A cyclic MAT2A inhibitor, a pharmaceutical composition comprising the same, and its application.

Abstract

This invention provides a cyclic MAT2A inhibitor, a pharmaceutical composition comprising the same, and its use. Specifically, this invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a cis-trans isomer, a solvate, a polymorph, a deuterated compound, or a combination thereof, wherein the variables are as defined herein, and the use of said compound and pharmaceutical compositions comprising the same in the preparation of a medicament for the prevention or treatment of MTAP- / -related cancers.

Description

Technical Field

[0001] Field of the Invention The present invention belongs to the field of medicinal chemistry. More specifically, the present invention relates to a paracyclic MAT2A inhibitor, a preparation method thereof, a pharmaceutical composition containing the same, and applications thereof. Prior Art

[0002] Background of the Invention Cancer is one of the leading causes of death worldwide. A limitation of commonly used treatments, such as chemotherapy and immunotherapy, is that their cytotoxicity is not restricted to cancer cells and can cause adverse reactions in normal tissues. Therefore, new strategies are needed to better target cancer cells.

[0003] Synthetic lethality occurs when two or more genes simultaneously exhibit defects in expression, leading to cell death. However, a defect in only one gene does not lead to cell death. This phenomenon is known as synthetic lethality. The concept of synthetic lethality originated from studies in fruit flies, which found that flies harboring mutations in two specific genes were incapable of survival, whereas mutations in either gene alone were not lethal. Therefore, synthetic lethality could be used to treat tumors with specific mutations. Specifically, some tumors harbor genetic defects compared to normal tissue. By artificially inhibiting a different signaling pathway, tumor tissue becomes more vulnerable while normal tissue is minimally affected, thereby achieving selective tumor destruction. PARP1 inhibitors are recognized as the first anticancer drugs to successfully utilize the concept of synthetic lethality. Because defects in tumor suppressor genes account for the vast majority of tumor-specific mutations, synthetic lethality could lead to more precise anticancer drugs.

[0004] Methionine adenosyltransferase 2A (MAT2A) is a key enzyme in the production of S-adenosylmethionine (SAM) in cells. It catalyzes the conversion of methionine (Met) and adenosine triphosphate (ATP) to SAM. SAM is a major methyl donor in cells. Various methyltransferases catalyze the transfer of methyl groups from SAM to a variety of substrates, including DNA, RNA, and proteins. Protein arginine N-methyltransferase 5 (PRMT5) is one such methyltransferase. Because methylthioadenosine (MTA) is structurally similar to SAM, it competes with SAM and inhibits PRMT5 activity. MTA can be converted to adenosine and 5-methylthioribose 1-phosphate by an enzyme called methylthioadenosine phosphorylase (MTAP), maintaining low MTA concentrations in normal cells. Because the MTAP gene is located near the tumor suppressor gene p16 / CDKN2a, it is co-deleted with p16 / CDKN2a in approximately 15% of human cancers. Solid tumors with a high prevalence of MTAP deficiency include gliomas, mesotheliomas, esophageal cancer, bladder cancer, pancreatic cancer, melanoma, non-small cell lung cancer, head and neck cancer, sarcomas, and cholangiocarcinoma. In these co-deficient tumor cells, MTAP loss leads to the accumulation of MTA. Abnormally elevated MTA inhibits PRMT5 in tumor tissues, making MTAP-deficient tumor cells more dependent on SAM production. Therefore, inhibiting MAT2A to reduce SAM levels could selectively kill MTAP-deficient tumor cells. MAT2A gene knockout in approximately 400 cancer cell lines revealed that a greater proportion of MTAP-deficient cells lost viability compared to MTAP-WT cells. Furthermore, knockdown of MAT2A protein reduced tumor growth in vivo. These results suggest that MAT2A inhibitors may provide a new therapeutic approach for patients with MTAP-deficient cancers.

[0005] IDE397 is a MAT2A inhibitor at the forefront of research and development. Preclinical studies have demonstrated significant efficacy in models of non-small cell lung cancer, bladder cancer, pancreatic cancer, head and neck cancer, gastric cancer, and esophageal cancer (AACR 2021). Phase II clinical trials have further demonstrated the compound's efficacy in patients with non-small cell lung cancer and urothelial cancer.

[0006] Therefore, there is an urgent need to develop a compound with good inhibitory effect on MAT2A for the preparation of drugs for the treatment of MTAP- / -related cancers. Summary of the Invention

[0007] Summary of the Invention The purpose of the present invention is to provide a novel structural cyclic compound with good MAT2A inhibitory effect, a pharmaceutical composition containing the same, and its use.

[0008] In a first aspect of the present invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form, or combination thereof. in, R 1 is selected from the group consisting of hydrogen, hydroxy, optionally substituted C 1-C 6 alkyl, optionally substituted C 2-C 6 alkenyl, optionally substituted C 2-C 6 alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, optionally substituted 6-10 membered aryl, optionally substituted 5-10 membered heteroaryl, -L 1-R 4 and -NR 5R 6; in R 1, the "optionally substituted" group means that the specified group is unsubstituted or substituted by one or more R 1s, and each R 1s is independently selected from the group consisting of halogen, hydroxy, amino, cyano, oxo, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 2-C 4 alkenyl, C 2-C 4 haloalkenyl, C 2-C 4 alkynyl, C 2-C 4 haloalkynyl, C 1-C 6 alkoxy-C 1-C 6 alkyl, hydroxy C 1-C 6 alkyl-(i.e. C 1-C 6 hydroxyalkyl), C 1-C 6 alkylamino, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy, 3-10 membered carbocyclic group, 、 、 and ; L 1 is selected from the group consisting of: -O-, -S-, -SO-, -SO 2- and -CO-; R 4 is selected from the group consisting of an optionally substituted C 1-C 6 alkyl group, an optionally substituted 3-10 membered carbocyclyl group, an optionally substituted 4-8 membered heterocyclyl group, an optionally substituted 6-10 membered aryl group, and an optionally substituted 5-10 membered heteroaryl group; in R 4, the “optionally substituted” group means that the designated group is unsubstituted or substituted by one or more R 4s, and each R 4s is independently selected from the group consisting of halogen, hydroxyl, amino, cyano, oxo, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy, C 2-C 4 alkenyl, C 2-C 4 haloalkenyl, C 2-C 4 alkynyl, C 2-C 4 haloalkynyl, C 1-C 6 alkoxy-C 1-C 6 alkyl, hydroxyl C 1-C 6 alkyl, amino C 1-C 6-membered alkyl, 3-10-membered carbocyclyl, 3-10-membered carbocyclyloxy, 4-8-membered heterocyclyl, 4-8-membered heterocyclyloxy, 6-10-membered aryl, 5-10-membered heteroaryl, 、 、 and ; R 5 is selected from the group consisting of: hydrogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl and 3-10 membered carbocyclyl; R6 is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 6-10 membered aryl, optionally substituted 5-10 membered heteroaryl, and In R 6, the “optionally substituted” means that the specified group is unsubstituted or substituted by one or more R 6s, and each R 6s is independently selected from the group consisting of deuterium, halogen, hydroxyl, amine, cyano, C 1-C 6 alkyl, C 1-C 6 haloalkyl, hydroxyl C 1-C 6 alkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy, C 2-C 4 alkenyl, C 2-C 4 haloalkenyl, C 2-C 4 alkynyl, C 2-C 4 haloalkynyl, 3-10 membered carbocyclyl optionally substituted by one or more R 8, 3-10 membered carbocyclyloxy optionally substituted by one or more R 8, 4-8 membered heterocyclyl optionally substituted by one or more R 8, 4-8 membered heterocyclyloxy optionally substituted by one or more R 8, C 1-C 6 alkylamino, (C 1-C 6 alkyl) 2amino, C1-C6alkoxy-C1-C6alkyl, amino C1-C6alkyl, 、 、 、 , 6-10 membered aryl optionally substituted by one or more R 9 and 5-10 membered heteroaryl optionally substituted by one or more R 9; R 2 is selected from the group consisting of: halogen, cyano, optionally substituted C 1-C 6 alkyl, optionally substituted C 2-C 6 alkenyl, optionally substituted C 2-C 6 alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, -L 2-R 10 and -NR 11R 12; in R 2, the "optionally substituted" means that the specified group is unsubstituted or substituted by one or more R 2s, and R 2s are each independently selected from the group consisting of: halogen, cyano, oxo, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy and 3-10 membered carbocyclyl; R 3 is selected from the group consisting of hydrogen, halogen, cyano, optionally substituted C 1-C 6 alkyl, optionally substituted C 2-C 6 alkenyl, optionally substituted C 2-C 6 alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, -L 2'-R 10' and -NR 11'R 12'; in R 3, the "optionally substituted" group means that the specified group is unsubstituted or replaced by one or more R 3s, and R 3s are each independently selected from the group consisting of halogen, cyano, oxo, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy and 3-10 membered carbocyclyl; L 2 and L 2 'are each independently selected from the group consisting of: -O-, -S-, -SO-, -SO 2- and -CO-; R 10 and R 10' are each independently selected from the group consisting of an optionally substituted C 1-C 6 alkyl group, an optionally substituted 3-10 membered carbocyclyl group, an optionally substituted 4-8 membered heterocyclyl group, an optionally substituted 6-10 membered aryl group, and an optionally substituted 5-10 membered heteroaryl group; in R 10 and R 10', "optionally substituted" means that the designated group is unsubstituted or substituted by one or more R 10s, and R 10s are each independently selected from the group consisting of halogen, cyano, C 1-C 6 alkyl group, C 1-C 6 haloalkyl group, C 1-C 6 alkoxy group, C 1-C 6 haloalkoxy group, a 3-10 membered carbocyclyl group, a 4-8 membered heterocyclyl group, a 6-10 membered aryl group, and a 5-10 membered heteroaryl group; R 11 and R 11 'are each independently selected from the group consisting of: hydrogen and C 1-C 6 alkyl; R 12 and R 12' are each independently selected from the group consisting of an optionally substituted C 1-C 6 alkyl group, an optionally substituted 3-10 membered carbocyclyl group, an optionally substituted 4-10 membered heterocyclyl group, an optionally substituted 6-10 membered aryl group, an optionally substituted 5-10 membered heteroaryl group, or In R 12 and R 12', the "optionally substituted" means that the specified group is unsubstituted or substituted by one or more R 12s, and R 12s are each independently selected from the group consisting of halogen, cyano, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy, 3-10 membered carbocyclyl, and 4-8 membered heterocyclyl; X 3 is selected from the group consisting of: CH and N; RX is selected from the group consisting of: methyl, ethyl, 3-4 membered carbocyclic group, halomethyl or halogen; RY is selected from the group consisting of hydrogen, methyl, halomethyl or halogen; X 1 is selected from the group consisting of CR 13 and N; X 2 is selected from the group consisting of CR 14 and N; R 13 and R 14 are each independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted C 1-C 6 alkyl, optionally substituted C 1-C 6 alkoxy, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-8 membered heterocyclyl; in R 13 and R 14, "optionally substituted" means that the designated group is unsubstituted or substituted by one or more R 13s or R 14s, and R 13s and R 14s are each independently selected from the group consisting of halogen and oxo; with the proviso that when R 1 and R 2 are both chlorine, and X 1 is CR 13, R 13 is not chlorine; Each R 7 is independently selected from the group consisting of C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy, 3-10 membered carbocyclyl, 4-8 membered heterocyclyl, amine, C 1-C 6 alkylamino (i.e., -NH(C 1-C 6 alkyl)), di(C 1-C 6 alkyl)amino (i.e., -N(C 1-C 6 alkyl) 2), 6-10 membered aryl, and 5-10 membered heteroaryl; Each R 8 is independently selected from the group consisting of: hydrogen, halogen, hydroxy, C 1-C 6 alkyl, C 1-C 6 haloalkyl or hydroxy C 1-C 6 alkyl; Each R 9 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In another preferred embodiment, R 1 is selected from the group consisting of hydrogen, hydroxy, optionally substituted C 1-C 6 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, -OR 4 and -NR 5R 6; preferably, R 1 is selected from the group consisting of hydrogen, hydroxy, optionally substituted 4-8 membered heterocyclyl or -NR 5R 6.

