluoromethyl)furan[2,3-f]quinazolin-7(6H)-one (S22)

[0245] The preparation was carried out according to the method described in Example 21. 1H NMR (400MHz, MeOD-d4) δ8.84(m,1H),8.75(s,1H),8.20(d,J=2.3Hz,1H),8.12(d,J=8.1Hz,1H) ,7.86(dd,J=8.2,5.0Hz,1H),7.18(s,1H),6.75(s,1H),3.31(s,3H).ESI-MS(m / z):361.2[M+H] + .

[0246] Example 23: Synthesis of 4-chloro-6-phenyl-9-((pyridin-2-ylmethyl)amino)furano[2,3-f]quinazolin-7(6H)-one (S23)

[0247] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(600MHz,MeOD-d4)δ8.75(s,1H),8.42(m,1H),8.14(s,1H),8.06-8.02(m,1H),7.84(s,1H),7.65(m ,2H),7.60(m,1H),7.36-7.31(m,2H),7.14(s,1H),6.50(s,1H),5.21(s,2H).ESI-MS(m / z):403.1[M+H] + .

[0248] Example 24: Synthesis of 4-chloro-6-phenyl-9-(pyridin-2-ylamino)furano[2,3-f]quinazolin-7(6H)-one (S24)

[0249] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(600MHz,MeOD-d4)δ8.55(s,1H),8.47(s,1H),8.19(s,1H),8.14-8.08(m,1H),7.73-7.67(m,2H),7. 67-7.62(m,1H),7.44(d,J=6.0Hz,2H),7.38(s,1H),7.17(s,1H),6.57(s,1H).ESI-MS(m / z):389.1[M+H] + .

[0250] Example 25: Synthesis of 4-chloro-6-phenyl-9-(pyridin-4-ylamino)furano[2,3-f]quinazolin-7(6H)-one (S25)

[0251] The preparation was carried out according to the preparation method of Example 1. 1H NMR(600MHz,MeOD-d4)δ8.75(s,4H),8.21(s,1H),7.71(t,J=7.2Hz,2H),7.66(t,J=8 .1Hz,1H),7.43(d,J=8.4Hz,2H),7.20(s,1H),6.62(s,1H).ESI-MS(m / z):389.1[M+H] + .

[0252] Example 26: Synthesis of 4-chloro-6-(1H-indazol-4-yl)-9-(methylamino)furano[2,3-f]quinazolin-7(6H)-one (S26)

[0253] Synthesis of S26-2: Compound S26-1 (250 mg, 1.53 mmol) was dissolved in ultra-dry tetrahydrofuran (15 mL). NaH (67.3 mg, 1.68 mmol) was added in portions under ice bath conditions, and the mixture was stirred for 30 minutes under ice bath conditions. Subsequently, SEMCl (280.5 mg, 1.68 mmol) was slowly added dropwise, and the reaction was carried out at room temperature for 2 hours. The reaction solution was extracted with water and EtOAc, and the organic phase was dried over anhydrous sodium sulfate. The intermediate S26-2 (199 mg) was purified by Flash column chromatography. 1 H NMR (600MHz, CDCl3) δ8.65(s,1H),8.20(d,J=7.8Hz,1H),7.96(d,J=8.4Hz,1H),7.56(t ,J=8.4Hz,1H),5.82(s,2H),3.56(t,J=8.4Hz,2H),0.88(t,J=8.4Hz,2H),-0.07(s,9H).

[0254] Synthesis of S26-3: Compound S26-2 (199 mg, 0.678 mmol) was dissolved in 15 mL of ethanol, and 20 mg of Pd / C was added. The reaction was carried out overnight under a hydrogen atmosphere. The reaction solution was then filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain compound S26-3 (197 mg). 1 H NMR (400MHz, CDCl3) δ7.95 (s, 1H), 7.21 (t, J = 7.8Hz, 1H), 6.96 (d, J = 8.4Hz, 1H), 6.39 (d, J = 7.4 Hz,1H),5.69(s,2H),4.13(s,2H),3.55(t,J=8.0Hz,2H),0.89(t,J=8.4Hz,2H),-0.07(s,9H).

[0255] Synthesis of S26-4: Refer to the synthesis of compound S1-6

[0256] Synthesis of S26-5: Refer to the synthesis of compound S1-7.

[0257] Synthesis of S26: In a 25 mL round-bottom flask, all of the compound S26-5 (65 mg, 0.124 mmol) from the previous step and 1 mL of trifluoroacetic acid were added. After stirring at room temperature for 1 h, the reaction was monitored by TLC until it was complete. The mixture was then purified by reverse HPLC to obtain a white solid (20 mg). 1 H NMR(400MHz,MeOD-d4)δ8.12(s,1H),7.85(s,1H),7.81(d,J=8.8Hz,1H),7.64(t,J=8.0Hz,1H),7 .22(d,J=7.6Hz,1H),7.12(d,J=2.0Hz,1H),6.43(s,1H),3.35(s,3H).ESI-MS(m / z):366.2[M+H] + .

[0258] Example 27: Synthesis of 4-chloro-9-((2-methyl-2H-indazol-5-yl)amino)-6-phenylfurano[2,3]-quinazolin-7(6H)-one (S27)

[0259] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(600MHz,MeOD-d4)δ8.54(s,1H),8.26(s,1H),8.18(s,1H),7.72-7.65(m,3H),7.64-7.60(m,1H),7.5 6(d,J=9.1Hz,1H),7.40(d,J=7.7Hz,2H),7.16(s,1H),6.6(s,1H),4.24(s,3H).ESI-MS(m / z):442.2[M+H] + .

[0260] Example 28: Synthesis of 4-chloro-9-(methylamino)-6-(pyridin-4-yl)furano[2,3-f]quinazolin-7(6H)-one (S28)

[0261] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(600MHz,MeOD-d4)δ8.98(d,J=5.6Hz,2H),8.11(s,1H),7.88(d,J=5.3Hz,2H),7.13(s,1H),6.68(s,1H),3.28(s,3H).ESI-MS(m / z):327.2[M+H] + .

[0262] Example 29: Synthesis of 4-chloro-6-(4-methoxyphenyl)-9-(methylamino)furano[2,3-f]quinazolin-7(6H)-one (S29)

[0263] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(600MHz,MeOD-d4)δ8.14(s,1H),7.31(d,J=8.4Hz,2H),7.20(d,J=7.8Hz,2H ),7.16(s,1H),6.59(s,1H),3.92(s,3H),3.36(s,3H).ESI-MS(m / z):356.2[M+H] + .

[0264] Example 30: Synthesis of 4-chloro-9-(methylamino)-6-(3-(trifluoromethyl)phenyl)furano[2,3-f]quinazolin-7(6H)-one (S30)

[0265] The preparation was carried out according to the preparation method of Example 1. 1 H NMR (600MHz, MeOD-d4) δ8.11(d,J=1.8Hz,1H),7.94(d,J=8.4Hz,1H),7.89(t,J=7.8Hz,1H),7.79(s,1 H),7.69(d,J=8.4Hz,1H),7.13(d,J=2.4Hz,1H),6.46(s,1H),3.31(s,3H).ESI-MS(m / z):394.1[M+H] + .

