Pyrimidin-2(1H)-one derivative, pharmaceutical composition thereof and use thereof

Abstract

Disclosed in the present invention are a pyrimidine-2(1H)-one derivative, a pharmaceutical composition thereof and the use thereof. Specifically disclosed are a compound represented by formula (III), a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof and the use thereof. The compound provided in the present invention has one or more of the following effects: (1) a good MAT2A enzyme inhibitory activity; (2) a good inhibitory activity against tumor cell proliferation; (3) a good metabolic stability; (4) a long half-life; (5) a long mean residence time; (6) a good tissue / plasma distribution ratio; (7) good exposure; (8) a high apparent volume of distribution; and (9) a good in vivo efficacy.

Description

Pyrimidine-2(1H)-one derivatives, their pharmaceutical compositions and their applications

[0001] This application claims priority to Chinese patent applications filed on November 15, 2024 (202411634566X), January 25, 2025 (2025101228530), March 7, 2025 (2025102744870), May 12, 2025 (2025106134883), September 30, 2025 (2025114328359), and November 10, 2025 (2025116411308). The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to pyrimidine-2(1H)-one derivatives, pharmaceutical compositions thereof, and their applications. Background Technology

[0003] Methionine adenosyltransferase 2A (MAT2A) is a type of methionine adenosyltransferase that is mainly expressed in extrahepatic tissues. Its expression in the liver is mainly limited to cases of cell dedifferentiation, such as fetal liver, liver injury, or hepatocellular carcinoma (HCC) (Lu, SC, etc., Physiol. Rev. 2012, 92(4), 1515-1542; Ramani, K., etc., Cancer 2011, 3(2), 1480-1497).

[0004] MAT2A, also known as S-adenosylmethionine synthase, catalyzes the synthesis of S-adenosyl-L-methionine (SAM), a key cofactor product, from methionine and ATP. SAM is an important intermediate metabolite, mainly involved in three key metabolic pathways: transmethylation, transsulfation, and polyamine synthesis. Therefore, intracellular SAM homeostasis is crucial for cell growth, survival, and differentiation. Protein arginine methyltransferase 5 (PRMT5) is a methyltransferase that utilizes the methyl donor of SAM. SAM plays an important role in the PRMT5 pathway and can affect PRMT5 activity. Studies have shown that MAT2A is a "synthetic lethal" target in MTAP-deficient tumors (McDonald, ER, etc., Cell 2017, 170(3), 577-592). shRNA screening was used to identify MAT2A and PRMT5 as susceptibility genes in MTAP-deficient cells. MTA, a substrate for the MTAP enzyme reaction, accumulates in large quantities in MTAP-deficient cancers. MTA is a potent endogenous selective inhibitor of PRMT5, leading to decreased PRMT5 methylation activity in MTAP-deficient cells. MAT2A deficiency selectively reduces the growth of MTAP-deficient cells and PRMT5 methylation activity. MAT2A is essential in MTAP-deficient cancers (Kryukov, GV, etc., Science 2016, 351(6278), 1214-8). Tumors carrying MTAP gene deletion have shown sensitivity to MAT2A inhibition, making them a highly attractive target for the treatment of MTAP-deficient cancers.

[0005] Currently, most of the MAT2A inhibitors reported domestically and internationally are in the preclinical or early clinical development stage, and no MAT2A inhibitors have been marketed yet. Therefore, the development of novel MAT2A inhibitors has broad application prospects. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a novel compound with MAT2A inhibitory activity.

[0007] This invention provides a compound of formula (III), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0008] Where A is

[0009] X is either N or CH;

[0010] U is O, S, or NR7;

[0011] Y is either N or CR5;

[0012] Y1 and Z1 are either N or C, respectively;

[0013] Z2 is CH or C;

[0014] It can be a single bond or a double bond;

[0015] Ring B is a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; the 5-6 membered heterocyclic ring and the 5-6 membered heteroaromatic ring are optionally replaced by 1 to 4 R8s at any position;

[0016] Ring C is a 5-membered heterocyclic ring or a 5-membered heteroaromatic ring;

[0017] o can be 0, 1, 2, 3, or 4;

[0018] R represents hydrogen or hydroxyl group C 1-6 Alkyl or C 1-3 Alkoxy C 1-6 alkyl;

[0019] R1 and R2 are independently hydrogen, halogen, cyano, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, pentafluoride sulfide, C 3-6 Monocyclic cycloalkyl, C 4-6 Bridged cycloalkyl, 3-6 membered heterocyclic alkyl, -CO(O)-halogenated C 1-3 Alkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, surrounded by 1-3 halogens or C 1-3 Alkyl-substituted C 3-6 Monocyclic cycloalkyl, with 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6 Bridged cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 3-8 membered heterocyclic alkyl groups;

[0020] R3 and R3' are independently hydrogen, hydroxyl, and C, respectively. 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C1-6 Alkyl, phenyl, 5-10 heteroaryl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkyl C 1-3 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, surrounded by 1 to 3 halogens or C 1-3 Alkyl-substituted phenyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 5-10-membered heteroaryl groups;

[0021] R and R3' are independent substituents, or R and R3' together with the atoms they are attached to form 5-8 membered heterocycles;

[0022] R4 is a halogenated C 1-6 Alkyl thio, pentafluoride thio, C substituted with one trimethylsilyl group 2-6 Alkyne group, C substituted with 1 to 3 halogens 3- 6-cyclic alkyl groups or 3-6-membered heterocyclic alkyl groups substituted with 1 to 3 halogens;

[0023] R5, R 5-1 R 5-2 R6, R 6-1 R 6-2 R 6-3 R 6-4 Each of the following is independently represented as hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, C 1-6 Alkylamino C 1-3 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

[0024] R 6-5 Each is independently deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1- 6-alkoxy, C 2-6 alkenyl, halogenated C2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, C 1-6 Alkylamino C 1-3 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

[0025] R4 and R5 are independent substituents, or R4 and R5 together with the atoms they are attached to form a 4-10 membered carbon ring; the 4-10 membered carbon ring is optionally substituted by 1 to 4 R8s at any position;

[0026] R7 represents hydrogen, hydroxyl group, and C. 1-6 Alkyl or C 1-6 Alkoxy;

[0027] R8 can be deuterium, halogen, oxo group (=O), hydroxyl group, amino group, mercapto group, or C. 1-6 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl or C 1-6 Alkylamino C 1-3 alkyl;

[0028] And the compound shown in formula (III) satisfies one of the following conditions:

[0029] (1) U is O, A is A1;

[0030] (2) U is O, A is A2; R 5-1 It is a halogen; R 6-1 It is deuterium;

[0031] (3) U is S or NR7, and A is A1, A2 or A3;

[0032] (4) R1 is C 4-6 Bridged cycloalkyl rings, surrounded by 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6 Bridged cycloalkyl, C 1-6 Alkyl thiols, halogenated C 1-6Alkyl thio, pentafluoride thio, or -CO(O)-halogenated C 1-3 Alkyl group, where A is A1, A2, A3, A4, or A5;

[0033] (5) R3 is a hydroxyl group, C 1-6 alkoxy or halogenated C 1-6 Alkoxy group, where A is A1, A2, or A3.

[0034] In some embodiments, in any of the compounds of the present invention (e.g., of formula (I), (II), (III), (III'), (IV), (IV-1), (V), (V-1), (V-2), or (VI)), their stereoisomers, or pharmaceutically acceptable salts, some groups are defined as described below, and the remaining groups are defined as described in any other embodiment (hereinafter referred to as "in some embodiments").

[0035] In some implementation schemes,

[0036] A is

[0037] X is either N or CH;

[0038] U is either O or S;

[0039] R represents hydrogen or hydroxyl group C 1-6 Alkyl or C 1-3 Alkoxy C 1-6 alkyl;

[0040] R1 and R2 are independently hydrogen, halogen, cyano, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, pentafluoride sulfide, C 3-6 Monocyclic cycloalkyl, C 4-6 Bridged cycloalkyl, 3-6 membered heterocyclic alkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, surrounded by 1-3 halogens or C 1-3 Alkyl-substituted C 3-6 Monocyclic cycloalkyl, with 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6-bridged cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 3-8 membered heterocyclic alkyl groups;

[0041] R3 and R3' are independently hydrogen, hydroxyl, and C, respectively. 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, 5-10 membered heteroaryl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkyl C 1-3 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, surrounded by 1 to 3 halogens or C 1-3 Alkyl-substituted phenyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 5-10-membered heteroaryl groups;

[0042] R and R3' are independent substituents, or R and R3' together with the atoms they are attached to form...

[0043] R6 can be hydrogen, deuterium, halogen, cyano, hydroxyl, amino, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino or C 1-6 Alkylamino C 1-3 alkyl;

[0044] R8 represents deuterium, halogen, oxo group, hydroxyl group, amino group, or C. 1-6 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C1-3 Alkyl or C 1-6 Alkylamino C 1-3 alkyl;

[0045] t is 1, 2, or 3;

[0046] m is 0, 1, or 2;

[0047] n can be 0, 1, 2, 3, or 4.

[0048] In some implementation schemes,

[0049] A is

[0050] X is either N or CH;

[0051] U is either O or S;

[0052] R represents hydrogen or hydroxyl group C 1-6 Alkyl or C 1-3 Alkoxy C 1-6 alkyl;

[0053] R1 and R2 are independently hydrogen, halogen, cyano, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, pentafluoride sulfide, C 3-6 Monocyclic cycloalkyl, C 4-6 Bridged cycloalkyl, 3-6 membered heterocyclic alkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, surrounded by 1-3 halogens or C 1-3 Alkyl-substituted C 3-6 Monocyclic cycloalkyl, with 1 to 3 halogens or C 1-3 Alkyl-substituted C 4- 6-bridged cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 3-8 membered heterocyclic alkyl groups;

[0054] R3 and R3' are independently hydrogen, hydroxyl, and C, respectively. 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C1-6 Alkyl, 5-10 membered heteroaryl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkyl C 1-3 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl group or the group with 1 to 3 halogens or C 1-3 Alkyl-substituted 5-10-membered heteroaryl groups;

[0055] R and R3' are independent substituents, or R and R3' together with the atoms they are attached to form...

[0056] R8 represents deuterium, halogen, oxo group, hydroxyl group, amino group, or C. 1-6 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl or C 1-6 Alkylamino C 1-3 alkyl;

[0057] t is 1, 2, or 3;

[0058] m is 0, 1, or 2;

[0059] n can be 0, 1, 2, 3, or 4.

[0060] In some implementation schemes,

[0061] A is

[0062] X is either N or CH;

[0063] U is O;

[0064] R is hydrogen;

[0065] R1 is a halogen, cyano, or C group. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1- 6-alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, pentafluoride sulfide, C 3-6 Monocyclic cycloalkyl, C 4-6 Bridged cycloalkyl, 3-6 membered heterocyclic alkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, surrounded by 1-3 halogens or C 1-3 Alkyl-substituted C 3-6 Monocyclic cycloalkyl, with 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6 Bridged cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 3-8 membered heterocyclic alkyl groups;

[0066] R2 is hydrogen or halogen;

[0067] R3 is hydrogen, C 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl, 5-10 heteroaryl, or with 1-3 halogens or C 1-3 Alkyl-substituted 5-10-membered heteroaryl groups;

[0068] R3' is hydrogen;

[0069] R6 is hydrogen, deuterium, or halogen (preferably hydrogen);

[0070] R8 is deuterium;

[0071] n is 0, 1, 2, 3 or 4 (preferably, n is 0).

[0072] In some implementation schemes,

[0073] A is

[0074] X is either N or CH;

[0075] U is either O or S;

[0076] Y is either N or CR5;

[0077] R represents hydrogen or hydroxyl group C 1-6 Alkyl or C 1-3 Alkoxy C 1-6 alkyl;

[0078] R1 is hydrogen, halogen, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, C 1-6Alkylamino, pentafluoride sulfide, -CO(O)-halogenated C 1-3 Alkyl, C 3-6 Monocyclic cycloalkyl, C 4-6 Bridged cycloalkyl, 3-6 membered heterocyclic alkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, surrounded by 1-3 halogens or C 1-3 Alkyl-substituted C 3-6 Monocyclic cycloalkyl, with 1 to 3 halogens or C 1- 3-alkyl substituted C 4-6 Bridged cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 3-8 membered heterocyclic alkyl groups;

[0079] R2 is hydrogen, halogen, or cyano;

[0080] R3 and R3' are independently hydrogen, hydroxyl, and C, respectively. 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl, C 1-6 Alkyl, 5-10 heteroaryl, or with 1-3 halogens or C 1-3 Alkyl-substituted 5-10-membered heteroaryl groups;

[0081] R and R3' are independent substituents, or R and R3' together with the atoms they are attached to form 5-8 membered heterocycles;

[0082] R4 is a halogenated C 1-6 Alkyl thio, pentafluoride thio, C substituted with one trimethylsilyl group 2-6 Alkyne group, C substituted with 1 to 3 halogens 3- 6-cyclic alkyl groups or 3-6-membered heterocyclic alkyl groups substituted with 1 to 3 halogens;

[0083] R5 and R6 are independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy;

[0084] R4 and R5 are independent substituents, or R4 and R5 together with the atoms they are attached to form a 4-8 membered carbon ring; the 4-8 membered carbon ring is optionally substituted by 1 to 4 R8s at any position;

[0085] R8 represents deuterium, halogen, oxo group, hydroxyl group, amino group, or C. 1-6 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C1-6 Alkylamino, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl or C 1-6 Alkylamino C 1-3 alkyl.

[0086] In some implementation schemes,

[0087] A is

[0088] X is either N or CH;

[0089] U is O, S, or NR7;

[0090] R represents hydrogen or hydroxyl group C 1-6 Alkyl or C 1-3 Alkoxy C 1-6 alkyl;

[0091] R1 is hydrogen, halogen, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkylthio, C 1-6 Alkylamino, pentafluoride sulfide, -CO(O)-halogenated C 1-3 Alkyl, C 3-6 Monocyclic cycloalkyl, C 4-6 Bridged cycloalkyl, 3-6 membered heterocyclic alkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, surrounded by 1-3 halogens or C 1-3 Alkyl-substituted C 3-6 Monocyclic cycloalkyl, with 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6 Bridged cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 3-8 membered heterocyclic alkyl groups;

[0092] R2 is hydrogen, halogen, or cyano;

[0093] R3 and R3' are independently hydrogen, hydroxyl, and C, respectively. 1-6 Alkoxy, C 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl, 5-10 heteroaryl, or with 1-3 halogens or C 1-3 Alkyl-substituted 5-10-membered heteroaryl groups;

[0094] R 5-1 R 5-2Each is independently hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino or C 1-6 Alkylamino C 1-3 alkyl;

[0095] R 6-1 R 6-2 Each of the following is independently represented as hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1- 6-alkoxy C 1-3 Alkyl, C 1-6 Alkylamino or C 1-6 Alkylamino C 1-3 alkyl;

[0096] R7 represents hydrogen, hydroxyl group, and C. 1-6 Alkyl or C 1-6 Alkyl group.

[0097] In some implementation schemes,

[0098] A is

[0099] X is either N or CH;

[0100] Y is either N or CR5;

[0101] U is either O or S;

[0102] Y1 and Z1 are either N or C, respectively;

[0103] Z2 is C;

[0104] It can be a single bond or a double bond;

[0105] Ring B is a 5-6 membered heterocycle or a 5-6 membered heteroaromatic ring; in the 5-6 membered heterocycle or 5-6 membered heteroaromatic ring, the heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; the 5-6 membered heteroaromatic ring has at least one heteroatom, and the heteroatom is N;

[0106] Ring C is a 5-membered heteroaromatic ring; in the 5-membered heteroaromatic ring, the heteroatom or heterogroup is selected from 1, 2 or 3 of N, NH, O, S and Se, and the number of heteroatoms or heterogroups is 1, 2 or 3; the 5-membered heteroaromatic ring has at least one heteroatom or heterogroup;

[0107] R represents hydrogen or hydroxyl group C 1-6 Alkyl or C 1-3 Alkoxy C 1-6 alkyl;

[0108] R1 is C 4-6 Bridged cycloalkyl rings, surrounded by 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6 Bridged ring cycloalkyl or pentafluoride sulfo;

[0109] R2 is hydrogen or halogen;

[0110] R3 and R3' are independently hydrogen, hydroxyl, and C, respectively. 1-6 Alkoxy, C 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl, 5-10 heteroaryl, or with 1-3 halogens or C 1-3 Alkyl-substituted 5-10-membered heteroaryl groups;

[0111] R and R3' are independent substituents, or R and R3' together with the atoms they are attached to form...

[0112] R4 is a C molecule that has been replaced by 1 to 3 halogens. 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups substituted with 1-3 halogens;

[0113] R5, R 5-1 R 5-2 and R6, R 6-1 R 6-2 R 6-3 R 6-4 Each of the following is independently represented as hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, C 1-6 Alkylamino C 1-3 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

[0114] R4 and R5 are independent substituents, or R4 and R5 together with the atoms they are attached to form a 4-10 membered carbon ring; the 4-10 membered carbon ring is optionally substituted by 1 to 4 R8s at any position;

[0115] R8 represents deuterium, halogen, oxo group, hydroxyl group, amino group, or C. 1-6 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl or C 1-6 Alkylamino C 1-3 alkyl;

[0116] t is 1, 2, or 3;

[0117] n can be 0, 1, 2, 3, or 4.

[0118] In some embodiments, the compound shown in formula (III) is a compound shown in formula (III').

[0119] Where A is

[0120] X is either N or CH;

[0121] Y is either N or CR5;

[0122] V is O, S, or NH;

[0123] V1, V2, V3, V4 and V5 are each independently N or CH;

[0124] R2 is hydrogen or halogen;

[0125] R3 is hydrogen, methyl, or deuterated methyl;

[0126] R4 is a C molecule that has been replaced by 1 to 3 halogens. 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups substituted with 1-3 halogens;

[0127] R5, R 5-1 R 5-2 R6, R 6-1 R 6-2 R 6-3 R 6-4 Each of the following is independently represented as hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, C 1-6 Alkylamino C 1-3 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

[0128] R4 and R5 are independent substituents, or R4 and R5 together with the atoms they are attached to form a 4-membered carbon ring; the 4-membered carbon ring is optionally substituted by 1 to 4 R8s at any position;

[0129] R8 is deuterium.

[0130] In some embodiments, the compound shown in formula (III) is a compound shown in formula (IV).

[0131] The definitions of X, U, R, R1, R2, R3, R3', R6, R8 and n are as described above.

[0132] In some embodiments, the compound as shown in formula (IV),

[0133] in,

[0134] X is either N or CH;

[0135] U is either O or S;

[0136] R is hydrogen;

[0137] R1 is hydrogen, halogen, cyano, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl thio, pentafluoride thio, C 3-6 Monocyclic cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted C 3-6 Monocyclic cycloalkyl;

[0138] R2 is hydrogen or halogen;

[0139] R3 represents hydrogen, hydroxyl group, and C. 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl, C 1-6 Alkyl, 5-10 heteroaryl, or with 1-3 halogens or C 1-3 Alkyl-substituted 5-10-membered heteroaryl groups;

[0140] R3' is hydrogen;

[0141] R6 is hydrogen or deuterium;

[0142] R8 is deuterium;

[0143] n can be 0, 1, 2, 3, or 4.

[0144] In some embodiments, the compound shown in formula (IV) is the compound shown in formula (IV-1).

[0145] The definitions of X, R1, R2, R3, R6, R8 and n are as described above.

[0146] In some embodiments, the compound as shown in formula (IV-1),

[0147] in,

[0148] X is either N or CH;

[0149] R1 is hydrogen, halogen, cyano, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl thio, pentafluoride thio, C 3-6 Monocyclic cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted C 3-6 Monocyclic cycloalkyl;

[0150] R2 is hydrogen or halogen;

[0151] R3 represents hydrogen, hydroxyl group, and C. 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl, C 1-6 Alkyl, 5-10 heteroaryl, or with 1-3 halogens or C 1-3 Alkyl-substituted 5-10-membered heteroaryl groups;

[0152] R6 is hydrogen or deuterium;

[0153] R8 is deuterium;

[0154] n can be 0, 1, 2, 3, or 4.

[0155] In some embodiments, the compound as shown in formula (IV-1),

[0156] in,

[0157] X is either N or CH;

[0158] R1 is a halogen or halogenated C. 1-6 Alkyl, pentafluoride sulfide, C 3-6 Monocyclic cycloalkyl;

[0159] R2 is hydrogen or halogen;

[0160] R3 is hydrogen, C 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl or C 1-3 Alkyl-substituted 5-10-membered heteroaryl groups;

[0161] R6 is hydrogen or deuterium;

[0162] R8 is deuterium;

[0163] n is 0 or 4.

[0164] In some embodiments, the compound shown in formula (III) is a compound shown in formula (V).

[0165] Among them, X, R2, R3, R 5-1 R 6-1 The definition is as described above.

[0166] In some embodiments, the compound as shown in formula (V),

[0167] X is either N or CH;

[0168] R2 is hydrogen or halogen;

[0169] R3 is hydrogen, methyl, or deuterated methyl;

[0170] R5-1 It is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1- 6-alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

[0171] R 6-1 It is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1- 6-alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl.

[0172] In some embodiments, the compound as shown in formula (V),

[0173] X is CH;

[0174] R2 is hydrogen;

[0175] R3 is hydrogen;

[0176] R 5-1 Halogen, C 1-6 Alkyl (e.g., methyl), halogenated C 1-6 Alkyl groups (e.g., CHF2);

[0177] R 6-1 It is either hydrogen or deuterium.

[0178] In some embodiments, the compound shown in formula (V) is a compound shown in formula (V-1) or a compound shown in formula (V-2).

[0179] Among them, X, R2, R3, R 6-1 As defined above, R 5-1 Halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl.

[0180] In some embodiments, the compounds shown as in formula (V-1) and as in formula (V-2),

[0181] X is either N or CH;

[0182] R2 is hydrogen or halogen;

[0183] R3 is hydrogen, methyl, or deuterated methyl;

[0184] R 5-1 Halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

[0185] R 6-1 It is hydrogen, deuterium, halogen or C 1-6 alkyl.

[0186] In some embodiments, the compounds shown as formula (V-1) and (V-2),

[0187] X is CH;

[0188] R2 is hydrogen;

[0189] R3 is hydrogen;

[0190] R 5-1 Halogen, C 1-6 Alkyl (e.g., methyl), halogenated C 1-6 Alkyl groups (e.g., CHF2);

[0191] R 6-1 It is either hydrogen or deuterium.

[0192] In some embodiments, the compound shown in formula (III) is a compound shown in formula (VI).

[0193] Among them, X, V, R2, R3, R 6-4 The definition is as described above.

[0194] In some embodiments, in the compound shown in formula (VI), wherein,

[0195] X is either N or CH;

[0196] V is O, S, or NH;

[0197] R2 is hydrogen or halogen;

[0198] R3 is hydrogen, methyl, or deuterated methyl;

[0199] R 6-4 It can be hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, C 1-6 Alkylamino C 1-3 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl.

[0200] In some embodiments, the compound as shown in formula (VI),

[0201] X is CH;

[0202] V is either O or S;

[0203] R2 is hydrogen;

[0204] R3 is hydrogen;

[0205] R 6-4 Halogen or C 1-6 Alkyl (e.g., methyl).

[0206] In some embodiments, the compound represented by formula (III) is a compound represented by formula (VII).

[0207] in,

[0208] A is

[0209] Y is either N or CR5;

[0210] R2 is hydrogen or halogen;

[0211] R3 is hydrogen, methyl, or deuterated methyl;

[0212] R4 is a C molecule that has been replaced by 1 to 3 halogens. 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups substituted with 1-3 halogens;

[0213] R5, R 5-1 R6 and R 6-1 Each of the following is independently represented as hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, C 1-6 Alkylamino C 1-3 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; (preferably, R5, R 5-1 R6 and R 6-1 They are independently hydrogen, deuterium, halogen, cyano, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl, wherein the heteroatom is selected from one, two, or three of N, O, and S, and the number of heteroatoms is one or two; more preferably, R6 and R 6-1 Independently, R5 and R6 are either hydrogen or deuterium. 5-1 Halogen and C are independently distinguished. 1-6 Alkyl or halogenated C 1-6 Alkyl groups, such as F, Cl, methyl, or halomethyl (e.g., difluoromethyl);

[0214] R4 and R5 are independent substituents, or R4 and R5 together with the atoms they are attached to form a 4-membered carbon ring; the 4-membered carbon ring is optionally substituted by 1 to 4 R8s at any position;

[0215] R8 is deuterium.

[0216] In some embodiments, the compound as shown in formula (III),

[0217] A is

[0218] X is CH;

[0219] U is O;

[0220] Y is either N or CR5;

[0221] R1 is a sulfide pentafluoride group;

[0222] R2 is hydrogen or halogen;

[0223] R3 is hydrogen, methyl, or deuterated methyl;

[0224] R3' is hydrogen;

[0225] R4 is a C molecule that has been replaced by 1 to 3 halogens. 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups substituted with 1-3 halogens;

[0226] R5, R 5-1 R6 and R 6-1 Each of the following is independently represented as hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, C 1-6 Alkylamino C 1-3 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; (preferably, R5, R 5-1 R6 and R 6-1 They are independently hydrogen, deuterium, halogen, cyano, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl, wherein the heteroatom is selected from one, two, or three of N, O, and S, and the number of heteroatoms is one or two; more preferably, R6 and R 6-1 Independently, R5 and R6 are either hydrogen or deuterium. 5-1 Halogen and C are independently distinguished. 1-6 Alkyl or halogenated C 1-6 Alkyl groups, such as F, Cl, methyl, or halomethyl (e.g., difluoromethyl);

[0227] R4 and R5 are independent substituents, or R4 and R5 together with the atoms they are attached to form a 4-membered carbon ring; the 4-membered carbon ring is optionally substituted by 1 to 4 R8s at any position;

[0228] R8 is deuterium.