[0009] In another preferred embodiment, R 1 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl (preferably C 1 -C 6 alkyl) and -NR 5R 6.

[0010] In another preferred embodiment, R 5 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; preferably, R 5 is hydrogen.

[0011] In another preferred embodiment, R6 is selected from the following group: optionally substituted C1-C6 alkyl, optionally substituted 3-10 membered carbocyclyl and optionally substituted 5-10 membered heteroaryl; preferably, R6 is selected from the following group: hydrogen, optionally substituted C1-C6 alkyl.

[0012] In another preferred embodiment, R 6s are each independently selected from the group consisting of deuterium, halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 2-C 4 alkynyl, C 1-C 3 alkoxy, C 1-C 3 haloalkoxy, and 6-10 membered aryl; preferably, R 6s are each independently selected from the group consisting of deuterium and halogen.

[0013] In another preferred embodiment, R 5 is hydrogen, and R 6 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl; and R 6s is deuterium.

[0014] In another preferred embodiment, R 2 is selected from the group consisting of halogen, optionally substituted C 1-C 6 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl and -L 2-R 10.

[0015] In another preferred embodiment, R2s are each independently selected from the group consisting of halogen, cyano, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and 3-8 membered carbocyclic group; preferably, R2s are each independently selected from the group consisting of halogen and C1-C6 alkyl.

[0016] In another preferred embodiment, R 3 is selected from the following group: hydrogen, halogen, optionally substituted C 1-C 6 alkyl, optionally substituted C 2-C 6 alkenyl, optionally substituted C 2-C 6 alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, -L 2'-R 10'; preferably, R 3 is selected from the following group: hydrogen, optionally substituted C 1-C 6 alkyl.

[0017] In another preferred embodiment, R 3s are each independently selected from the group consisting of halogen, cyano, oxo, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy and 3-8 membered carbocyclic group.

[0018] In another preferred embodiment, R 10 and R 10′ are each independently selected from the following group: optionally substituted C 1-C 6 alkyl, optionally substituted 3-8 membered carbocyclic group, optionally substituted 4-8 membered heterocyclic group.

[0019] In another preferred embodiment, R 10s are each independently selected from the following group: halogen, cyano, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy, 3-8 membered carbocyclyl, 4-8 membered heterocyclyl.

[0020] In another preferred embodiment, R2 is selected from the following group: halogen (such as F, Cl, Br), optionally substituted C1-C6 alkyl (preferably, C1-C6 alkyl or C1-C6 haloalkyl, more preferably, C1-C6 haloalkyl such as trifluoromethyl), and optionally substituted 3-10 membered carbocyclyl (preferably, 3-10 membered carbocyclyl, more preferably, C3-C6 cycloalkyl, most preferably, selected from cyclopropyl and cyclobutyl).

[0021] In another preferred embodiment, R 3 is -L 2'-R 10'; wherein L 2' is -O- and R 10' is an optionally substituted C 1-C 6 alkyl group (preferably, R 10' is a C 1-C 6 alkyl group; more preferably, R 10' is a methyl group).

[0022] In another preferred embodiment, R 3 is hydrogen.

[0023] In another preferred embodiment, R 3 is hydrogen or -L 2'-R 10'; wherein L 2' is -O- and R 10' is methyl (ie, R 3 is hydrogen or methoxy).

[0024] In another preferred embodiment, R 13 and R 14 are each independently selected from the following group: hydrogen, halogen, cyano, C 1-C 4 alkyl or C 1-C 4 haloalkyl.

[0025] In another preferred embodiment, R 13 is hydrogen or halogen (such as F).

[0026] In another preferred embodiment, X 1 is CR 13; preferably, CH or CF.

[0027] In another preferred embodiment, X 1 is CR 13; preferably, it is CH.

[0028] In another preferred embodiment, X 2 is CR 14; preferably, it is CR 14 and R 14 is selected from the following group: hydrogen, halogen (such as F), C 1-C 4 alkyl (such as methyl) and optionally substituted 3-10 membered carbocyclic group (preferably, 3-4 membered carbocyclic group, more preferably 3-4 membered saturated carbocyclic group, such as cyclopropyl).

[0029] In another preferred embodiment, X 2 is CR 14; preferably, it is CR 14 and R 14 is selected from the following group: hydrogen, halogen (such as F), C 1-C 4 alkyl (such as methyl).

[0030] In another preferred embodiment, X3 is N.

[0031] In another preferred embodiment, in RX, the 3-4 membered carbocyclic group is a 3-4 membered saturated carbocyclic group; preferably, it is a cyclopropyl group.

[0032] In another preferred embodiment, RX is selected from the group consisting of methyl, ethyl, halomethyl or halogen.

[0033] In another preferred embodiment, RX is methyl, halogen or cyclopropyl.

[0034] In another preferred embodiment, RX is methyl or halogen.

[0035] In another preferred embodiment, RY is hydrogen, methyl or halogen (such as F).

[0036] In another preferred embodiment, R 1 is selected from the group consisting of hydrogen, hydroxy, optionally substituted C 1-C 6 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, -OR 4 and -NR 5R 6; the "optionally substituted" in R 1 means that the specified group is unsubstituted or substituted by one or more R 1s, and each R 1s is independently selected from the group consisting of halogen, hydroxy, amine, cyano, oxo, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy-C 1-C 6 alkyl, hydroxy C 1-C 6 alkyl, C 1-C 6 alkylamino, C 1-C 6 alkoxy and C 1-C 6 haloalkoxy.

[0037] In another preferred embodiment, R 1 is selected from the group consisting of hydrogen, hydroxy, an optionally substituted 4-8 membered heterocyclic group, or -NR 5R 6; wherein the heterocyclic group is optionally substituted by a substituent selected from the group consisting of halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3 haloalkoxy, hydroxy, and amino; R 5 is selected from the group consisting of: hydrogen and C 1-C 6 alkyl; R 6 is selected from the group consisting of optionally substituted C 1-C 6 alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 5-10 membered heteroaryl; in R 6, the "optionally substituted" means that the specified group is unsubstituted or substituted by one or more R 6s, and each R 6s is independently selected from the group consisting of deuterium, halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 2-C 4 alkynyl, C 1-C 3 alkoxy, C 1-C 3 haloalkoxy, and 6-10 membered aryl.

[0038] In another preferred embodiment, R1 is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 4-8 membered heterocyclyl, or -NR5R6; wherein R5 is hydrogen, and R6 is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, and optionally substituted 5-10 membered heteroaryl; preferably, in R6, the "optionally substituted" means that the specified group is unsubstituted or substituted by one or more R6s, and R6s is deuterium or C1-C6 alkyl.

[0039] In another preferred embodiment, in R 1, the 5-10 membered heteroaryl group is a 9-10 membered heteroaryl group.

[0040] In another preferred embodiment, in R 1, the heteroaryl group contains only 1, 2, 3 or 4 N as heteroatoms.

[0041] In another preferred embodiment, R 1 is selected from the group consisting of hydrogen, optionally substituted C 1-C 6 alkyl and -NR 5R 6; wherein R 5 is hydrogen, and R 6 is selected from the group consisting of hydrogen, optionally substituted C 1-C 6 alkyl.

[0042] In another preferred embodiment, R 2 is selected from the group consisting of halogen, optionally substituted C 1-C 6 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, and -L 2-R 10; in R 2, the "optionally substituted" group means that the designated group is unsubstituted or substituted by one or more R 2s, and each R 2s is independently selected from the group consisting of halogen, cyano, oxo, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy, and 3-8 membered carbocyclyl; R 3 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-C 6 alkyl, optionally substituted C 2-C 6 alkenyl, optionally substituted C 2-C 6 alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl, -L 2'-R 10'; in R 3, the "optionally substituted" group means that the specified group is unsubstituted or substituted by one or more R 3s, and each R 3s is independently selected from the group consisting of halogen, cyano, oxo, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy, and 3-8 membered carbocyclyl; R 10 and R 10' are each independently selected from the following group: optionally substituted C 1-C 6 alkyl, optionally substituted 3-8 membered carbocyclyl, optionally substituted 4-8 membered heterocyclyl; in R 10 and R 10', the "optionally substituted" means that the specified group is unsubstituted or substituted by one or more R 10s, and R 10s are each independently selected from the following group: halogen, cyano, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy, 3-8 membered carbocyclyl, 4-8 membered heterocyclyl.

[0043] In another preferred embodiment, R<2> is selected from the group consisting of halogen, optionally substituted C<1>-C<6> alkyl (preferably, C<1>-C<6> haloalkyl), and optionally substituted 3-10-membered carbocyclyl. In another preferred embodiment, the 3-10-membered carbocyclyl is a 3-10-membered saturated carbocyclyl; preferably, a 3-4-membered saturated carbocyclyl. In another preferred embodiment, each R<2s> is independently selected from the group consisting of halogen and C<1>-C<6> alkyl.

[0044] In another preferred embodiment, RX is selected from the group consisting of methyl, ethyl, halomethyl and halogen; X1 is selected from the group consisting of CR13 and N; X2 is selected from the group consisting of CR14 and N; and R13 and R14 are each independently selected from the group consisting of hydrogen, halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl.

[0045] In another preferred embodiment, the additional condition is that when Rx and R2 are both chlorine, and X1 is CR13, R13 is not chlorine.

[0046] In another preferred embodiment, X 3 is selected from the following group: CH and N; RX is methyl or halogen; RY is hydrogen, methyl or halogen.

[0047] In another preferred embodiment, R1, R2, R3, RX, RY, X1 and X2 are each independently a corresponding group of the specific compounds shown in Table A and the Examples.

[0048] In another preferred embodiment, the compound is selected from the following Table A: Table A .

[0049] In a second aspect of the present invention, a pharmaceutical composition is provided, comprising: (1) a therapeutically effective amount of the compound of the first aspect, or one or more of its pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, cis-trans isomers, solvates, polymorphs and deuterated forms as an active ingredient; and (2) Optionally, a pharmaceutically acceptable carrier.

[0050] In a third aspect of the present invention, there is provided use of the compound according to the first aspect, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph or deuterated form thereof, or the pharmaceutical composition according to the second aspect, in the preparation of a medicament for preventing or treating MTAP- / -related cancers.

[0051] In another preferred embodiment, the cancer is selected from the group consisting of: glioma, mesothelioma, esophageal cancer, bladder cancer, urothelial cancer, pancreatic cancer, melanoma, non-small cell lung cancer, head and neck cancer, sarcoma, bile duct cancer, liver cancer, breast cancer, skin cancer, intestinal cancer, gastric cancer, kidney cancer, urethral cancer, prostate cancer, testicular cancer, uterine cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, multiple myeloma, spinal neurofibroma, astrocytoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma and non-Hodgkin's lymphoma.

[0052] In another preferred embodiment, the MTAP - / - related cancer is an MTAP-deficient cancer.

[0053] In a fourth aspect of the present invention, a compound as described in the first aspect, or a pharmaceutical composition as described in the second aspect is provided for use in preventing or treating MTAP - / - related cancers.

[0054] In another preferred embodiment, the cancer is selected from the group consisting of: glioma, mesothelioma, esophageal cancer, bladder cancer, urothelial cancer, pancreatic cancer, melanoma, non-small cell lung cancer, head and neck cancer, sarcoma, bile duct cancer, liver cancer, breast cancer, skin cancer, intestinal cancer, gastric cancer, kidney cancer, urethral cancer, prostate cancer, testicular cancer, uterine cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, multiple myeloma, spinal neurofibroma, astrocytoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma and non-Hodgkin's lymphoma.

[0055] In another preferred embodiment, the MTAP - / - related cancer is an MTAP-deficient cancer.