[0266] Example 31: Synthesis of 4-chloro-6-(3-methoxyphenyl)-9-(methylamino)furano[2,3-f]quinazolin-7(6H)-one (S31)

[0267] The preparation was carried out according to the preparation method of Example 1. 1 H NMR (600MHz, MeOD-d4) δ8.09(d,J=1.8Hz,1H),7.56(t,J=7.8Hz,1H),7.17(dd,J=8.4,1.8Hz,1H),7.11(d,J=2.4Hz,1H ),6.95(t,J=1.8Hz,1H),6.93(dd,J=7.2,0.6Hz,1H),6.54(s,1H),3.86(s,3H),3.29(s,3H).ESI-MS(m / z):356.2[M+H] + .

[0268] Example 32: Synthesis of 4-chloro-6-(4-fluorophenyl)-9-(methylamino)furan[2,3-f]quinazolin-7(6H)-one (S32)

[0269] The preparation was carried out according to the preparation method of Example 1. 1 H NMR (400MHz, MeOD-d4) δ8.07(d,J=2.0Hz,1H),7.39(d,J=6.8Hz,4H),7.10(d,J=2.0Hz,1H),6.50(s,1H),3.26(s,3H).ESI-MS(m / z):344.1[M+H] + .

[0270] Example 33: Synthesis of 4-chloro-6-(5-fluoropyridin-3-yl)-9-(methylamino)furano[2,3-f]quinazolin-7(6H)-one (S33)

[0271] The preparation was carried out according to the preparation method of Example 21. 1 H NMR(600MHz,MeOD-d4)δ8.73(s,1H),8.50(s,1H),8.11(s,1H),7.88(d,J=8 .8Hz,1H),7.14(s,1H),6.59(s,1H),3.29(s,3H).ESI-MS(m / z):345.2[M+H] + .

[0272] Example 34: Synthesis of 6-(3-fluorophenyl)-9-(methylamino)-4-(trifluoromethyl)furan[2,3-f]quinazolin-7(6H)-one (S34)

[0273] The preparation was carried out in accordance with Example 21. 1 H NMR(600MHz,MeOD-d4)δ8.18(s,1H),7.72-7.66(m,1H),7.39(t,J=8.4Hz,1H),7. 28-7.22(m,2H),7.16(s,1H),6.75(s,1H),3.29(s,3H).ESI-MS(m / z):378.1[M+H] + .

[0274] Example 35: Synthesis of 9-(methylamino)-6-(2-methylpyridin-3-yl)-4-(trifluoromethyl)furano[2,3-f]quinazolin-7(6H)-one (S35)

[0275] The preparation was carried out according to the preparation method of Example 21. 1H NMR (600MHz, MeOD-d4) δ8.77(d,J=5.4Hz,1H),8.21(s,1H),8.16(d,J=8.4Hz,1H),7.79(dd,J= 6.6,6.0Hz,1H),7.18(s,1H),6.71(s,1H),3.31(s,3H),2.43(s,3H).ESI-MS(m / z):375.2[M+H] + .

[0276] Example 36: Synthesis of 4-bromo-9-(methylamino)-6-phenylfurano[2,3-f]quinazolin-7(6H)-one (S36)

[0277] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(600MHz,MeOD-d4)δ8.14(s,1H),7.71-7.61(m,3H),7.41(s,2H),7.08(s,1H),6.68(s,1H),3.33(s,3H).ESI-MS(m / z):370.1[M+H] + .

[0278] Example 37: Synthesis of 4-bromo-9-(methylamino)-6-(pyridin-3-yl)furan[2,3-f]quinazolin-7(6H)-one (S37)

[0279] The preparation was carried out according to the preparation method of Example 1. 1 H NMR (400MHz, MeOD-d4) δ8.82(d,J=5.2Hz,1H),8.70(s,1H),8.12(d,J=1.2Hz,1H),8.08(d,J=8.0Hz,1H) ,7.84(dd,J=8.4,5.2Hz,1H),7.07(d,J=2.4Hz,1H),6.70(s,1H),3.29(s,3H).ESI-MS(m / z):371.1[M+H] + .

[0280] Example 38: Synthesis of 4-bromo-6-(3-fluorophenyl)-9-(methylamino)furan[2,3-f]quinazolin-7(6H)-one (S38)

[0281] The preparation was carried out according to the preparation method of Example 1. 1H NMR(600MHz,MeOD-d4)δ8.12(d,J=2.4Hz,1H),7.72-7.67(m,1H),7.42-7.37(m,1H),7.26 -7.22(m,2H),7.07(d,J=1.8Hz,1H),6.70(s,1H),3.31(s,3H).ESI-MS(m / z):388.1[M+H] + .

[0282] Example 39: Synthesis of 4-bromo-9-(methylamino)-6-(2-methylpyridin-3-yl)furano[2,3-f]quinazolin-7(6H)-one (S39)

[0283] The preparation was carried out according to the preparation method of Example 1. 1 H NMR (400MHz, MeOD-d4) δ8.78(d,J=5.2Hz,1H),8.18(d,J=8.4Hz,1H),8.13(d,J=2.4Hz,1H),7.82(dd,J= 8.4,5.6Hz,1H),7.07(d,J=2.4Hz,1H),6.70(s,1H),3.28(s,3H),2.44(s,3H).ESI-MS(m / z):385.2[M+H] + .

[0284] Example 40: Synthesis of 4-cyclopropyl-9-(methylamino)-6-phenylfurano[2,3-f]quinazolin-7(6H)-one (S40)

[0285] Synthesis of S40-2: Under a nitrogen atmosphere, compound S21-3 (250 mg, 0.92 mmol), cyclopropylboronic acid (102 mg, 1.20 mmol), potassium phosphate (683.5 mg, 3.22 mmol), tricyclohexylphosphine (25.8 mg, 1.192 mmol), and palladium acetate (10 mg, 0.046 mmol) were added sequentially to a mixed solvent of toluene (4 mL) and water (0.2 mL), and reacted overnight at 100 °C. The reaction solution was extracted with water and EtOAc, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography to obtain intermediate S40-2. 1H NMR (400MHz, CDCl3) δ7.72(d,J=2.0Hz,1H),6.91(d,J=2.4Hz,1H),6.58(d,J=12.4Hz ,1H),3.99(s,3H),2.16(tt,J=8.7,5.0Hz,1H),1.17-1.09(m,2H),0.92-0.86(m,2H).

[0286] Synthesis of S40: The preparation method of Example 1 was followed, but S1-4 was replaced with S40-2 to obtain compound S40. 1 H NMR(400MHz,MeOD-d4)δ8.04(s,1H),7.71-7.59(m,3H),7.37(d,J=6.8Hz,2H),7.23(s,1H),5.99(s, 1H),3.33(s,3H),2.27-2.15(m,1H),1.13-1.07(m,2H),0.62-0.57(m,2H).ESI-MS(m / z):332.2[M+H] + .

[0287] Example 41: Synthesis of 4-methoxy-9-(methylamino)-6-phenylfurano[2,3-f]quinazolin-7(6H)-one (S41)

[0288] The preparation was carried out according to the preparation method of Example 1. 1 H NMR (600MHz, MeOD-d4) δ7.99(d,J=2.4Hz,1H),7.69(t,J=7.2Hz,2H),7.63(t,J=7.2Hz,1H),7.45(d,J =7.2Hz,2H),7.09(d,J=1.8Hz,1H),5.93(s,1H),3.74(s,3H),3.36(s,3H).ESI-MS(m / z):322.3[M+H] + .