[0229] In some embodiments, the compound shown in formula (III),

[0230] Where A is

[0231] X is either N or CH;

[0232] U is O, S, or NR7;

[0233] Y is either N or CR5;

[0234] Y1 and Z1 are either N or C, respectively;

[0235] It can be a single bond or a double bond;

[0236] Ring B is a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; the 5-6 membered heterocyclic ring and the 5-6 membered heteroaromatic ring are optionally replaced by 1 to 4 R8s at any position;

[0237] R represents hydrogen or hydroxyl group C 1-6 Alkyl or C 1-3 Alkoxy C 1-6 alkyl;

[0238] R1 and R2 are independently hydrogen, halogen, cyano, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, pentafluoride sulfide, C 3-6 Monocyclic cycloalkyl, C 4-6 Bridged cycloalkyl, 3-6 membered heterocyclic alkyl, -CO(O)-halogenated C 1-3 Alkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, surrounded by 1-3 halogens or C 1-3 Alkyl-substituted C 3-6 Monocyclic cycloalkyl, with 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6 Bridged cycloalkyl groups or those with 1 to 3 halogens or C 1-3Alkyl-substituted 3-8 membered heterocyclic alkyl groups;

[0239] R3 and R3' are independently hydrogen, hydroxyl, and C, respectively. 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, phenyl, 5-10 heteroaryl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkyl C 1-3 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, surrounded by 1 to 3 halogens or C 1-3 Alkyl-substituted phenyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 5-10-membered heteroaryl groups;

[0240] R and R3' are independent substituents, or R and R3' together with the atoms they are attached to form 5-8 membered heterocycles;

[0241] R4 is a halogenated C 1-6 Alkyl thio, pentafluoride thio, C substituted with one trimethylsilyl group 2-6 Alkyne group, C substituted with 1 to 3 halogens 3- 6-cycloalkyl or 3-6-membered heterocyclic alkyl groups substituted with 1 to 3 halogens;

[0242] R5, R 5-1 R 5-2 and R6, R 6-1 R 6-2 R 6-3 Each of the following is independently represented as hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1- 6-alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, C 1-6 Alkylamino C 1-3 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

[0243] R4 and R5 are independent substituents, or R4 and R5 together with the atoms they are attached to form a 4-10 membered carbon ring; the 4-10 membered carbon ring is optionally substituted by 1 to 4 R8s at any position;

[0244] R7 represents hydrogen, hydroxyl group, and C. 1-6 Alkyl or C 1-6 Alkoxy;

[0245] R8 can be deuterium, halogen, oxo group (=O), hydroxyl group, amino group, mercapto group, or C. 1-6 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl or C 1-6 Alkylamino C 1-3 alkyl;

[0246] And the compound shown in formula (III) satisfies one of the following conditions:

[0247] (1) U is O, A is A1;

[0248] (2) U is O, A is A2; R 5-1 It is a halogen; R 6-1 It is deuterium;

[0249] (3) U is S or NR7, and A is A1, A2 or A3;

[0250] (4) R1 is C 4-6 Bridged cycloalkyl rings, surrounded by 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6 Bridged cycloalkyl, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl thio, pentafluoride thio, or -CO(O)-halogenated C 1-3 Alkyl group, where A is A1, A2, A3, or A4;

[0251] (5) R3 is a hydroxyl group, C 1-6 alkoxy or halogenated C 1-6 Alkoxy group, where A is A1, A2, or A3.

[0252] In some embodiments, the compound shown in formula (III),

[0253] A is

[0254] X is either N or CH;

[0255] Y is either N or CR5;

[0256] U is either O or S;

[0257] Y1 and Z1 are either N or C, respectively;

[0258] It can be a single bond or a double bond;

[0259] Ring B is a 5-6 membered heterocycle or a 5-6 membered heteroaromatic ring; in the 5-6 membered heterocycle or 5-6 membered heteroaromatic ring, the heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; the 5-6 membered heteroaromatic ring has at least one heteroatom, and the heteroatom is N;

[0260] R represents hydrogen or hydroxyl group C 1-6 Alkyl or C 1-3 Alkoxy C 1-6 alkyl;

[0261] R1 is C 4-6 Bridged cycloalkyl rings, surrounded by 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6 Bridged ring cycloalkyl or pentafluoride sulfo;

[0262] R2 is hydrogen or halogen;

[0263] R3 and R3' are independently hydrogen, hydroxyl, and C, respectively. 1-6 Alkoxy, C 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl, 5-10 heteroaryl, or with 1-3 halogens or C 1-3 Alkyl-substituted 5-10-membered heteroaryl groups;

[0264] R and R3' are independent substituents, or R and R3' together with the atoms they are attached to form...

[0265] R4 is a C molecule that has been replaced by 1 to 3 halogens. 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups substituted with 1-3 halogens;

[0266] R5, R 5-1 R 5-2 R6, R 6-1 R 6-2 and R 6-3 Each of the following is independently represented as hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1- 6-alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, C 1-6 Alkylamino C 1-3 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

[0267] R4 and R5 are independent substituents, or R4 and R5 together with the atoms they are attached to form a 4-10 membered carbon ring; the 4-10 membered carbon ring is optionally substituted by 1 to 4 R8s at any position;

[0268] R8 represents deuterium, halogen, oxo group, hydroxyl group, amino group, or C. 1-6 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl or C 1-6 Alkylamino C 1-3 alkyl;

[0269] t is 1, 2, or 3;

[0270] n can be 0, 1, 2, 3, or 4.

[0271] In some embodiments, the compound shown in formula (III) is a compound shown in formula (III').

[0272] Where A is

[0273] X is either N or CH;

[0274] Y is either N or CR5;

[0275] V is O, S, or NH;

[0276] V1, V2, and V3 are each independently N or CH;

[0277] R2 is hydrogen or halogen;

[0278] R3 is hydrogen, methyl, or deuterated methyl;

[0279] R4 is a C molecule that has been replaced by 1 to 3 halogens. 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups substituted with 1-3 halogens;

[0280] R5, R 5-1 R 5-2 R6, R 6-1 R 6-2 and R 6-3 Each of the following is independently represented as hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1- 6-alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, C 1-6 Alkylamino C 1-3 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

[0281] R4 and R5 are independent substituents, or R4 and R5 together with the atoms they are attached to form a 4-membered carbon ring; the 4-membered carbon ring is optionally substituted by 1 to 4 R8s at any position;

[0282] R8 is deuterium.

[0283] In some implementations, R4 is a C substituted with 1 to 3 halogens. 3-6 The cycloalkyl group or a 3-6 membered heterocyclic alkyl group substituted with 1 to 3 halogens, wherein the heteroatoms are selected from 1, 2, or 3 of N, O, and S, and the number of heteroatoms is 1 or 2. Preferably, R4 is a C substituted with 1 to 3 halogens. 3-6 Cycloalkyl groups, such as R4, are cyclopropyl groups substituted with 1 to 3 halogens.

[0284] In some implementation schemes, R5, R 5-1 R 5-2 R6, R 6-1 R 6-2 R 6-3 R 6-4 They are independently hydrogen, deuterium, halogen, cyano, and C, respectively.1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl; preferably, in the 3-6 membered heterocyclic alkyl, the heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1 or 2; more preferably, R6, R 6-1 R 6-2 and R 6-3 R can be either hydrogen or deuterium, respectively. 6-4 Each independently can be either hydrogen or C. 1-6 Alkyl, R5, R 5-1 and R 5-2 Halogen and C are independently distinguished. 1-6 Alkyl or halogenated C 1-6 Alkyl, such as F, Cl, methyl or halomethyl (e.g. difluoromethyl).

[0285] In some implementation schemes, R 6-5 Each is independently deuterium, halogen, cyano, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl, preferably, wherein the heteroatom in the 3-6 membered heterocyclic alkyl is selected from one, two, or three of N, O, and S, and the number of heteroatoms is one or two; more preferably, R 6-5 It can be F, Cl, or methyl.

[0286] In some implementations, R8 is deuterium.

[0287] In some implementations, R1 is a halogenated C 1-6 Alkyl (e.g., trifluoromethyl), A is R6, m, n and R8 can be as described in any embodiment of the present invention.

[0288] In some implementations, U is O.

[0289] In some implementations, X is CH.

[0290] In some implementations, R is hydrogen, hydroxyl group, or C. 1-3 Alkyl or C 1-3 Alkoxy C 1-3Alkyl group; preferably hydrogen, -CH2OH or -CH2OCH3; more preferably hydrogen.

[0291] In some implementations, R and R3' are formed together with the atoms they are bonded to. t can be 1, 2, or 3.

[0292] In some implementations, R and R3' are formed together with the atoms they are bonded to. R3 is -CH3.

[0293] In some implementations, A1 is... m is 0, 1, or 2; n is 0, 1, 2, 3, or 4 (preferably n is 1, 2, 3, or 4); R6 is deuterium or halogen; R8 is deuterium.

[0294] In some implementations, A1 is... m is 0, 1, or 2; n is 0, 1, 2, 3, or 4 (preferably, n is 1, 2, 3, or 4); R8 is deuterium.

[0295] In some implementations, A1 is... n is 0, 1, 2, 3 or 4 (preferably, n is 1, 2, 3 or 4); R6 is H, deuterium or halogen; R8 is deuterium.

[0296] In some implementations, A1 is... n is 0, 1, 2, 3 or 4 (preferably, n is 1, 2, 3 or 4); R8 is deuterium.

[0297] In some implementation schemes, A is (For example ), (For example ),

[0298] In some implementation schemes, A is

[0299] In some implementations, R1 is -SF5; A is A1, A2, A3 or A4.

[0300] In some implementations, R1 is -SF5; A4 is A 4-1 A 4-2 A 4-3 A 4-4 A 4-5 Or A 4-6 .

[0301] In some embodiments, R3 is H, -CH3, -CD3, -OH, -OCH3 or -CH2CHF2; R3' is H; preferably, R3 is H; R3' is H.

[0302] In some implementation schemes, A is Y is N or CH; R4 is

[0303] In some implementation schemes, A is Y is CR5; R4 and R5 together with the atoms they are attached to form a 4-membered carbon ring; the 4-membered carbon ring is unsubstituted, or optionally substituted by 1 to 4 R8s at any position; R8 is deuterium.

[0304] In some implementation schemes, A is R 5-1 and R 5-2 It can be Cl, methyl, trifluoromethyl, difluoromethyl, vinyl, or cyclopropyl.

[0305] In some implementation schemes, A is A5; A5 is V is either O or S; R 6-4 Halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl or C 3-6 Cycloalkyl.

[0306] In some implementation schemes, A is A5; A5 is V is O or S (preferably S); R 6-4 It is Cl, methyl, trifluoromethyl, difluoromethyl, vinyl, or cyclopropyl, more preferably, R 6-4 It is either Cl or methyl.

[0307] This invention provides a compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts.

[0308] Where A is

[0309] X is either N or CH;

[0310] U is O, S, or NR7;

[0311] Y is either N or CR5;

[0312] R represents hydrogen or hydroxyl group C 1-6 Alkyl or C 1-3 Alkoxy C 1-6 alkyl;

[0313] R1 and R2 are independently hydrogen, halogen, cyano, and C, respectively.1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, pentafluoride sulfide, C 3-6 Monocyclic cycloalkyl, C 4-6 Bridged cycloalkyl, 3-6 membered heterocyclic alkyl, -CO(O)-halogenated C 1-3 Alkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, surrounded by 1-3 halogens or C 1-3 Alkyl-substituted C 3-6 Monocyclic cycloalkyl, with 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6 Bridged cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 3-8 membered heterocyclic alkyl groups;

[0314] R3 and R3' are independently hydrogen, hydroxyl, and C, respectively. 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, phenyl, 5-10 heteroaryl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkyl C 1-3 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, surrounded by 1 to 3 halogens or C 1-3 Alkyl-substituted phenyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 5-10-membered heteroaryl groups;

[0315] R and R3' are independent substituents, or R and R3' together with the atoms they are attached to form 5-8 membered heterocycles;

[0316] R4 is a halogenated C 1-6 Alkyl thio, pentafluoride thio, C substituted with one trimethylsilyl group 2-6 Alkyne group, C substituted with 1 to 3 halogens 3-6-cycloalkyl or 3-6-membered heterocyclic alkyl groups substituted with 1 to 3 halogens;

[0317] R5, R 5-1 R 5-2 and R6, R 6-1 R 6-2 Each of the following is independently represented as hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino or C 1-6 Alkylamino C 1-3 alkyl;

[0318] R4 and R5 are independent substituents, or R4 and R5 together with the atoms they are attached to form a 4-10 membered carbon ring; the 4-10 membered carbon ring is optionally substituted by 1 to 4 R8s at any position;

[0319] R7 represents hydrogen, hydroxyl group, and C. 1-6 Alkyl or C 1-6 Alkoxy;

[0320] R8 can be deuterium, halogen, oxo group (=O), hydroxyl group, amino group, mercapto group, or C. 1-6 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl or C 1-6 Alkylamino C 1-3 alkyl;

[0321] And the compound shown in formula (II) satisfies one of the following conditions:

[0322] (1) U is O, A is A1;

[0323] (2) U is O, A is A2; R 5-1 It is a halogen; R6-1 It is deuterium;

[0324] (3) U is S or NR7, and A is A1, A2 or A3;

[0325] (4) R1 is C 4-6 Bridged cycloalkyl rings, surrounded by 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6 Bridged cycloalkyl, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl thio, pentafluoride thio, or -CO(O)-halogenated C 1-3 Alkyl group, where A is A1, A2, or A3;

[0326] (5) R3 is a hydroxyl group, C 1-6 alkoxy or halogenated C 1-6 Alkoxy group, where A is A1, A2, or A3.

[0327] In some implementations, in formula (II), R is hydrogen, hydroxyl group, or C. 1-3 Alkyl or C 1-3 Alkoxy C 1-3 Alkyl group; preferably hydrogen, -CH2OH or -CH2OCH3; more preferably hydrogen.

[0328] In some implementations, in formula (II), R and R3' together with the atoms they are attached to form t can be 1, 2, or 3.

[0329] In some implementations, in formula (II), R3 is -CH3 or

[0330] In some implementations, in formula (II), R and R3' together with the atoms they are attached to form

[0331] In some implementations, in formula (II), R and R3' together with the atoms they are attached to form R3 is -CH3.

[0332] In some implementations, in equation (II), A1 is... m is 0, 1, or 2; n is 0, 1, 2, 3, or 4 (preferably, n is 1, 2, 3, or 4); R8 is deuterium.

[0333] In some implementations, in equation (II), A1 is... R4 and R5 are independent substituents.

[0334] In some implementations, in equation (II), A1 is...

[0335] In some implementations, in equation (II), A1 is... R4 and R5 form with their adjacent benzene rings. in It can be a single or double bond independently, and n is 0, 1, 2, 3 or 4.

[0336] In some implementations, in equation (II), A1 is... in Independently, it can be a single bond or a double bond, when When it is a single bond, n is 0, 1, 2, 3, or 4; when When it is a double bond, n is 0, 1 or 2.

[0337] In some implementations, in equation (II), A1 is... n is 0, 1, 2, 3 or 4 (preferably, n is 1, 2, 3 or 4); R8 is deuterium.

[0338] In some implementation schemes, A is

[0339] X is either N or CH;

[0340] U is either O or S;

[0341] Y is either N or CR5;

[0342] R represents hydrogen or hydroxyl group C 1-6 Alkyl or C 1-3 Alkoxy C 1-6 alkyl;

[0343] R1 is hydrogen, halogen, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, C 1-6 Alkylamino, pentafluoride sulfide, -CO(O)-halogenated C 1-3 Alkyl, C 3-6 Monocyclic cycloalkyl, C 4-6 Bridged cycloalkyl, 3-6 membered heterocyclic alkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, surrounded by 1-3 halogens or C 1-3 Alkyl-substituted C 3-6 Monocyclic cycloalkyl, with 1 to 3 halogens or C 1- 3-alkyl substituted C 4-6 Bridged cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 3-8 membered heterocyclic alkyl groups;

[0344] R2 is hydrogen, halogen, or cyano;

[0345] R3 and R3' are independently hydrogen, hydroxyl, and C, respectively. 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl or C 1-6 Alkoxy;

[0346] R and R3' are independent substituents, or R and R3' together with the atoms they are attached to form 5-8 membered heterocycles;

[0347] R4 is a halogenated C 1-6 Alkyl thio, pentafluoride thio, C substituted with one trimethylsilyl group 2-6 Alkyne group, C substituted with 1 to 3 halogens 3- 6-cycloalkyl or 3-6-membered heterocyclic alkyl groups substituted with 1 to 3 halogens;

[0348] R5 and R6 are independently hydrogen, deuterium, halogen, cyano, hydroxyl, amino, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy;

[0349] R4 and R5 are independent substituents, or R4 and R5 together with the atoms they are attached to form a 4-8 membered carbon ring; the 4-8 membered carbon ring is optionally substituted by 1 to 4 R8s at any position;

[0350] R8 represents deuterium, halogen, oxo group, hydroxyl group, amino group, or C. 1-6 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl or C 1-6 Alkylamino C 1-3 alkyl.

[0351] In some implementation schemes, A is

[0352] X is either N or CH;

[0353] U is O, S, or NR7;

[0354] R1 is hydrogen, halogen, or C. 1-6 Alkyl, Halogenated C 1-6Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, -CO(O)-halogenated C 1-3 Alkyl, C 3-6 Monocyclic cycloalkyl, C 4-6 Bridged cycloalkyl, 3-6 membered heterocyclic alkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, surrounded by 1-3 halogens or C 1-3 Alkyl-substituted C 3-6 Monocyclic cycloalkyl, with 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6 Bridged cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 3-8 membered heterocyclic alkyl groups;

[0355] R2 is hydrogen, halogen, or cyano;

[0356] R3 and R3' are independently hydrogen and C, respectively. 1-6 Alkyl, deuterated methyl or halogenated C 1-6 alkyl;

[0357] R 5-1 R 5-2 Each is independently hydrogen, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino or C 1-6 Alkylamino C 1-3 alkyl;

[0358] R 6-1 R 6-2 Each of the following is independently represented as hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C1-3 Alkyl, Halogenated C 1- 6-alkoxy C 1-3 Alkyl, C 1-6 Alkylamino or C 1-6 Alkylamino C 1-3 alkyl;

[0359] R7 represents hydrogen, hydroxyl group, and C. 1-6 Alkyl or C 1-6 Alkyl group.

[0360] In some embodiments, the compound shown in formula (II), its stereoisomers, or pharmaceutically acceptable salts,

[0361] Where A is

[0362] X is either N or CH;

[0363] U is either O or S;

[0364] R represents hydrogen or hydroxyl group C 1-6 Alkyl or C 1-3 Alkoxy C 1-6 alkyl;

[0365] R1 and R2 are independently hydrogen, halogen, cyano, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, pentafluoride sulfide, C 3-6 Monocyclic cycloalkyl, C 4-6 Bridged cycloalkyl, 3-6 membered heterocyclic alkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, surrounded by 1-3 halogens or C 1-3 Alkyl-substituted C 3-6 Monocyclic cycloalkyl, with 1 to 3 halogens or C 1-3 Alkyl-substituted C 4- 6-bridged cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 3-8 membered heterocyclic alkyl groups;

[0366] R3 and R3' are independently hydrogen, hydroxyl, and C, respectively. 1-6Alkyl, deuterated methyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, 5-10 membered heteroaryl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkyl C 1-3 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group;

[0367] R and R3' are independent substituents, or R and R3' together with the atoms they are attached to form...

[0368] R8 represents deuterium, halogen, oxo group, hydroxyl group, amino group, or C. 1-6 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl or C 1-6 Alkylamino C 1-3 alkyl;

[0369] t is 1, 2, or 3;

[0370] m is 0, 1, or 2;

[0371] n can be 0, 1, 2, 3, or 4.

[0372] This invention provides a compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts.

[0373] Where A is

[0374] X is either N or CH;

[0375] U is O, S, or NR7;

[0376] Y is either N or CR5;

[0377] R1 and R2 are independently hydrogen, halogen, cyano, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, pentafluoride sulfide, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -CO(O)-halogenated C 1-3 Alkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, surrounded by 1-3 halogens or C 1-3 Alkyl-substituted C 3-6 Cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 3-8 membered heterocyclic alkyl groups;

[0378] R3 and R3' are independently hydrogen, hydroxyl, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkyl C 1-3 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group;

[0379] R4 is -CF2Cl, a halogenated C 1-6 Alkyl thio, pentafluoride thio, C substituted with one trimethylsilyl group 2-6 Alkyne group, C substituted with 1 to 3 halogens 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups substituted with 1-3 halogens;

[0380] R5 and R6 are independently hydrogen, halogen, cyano, hydroxyl, amino, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3Alkyl, C 1-6 Alkylamino or C 1-6 Alkylamino C 1-3 alkyl;

[0381] R4 and R5 are independent substituents, or R4 and R5 are linked together to form a 4-10 membered cycloalkenyl group; the 4-10 membered cycloalkenyl group is unsubstituted, or selectively substituted by 1 to 3 R8s at any position;

[0382] R7 represents hydrogen, hydroxyl group, and C. 1-6 Alkyl or C 1-6 Alkoxy;

[0383] R8 can be hydrogen, halogen, oxo group, hydroxyl group, amino group, mercapto group, or C. 1-6 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl or C 1-6 Alkylamino C 1-3 alkyl;

[0384] And the compound shown in formula (I) satisfies one of the following conditions:

[0385] (1) U is O, A is A1;

[0386] (2) U is S or NR7, and A is A1, A2 or A3;

[0387] (3) R1 is C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl thio, pentafluoride thio, or -CO(O)-halogenated C 1-3 Alkyl group, where A is A1, A2, or A3;

[0388] (4) R3 is a hydroxyl group, C 1-6 alkoxy or halogenated C 1-6 Alkoxy group, where A is A1, A2, or A3.

[0389] In some implementation schemes, A is

[0390] X is either N or CH;

[0391] U is either O or S;

[0392] Y is either N or CR5;

[0393] R1 is hydrogen, halogen, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, -CO(O)-halogenated C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, surrounded by 1-3 halogens or C 1- 3-alkyl substituted C 3-6 Cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 3-8 membered heterocyclic alkyl groups;

[0394] R2 is hydrogen, halogen, or cyano;

[0395] R3 and R3' are independently hydrogen and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0396] R4 is -CF2Cl, a halogenated C 1-6 Alkyl thio, pentafluoride thio, C substituted with one trimethylsilyl group 2-6 Alkyne group, C substituted with 1 to 3 halogens 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups substituted with 1-3 halogens;

[0397] R5 and R6 are independently hydrogen, halogen, cyano, hydroxyl, amino, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkoxy;

[0398] R4 and R5 are independent substituents, or R4 and R5 are linked together to form a 4-8 membered cycloalkenyl group; the 4-8 membered cycloalkenyl group is unsubstituted, or selectively substituted by 1 to 3 R8s at any position;

[0399] R8 represents hydrogen, halogen, oxo group, hydroxyl group, amino group, or C. 1-6 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl or C1-6 Alkylamino C 1-3 alkyl.

[0400] In some implementation schemes,

[0401] A is

[0402] X is either N or CH;

[0403] U is either S or NR7;

[0404] R1 is hydrogen, halogen, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, -CO(O)-halogenated C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, surrounded by 1-3 halogens or C 1- 3-alkyl substituted C 3-6 Cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 3-8 membered heterocyclic alkyl groups;

[0405] R2 is hydrogen, halogen, or cyano;

[0406] R3 and R3' are independently hydrogen and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0407] R5 and R6 are independently hydrogen, halogen, cyano, hydroxyl, amino, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino or C 1-6 Alkylamino C 1-3 alkyl;

[0408] R7 represents hydrogen, hydroxyl group, and C. 1-6 Alkyl or C 1-6 Alkyl group.

[0409] In some implementations, in equation (I), A1 is... R4 and R5 are linked together to form a 4-8 membered cycloalkenyl group; the 4-8 membered cycloalkenyl group is unsubstituted, or selectively substituted by 1 to 4 R8 groups at any position; R8 is hydrogen, deuterium, halogen, oxo group, hydroxyl group, amino group, C 1-4 Alkyl, C 1-4 Alkylene, Halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkylene, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 Alkoxy C 1-3 Alkyl, Halogenated C 1-4 Alkoxy C 1-3 Alkyl or C 1-4 Alkylamino C 1-3 alkyl.

[0410] In some implementations, in equation (I), A1 is... m is 0, 1, or 2; n is 1, 2, 3, or 4; R8 is hydrogen, deuterium, oxo group, halogen, oxo group, or C. 1-4 Methoxy, C 1-4 Methylene, halogenated C 1-4 Methoxy or halogenated C 1-4 Methylene; or, two R8 atoms together with the carbon atom they are attached to form a C group. 3-6 Cycloalkyl groups; or two R8 groups linked together to form a C12 group. 3-6 Cycloalkyl group.