[0056] In a fifth aspect of the present invention, a method for treating or preventing MTAP- / -related cancer is provided, comprising the steps of administering to a subject in need thereof a therapeutically effective amount of the compound of the first aspect, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph or deuterated form thereof, or the pharmaceutical composition of the second aspect, thereby treating or preventing MTAP- / -related cancer.

[0057] In another preferred embodiment, the cancer is as defined above.

[0058] In another preferred embodiment, the MTAP - / - related cancer is as defined above.

[0059] In a sixth aspect of the present invention, a method for inhibiting cell proliferation activity is provided, comprising the steps of: The cells are contacted with the compound described in the first aspect, thereby inhibiting the proliferation activity of the cells.

[0060] In another preferred embodiment, the method is non-therapeutic in vitro.

[0061] In another preferred embodiment, the cells are cancer cells.

[0062] In another preferred embodiment, the cells are MTAP - / - cells (i.e., MTAP-deficient cells).

[0063] In another preferred embodiment, the cells are selected from the following group: HCT116 MTAP - / - cells, HCC15, NCI-H2052, LN18, NCI-H838, LU99, DOHH2, HT-1080, MKN45, THP-1, MCF7, Mia Paca2, U87MG, UMUC3, or a combination thereof.

[0064] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail 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 listed here one by one. Implementation Method

[0065] Detailed description of preferred embodiments After extensive and in-depth research, the inventors synthesized for the first time a series of novel cyclic compounds, such as those shown in Formula I. They then conducted biological activity tests and unexpectedly discovered that these compounds exhibited potent inhibitory effects on MAT2A. Therefore, they can be used to prepare drugs for treating MTAP- / --associated cancers. This work led to the completion of the present invention. Terminology

[0066] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0067] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of." Group Definition

[0068] Definitions of standard chemical terms can be found in the literature, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Conventional methods, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy, and pharmacological methods, are employed, unless otherwise indicated. Terms used herein in descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry are those known in the art, unless specifically defined. Standard techniques can be used in chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. For example, reactions and purifications can be performed using manufacturer's instructions for kits, or as is known in the art or as described herein. The techniques and methods described above can generally be performed according to conventional methods well known in the art, as described in the various general and more specific literature cited and discussed herein. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.

[0069] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0070] The section headings used herein are for organizational purposes only and should not be construed as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are incorporated herein by reference in their entirety.

[0071] Certain chemical groups defined herein are preceded by a shorthand notation to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl refers to an alkyl group, as defined below, having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the shorthand notation does not include carbons that may be present in substituents of the group.

[0072] In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below unless otherwise specified.

[0073] In this application, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0074] "Hydroxy" refers to an -OH group.

[0075] "Hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl group, as defined below, substituted with a hydroxy (-OH) group.

[0076] "Carbonyl" refers to a -C(=O)- group.

[0077] "Nitro" refers to -NO2.

[0078] "Cyano" refers to -CN.

[0079] "Amine" refers to -NH2.

[0080] "Substituted amino" refers to an amino group substituted with one or two alkyl groups, alkylcarbonyl groups, arylalkyl groups, or heteroarylalkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkylamide, arylalkylamino, or heteroarylalkylamino.

[0081] "Carboxyl" refers to -COOH.

[0082] In the present application, as a group or as part of another group (for example, as used in a group such as a halogen-substituted alkyl group), the term "alkyl" refers to a fully saturated straight or branched hydrocarbon chain radical consisting only of carbon atoms and hydrogen atoms, having, for example, 1 to 12 (C1-C12 alkyl) (preferably 1 to 8 (C1-C8 alkyl), more preferably 1 to 6 (C1-C6 alkyl)) carbon atoms, and connected to the rest of the molecule by one or more single bonds, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl. For the purposes of the present invention, the term "alkyl" preferably refers to an alkyl group containing 1 to 6 carbon atoms.

[0083] In the present application, the term "alkenyl" as a group or part of another group means a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (C2-C14 alkenyl) (preferably 2 to 10 (C2-C10 alkenyl), more preferably 2 to 6 (C2-C6 alkenyl)) carbon atoms and connected to the rest of the molecule by one or more single bonds, such as, but not limited to, ethenyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, etc.

[0084] As used herein, the term "alkynyl" as a group or as part of another group refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having, for example, 2 to 14 (C2-C14 alkynyl) (preferably 2 to 10 (C2-C10 alkynyl), more preferably 2 to 6 (C2-C6 alkynyl)) carbon atoms and connected to the rest of the molecule by one or more single bonds, such as, but not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0085] In the present application, the term "carbocyclic ring" as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, which may include a fused ring system, a bridged ring system, or a spirocyclic ring system, having 3 to 15 carbon atoms (i.e., C3-C15 or 3-15-membered carbocyclic ring), preferably 3 to 10 carbon atoms (i.e., C3-C10 or 3-10-membered carbocyclic ring), more preferably 3 to 8 carbon atoms (i.e., C3-C8 or 3-8-membered carbocyclic ring), and more preferably 3 to 6 carbon atoms (i.e., C3-C6 or 3-6-membered carbocyclic ring), and is a saturated or unsaturated ring (e.g., cycloalkyl, cycloalkenyl, etc.) and may be linked to the rest of the molecule via one or more single bonds via any suitable carbon atom. Unless otherwise specified in the specification, the carbon atoms in the carbocyclic group may be optionally oxidized. Examples of carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, 2,3-dihydroindanyl, octahydro-4,7-methylene-1H-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, 1H-indenyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocyclohepten-5, 5,6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl, 1,2,3,4-tetrahydro-naphthyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, 1H-indenyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocyclohepten-5, 1,2,3,4-tetrahydro-naphthyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, 1H-indenyl, 6,7,8,9,10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl and octahydro-2,5-methylene-pentalenyl, etc.

[0086] In this application, as a group or part of other groups, the term "cycloalkyl" (such as "C3-C6 alkyl") refers to the above-mentioned fully saturated carbocyclic ring (group), typical cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, etc.

[0087] In the present application, as a group or part of other groups, the term "cycloalkenyl" (such as "C4-C6 cycloalkenyl") refers to a partially unsaturated carbon ring (radical). Typical cycloalkenyl groups include but are not limited to cyclobutenyl, cyclopentenyl, cyclohexenyl, etc.

[0088] As used herein, the term "heterocyclic group," as a group or as part of another group, refers to a stable 3- to 20-membered non-aromatic cyclic group (i.e., a 3-20-membered heterocyclic group) composed of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. Unless otherwise specified herein, a heterocyclic group can be a monocyclic, bicyclic, tricyclic, or multicyclic ring system, which may include fused, bridged, or spirocyclic ring systems. The nitrogen, carbon, or sulfur atoms in the heterocyclic group may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclic group may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule via a carbon atom or a heteroatom and by one or more single bonds. In heterocyclic groups containing fused rings, one or more rings may be aryl or heteroaryl, as defined below, provided that the point of attachment to the remainder of the molecule is a non-aromatic ring atom. For the purposes of the present invention, the heterocyclic group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged, or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur (i.e., a 4-11-membered heterocyclic group), and more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged, or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur (i.e., a 4-8-membered heterocyclic group). Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, oxazolinyl, piperidine, homopiperidine, piperidinyl, thioxazolinyl, 2-azabicyclo[2.2.2]octanyl, 2,7-diaza-spiro[3.5]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptane-2 -yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, thiophene, dioxolane, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, dihydroindole, octahydroindole, octahydroisoindole, pyrrolidinyl, pyrazolidinyl, phthalimide and the like.

[0089] As used herein, the term "aryl," as a group or as part of another group, refers to a conjugated hydrocarbon ring system radical having 6 to 18 carbon atoms (preferably 6 to 10 carbon atoms, i.e., C6-C10 aryl or 6-10 membered aryl). For the purposes of this invention, an aryl group can be a monocyclic, bicyclic, tricyclic, or higher ring system, and can also be fused to a carbocyclic or heterocyclic group as defined above, provided that the aryl group is attached to the remainder of the molecule via one or more single bonds through an atom in the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazol-3(4H)-on-7-yl, and the like.

[0090] In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted by an aryl group as defined above.

[0091] As used herein, the term "heteroaryl," as a group or as part of another group, refers to a 5- to 16-membered conjugated ring system having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified herein, a heteroaryl group may be monocyclic, bicyclic, tricyclic, or higher ring system, and may be fused to a carbocyclic or heterocyclic group as defined above, provided that the heteroaryl group is attached to the remainder of the molecule through one or more single bonds via atoms in the heteroaromatic ring. The nitrogen, carbon, or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atom may be optionally quaternized. For the purposes of the present invention, heteroaryl is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5- to 10-membered aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur (also referred to as a 5-10-membered heteroaryl group) or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur (also referred to as a 5-6-membered heteroaryl group or a 5 or 6-membered heteroaryl group). Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridinyl, pyrimid ... oxazolyl, cinnolinyl, quinazolinyl, phenylthio, indolizinyl, o-phenanthroline, isoxazolyl, phenanthroline, phenanthroline, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridinyl, [1,2,4]triazolo[4,3-b]thiazolinyl, [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]thiazolinyl, imidazo[1,2-a]pyridine, and the like.

[0092] As used herein, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above.

[0093] In this application, the term "absent" means that the two sides of the group defined above are directly connected by a chemical bond. For example, "ABC in which B is absent" means "AC".

[0094] In this application, “ " ” indicates the attachment position of the group R.

[0095] In this application, unless otherwise indicated in a claim, "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both cases where the event or circumstance occurs and cases where it does not occur. For example, "optionally substituted aryl" means that the hydrogen atoms on the aryl group may or may not be substituted, and the description includes both substituted and unsubstituted aryl groups. For example, in the absence of explicit listing of substituents, the terms "optionally substituted", "substituted" or "substituted by" as used herein mean that one or more hydrogen atoms on a given atom or group are independently replaced by one or more, for example 1, 2, 3 or 4, substituents independently selected from the group consisting of: deuterium (D), halogen, -OH, oxo (=O), mercapto, cyano, -CD3, -C1-C6 alkyl (preferably -C1-3 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl (preferably C3-C8 cycloalkyl), aryl, heterocyclyl (preferably 3-8 membered heterocyclyl), heteroaryl, aryl-C1-C6 alkyl-, heteroaryl-C1-C6 alkyl-, C1-C6 haloalkyl-, -OC1-C6 alkyl (preferably -OC1-C3 alkyl), -OC2-C6 alkynyl, cycloalkyl (preferably C3-C8 cycloalkyl), aryl, heterocyclyl (preferably 3-8 membered heterocyclyl), heteroaryl, aryl-C1-C6 alkyl-, heteroaryl-C1-C6 alkyl-, C1-C6 haloalkyl-, -OC1-C6 alkyl (preferably -OC1-C3 alkyl), -OC2-C6 6 alkenyl, -O cycloalkyl, -O heterocyclyl, -O aryl, -O heteroaryl, -OC 1-C 6 alkylphenyl, -C 1-C 6 alkyl-OH (preferably -C 1-C 4 alkyl-OH), -C 1-C 6 alkyl-SH, -C 1-C 6 alkyl-OC 1-C 6 alkyl, -OC 1-C 6 haloalkyl, -NH 2, -C 1-C 6 alkyl-NH 2 (preferably -C 1-C 3 alkylNH 2), -N(C 1-C 6 alkyl) 2 (preferably N(C 1-C 3 alkyl) 2), -NH(C 1-C 6 alkyl) (preferably -NH(C 1-C 3 alkyl)), -N(C 1-C 6 alkyl)(C 1-C 6 alkylphenyl), -NH(C 1-C 6 alkylphenyl), -N(C 1-C 6 alkyl) (aryl), -NH(aryl), nitro, -C(O)-OH, -C(O)OC 1-C 6 alkyl (preferably -C(O)OC 1-C 3 alkyl), -CONR iR ii (wherein R i and R ii are H, D and C 1- 6 alkyl,-C 1-C 6 alkyl), -NHC(O)(C 1-C 6 alkyl), -NHC(O)(phenyl), -N(C 1-C 6 alkyl)C(O)(C 1-C 6 alkyl), -N(C 1-C 6 alkyl)C(O)(phenyl), -C(O)C 1-C 6 alkyl, -C(O)heteroaryl (preferably -C(O)-5-7 membered heteroaryl), -C(O)C 1-C 6 alkylphenyl, -C(O)C 1-C 6 haloalkyl, -OC(O)C 1-C 6 alkyl (preferably -OC(O)C 1-C 3 alkyl), -S(O) 2-C 1-C 6 alkyl, -S(O)-C 1-C 6 alkyl, -S(O) 2-phenyl, -S(O) 2-C 1-C 6 haloalkyl, -S(O) 2NH 2, -S(O) 2NH(C 1-C 6 alkyl), -S(O) 2NH(phenyl), -NHS(O) 2(C 1-C 6 alkyl), -NHS(O) 2(phenyl) and -NHS(O) 2(C 1-C 6 haloalkyl), wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, aryl, heterocyclyl and heteroaryl groups is optionally further substituted with one or more substituents selected from the group consisting of halogen, -OH, oxo (=O), -NH 2, cycloalkyl, 3-8 membered heterocyclyl, C 1-C 4 alkyl, C 1-C 4 haloalkyl-, -OC 1-C 4 alkyl, -C 1-C 4 alkyl-OH, -C 1-C 4 alkyl-OC 1-C 4 alkyl, -OC 1-C 4 haloalkyl, cyano, nitro, -C(O)-OH, -C(O)OC 1-C alkyl), -CON(C 1-C 6 alkyl) 2, CONH(C 1-C 6 alkyl), -CONH 2, -NHC(O)(C 1-C 6 alkyl), -NH(C 1-C 6 alkyl)C(O)(C 1-C 6 alkyl), -SO 2(C 1-C 6 alkyl), -SO 2(phenyl), -SO 2(C 1-C 6 haloalkyl), -SO 2NH 2, -SO 2NH(C 1-C 6 alkyl), -SO 2NH(phenyl), -NHSO 2(C 1-C 6 alkyl), -NHSO 2(phenyl) and -NHSO 2(C 1-C 6 haloalkyl). When an atom or group is substituted with multiple substituents, the substituents may be the same or different. As used herein, the terms "part," "structure," "chemical part," "group," and "chemical group" refer to specific fragments or functional groups in a molecule. A chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule.