[0289] Example 42: Synthesis of 6-(3-fluoro-2-methylphenyl)-9-(methylamino)-4-(trifluoromethyl)furano[2,3-f]quinazolin-7(6H)-one (S42)

[0290] The preparation was carried out according to the preparation method of Example 21. 1H NMR (400MHz, DMSO-d6) δ8.36(d,J=2.4Hz,1H),8.34-8.28(brs,1H),7.48(q,J=14.8Hz,1H),7.44-7.34(m,1H),7.22(t,J =2.0Hz,1H),7.18(d,J=7.6Hz,1H),6.47(s,1H),3.14(d,J=4.4Hz,3H),1.90(d,J=2.0Hz,3H).ESI-MS(m / z):392.2[M+H] + .

[0291] Example 43: Synthesis of 6-(1H-indazol-4-yl)-9-(methylamino)-4-(trifluoromethyl)furano[2,3-f]quinazolin-7(6H)-one (S43)

[0292] The preparation was carried out according to the preparation method of Example 26. 1 H NMR (400MHz, MeOD-d4) δ8.21(d,J=2.4Hz,1H),7.84(s,1H),7.81(d,J=8.8Hz,1H),7.69-7.62( m,1H),7.23(d,J=7.2Hz,1H),7.16(s,1H),6.68(s,1H),3.35(s,3H).ESI-MS(m / z):400.1[M+H] + .

[0293] Example 44: Synthesis of 4-bromo-6-(3-fluoro-2-methylphenyl)-9-(methylamino)furano[2,3-f]quinazolin-7(6H)-one (S44)

[0294] The preparation was carried out according to the preparation method of Example 1. 1 H NMR (400MHz, MeOD-d4): δ8.12(d,J=2.0Hz,1H),7.54-7.45(m,1H),7.34(t,J=8.8Hz,1H),7.15(d, J=8.0Hz,1H),7.07(d,J=2.4Hz,1H),6.60(s,1H),2.01(d,J=2.0Hz,3H).ESI-MS(m / z):402.1[M+H] + .

[0295] Example 45: Synthesis of 4-bromo-6-(1H-indazol-4-yl)-9-(methylamino)furano[2,3-f]quinazolin-7(6H)-one (S45)

[0296] The preparation was carried out according to the preparation method of Example 26.1 H NMR (400MHz, MeOD-d4) δ8.12(d,J=2.4Hz,1H),7.84(s,1H),7.80(d,J=8.4Hz,1H),7.64(dd,J=8.4,7.2H z,1H),7.21(d,J=7.6Hz,1H),7.05(d,J=2.4Hz,1H),6.59(s,1H),3.33(s,3H).ESI-MS(m / z):410.1[M+H] + .

[0297] Example 46: Synthesis of 4-chloro-9-(methylamino)-6-(2-(trifluoromethyl)pyridin-3-yl)furano[2,3-f]quinazolin-7(6H)-one (S46)

[0298] The preparation was carried out according to the preparation method of Example 21. 1 H NMR (400MHz, MeOD-d4) δ8.93(d,J=4.0Hz,1H),8.11(d,J=2.4Hz,1H),8.07(d,J=7.6Hz,1H),7.95( dd,J=8.0,4.8Hz,1H),7.13(d,J=2.4Hz,1H),6.40(s,1H),3.35(s,3H).ESI-MS(m / z):395.1[M+H] + .

[0299] Example 47: Synthesis of 6-(3-(benzyloxy)phenyl)-4-chloro-9-(methylamino)furan[2,3-f]quinazolin-7(6H)-one (S47)

[0300] The preparation was carried out according to the preparation method of Example 1. 1 H NMR (400MHz, CDCl3) δ7.75 (d, J = 2.4Hz, 1H), 7.51-7.30 (m, 7H), 7.14-7.08 (m, 1H), 6. 95(d,J=2.0Hz,1H),6.92-6.86(m,2H),5.07(q,J=13.2Hz,2H),3.31(d,J=4.8Hz,3H).

[0301] Example 48: Synthesis of 4-chloro-6-(3-fluoro-2-methylphenyl)-9-(methylamino)furano[2,3-f]quinazolin-7(6H)-one (S48)

[0302] The preparation was carried out according to the preparation method of Example 1. 1H NMR(400MHz,MeOD-d4)δ8.11(d,J=2.0Hz,1H),7.52-7.45(m,1H),7.34(t,J=9.2Hz,1H),7. 16-7.11(m,2H),6.43(s,1H),3.31(s,3H),2.01(d,J=1.2Hz,3H).ESI-MS(m / z):358.2[M+H] + .

[0303] Example 49: Synthesis of 4-chloro-9-(methylamino)-6-(o-tolyl)furano[2,3-f]quinazolin-7(6H)-one (S49)

[0304] The preparation was carried out according to the preparation method of Example 1. 1 H NMR (600MHz, MeOD-d4) δ8.13(d,J=1.8Hz,1H),7.55-7.51(m,2H),7.49-7.46(m,1H),7.28(d,J=7. 8Hz,1H),7.14(d,J=2.4Hz,1H),6.42(s,1H),3.34(s,3H),2.10(s,3H).ESI-MS(m / z):340.3[M+H] + .

[0305] Example 50: Synthesis of 4-chloro-6-(3-hydroxyphenyl)-9-(methylamino)furano[2,3-f]quinazolin-7(6H)-one (S50)

[0306] Compound S47 (15 mg, 0.035 mmol) was dissolved in ultradry DCM (0.5 mL) in a 25 mL flask. Under nitrogen protection, N,N-dimethylaniline (4.24 mg, 0.104 mmol) was added, followed by stirring and the addition of anhydrous aluminum chloride. The reaction was allowed to proceed for 4 hours. After the reaction was complete, the solution was evaporated to dryness, neutralized with saturated sodium bicarbonate solution, extracted with DCM, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by Flash column chromatography to obtain S50. 1 H NMR(600MHz,MeOD-d4)δ8.03(d,J=1.8Hz,1H),7.41(t,J=8.4Hz,1H),7.04(d,J=1.8Hz,1H) ,6.96(dd,J=8.4,1.8Hz,1H),6.75(d,J=7.8Hz,1H),6.72(s,1H),6.52(s,1H),3.22(s,3H).

[0307] Example 51: Synthesis of 6-(3-aminophenyl)-4-chloro-9-(methylamino)furano[2,3-f]quinazolin-7(6H)-one (S51)

[0308] Compound S52 (80.5 mg, 0.217 mmol) was dissolved in a mixed solution of 4 mL ethanol and 1.2 mL water. Iron powder (60.88 mg, 1.09 mmol) and ammonium chloride (116.31 mg, 2.17 mmol) were added. The reaction solution was heated at 80 °C for 3 hours. The mixture was filtered while hot, and the filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography to obtain S51 (34 mg). 1 H NMR (600MHz, MeOD-d4) δ8.11(d,J=1.8Hz,1H),7.67(t,J=8.4Hz,1H),7.39(dd,J=8.4,2.4Hz,1H ),7.23-7.20(m,2H),7.12(d,J=1.8Hz,1H),6.55(s,1H),3.32(s,3H).ESI-MS(m / z):341.1[M+H] + .