[0411] In some implementations, in equation (I), A2 is... R5 can be H, F, Cl, -CH3, -OCH3, -OCF3, -OCHF2, -CN, or R6 can be H, D, F, Cl, -CH3, -OCH3, -OCF3, -NH2, -OCHF2, or -CN.

[0412] In some implementations, A in equation (I) is R5 can be H, F, Cl, -CH3, -OCH3, -OCF3, -OCHF2, or -CN.

[0413] In some implementations, in equation (I), A1 is...

[0414] In some implementations, in equation (I), A1 is...

[0415] In some implementations, in formula (I), formula (II), or formula (III), R1 is -CF3, -SF5, -SCF3, -CO(O)CF3,

[0416] In some implementations, in formula (I), formula (II), or formula (III), R1 is -SF5, -SCF3, -CO(O)CF3,

[0417] In some implementations, in formula (I), formula (II), or formula (III), R1 is -SF5, -SCF3, -CO(O)CF3, A can be A1, A2, or A3.

[0418] In some implementations, R1 is C in equation (I), equation (II), or equation (III). 4-6 Bridged cycloalkyl rings, surrounded by 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6 Bridged cycloalkyl, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl thio, pentafluoride thio, or -CO(O)-halogenated C 1-3 Alkyl group, where A is A1, A2, or A3.

[0419] In some implementations, U is S or O in formula (I), formula (II) or formula (III).

[0420] In some implementations, U is S in formula (I), formula (II) or formula (III).

[0421] In some implementations, in formula (I), formula (II) or formula (III), U is S; A is A1, A2 or A3.

[0422] In some implementations, in formula (I), formula (II), or formula (III), R1 is F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CF3, -CHF2, -OCF2Cl, -CF2CH3, -CH2CF3, -CF(CH3)2, -OCH3, -OCHF2, -OCF3,

[0423] In some implementations, in formula (I), formula (II), or formula (III), R1 is F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CF3, -CHF2, -OCF2Cl, -CF2CH3, -CH2CF3, -CF(CH3)2, -OCH3, -OCHF2, -OCF3, A is A1.

[0424] In some implementations, R2 is H, F, Cl, or -CN in formula (I), formula (II), formula (III), or formula (III').

[0425] In some implementations, R2 is H in formula (I), formula (II), formula (III) or formula (III').

[0426] In some embodiments, in formula (I), formula (II), formula (III) or formula (III'), R3 is H, -CH3, -CD3, -OH, -OCH3, -CH2CHF2 or

[0427] In some implementations, R3' in formula (I), formula (II) or formula (III) is H, -CH3 or -CD3.

[0428] In some implementations, R3' is H in formula (I), formula (II) or formula (III).

[0429] In some implementations, R3 is H in formula (I), formula (II) or formula (III); R3' is H.

[0430] In some implementations, in formula (I), formula (II) or formula (III), R3 is H, -CH3, -CD3, -OH, -OCH3 or -CH2CHF2; and R3' is H.

[0431] In some implementations, in formula (I), formula (II), formula (III) or formula (III'), R3 is -OH, -OCH3 or -OCH2CHF2; R3' is H; and A is A1, A2 or A3.

[0432] In some implementations, A is in equation (I), equation (II), equation (III), or equation (III'). Y is N or CR5; R4 is... -SF5 or -SCF3; R5 is H, F, Cl, -CH3, -OCH3, -OCF3, -OCHF2 or -CN; R6 is H.

[0433] In some implementations, R6 is F or D in formula (I), formula (II), formula (III) or formula (III').

[0434] In some implementations, R8 in formula (I), formula (II) or formula (III) is D, oxo group (=O), F, =CF2, -OCH2CF3.

[0435] In some implementations, in equation (I), equation (II), or equation (III), A1 is...

[0436] The compounds of this invention, their stereoisomers or pharmaceutically acceptable salts, have any of the following structures: (For example ),

[0437] (For example ), Its stereoisomers or pharmaceutically acceptable salts.

[0438] In some embodiments, the compound represented by formula (III) is a single transisomer of the compound of the following formula.

[0439] The single isomer with a short UPCC retention time is specified as follows: Analytical column: (R,R)WHELK-O1 25*250mm, 5um (Regis); flow rate: 3.0mL / min; column temperature: 40℃; detection wavelength: 214 and / or 254nM; mobile phase: CO2 / [MeOH(0.2% NH3(7M in MeOH)] = 70 / 30; preferably, the retention time of the compound with the short retention time is approximately 0.75-0.90 min, for example, approximately 0.821 min.

[0440] The single isomer is:

[0441] In some embodiments, the compound represented by formula (III) is a single transisomer of the compound of the following formula.

[0442] The UPCC retention time of the single isomer with longer retention time is as follows: analytical column: (R,R)WHELK-O1 25*250mm, 5um (Regis), flow rate: 3.0mL / min; column temperature: 40℃, detection wavelength: 214 and / or 254nM; mobile phase: CO2 / [MeOH(0.2% NH3(7M in MeOH)]=70 / 30; preferably, the retention time of the compound with longer retention time is about 1.60-1.70min, for example, about 1.687min;

[0443] The single isomer is:

[0444] In some embodiments, the compound represented by formula (III) is a single transisomer of the compound of the following formula.

[0445] The UPCC retention time of the single isomer is relatively short: analytical column: (R,R)WHELK-O1 25*250mm, 5um (Regis), flow rate: 3.0mL / min; column temperature: 40℃; detection wavelength: 214 and / or 254nM; mobile phase: CO2 / [MeOH(0.2%NH3(7M in MeOH)]=70 / 30; preferably, the retention time of the compound with the short retention time is about 0.75-0.90min, for example, about 0.822min;

[0446] The single isomer is:

[0447] In some embodiments, the compound represented by formula (III) is a single transisomer of the compound of the following formula.

[0448] The UPCC retention time of the single isomer is relatively long: analytical column: (R,R)WHELK-O1 25*250mm, 5um (Regis), flow rate: 3.0mL / min; column temperature: 40℃; detection wavelength: 214 and / or 254nM; mobile phase: CO2 / [MeOH(0.2% NH3(7M in MeOH)]=70 / 30; preferably, the retention time of the compound with the long retention time is about 1.85-1.95min, for example, about 1.903min;

[0449] The single isomer is:

[0450] In some embodiments, the compounds of the present invention are transisomers of the following formula:

[0451] The blocked isomers elute first under the following SFC separation conditions: the chromatographic column is (R,R)WHELK-O1 25*250mm, 10um (Regis); the mobile phase is CO2 / [MeOH(0.2% NH3(7M in MeOH)]=55 / 45.

[0452] In some embodiments, the compounds of the present invention are transisomers of the following formula:

[0453] The regressed isomer eluted under the following SFC separation conditions: the chromatographic column was (R,R)WHELK-O1 25*250mm, 10um (Regis); the mobile phase was CO2 / [MeOH(0.2% NH3(7M in MeOH)]=55 / 45.

[0454] In some embodiments, the compounds of the present invention are transisomers of the following formula:

[0455] The blocked isomer eluted first under the following SFC resolution conditions: the chromatographic column was (S,S)WHELK-O1 25*250mm, 10um (Regis); the mobile phase was CO2 / [MeOH(0.2% NH3(7M in MeOH)]=52.5 / 47.5.

[0456] In some embodiments, the compounds of the present invention are transisomers of the following formula:

[0457] The blocked isomer eluted under the following SFC resolution conditions: the chromatographic column was (S,S)WHELK-O1 25*250mm, 10um (Regis); the mobile phase was CO2 / [MeOH(0.2% NH3(7M in MeOH)]=52.5 / 47.5.

[0458] The stereochemical definitions and rules used in this invention generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994. The term “stereoisomer” as used in this invention refers to optical isomers, geometric isomers, or transisomers, and combinations thereof. These stereoisomers can be separated, purified, and enriched by asymmetric synthesis, chromatography, or chiral separation methods (including but not limited to thin-layer chromatography, rotational chromatography, column chromatography, gas chromatography, high-performance liquid chromatography, etc.), and can also be obtained through chiral resolution by bonding (chemical bonding, etc.) or salt formation (physical bonding, etc.) with other chiral compounds. The term “single stereoisomer” means that the mass content of one stereoisomer of the compound is not less than 90%, preferably not less than 95%, relative to all stereoisomers of the compound. Individual stereoisomers and mixtures thereof are included within the scope of this invention. This invention encompasses all combinations and subsets of stereoisomers of all specific groups defined above. The "stereoisomers" referred to in this invention are preferably optical isomers and / or transisomers.

[0459] The term "optical isomers" includes enantiomers, diastereomers, and mixtures thereof. For example, racemic mixtures. An enantiomer is a non-overlapping, mirror-image isomer of a compound. A diastereomer is a stereoisomer with two or more chiral centers whose molecules are not mirror images of each other. Diastereomers typically possess different physical properties, such as melting point, boiling point, spectral properties, and reactivity.

[0460] The term "geometric isomers" includes cis-trans isomers. This is a stereoisomerism phenomenon present in certain double-bonded or cyclic compounds. Due to the presence of double bonds or rings, the free rotation of these molecules is hindered, resulting in two different stereoisomers, called cis and trans isomers, respectively.

[0461] The term "restricted rotation isomer" refers to stereoisomers that are formed due to the impeded rotation around a single bond. These are conformational isomers that can be separated from each other due to the energy difference caused by stereo strain or other contributing factors that impede the rotation of the single bond.

[0462] The present invention also provides a method for preparing the stereoisomers or pharmaceutically acceptable salts of the compounds shown in formula (II) or (III), comprising one or more of the following methods:

[0463] In general reaction formula 1, R, R1, R2, R3, R3', X, A, and U are defined as previously. X-1 and NH(R3)(R 3’ The compounds shown in formula (II) or formula (III) are obtained by substitution reaction.

[0464] In general formula 2, M is a halogen; R, R1, R2, X, and A are defined as previously stated. Cyclic closure of X-3 yields the compound shown in formula X-1-2.

[0465] In general formula 3, M is a halogen; R, R1, R2, X, and A are defined as previously stated. X-2 and A-NH2 undergo a condensation reaction to yield the compound shown in formula X-3.

[0466] The compounds shown in formula (I), (II) or (III), their stereoisomers or pharmaceutically acceptable salts, can be synthesized by conventional chemical methods.

[0467] The present invention also provides the compounds shown in Formula X-1, their stereoisomers or pharmaceutically acceptable salts;

[0468] The definitions of R, R1, R2, X, A, and U are as described above.

[0469] Preferably, the compound represented by formula X-1 is any of the following compounds:

[0470] (For example ),

[0471] (For example ),

[0472] Generally, salts can be prepared by reacting a free base or acid with an equisional or excess amount of an acid (inorganic or organic) or a base (inorganic or organic) in a suitable solvent or solvent combination.

[0473] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of an active ingredient and pharmaceutically acceptable excipients; said active ingredient comprising one or more of the compounds described above, their stereoisomers, or pharmaceutically acceptable salts.

[0474] In some embodiments, the active ingredient in the pharmaceutical composition may also include other cancer therapeutic agents.

[0475] On the other hand, the present invention also provides a pharmaceutical composition comprising (i) the compound described above, its stereoisomers, or pharmaceutically acceptable salts; and (ii) pharmaceutically acceptable excipients. Preferably, the compound described above, its stereoisomers, or pharmaceutically acceptable salts are the active ingredients.

[0476] In some embodiments, the pharmaceutical composition is used as a drug.

[0477] On the other hand, the present invention also provides the use of the compounds described above, their stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical compositions as medicines.

[0478] On the other hand, the present invention also provides the aforementioned compound, its stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition thereof, as a medicament.

[0479] On the other hand, the present invention also provides the use of the compounds described above, their stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical compositions in the preparation of pharmaceuticals.

[0480] On the other hand, the present invention also provides the use of the compounds described above, their stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical compositions as MAT2A inhibitors.

[0481] On the other hand, the present invention also provides the aforementioned compounds, stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical compositions thereof, as MAT2A inhibitors.

[0482] On the other hand, the present invention also provides the use of the compounds described above, their stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical compositions thereof in the preparation of MAT2A inhibitors.

[0483] On the other hand, the present invention also provides the use of the compounds described above, their stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical compositions thereof in the preparation of medicaments for treating MAT2A-mediated related diseases. The related diseases are cancers; more preferably, cancers with MTAP deficiency, reduced activity, or no activity.

[0484] On the other hand, the present invention also provides the use of the compounds described above, their stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical compositions thereof in the preparation of drugs for treating and / or alleviating cancer; wherein the cancer is more preferably a cancer lacking, with reduced or no MTAP activity.

[0485] On the other hand, the present invention also provides the use of the compounds described above, their stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical compositions thereof in the preparation of medicaments for treating and / or alleviating lung adenocarcinoma, melanoma, pancreatic cancer, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal cancer, glioblastoma and / or mesothelioma.

[0486] On the other hand, the present invention also provides the use of the compounds described above, their stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical compositions thereof in the treatment of cancer; wherein the cancer is more preferably a cancer lacking, with reduced activity, or without MTAP.

[0487] On the other hand, the present invention also provides the use of the compounds described above, their stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical compositions thereof in the treatment and / or relief of lung adenocarcinoma, melanoma, pancreatic cancer, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal cancer, glioblastoma and / or mesothelioma.

[0488] On the other hand, the present invention further provides a method for treating cancer with the compound as described above, its stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical composition, comprising: administering a therapeutically required dose of the compound as described above or a pharmaceutically acceptable salt, or the pharmaceutical composition to a mammal.

[0489] The mammal in question is preferably a human.

[0490] On the other hand, the present invention further provides the compounds shown above, their stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical compositions may be used in combination with one or more other kinds of therapeutic agents and / or treatments for the treatment and / or relief of cancer.

[0491] Unless otherwise stated, the following terms appearing in this specification and claims have the following meanings:

[0492] Term "C" t-q "" refers to the range from the starting point to the ending point, where t and q, and all points within the range, are integers representing the number of carbon atoms, for example, C. 1-4 This indicates that the number of carbon atoms is 1, 2, 3, or 4; C 1-6 This indicates that the number of carbon atoms is 1, 2, 3, 4, 5, or 6; C 3-8 This indicates that the number of carbon atoms is 3, 4, 5, 6, 7, or 8; C t-qIt can be used in conjunction with any group containing carbon atoms to specify the number of carbon atoms, such as C. 1-6 Alkyl, C 1-4 Alkylene, C 3-8 cycloalkyl, C 6-10 Aryl, C 1-4 Alkoxy, C 3-8 cycloalkyl C 1-4 Alkyl groups, etc.

[0493] The term "alkyl" refers to a saturated straight-chain or branched hydrocarbon group containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8, 1-6, 1-4, or 1-3 carbon atoms. Representative examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, n-heptyl, octyl, nonyl, decyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 1-ethyl-2-methylpropyl, and 1,1,2-trimethylpropyl. 1,1-Dimethylbutyl, 1,2-Dimethylbutyl, 2,2-Dimethylbutyl, 1,3-Dimethylbutyl, 2,3-Dimethylbutyl, 2-Ethylbutyl, 2-Methylpentyl, 3-Methylpentyl, 4-Methylpentyl, 4,4-Dimethylpentyl, 2-Methylhexyl, 3-Methylhexyl, 4-Methylhexyl, 5-Methylhexyl, 2,3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, 2,2,4-Trimethylpentyl, Undecyl, Dodecyl, and their various isomers, etc.

[0494] The term "alkylene" refers to a saturated straight-chain or branched non-bridged divalent alkyl group containing 1-20 carbon atoms, preferably 1-6 carbon atoms, more preferably 1-4 or 1-3 carbon atoms, such as methylene (=CH2), ethylene (=CHCH3), 2-isopropylidene (=CH(CH3)2), etc.

[0495] The term "cycloalkyl" refers to a monocyclic or polycyclic group containing 3-20 carbon atoms and either saturated or partially unsaturated (containing one or two double bonds). "Cycloalkyl" is preferably a 3-10 member monocyclic alkyl group, more preferably a 3-8 or 3-6 member monocyclic alkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and 1,3-cyclohexadienyl. "Polycyclic cycloalkyl" includes "bridged cycloalkyl," "fused cycloalkyl," and "spirocycloalkyl," such as tetrahydronaphthyl, 2,3-dihydroindene, bicyclo[1.1.1]pentyl, spiro[2.2]pentyl, etc. Monocyclic or polycyclic cycloalkyl groups can be linked to a parent molecule via any carbon atom on the ring.

[0496] The term "carbocyclic ring" refers to a non-aromatic carbocyclic group with a certain number of atoms, whether substituted or unsubstituted, saturated or unsaturated, including monocyclic, polycyclic, and spirocyclic rings.

[0497] The term "cycloalkenyl" refers to a partially unsaturated cycloalkyl group having one or more (e.g., 1, 2, or 3) carbon-carbon sp2 double bonds and lacking aromaticity. For example...

[0498] The term "heterocyclic" refers to a non-aromatic cyclic group composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur, or boron, which is saturated or partially unsaturated (containing one or two double bonds). This cyclic group can be monocyclic or polycyclic, preferably monocyclic, bicyclic, or tricyclic. Preferably, the heteroatoms can be the same or different, and the heterocycle can contain one or more types, with the number of heteroatoms being one, two, three, or four. The "heterocyclic" is preferably a 3-10 membered monocyclic ring, more preferably a 3-8, 3-6, or 4-8 membered monocyclic ring.

[0499] The term "heterocyclic alkyl" refers to a non-aromatic cyclic group consisting of a carbon atom and heteroatoms selected from nitrogen, oxygen, sulfur, or boron, which is saturated or partially unsaturated (containing one or two double bonds). This cyclic group can be monocyclic or polycyclic, preferably monocyclic, bicyclic, or tricyclic. In this invention, the number of heteroatoms in the "heterocyclic alkyl" is preferably 1, 2, 3, or 4. The nitrogen, sulfur, or boron atom in the heterocyclic alkyl group may optionally be oxidized (=O). The carbon atom may be further oxidized (=O) or thiolated (=S). The nitrogen atom may optionally be further substituted with other groups to form a tertiary amine or quaternary ammonium salt. The "heterocyclic alkyl" is preferably a 3-10 membered monocyclic ring, more preferably a 3-8, 3-6, or 4-8 membered monocyclic ring. Representative examples include, but are not limited to: aziridinyl, aziridine, tetrahydrofuran-2-yl, morpholinyl, thiomorpholinyl, thiomorpholin-S-oxide-4-yl, piperidinyl, pyrrolyl, piperazinyl, homopiperazinyl, 1,4-dioxanecycloyl, pyranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, dihydropyrazolyl, 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl, 1,1-tetrahydro-2H-thiaranyl, 1-imino-1-oxytetrahydro-2H-thiaranyl, 1,1-tetrahydrothiaphenyl, 1-imino-1-oxy Tetrahydrothiopheneyl, 1,1-dioxo-3,4-dihydro-2H-thioranyl, 1-imino-1-oxo-3,4-dihydro-2H-thioranyl, 1,1-dioxo-2,3-dihydrothiopheneyl, 1-imino-1-oxo-2,3-dihydrothiopheneyl, 1,3-dioxopentyl, 1,3-dioxacyclopentenyl, 1,3-oxothiacyclopentenyl, 1,3-oxothiacyclopentenyl, 1,4-dioxa-2-hexenyl, 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, 1,2,3,4-tetrahydropyrazinyl, 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, etc. "Polycyclic heterocyclic alkyl" includes "fused heterocyclic groups," "spirocyclic groups," and "bridged heterocyclic groups." "Fused heterocyclic groups" comprise monocyclic heterocyclic alkyl rings fused to cycloalkyl or heterocyclic alkyl groups. The monocyclic and polycyclic heterocyclic alkyl groups can be linked to the parent molecule via any ring atom on the ring. The aforementioned ring atoms specifically refer to carbon and / or nitrogen atoms that form the ring backbone.

[0500] The term "cycloalkylalkyl" refers to a cycloalkyl group that is linked to the parent structure via an alkyl group. Therefore, "cycloalkylalkyl" encompasses the definitions of alkyl and cycloalkyl groups described above.

[0501] The term "heterocyclic alkyl alkyl" refers to a heterocyclic alkyl group that is linked to the parent structure via an alkyl group. Therefore, "heterocyclic alkyl alkyl" encompasses the definitions of alkyl and heterocyclic alkyl groups described above.

[0502] The term "alkenyl" refers to a straight-chain, branched, or cyclic non-aromatic hydrocarbon group containing at least one carbon-carbon double bond. It may contain 1-3 carbon-carbon double bonds, preferably 1. The term "C"... 2-4 "Alkenyl" refers to an alkenyl group having 2-4 carbon atoms; the term "C" is used to indicate this. 2-6 "Alkenyl" refers to an alkenyl group having 2-6 carbon atoms, including vinyl, propenyl, butenyl, 2-methylbutenyl, and cyclohexenyl. The alkenyl group can be substituted.

[0503] The term "alkynyl" refers to a straight-chain, branched, or cyclic hydrocarbon group containing at least one carbon-carbon triple bond. It may contain 1-3 carbon-carbon triple bonds, preferably 1. The term "C"... 2-6 "Alynyl" refers to an alkynyl group with 2-6 carbon atoms, including ethynyl, propynyl, butynyl and 3-methylbutynyl.

[0504] The term "alkoxy" refers to a non-cyclic alkyl group having the stated number of carbon atoms connected by an oxygen bridge. Thus, "alkoxy" encompasses the definition of alkyl groups described above, examples of which include, but are not limited to: -OCH3, -OCH2CH3, and -OCH(CH3)2.

[0505] The term "cycloalkyloxy" refers to a cycloalkyl group connected to the parent nucleus via an oxygen group. Therefore, "cycloalkyloxy" encompasses the definition of cycloalkyl groups described above, with examples including, but not limited to:

[0506] The term "heterocyclic alkyloxy group" refers to a heterocyclic alkyl group connected to the parent structure via an oxygen group. Therefore, "heterocyclic alkyloxy group" encompasses the definition of a heterocyclic alkyl group described above, with examples including but not limited to:

[0507] The term "alkoxyalkyl" refers to an alkoxy group that is linked to the parent nucleus structure via an alkyl group. Thus, "alkoxyalkyl" encompasses the definitions of alkyl and alkoxy groups described above, with examples including but not limited to: -CH2OCH3, -CH2OCH2CH3, -CH2OCH(CH3)2, -CH2CH2OCH3, -CH2CH2OCH2CH3, and -CH2CH2OCH(CH3)2.

[0508] The term "alkathioyl" refers to a non-cyclic alkyl group having the stated number of carbon atoms connected by a sulfur bridge. Thus, "alkathioyl" includes the definition of alkyl groups described above, examples of which include, but are not limited to: -SCH3, -SCH2CH3.

[0509] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0510] The term "halogenated alkyl" refers to an alkyl group that has been arbitrarily substituted with a halogen. Thus, "halogenated alkyl" encompasses the definitions of halogen and alkyl group mentioned above.

[0511] The term "haloalkoxy" refers to an alkoxy group that has been substituted with a halogen in any way. Therefore, "haloalkoxy" encompasses the definitions of halogen and alkoxy group mentioned above.

[0512] The term "haloalkylthio" refers to an alkylthio group that has been arbitrarily substituted with a halogen. Therefore, "haloalkylthio" encompasses the definitions of halogen and alkylthio group mentioned above.

[0513] The term "amino" refers to -NH2.

[0514] The term "alkylamino" refers to an amino group in which at least one hydrogen atom is replaced by an alkyl group, including "monoalkylamino" and "dialkylamino," examples of which include, but are not limited to: -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH3)(CH2CH3), and -N(CH3)(CH2CH2CH3). The term "aminoalkyl" refers to an alkyl group in which any one hydrogen atom is replaced by an amino group, examples of which include, but are not limited to: -CH2NH2 and -CH2CH2NH2. Thus, "aminoalkyl" and "alkylamino" encompass the definitions of alkyl and amino groups described above.

[0515] The term "alkylaminoalkyl" refers to an alkyl group in which any one hydrogen atom is replaced by an alkylamino group, examples of which include, but are not limited to: -CH2N(CH3)2, -CH2CH2N(CH3)2, -CH2CH2CH2N(CH3)2, and -CH2NHCH3. Thus, "alkylaminoalkyl" encompasses the definitions of alkylamino and alkyl groups as described above.

[0516] The term "hydroxyl group" refers to -OH.

[0517] The term "oxo" refers to the =O group, such as the =O part in carbonyl (-CO-), nitrosyl (-N=O), sulfinyl (-SO-), or sulfonyl (-SO2-).

[0518] The term "cyano" refers to -CN.

[0519] The term "thiol" refers to -SH.

[0520] The term "pentafluoride sulfur group" refers to -SF5.

[0521] The "room temperature" mentioned in this invention refers to 15-30℃.

[0522] Generally, the term "substituted" indicates that one or more hydrogen atoms in a given structure are substituted by a specific substituent. Further, when the group is substituted by more than one of the substituents, the substituents are independent of each other; that is, the more than one substituent can be different or the same. Unless otherwise explicitly stated, a substituent can be substituted at each substituted position of the substituted group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be substituted at the same or different positions.