[0096] In the present invention, (C 1 -C 4 alkyl) 2 amine represents an amine substituted with two C 1 -C 4 alkyl groups, for example, 、 、 、 or wait.

[0097] In the present invention, "plurality" refers to 2, 3 or 4. Active ingredient

[0098] As used herein, "compound of the present invention" or "active ingredient" refers to the compound represented by Formula I, and also includes pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, cis-trans isomers, solvates, polymorphs, deuterated forms, or combinations thereof.

[0099] "Stereoisomers" are compounds composed of the same atoms, bonded by the same bonds, but with different three-dimensional structures. The present invention is intended to encompass various stereoisomers and mixtures thereof.

[0100] When the compounds of the present invention contain olefinic double bonds, and unless specified otherwise, it is intended that the compounds of the present invention include both E- and Z- geometric isomers.

[0101] "Tautomers" refer to isomers formed when a proton is shifted from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention are intended to be encompassed within the scope of the present invention.

[0102] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms and, therefore, may give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral carbon atom may be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the present invention may be prepared using racemates, diastereomers, or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0103] Conventional techniques for preparing / isolating individual isomers include chiral synthesis from appropriate optically pure precursors, or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography, see, for example, Gerald Gübitz and Martin G. Schmid (eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, vol. 243, 2004; AM Stalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3:341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128.

[0104] In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0105] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, caproate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, and naphthalene disulfonate. These salts can be prepared by methods known in the art.

[0106] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines, and basic ion exchange resins, such as amine, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperidine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art. Pharmaceutical compositions and methods of administration

[0107] Because the compounds of the present invention have excellent inhibitory activity against methionine adenosyltransferase 2A (MAT2A), the compounds of the present invention and their various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, as well as pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent, and alleviate MTAP-deficient (MTAP- / -) type cancers or tumors (such as those specific tumors listed elsewhere in this document).

[0108] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-500 mg per dose. Preferably, "one dose" refers to one capsule or tablet.

[0109] In this application, a "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). This medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, promote absorption of the active ingredient, and thereby exert its biological activity.

[0110] The compounds of general formula (I) can be used in combination with other drugs known to treat or ameliorate similar conditions. When administered in combination, the original drug's route of administration and dosage can remain unchanged, while the compound of formula I is administered simultaneously or subsequently. When the compound of formula I is administered simultaneously with one or more other drugs, a pharmaceutical composition containing both one or more known drugs and the compound of formula I may be preferably used. Drug combination also includes administering the compound of formula I and one or more other known drugs during overlapping time periods. When the compound of formula I is administered in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than when administered alone.

[0111] The drugs or active ingredients that can be used in combination with the compound of formula (I) include but are not limited to: chemotherapy drugs (such as docetaxel, paclitaxel, gemcitabine, etc.), PD-1 inhibitors (such as nivolumab, pembrolizumab, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, etc.), CD20 antibodies (such as rituximab, etc.), (such as rituximab, ibrutinib, etc.), KRAS inhibitors (such as AMG510, etc.), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocatinib), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, osimertinib, etc.), VEGFR inhibitors (such as sorafenib, pazopanib, regorafenib, cabozantinib, sunitinib, etc.), PI3K inhibitors agents (such as Dactolisib, Taselisib, etc.), BTK inhibitors (such as Ibrutinib, Tilabrutinib, Acalabrutinib, Zanubrutinib, Vecabuzinib, etc.), HDAC inhibitors (such as Vorinostat, Fimepinostat, Givinostat, Tucidinostat, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib, etc.), ERK inhibitors (such as BVD523, HH2710, etc.), mTOR inhibitors (such as Visusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068), SOS1 inhibitors (such as BI1701963, etc.), PRMT inhibitors or a combination thereof.

[0112] As used herein, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.

[0113] In this application, "pharmaceutically acceptable carrier" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant government regulatory authorities as acceptable for human or livestock use.

[0114] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0115] 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 ingredients: (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, such as glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, 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, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain a buffering agent.

[0116] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and release of the active compound or compounds in such compositions can be delayed in a specific portion of the digestive tract. Examples of useful encapsulating components include polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0117] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof.

[0118] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0119] In addition to the active compounds, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0120] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0121] The "tumor (cancer)" of the present invention (such as MTAP-deficient tumor (cancer) or MTAP- / related tumor (cancer)) includes but is not limited to glioma, mesothelioma, esophageal cancer, bladder cancer, urothelial cancer, pancreatic cancer, melanoma, non-small cell lung cancer, head and neck cancer, sarcoma, bile duct cancer, liver cancer, breast cancer, skin cancer, intestinal cancer, gastric cancer, kidney cancer, urethra cancer, prostate cancer, testicular cancer, uterine cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, multiple myeloma, spinal neurofibroma, astrocytoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma and non-Hodgkin's lymphoma. As used herein, the terms "preventive", "prevention" and "prevent" include reducing the likelihood of the occurrence or worsening of a disease or condition in a patient.

[0122] The term "treat" and other similar synonyms as used herein include the following meanings: (i) preventing a disease or condition from occurring in a mammal, particularly where such mammal is susceptible to the disease or condition but has not yet been diagnosed as having the disease or condition; (ii) inhibiting the disease or condition, that is, arresting its development; (iii) alleviate the disease or condition, that is, cause the disease or condition to regress; or (iv) Alleviate the symptoms of the disease or condition.

[0123] As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to an amount of at least one agent or compound sufficient, upon administration, to provide some relief from one or more symptoms of the disease or condition being treated. This can result in a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, a therapeutically effective amount is the amount of a composition comprising a compound disclosed herein that provides a clinically significant relief of the condition. Techniques such as dose escalation studies can be used to determine the effective amount appropriate for any individual case.

[0124] As used herein, the terms "administer," "administer," "dosing," and the like refer to methods that enable a compound or composition to be delivered to the desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

[0125] As used herein, the terms "pharmaceutical combination," "drug combination," "combination therapy," "administration of an additional therapy," "administration of an additional therapeutic agent," and the like refer to a pharmaceutical therapy obtained by mixing or combining more than one active ingredient, and include both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient as a single entity or single dosage form. The term "non-fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient as separate entities, either concurrently, in combination, or sequentially at variable intervals. This also applies to cocktail therapies, e.g., administration of three or more active ingredients.

[0126] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg per dose. Preferably, "one dose" refers to one capsule or tablet.

[0127] Compared with the prior art, the present invention has the following beneficial effects: (1) The present invention provides a novel compound as shown in Formula I or a pharmaceutically acceptable salt thereof; (2) The compounds of the present invention can inhibit MAT2A and can be used to prepare drugs for treating MTAP- / -related cancers. (3) The compounds of the present invention have excellent proliferation inhibitory activity against MTAP-deficient (MTAP- / -) cells. (4) The compounds of the present invention have excellent selective cell proliferation inhibitory activity. The proliferation inhibitory activity of the compounds of the present application on MTAP-deficient (MTAP- / -) cells is significantly better than that on MTAP-non-deficient (MTAPwt) cells, and even has basically no proliferation inhibitory activity on MTAP-non-deficient (MTAPwt) cells.

[0128] The present invention is further illustrated below with reference to specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit its scope. Experimental procedures in the following examples, where specific conditions are not specified, were generally performed under conventional conditions or according to the manufacturer's recommendations. Unless otherwise indicated, percentages and parts are by weight.

[0129] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

[0130] In each example, 1H NMR was recorded by a BRUKER AVANCE NEO 400 MHz nuclear magnetic resonance instrument, and chemical shifts were expressed in δ (ppm); liquid chromatography-mass spectrometry (LCMS) was recorded by Shimadzu LC-20AD, SIL-20A, CTO-20AC, SPD-M20A, CBM-20A, or LCMS-2020 mass spectrometers; and preparative HPLC separations were performed using a Gilson-281 liquid chromatograph.

[0131] Example 1 Synthesis of Compound 1 The synthetic route of compound 1 is as follows:

[0132] (1) Compound 1-1 (5 g, 21.36 mmol) was added to sulfone chloride (15 mL) and heated under reflux for two hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in acetic acid (30 mL). Anhydrous hydrazine (2.89 mL, 92.90 mmol) was added and heated under reflux at 120°C overnight. The reaction solution was directly concentrated to dryness and added to water (20 mL) to precipitate a solid. The solid was filtered, and the filter cake was filtered under reduced pressure and dried under vacuum overnight to obtain compound 1-2. MS-ESI [M+H] +, calculated value: 231, found value: 231.

[0133] (2) Compound 1-2 (3 g, 13.03 mmol) was dissolved in phosphorus oxychloride (30 mL), and the mixture was stirred at 100°C overnight. The reaction mixture was concentrated under reduced pressure to remove the phosphorus oxychloride. The crude oil was then slowly added dropwise to ice water (50 mL) with thorough stirring. The pH was adjusted to 8 with a 2 mol / L aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent removed from the filtrate under reduced pressure. Compound 1-3 was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford compound 1-3. MS-ESI [M+H] + calcd. 267, found 267.

[0134] (3) Methylamine hydrochloride (379.28 mg, 5.62 mmol) and sodium carbonate (1964.76 mg, 18.54 mmol) were added to a solution of compound 1-3 (1500 mg, 5.62 mmol) in N,N-dimethylformamide (20 mL), and the mixture was stirred at 120°C overnight. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:4) to obtain compound 1-4. MS-ESI [M+H] + calcd. 262, found 262.