[0309] Example 52: Synthesis of 4-chloro-9-(methylamino)-6-(3-nitrophenyl)furano[2,3-f]quinazolin-7(6H)-one (S52)

[0310] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(600MHz,MeOD-d4)δ8.49(d,J=8.4Hz,1H),8.36(s,1H),8.12(d,J=1.8Hz,1H),7.93(t,J=8.4Hz,1 H),7.84(d,J=7.8Hz,1H),7.14(d,J=2.4Hz,1H),6.55(s,1H),3.31(s,3H).ESI-MS(m / z):371.1[M+H] + .

[0311] Example 53: Synthesis of 4-chloro-6-(2-chlorophenyl)-9-(methylamino)furano[2,3-f]quinazolin-7(6H)-one (S64)

[0312] The preparation was carried out according to the preparation method of Example 1. 1H NMR(400MHz,MeOD-d4)δ8.11(d,J=2.4Hz,1H),7.77-7.74(m,1H),7.65-7.59(m,2H),7.53 -7.50(m,1H),7.13(d,J=2.0Hz,1H),6.38(s,1H),3.32(s,3H).ESI-MS(m / z):360.0[M+H] + .

[0313] Example 54: Synthesis of 4-chloro-9-(methylamino)-6-(pyridin-2-yl)furano[2,3-f]quinazolin-7(6H)-one (S66)

[0314] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(400MHz,MeOD-d4)δ8.75(dd,J=4.8,1.2Hz,1H),8.19(td,J=8.0,2.0Hz,1H),8.14-8.09(m,1H),7.73-7.65(m ,1H),7.61(d,J=8.0Hz,1H),7.12(t,J=2.4Hz,1H),6.39(d,J=1.6Hz,1H),3.30(s,3H).ESI-MS(m / z):327.1[M+H] + .

[0315] Example 55: Synthesis of 6-(2-methoxyphenyl)-9-(methylamino)-4-(trifluoromethyl)furano[2,3-f]quinazolin-7(6H)-one (S93)

[0316] The preparation was carried out according to the preparation method of Example 21. 1 H NMR(400MHz,MeOD-d4)δ8.18(d,J=2.4Hz,1H),7.65-7.58(m,1H),7.34(dd,J=7.6,2.4Hz,1H),7.31(dd,J=6.0,1.2Hz, 1H),7.22(td,J=8.0,1.2Hz,1H),7.17-7.14(m,1H),6.74(s,1H),3.77(s,3H),3.32(s,3H).ESI-MS(m / z):390.2[M+H] + .

[0317] Example 56: Synthesis of 2-(3-(4-chloro-9-(methylamino)-7-oxofurano[2,3-f]quinazolin-6(7H)-yl)phenoxy)-N-(3-(4-chloro-9-(methylamino)-7-oxofurano[2,3-f]quinazolin-6(7H)-yl)phenyl)acetamide (S99)

[0318] Synthesis of S99-1: In a 250 μL solution of S51 (15 mg, 0.044 mmol) in DCM, TEA (8.89 mg, 0.088 mmol) and chloroacetyl chloride (5.96 mg, 0.0528 mmol) were added sequentially. The reaction mixture was heated at 35 °C for 2 hours, and then the reaction was stopped. The reaction mixture was extracted with DCM, and the organic phase was washed with water and saturated sodium bicarbonate solution, respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography to obtain intermediate S99-1.

[0319] Synthesis of S99: In a DMF solution (0.5 mL) of S50 (16.5 mg, 0.0484 mmol), cesium carbonate (28.67 mg, 0.088 mmol), sodium iodide (3.5 mg, 0.022 mmol), and compound S99-1 (18.36 mg, 0.044 mmol) were added sequentially. The reaction solution was heated at 80 °C for 4 hours, concentrated under reduced pressure, and purified by reverse-phase preparative HPLC to obtain compound S99 as a white solid. 1 H NMR(600MHz,DMSO-d6)δ10.34(s,1H),8.28-8.20(m,2H),8.17-8.09(m,2H),7.77-7.71(m,1H),7.66(s,1H),7.56-7.52(m,2H),7.19 -7.13(m,2H),7.09-6.99(m,3H),6.93(d,J=7.8Hz,1H),6.38-6.30(m,2H),4.79(s,2H),3.14-3.08(m,6H).ESI-MS(m / z):722.2[M+H] + .

[0320] Example 57: Synthesis of 4-chloro-6-(2-methoxyphenyl)-9-(methylamino)furano[2,3-f]quinazolin-7(6H)-one (S101)

[0321] The preparation was carried out according to the preparation method of Example 1. 1H NMR (400MHz, MeOD-d4) δ8.18(d,J=2.4Hz,1H),7.61(ddd,J=9.2,7.6,1.6Hz,1H),7.34(dd,J=7.6,1.6Hz,1H),7.31(dd,J=8.4 ,1.2Hz,1H),7.21(td,J=7.6,1.2Hz,1H),7.17-7.14(m,1H),6.74(s,1H),3.77(s,3H),3.32(s,3H).ESI-MS(m / z):356.2[M+H] + .

[0322] Example 58: Synthesis of 2-(4-chloro-9-(methylamino)-7-oxofurano[2,3-f]quinazolin-6(7H)-yl)benzonitrile (S102)

[0323] The preparation was carried out according to the preparation method of Example 1. 1 H NMR (400MHz, MeOD-d4) δ8.09(d,J=2.4Hz,1H),8.05(dd,J=7.6,1.6Hz,1H),7.97(td,J=8.0,1.6Hz,1H),7.78(t, J=7.6Hz,1H),7.63(d,J=8.0Hz,1H),7.11(d,J=2.4Hz,1H),6.39(s,1H),3.27(s,3H).ESI-MS(m / z):351.2[M+H] + .

[0324] Example 59: Synthesis of 4-chloro-9-(methylamino)-6-(2-(trifluoromethyl)phenyl)furano[2,3-f]quinazolin-7(6H)-one (S103)

[0325] The preparation was carried out according to the preparation method of Example 1. 1 H NMR (400MHz, MeOD-d4) δ8.10(d,J=2.0Hz,1H),8.02(d,J=7.6Hz,1H),7.94(t,J=8.0Hz,1H),7.83(t,J=8.0 Hz,1H),7.55(d,J=8.0Hz,1H),7.11(d,J=2.0Hz,1H),6.31(s,1H),3.28(s,3H).ESI-MS(m / z):394.1[M+H] + .

[0326] Example 60: Synthesis of 6-(2-bromophenyl)-4-chloro-9-(methylamino)furano[2,3-f]quinazolin-7(6H)-one (S104)

[0327] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(400MHz,MeOD-d4)δ8.10(d,J=2.4Hz,1H),7.92(dd,J=8.0,1.6Hz,1H),7.66(td,J=7.6,1.2Hz, 1H),7.56-7.49(m,2H),7.12(d,J=2.4Hz,1H),6.36(s,1H),3.29(s,3H).ESI-MS(m / z):404.1[M+H] + .