[0523] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...each independently is" used in this application should be interpreted broadly, meaning that the described entities are independent of each other and can independently be the same or different specific functional groups. More specifically, the descriptive phrase "...independently is" can mean either that the specific options expressed by the same symbol in different functional groups do not affect each other, or that the specific options expressed by the same symbol in the same functional group do not affect each other.

[0524] The term “optionally replaced by…” means either “replaced by…” or “not replaced”.

[0525] In this invention, when the bonding with a substituent intersects with the bonding of two atoms in the connecting ring, then such a substituent can be bonded to any bondable ring atom on the ring.

[0526] In this invention, any combination of variables is permitted only if such a combination produces a stable compound.

[0527] The “pharmaceutically acceptable salts” described in this invention are discussed in Berge, et al., “Pharmaceutically acceptable salts”, J. Pharm. Sci., 66, 1-19 (1977). The compounds described in this invention may have acidic, basic or amphoteric groups. Typical pharmaceutically acceptable salts include salts prepared by reacting the compounds of this invention with an acid or base.

[0528] The compounds of the present invention have one or more of the following effects: (1) good MAT2A enzyme inhibitory activity; (2) good anti-tumor cell proliferation inhibitory activity; (3) good metabolic stability; (4) long half-life; (5) long mean residence time; (6) good tissue / plasma distribution ratio; (7) good exposure; (8) high apparent volume of distribution; (9) good in vivo efficacy.

[0529] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0530] The reagents and raw materials used in this invention are all commercially available. Detailed Implementation

[0531] The structures of all compounds in this invention can be determined by nuclear magnetic resonance (NMR). 1 Identification by 1H NMR and / or mass spectrometry (MS).

[0532] 1 10 H NMR chemical shifts (δ) were recorded in pPM (10 -6 NMR was performed using a Bruker AVANCE-400 spectrometer. Suitable solvents were deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and deuterated dimethyl sulfoxide (DMSO-d6), with tetramethylsilane as an internal standard (TMS).

[0533] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 HPLC / 6120 mass spectrometer with an Ultimate C18 column (3.0 × 50 mm, 3 μm) at 40 °C; or a Thermo UltiMate 3000 HPLC / MSQ PLUS mass spectrometer with an XBridge C18 column (3.0 × 50 mm, 3.5 μm) at 30 °C. Agilent gradient elution conditions: 95-5% solvent A1 and 5-95% solvent B1 (0-2.0 min), then 95% solvent B1 and 5% solvent A1 (hold for 1.1 min). Percentages represent the volume percentage of a specific solvent in the total solvent volume. Solvent A1: 0.01% aqueous solution of trifluoroacetic acid (TFA); Solvent B1: 0.01% acetonitrile solution of trifluoroacetic acid; percentages represent the volume percentage of the solute in the solution. Thermo gradient elution condition 2: 95-5% solvent A2 and 5-95% solvent B2 (0-2 min), then 95% solvent B2 and 5% solvent A2 (hold for 1.8 min), where the percentage is the volume percentage of a particular solvent in the total solvent volume. Solvent A2: 10 mM ammonium bicarbonate aqueous solution; Solvent B2: acetonitrile.

[0534] All compounds of this invention can be separated by preparative high-performance liquid chromatography or rapid column chromatography.

[0535] Preparative high-performance liquid chromatography (prep-HPLC) was performed using a Shimadzu LC-20 preparative HPLC system. The chromatographic columns were either a Welch Xtimate C18 (21.2 × 250 mm, 10 μm) or a Welch Xtimate XB-C18 (30 × 250 mm, 10 μm). Alkaline conditions: Mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution; Mobile phase B: acetonitrile. Acidic conditions: Mobile phase A: 0.1% trifluoroacetic acid aqueous solution; Mobile phase B: acetonitrile. Detection wavelengths: 214 nm & 254 nm; Flow rate: 15.0 mL / min.

[0536] The fast column chromatography (Flash system / Cheetah™) used was an Agera Technologies MP200, with the accompanying normal phase separation column being a Flash column Silica-CS (25g, 40g, 80g, 120g or 330g) manufactured by Tianjin Bona Agera, and the elution system being ethyl acetate / petroleum ether or dichloromethane / methanol; the reversed phase separation column was a C18 reversed phase column (12g, 20g or 40g) manufactured by Changzhou Sante Technology, and the elution system being acetonitrile / trifluoroacetic acid aqueous solution or acetonitrile / ammonium bicarbonate aqueous solution.

[0537] The thin-layer silicone sheet (prep-TLC) is either Yantai Huanghai HSGF254 or Qingdao GF254 silicone sheet.

[0538] All compounds of this invention can be analyzed by ultra-high performance liquid chromatography, high performance liquid chromatography, or ultra-high performance combined phase chromatography.

[0539] Ultra-high performance liquid chromatography (UPLC) was performed using a Waters ACQUITY H-class column: Waters ACQUITY UPLC BEH Shield RP18 2.1mm*100mm, 1.7um, 5μm. Mobile phase A: 5mm potassium dihydrogen phosphate buffer, adjusted to pH 2.5 with phosphoric acid; mobile phase B: acetonitrile. Gradient elution was performed with mobile phase B from 10% to 40% for 5 minutes, then from 40% to 90% for 2 minutes, holding mobile phase B at 90% for 6 minutes, and finally from 90% to 10% for 2 minutes. Detection wavelength: 214nm; column temperature: 40℃; flow rate: 0.4mL / min.

[0540] High-performance liquid chromatography (HPLC) was performed using a Waters e2695,2498 UV / VISDetector; the column was a Welch Xtimate C18 4.6mm*150mm, 5μm; mobile phase A: acetonitrile; mobile phase B: 10mg potassium dihydrogen phosphate buffer, adjusted to pH 8.0 with ammonia. Gradient elution was performed: mobile phase B held at 90% for 5 minutes; B eluted from 90% to 70% for 5 minutes; B eluted from 70% to 40% for 4 minutes; B eluted from 40% to 15% for 12 minutes; B eluted from 15% to 90% for 2 minutes; and B held at 90% for 2 minutes. Detection wavelengths: 214 & 262 nm; column temperature: 35℃; flow rate: 1 mL / min.

[0541] The chiral analysis of the compounds of this invention was performed using an ultra-high performance combined phase chromatograph (UPCC) (Waters). The analytical column was (R,R)WHELK-O1 25*250mm, 5um (Regis). The flow rate was 3.0mL / min. The column temperature was 40℃. The injection volume was 3μL. The detection wavelength was 214 and / or 254nM. The mobile phase was CO2 / [MeOH (0.2% NH3 (7M in MeOH)] = 70 / 30.

[0542] Microwave reaction is used in the embodiments of the present invention. Initiator+Microwave System EU(356006) type microwave reactor.

[0543] Unless otherwise specified in the embodiments of the present invention, all reactions can be carried out under a nitrogen atmosphere or an argon atmosphere; in all post-reaction processing, the organic phase after extraction can be dried using anhydrous sodium sulfate or anhydrous magnesium sulfate.

[0544] A hydrogen or nitrogen atmosphere can be achieved by: 1) connecting a hydrogen or nitrogen balloon with a volume of about 1L to the reaction system; 2) continuously introducing hydrogen or nitrogen directly into the reaction system at atmospheric pressure; 3) replacing the hydrogen or nitrogen atmosphere with a sealing tube and then sealing it.

[0545] Synthesis of intermediates

[0546] Synthesis of bicyclo[4.2.0]oct-1(6),2,4-trien-2-amine(3A)

[0547] Step 1: Under ice bath conditions, a tetrahydrofuran solution (10M, 2.55mL) of the borane dimethyl sulfide complex was added to a tetrahydrofuran solution (50mL) of 2-(2,6-dibromophenyl)acetic acid (5g, 17mmol). After the addition was complete, the reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was cooled to 0°C, and water and dilute hydrochloric acid (1M) were slowly added to quench the reaction. The aqueous phase was extracted with ethyl acetate, and the organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 2-(2,6-dibromophenyl)ethane-1-ol (3.16g) as a pale yellow solid.

[0548] Step 2: A solution of 2-(2,6-dibromophenyl)ethyl-1-ol (3.2 g, 11.3 mmol), N-bromosuccinimide (2.2 g, 12.4 mmol), and triphenylphosphine (3.3 g, 12.4 mmol) in dichloromethane (60 mL) was stirred at room temperature for 18 hours. Tert-butanol peroxide (1 mL) was added to the reaction mixture, and stirring continued for 2 hours. The reaction was then quenched with a saturated aqueous solution of sodium bisulfite. The aqueous phase was extracted with dichloromethane, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1) to give 1,3-dibromo-2-(2-bromoethyl)benzene (3.6 g) as a pale yellow solid.

[0549] Step 3: At -70°C, a tetrahydrofuran solution (2.5 M, 0.63 mL) of n-butyllithium was slowly added dropwise to a tetrahydrofuran solution of 1,3-dibromo-2-(2-bromoethyl)benzene (600 mg, 1.75 mmol) (3 mL). The reaction system was stirred at this temperature for 2 hours. The reaction solution was poured into a saturated ammonium chloride aqueous solution, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 20 / 1) to give 2-bromobicyclo[4.2.0]octyl-1(6),2,4-triene (280 mg) as a pale yellow oily liquid.

[0550] Step 4: A solution of 2-bromobicyclo[4.2.0]oct-1(6),2,4-triene (280 mg, 1.5 mmol), tert-butyl carbamate (269 mg, 2.3 mmol), palladium acetate (17 mg, 0.08 mmol), cesium carbonate (997 mg, 3.1 mmol), and X-Phos (73 mg, 0.15 mmol) in 1,4-dioxane (5 mL) was purged three times with nitrogen, heated under reflux and stirred for 1.5 hours, cooled, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain bicyclo[4.2.0]oct-1(6),2,4-trien-2-ylcarbamate (185 mg) as a yellow oil. m / z: [M+Na] +242.0.

[0551] Step 5: Add 1.5 mL of trifluoroacetic acid to a 3 mL solution of bicyclo[4.2.0]octyl-1(6),2,4-trien-2-ylcarbamate (180 mg, 0.82 mmol) in dichloromethane. Stir the reaction mixture at room temperature for 1.5 hours and concentrate under reduced pressure. Dilute the residue with dichloromethane, wash with saturated sodium bicarbonate solution, separate the organic phase, and concentrate under reduced pressure to obtain bicyclo[4.2.0]octyl-1(6),2,4-trien-2-amine (3A, 91 mg) as a yellow solid. m / z: [M+H] + 120.2.

[0552] Synthesis of 2-((trifluoromethyl)thio)pyridine-3-amine (4A)

[0553] Step 1: Under ice bath conditions, sodium hydroxide (60%, 5.8 g, 145 mmol) was added to 2-bromo-3-aminopyridine (10 g, 57.8 mmol) in N,N-dimethylformamide (30 mL). The reaction system was stirred at 0 °C for 0.5 hours, then p-methoxybenzyl chloride (22.6 g, 145 mmol) was added, and the reaction system was stirred at 0 °C for another 2 hours. The reaction was quenched with saturated ammonium chloride aqueous solution. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give 2-bromo-N,N-di(4-methoxybenzyl)pyridine-3-amine (20 g) as a yellow oil. m / z: [M+H] + 413.0.

[0554] Step 2: 2-Bromo-N,N-Di(4-methoxybenzyl)pyridine-3-amine (3 g, 7.3 mmol), silver trifluoromethanethiol (2 g, 9.6 mmol), 2,2'-bipyridine (1.7 g, 10.9 mmol), cuprous iodide (1.4 g, 7.3 mmol), and acetonitrile (30 mL) were added to a sealed tube. After purging with nitrogen, the tube was sealed and stirred overnight at 110 °C. The reaction solution was diluted with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give N,N-Di(4-methoxybenzyl)-2-((trifluoromethyl)thio)pyridine-3-amine (2.3 g) as a pale yellow oil. m / z: [M+H] + 435.0.

[0555] Step 3: Add 3 mL of trifluoroacetic acid to a solution of N,N-bis(4-methoxybenzyl)-2-((trifluoromethyl)thio)pyridine-3-amine (2.3 g, 5.3 mmol) in dichloromethane (3 mL). Stir the reaction mixture at 50 °C for 1 hour and concentrate under reduced pressure. Dilute the residue with dichloromethane, wash with saturated sodium bicarbonate aqueous solution, separate the organic phase, and concentrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give 2-((trifluoromethyl)thio)pyridine-3-amine (4A, 1 g) as a yellow solid. m / z: [M+H] + 195.0.

[0556] Synthesis of 7,7-difluorobicyclo[4.2.0]oct-1(6),2,4-trien-2-amine(5A)

[0557] Step 1: A solution of 2-(2,6-dibromophenyl)acetic acid (5 g, 17 mmol), N,O-dimethylhydroxylamine hydrochloride (2.5 g, 25.5 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.9 g, 25.5 mmol), and 4-dimethylaminopyridine (6.2 g, 51 mmol) in dichloromethane (50 mL) was stirred at room temperature for 5 hours. The reaction was quenched with water, and the aqueous phase was extracted with dichloromethane. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give 2-(2,6-dibromophenyl)-N-methoxy-N-methylacetamide (5.5 g) as a white solid. m / z: [M+H] + 337.8.

[0558] Step 2: At -70°C, a tetrahydrofuran solution (1M, 25mL) of tert-butyllithium was added to a tetrahydrofuran solution of 2-(2,6-dibromophenyl)-N-methoxy-N-methylacetamide (5.5g, 16.3mmol) (50mL). The reaction mixture was stirred at this temperature for 5 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution. The aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give 2-bromobicyclo[4.2.0]oct-1(6),2,4-trien-7-one (1.6g) as a white solid. 1 H NMR (400MHz, CDCl3): δ7.67-7.61(m,1H),7.32-7.27(m,2H),3.97(s,2H).

[0559] Step 3: 2-Bromobicyclo[4.2.0]oct-1(6),2,4-trien-7-one (500 mg, 2.54 mmol) and bis(2-methoxyethyl)aminosulfur trifluoride (BAST) (6 g, 27 mmol) were added to a microwave tube and stirred at 70°C for 2 hours under microwave conditions. The reaction mixture was then added dropwise to a saturated sodium bicarbonate aqueous solution under ice-water bath conditions. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 2-bromo-7,7-difluorobicyclo[4.2.0]oct-1(6),2,4-triene (0.35 g) as a pale yellow oil.

[0560] Step 4: A solution of 2-bromo-7,7-difluorobicyclo[4.2.0]oct-1(6),2,4-triene (350 mg, 1.6 mmol), tert-butyl carbamate (280 mg, 2.4 mmol), palladium acetate (72 mg, 0.32 mmol), cesium carbonate (1 g, 3.2 mmol), and X-Phos (310 mg, 0.64 mmol) in acetonitrile (2 mL) was placed in a microwave-safe tube and stirred at 95 °C for 1 hour under microwave conditions. The reaction solution was diluted with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to obtain (7,7-difluorobicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)tert-butyl carbamate (350 mg) as a yellow solid. m / z: [M+Na] + 278.0.

[0561] Step 5: Add 0.5 mL of trifluoroacetic acid to a solution of (7,7-difluorobicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)carbamate tert-butyl in dichloromethane (1 mL). Stir the reaction mixture at room temperature for 1 hour and concentrate under reduced pressure. Dilute the residue with dichloromethane, wash with saturated sodium bicarbonate solution, separate the organic phase, and concentrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to obtain 7,7-difluorobicyclo[4.2.0]oct-1(6),2,4-trien-2-amine (5A, 220 mg) as a yellow oil. m / z: [M+H] + 156.0.

[0562] Synthesis of 2-(1-fluorocyclopropyl)aniline (6A)

[0563] Step 1: Benzyl bromide (25 g, 146 mmol) and potassium carbonate (20.6 g, 149 mmol) were added sequentially to a mixed solution of methyl 2-aminobenzoate (7.5 g, 49.6 mmol) in methanol (25 mL) and water (25 mL). The reaction system was stirred at 80 °C for 10 hours. The solid was removed by filtration, and the filtrate was extracted with water and ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give methyl 2-(dibenzylamino)benzoate (5.3 g) as a yellow oil. m / z: [M+H] + 332.2.

[0564] Step 2: A 1M, 47.6 mL solution of magnesium ethyl bromide in tetrahydrofuran was slowly added to a 50 mL solution of methyl 2-(dibenzylamino)benzoate (5.26 g, 15.9 mmol) and tetraisopropyl titanate (6.77 g, 23.8 mmol) in tetrahydrofuran. The reaction mixture was heated under reflux and stirred for 2 hours. The reaction was quenched with saturated ammonium chloride aqueous solution. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 1-(2-(dibenzylamino)phenyl)cycloprop-1-ol (1.1 g) as a yellow oil. m / z: [M+H] + 330.0.

[0565] Step 3: Under ice bath conditions, BAST (1.1 g, 5.0 mmol) was added to a solution of 1-(2-(dibenzylamino)phenyl)cycloprop-1-ol (1.1 g, 3.3 mmol) in 10 mL of dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water, and the aqueous phase was extracted with dichloromethane. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give N,N-dibenzyl-2-(1-fluorocyclopropyl)aniline (800 mg) as a yellow oil. m / z: [M+H] + 332.0.

[0566] Step 4: Palladium on carbon (10%, 0.2 g) was added to a methanol (10 mL) solution of N,N-dibenzyl-2-(1-fluorocyclopropyl)aniline (800 mg, 2.4 mmol). After purging the reaction system with hydrogen, the mixture was stirred at room temperature for 8 hours under a hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether / ethyl acetate = 5 / 3) to give 2-(1-fluorocyclopropyl)aniline (6A, 200 mg) as a yellow oil. m / z: [M+H] + 152.0.

[0567] Synthesis of bicyclo[4.2.0]octyl-1(6),2,4-trien-7,7,8,8-d4-2-amine (14A)

[0568] Step 1: Potassium hydroxide (7.6 g, 136 mmol) was added to a mixture of 2-(2,6-dibromophenyl)acetic acid (10 g, 34 mmol) and heavy water (60 mL). The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was cooled to 0 °C, and hydrochloric acid (6 M) was slowly added to adjust the pH to approximately 2. The aqueous phase was extracted with ethyl acetate, and the organic layers were combined and concentrated under reduced pressure to obtain 2-(2,6-dibromophenyl)acetic acid-2,2-d2 (10 g) as a white solid. 1 H NMR (400MHz, D2O): δ7.49 (d, J = 8.0 Hz, 2H), 6.93 (dd, J = 10.2, 5.9 Hz, 1H).

[0569] Step 2: Add N,N-dimethylformamide (0.1 mL) and oxaloyl chloride (4.12 g, 32.4 mmol) to a solution of 2-(2,6-dibromophenyl)acetic acid-2,2-d2 (8 g, 27.0 mmol) in dichloromethane (100 mL). Stir the reaction mixture at room temperature for 2 hours. Add methanol (3 mL) to the reaction mixture and continue stirring for 0.5 hours. Concentrate the reaction mixture under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain methyl 2-(2,6-dibromophenyl)acetic acid ester-d2 (8.2 g) as a colorless liquid. 1 H NMR (400MHz, CDCl3): δ7.47 (d, J=8.0Hz, 2H), 7.00-6.88 (m, 1H), 3.66 (s, 3H).

[0570] Step 3: At -20°C, lithium tetradeuterium aluminum oxide (0.4 g, 9.67 mmol) was added in portions to a tetrahydrofuran (30 mL) solution of methyl 2-(2,6-dibromophenyl)acetate-d2 (3.0 g, 9.67 mmol) and stirred for 4 hours. The reaction was quenched with heavy water (3 mL), followed by the addition of ethyl acetate (50 mL) and stirring for another 0.5 hours. The mixture was then filtered and washed. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 2-(2,6-dibromophenyl)ethyl-1,1,2,2-d4-1-ol (1.7 g) as a white solid. 1 H NMR (400MHz, CDCl3): δ7.45 (d, J=8.0Hz, 2H), 6.94-6.82 (m, 1H).

[0571] Step 4: Triphenylphosphine (1.9 g, 7.2 mmol) and N-bromosuccinimide (1.4 g, 7.8 mmol) were added sequentially to a solution of 2-(2,6-dibromophenyl)ethyl-1,1,2,2-d4-1-ol (1.7 g, 6.0 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 24 hours, and then rapidly filtered through a thin silica gel filter. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 19 / 1) to give 1,3-dibromo-2-(2-bromoethyl-1,1,2,2-d4)benzene (1.8 g) as a pale yellow solid. 1 H NMR (400MHz, CDCl3): δ7.45 (d, J = 8.0 Hz, 2H), 6.91 (t, J = 8.0 Hz, 1H).

[0572] Step 5: At -70°C, a tetrahydrofuran solution (1.6 M, 3 mL) of n-butyllithium was slowly added dropwise to a tetrahydrofuran solution (10 mL) of 1,3-dibromo-2-(2-bromoethyl-1,1,2,2-d4)benzene (1.8 g, 5.2 mmol). The reaction system was stirred at this temperature for 2 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 to 9 / 1) to give 2-bromobicyclo[4.2.0]octyl-1(6),2,4-triene-7,7,8,8-d4 (750 mg) as a colorless liquid. 1 H NMR (400MHz, CDCl3): δ7.29 (t, J=5.2Hz, 1H), 7.08 (dd, J=8.0, 7.3Hz, 1H), 7.00 (d, J=7.2Hz, 1H).

[0573] Step 6: A solution of 2-bromobicyclo[4.2.0]oct-1(6),2,4-trien-7,7,8,8-d4 (500 mg, 2.67 mmol), tert-butyl carbamate (465 mg, 4.0 mmol), palladium acetate (30 mg, 0.13 mmol), cesium carbonate (1.73 mg, 5.34 mmol), and X-Phos (127 mg, 0.27 mmol) in 1,4-dioxane (6 mL) was purged three times with nitrogen, heated under reflux and stirred for 2 hours, cooled, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give tert-butyl (bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl-7,7,8,8-d4) carbamate (420 mg) as a white solid. m / z: [M+H-Bu] + 168.0. 1H NMR (400MHz, CDCl3): δ7.31-7.26 (m, 1H), 7.17-7.11 (m, 1H), 6.77 (d, J = 7.2Hz, 1H), 1.52 (s, 9H).

[0574] Step 7: 280 mg (1.25 mmol) of tert-butyl (bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl-7,7,8,8-d4) carbamate was dissolved in dichloromethane (4 mL), and then trifluoroacetic acid (1 mL) was added. After stirring at room temperature for 2 hours, the solvent was removed by rotary evaporation, and the mixture was neutralized with a saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure to obtain bicyclo[4.2.0]oct-1(6),2,4-trien-7,7,8,8-d4-2-amine (14A, 152 mg) as a pale yellow oil. m / z: [M+H] + 124.0.

[0575] Synthesis of 2-chlorophenyl-3-d-amine (15A)

[0576] Step 1: Under ice bath conditions, sodium hydroxide (60%, 2.4g, 60.6mmol) was added to a solution of 3-bromo-2-chloroaniline (5g, 24.2mmol) in N,N-dimethylformamide (50mL). After stirring at room temperature for 0.5 hours, p-methoxybenzyl chloride (9.5g, 60.1mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 2 hours. The reaction was quenched with saturated ammonium chloride aqueous solution. The aqueous phase was extracted with ethyl acetate, the organic phases were combined and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether / ethyl acetate = 100–3 / 1) to obtain 3-bromo-2-chloro-N,N-bis(4-methoxybenzyl)aniline (10g) as a yellow oil. m / z: [M+H] + 446.2.

[0577] Step 2: A mixed solution of 3-bromo-2-chloro-N,N-bis(4-methoxybenzyl)aniline (400 mg, 0.9 mmol), palladium acetate (20 mg, 0.09 mmol), n-butyldi(1-adamantyl)phosphine (65 mg, 0.18 mmol), potassium phosphate (290 mg, 1.35 mmol), toluene (4 mL), and deuterated methanol-d4 (1 mL) was placed in a microwave tube and microwaved at 85 °C for 1 hour. The reaction was quenched with water, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether / ethyl acetate = 100–2 / 1) to give 2-chloro-N,N-bis(4-methoxybenzyl)aniline-3-d (270 mg) as a dark yellow oil. m / z: [M+H] + 369.2.

[0578] Step 3: A solution of 2-chloro-N,N-bis(4-methoxybenzyl)aniline-3-d (270 mg, 0.73 mmol) in trifluoroacetic acid (3 mL) was stirred at 70 °C for 2 hours, concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The pH was adjusted to neutral with saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure to obtain 2-chlorophenyl-3-d-amine (15A, 100 mg) as a yellow oil. m / z: [M+H] + 129.2.

[0579] Synthesis of 2-chlorophenyl-6-d-amine (13A)

[0580] Using the synthetic method for 2-chlorophenyl-3-d-amine (15A), 2-chlorophenyl-6-d-amine (13A) was obtained by reacting 2-bromo-6-chloroaniline. It was a colorless oil. m / z: [M+H] + 129.2.

[0581] Synthesis of 2-chlorophenyl-4-d-amine (16A)

[0582] Using the synthetic method for 2-chlorophenyl-3-d-amine (15A), 2-chlorophenyl-4-d-amine (16A) was obtained by reacting 4-bromo-2-chloroaniline. It was a colorless oil. m / z: [M+H] + 129.2.