[0135] (4) Compound 1-5 (61.16 mg, 0.45 mmol), sodium carbonate (76.97 mg, 0.73 mmol), and bis(diphenylphosphino)ferrocenepalladium dichloride (26.94 mg, 0.04 mmol) were added to a solution of compound 1-4 (95 mg, 0.36 mmol) in 1,4-dioxane (4 mL) and water (1 mL). The mixture was stirred at 110°C overnight under nitrogen. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (Puningtech-Pntulips-C18-5μm-21.2×150mm, A: 0.05% trifluoroacetic acid / water B: acetonitrile, 0-32% B) to give compound 1. MS-ESI [M+H] +, calculated value: 319, found value: 319. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.95 – 8.73 (m, 2H), 8.57 (d, J = 8.7 Hz, 1H), 8.01 (s, 1H), 7.76 (s, 1H), 7.67 – 7.46 (m, 1H), 3.24 (d, J = 3.5 Hz, 3H), 2.36 (d, J = 15.8 Hz, 3H).

[0136] Example 2 Synthesis of Compound 2 The synthetic route of compound 2 is as follows:

[0137] To a solution of compound 1-4 (95 mg, 0.36 mmol) in 1,4-dioxane (4 mL) and water (1 mL) were added compound 2-1 (56 mg, 0.36 mmol), sodium carbonate (76.97 mg, 0.73 mmol), and bis(diphenylphosphino)ferrocenepalladium dichloride (26.94 mg, 0.04 mmol). The mixture was stirred at 110°C overnight under nitrogen. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (Puningtech-Pntulips C18 5μm-21.2×150mm, A: 0.1% formic acid / water B: acetonitrile, 0-47% B) to afford compound 2. MS-ESI [M+H] + calcd: 338, found: 338. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 8.7 Hz, 1H), 8.27 (d, J = 7.6 Hz, 1H), 8.15 – 8.01 (m, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.64 – 7.53 (m, 3H), 7.49 (s, 1H), 3.12 (d, J = 4.3 Hz, 3H).

[0138] Example 3 Synthesis of Compound 3 Synthesize Reference Example 1, using deuterated methylamine to replace methylamine to obtain compound 3. MS-ESI [M+H] +, calculated value 322, The measured value is 322. 1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.63 (dd, J = 4.8, 1.8 Hz, 1H), 8.15 – 8.00 (m, 2H), 7.75 (dd, J = 7.6, 1.8 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.42 (dd, J = 7.6, 5.0 Hz, 1H), 2.23 (s, 3H).

[0139] Example 4 Synthesis of Compound 4

[0140] (1) To a solution of compound 1-3 (500 mg, 1.87 mmol) in dimethylsulfoxide (7 mL) were added 4-methoxybenzylamine (256.86 mg, 1.87 mmol) and sodium carbonate (496.15 mg, 4.68 mmol), and the mixture was stirred at 130°C overnight. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 6%-10%) to obtain compound 4-1. MS-ESI [M+H] +, calculated value 368, found value 368.

[0141] (2) Compound 1-5 (294.32 mg, 2.15 mmol), sodium carbonate (438.07 mg, 4.13 mmol), and bis(diphenylphosphino)ferrocenepalladium dichloride (245.27 mg, 0.33 mmol) were added to a solution of compound 4-1 (607 mg, 1.65 mmol) in 1,4-dioxane (10 mL) and water (2.2 mL). The mixture was stirred at 110°C overnight under nitrogen. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (methanol / dichloromethane = 2%-3%) to obtain compound 4-2. MS-ESI [M+H] +, calculated value 425, found value 425.

[0142] (3) Compound 4-2 (400 mg, 0.94 mmol) was dissolved in a mixture of trifluoroacetic acid (4 mL) and trifluoromethanesulfonic acid (0.4 mL) at 0°C. The mixture was stirred under nitrogen for 10 minutes. The reaction was monitored by LCMS until complete. The reaction solution was concentrated, and the crude product was purified by preparative reverse phase chromatography (Waters-CORTECS C18 2.7µm-4.6×30mm; 25 ml / min; 25°C; 0%-100% acetonitrile / 0.05% NH4HCO3 aqueous buffer) to give compound 4. MS-ESI [M+H]+, calculated value: 305, found value: 305. 1H NMR (400 MHz, DMSO-d6) δ 8.70 – 8.52 (m, 2H), 8.25 (dd, J = 8.8, 1.8 Hz, 1H), 7.78 (dd, J = 7.6, 1.8 Hz, 1H), 7.59 – 7.35 (m, 4H), 2.23 (s, 3H).

[0143] Example 5 Synthesis of Compound 5 Synthesize reference example 4, use the corresponding pyridine boronic acid to replace 1-5 to obtain compound 5. MS-ESI [M+H] +, calcd. 319, The measured value is 319. 1H NMR (400 MHz, CDCl 3) δ 8.55 (d, J = 5.2 Hz, 1H), 8.13 – 8.03 (m, 2H), 7.59 (d, J = 0.8 Hz, 1H), 7.19 (d, J = 5.2 Hz, 1H), 5.88 (s, 2H), 2.22 (s, 3H), 2.02 (s, 3H).

[0144] Example 6 Synthesis of Compound 6

[0145] (1) Compound 6-1 (206.60 mg, 0.82 mmol), sodium carbonate (115.28 mg, 1.09 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (92.50 mg, 0.11 mmol) were added to a solution of compound 4-1 (200 mg, 0.54 mmol) in 1,4-dioxane (10 mL) and water (2.2 mL). The mixture was stirred at 110°C overnight under nitrogen. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (methanol / dichloromethane = 2%-3%) to obtain compound 6-2. MS-ESI [M+H] +, calculated value 440, found value 440.

[0146] (2) A solution of sodium nitrite (29.91 mg, 0.43 mmol) in water (1 mL) was added dropwise to a solution of compound 6-2 (127 mg, 0.29 mmol) in pyridine hydrogen fluoride (3 mL) at -10°C. After the addition was complete, the reaction was stirred at 20°C for 1 hour. The reaction was monitored by LCMS. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, and concentrated. The crude product was purified by silica gel column gradient chromatography (methanol / dichloromethane = 2%-3%) to obtain compound 6-3. MS-ESI [M+H] +, calculated value 443, found value 443.

[0147] (3) Compound 6-3 (95 mg, 0.21 mmol) was dissolved in a mixture of trifluoroacetic acid (4 mL) and trifluoromethanesulfonic acid (0.4 mL) at 0°C. The mixture was stirred under nitrogen for 10 minutes. The reaction was monitored for completion by LCMS. The reaction solution was concentrated, and the crude product was purified by preparative reverse-phase chromatography (Waters-CORTECS C18 2.7µm-4.6×30mm; 25 ml / min; 25°C; 0%-100% acetonitrile / 0.05% NH4HCO3 aqueous buffer) to give compound 6. MS-ESI [M+H]+, calculated value: 323, found value: 323. 1H NMR (400 MHz, CDCl 3) δ 8.68 (dd, J = 8.4, 5.6 Hz, 1H), 8.18 – 8.04 (m, 2H), 7.68 (s, 1H), 7.11 (dd, J = 8.4, 5.6 Hz, 1H), 5.96 (s, 2H), 2.40 (s, 3H).

[0148] Example 7 Synthesis of Compound 7

[0149] (1) Compound 1-5 (276.41 mg, 2.02 mmol), sodium carbonate (545.77 mg, 5.15 mmol), and bis(diphenylphosphino)ferrocenepalladium dichloride (305.57 mg, 0.41 mmol) were added to a solution of compound 1-3 (550 mg, 2.06 mmol) in 1,4-dioxane (10 mL) and water (2.2 mL). The mixture was stirred at 110°C under nitrogen for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (methanol / dichloromethane = 2%-3%) to obtain compound 7-1. MS-ESI [M+H] +, calculated value: 324, found value: 324.

[0150] (2) Under nitrogen protection, compound 7-1 (249 mg, 0.77 mmol), tetrakis(triphenylphosphine)palladium (177.78 mg, 0.15 mmol), triethylamine (1.28 ml, 9.23 mmol), and formic acid (0.04 ml, 0.92 mmol) were dissolved in N,N-dimethylformamide (3 mL). The mixture was stirred at 110°C for 40 minutes under nitrogen protection. The reaction was monitored by LCMS. The crude product was purified by preparative reverse phase chromatography (Waters-CORTECS-C18-2.7µm-4.6×30mm; 25 ml / min; 25°C; 0%-100% acetonitrile / 0.05% NH4HCO3 aqueous buffer) to give compound 7. MS-ESI [M+H]+, calculated value 290, found value 290. 1H NMR (400 MHz, CDCl 3) δ 9.64 (d, J = 0.8 Hz, 1H), 8.70 (dd, J = 4.8, 1.6 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.09 (dd, J = 8.4, 1.6 Hz, 1H), 7.83 – 7.80 (m, 1H), 7.66 (dd, J= 7.6, 1.8 Hz, 1H), 7.32 (dd, J = 7.6, 4.8 Hz, 1H), 2.30 (s, 3H).

[0151] Example 8 Synthesis of Compound 8

[0152] The synthetic route of compound 8 is as follows:

[0153] (1) Compound 8-1 (2 g, 7.60 mmol) was added to sulfonyl chloride (20 mL), and two drops of dry N,N-dimethylformamide solution were added. The mixture was heated under reflux for two hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in acetic acid (30 mL). Anhydrous hydrazine (1.52 g, 30.41 mmol) was added, and the mixture was heated at 120°C and refluxed overnight. The reaction solution was directly concentrated to dryness and added to water (20 mL). The solid precipitated and was filtered. The filter cake was vacuum dried overnight to obtain compound 8-2. MS-ESI [M+H] +, calculated value 259, found value 259.

[0154] (2) Compound 8-2 (3 g, 13.03 mmol) was dissolved in phosphorus oxychloride (30 mL), and the mixture was stirred at 100°C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the phosphorus oxychloride. The crude oil was then slowly added dropwise to ice water (50 mL) with thorough stirring. The pH was adjusted to 8 with a 2 mol / L aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent removed from the filtrate under reduced pressure. Compound 8-3 was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 8-3. MS-ESI [M+H] +, calculated value: 295, found value: 295.

[0155] (3) To a solution of compound 8-3 (700 mg, 2.37 mmol) in dimethylsulfoxide (10 mL) were added p-methoxybenzylamine (324 mg, 2.37 mmol) and sodium carbonate (752 mg, 7.10 mmol), and the mixture was stirred at 130°C overnight. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 8-4. MS-ESI [M+H] + Calcd. 396 Found 396.

[0156] (4) Compound 8-4 (230 mg, 0.58 mmol) was dissolved in 1,4-dioxane (5 mL). Potassium cyclopropyltrifluoroborate (103 mg, 0.70 mmol), sodium carbonate (184 mg, 1.74 mmol), and 1,1'-bis(dicyclohexylphosphino)ferrocenepalladium dichloride (88 mg, 0.13 mmol) were added under nitrogen. The mixture was stirred at 90 °C for 3 h in a microwave oven under nitrogen. The reaction was monitored for completion by LCMS. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain 8-6. MS-ESI [M+H] +, calculated value: 358, found value: 358.

[0157] (5) Compound 1-5 (61.16 mg, 0.45 mmol), sodium carbonate (71 mg, 0.67 mmol), and bis(diphenylphosphino)ferrocenepalladium dichloride (36.6 mg, 0.04 mmol) were added to a solution of compound 8-6 (80 mg, 0.22 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL). The mixture was stirred at 110°C overnight under nitrogen. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (methanol / dichloromethane = 2%-3%) to obtain 8-7. MS-ESI [M+H] +, calculated value: 415, found value: 415.