[0328] Example 61: Synthesis of 4-chloro-9-(methylamino)-6-(m-tolyl)furano[2,3-f]quinazolin-7(6H)-one (S105)

[0329] The preparation was carried out according to the preparation method of Example 1. 1 H NMR (400MHz, MeOD-d4) δ8.12(d,J=2.4Hz,1H),7.55(t,J=7.6Hz,1H),7.45(d,J=7.6Hz,1H),7.22(s,1H),7. 17(d,J=7.6Hz,1H),7.14(d,J=2.4Hz,1H),6.52(s,1H),3.34(s,3H),2.47(s,3H).ESI-MS(m / z):340.1[M+H] + .

[0330] Example 62: Synthesis of 4-chloro-6-(3-chlorophenyl)-9-(methylamino)furano[2,3-f]quinazolin-7(6H)-one (S106)

[0331] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(400MHz,MeOD-d4)δ8.10(d,J=2.4Hz,1H),7.70-7.61(m,2H),7.49(s,1H),7.38-7 .29(m,1H),7.12(d,J=2.0Hz,1H),6.51(s,1H),3.30(s,3H).ESI-MS(m / z):360.1[M+H] + .

[0332] Example 63: Synthesis of 4-chloro-6-(2-cyclopropylphenyl)-9-(methylamino)furano[2,3-f]quinazolin-7(6H)-one (S107)

[0333] The preparation was carried out according to the preparation method of Example 1.1 H NMR (400MHz, MeOD-d4) δ8.11(d,J=2.4Hz,1H),7.52(td,J=7.6,1.2Hz,1H),7.44(td,J=7.6,1.6Hz,1H),7.29-7.24(m,2H),7.13(d,J= 2.0Hz,1H),6.44(s,1H),3.31(s,3H),1.63-1.55(m,1H),0.83-0.77(m,2H),0.69-0.61(m,1H),0.53(m,1H).ESI-MS(m / z):366.2[M+H] + .

[0334] Example 64: Synthesis of 4-chloro-6-(5-fluoro-2-methylphenyl)-9-(methylamino)furano[2,3-f]quinazolin-7(6H)-one (S108)

[0335] The preparation was carried out according to the preparation method of Example 1. 1 H NMR (400MHz, MeOD-d4) δ8.12(d,J=2.0Hz,1H),7.54(dd,J=8.8,5.6Hz,1H),7.29(td,J=8.4,2. 8Hz,1H),7.19-7.09(m,2H),6.44(s,1H),3.31(s,3H),2.05(s,3H).ESI-MS(m / z):358.2[M+H] + .

[0336] Example 65: Synthesis of 4-chloro-6-(2-chloro-5-fluorophenyl)-9-(methylamino)furano[2,3-f]quinazolin-7(6H)-one (S109)

[0337] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(400MHz,MeOD-d4)δ8.12(d,J=2.0Hz,1H),7.83-7.75(m,1H),7.48-7.41(m, 2H),7.15(d,J=2.0Hz,1H),6.46(s,1H),3.30(s,3H).ESI-MS(m / z):378.1[M+H] + .

[0338] Example 66: Synthesis of 4-chloro-9-((2,2-difluoroethyl)amino)-6-(o-tolyl)furano[2,3-f]quinazolin-7(6H)-one (S110)

[0339] The preparation was carried out according to the preparation method of Example 1.1 H NMR(400MHz,MeOD-d4)δ8.11(d,J=2.0Hz,1H),7.57-7.40(m,3H),7.25(d,J=6.8Hz,1H),7.12(d,J=2.0Hz, 1H),6.40(s,1H),6.30(tt,J=56.4,4.4Hz,1H),4.23-4.09(m,2H),2.06(s,3H).ESI-MS(m / z):390.1[M+H] + .

[0340] Example 67: Synthesis of 4-chloro-6-(2-cyclopropylpyridin-3-yl)-9-(methylamino)furano[2,3-f]quinazolin-7(6H)-one (S111)

[0341] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(600MHz,MeOD-d4)δ8.64(dd,J=5.4,1.8Hz,1H),8.13(d,J=2.4Hz,1H),7.90-7.86(m,1H),7.56-7.50(m,1H),7.15(d,J=2.4Hz,1H) ,6.55-6.51(m,1H),3.32(s,3H),1.93-1.81(m,1H),1.25-1.13(m,1H),1.05-0.94(m,2H),0.88-0.81(m,1H).ESI-MS(m / z):367.3[M+H] + .

[0342] Example 68: Synthesis of 4-chloro-9-(prop-2-yn-1-ylamino)-6-(o-tolyl)furano[2,3-f]quinazolin-7(6H)-one (S112)

[0343] The preparation was carried out according to the preparation method of Example 1. 1 H NMR (600MHz, MeOD-d4) δ8.09(d,J=1.2Hz,1H),7.50(q,J=8.4Hz,2H),7.46(t,J=7.8Hz,1H),7.24(d,J=7.8 Hz,1H),7.12-7.09(m,1H),6.39(s,1H),4.56(s,2H),2.71(s,1H),2.06(s,3H).ESI-MS(m / z):364.2[M+H] + .

[0344] Example 69: Synthesis of 4-methyl-9-(methylamino)-6-phenylfurano[2,3-f]quinazolin-7(6H)-one (S113)

[0345] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(400MHz,MeOD-d4)δ8.07(d,J=2.0Hz,1H),7.72-7.59(m,3H),7.43-7.37(m,2H),7.16( d,J=2.0Hz,1H),6.37(d,J=1.2Hz,1H),3.37(s,3H),2.48(s,3H).ESI-MS(m / z):306.2[M+H] + .

[0346] Example 70: Synthesis of 4-bromo-9-(methylamino)-6-(o-tolyl)furano[2,3-f]quinazolin-7(6H)-one (S114)

[0347] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(600MHz,MeOD-d4)δ8.12(s,1H),7.50(m,3H),7.27(m,1H),7.07(s,1H),6.57(s,1H),3.42(s,3H),2.09(s,3H).ESI-MS(m / z):384.1[M+H] + .

[0348] Example 71: Synthesis of 4-bromo-6-(1H-indazol-4-yl)-9-(pyridin-4-ylamino)furano[2,3-f]quinazolin-7(6H)-one (S115)

[0349] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(400MHz,MeOD-d4)δ8.91-8.65(m,4H),8.24(s,1H),7.94-7.81(m,2H),7.68(t,J= 8.0Hz,1H),7.27(d,J=7.2Hz,1H),7.14(s,1H),6.74(s,1H).ESI-MS(m / z):473.1[M+H] + .

[0350] Example 72: Synthesis of 4-bromo-6-(3-fluoro-2-methylphenyl)-9-((2-methyl-2H-indazol-5-yl)amino)furano[2,3-f]quinazolin-7(6H)-one (S116)

[0351] The preparation was carried out according to the preparation method of Example 1. 1 H NMR (600MHz, MeOD-d4) δ8.56-8.54(m,1H),8.28(s,1H),8.20(d,J=1.8Hz,1H),7.70(d,J=9.0Hz,1H),7.58(d,J=9.6Hz,1H),7.53-7.46(m, 1H),7.34(t,J=9.0Hz,1H),7.17(d,J=7.8Hz,1H),7.12(d,J=2.4Hz,1H),6.66(s,1H),4.25(s,3H),2.02(s,3H).ESI-MS(m / z):518.1[M+H] + .