[0583] Synthesis of bicyclo[4.2.0]oct-1(6),2,4-trien-5-d-2-amine (17A)

[0584] Step 1: The toluene (36 mL) solution of 2,5-dibromobicyclo[4.2.0]octyl-1(6),2,4-triene (2 g, 7.64 mmol), benzophenone imine (1.66 g, 9.17 mmol), tris(dibenzylideneacetone)dipalladium (350 mg, 0.38 mmol), sodium tert-butoxide (2.2 g, 22.9 mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (480 mg, 0.76 mmol) was purged with nitrogen three times, heated to 80 °C, and stirred for 20 hours. After cooling the reaction solution to room temperature, it was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (ethyl acetate / petroleum ether = 1 / 10 to 1 / 5) to obtain N-(5-bromobicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-1,1-diphenylformamidin (1.2 g) as a yellow oil. m / z:[M+H] + 362.0.

[0585] Step 2: A solution of N,N-dimethylformamide (5 mL) containing N-(5-bromobicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-1,1-diphenylformamide (500 mg, 1.38 mmol), deuterated formic acid (330 mg, 6.9 mmol), triethylamine (1.4 g, 13.8 mmol), and tetra(triphenylphosphine)palladium (160 mg, 0.14 mmol) was purged with nitrogen and heated to 100 °C and stirred for 3 hours. The reaction was quenched with water, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether = 1 / 10 to 1 / 3) to obtain N-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl-5-d)-1,1-diphenylformamide (300 mg) as a light yellow oil. m / z:[M+H] + 285.2.

[0586] Step 3: Add concentrated hydrochloric acid (0.5 mL) to a tetrahydrofuran (3 mL) solution of N-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl-5-d)-1,1-dibenzomidine (300 mg, 1.1 mmol) and stir at room temperature for 3 hours. Add water (3 mL) to the reaction solution, adjust the pH of the reaction solution to 8-9 with ammonia, extract the aqueous phase with ethyl acetate, combine the organic phases and concentrate under reduced pressure. The residue is purified by Flash column chromatography (ethyl acetate / petroleum ether = 1 / 10-1 / 3) to obtain bicyclo[4.2.0]oct-1(6),2,4-trien-5-d-2-amine (17A, 100 mg) as a light yellow oil. m / z: [M+H] + 121.2.

[0587] Compound Synthesis

[0588] Example 1: Synthesis of 4-amino-1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2(1H)-thione (compound 1)

[0589] Step 1: Under ice bath conditions, sodium hydroxide (60%, 1.0 g, 25.0 mmol) was added to a solution of 2-chloro-6-(trifluoromethyl)nicotinamide (1-1, 1.0 g, 4.45 mmol) in N,N-dimethylformamide (20 mL). After the addition was complete, the reaction system was stirred at this temperature for 15 minutes. Benzene 1-chloro-2-isothiocyanate (1A, 1.0 g, 5.9 mmol) was added, and the reaction solution was brought to room temperature and stirred for 30 minutes. The reaction was quenched with a saturated aqueous solution of ammonium chloride. The aqueous phase was extracted with ethyl acetate, and the organic phase was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0–1 / 10) to give 1-(2-chlorophenyl)-2-thio-7-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (1-2, 0.7 g, yield: 44%) as an off-white solid. m / z[M+H] + 358.0; 1 H NMR (400MHz, DMSO-d6): δ13.41 (s, 1H), 8.71 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.72-7.60 (m, 1H), 7.53 (d, J = 3.0 Hz, 3H).

[0590] Step 2: To a solution of 1-(2-chlorophenyl)-2-thio-7-(trifluoromethyl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (1-2, 500 mg, 1.4 mmol) in acetonitrile (50 mL), N,N-diisopropylethylamine (0.89 g, 6.89 mmol) and phosphorus oxychloride (0.54 g, 3.54 mmol) were added sequentially. The reaction mixture was stirred at 85 °C for 30 minutes. After cooling the reaction system to room temperature, it was concentrated under reduced pressure. The residue was mixed in tetrahydrofuran (50 mL), and ammonia-methanol solution (7 M, 15 mL) was added, and the mixture was stirred for 15 minutes. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / ethyl acetate = 0–1 / 10), then slurried with methyl tert-butyl ether, filtered, and the filter cake was dried under vacuum to give compound 1 (150 mg, yield: 30%) as a yellow solid. m / z[M+H] + 357.0; 1 H NMR (400MHz, DMSO-d6): δ9.09 (s, 1H), 8.94 (s, 1H), 8.87 (d, J = 8.0Hz, 1H), 7.90 (d, J = 8.0Hz, 1H), 7.64-7.55 (m, 1H), 7.50-7.38 (m, 3H).

[0591] Example 2: Synthesis of 4-amino-1-(2-chloro-6-fluorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2(1H)-thione (compound 2)

[0592] Compound 2, a yellow solid, was obtained by reacting benzene (2A) with 1-chloro-3-fluoro-2-isothiocyanate using the same method as compound 1. (m / z[M+H]) + 375.0; 1 H NMR (400MHz, DMSO-d6): 9.25 (s, 1H), 9.11 (s, 1H), 8.92 (d, J = 8.0Hz, 1H), 7.97 (d, J = 8.0Hz, 1H), 7.59-7.49 (m, 2H), 7.45-7.39 (m, 1H).

[0593] Example 3: Synthesis of 4-amino-1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one (compound 3)

[0594] Step 1: Oxaloyl chloride (225 mg, 1.78 mmol) was added to a solution of 2-chloro-6-(trifluoromethyl)nicotinamide (1-1, 250 mg, 1.12 mmol) in 1,2-dichloroethane (5 mL). The reaction mixture was refluxed and stirred at 85 °C for 2 hours, then concentrated under reduced pressure. A mixed solution of bicyclo[4.2.0]octyl-1(6),2,4-trien-2-amine (3A, 90 mg, 0.76 mmol) in 1,2-dichloroethane (6 mL) and tetrahydrofuran (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give N-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-ylcarbamoyl)-2-chloro-6-(trifluoromethyl)nicotinamide (3-1, 160 mg, yield: 57%) as an off-white solid. m / z [M+H] + 370.0.

[0595] Step 2: At -70°C, a tetrahydrofuran solution (1 M, 1.1 mL) of lithium bis(trimethylsilylamino)carbamoyl (15 mL) in N-(bicyclo[4.2.0]octyl-1(6),2,4-trien-2-ylcarbamoyl)-2-chloro-6-(trifluoromethyl)nicotinamide (3-1, 160 mg, 0.43 mmol) was added. The reaction system was brought to room temperature and stirred for 1 hour. The reaction was quenched by adding ice-cold saturated ammonium chloride aqueous solution. The resulting mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (3-2, 40 mg, yield: 28%) as an off-white solid. m / z[M+H] + 334.0.

[0596] Step 3: To a solution of 1-(bicyclo[4.2.0]octyl-1(6),2,4-trien-2-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (3-2, 40 mg, 0.12 mmol) in acetonitrile (5 mL), N,N-diisopropylethylamine (78 mg, 0.6 mmol) and phosphorus oxychloride (55 mg, 0.36 mmol) were added sequentially. The reaction mixture was stirred at 85 °C for 15 minutes. The reaction mixture was concentrated under reduced pressure. The residue was mixed in tetrahydrofuran (5 mL), and ammonia-methanol solution (7 M, 1.5 mL) was added, followed by stirring for 30 minutes. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (elution conditions: 15%–75% acetonitrile in 10 mM ammonium bicarbonate aqueous solution, elution time 20 min) to give compound 3 (3.1 mg, yield: 8%) as a white solid. m / z [M+H] + 333.0; 1 H NMR (400MHz, DMSO-d6): δ8.78(d,J=8.2Hz,1H),8.53-8.41(m,2H),7.78(d,J=8.2Hz, 1H),7.30-7.24(m,1H),7.10(d,J=7.8Hz,2H),3.19-3.13(m,2H),2.95-2.87(m,2H).

[0597] Chirality analysis of compound 3 was performed (UPCC (Waters), chiral column OX 4.6×100mm, 5um (Daicel), mobile phase CO2 / MeOH [(0.2% NH3 (7M in MeOH)] = 60 / 40, flow rate: 3.0 mL / min, pressure: 2000 psi, column temperature: 40℃). The results showed that compound 3 was a single peak, did not contain the blocked isomer, and the peak elution time was 1.924 min.

[0598] Example 4: Synthesis of 4-amino-7-(trifluoromethyl)-1-(2-((trifluoromethyl)thio)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (compound 4)

[0599] Using the same synthetic method as compound 3, compound 4 was obtained as a white solid by reacting it with 2-((trifluoromethyl)thio)pyridine-3-amine (4A). m / z[M+H] + 408.0; 1 H NMR (400MHz, CD3OD): δ8.76 (d, J = 8.0 Hz, 1H), 8.73-8.70 (m, 1H), 7.96-7.90 (m, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.68-7.64 (m, 1H).

[0600] Example 5: Synthesis of 4-amino-1-(7,7-difluorobicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one (compound 5)

[0601] Compound 5 was obtained as a white solid by reacting it with 7,7-difluorobicyclo[4.2.0]oct-1(6),2,4-trien-2-amine(5A) using the synthetic method for compound 3. m / z[M+H] + 369.0; 1 H NMR (400MHz, CD3OD): δ8.70 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.56-7.48 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 3.63-3.55 (m, 2H).

[0602] Example 6: Synthesis of 4-amino-1-(2-(1-fluorocyclopropyl)phenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2(1H)-one (compound 6)

[0603] Compound 6 was obtained as a white solid by reacting 2-(1-fluorocyclopropyl)aniline (6A) with the synthetic method used for compound 3. m / z[M+H] + 365.0; 1 H NMR (400MHz, CD3OD): 8.69 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.60-7.48 (m, 3H), 7.33 (d, J = 8.0 Hz, 1H), 1.12-0.99 (m, 2H), 0.95-0.74 (m, 2H).

[0604] Example 7: Synthesis of 1-(2-chlorophenyl)-4-(hydroxyamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2(1H)-one (compound 7)

[0605] Step 1: Oxaloyl chloride (12 g, 94.5 mmol) was added to a solution of 2-chloro-6-(trifluoromethyl)nicotinamide (1-1, 14 g, 62.3 mmol) in 1,2-dichloroethane (300 mL). The reaction mixture was refluxed and stirred at 85 °C for 2 hours, then concentrated under reduced pressure. A solution of 2-chloroaniline (7A, 14 g, 110 mmol) in 1,2-dichloroethane (300 mL) was added. The reaction mixture was stirred at room temperature for another 2 hours, then concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 2-chloro-N-((2-chlorophenyl)carbamoyl)-6-(trifluoromethyl)nicotinamide (7-1, 19 g, yield: 81%) as an off-white solid. m / z [M+H] + 378.0.

[0606] Step 2: At -70°C, a tetrahydrofuran solution (1M, 82mL) of lithium bis(trimethylsilylamino)carbamoyl (7-1, 9.2g, 24.3mmol) in nicotinamide (1L) was added. The reaction mixture was stirred at 55°C for 1 hour, and the reaction was quenched with ice-cold saturated ammonium chloride solution. The resulting mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (7-2, 5.5g, yield: 66%) as a white solid. m / z [M+H] + 342.0.

[0607] Step 3: To a solution of 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (7-2, 200 mg, 0.59 mmol) in acetonitrile (20 mL), N,N-diisopropylethylamine (0.38 g, 2.95 mmol) and phosphorus oxychloride (0.19 g, 1.22 mmol) were added. The reaction mixture was stirred at 85 °C for 30 min. The mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 mL). Freshly prepared hydroxylamine methanol solution (5 M, 0.5 mL) was added, and the mixture was stirred for 15 min. The residue was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 7 (42 mg, yield: 20%) as a yellowish-brown solid. m / z [M+H] + 357.0; 1 H NMR (400MHz, DMSO-d6): 11.17 (s, 1H), 10.64 (s, 1H), 8.42 (d, J = 8.0Hz, 1H), 7.74-7.42 (m, 5H).

[0608] Example 8: Synthesis of 1-(2-chlorophenyl)-4-(methoxyamino)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidine-2(1H)-one (compound 8)

[0609] To a solution of 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (7-2, 200 mg, 0.59 mmol) in acetonitrile (20 mL), N,N-diisopropylethylamine (0.38 g, 2.95 mmol) and phosphorus oxychloride (0.19 g, 1.22 mmol) were added, and the reaction mixture was stirred at 85 °C for 30 min. The mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 mL). Freshly prepared methoxyhydroxylamine methanol solution (5 M, 0.5 mL) was added, and the mixture was stirred for 15 min. The residue was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 8 (105 mg, yield: 48%) as a yellowish-brown solid. m / z [M+H] + 371.0; 1 H NMR (400MHz, DMSO-d6): 10.96 (s, 1H), 8.51-8.38 (m, 1H), 7.67-7.47 (m, 5H), 3.92 (s, 3H).

[0610] Example 9: Synthesis of 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-4-((2,2-difluoroethyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one (compound 9)

[0611] To a solution of 1-(bicyclo[4.2.0]octyl-1(6),2,4-trien-2-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2,4(1H,3H)-dione (3-2, 50 mg, 0.15 mmol) in acetonitrile (3 mL), N,N-diisopropylethylamine (97 mg, 0.75 mmol) and phosphorus oxychloride (69 mg, 0.45 mmol) were added sequentially. The reaction mixture was stirred at 85 °C for 15 min. The reaction mixture was concentrated under reduced pressure. The residue was mixed in tetrahydrofuran (1 mL) and slowly added dropwise to a solution of 2,2-difluoroethylamine (36.5 mg, 0.45 mmol) in tetrahydrofuran (3 mL). The reaction mixture was stirred at room temperature for 30 min. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (elution conditions: 15%–65% acetonitrile in 10 mM ammonium bicarbonate aqueous solution, elution time 20 min) to give compound 9 (3.0 mg, yield: 5%) as a white solid. m / z [M+H] + 397.0.

[0612] Example 10: Synthesis of 4-amino-1-(2-chloropyridin-3-yl)-7-(trifluoromethyl)quinazolin-2(1H)-thione (compound 10)

[0613] Step 1: To a solution of ethyl 2-iodo-4-(trifluoromethyl)benzoate (10⁻¹, 1.04 g, 3.03 mmol) in 1,4-dioxane (15 mL), 2-chloropyridin-3-amine (10A, 410 mg, 3.2 mmol), X-Phos (290 mg, 0.6 mmol), palladium acetate (68 mg, 0.3 mmol), and cesium carbonate (2.95 g, 9.1 mmol) were added. The reaction mixture was refluxed and stirred overnight under nitrogen atmosphere. The mixture was diluted with ethyl acetate, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give ethyl 2-((2-chloropyridin-3-yl)amino)-4-(trifluoromethyl)benzoate (10⁻², 120 mg, yield: 12%) as an off-white solid. m / z [M+H] + 345.0.

[0614] Step 2: A solution of ethyl 2-((2-chloropyridin-3-yl)amino)-4-(trifluoromethyl)benzoate (10⁻², 120 mg, 0.35 mmol) in ammonia-methanol (7 M, 5 mL) was stirred overnight at 65 °C in a sealed tube. The reaction solution was concentrated under reduced pressure to obtain crude 2-((2-chloropyridin-3-yl)amino)-4-(trifluoromethyl)benzamide (10⁻³, 120 mg). m / z [M+H] + 316.0.

[0615] Step 3: Sodium hydroxide (76 mg, 60%, 1.9 mmol) and N,N'-thiocarbonyldiimidazole (200 mg, 1.14 mmol) were added sequentially to a tetrahydrofuran (5 mL) solution of 2-((2-chloropyridin-3-yl)amino)-4-(trifluoromethyl)benzamide (10⁻³, 120 mg, 0.38 mmol). The reaction mixture was stirred at room temperature for 1 hour, and the reaction was quenched with 2 drops of water. The reaction system was directly concentrated under reduced pressure, and the residue was purified by prep-TLC (petroleum ether / ethyl acetate = 4 / 1) to give 1-(2-chloropyridin-3-yl)-2-thio-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one (10⁻⁴, 115 mg, two-step yield: 85%) as a yellow solid. m / z [M+H] + 358.0.

[0616] Step 4: N,N-diisopropylethylamine (0.41 g, 3.2 mmol) and phosphorus oxychloride (0.2 g, 1.28 mmol) were added to a solution of 1-(2-chloropyridin-3-yl)-2-thio-7-(trifluoromethyl)-2,3-dihydroquinazolin-4(1H)-one (10⁻⁴, 115 mg, 0.32 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at 85 °C for 30 min. The mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). Ammonia-methanol solution (7 M, 2 mL) was added, and the mixture was stirred for 30 min. The residue was concentrated under reduced pressure, and the residue was purified by prep-HPLC (elution conditions: 15%–75% acetonitrile in 10 mM ammonium bicarbonate aqueous solution, elution time 20 min) to give compound 10 (13 mg, yield: 11%) as a yellow solid. m / z [M+H] + 357.0.

[0617] Example 11: Synthesis of 4-amino-1-(2-chlorophenyl)-7-((trifluoromethyl)thio)pyrido[2,3-d]pyrimidine-2(1H)-one (compound 11)

[0618] Step 1: To a solution of 2,6-dibromo-3-pyridinecarboxylic acid (11-1, 2.2 g, 7.8 mmol) in N,N-dimethylformamide (20 mL), 4-methoxybenzylamine (11-2, 1.3 g, 9.4 mmol), N,N-diisopropylethylamine (3.0 g, 23.5 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (4.5 g, 11.8 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water, filtered, and the filter cake was dried under vacuum to obtain 2,6-dibromo-N-(4-methoxybenzyl)nicotinamide (11-3, 1.5 g, yield: 48%) as an off-white solid. m / z[M+H] + 399.1.

[0619] Step 2: Sodium hydroxide (0.45 g, 11.3 mmol, 60%) was added to a solution of 2,6-dibromo-N-(4-methoxybenzyl)nicotinamide (11-3, 1.5 g, 3.75 mmol) in N,N-dimethylformamide (15 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then 2-chlorophenyl isocyanate (11A, 690 mg, 4.5 mmol) was added. The mixture was stirred at room temperature for 2 hours. Ice was added until a solid precipitated. The solid was filtered, and the filter cake was dried under vacuum to give 7-bromo-1-(2-chlorophenyl)-3-(4-methoxybenzyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (11-4, 1.4 g, yield: 79%) as a white solid. m / z[M+H] + 472.0.

[0620] Step 3: Add 7-bromo-1-(2-chlorophenyl)-3-(4-methoxybenzyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (11-4, 200 mg, 0.42 mmol), silver trifluoromethanethiol (116 mg, 0.55 mmol), 2,2'-bipyridine (98 mg, 0.63 mmol), cuprous iodide (80 mg, 0.42 mmol), and acetonitrile (10 mL) to a sealed tube. After purging with nitrogen, stir overnight at 110 °C. Dilute the reaction solution with ethyl acetate, filter, and concentrate the filtrate under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether / ethyl acetate = 1 / 4) to give 1-(2-chlorophenyl)-3-(4-methoxybenzyl)-7-((trifluoromethyl)thio)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (11-5, 160 mg, yield: 77%) as a pale yellow solid. m / z[M+H] + 494.0.

[0621] Step 4: A solution of 1-(2-chlorophenyl)-3-(4-methoxybenzyl)-7-((trifluoromethyl)thio)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (11-5, 160 mg, 0.32 mmol) and cerium ammonium nitrate (530 mg, 0.96 mmol) in water (3 mL) and acetonitrile (10 mL) was stirred at 90 °C for 2 hours. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether / ethyl acetate = 1 / 4) to give 1-(2-chlorophenyl)-7-((trifluoromethyl)thio)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (11-6, 50 mg, yield: 41%) as a pale yellow solid. m / z [M+H] + 374.0.

[0622] Step 5: Add N,N-diisopropylethylamine (21 mg, 0.16 mmol) and phosphorus oxychloride (25 mg, 0.16 mmol) to a solution of 1-(2-chlorophenyl)-7-((trifluoromethyl)thio)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (11-6, 20 mg, 0.05 mmol) in acetonitrile (5 mL). Stir the reaction mixture at 90 °C for 1 hour. Concentrate under reduced pressure, dissolve the residue in tetrahydrofuran (2 mL), add ammonia-methanol solution (7 M, 2 mL), and stir for 20 minutes. Concentrate under reduced pressure, and purify the residue by prep-HPLC (elution conditions: 15%–55% acetonitrile in 10 mM ammonium bicarbonate aqueous solution, elution time 20 minutes) to give compound 11 (5.2 mg, yield: 26%) as a white solid. m / z [M+H] + 373.0.

[0623] Example 12: Synthesis of 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-4-((methyl-d3)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one (compound 12)

[0624] A solution of 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2,4(1H,3H)-dione (3-2, 20 mg, 0.06 mmol), N,N-diisopropylethylamine (40 mg, 0.3 mmol), and phosphorus oxychloride (23 mg, 0.15 mmol) in acetonitrile (5 mL) was refluxed and stirred for 0.5 hours. The mixture was cooled and concentrated under reduced pressure. Tetrahydrofuran (3 mL) was added to the residue. Methyl-d3-amine (10.2 mg, 0.3 mmol) was added dropwise to the above solution under ice bath conditions. The reaction mixture was stirred at room temperature for 2 hours. The residue was concentrated under reduced pressure and purified by prep-HPLC (elution conditions: 15%–70% acetonitrile in 0.05% trifluoroacetic acid aqueous solution, elution time 20 min) to give compound 12 (2.6 mg, yield: 12%) as a pale yellow solid. m / z [M+H] + 350.2; 1 H NMR (400MHz, DMSO-d6): δ9.00(s,1H),8.75(d,J=8.2Hz,1H),7.79(d,J=8.2Hz,1H),7 .28(t,J=7.8Hz,1H), 7.11(dd,J=7.6,2.8Hz,2H), 3.16(d,J=4.0Hz,2H), 2.91(s,2H).

[0625] Example 13: Synthesis of 4-amino-1-(2-chlorophenyl-6-d)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2(1H)-one (compound 13)

[0626] Step 1: Using the synthetic method described in Step 1 of Example 7, compound 1-1 was reacted with 13A to obtain 2-chloro-N-((2-chlorophenyl-6-d)carbamoyl)-6-(trifluoromethyl)nicotinamide (13-1) as a white solid. m / z [M+H] + 379.0.

[0627] Step 2: A solution of 2-chloro-N-((2-chlorophenyl-6-d)carbamoyl)-6-(trifluoromethyl)nicotinamide (13-1, 400 mg, 1.1 mmol), N,N-diisopropylethylamine (420 mg, 3.3 mmol), and N,N-dimethylformamide (2 mL) was placed in a microwave-safe tube and microwaved at 100 °C for 1.5 hours. After cooling to room temperature, the reaction was quenched with water. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether / ethyl acetate = 100–3 / 1) to give 1-(2-chlorophenyl-6-d)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (13-2, 150 mg, yield: 41%) as a pale yellow solid. m / z[M+H] + 343.0.

[0628] Step 3: To a solution of 1-(2-chlorophenyl-6-d)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (13-2, 150 mg, 0.44 mmol) in acetonitrile (3 mL), N,N-diisopropylethylamine (510 mg, 3.96 mmol) and phosphorus oxychloride (200 mg, 1.32 mmol) were added sequentially. The reaction mixture was heated under reflux and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was mixed with acetonitrile (3 mL), and ammonia methanol solution (7 M, 3 mL) was added and stirred for 30 minutes. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (elution conditions: 10%–85% acetonitrile in 10 mM ammonium bicarbonate aqueous solution, elution time 20 min) to give compound 13 (63 mg, yield: 42%) as a white solid. m / z [M+H] + 342.0; 1 H NMR (400MHz, CD3OD): δ8.83 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.66-7.62 (m, 1H), 7.55-7.47 (m, 2H).

[0629] Example 14: Synthesis of 4-amino-1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl-7,7,8,8-d4)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one (compound 14)

[0630] Step 1: Add oxalyl chloride (186 mg, 1.47 mmol) to a tetrahydrofuran (7 mL) solution of 2-chloro-6-(trifluoromethyl)nicotinamide (1-1, 300 mg, 1.34 mmol). Reflux the reaction mixture at 85 °C with stirring for 2 hours, concentrate under reduced pressure, and dissolve the residue in tetrahydrofuran (4 mL) solution. Add a tetrahydrofuran (3 mL) solution of bicyclo[4.2.0]oct-1(6),2,4-trien-2-amine 7,7,8,8-d4-2-amine (14A, 152 mg, 1.2 mmol) to the above solution. Stir at room temperature for 2 hours, then concentrate under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give N-((bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl-7,7,8,8-d4)carbamoyl)-2-chloro-6-(trifluoromethyl)nicotinamide (14-1, 460 mg) as a pale yellow solid. m / z [M+H] + 374.0; 1 H NMR (400MHz, CDCl3): δ10.23(s,1H),9.76(s,1H),8.23(d,J=7.8Hz,1H),7.77(d ,J=7.8Hz,1H),7.23(d,J=8.3Hz,1H),7.20-7.15(m,1H),6.90(d,J=7.1Hz,1H).

[0631] Step 2: Add potassium carbonate (340 mg, 2.5 mmol) to a solution of N,N-dimethylformamide (10 mL) of N-((bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl-7,7,8,8-d4)carbamoyl)-2-chloro-6-(trifluoromethyl)nicotinamide (14-1, 460 mg, 1.23 mmol). The reaction system was stirred at 80°C for 5 hours, and the reaction was quenched with saturated sodium chloride aqueous solution. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl-7,7,8,8-d4)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (14-2, 300 mg, two-step yield: 73%) as a pale yellow solid. m / z[M+H] + 338.0; 1 H NMR (400MHz, CDCl3): δ8.68 (d, J = 7.9 Hz, 1H), 8.45 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.35 (dd, J = 8.1, 7.4 Hz, 1H), 7.16 (t, J = 7.6 Hz, 2H).