[0158] (6) Compound 8-7 (50 mg, 0.12 mmol) was dissolved in a mixture of trifluoroacetic acid (1 mL) and trifluoromethanesulfonic acid (0.2 mL) at 0°C. The mixture was stirred under nitrogen for 60 min. The reaction was monitored by LCMS until complete. The reaction solution was concentrated, and the crude product was purified by preparative HPLC (Waters-CORTECS-C18-2.7µm-4.6×30mm; 25 ml / min; 25°C; 0%-100% acetonitrile / 0.05% NH4HCO3 aqueous buffer) to give compound 8. MS-ESI [M+H]+, calculated value: 295, found value: 295. 1H NMR (400 MHz, DMSO-d 6) δ 8.52 (dd, J = 4.8, 1.6 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.67 (dd, J= 7.6, 1.6 Hz, 1H), 7.49 (dd, J = 8.4, 7.2 Hz, 1H), 7.39 – 7.30 (m, 3H), 2.20 (s, 3H), 2.13 (td, J = 8.4, 4.0 Hz, 1H), 1.08 – 1.02 (m, 2H), 0.94 – 0.82 (m, 2H).

[0159] Example 9 Synthesis of Compound 9

[0160] The synthetic route of compound 9 is as follows:

[0161] (1) Lithium diisopropylamide (2 mol / L, 30.86 mL, 61.73 mmol) was added dropwise to tetrahydrofuran (70 mL) at -70°C. Compound 9-1 (10 g, 41.15 mmol) was then slowly added dropwise to the reaction solution over a period of about 20 minutes. After gradually warming to room temperature and stirring for 1.5 hours, carbon dioxide gas was introduced into the reaction solution and stirred for another hour. The reaction was quenched with 3 mol / L hydrochloric acid, and the pH of the solution was adjusted to 1-2. The mixture was then extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent to obtain compound 9-2.

[0162] (2) Compound 9-2 (8 g, 27.87 mmol) and potassium carbonate (5.78 g, 41.81 mmol) were dissolved in N,N-dimethylformamide (60 mL). Iodomethane (2.49 mL, 30.66 mmol) was added dropwise to the reaction mixture at 0°C, and then stirred at 25°C for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. Purification by column chromatography (petroleum ether:ethyl acetate = 50:1) afforded compound 9-3 as a colorless oil.

[0163] (3) Compound 9-3 (8 g, 26.58 mmol) and N,N-diisopropylethylamine (22.02 mL, 132.88 mmol) were dissolved in methanol (40 mL) and N,N-dimethylformamide (40 mL). Palladium acetate (298.32 mg, 1.33 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.54 g, 2.66 mmol) were added to the reaction solution. The reaction solution was then stirred at 80 °C for 16 hours under a carbon monoxide atmosphere. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. Compound 9-4 was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 9-4.

[0164] (4) Compound 9-4 (3.0 g, 10.71 mmol) was dissolved in tetrahydrofuran (15 mL) and water (15 mL). Solid sodium hydroxide (1.285 g, 32.12 mmol) was added to the reaction solution at 0°C. The mixture was then stirred at 25°C for 3 hours. The reaction solution was quenched with 3 mol / L hydrochloric acid at 0-10°C and the pH of the solution was adjusted to 1-2. The mixture was then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent to obtain compound 9-5.

[0165] (5) Compound 9-5 (2.3 g, 9.12 mmol) was dissolved in sulfonyl chloride (20 mL). Two drops of dry N,N-dimethylformamide were added and the mixture was heated under reflux at 80 °C for 2 h under nitrogen. The reaction solution was concentrated to dryness and dissolved and concentrated with toluene (20 mL) three times to obtain crude compound 9-6.

[0166] (6) Compound 9-6 (2.8 g, 9.69 mmol) was dissolved in acetic acid (25 mL), and hydrazine hydrate (2.85 g, 48.44 mmol) was added. The mixture was heated at reflux at 120°C for 12 h. The reaction solution was concentrated to dryness, and water was added to disperse the solid. The solid was filtered, and the filter cake was vacuum dried overnight to obtain a light yellow solid, compound 9-7. MS-ESI [M+H] + calcd. 249, found 249.

[0167] (7) Compound 9-7 (2.3 g, 9.27 mmol) was dissolved in phosphorus oxychloride (20 mL) and stirred at 100°C for 2 hours. The reaction solution was directly concentrated to remove the phosphorus oxychloride. The oil was then dissolved in ethyl acetate and the solution was slowly added dropwise to an aqueous sodium bicarbonate solution with thorough stirring. The mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent removed from the filtrate under reduced pressure. Purification by column chromatography (petroleum ether:ethyl acetate = 8:1) afforded compound 9-8 as an off-white solid. MS-ESI [M+H] + Calcd. 285 Found. 285.

[0168] (8) Compound 9-8 (700 mg, 2.46 mmol) was dissolved in N-methylpyrrolidone (7 mL), and (2,4-dimethoxyphenyl)methylamine (410.6 mg, 2.46 mmol) and N,N-diisopropylethylamine (634.8 mg, 4.91 mmol) were added. The mixture was stirred at 130°C for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 9-9. MS-ESI [M+H] + Calcd. 416 Found 416.

[0169] (9) Compound 9-9 (270 mg, 0.65 mmol) was dissolved in 1,4-dioxane (10 mL) and water (1 mL). 2-Methylarsidine-3-boronic acid (177.8 mg, 1.30 mmol), sodium bicarbonate (136.4 mg, 1.62 mmol), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (53.2 mg, 0.06 mmol) were added under nitrogen. The mixture was stirred at 105 °C for 3 h under nitrogen. The reaction solution was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 9-10. MS-ESI [M+H] +, calculated value: 473, found value: 473.

[0170] (10) Compound 9-10 (160 mg, 0.34 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) and trifluoromethanesulfonic acid (0.2 mL) were then added dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was directly concentrated, and the oily substance was dissolved in dichloromethane. The solution was then slowly added dropwise to an icy sodium bicarbonate aqueous solution with sufficient stirring. The aqueous solution was adjusted to pH = 8 and extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. Compound 9 was purified by column chromatography (dichloromethane:methanol = 10:1) to give compound 9. MS-ESI [M+H] +, calculated value: 323, found value: 323. 1H NMR (400 MHz, DMSO-d 6) δ 8.55 (dd, J = 1.6, 4.8 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.30 - 8.24 (m, 1H), 7.73 (dd, J = 1.6, 7.6 Hz, 1H), 7.62 (s, 2H), 7.35 (dd, J = 5.2, 7.6 Hz, 1H), 2.21 (s, 3H).

[0171] Example 10 Synthesis of Compound 10

[0172] The synthetic route of compound 10 is as follows:

[0173] (1) Compound 10-1 (3.0 g, 11.15 mmol) was dissolved in methanol (30 ml), and sulfonyl chloride (1.21 ml, 16.73 mmol) was added. The mixture was heated to 70°C and stirred for 2 hours under a nitrogen atmosphere. The reaction was monitored for completion by LCMS. The reaction solution was concentrated, and the crude product was purified by silica gel chromatography using 3%-5% ethyl acetate / petroleum ether to obtain compound 10-2.

[0174] (2) Compound 10-2 (1.50 g, 5.30 mmol) and tributyl(1-ethoxyethylene)tin (2.69 ml, 7.95 mmol) were dissolved in 1,4-dioxane (25 ml). Tetrakis(triphenylphosphine)palladium (1.23 g, 1.06 mmol) was added under a nitrogen atmosphere and stirred at 100°C for 12 hours. The reaction was monitored by LCMS. The reaction solution was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried, and concentrated to give compound 10-3. MS-ESI [M+H] + Calcd. 275 Found. 275. 1H NMR (400 MHz, CDCl 3) δ 7.87 – 7.81 (m, 1H), 7.64 – 7.59 (m, 1H), 7.52 (d, J = 8.4 Hz, 1H), 4.37 (d, J = 2.8 Hz, 1H), 4.27 (d, J = 2.8 Hz, 1H), 3.84 – 3.79 (m, 5H), 1.25 (d, J = 7.2 Hz, 3H).

[0175] (3) Compound 10-3 (998 mg, 2.55 mmol) was dissolved in a solution of hydrochloric acid in 1,4-dioxane (4 mol / L, 10 ml) at room temperature and stirred at 25°C for 2 hours. The reaction was monitored for completion by LCMS. The reaction solution was concentrated to obtain crude compound 10-4. MS-ESI [M+H] + calcd. 247 found 247.

[0176] (4) Compound 10-4 (1.0 g, 4.07 mmol) and hydrazine hydrate (1 ml, 20.58 mmol) were dissolved in ethanol (10 ml), heated to 90 °C under nitrogen atmosphere, and refluxed with stirring for 2 hours. The reaction was monitored by LCMS. The reaction solution was concentrated, and the crude product was purified by silica gel chromatography: methanol / dichloromethane = 2%-3% gradient to obtain compound 10-5. MS-ESI [M+H] +, calculated value 229, found value 229. 1H NMR (400 MHz, CDCl 3) δ 10.26 (s, 1H), 8.73 – 8.67 (m, 1H), 8.00 (dd, J = 8.4, 1.8 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 2.57 (s, 3H).

[0177] (5) Compound 10-5 (551 mg, 2.41 mmol) was dissolved in phosphorus oxychloride (7 ml) and heated to 110 °C under a nitrogen atmosphere with reflux and stirring for 1 hour. The reaction was monitored by LCMS. The reaction solution was concentrated, and the crude product was purified by silica gel chromatography using a gradient of methanol / dichloromethane = 5% to 7% to obtain compound 10-6. MS-ESI [M+H] +, calculated value: 247, found value: 247. 1H NMR (400 MHz, CDCl 3) δ 8.54 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.11 (dd, J = 8.4, 1.6 Hz, 1H), 2.98 (s, 3H).

[0178] (6) Compound 10-6 (100 mg, 0.41 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). 2-Methylarsidine-3-boronic acid (72.18 mg, 0.53 mmol), sodium carbonate (107.44 mg, 1.01 mmol) and 1,1-bis(diphenylphosphine)dichloroferric palladium (60.16 mg, 0.06 mmol) were added under nitrogen protection. The mixture was stirred at 100 °C overnight under nitrogen protection. The reaction was monitored by LCMS until completion. After the reaction solution was concentrated, the crude product was purified by silica gel chromatography: methanol / dichloromethane = 5%-7% gradient to obtain the crude compound. The crude product was purified by reverse phase chromatography (Waters-CORTECS-C18-2.7µm-4.6×30mm; 25 ml / min; 25°C; 0%-100% acetonitrile / 0.05% formic acid aqueous buffer) to afford compound 10. MS-ESI [M+H] + , calculated value: 304, found value: 304. 1H NMR (400 MHz, CDCl 3) δ 8.82 – 8.64 (m, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.38 (t, J = 5.6 Hz, 1H), 3.16 (s, 3H), 2.37 (s, 3H).

[0179] Example 11 Synthesis of Compound 11

[0180] The synthetic route of compound 11 is as follows:

[0181] Compound 10-6 (100 mg, 0.41 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). 2-Chlorophenylboronic acid (83.35 mg, 0.53 mmol), sodium carbonate (107.44 mg, 1.01 mmol) and 1,1-bis(diphenylphosphine)dichloroferroni palladium (60.16 mg, 0.06 mmol) were added under nitrogen protection. The mixture was stirred at 100 ° C overnight under nitrogen protection. The reaction was completed by LCMS monitoring. The reaction solution was concentrated and the crude product was purified by silica gel chromatography: methanol: dichloromethane = 1%-2% gradient to obtain the crude compound. The crude product was purified by reverse-phase chromatography (Waters-CORTECS-C18-2.7µm-4.6×30mm; 25 ml / min; 25°C; 0%-100% acetonitrile / 0.05% NH₄HCO₃ aqueous buffer) to afford product 11. MS-ESI [M+H] + calcd: 323, found: 323. 1H NMR (400 MHz, CDCl₃) δ 8.31 (d, J = 8.8 Hz, 1H), 8.11 (dd, J = 8.8, 1.6 Hz, 1H), 7.92 – 7.86 (m, 1H), 7.63 – 7.48 (m, 4H), 3.15 (s, 3H).