[0352] Example 73: Synthesis of 9-(methylamino)-6-(o-tolyl)-4-(trifluoromethyl)furano[2,3-f]quinazolin-7(6H)-one (S117)

[0353] The preparation was carried out according to the preparation method of Example 21. 1 H NMR (400MHz, MeOD-d4): δ8.20(d,J=2.4Hz,1H),7.57-7.45(m,3H),7.29(d,J=7.6Hz ,1H),7.17(s,1H),6.65(s,1H),3.33(s,3H),2.08(s,3H).ESI-MS(m / z):374.2[M+H] + .

[0354] Example 74: Synthesis of 4-chloro-9-(methylamino)-6-(3-vinylphenyl)furano[2,3-f]quinazolin-7(6H)-one (S118)

[0355] The preparation was carried out according to the preparation method of Example 1. 1 H NMR (600MHz, MeOD-d4) δ8.14(d,J=2.4Hz,1H),7.71(d,J=7.8Hz,1H),7.65(t,J=7.8Hz,1H),7.50(s,1H),7.30(d,J=7.2Hz,1H),7.16(d,J=2. 4Hz,1H),6.86(dd,J=18.0,11.4Hz,1H),6.56(s,1H),5.92(d,J=17.4Hz,1H),5.39(d,J=10.8Hz,1H),3.35(s,3H).ESI-MS(m / z):352.2[M+H] + .

[0356] Example 75: Synthesis of 9-amino-4-chloro-6-(o-tolyl)furano[2,3-f]quinazolin-7(6H)-one (S119)

[0357] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(400MHz,MeOD-d4)δ8.14(d,J=2.4Hz,1H),7.58-7.52(m,2H),7.52-7.45(m,1H),7.30( d,J=7.6Hz,1H),7.16(d,J=2.4Hz,1H),6.43(s,1H),2.11(s,3H).ESI-MS(m / z):326.1[M+H] + .

[0358] Example 76: Synthesis of 9-amino-6-(o-tolyl)-4-(trifluoromethyl)furano[2,3-f]quinazolin-7(6H)-one (S120)

[0359] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(400MHz,MeOD-d4)δ8.20(d,J=2.4Hz,1H),7.58-7.52(m,2H),7.51-7.44(m,1H),7.30 (d,J=7.6Hz,1H),7.19-7.16(m,1H),6.65(s,1H),2.09(s,3H).ESI-MS(m / z):360.1[M+H] + .

[0360] Example 77: Synthesis of 9-amino-4-bromo-6-(o-tolyl)furan[2,3-f]quinazolin-7(6H)-one (S121)

[0361] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(400MHz,MeOD-d4)δ8.16(d,J=2.4Hz,1H),7.57-7.53(m,2H),7.53-7.45(m,1H),7.31( d,J=7.6Hz,1H),7.11(d,J=2.0Hz,1H),6.61(s,1H),2.12(s,3H).ESI-MS(m / z):370.0[M+H] + .

[0362] Example 78: Synthesis of 9-amino-4-chloro-6-(2-chlorophenyl)furano[2,3-f]quinazolin-7(6H)-one (S122)

[0363] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(400MHz,MeOD-d4)δ8.12(d,J=2.4Hz,1H),7.78-7.73(m,1H),7.67-7.58(m,2H ),7.55-7.51(m,1H),7.15(d,J=2.2Hz,1H),6.41(s,1H).ESI-MS(m / z):346.1[M+H] + .

[0364] Example 79: Synthesis of 9-amino-6-(2-chlorophenyl)-4-(trifluoromethyl)furano[2,3-f]quinazolin-7(6H)-one (S123)

[0365] The preparation was carried out according to the preparation method of Example 21. 1 H NMR(400MHz,MeOD-d4)δ8.21(d,J=2.4Hz,1H),7.81-7.75(m,1H),7.68-7.59(m,2 H),7.58-7.52(m,1H),7.21-7.14(m,1H),6.63(s,1H).ESI-MS(m / z):380.1[M+H] + .

[0366] Example 80: Synthesis of 9-amino-4-bromo-6-(2-chlorophenyl)furano[2,3-f]quinazolin-7(6H)-one (S124)

[0367] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(400MHz,MeOD-d4)δ8.14(d,J=2.4Hz,1H),7.80-7.75(m,1H),7.68-7.58(m,2H ),7.56-7.51(m,1H),7.09(d,J=2.0Hz,1H),6.58(s,1H).ESI-MS(m / z):390.0[M+H] + .

[0368] Example 81: Synthesis of 4-chloro-6-(3-iodophenyl)-9-(methylamino)furano[2,3-f]quinazolin-7(6H)-one (S125)

[0369] The preparation was carried out according to the preparation method of Example 1. 1H NMR(400MHz,MeOD-d4)δ8.17(d,J=2.0Hz,1H),8.05-7.98(m,1H),7.86(s,1H),7.50-7 .44(m,2H),7.19(d,J=2.4Hz,1H),6.56(s,1H),5.04(s,3H).ESI-MS(m / z):452.0[M+H] + .

[0370] Example 82: Synthesis of 6-(3-bromophenyl)-4-chloro-9-(methylamino)furano[2,3-f]quinazolin-7(6H)-one (S126)

[0371] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(600MHz,MeOD-d4)δ8.13(d,J=2.4Hz,1H),7.81(d,J=8.4Hz,1H),7.66(s,1H),7.61(t,J=7.8Hz,1 H),7.41(d,J=7.2Hz,1H),7.15(d,J=2.4Hz,1H),6.53(s,1H),3.37(s,3H).ESI-MS(m / z):403.2[M+H] + .

[0372] Example 83: Synthesis of 3-(4-chloro-9-(methylamino)-7-oxofurano[2,3-f]quinazolin-6(7H)-yl)-N-(3-(4-chloro-9-(methylamino)-7-oxofurano[2,3-f]quinazolin-6(7H)-yl)phenyl)benzamide (S127)

[0373] Synthesis of S127-2: In a 250 μL solution of S127-1 (15.7 mg, 0.044 mmol) in DMF, DIPEA (17 mg, 0.132 mmol) and HATU (18.4 mg, 0.0484 mmol) were added and stirred for 5 minutes. Then, S51 (15 mg, 0.044 mmol) was added and stirred overnight. The reaction solution was extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography to obtain intermediate S127-2 (15 mg).

[0374] Synthesis of S127: Prepared according to the method described in Example 1, except that the solvent acetonitrile was replaced with DMF. ESI-MS (m / z): 692.1 [M+H] + .

[0375] Example 84: Synthesis of compounds S128 and S129.

[0376] The compound was prepared according to the method described in Example 1 and purified using a chiral SFC column (column: AD-H / SFC 20mm ID×250mmL, 5μM; mobile phase: mobile phase A was CO2, mobile phase B was isopropanol; isocratic elution conditions: 5% B (v / v), 12min; flow rate: 50g / min; detector: PDA; column temperature: 35℃; back pressure: 100Bar). The first peak obtained was compound S128 (retention time: 5.97min), and the second peak obtained was S129 (retention time: 7.63min). The absolute configuration of compound S129 was confirmed by single-crystal diffraction experiments.