[0632] Step 3: To a solution of 1-(bicyclo[4.2.0]octyl-1(6),2,4-trien-2-yl-7,7,8,8-d4)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (14-2, 100 mg, 0.30 mmol) in acetonitrile (5 mL), N,N-diisopropylethylamine (382 mg, 2.96 mmol) and phosphorus oxychloride (136 mg, 0.89 mmol) were added sequentially. The reaction mixture was stirred at 85 °C for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL), and ammonia-methanol solution (7 M, 5 mL) was added, followed by stirring for 10 minutes. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (elution conditions: 15%–75% acetonitrile in 10 mM ammonium bicarbonate aqueous solution, elution time 20 min) to give compound 14 (45.5 mg, yield: 46%) as a white solid. m / z [M+H] + 337.0; 1 H NMR (400MHz, DMSO-d6): δ8.83 (d, J = 8.0 Hz, 2H), 8.65 (s, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.31-7.25 (m, 1H), 7.11 (d, J = 7.2 Hz, 2H).

[0633] Example 15: Synthesis of 4-amino-1-(2-chlorophenyl-3-d)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2(1H)-one (compound 18)

[0634] Using the same synthetic method as compound 13, compound 15 was obtained as a white solid from 2-chloro-6-(trifluoromethyl)nicotinamide (1-1) and 2-chlorophenyl-3-d-amine (15A). m / z[M+H] + 342.0; 1 H NMR (400MHz, CD3OD): δ8.74 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.53-7.47 (m, 2H), 7.43 (dd, J = 5.8, 3.7 Hz, 1H).

[0635] Example 16: Synthesis of 4-amino-1-(2-chlorophenyl-4-d)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2(1H)-one (compound 16)

[0636] Compound 16 was obtained as a white solid by reacting 2-chloro-6-(trifluoromethyl)nicotinamide (1-1) and 2-chlorophenyl-4-d-amine (16A) using the same method as compound 13. m / z: [M+H] + 342.0; 1 H NMR (400MHz, CD3OD): δ8.62 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.54-7.48 (m, 1H), 7.40-7.36 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H).

[0637] Example 17: Synthesis of 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-4-((2-methyl-2H-indazol-5-yl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one (compound 17)

[0638] Using the synthetic method for compound 12, compound 17 was obtained as a white solid by reacting 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2,4(1H,3H)-dione (3-2) with 2-methyl-2H-indazole-5-amine. m / z: [M+H] + 463.1; 1 H NMR (400MHz, DMSO-d6): δ9.13(d,J=8.2Hz,1H),8.41(s,1H),8.24(s,1H),7.88(d,J=8.2Hz,1H),7.66(d,J=9.2Hz,1 H), 7.53 (d, J = 9.0Hz, 1H), 7.33-7.26 (m, 1H), 7.14 (t, J = 7.4Hz, 2H), 4.19 (s, 3H), 3.17 (d, J = 4.0Hz, 2H), 2.94 (s, 2H).

[0639] Example 18: Synthesis of 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one (compound 18)

[0640] Compound 18 was obtained as a yellow solid by reacting 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (3-2) with methylamine ethanol solution (30%) using the same method as compound 12. m / z:[M+H] + 347.2; 1 H NMR (400MHz, DMSO-d6): δ9.02(d,J=3.8Hz,1H),8.75(d,J=8.0Hz,1H),7.79(d,J=8.2Hz,1H), 7.28(t,J=7.6Hz,1H), 7.11(d,J=6.2Hz,2H), 3.16(s,2H), 3.01(d,J=4.2Hz,3H), 2.91(s,2H).

[0641] Example 19: Synthesis of 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-4-(ethylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one (compound 19)

[0642] Compound 19 was obtained as a yellow solid by reacting 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (3-2) with an aqueous solution of ethylamine (80%) using the same method as compound 12. m / z: [M+H] + 361.2; 1 HNMR (400MHz, DMSO-d6): δ8.93(s,1H),8.79(d,J=8.2Hz,1H),7.76(d,J=8.2Hz,1H),7.25(t,J=7.8 Hz,1H),7.08(d,J=7.8Hz,2H),3.61-3.46(m,2H),3.13(s,2H),2.88(s,2H),1.22(t,J=7.2Hz,3H).

[0643] Example 20: Synthesis of 4-amino-1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl-7,7,8,8-d4)-7-chloro-6-fluoroquinazoline-2(1H)-one (compound 20)

[0644] Steps 1-2: Using the synthetic method of compound 14-2, 4-chloro-2,5-difluorobenzamide (20-1) and bicyclo[4.2.0]oct-1(6),2,4-trien-7,7,8,8-d4-2-amine (14A) were reacted to yield 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl-7,7,8,8-d4)-7-chloro-6-fluoroquinazoline-2,4(1H,3H)-dione (20-3), a pale yellow solid. m / z:[M+H] + 321.0.

[0645] Step 3: To a solution of 1-(bicyclo[4.2.0]octyl-1(6),2,4-trien-2-yl-7,7,8,8-d4)-7-chloro-6-fluoroquinazoline-2,4(1H,3H)-dione (20-3, 20 mg, 0.06 mmol) in acetonitrile (4 mL), N,N-diisopropylethylamine (80 mg, 0.62 mmol) and phosphorus oxychloride (30 mg, 0.20 mmol) were added sequentially. The reaction mixture was stirred at 85 °C for 1 hour. The reaction mixture was cooled to room temperature, ammonia (1 mL) was added, and the mixture was stirred for 10 minutes. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (elution conditions: 5%–95% acetonitrile / water, elution time 16 minutes) to give compound 20 (5.2 mg, yield: 26%) as a white solid. m / z: [M+H] + 320.0; 1 H NMR (400MHz, DMSO-d6): δ8.24(d,J=9.9Hz,1H),8.16(d,J=22.8Hz,2H),7.38(t,J =7.7Hz, 1H), 7.21 (d, J = 7.2Hz, 1H), 7.11 (d, J = 8.1Hz, 1H), 6.60 (d, J = 6.4Hz, 1H).

[0646] Example 21: Synthesis of 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl-7,7,8,8-d4)-7-chloro-4-methyl-4,5-dihydropyrrolo[2,3,4-de]quinazolin-2(1H)-one (compound 21)

[0647] Steps 1-2: Using the synthetic method of compound 3-2, 4-chloro-2-fluoro-6-(methoxymethyl)benzamide (21-1, synthesized using the method disclosed in Example 1 of WO2024002024A1) and bicyclo[4.2.0]oct-1(6),2,4-trien-7,7,8,8-d4-2-amine (14A) were reacted to give 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl-7,7,8,8-d4)-7-chloro-5-(methoxymethyl)quinazoline-2,4(1H,3H)-dione (21-3) as a white solid. m / z: [M+H] + 347.0.

[0648] Step 3: Using the synthetic method of compound 12, compound 21-3 was reacted with methylamine ethanol solution (30%) to obtain 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl-7,7,8,8-d4)-7-chloro-5-(methoxymethyl)-4-(methylamino)quinazolin-2(1H)-one (21-4) as a white solid. m / z:[M+H] + 360.0.

[0649] Step 4: Boron tribromide (0.2 mL) was added to a solution of 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl-7,7,8,8-d4)-7-chloro-5-(methoxymethyl)-4-(methylamino)quinazolin-2(1H)-one (21-4, 20 mg, 0.06 mmol) in dichloromethane (2 mL). The reaction mixture was stirred overnight at room temperature. The reaction was quenched with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was purified by prep-HPLC (elution conditions: 5%–95% acetonitrile / water, elution time 16 min) to give compound 21 (6 mg, yield: 33%) as a white solid. m / z: [M+H] + 328.0; 1 H NMR (400MHz, DMSO-d6): δ7.37(t,J=7.7Hz,1H),7.29(s,1H),7.19(d,J=7.2Hz,1H),7.15(d,J=8.1Hz,1H),6.37(s,1H),4.88(s,2H),3.20(s,3H).

[0650] Example 22: Synthesis of 1-(2-chlorophenyl)-4-((methyl-d3)amino)-7-((trifluoromethyl)thio)pyrido[2,3-d]pyrimidin-2(1H)-one (compound 22)

[0651] Using the synthetic method for compound 12, compound 22 was obtained as a yellow solid by reacting 1-(2-chlorophenyl)-7-((trifluoromethyl)thio)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (11-6) with methyl-d3-amine. m / z: [M+H] + 390.0.

[0652] Example 23: Synthesis of 4-amino-1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-7-chloroquinazoline-2(1H)-one (compound 23)

[0653] Step 1: Add bicyclo[4.2.0]oct-1(6),2,4-trien-2-ylamino)-4-chlorobenzonitrile (23-1, 500 mg, 1.9 mmol) to a 1,4-dioxane (5 mL) solution of 4-chloro-2-iodobenzonitrile (23-1, 500 mg, 1.9 mmol), X-Phos (181 mg, 0.38 mmol), palladium acetate (43 mg, 0.19 mmol), and cesium carbonate (1.85 g, 5.7 mmol). The reaction mixture was refluxed and stirred overnight under nitrogen atmosphere. The mixture was diluted with ethyl acetate, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give 2-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-ylamino)-4-chlorobenzonitrile (23-2, 120 mg, yield: 24%) as an off-white solid. m / z:[M+H] + 255.2.

[0654] Step 2: Hydrogen peroxide (160 mg, 4.7 mmol) and sodium hydroxide (94 mg, 2.4 mmol) were added sequentially to a dimethyl sulfoxide (DMSO) solution of 2-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-ylamino)-4-chlorobenzonitrile (23-2, 120 mg, 0.47 mmol) in 1 mL. The reaction mixture was stirred at room temperature for 16 hours, and then quenched in ice water. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give 2-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-ylamino)-4-chlorobenzamide (23-3, 110 mg, yield: 86%) as a pale yellow solid. m / z: [M+H] + 273.2.

[0655] Step 3: Sodium hydroxide (80 mg, 60%, 2.0 mmol) and N,N'-carbonyldiimidazole (195 mg, 1.2 mmol) were added sequentially to a tetrahydrofuran (5 mL) solution of 2-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-ylamino)-4-chlorobenzamide (23-3, 110 mg, 0.4 mmol). The reaction mixture was stirred at room temperature for 1 hour, and the reaction was quenched with 2 drops of water. The reaction system was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-7-chloroquinazoline-2,4(1H,3H)-dione (23-4, 50 mg, yield: 42%) as a yellow solid. m / z: [M+H] + 299.2.

[0656] Step 4: To a solution of 1-(bicyclo[4.2.0]octyl-1(6),2,4-trien-2-yl)-7-chloroquinazoline-2,4(1H,3H)-dione (23-4, 50 mg, 0.17 mmol) in acetonitrile (3 mL), N,N-diisopropylethylamine (110 mg, 0.85 mmol) and phosphorus oxychloride (78 mg, 0.51 mmol) were added. The reaction mixture was stirred at 85 °C for 30 min. The mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). Ammonia-methanol solution (7 M, 3 mL) was added, and the mixture was stirred for 30 min. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (elution conditions: 15%–75% acetonitrile in 10 mM ammonium bicarbonate aqueous solution, elution time 20 min) to give compound 23 (12.8 mg, yield: 24%) as an off-white solid. m / z:[M+H] + 298.0.

[0657] Example 24: Synthesis of 1-(2-chlorophenyl-4-d)-4-((methyl-d3)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one (compound 24)

[0658] Using the synthetic method for compound 12, compound 24 was obtained as an off-white solid by reacting 1-(2-chlorophenyl-4-d)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (16-2) with methyl-d3-amine. m / z: [M+H] + 359.0.

[0659] Example 25: 4-Amino-1-(2-chlorophenyl)-7-(pentafluoro-λ) 6Synthesis of 25-(thio)quinazolin-2(1H)-one and resolution of its transisomeric isomers 25-1 and 25-2

[0660] Step 1: To 2-fluoro-4-(pentafluoro-λ) 6 To a solution of 2-thiobenzoic acid (25-1, 100 mg, 0.38 mmol) in dichloromethane (4 mL), oxalyl chloride (50.1 mg, 0.39 mmol) and one drop of N,N-dimethylformamide were added. The reaction mixture was stirred at room temperature for 30 minutes, and then ammonia (0.1 mL) was added. Stirring was continued at room temperature for 20 minutes, followed by concentration under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 2) to give 2-fluoro-4-(pentafluoro-λ) 6 (-Thio)benzamide (25-2, 71 mg, yield: 71%) is a white solid. m / z [M+H] + 266.0.

[0661] Step 2: To 2-fluoro-4-(pentafluoro-λ) 6 Oxaloyl chloride (51 mg, 0.4 mmol) was added to a tetrahydrofuran (3 mL) solution of (25-2, 71 mg, 0.27 mmol) thiobenzoamide. The reaction mixture was refluxed and stirred at 80 °C for 40 min, cooled to room temperature, and 2-chloroaniline (7A, 37 μL, 0.35 mmol) was added. The reaction mixture was stirred at room temperature for another 50 min, and the reaction was quenched with a saturated aqueous solution of ammonium chloride. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 2) to give N-((2-chlorophenyl)carbamoyl)-2-fluoro-4-(pentafluoro-λ) 6 (-Thio)benzamide (25-3, 114 mg) is a white solid. m / z [M+H] + 419.0.

[0662] Step 3: Add N-((2-chlorophenyl)carbamoyl)-2-fluoro-4-(pentafluoro-λ) 6 Potassium carbonate (113 mg, 0.82 mmol) was added to a solution of 3 mL of N,N-dimethylformamide containing 25-3 (114 mg, 0.27 mmol). The reaction mixture was stirred at 80 °C for 2 hours, quenched with saturated sodium chloride solution, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 4) to give 1-(2-chlorophenyl)-7-(pentafluoro-λ) 6(-Thio)quinazolin-2,4(1H,3H)-dione (25-4, 80 mg, two-step yield: 74%) is a pale yellow solid. m / z [M+H] + 399.0.

[0663] Step 4: To 1-(2-chlorophenyl)-7-(pentafluoro-λ) 6 To a solution of 1,4-dioxane (3 mL) of 2,4(1H,3H)-dione (25-4, 80 mg, 0.2 mmol), N,N-diisopropylethylamine (130 mg, 1.01 mmol) and phosphorus oxychloride (92.5 mg, 0.6 mmol) were added sequentially. The reaction mixture was stirred at 100 °C for 1 hour. The reaction mixture was cooled to room temperature, and ammonia (0.1 mL) was added, followed by stirring for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by prep-HPLC (elution conditions: 5%–95% acetonitrile / water, elution time 16 min) to give compound 25 (8.5 mg, yield: 11%) as a white solid. m / z: [M+H] + 398.0.

[0664] Compound 25 (1.1 g) was separated by SFC (SFC-150 (Waters), chiral column (R,R)WHELK-O1 25*250mm, 10um (Regis); mobile phase: CO2 / [MeOH (0.2% NH3 (7M in MeOH)] = 55 / 45; flow rate: 100 mL / min) to obtain compounds 25-1 (496 mg, first elution peak, UPCC retention time 0.821 min) and 25-2 (518 mg, second elution peak, UPCC retention time 1.687 min), both white solids.

[0665] Compound 25-1: m / z: [M+H] + 398.0; 1 H NMR (400MHz, DMSO-d6): δ8.49 (bs, 1H), 8.38-8.43 (m, 2H), 7.75-7.81 (m, 2H), 7.65-7.52 (m, 3H), 6.55 (d, J = 2.2Hz, 1H).

[0666] Compound 25-2: m / z: [M+H] + 398.0; 1H NMR (400MHz, DMSO-d6): δ8.49 (bs, 1H), 8.38-8.43 (m, 2H), 7.75-7.81 (m, 2H), 7.65-7.52 (m, 3H), 6.55 (d, J = 2.2Hz, 1H).

[0667] Example 26: 4-Amino-1-(bicyclo[4.2.0]oct-1,3,5-trien-2-yl-7,7,8,8-d4)-7-(pentafluoro-λ) 6 Synthesis of 26-(thio)quinazolin-2(1H)-one

[0668] Using the synthetic method of compound 20, 2-fluoro-4-(pentafluoro-λ) 6 The reaction of thiobenzamide (25-2) with bicyclo[4.2.0]oct-1(6),2,4-trien-7,7,8,8-d4-2-amine (14A) yields compound 26 as a white solid. m / z[M+H] + 394.0; 1 H NMR (400MHz, DMSO-d6): δ8.36 (m, 3H), 7.76 (dd, J=8.8, 2.0Hz, 1H), 7.40 (t, J=7 .7Hz, 1H), 7.24 (d, J = 7.2Hz, 1H), 7.16 (d, J = 8.1Hz, 1H), 6.91 (d, J = 1.9Hz, 1H).

[0669] Example 27: Synthesis of 4-amino-1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-7-cyclopropylquinazolin-2(1H)-one (compound 27)

[0670] Step 1: The mixture of 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-7-chloroquinazoline-2,4(1H,3H)-dione (23-4, 60 mg, 0.2 mmol), cyclopropylboronic acid (51.5 mg, 0.6 mmol), tetrakis(triphenylphosphine)palladium (34.7 mg, 0.03 mmol) and tripotassium phosphate (212 mg, 1 mmol) in water (0.5 mL) and toluene (3 mL) was purged with nitrogen three times. The reaction system was microwave-heated to 120 °C and stirred for 1.5 hours. After cooling to room temperature, the aqueous phase was extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether / ethyl acetate = 4 / 1 to 1 / 1) to give 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-7-cyclopropylquinazolin-2,4(1H,3H)-dione (27-1, 20 mg, yield: 32%) as an off-white solid. m / z: [M+H] + 305.2.

[0671] Step 2: A solution of 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-7-cyclopropylquinazolin-2,4(1H,3H)-dione (27-1, 20 mg, 0.07 mmol), phosphorus oxychloride (30 mg, 0.2 mmol), and N,N-diisopropylethylamine (43 mg, 0.33 mmol) in acetonitrile (3 mL) was stirred at 90 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was diluted with tetrahydrofuran and slowly added to an ammonia-methanol solution (7 M, 3 mL). The resulting mixture was stirred for another 40 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by prep-HPLC (elution conditions: 15%–75% acetonitrile in 10 mM ammonium bicarbonate aqueous solution, elution time 20 min) to give compound 27 (2.1 mg, yield 10%) as a pale yellow solid. m / z: [M+H] + 304.2.

[0672] Example 28: Synthesis of 4-amino-1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-7-(trifluoromethyl)quinazolin-2(1H)-one (compound 28)

[0673] Compound 28 was synthesized using the same method as compound 23, by reacting 2-iodo-4-(trifluoromethyl)benzonitrile (28-1) with bicyclo[4.2.0]oct-1(6),2,4-trien-2-amine (3A) to obtain compound 28 as a white solid. m / z[M+H] + 332.0.

[0674] Example 29: Synthesis of 4-amino-1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-7-cyclopropylpyrido[2,3-d]pyrimidin-2(1H)-one (compound 29)

[0675] Compound 29 was obtained as a white solid by reacting 2-chloro-6-cyclopropylnicotinamide (29-1) with bicyclo[4.2.0]oct-1(6),2,4-trien-2-amine (3A) using the synthetic method of compound 3. m / z[M+H] + 305.2; 1 H NMR (400MHz, DMSO-d6): δ8.33(d,J=8.0Hz,1H),8.06(d,J=36.0Hz,2H),7.30-7.21 (m,1H),7.17(d,J=8.0Hz,1H),7.08(d,J=7.2Hz,1H),7.01(d,J=8.0Hz,1H),3.15(m 2H),2.87(s,2H),2.04(m,1H),0.87(m,2H),0.61(m,2H).

[0676] Example 30: Synthesis of 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-7-cyclopropyl-4-((2-methyl-2H-indazol-5-yl)amino)pyrido[2,3-d]pyrimidin-2(1H)-one (compound 30)

[0677] Using the synthetic method for compound 12, compound 30 was obtained as a white solid by reacting 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-7-cyclopropylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (29-3) with 2-methyl-2H-indazole-5-amine. m / z[M+H] + 435.2.

[0678] Example 31: Synthesis of 4-amino-1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl-5-d)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one (compound 31)

[0679] Compound 31 was obtained as a white solid by reacting a bicyclic [4.2.0]oct-1(6),2,4-trien-5-d-2-amine (17A) using the synthetic method for compound 3. m / z[M+H] + 334.0; 1H NMR (400MHz, DMSO-d6): δ8.79(d,J=8.1Hz,1H),8.48(d,J=27.0Hz,2H),7.78(d,J=8.1Hz,1 H), 7.27 (d, J = 8.2Hz, 1H), 7.11 (d, J = 8.0Hz, 1H), 3.16 (t, J = 4.3Hz, 2H), 2.98-2.86 (m, 2H).

[0680] Example 32: Synthesis of 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl-5-d)-4-((2-methyl-2H-indazol-5-yl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one (compound 32)

[0681] Using the synthetic method for compound 12, compound 32 was obtained as a white solid by reacting 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl-5-d)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (31-2) with 2-methyl-2H-indazole-5-amine. m / z[M+H] + 464.2; 1 H NMR (400MHz, DMSO-d6): δ10.39(s,1H),9.18(d,J=8.1Hz,1H),8.45(s,1H),8.30(s,1H),7.92(d,J=8.1Hz,1H),7.71(d,J=9.2H z, 1H), 7.59 (d, J = 9.3Hz, 1H), 7.39-7.31 (m, 1H), 7.20 (d, J = 8.3Hz, 1H), 4.24 (s, 3H), 3.23 (t, J = 4.2Hz, 2H), 3.03-2.96 (m, 2H).

[0682] Example 33: Synthesis of 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-7-cyclopropyl-4-((2-methyl-2H-indazol-5-yl)amino)quinazolin-2(1H)-one (compound 33)

[0683] Using the synthetic method for compound 12, compound 33 was obtained as a white solid by reacting 1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione (27-1) with 2-methyl-2H-indazole-5-amine. m / z[M+H] + 434.2.

[0684] Example 34: Synthesis of 4-amino-1-(bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl-5-d)-7-(trifluoromethyl)quinazolin-2(1H)-one (compound 34)

[0685] Compound 34 was obtained as a white solid by reacting 2-fluoro-4-(trifluoromethyl)benzamide (34-1) with bicyclo[4.2.0]oct-1(6),2,4-trien-5-d-2-amine (17A) using the synthetic method for compound 3. m / z[M+H] + 333.0; 1 H NMR (400MHz, DMSO-d6): δ8.40-8.33(m,2H),8.26(s,1H),7.57(d,J=8.3Hz,1H),7.40(d,J=8 .2Hz,1H),7.15(d,J=8.1Hz,1H),6.77(s,1H),3.23(q,J=5.2,4.7Hz,2H),2.98-2.90(m,2H).

[0686] Example 35: 4-Amino-1-(2-chloropyridin-3-yl)-7-(pentafluoro-λ) 6 Synthesis of 35-thio)quinazolin-2(1H)-one

[0687] Using the synthetic method of compound 20, 2-fluoro-4-(pentafluoro-λ) 6 The reaction of thiobenzamide (25-2) and 2-chloropyridin-3-amine (10A) gives compound 35 as a white solid. m / z [M+H] + 399.0; 1 H NMR (400MHz, DMSO-d6): δ8.62(dd,J=4.8,1.7Hz,1H),8.56(m,2H),8.43(d,J=8.9Hz,1H),8.15(dd, J=7.8,1.7Hz,1H),7.85(dd,J=8.8,2.1Hz,1H),7.72(dd,J=7.8,4.8Hz,1H),6.61(d,J=2.0Hz,1H).

[0688] Example 36: 4-Amino-1-(2-(difluoromethyl)phenyl)-7-(pentafluoro-λ) 6 Synthesis of 36-thio)quinazolin-2(1H)-one

[0689] Using the synthetic method of compound 20, 2-fluoro-4-(pentafluoro-λ)6 The reaction of 2-(difluoromethyl)aniline (18A) with thiobenzamide (25-2) yields compound 36 as a white solid. m / z [M+H] + 414.0; 1 H NMR (400MHz, DMSO-d6): δ 8.54-8.31 (m, 3H), 7.86 (d, J = 7.4Hz, 1H), 7.83-7.69 (m, 3H), 7.48 (d, J = 7.6Hz, 1H), 6.84 (t, J = 54.1Hz, 1H), 6.51 (s, 1H).

[0690] Example 37: 4-Amino-1-(bicyclo[4.2.0]oct-1,3,5-trien-2-yl)-7-(pentafluoro-λ) 6 Synthesis of 3-thio)quinazolin-2(1H)-one (compound 37)

[0691] Using the synthetic method of compound 20, 2-fluoro-4-(pentafluoro-λ) 6 The reaction of thiobenzamide (25-2) with bicyclo[4.2.0]oct-1(6),2,4-trien-2-amine (3A) yields compound 37 as a white solid. m / z[M+H] + 390.0; 1 H NMR (400MHz, DMSO-d6): δ8.36(m,3H),7.76(d,J=8.6Hz,1H),7.40(t,J=7.5Hz,1H), 7.24(d,J=6.9Hz,1H),7.16(d,J=7.8Hz,1H),6.91(s,1H),2.99(m,2H),2.88(m,2H).