[0182] Biological Experiment Example 1

[0183] Principle: MAT2A catalyzes the conversion of L-methionine and ATP to S-adenosylmethionine (SAM) and phosphate. Phosphate reacts with sulfuric acid and ammonium molybdate to form malachite green phosphomolybdate for detection.

[0184] Experimental materials: MAT2A enzyme was purchased from BPS (Cat. No. 71401-1); Tris (hydroxymethylaminomethane) was purchased from Life Science (Cat. No. 0497); fetal bovine serum (BSA) was purchased from Sigma (Cat. No. V900933); L-methionine was purchased from Adams (Cat. No. 1100469); ATP was purchased from Sigma (Cat. No. A7699); magnesium chloride was purchased from Sigma (Cat. No. M8266); potassium chloride was purchased from Sigma (Cat. No. 7447-40-7); polyoxyethylene lauryl ether (Brij35) was purchased from Sigma (Cat. No. B4184); ethylenediaminetetraacetic acid (EDTA) was purchased from Sigma (Cat. No. M1644); dimethyl sulfoxide (DMSO) was purchased from Sigma (Cat. No. D2650); BIOMOL® Green was purchased from Enzo (catalog number BML-AK111-0250); 384-well plates were purchased from Corning (catalog number 3765); centrifuge was purchased from Eppendorf (model 5430); microplate reader was purchased from Bio Tek (model Synergy 2); and pipette was purchased from Labcyte (model Echo 550).

[0185] Experimental Methods: Prepare a buffer solution consisting of 50 mM Tris, pH 7.5, 50 mM potassium chloride, 10 mM magnesium chloride, 0.01% Brij-35, 1 mM EDTA, and 0.1% BSA. Test compounds were diluted starting at a final concentration of 10 μM and tested in duplicate at 10 concentrations in 3-fold dilutions. Serial dilutions were performed in a 384-well plate to yield 10 different concentrations of 100-fold the final concentration. Then, using an Echo550, transfer 250 nL of the solution to a 384-well plate for later use. Add 250 nL of 100% DMSO to each of the negative and positive control wells. Prepare a MAT2A enzyme solution at a final concentration of 1.67-fold using the buffer solution. Add 15 μL of the 1.67-fold final concentration of the MAT2A enzyme solution to each of the compound and positive control wells; add 15 μL of the buffer solution to the negative control well. Centrifuge at 1000 rpm for 60 seconds, shake to mix, and incubate for 15 minutes. Prepare a substrate mixture solution (L-methionine and ATP) at 2.5 times the final concentration using buffer. Add 10 μL of this 2.5-fold final concentration to initiate the reaction. Centrifuge the 384-well plate at 1000 rpm for 60 seconds, shake to mix, and incubate for 150 minutes. Terminate the reaction by adding 50 μL of BIOMOL® Green, centrifuge at 1000 rpm for 60 seconds, and incubate for 15 minutes. Read the OD620 value and process the data.

[0186] Experimental data: The specific test results are shown in Table 1: Table 1 MAT2A IC50 data of some compounds Test compound MAT2A IC 50 (nM) Compound 1 A Compound 4 A Compound 9 A A indicates 0 < IC 50 < 200 nM, B indicates 200 nM ≤ IC 50 < 1000 nM, C indicates 1000 nM ≤ IC 50 < 10000 nM, and D indicates IC 50 ≥ 10000 nM.

[0187] As can be seen from the test data in Table 1, the spirocyclic compound represented by Formula I of the present invention has a good inhibitory effect on MAT2A and has the potential to be used to prepare drugs for preventing or treating MTAP- / -related cancers.

[0188] Biological Experiment Example 2 Proliferation inhibitory activity of HCT116 MTAP - / - and HCT 116 MTAP wt cells

[0189] Principle: HCT116 MTAP - / - cells lack MTAP and have elevated MTA levels; HCT 116 MTAP wt cells do not lack MTAP and have normal MTA levels. These two cell lines are used to determine whether compounds exhibit synergistic MTA inhibitory activity.

[0190] Experimental materials: HCT116 MTAP - / - and HCT 116 MTAP wt cells were purchased from Horizon; CellTiter-Glo reagent was purchased from Promega (Cat. No. G7571); RPMI-1640 was purchased from ATCC (Cat. No. 30-2001); fetal bovine serum (FBS) was purchased from EXCELL (Cat. No. FND500); penicillin-streptomycin was purchased from Gibco (Cat. No. 15140-122); 0.25% trypsin-ethylenediaminetetraacetic acid digestion solution (Trypsin-EDTA) was purchased from Gibco (Cat. No. 25200-072); dimethyl sulfoxide (DMSO) was purchased from Sigma (Cat. No. D2650); 96-well plates were purchased from Corning (Cat. No. 3610); incubator was purchased from NuAire (Model NU-5700E); inverted microscope was purchased from Nikon (Model: TS-100); the automatic cell counter was purchased from Life technologies (Model: Countess II); the microplate reader was purchased from PerkinElmer (Model: Envision); the data processing software was GraphPad Prism 5.0.

[0191] Experimental Methods: HCT116 MTAP - / - or HCT116 MTAP wt cells in logarithmic growth phase were resuspended in growth medium (RPMI-1640 + 10% FBS) and diluted to the target density (5000 / mL). 100 μL of the cell suspension was seeded into each well of a 96-well plate and incubated overnight in a 37°C incubator. The culture medium served as a background control. Cells were starved with 80 μL of serum-free culture medium for 4 hours. Test compounds were dissolved in DMSO to prepare a 10 mmol / L stock solution. The stock solution was first diluted to 2 mmol / L (200×) with DMSO, followed by a three-fold serial dilution for a total of 10 concentrations. 3 μL of each concentration was diluted 2× with 297 μL of growth medium. 80 μL / well was then added to the seeded 96-well plate. Cells treated with test compounds were incubated in a 37°C, 5% CO2 incubator for 120 hours. A 96-well plate was equilibrated at room temperature, and 40 μL of CellTiter-Glo reagent was added to each well. Mixed on a vortex for 2 minutes, the cells were incubated at room temperature for 60 minutes, and luminescence was read using an EnVision microplate reader. GraphPad Prism 5.0 software was used to calculate the IC50 values of the compounds. The results are shown in Table 2. Table 2 Compound IC 50 (nM) HCT116 MTAP - / - HCT116 MTAP wt Compound 1 B ND Compound 3 B ND Compound 4 A D Compound 6 B ND Compound 8 B ND Compound 9 A ND A indicates 0 < IC 50 < 100 nM, B indicates 100 nM ≤ IC 50 < 1000 nM, C indicates 1000 nM ≤ IC 50 < 10000 nM, D indicates IC 50 ≥ 10000 nM, and ND indicates not detected.

[0192] Biological Example 3 Inhibitory effects on proliferation of tumor cells expressing wild-type or null MTAP genes

[0193] Assay Principle: Human tumor cell lines HCC15, NCI-H2052, LN18, NCI-H838, LU99, DOHH2, HT-1080, MKN45, THP-1, MCF7, Mia-Paca2, U87-MG, and UMUC3 are all MTAP gene-deficient cell lines. NCI-H1944, ASPC-1, U251, and HT-1376 are MTAP gene-wild-type cell lines. The compounds of this invention inhibit the proliferation of MTAP-deficient cell lines by binding to MAT2A, but have little inhibitory effect on MTAP-wild-type cells.

[0194] Experimental materials: The information of the cell lines used in the above experiments is detailed in Table 3; CellTiter-GloR was purchased from Promega (Cat. No. G7571); Luminescent Cell Viability Detection Kit was purchased from VEKY-BIO (Cat. No. A2010003N); RPMI-1640 was purchased from Viva cell (Cat. No. C3010-0500); DMEM was purchased from Viva cell (Cat. No. C3113-0500); EMEM was purchased from Vicente (Cat. No. 320-005-CL); fetal bovine serum (FBS) was purchased from Biosera (Cat. No. FB-1058 / 500); horse serum (FBS) was purchased from Gibco (Cat. No. 16050-122); NEAA was purchased from Vicente (Cat. No. 321-011-EL); penicillin-streptomycin was purchased from BasalMedia (Cat. No. S110JV); Sodium Pyruvate was purchased from McLean (Cat. No. P6033); 0.25% trypsin-ethylenediaminetetraacetic acid digestion solution (Trypsin-EDTA) was purchased from BasalMedia (Cat. No. S310KJ); dimethyl sulfoxide (DMSO) was purchased from Sinopharm (Cat. No. 30072418); 96-well plates for 2D culture (for H838 cell line only) were purchased from Corning (Cat. No. 3610); 96-well plates for 3D culture (for all cell lines except H383 cell line) were purchased from Corning (Cat. No. 3707); an incubator was purchased from PHCbi (Model MCO-18AC); an inverted microscope was purchased from Mingmei (Model MI52-0); an automated cell counter was purchased from BodBoge (Model JSY-SC-031N); and a microplate reader was purchased from PerkinElmer (Model Envision). The data processing software used was GraphPad Prism 8.0.

[0195] Experimental Method: Resuspend the cells in the logarithmic growth phase in growth medium and dilute to the appropriate density (approximately 6250 cells / mL). 80 μL of the cell suspension was seeded into each well of a 96-well plate and incubated overnight at 37°C in a 5% CO2 incubator. Culture medium served as a background control. The test compound was dissolved in DMSO to prepare a 10 mmol / L stock solution. The stock solution was first diluted to 2 mmol / L with DMSO and then serially diluted 5-fold to a total of nine concentrations. 2 μL of each concentration was diluted with 78 μL of growth medium. 20 μL / well was then added to the 96-well plate seeded with cells. The cells were incubated at 37°C in a 5% CO2 incubator for 6 days, with the medium changed and incubation continued for up to 10 days. A 96-well plate was equilibrated at room temperature. 100 μL of Luminescent Cell Viability Detection reagent or 25 μL of CellTiter-Glo reagent was added to each well. The cells were incubated at room temperature for 10 minutes. Luminescence values were read using an EnVision microplate reader, and IC50 values of the compounds were calculated using GraphPad Prism 8.0 software. Specific test results are shown in Table 4. Table 3: Cell line name, cancer, cell source and culture medium information Cell name Cancer types Cell source culture medium HCC15 lung cancer Nanjing Kebai RPMI-1640 + 10% FBS NCI-H2052 Mesothelioma Nanjing Kebai RPMI-1640 + 10% FBS LN18 Human brain glial cells blastoma Nanjing Kebai DMEM + 10% FBS NCI-H838 Lung adenocarcinoma Nanjing Kebai RPMI-1640 + 10% FBS LU99 Giant cell carcinoma of the lung Nanjing Kebai RPMI-1640 + 10% FBS DOHH2 B-cell lymphoma Nanjing Kebai RPMI-1640 + 10% FBS HT-1080 Fibrosarcoma Nanjing Kebai EMEM + 10% FBS + 1% NEAA + 1mM Sodium Pyruvate (NaP) MKN45 Gastric cancer Nanjing Kebai RPMI-1640 + 10% FBS THP-1 Acute mononuclear leukemia leukemia Nanjing Kebai RPMI-1640 + 10% FBS MCF7 Breast cancer Wuhan Punosai EMEM+1%NEAA+10% FBS Mia-Paca2 pancreatic cancer Nanjing Kebai DMEM+10%FBS+5% horse serum U87-MG Human brain star Glioblastoma Nanjing Kebai EMEM + 1% NEAA + 1mM Sodium Pyruvate (NaP) + 10% FBS UMUC3 bladder cancer Nanjing Kebai EMEM + 10% FBS + 1% NEAA + 1mM Sodium Pyruvate (NaP) NCI-H1944 Human lung adenocarcinoma Wuhan Punosai RPMI-1640 + 10% FBS ASPC-1 pancreatic cancer Wuhan Punosai RPMI-1640 + 10% FBS U251 Glioblastoma Nanjing Kebai EMEM + 10% FBS + 1% NEAA + 1mM Sodium Pyruvate (NaP) HT-1376 bladder cancer Nanjing Kebai EMEM+ 10% FBS + 1% NEAA + 1mM Sodium Pyruvate (NaP) Table 4: Effect of compound 4 on the proliferation of cell lines with various MTAP gene phenotypes Cell name MTAP Type IC 50 HCC15 Missing B NCI-H2052 Missing A LN18 Missing B NCI-H838 Missing A LU99 Missing B DOHH2 Missing B HT-1080 Missing B MKN45 Missing B THP-1 Missing B MCF7 Missing B Mia Paca2 Missing C U87MG Missing C UMUC3 Missing NT NCI-H1944 wild type C ASPC-1 wild type D U251 wild type D HT-1376 wild type NT A indicates 0 < IC 50 < 100 nM, B indicates 100 nM ≤ IC 50 < 1000 nM, C indicates 1000 nM ≤ IC 50 < 10000 nM, D indicates IC 50 ≥ 10000 nM, ND indicates not detected, and NT indicates not tested.