[0377] S128: 1 H NMR(600MHz, DMSO-d6)δ8.25(d,J=1.2Hz,1H),8.05-8.00(m,1H),7.51-7.37(m,3H),7.23(d,J=7.2Hz, 1H),7.16(d,J=1.8Hz,1H),6.18(s,1H),3.11(d,J=4.8Hz,3H),1.97(s,3H).ESI-MS(m / z):340.3[M+H] + .

[0378] S129: 1 H NMR (400MHz, DMSO-d6) δ8.25 (s, 1H), 8.09-7.97 (m, 1H), 7.53-7.38 (m, 3H), 7.23 (d, J = 7.2Hz, 1H),7.17(s,1H),6.18(s,1H),3.11(d,J=3.6Hz,3H),1.97(s,3H).ESI-MS(m / z):340.3[M+H] + .

[0379] Example 85: Synthesis of 4-bromo-6-(2-methoxyphenyl)-9-(methylamino)furano[2,3-f]quinazolin-7(6H)-one (S130)

[0380] The preparation was carried out according to the preparation method of Example 1. 1H NMR(400MHz,MeOD-d4)δ8.11(d,J=2.0Hz,1H),7.61(td,J=8.8,2.0Hz,1H),7.37-7.28(m,2H),7.21(t, J=7.6Hz,1H),7.06(d,J=2.4Hz,1H),6.67(s,1H),3.78(s,3H),3.31(s,3H).ESI-MS(m / z):400.2[M+H] + .

[0381] Example 86: Synthesis of 4-chloro-9-((methyl-d3)amino)-6-(o-tolyl)furano[2,3-f]quinazolin-7(6H)-one (S131)

[0382] The preparation was carried out according to the preparation method of Example 1. 1 H NMR(400MHz,MeOD-d4)δ8.13(d,J=2.0Hz,1H),7.53(dd,J=4.3,1.2Hz,2H),7.51-7.45(m,1H),7 .28(d,J=7.6Hz,1H),7.14(d,J=2.0Hz,1H),6.41(s,1H),2.10(s,3H).ESI-MS(m / z):343.2[M+H] + .

[0383] Test Example 1: Inhibitory Activity Test of Quinazolinone Five-Membered Heterocyclic Derivatives Against MAT2A

[0384] To determine the inhibitory activity of the compound against MAT2A, a method for detecting MAT2A enzyme activity was established. The reaction conditions were as follows: the protein was diluted to 200 nM in enzyme activity reaction buffer (50 mM Tris, pH 8.0, 50 mM KCl, 15 mM MgCl2, 0.3 mM EDTA, 0.005% [w / v] bovine serum albumin [BSA]), and the compound was diluted to a final concentration of 20× with DMSO. 20 μL of MAT2A protein dilution buffer was added to 2 μL of the test compound, followed by 20 μL of substrate mix (500 μM ATP, 400 μM L-methionine) to initiate the enzyme activity reaction, and the mixture was incubated at 25 °C for 60 minutes. After the reaction was terminated, the activity was measured using PiColorLock. TM (Abcam) measures the amount of phosphate generated in the enzymatic reaction, and uses the amount of phosphate generated to determine the formation of SAM in the reaction. To calculate the inhibitory effect of the compound on MAT2A enzyme activity, the inhibition rate of the compound was normalized to positive and negative controls: Inhibition rate % = (1 - (Abcam) / ( ... 待测 样品 -Abs阴性对照样品平均值 ) / (Abs 阳性对照样品平均值 -Abs 阴性样品平均值 ))×100%. IC 50 The values ​​were determined by fitting the data to a standard four-parameter dose-response equation using GraphPad Prism software.

[0385] The IC50 assay was used to test the inhibitory activity of the compound against the MAT2A enzyme. 50 The table below shows the values: A = 0-100 nM; B = 100-500 nM; C => 500 nM.

[0386] Table 1. Inhibitory activity of compounds against MAT2A enzyme

[0387] The results showed that the compound of the present invention has a good inhibitory effect on MAT2A enzyme activity.

[0388] Test Example 2: The effect of quinazolinone five-membered heterocyclic derivatives on HCT116 MTAP - / - and HCT116 MTAP + / + Cell antiproliferative activity test

[0389] Cells were seeded at a density of 400 cells per well in 384-well cell culture plates and cultured overnight at 37°C and 5% CO2 to allow for cell adhesion. The highest concentration of the compound was 10 μM, and it was serially diluted at a 1:2 ratio before being added to the cell culture plates. After co-incubating the cells with the compound for 10 days, cell viability was assessed using the CellTiter-Meiluncell cell viability assay kit (Meilun, PWL214). The GI50 value was calculated using a variable slope (four-parameter) nonlinear regression (curve fitting) with GraphPad Prism software.

[0390] Test compound for HCT116 MTAP - / - and HCT116 MTAP + / + Inhibit active IC 50 The values ​​are shown in the table below, where: A = 0-200nM; B = 200-500nM; C = 500-5000nM; D = >5000nM.

[0391] Table 2. Antiproliferative activity of compounds against HCT116 MTAP- / - and HCT116 MTAP+ / + cells

[0392] The results show that some of the compounds in this invention are effective against HCT116 MTAP. - / - It has a good inhibitory effect on cancer cell proliferation and good selectivity for MTAP deletion mutant cells.

[0393] Test Example 3: Pharmacokinetic Properties of Quinazolinone Five-Membered Heterocyclic Derivatives

[0394] This experiment has been reviewed and approved by the Laboratory Animal Management and Use Committee of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences (IACUC Approval No.: 2023-10-ZMY-03). Two routes of administration were used: oral and intravenous. The solvent used was physiological saline containing 5% DMSO, 5% PEG400, and 90% physiological saline containing 10% hydroxypropyl-β-cyclodextrin. After blood sample collection, plasma was immediately separated by centrifugation, and the concentration of compounds in the plasma was quantitatively analyzed using liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0395] Table 3 Pharmacokinetic properties of some compounds

[0396] As shown in Table 3, the compounds of the present invention have good oral exposure and oral bioavailability in mice.

[0397] Test Example 4: Mouse Tumor Pharmacodynamic Model of Quinazolinone Five-Membered Heterocyclic Derivative

[0398] First, female BALB / c nude mice were injected with 1×10 g of vaccine under their armpits. 7 HCT116 MTAP - / - Cells were used to construct a mouse xenograft tumor model, and when the tumor volume grew to 150-250 mm... 3 Mice were randomly divided into groups of five. The solvent used in the experiment was physiological saline containing 5% DMSO, 5% PEG400, and 90% hydroxypropyl-β-cyclodextrin. Compound S49 was administered at two doses of 10 mg / kg and 30 mg / kg, and the positive control compound AG-270 was administered at a single dose of 50 mg / kg, all orally once daily. Changes in tumor volume and body weight were observed and recorded daily. After the last administration, the mice were euthanized, and subcutaneous tumors were isolated for biochemical analysis. The tumor volume was calculated using the following formula: (tumor length × tumor width) 2 ) / 2.

[0399] Positive control compound AG-270:

[0400] As shown in Figure 1, the compound of the present invention has good in vivo efficacy in mice.