[0692] Example 38: 4-Amino-1-(2-chlorophenyl-4-d)-7-(pentafluoro-λ) 6 Synthesis of 38 (-thio)quinazolin-2(1H)-one

[0693] Using the synthetic method of compound 20, 2-fluoro-4-(pentafluoro-λ) 6 The reaction of 2-thiobenzamide (25-2) and 2-chlorophenyl-4-d-amine (16A) yields compound 38 as a white solid. m / z [M+H] + 399.0; 1H NMR (400MHz, DMSO-d6): δ8.50 (s, 1H), 8.41 (m, 2H), 7.78 (m, 2H), 7.60 (d, J = 8.2Hz, 1H), 7.58 (s, 1H), 6.55 (d, J = 1.6Hz, 1H).

[0694] Example 39: 4-Amino-7-(pentafluoro-λ) 6 Synthesis of (-thio)-1-(o-tolyl)quinazolin-2(1H)-one (compound 39) and resolution of its transisomeric derivatives 39-1 and 39-2

[0695] Using the synthetic method of compound 20, 2-fluoro-4-(pentafluoro-λ) 6 The reaction of 2-thiobenzamide (25-2) and 2-methylaniline (19A) yields compound 39 as a white solid. (m / z [M+H]) + 378.1; 1 H NMR (400MHz, DMSO-d6): δ8.39(m,2H),8.30(s,1H),7.75(dd,J=8.8,1.9Hz,1H),7.45(m,3H),7.27(d,J=7.0Hz,1H),6.57(d,J=2.0Hz,1H),1.96(s,3H).

[0696] Compound 39 was separated by SFC (SFC-150 (Waters), chiral column (S,S)WHELK-O1 25*250mm, 10um (Regis); mobile phase: CO2 / [MeOH (0.2% NH3 (7M in MeOH)] = 52.5 / 47.5; flow rate: 120 mL / min) to obtain compounds 39-2 (first elution peak, UPCC retention time 1.903 min) and 39-1 (518 mg, second elution peak, UPCC retention time 0.822 min), both white solids.

[0697] Compound 39-1: m / z: [M+H] + 378.1; 1 H NMR (400MHz, DMSO-d6): δ8.39(m,2H),8.30(s,1H),7.75(dd,J=8.8,1.9Hz,1H),7.45(m,3H),7.27(d,J=7.0Hz,1H),6.57(d,J=2.0Hz,1H),1.96(s,3H).

[0698] Compound 39-2: m / z: [M+H] + 378.1;1 H NMR (400MHz, DMSO-d6): δ8.39(m,2H),8.30(s,1H),7.75(dd,J=8.8,1.9Hz,1H),7.45(m,3H),7.27(d,J=7.0Hz,1H),6.57(d,J=2.0Hz,1H),1.96(s,3H).

[0699] Example 40: 4-Amino-1-(2-methylpyridin-3-yl)-7-(pentafluoro-λ) 6 Synthesis of β-thio)quinazolin-2(1H)-one (compound 40)

[0700] Using the synthetic method of compound 20, 2-fluoro-4-(pentafluoro-λ) 6 The reaction of thiobenzamide (25-2) and 3-amino-2-methylpyridine (20A) yields compound 40 as a white solid. m / z [M+H] + 379.0; 1 H NMR (400MHz, DMSO-d6): δ8.62 (dd, J=4.7, 1.3Hz, 1H), 8.49 (bs, 1H), 8.41 (m 2H), 7.83-7.76 (m, 2H), 7.49 (dd, J=7.8, 4.8Hz, 1H), 6.55 (d, J=2.0Hz, 1H), 2.18 (s, 3H).

[0701] Example 41: 4-Amino-1-(2-(difluoromethyl)pyridin-3-yl)-7-(pentafluoro-λ) 6 Synthesis of β-thio)quinazolin-2(1H)-one (compound 41)

[0702] Using the synthetic method of compound 20, 2-fluoro-4-(pentafluoro-λ) 6 The reaction of 2-(difluoromethyl)pyridin-3-amine (21A) with thiobenzamide (25-2) yields compound 41 as a white solid. m / z [M+H] + 415.0; 1 H NMR (400MHz, DMSO-d6): δ8.89 (dd, J=4.6, 1.3Hz, 1H), 8.48 (m 2H),8.39(d,J=8.8Hz,1H),8.07(d,J=8.0Hz,1H),7.87(dd,J=8.1,4.7Hz,1H ), 7.80 (dd, J = 8.8, 2.1 Hz, 1H), 6.90 (t, J = 53.0 Hz, 1H), 6.52 (d, J = 2.1 Hz, 1H).

[0703] Example 42: 4-Amino-1-(2,3-dihydrobenzofuran-4-yl)-7-(pentafluoro-λ) 6 Synthesis of β-thio)quinazolin-2(1H)-one (compound 42)

[0704] Using the synthetic method of compound 20, 2-fluoro-4-(pentafluoro-λ) 6 The reaction of thiobenzamide (25-2) and 2,3-dihydro-4-aminobenzofuran (22A) yields compound 42 as a white solid. m / z [M+H] + 406.1; 1 H NMR (400MHz, DMSO-d6): δ8.36(m,3H),7.76(dd,J=8.8,2.1Hz,1H),7.31(t,J=7.9Hz, 1H), 6.93 (d, J = 8.0Hz, 1H), 6.79 (m, 2H), 4.62-4.48 (m, 2H), 2.95 (m, 1H), 2.79 (m, 1H).

[0705] Example 43: 4-Amino-1-(imidazo[1,2-a]pyridin-5-yl)-7-(pentafluoro-λ) 6 Synthesis of β-thio)quinazolin-2(1H)-one (compound 43)

[0706] Using the synthetic method of compound 20, 2-fluoro-4-(pentafluoro-λ) 6 The reaction of thiobenzamide (25-2) with imidazo[1,2-a]pyridine-5-amino (23A) gives compound 43 as a white solid. m / z [M+H] + 404.0; 1 H NMR (400MHz, DMSO-d6): δ8.63(m2H),8.45(d,J=9.2Hz,1H),7.85(d,J=8.7Hz,1H),7.80(d,J= 9.0Hz,1H),7.77(s,1H),7.61(s,1H),7.52-7.41(m,1H),7.21(d,J=7.0Hz,1H),6.55(s,1H).

[0707] Example 44: 4-Amino-1-(2-chlorothiophene-3-yl)-7-(pentafluoro-λ) 6 Synthesis of β-thio)quinazolin-2(1H)-one (compound 44)

[0708] Using the synthetic method of compound 20, 2-fluoro-4-(pentafluoro-λ) 6 The reaction of 2-thiophene-3-amine with thiophene-3-amine yields compound 44, a white solid. (m / z [M+H]) + 404.1; 1 H NMR (400MHz, DMSO-d6): δ8.47(d,J=30.1Hz,2H),8.39(d,J=8.8Hz,1H),7.81(dd,J= 8.8, 2.1Hz, 1H), 7.74 (d, J = 5.8Hz, 1H), 7.15 (d, J = 5.8Hz, 1H), 6.76 (d, J = 2.0Hz, 1H).

[0709] Example 45: 4-Amino-1-(1-methyl-1H-pyrazole-5-yl)-7-(pentafluoro-λ) 6 Synthesis of β-thio)quinazolin-2(1H)-one (compound 45)

[0710] Using the synthetic method of compound 20, 2-fluoro-4-(pentafluoro-λ) 6 The reaction of 1-thio)benzamide (25-2) with 1-methyl-1H-pyrazole-5-amine yields compound 45 as a white solid. (m / z [M+H]) + 368.1; 1 H NMR (400MHz, DMSO-d6): δ8.56 (d, J = 22.3Hz, 2H), 8.39 (d, J = 8.8Hz, 1H), 7.84 (dd, J = 8.8, 2. 0Hz, 1H), 7.65 (d, J = 1.8Hz, 1H), 6.79 (d, J = 2.0Hz, 1H), 6.41 (d, J = 1.8Hz, 1H), 3.56 (s, 3H).

[0711] Example 46: 4-Amino-1-(2-methylfuran-3-yl)-7-(pentafluoro-λ) 6 Synthesis of β-thio)quinazolin-2(1H)-one (compound 46)

[0712] Using the synthetic method of compound 20, 2-fluoro-4-(pentafluoro-λ) 6 The reaction of thiobenzamide (25-2) with 2-methylfuran-3-amine yields compound 46 as a white solid. (m / z [M+H]) + 368.2.

[0713] Biological Examples

[0714] Example 1: Detection of MAT2A enzyme inhibitory activity

[0715] MAT2A catalyzes the reaction of L-methionine and ATP to produce S-adenosylmethionine (SAM), inorganic phosphate, and inorganic diphosphate. Malachite green reacts with inorganic phosphate to form a green phosphomolybdic acid complex. The absorbance of this green phosphomolybdic acid complex at 620-640 nm is directly proportional to the concentration of free inorganic phosphate in the solution. By detecting the content of inorganic phosphate in the sample, the enzyme inhibitory activity of MAT2A can be indirectly reflected.

[0716] The test compound was prepared with DMSO and serially diluted to a final initial concentration of 1 μM in the reaction system. Ten 1:3 dilutions were performed. The different concentrations of the test compound were transferred to 384-well plates. Experimental buffer (50 mM Tris pH 7.5, 50 mM KCl, 10 mM MgCl2, 10 mM DTT) was prepared. 2×MAT2A recombinant protein was prepared with the buffer and added to the 384-well plate. A 2×L-methionine and ATP mixture was prepared with the buffer and added to the 384-well plate. The enzymatic reaction was initiated and incubated at room temperature for 120 minutes. 20 μL of colorimetric assay reagent was added to the above system, and the mixture was incubated at room temperature for 15 minutes. The absorbance was measured at 630 nm. The inhibition rate of the compound on enzyme activity was calculated. The inhibition rate and the logarithm of the compound concentration were fitted using a nonlinear regression (dose-response-variable slope) to obtain the IC50 of the test compound. 50 Values. The results are shown in Table 1 (A is ≤50nM, B is >50nM and ≤500nM, C is >500nM):

[0717] Table 1

[0718] The compounds of this invention exhibit good MAT2A enzyme inhibitory activity.

[0719] Example 2: Detection of Cell Inhibitory Activity

[0720] MAT2A inhibition and MTAP-deficient tumors exhibit a "synthetic lethal" effect. This experiment used MATP-knockout HCT116 MATP- / - cells to assess the antiproliferative activity of the compounds.

[0721] On day 1, the density of the HCT116 MTAP- / - cell (Genjing Bio) suspension was adjusted to 1.05 × 10⁻⁶. 4Cells / mL were seeded at 95 μL / well in a 96-well plate, resulting in 1000 cells per well. The cell culture plate was incubated overnight at 37°C with 5% CO2. The next day, the test compound was serially diluted with 100% DMSO, then diluted 10-fold with complete culture medium, and 5 μL was added to the cell culture plate. The final DMSO concentration was adjusted to 0.5%, and the plate was centrifuged at 1000 rpm for 1 minute. The maximum concentration of the test compound was 1 μM. The plate was incubated at 37°C with 5% CO2 for 144 hours. Cell Titer-Glo (Cell Titer-glo, Promega) assay reagent was added to each well, and the plate was shaken in the dark for 10 minutes. After standing, the chemiluminescence was detected using TECAN. % Inhibition rate = 100 - (sample signal ratio - MIN) / (MAX - MIN) × 100%

[0722] MAX: DMSO signal value, MIN: negative control well signal value.

[0723] The data were analyzed using GraphPad Prism software, the dose-inhibition rate curves of the compounds were fitted, and the IC50 of the compounds was calculated. 50 Value. HCT116 MTAP- / - Cell inhibitory activity IC50 50 The results are shown in Table 2 (A is ≤50nM, B is >50nM and ≤500nM, C is >500nM):

[0724] Table 2

[0725] The compounds of this invention exhibit good anti-tumor cell proliferation inhibitory activity.

[0726] Example 3: Liver microsomal metabolic stability test

[0727] The analyte was dissolved in dimethyl sulfoxide to prepare a 10 mM stock solution. 2 μL of the 10 mM stock solution was added to 198 μL of 50% acetonitrile (ACN) to prepare a 0.1 mM working solution. 200 μL of ACN-IS (acetonitrile solution containing internal standard) was added to the deep-well plate and stored at 2–8 °C for later use. NADPH was dissolved in phosphate buffer (pH = 7.4) to prepare a 5 mM NADPH solution.

[0728] Prepare a 0.63 mg / mL liver microsome solution by adding 5 μL (20 mg / mL) of each liver microsome to 153 μL of phosphate buffer. Take 158 μL of the liver microsome solution and add 2 μL of positive control (Verapamil) or the working solution of the test compound (0.1 mM), then mix thoroughly by inverting. Incubate the reaction system in a 37°C water bath at 100–200 rpm for 5 minutes.

[0729] Sample at 0 min: Add 24 μL of the reaction mixture to the precipitant, then add 6 μL of NADPH solution. Samples at other time points: Directly add 34 μL of NADPH solution to start the reaction and mix well. At 5, 15, 30, and 60 min, add 30 μL of the reaction mixture to 200 μL of ACN-IS to terminate the reaction and vortex mix well.

[0730] The reacted sample was centrifuged at 4℃ and 4000 rpm for 10 minutes. 50 μL of the supernatant was added to 150 μL of an aqueous solution containing 0.1% formic acid, vortexed, and then analyzed by LC-MS / MS. The LC-MS / MS responses of the samples at each time point were obtained, and the residual rate of the original sample at each time point relative to the 0 min time point was calculated. The logarithm of the residual rate was plotted against the incubation time to calculate the elimination half-life T. 1 / 2 and inherent clearance rate CL int The results of the mouse liver microsomal metabolic stability test are shown in Table 3-1, and the results of the liver microsomal metabolic stability test for other species are shown in Table 3-2.

[0731] Table 3-1

[0732] Table 3-2

[0733] Note: NA* indicates that the clearance rate of compound 25 in the liver microsomes of this species is <0.1 μL / min / mg, and T cannot be accurately calculated. 1 / 2 .

[0734] The compounds of this invention exhibit good metabolic stability.

[0735] Example 4: Canine Pharmacokinetic Study

[0736] The test compound was administered to beagle dogs (6-10 months old, half male and half female) (purchased from Shanghai Xingang Experimental Animal Farm) by gavage (PO), with 4 dogs in each group. The solvent was Solutol HS15:20% HP-β-CD=6:94 (v:v), and the administration volume was 5 mL / kg.

[0737] At the following set time points, approximately 600 μL of blood was collected via venous access in the limbs or (or inguinal artery / vein), and mixed thoroughly in a heparin sodium anticoagulant tube. Blood collection times for the treatment group were: before administration and 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration.

[0738] Blood samples were collected and placed on wet ice for centrifugation to separate plasma (centrifugation conditions: 2000g, 10 minutes, 4℃). Collected plasma was stored at -80℃ before analysis. Plasma samples were analyzed using LC-MS / MS (API5500). Based on the drug's blood concentration data, various pharmacokinetic parameters were calculated using a non-compartmental model. The results are shown in Table 4.

[0739] Table 4

[0740] The compounds of this invention have a relatively long in vivo half-life (T1). 1 / 2 ) and exposure (AUC) 0-24 This helps meet the clinical need for convenient and once-weekly oral administration.

[0741] Example 5: Pharmacokinetic Study in Rats

[0742] The test compound was administered intravenously (IV) to male SD rats (6-7 weeks old, purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd.), with 3 rats per group. Rats were fasted for 12 hours prior to administration but allowed free access to water, and were reintroduced to food 2 hours after administration. Solvent: IV: 10% (v / v) DMSO + 10% (v / v) Solutol HS15 + 80% 0.9% sodium chloride solution, administration volume 5 mL / kg.

[0743] At the following set time points, approximately 200-250 μL of blood was collected through the orbit (or suitable site) and placed in EDTA-K2 test tubes. Blood collection times for the intravenous administration group were: 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration.

[0744] Blood samples were collected and placed on wet ice for centrifugation to separate plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8℃). Collected plasma was stored at -80℃ before analysis. Plasma samples were analyzed using LC-MS / MS (API5500). Based on the drug's blood concentration data, various pharmacokinetic parameters were calculated using a non-compartmental model. The results are shown in Table 5.

[0745] Table 5

[0746] The compounds of this invention have a relatively long in vivo half-life (T1). 1 / 2 ) and mean residence time (MRT); with a high apparent volume of distribution (V z This facilitates the penetration of tumor tissue.

[0747] Example 6: Study on tissue distribution in rats

[0748] The test compound was administered to SD rats (6-7 weeks old, male) (purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd.) via gavage (PO), with two rats per group. Rats were fasted for 12 hours prior to administration but allowed free access to water, and were reintroduced to food 2 hours after administration. The solvent was 6% Solutol Hs15 + 94% 20% Hp-β-CD aqueous solution. The dosage was 5 mg / kg, and the administration volume was 10 mL / kg. Blood and tissue samples were collected at 1 h and 6 h after administration.

[0749] After blood samples were collected, they were placed on wet ice and centrifuged to separate the plasma (centrifugation conditions: 3500 rpm, 10 minutes, 2-8℃). The collected plasma was stored at -80℃ before analysis. For each tissue sample, 5 times the volume of 50% methanol and steel balls were added, and the samples were placed in a tissue homogenizer. The homogenizer was homogenized at 60Hz for 30 seconds, with a 10-second interval, followed by another 30-second homogenization. This process was repeated twice. The homogenized tissue samples were then frozen at -80℃ for later analysis.

[0750] The concentrations of compounds in plasma and tissue samples were analyzed using LC-MS / MS (API5500). The T / P value was calculated as tissue compound concentration / plasma compound concentration. The results are shown in Table 6.

[0751] Table 6

[0752] The compounds of this invention exhibit good tissue / plasma distribution ratios in major target organ tissues.

[0753] Example 7: Pharmacokinetic Study in Mice

[0754] The test compound was administered to male ICR mice (purchased from Shanghai Silex Laboratory Animal Co., Ltd.) via gavage (PO) or intravenous (IV), with three mice in each group. Mice were fasted for 12 hours prior to administration but allowed free access to water, and were fed again 2 hours after administration. Solvent: IV: 10% (v / v) DMSO + 10% (v / v) Solutol HS15 + 80% 0.9% sodium chloride solution, administered by gavage; or 6% Solutol Hs15 + 94% 20% Hp-β-CD aqueous solution, administered at a volume of 10 mL / kg in water.

[0755] Approximately 60 μL of blood was collected via the orbital rim (or other suitable site) at the following time points and placed in EDTA-K2 tubes. Blood collection times for the intravenous administration group were: before administration, and 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. Blood collection times for the oral administration group were: before administration, and 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration.

[0756] Blood samples were collected and placed on wet ice for centrifugation to separate plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8℃). Collected plasma was stored at -80℃ before analysis. Plasma samples were analyzed using LC-MS / MS (API5500). Based on the drug's blood concentration data, non-compartmental models were used to calculate various pharmacokinetic parameters. The results are shown in Tables 7 and 8.

[0757] Table 7

[0758] Table 8

[0759] The compounds of this invention have a relatively long in vivo half-life (T1). 1 / 2 It also has a high apparent volume of distribution (V) and a high mean residence time (MRT). z This facilitates the penetration of tumor tissue.

[0760] Example 8: Study on the distribution of mouse brain tissue

[0761] The test compound was administered to male ICR mice (purchased from Shanghai Silex Laboratory Animal Co., Ltd.) via gavage (PO) or intravenous (IV), with three mice in each group. Mice were fasted for 12 hours prior to administration but allowed free access to water, and were fed again 2 hours after administration. Solvent: IV: 10% (v / v) DMSO + 10% (v / v) Solutol HS15 + 80% 0.9% sodium chloride solution, administered by gavage; or 6% Solutol Hs15 + 94% 20% Hp-β-CD aqueous solution, 10 mL / kg. Blood and brain tissue were collected 24 hours after administration. Blood samples were placed on wet ice and centrifuged to separate plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8℃). Collected plasma was stored at -80℃ before analysis. Brain tissue was rinsed thoroughly with physiological saline, blotted dry with absorbent paper, weighed, and frozen at -80℃ for later use.

[0762] The concentrations of compounds in plasma and brain tissue samples were analyzed using LC-MS / MS (API5500). The results are shown in Tables 9 and 10.

[0763] Table 9

[0764] Table 10

[0765] The compounds of this invention have a good brain tissue / plasma distribution ratio, which is expected to achieve better therapeutic effects for the treatment of brain metastases of tumors.

[0766] Example 9: In vivo efficacy experiment of human colon cancer HCT116 MTAP- / - cell subcutaneous xenograft tumor model in mice

[0767] Cell culture: Human colon cancer HCT116 MTAP- / - cells were cultured in a monolayer in MC COY'S 5A medium containing 10% fetal bovine serum at 37°C in a constant temperature incubator containing 5% CO2. Tumor cells were passaged twice a week. Cells in the exponential growth phase were harvested and counted for seeding.

[0768] Experimental animals: BALB / c nude mice, female, 6-8 weeks old, 18-22g.

[0769] Four experimental groups were set up: Vehicle, Compound 25, Compound 39, and Ref. A, as shown in Table 11 below:

[0770] Table 11

[0771] Experimental methods: HCT116 MTAP- / - cell line (5.0 × 10⁻⁶) was used. 6 Each mouse was injected subcutaneously with 0.1 mL of a PBS and matrix gel mixture (1:1 ratio) onto the right back of the experimental mice. Tumor growth was monitored periodically until the tumor reached approximately 100 mm in size. 3 Mice were randomly grouped according to tumor size and body weight, and administered medication according to the dosing schedule shown in Table 11. Throughout the experiment, mouse body weight and tumor size were measured twice a week.

[0772] Formula for calculating tumor size: Tumor volume (mm) 3 = 0.5 × (tumor long diameter × tumor short diameter) 2 The experimental results are shown in Table 12:

[0773] Table 12

[0774] The compounds of this invention have good in vivo efficacy.

[0775] Note: Ref. A in biological examples 3-9 is compound 167 disclosed in WO2020123395A1, with the following structure:

Claims

1. A compound of formula (III), its stereoisomer, or a pharmaceutically acceptable salt, in, A is X is either N or CH; U is O, S, or NR7; Y is either N or CR5; Y1 and Z1 are either N or C, respectively; Z2 is CH or C; It can be a single bond or a double bond; Ring B is a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; the 5-6 membered heterocyclic ring and the 5-6 membered heteroaromatic ring are optionally replaced by 1 to 4 R8s at any position; Ring C is a 5-membered heterocyclic ring or a 5-membered heteroaromatic ring; o can be 0, 1, 2, 3, or 4; R is hydrogen, hydroxy C 1-6 alkyl or C 1-3 alkoxy C 1-6 alkyl; R1 and R2 are independently hydrogen, halogen, cyano, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, pentafluoride sulfide, C 3-6 Monocyclic cycloalkyl, C 4-6 Bridged cycloalkyl, 3-6 membered heterocyclic alkyl, -CO(O)-halogenated C 1-3 Alkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, surrounded by 1-3 halogens or C 1-3 Alkyl-substituted C 3-6 Monocyclic cycloalkyl, with 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6 Bridged cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 3-8 membered heterocyclic alkyl groups; R3 and R3' are independently hydrogen, hydroxyl, and C, respectively. 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, phenyl, 5-10 heteroaryl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkyl C 1-3 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, surrounded by 1 to 3 halogens or C 1-3 Alkyl-substituted phenyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 5-10-membered heteroaryl groups; R and R3' are independent substituents, or R and R3' together with the atoms they are attached to form 5-8 membered heterocycles; R4 is a halogenated C 1-6 Alkyl thio, pentafluoride thio, C substituted with one trimethylsilyl group 2-6 Alkyne group, C substituted with 1 to 3 halogens 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups substituted with 1-3 halogens; R5, R 5-1 R 5-2 R6, R 6-1 R 6-2 R 6-3 and R 6-4 Each of the following is independently represented as hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1- 6-alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2- 6-acetylinyl, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, C 1-6 Alkylamino C 1-3 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; R 6-5 Each is independently deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1- 6-alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, C 1-6 Alkylamino C 1-3 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; R4 and R5 are independent substituents, or R4 and R5 together with the atoms they are attached to form a 4-10 membered carbon ring; the 4-10 membered carbon ring is optionally substituted by 1 to 4 R8s at any position; R7is hydrogen, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy; R8 can be independently represented by deuterium, halogen, oxo group (=O), hydroxyl group, amino group, mercapto group, or C. 1-6 Alkyl, C 1-6 Alkylene, Halogenated C 1- 6-alkyl, halogenated C 1-6 Alkylene, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1- 6-alkoxy C 1-3 Alkyl or C 1-6 Alkylamino C 1-3 alkyl; And the compound shown in formula (III) satisfies one of the following conditions: (1) U is O, A is A1; (2) U is O, A is A2; R 5-1 is halogen; R 6-1 is deuterium; (3) U is S or NR7, and A is A1, A2 or A3; (4) R1 is C 4-6 Bridged cycloalkyl rings, surrounded by 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6 Bridged cycloalkyl, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl thio, pentafluoride thio, or -CO(O)-halogenated C 1-3 Alkyl group, where A is A1, A2, A3, A4, or A5; (5) R3is hydroxy, C 1-6 alkoxy or haloC 1-6 alkoxy, A is A1, A2or A3.