[0196] The applicant declares that the present invention illustrates the spirocyclic compounds, pharmaceutical compositions containing them, and their applications through the aforementioned examples. However, the present invention is not limited to these examples, nor does it imply that the present invention must rely on these examples for its implementation. All documents mentioned in this application are incorporated by reference in this application, just as if each document were individually incorporated by reference. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions for raw materials in the products of the present invention, addition of auxiliary ingredients, and selection of specific methods, etc., fall within the scope of protection and disclosure of the present invention.

Claims

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a cis-trans isomer, a polymorph, a deuterated compound, or a combination thereof, wherein, R1 is selected from the group consisting of: hydrogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3-10 member carbocyclic, optionally substituted 4-8 member heterocyclic, optionally substituted 6-10 member aryl, optionally substituted 5-10 member heteroaryl, -L1-R4, and -NR5R6; wherein "optionally substituted" in R1 means that the specified group is unsubstituted or replaced by one or more R1s. The R1s are each independently selected from the group consisting of: halogen, hydroxyl, amino, cyano, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxyC1-C6 alkyl-, C1-C6 alkylamine, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-10 carbon cyclic groups, ..., and; L1 is selected from the group consisting of: -O-, -S-, -SO-, -SO2- and -CO-; R4 is selected from the group consisting of: optionally substituted C1-C6 alkyl groups, optionally substituted 3-10 member carbocyclic groups, optionally substituted 4-8 member heterocyclic groups, optionally substituted 6-10 member aryl groups, and optionally substituted 5-10 member heteroaryl groups; wherein "optionally substituted" in R4 means that the specified group is unsubstituted or substituted by one or more R4s, and each R4s is independently selected from the group consisting of: halogen, hydroxyl, amino, cyano, oxo, C1-C6 alkyl, ... R5 is selected from the group consisting of: 6-alkoxy, C1-C6 haloalkoxy, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy C1-C6 alkyl, amino C1-C6 alkyl, 3-10-membered carbocyclic, 3-10-membered carbocyclic oxy, 4-8-membered heterocyclic, 4-8-membered heterocyclic oxy, 6-10-membered aryl, 5-10-membered heteroaryl, and; R5 is selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl and 3-10-membered carbocyclic; R6 is selected from the group consisting of: hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3-10-membered carbocyclic, optionally substituted 4-10-membered heterocyclic, optionally substituted 6-10-membered aryl, optionally substituted 5-10-membered heteroaryl, and;In R6, "optional substitution" means that the specified group is unsubstituted or substituted by one or more R6s, and each R6s is independently selected from the group consisting of: deuterium, halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 ynyl, C2-C4 haloynyl, 3-10 member carbocyclic group optionally substituted by one or more R8s, 3-10 member carbocyclic oxy group optionally substituted by one or more R8s, 4-8 member heterocyclic group optionally substituted by one or more R8s, 4-8 member heterocyclic oxy group optionally substituted by one or more R8s, C1-C6 alkylamino, (C1-C6 alkyl)2amino, C1-C6 alkoxy-C1-C6 alkyl, aminoC1-C6 alkyl, etc.

1. Optionally substituted 6-10 aryl groups and 5-10 heteroaryl groups substituted with one or more R9 groups; R2 is selected from the group consisting of halogens, cyano groups, optionally substituted C1-C6 alkyl groups, optionally substituted C2-C6 alkenyl groups, optionally substituted C2-C6 alkynyl groups, optionally substituted 3-10 carbocyclic groups, optionally substituted 4-8 heterocyclic groups, -L2-R10, and -NR11R12; wherein "optionally substituted" in R2 means that the specified group is unsubstituted or substituted by one or more R2s, and each R2s is independently selected from the group consisting of halogens, cyano groups, oxo groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkoxy groups, and 3-10 carbocyclic groups; R3 is selected from the group consisting of: hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-10 member carbocyclic group, optionally substituted 4-8 member heterocyclic group, -L2'-R10' and -NR11'R12'; in R3, "optionally substituted" means that the specified group is unsubstituted or substituted by one or more R3s, and each R3s is independently selected from the group consisting of: halogen, cyano, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and 3-10 member carbocyclic group; L2 and L2' are each independently selected from the group consisting of: -O-, -S-, -SO-, -SO2- and -CO-; R10 and R10' are each independently selected from the following group: optionally substituted C1-C6 alkyl, optionally substituted 3-10 member carbocyclic, optionally substituted 4-8 member heterocyclic, optionally substituted 6-10 member aryl and optionally substituted 5-10 member heteroaryl.In R10 and R10', "optional substitution" means that the specified group is unsubstituted or substituted by one or more R10s, and each R10s is independently selected from the group consisting of: halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-10 member carbocyclic, 4-8 member heterocyclic, 6-10 member aryl and 5-10 member heteroaryl; R11 and R11' are each independently selected from the group consisting of: hydrogen and C1-C6 alkyl; R12 and R12' are each independently selected from the group consisting of: optionally substituted C1-C6 alkyl, optionally substituted 3-10 member carbocyclic, optionally substituted 4-10 member heterocyclic, optionally substituted 6-10 member aryl, optionally substituted 5-10 member heteroaryl, or; wherein, "optionally substituted" in R12 and R12' means that the specified group is unsubstituted or substituted by one or more R12s, and R12s are each independently selected from the group consisting of: halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-10 member carbocyclic and 4-8 member heterocyclic; X3 is N; RX is selected from the group consisting of: methyl, ethyl, 3-4 member carbocyclic, halomethyl or halogen; RY is selected from the group consisting of: hydrogen, methyl, halomethyl or halogen; X1 is CR13; X2 is CR14; R13 and R14 are each independently selected from the group consisting of: hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-10 member carbocyclic group and optionally substituted 4-8 member heterocyclic group; wherein, "optionally substituted" in R13 and R14 means that the specified group is unsubstituted or substituted by one or more R13s or R14s, and R13s and R14s are each independently selected from the group consisting of: halogen and oxo (=O); with the additional condition that R13 is not chlorine when both RX and R2 are chlorine and X1 is CR13; Each R7 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-10 member carbocyclic, 4-8 member heterocyclic, amino, C1-C6 alkylamino, di(C1-C6 alkyl)amino, 6-10 member aryl, and 5-10 member heteroaryl; Each R8 is independently selected from the group consisting of: hydrogen, halogen, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, or hydroxyC1-C6 alkyl; Each R9 is independently selected from the group consisting of: hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

2. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, cis-trans isomer, polymorph, deuterated compound, or combination thereof, characterized in that R1 is selected from the group consisting of hydrogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted 3-10 member carbocyclic group, optionally substituted 4-8 member heterocyclic group, optionally substituted 5-10 member heteroaryl, -OR4 and -NR5R6; wherein "optionally substituted" in R1 means that the specified group is unsubstituted or substituted by one or more R1s, and each R1s is independently selected from the group consisting of halogen, hydroxyl, amino, cyano, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkylamine, C1-C6 alkoxy and C1-C6 haloalkoxy.

3. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, cis-trans isomer, polymorph, deuterated compound, or combination thereof, characterized in that R2 is selected from the group consisting of halogens, optionally substituted C1-C6 alkyl groups, optionally substituted 3-10-membered carbocyclic groups, optionally substituted 4-8-membered heterocyclic groups, and -L2-R10; wherein "optionally substituted" in R2 means that the specified group is unsubstituted or substituted by one or more R2s, and each R2s is independently selected from the group consisting of halogens, cyano groups, oxo groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkoxy groups, and 3-8-membered carbocyclic groups; R3 is selected from the group consisting of: hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-10 member carbocyclic group, optionally substituted 4-8 member heterocyclic group, -L2'-R10'; where "optionally substituted" in R3 means that the specified group is unsubstituted or substituted by one or more R3s, and each R3s is independently selected from the group consisting of: halogen, cyano, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and 3-8 member carbocyclic group; R10 and R10' are each independently selected from the group consisting of: optionally substituted C1-C6 alkyl, optionally substituted 3-8 member carbocyclic, optionally substituted 4-8 member heterocyclic; wherein "optionally substituted" means that the specified group is unsubstituted or substituted by one or more R10s, and R10s are each independently selected from the group consisting of: halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-8 member carbocyclic, 4-8 member heterocyclic.

4. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, cis-trans isomer, polymorph, deuterated compound, or combination thereof, characterized in that RX is selected from the group consisting of methyl, ethyl, halomethyl, and halogen; X1 is CR13; X2 is CR14; R13 and R14 are each independently selected from the group consisting of hydrogen, halogen, cyano, C1-C4 alkyl, or C1-C4 haloalkyl; with the additional condition that R13 is not chlorine when RX and R2 are both chlorine and X1 is CR13.

5. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, cis-trans isomer, polymorph, deuterated compound, or combination thereof, characterized in that RX is methyl or halogen; and RY is hydrogen, methyl, or halogen.

6. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, cis-trans isomer, polymorph, deuterated derivative, or combination thereof, characterized in that R1 is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl groups, and -NR5R6; wherein, R5 is hydrogen, and R6 is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, and optionally substituted 5-10 heteroaryl groups; in R6, "optionally substituted" means that the specified group is unsubstituted or substituted by one or more R6s, and R6s is deuterium or C1-C6 alkyl; R2 is selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, and optionally substituted 3-10 carbon cycloyl groups; in R2, "optionally substituted" is as described in claim 1; R3 is hydrogen or -L2'-R10'; wherein L2' is -O- and R10' is methyl; X1 is CR13; X2 is CR14; X3 is N; R13 and R14 are each independently selected from the group consisting of hydrogen, halogen, cyano, C1-C4 alkyl, or C1-C4 haloalkyl; RX is methyl, halogen, or cyclopropyl; RY is hydrogen, methyl, or halogen.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, cis-trans isomer, polymorph, deuterated compound, or combination thereof, characterized in that the compound is selected from Table A below: Table A.

8. A pharmaceutical composition, characterized in that the pharmaceutical composition comprises: (1) One or more of the compounds described in any one of claims 1 to 7, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, tautomers, cis-trans isomers, polymorphs and deuterated derivatives, as the active ingredient; and (2) optionally, a pharmaceutically acceptable carrier.

9. Use of any compound as claimed in any one of claims 1-7, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, tautomer, cis-trans isomer, polymorph, or deuterated compound, or a pharmaceutical composition as claimed in claim 8, in the preparation of a medicament for the prevention or treatment of MTAP- / -related cancers.

10. The use as claimed in claim 9, characterized in that the cancer is selected from: glioma, mesothelioma, esophageal cancer, bladder cancer, urethral cancer, pancreatic cancer, melanoma, non-small cell lung cancer, head and neck cancer, sarcoma, bile duct cancer, liver cancer, breast cancer, skin cancer, intestinal cancer, stomach cancer, kidney cancer, urethral cancer, prostate cancer, testicular cancer, uterine cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, multiple myeloma, neurofibroma, astrocytoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.