[0401] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound represented by formula IA, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, hydrate, solvate, or prodrug thereof, characterized in that, In the formula, Indicates a double bond or a single bond; X, Y1, and Y2 are each independently selected from C, CH2, CH, CR', O, S, N, NH, or NR'; R' is selected from: H, deuterium, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy; n is selected from 0, 1, 2, 3; m is selected from 1, 2, 3, 4, 5, 6; L1 is selected from C14, -O-, -NH-, -NR'-, substituted or unsubstituted. 1-6 Alkylene; R1 is selected from the following group: halogen, amide, cyano, amino, hydroxyl, amino, oxo (=O), carboxyl, ester, nitro, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-7 membered heterocyclic, 5-7 membered heterocyclic oxygen, halogenated C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyloxy; R4 and R5 are each independently selected from the following group of substituent or unsubstituted groups: H, D, amide, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 cycloalkyl-C 1-6 Alkylene-, C 3-10 Cycloalkoxy, 5-10 membered heterocyclic group, 5-10 membered heterocyclic group -C 1-6 alkylene-, 5-10 membered heterocyclic hydroxyl groups, C 3-6 Cycloalkyloxy, C 6-10 Aryl, C 6-10 Aryl-C 1-6 alkylene-, 5-10 heteroaryl, 5-10 heteroaryl-C 1-6 Alkylene-, C 3-10 Cycloalkoxy-C 1-6 alkylene-; Alternatively, R4 and R5, together with the N atom they are connected to, can form substituted or unsubstituted subgroups: 4-9 membered nitrogen-containing heterocyclic groups or 4-9 membered nitrogen-containing heteroaryl groups; Ring A is selected from the following group, either substituted or unsubstituted: C6-C 10 Aryl, 5-10 heteroaryl, 3-10 heterocyclic; R3 is selected from the following group of substituted or unsubstituted groups: D, halogen, amide, cyano, hydroxyl, amino, amino, oxo (=O), carboxyl, ester, nitro, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, halogenated C 3-6 cycloalkyl, 5-7 membered heterocyclic, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy; R is selected from the following group, whether substituted or unsubstituted: H, deuterium, halogen, hydroxyl, amide, amino, amino, oxo (=O), carboxyl, ester, nitro, cyano, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -NHC(O)OC 1-6 Alkyl group, -CONH(C) 1-6 Alkyl), -CONH(C) 3-6 cycloalkyl), -(C 1-6 alkylene)COOH, -O-(C 1-6 alkylene)phenyl, -O-(C 1-6 alkylene) 5-6-membered heteroaryl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 5-7 membered heterocyclic groups, 5-7 membered heterocyclic oxy groups, phenyl, benzyl; or two adjacent or common ring atoms of two R groups forming a 5-7 membered heterocyclic group, C 3-6 cycloalkyl, 5-6 membered heteroaryl, phenyl; Unless otherwise specified, substitution refers to the substitution of one or more hydrogen atoms on a group by a group selected from the group consisting of: deuterium, halogen, amino, amine, oxo (=O), carboxyl, amide, hydroxyl, cyano, ester, nitro, phenyl, benzyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 5-7 membered heterocyclic groups, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy group, -NH-C(O)-C 1-6 Alkyl, -NH-C(O)-C 1-6 Alkoxy, sulfonyl, 5-7 membered heterocyclic group -C 1-6 Alkylene-.

2. The compound as described in claim 1, characterized in that, The compound has the structure shown in formula (II): Wherein, R1, R4, R5, L1, R, m and ring A are as described in claim 1.

3. The compound as described in claim 1, characterized in that, R4 is selected from the following groups: H, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl groups; and / or R5 is selected from the following group of substituent or unsubstituted groups: H, amide, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-9 cycloalkyl, C 3-7 Cycloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, phenyl-C 1-6 Alkylene-, 5-7 membered heterocyclic group, 5-7 membered heterocyclic group-C 1-6 alkylene-, benzyl, 5-9-membered heteroaryl, 5-9-membered heteroaryl-C 1-6 Alkylene-, C 3-7 Cycloalkoxy-C 1-6 alkylene-; Alternatively, when R4 and R5 are linked to form a ring, R4 and R5, along with the N atom they are connected to, together form a substituted or unsubstituted 4-7 membered nitrogen-containing heterocyclic group or a 4-7 membered nitrogen-containing heteroaryl group. The substitution refers to substitution by one or more groups selected from the group consisting of: deuterium, halogen, amino, oxo (=O), carboxyl, amide, hydroxyl, cyano, ester, nitro, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 5-7 membered heterocyclic groups, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 5-7 membered heterocyclic group -C 1-6 Alkylene-.

4. The compound according to claim 1, characterized in that, R1 is selected from the following group: halogens, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-7 membered heterocyclic groups, halogenated C 3-6 cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy.

5. The compound according to claim 1, characterized in that, The compound forms a dimer structure as shown in formula (IV): Da-W-Db (IV) In the formula, Da and Db are each independently selected from compounds represented by formula (I'-A): Wherein, Y1, Y2, ring A, n, m, X, L1, R1, R, R3, R4, and R5 are as described in claim 1; W is a divalent linker, having the structure shown below: -Wa-L-Wb-; in, Wa and Wb are each independently selected from the following groups: none, -O-, -S-, -NR a -, -CO-, -COO-, -SO-, -SO2-, -CO-NR a -、-NR a -CO-, -SO-N(R) a )-、-N(R a -SO-, -NR a -COO-、-COO-NR a -、C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group; L is selected from the following group: -O-, -S-, -NR a -, -CO-, -COO-, -SO-, -SO2-, -CO-NR a -、-NR a -CO-, -SO-N(R) a )-、-N(R a -SO-, -NR a -COO-、-COO-NR a -、C 1-6 Alkylene, C 2-6 alkenyl, C6 arylene, 4-7 membered heterocyclic, C 3-9 Cycloalkylene; R a Each is independently selected from the following groups: H, deuterium, cyano, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, or substituted or unsubstituted C4 groups 3-6 Cycloalkyl groups (preferably substituted with C) 1-6 Alkyl substitution and / or halogen substitution).

6. The compound as described in claim 1, characterized in that, The compounds mentioned are selected from the compounds shown in Table 1: Table 1 7. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: (i) the compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, hydrate, solvate, or prodrug thereof; and (ii) Pharmaceutically acceptable carriers.

8. Use of the compound according to claim 1, characterized in that, Used to prepare (i) MAT2A enzyme inhibitors, and / or (ii) drugs for the prevention and treatment of MAT2A-related cancers.

9. The use as described in claim 8, characterized in that, The cancers mentioned are selected from solid tumors and liquid tumors; preferably, they are selected from the group consisting of glioblastoma, melanoma, urothelial carcinoma, pancreatic cancer, non-small cell lung cancer, colorectal cancer, ovarian cancer, lung cancer, breast cancer, leukemia, liver cancer, thyroid cancer, stomach cancer, bladder cancer, lymphoma, gallbladder cancer, brain cancer, or combinations thereof.

10. A method for inhibiting MAT2A enzyme activity, characterized in that, Contacting the compound of any one of claims 1-6, or its stereoisomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, or the pharmaceutical composition of claim 7, with a protein or cell thereby inhibiting MAT2A enzyme activity.

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