2. The compound of formula (III) as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts, characterized in that, In the compound shown in formula (III), A is X is either N or CH; U is either O or S; Y is either N or CR5; Y1 and Z1 are either N or C, respectively; Z2 is C; It can be a single bond or a double bond; Ring B is a 5-6 membered heterocycle or a 5-6 membered heteroaromatic ring; in the 5-6 membered heterocycle and the 5-6 membered heteroaromatic ring, the heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; the 5-6 membered heteroaromatic ring has at least one heteroatom, and the heteroatom is N; Ring C is a 5-membered heteroaromatic ring; in the 5-membered heteroaromatic ring, the heteroatom or heterogroup is selected from 1, 2 or 3 of N, NH, O, S and Se, and the number of heteroatoms or heterogroups is 1, 2 or 3; the 5-membered heteroaromatic ring has at least one heteroatom or heterogroup; R is hydrogen, hydroxy C 1-6 alkyl or C 1-3 alkoxy C 1-6 alkyl; R1is C 4-6 bridged cycloalkyl, C 1-3 alkyl-substituted C 4-6 bridged cycloalkyl or pentafluorosulfanyl; R2 is hydrogen or halogen; R3and R3' are each independently hydrogen, hydroxyl, C 1-6 alkoxy, C 1-6 alkyl, deuterated methyl, haloC 1-6 alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl substituted with 1-3 halo or C 1-3 alkyl; and R4is hydrogen or C1-6alkyl. R and R3' are independent substituents, or R and R3' together with the atoms they are attached to form... R4is C3-6cycloalkyl or 3-6 membered heterocycloalkyl substituted with 1-3 halogen; 3-6 R4is C3-6cycloalkyl or 3-6 membered heterocycloalkyl substituted with 1-3 halogen; R5, R 5-1 R 5-2 R6, R 6-1 R 6-2 R 6-3 and R 6-4 Each of the following is independently represented as hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1- 6-alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2- 6-acetylinyl, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, C 1-6 Alkylamino C 1-3 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; R4 and R5 are independent substituents, or R4 and R5 together with the atoms they are attached to form a 4-10 membered carbon ring; the 4-10 membered carbon ring is optionally substituted by 1 to 4 R8s at any position; R8 can be independently represented by deuterium, halogen, oxo group, hydroxyl group, amino group, or C. 1-6 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl or C 1-6 Alkylamino C 1-3 alkyl; t is 1, 2, or 3; n can be 0, 1, 2, 3, or 4.

3. The compound of formula (III) as described in claim 1 or 2, its stereoisomer, or a pharmaceutically acceptable salt, characterized in that, The compound shown in formula (III) is the same as the compound shown in formula (III'). Where A is X is either N or CH; Y is either N or CR5; V is O, S, or NH; V1, V2, V3, V4 and V5 are each independently N or CH; R2 is hydrogen or halogen; R3 is hydrogen, methyl, or deuterated methyl; R4is C3-6cycloalkyl or 3-6 membered heterocycloalkyl substituted with 1-3 halogen; 3-6 R4is C3-6cycloalkyl or 3-6 membered heterocycloalkyl substituted with 1-3 halogen; R5, R 5-1 R 5-2 R6, R 6-1 R 6-2 R 6-3 and R 6-4 Each of the following is independently represented as hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1- 6-alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2- 6-acetylinyl, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, C 1-6 Alkylamino C 1-3 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; R4 and R5 are independent substituents, or R4 and R5 together with the atoms they are attached to form a 4-membered carbon ring; the 4-membered carbon ring is optionally substituted by 1 to 4 R8s at any position; R8 is deuterium.

4. The compound of formula (III) as claimed in any one of claims 1 to 3, its stereoisomer, or a pharmaceutically acceptable salt, characterized in that, The compound shown in formula (III) is any of the following schemes: Option 1: In the compound shown in formula (III), A is X is either N or CH; U is O, S, or NR7; Y is either N or CR5; Y1 and Z1 are either N or C, respectively; It can be a single bond or a double bond; Ring B is a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; the 5-6 membered heterocyclic ring and the 5-6 membered heteroaromatic ring are optionally replaced by 1 to 4 R8s at any position; R is hydrogen, hydroxy C 1-6 alkyl or C 1-3 alkoxy C 1-6 alkyl; R1 and R2 are independently hydrogen, halogen, cyano, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, pentafluoride sulfide, C 3-6 Monocyclic cycloalkyl, C 4-6 Bridged cycloalkyl, 3-6 membered heterocyclic alkyl, -CO(O)-halogenated C 1-3 Alkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, surrounded by 1-3 halogens or C 1-3 Alkyl-substituted C 3-6 Monocyclic cycloalkyl, with 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6 Bridged cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 3-8 membered heterocyclic alkyl groups; R3 and R3' are independently hydrogen, hydroxyl, and C, respectively. 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, phenyl, 5-10 heteroaryl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkyl C 1-3 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, surrounded by 1 to 3 halogens or C 1-3 Alkyl-substituted phenyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 5-10-membered heteroaryl groups; R and R3' are independent substituents, or R and R3' together with the atoms they are attached to form 5-8 membered heterocycles; R4 is a halogenated C 1-6 Alkyl thio, pentafluoride thio, C substituted with one trimethylsilyl group 2-6 Alkyne group, C substituted with 1 to 3 halogens 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups substituted with 1-3 halogens; R5, R 5-1 R 5-2 and R6, R 6-1 R 6-2 R 6-3 Each of the following is independently represented as hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, C 1-6 Alkylamino C 1-3 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; R4 and R5 are independent substituents, or R4 and R5 together with the atoms they are attached to form a 4-10 membered carbon ring; the 4-10 membered carbon ring is optionally substituted by 1 to 4 R8s at any position; R7is hydrogen, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy; R8 can be deuterium, halogen, oxo group (=O), hydroxyl group, amino group, mercapto group, or C. 1-6 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl or C 1-6 Alkylamino C 1-3 alkyl; And the compound shown in formula (III) satisfies one of the following conditions: (1) U is O, A is A1; (2) U is O, A is A2; R 5-1 is halogen; R 6-1 is deuterium; (3) U is S or NR7, and A is A1, A2 or A3; (4) R1 is C 4-6 Bridged cycloalkyl rings, surrounded by 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6 Bridged cycloalkyl, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl thio, pentafluoride thio, or -CO(O)-halogenated C 1-3 Alkyl group, where A is A1, A2, A3, or A4; (5) R3is hydroxy, C 1-6 alkoxy or haloC 1-6 alkoxy, A is A1, A2or A3; Option 2: In the compound shown in formula (III), A is X is either N or CH; Y is either N or CR5; U is either O or S; Y1 and Z1 are either N or C, respectively; It can be a single bond or a double bond; Ring B is a 5-6 membered heterocycle or a 5-6 membered heteroaromatic ring; in the 5-6 membered heterocycle or 5-6 membered heteroaromatic ring, the heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; the 5-6 membered heteroaromatic ring has at least one heteroatom, and the heteroatom is N; R is hydrogen, hydroxy C 1-6 alkyl or C 1-3 alkoxy C 1-6 alkyl; R1is C 4-6 bridged cycloalkyl, C 1-3 alkyl-substituted C 4-6 bridged cycloalkyl or pentafluorosulfanyl; R2 is hydrogen or halogen; R3and R3' are each independently hydrogen, hydroxyl, C 1-6 alkoxy, C 1-6 alkyl, deuterated methyl, haloC 1-6 alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl substituted with 1-3 halo or C 1-3 alkyl; and R4is hydrogen or C1-6alkyl. R and R3' are independent substituents, or R and R3' together with the atoms they are attached to form... R4is C3-6cycloalkyl or 3-6 membered heterocycloalkyl substituted with 1-3 halogen; 3-6 R4is C3-6cycloalkyl or 3-6 membered heterocycloalkyl substituted with 1-3 halogen; R5, R 5-1 R 5-2 R6, R 6-1 R 6-2 and R 6-3 Each of the following is independently represented as hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, C 1-6 Alkylamino C 1-3 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic alkyl; R4 and R5 are independent substituents, or R4 and R5 together with the atoms they are attached to form a 4-10 membered carbon ring; the 4-10 membered carbon ring is optionally substituted by 1 to 4 R8s at any position; R8 represents deuterium, halogen, oxo group, hydroxyl group, amino group, or C. 1-6 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl or C 1-6 Alkylamino C 1-3 alkyl; t is 1, 2, or 3; n can be 0, 1, 2, 3, or 4; Option 3: The compound shown in formula (III) is the same as the compound shown in formula (III'). A is X is either N or CH; Y is either N or CR5; V is O, S, or NH; V1, V2, and V3 are each independently N or CH; R2 is hydrogen or halogen; R3 is hydrogen, methyl, or deuterated methyl; R4is C3-6cycloalkyl or 3-6 membered heterocycloalkyl substituted with 1-3 halogen; 3-6 R4is C3-6cycloalkyl or 3-6 membered heterocycloalkyl substituted with 1-3 halogen; R5, R 5-1 R 5-2 and R6, R 6-1 R 6-2 R 6-3 Each of the following is independently represented as hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, C 1-6 Alkylamino C 1-3 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; R4 and R5 are independent substituents, or R4 and R5 together with the atoms they are attached to form a 4-membered carbon ring; the 4-membered carbon ring is optionally substituted by 1 to 4 R8s at any position; R8 is deuterium; Option 4: The compound shown in formula (III) is the same as the compound shown in formula (II); Where A is X is either N or CH; U is O, S, or NR7; Y is either N or CR5; R is hydrogen, hydroxy C 1-6 alkyl or C 1-3 alkoxy C 1-6 alkyl; R1 and R2 are independently hydrogen, halogen, cyano, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, pentafluoride sulfide, C 3-6 Monocyclic cycloalkyl, C 4-6 Bridged cycloalkyl, 3-6 membered heterocyclic alkyl, -CO(O)-halogenated C 1-3 Alkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, surrounded by 1-3 halogens or C 1-3 Alkyl-substituted C 3-6 Monocyclic cycloalkyl, with 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6 Bridged cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 3-8 membered heterocyclic alkyl groups; R3 and R3' are independently hydrogen, hydroxyl, and C, respectively. 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, phenyl, 5-10 heteroaryl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkyl C 1-3 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, surrounded by 1 to 3 halogens or C 1-3 Alkyl-substituted phenyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 5-10-membered heteroaryl groups; R and R3' are independent substituents, or R and R3' together with the atoms they are attached to form 5-8 membered heterocycles; R4 is a halogenated C 1-6 Alkyl thio, pentafluoride thio, C substituted with one trimethylsilyl group 2-6 Alkyne group, C substituted with 1 to 3 halogens 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups substituted with 1-3 halogens; R5, R 5-1 R 5-2 and R6, R 6-1 R 6-2 Each of the following is independently represented as hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino or C 1-6 Alkylamino C 1-3 alkyl; R4 and R5 are independent substituents, or R4 and R5 together with the atoms they are attached to form a 4-10 membered carbon ring; the 4-10 membered carbon ring is optionally substituted by 1 to 4 R8s at any position; R7is hydrogen, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy; R8is deuterium, halogen, oxo (=0), hydroxyl, amino, thiol, C 1-6 alkyl, C 1-6 alkylene, haloC 1-6 alkyl, haloC 1-6 alkylene, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkoxyC 1-3 alkyl, haloC 1-6 alkoxyC 1-3 alkyl or C 1-6 alkylaminoC 1-3 alkyl; And the compound shown in formula (II) satisfies one of the following conditions: (1) U is O, A is A1; (2) U is O, A is A2; R 5-1 It is a halogen; R 6-1 It is deuterium; (3) U is S or NR7, and A is A1, A2 or A3; (4) R1 is C 4-6 Bridged cycloalkyl rings, surrounded by 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6 Bridged cycloalkyl, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl thio, pentafluoride thio, or -CO(O)-halogenated C 1-3 Alkyl group, where A is A1, A2, or A3; (5) R3 is a hydroxyl group, C 1-6 alkoxy or halogenated C 1-6 Alkoxy group, where A is A1, A2, or A3; Option 5: The compound shown in formula (III) is the same as the compound shown in formula (II). Where A is X is either N or CH; U is either O or S; R represents hydrogen or hydroxyl group C 1-6 Alkyl or C 1-3 Alkoxy C 1-6 alkyl; R1 and R2 are independently hydrogen, halogen, cyano, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, pentafluoride sulfide, C 3-6 Monocyclic cycloalkyl, C 4-6 Bridged cycloalkyl, 3-6 membered heterocyclic alkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, surrounded by 1-3 halogens or C 1-3 Alkyl-substituted C 3-6 Monocyclic cycloalkyl, with 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6 Bridged cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 3-8 membered heterocyclic alkyl groups; R3 and R3' are independently hydrogen, hydroxyl, and C, respectively. 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, 5-10 membered heteroaryl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkyl C 1-3 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; R and R3' are independent substituents, or R and R3' together with the atoms they are attached to form... R8 represents deuterium, halogen, oxo group, hydroxyl group, amino group, or C. 1-6 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl or C 1-6 Alkylamino C 1-3 alkyl; t is 1, 2, or 3; m is 0, 1, or 2; n can be 0, 1, 2, 3, or 4; Option Six: The compound shown in formula (III) is the same as the compound shown in formula (I). Where A is X is either N or CH; U is O, S, or NR7; Y is either N or CR5; R1 and R2 are independently hydrogen, halogen, cyano, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, pentafluoride sulfide, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -CO(O)-halogenated C 1-3 Alkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, surrounded by 1-3 halogens or C 1-3 Alkyl-substituted C 3-6 Cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 3-8 membered heterocyclic alkyl groups; R3 and R3' are independently hydrogen, hydroxyl, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkyl C 1-3 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; R4 is -CF2Cl, a halogenated C 1-6 Alkyl thio, pentafluoride thio, C substituted with one trimethylsilyl group 2-6 Alkyne group, C substituted with 1 to 3 halogens 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups substituted with 1-3 halogens; R5 and R6 are independently hydrogen, halogen, cyano, hydroxyl, amino, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino or C 1-6 Alkylamino C 1-3 alkyl; R4 and R5 are independent substituents, or R4 and R5 are linked together to form a 4-10 membered cycloalkenyl group; the 4-10 membered cycloalkenyl group is unsubstituted, or selectively substituted by 1 to 3 R8s at any position; R7 represents hydrogen, hydroxyl group, and C. 1-6 Alkyl or C 1-6 Alkoxy; R8 can be hydrogen, halogen, oxo group, hydroxyl group, amino group, mercapto group, or C. 1-6 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl or C 1-6 Alkylamino C 1-3 alkyl; And the compound shown in formula (I) satisfies one of the following conditions: (1) U is O, A is A1; (2) U is S or NR7, and A is A1, A2 or A3; (3) R1 is C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl thio, pentafluoride thio, or -CO(O)-halogenated C 1-3 Alkyl group, where A is A1, A2, or A3; (4) R3 is a hydroxyl group, C 1-6 alkoxy or halogenated C 1-6 Alkoxy group, where A is A1, A2, or A3.

5. The compound of formula (III) as described in any one of claims 1-4, its stereoisomer, or a pharmaceutically acceptable salt, characterized in that, The compound shown in formula (III) is any of the following schemes, Option 1: A is X is either N or CH; U is either O or S; R represents hydrogen or hydroxyl group C 1-6 Alkyl or C 1-3 Alkoxy C 1-6 alkyl; R1 and R2 are independently hydrogen, halogen, cyano, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, pentafluoride sulfide, C 3-6 Monocyclic cycloalkyl, C 4-6 Bridged cycloalkyl, 3-6 membered heterocyclic alkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, surrounded by 1-3 halogens or C 1-3 Alkyl-substituted C 3-6 Monocyclic cycloalkyl, with 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6 Bridged cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 3-8 membered heterocyclic alkyl groups; R3 and R3' are independently hydrogen, hydroxyl, and C, respectively. 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, 5-10 membered heteroaryl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkyl C 1-3 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, surrounded by 1 to 3 halogens or C 1-3 Alkyl-substituted phenyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 5-10-membered heteroaryl groups; R and R3' are independent substituents, or R and R3' together with the atoms they are attached to form... R6 can be hydrogen, deuterium, halogen, cyano, hydroxyl, amino, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino or C 1-6 Alkylamino C 1-3 alkyl; R8 represents deuterium, halogen, oxo group, hydroxyl group, amino group, or C. 1-6 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl or C 1-6 Alkylamino C 1-3 alkyl; t is 1, 2, or 3; m is 0, 1, or 2; n can be 0, 1, 2, 3, or 4; Option 2: A is X is either N or CH; U is either O or S; R represents hydrogen or hydroxyl group C 1-6 Alkyl or C 1-3 Alkoxy C 1-6 alkyl; R1 and R2 are independently hydrogen, halogen, cyano, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, pentafluoride sulfide, C 3-6 Monocyclic cycloalkyl, C 4-6 Bridged cycloalkyl, 3-6 membered heterocyclic alkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, surrounded by 1-3 halogens or C 1-3 Alkyl-substituted C 3-6 Monocyclic cycloalkyl, with 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6 Bridged cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 3-8 membered heterocyclic alkyl groups; R3 and R3' are independently hydrogen, hydroxyl, and C, respectively. 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, 5-10 membered heteroaryl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkyl C 1-3 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl group or the group with 1 to 3 halogens or C 1-3 Alkyl-substituted 5-10-membered heteroaryl groups; R and R3' are independent substituents, or R and R3' together with the atoms they are attached to form... R8 represents deuterium, halogen, oxo group, hydroxyl group, amino group, or C. 1-6 Alkyl, C 1-6 Alkylene, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkylene, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl or C 1-6 Alkylamino C 1-3 alkyl; t is 1, 2, or 3; m is 0, 1, or 2; n can be 0, 1, 2, 3, or 4; Option 3: A is X is either N or CH; U is O; R is hydrogen; R1 is a halogen, cyano, or C group. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1- 6-alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, pentafluoride sulfide, C 3-6 Monocyclic cycloalkyl, C 4-6 Bridged cycloalkyl, 3-6 membered heterocyclic alkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, surrounded by 1-3 halogens or C 1-3 Alkyl-substituted C 3-6 Monocyclic cycloalkyl, with 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6 Bridged cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted 3-8 membered heterocyclic alkyl groups; R2 is hydrogen or halogen; R3 is hydrogen, C 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl, 5-10 heteroaryl, or with 1-3 halogens or C 1-3 Alkyl-substituted 5-10-membered heteroaryl groups; R3' is hydrogen; R6 is hydrogen, deuterium, or halogen (preferably hydrogen); R8 is deuterium; n is 0, 1, 2, 3 or 4 (preferably, n is 0); Option 4: A is X is CH; U is O; Y is either N or CR5; R1 is a sulfide pentafluoride group; R2 is hydrogen or halogen; R3 is hydrogen, methyl, or deuterated methyl; R3' is hydrogen; R4 is a C molecule that has been replaced by 1 to 3 halogens. 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl groups substituted with 1-3 halogens; R5, R 5-1 R6 and R 6-1 Each of the following is independently represented as hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, C 1-6 Alkylamino C 1-3 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; (preferably, R5, R 5-1 R6 and R 6-1 They are independently hydrogen, deuterium, halogen, cyano, and C, respectively. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl, wherein the heteroatom is selected from one, two, or three of N, O, and S, and the number of heteroatoms is one or two; more preferably, R6 and R 6-1 R5 and R6 are independently hydrogen or deuterium, respectively. 5-1 Halogen and C are independently distinguished. 1-6 Alkyl or halogenated C 1-6 Alkyl groups, such as F, Cl, methyl, or halomethyl (e.g., difluoromethyl); R4 and R5 are independent substituents, or R4 and R5 together with the atoms they are attached to form a 4-membered carbon ring; the 4-membered carbon ring is optionally substituted by 1 to 4 R8s at any position; R8 is deuterium.

6. The compound of formula (III) as claimed in any one of claims 1 to 5, its stereoisomer, or a pharmaceutically acceptable salt, characterized in that, It satisfies one or more of the following conditions: (1) R is hydrogen, hydroxyl group C 1-3 Alkyl or C 1-3 Alkoxy C 1-3 Alkyl group; preferably hydrogen, -CH2OH or -CH2OCH3; more preferably hydrogen; (2) R and R3' together with the atoms they are attached to form t is 1, 2, or 3; (3) In A, A1 is m is 0, 1, or 2; n is 0, 1, 2, 3, or 4 (preferably n is 1, 2, 3, or 4); R6 is deuterium or halogen; R8 is deuterium; (4) In A, A1 is m is 0, 1, or 2; n is 0, 1, 2, 3, or 4 (preferably n is 1, 2, 3, or 4); R8 is deuterium; (5) In A, A1 is Among them, R4 and R5 form with their adjacent benzene rings. in It can be a single bond or a double bond, and n can be 0, 1, 2, 3 or 4; (6) In A, A1 is n is 0, 1, 2, 3 or 4 (preferably, n is 1, 2, 3 or 4); R6 is H, deuterium or halogen; R8 is deuterium; (7) In A, A1 is n is 0, 1, 2, 3 or 4 (preferably, n is 1, 2, 3 or 4); R8 is deuterium; (8) R1 is -CF3, -SF5, -SCF3, -CO(O)CF3, (9) R1 is -SF5, -SCF3, -CO(O)CF3, A can be A1, A2, or A3; (10) R1 is C 4-6 Bridged cycloalkyl rings, surrounded by 1 to 3 halogens or C 1-3 Alkyl-substituted C 4-6 Bridged cycloalkyl, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl thio, pentafluoride thio, or -CO(O)-halogenated C 1-3 Alkyl group, where A is A1, A2, or A3; (11) R1 is -SF5; A is A1, A2, A3 or A4; (12)R1-SF5;A4-A 4-1 , A 4-2 , A 4-3 , A 4-4 , A 4-5 Some A 4-6 ; (13) U is S or O, preferably U is S; (14) U is S, and A is A1, A2 or A3; (15)R1 is F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CF3, -CHF2, -OCF2Cl, -CF2CH3, -CH2CF3, -CF(CH3)2, -OCH3, -OCHF2, -OCF3, (16)R1 is F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CF3, -CHF2, -OCF2Cl, -CF2CH3, -CH2CF3, -CF(CH3)2, -OCH3, -OCHF2, -OCF3, A is A1; (17) R2 is H, F, Cl or -CN; (18) R3 is H, -CH3, -CD3, -OH, -OCH3, -CH2CHF2 or (19) R3' is H, -CH3 or -CD3, preferably H; (20) R8 is D, oxo group (=O), F, =CF2 or -OCH2CF3; (21)A is (For example )、 (For example )、 (22) R4 is C substituted with 1 to 3 halogens. 3-6 The cycloalkyl group or a 3-6 membered heterocyclic alkyl group substituted with 1 to 3 halogens, wherein the heteroatoms are selected from 1, 2, or 3 of N, O, and S, and the number of heteroatoms is 1 or 2. Preferably, R4 is a C substituted with 1 to 3 halogens. 3-6 Cycloalkyl groups, such as R4, are cyclopropyl groups substituted with 1 to 3 halogens; (23)R5, R 5-1 R 5-2 R6, R 6-1 R 6-2 R 6-3 and R 6-4 They are independently hydrogen, deuterium, halogen, cyano, and C, respectively. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl; preferably, in the 3-6 membered heterocyclic alkyl, the heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1 or 2; more preferably, R6, R 6-1 R 6-2 and R 6-3 R can be either hydrogen or deuterium, respectively. 6-4 It is hydrogen or C 1-6 Alkyl, R5, R 5-1 and R 5-2 Halogen and C are independently distinguished. 1-6 Alkyl or halogenated C 1-6 Alkyl groups, such as F, Cl, methyl, or halomethyl (e.g., difluoromethyl); or, (24)R 6-5 Each is independently deuterium, halogen, cyano, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl; preferably, in the 3-6 membered heterocyclic alkyl, the heteroatom is selected from one, two, or three of N, O, and S, and the number of heteroatoms is one or two; R 6-5 Further preferred are F, Cl, or methyl.

7. The compound of formula (III) as claimed in any one of claims 1 to 6, its stereoisomer, or a pharmaceutically acceptable salt, characterized in that, It satisfies one or more of the following conditions: (1) R and R3' together with the atoms they are attached to form R3 is -CH3; (2) A is Y is N or CR5; R4 is... -SF5 or -SCF3; R5 is H, F, Cl, -CH3, -OCH3, -OCF3, -OCHF2 or -CN; R6 is H; (3) A is Y is N or CH; R4 is (4) A is Y is CR5; R4 and R5 together with the atoms they are attached to form a 4-membered carbon ring; the 4-membered carbon ring is optionally replaced by 1 to 4 R8s at any position; R8 is deuterium; (5) A is R 5-1 and R 5-2 Each can be independently Cl, methyl, trifluoromethyl, difluoromethyl, vinyl, or cyclopropyl; (6) A is A5; A5 is V is either O or S; R 6-4 Halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl or C 3-6 cycloalkyl; (7) R3 is H, -CH3, -CD3, -OH, -OCH3 or -CH2CHF2; R3' is H; preferably, R3 is H; R3' is H; or, (8) R3 is -OH, -OCH3 or -OCH2CHF2; R3' is H; A is A1, A2 or A3.

8. The compound of formula (III) as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts, characterized in that, The compound represented by formula (III) is a compound represented by formula (IV) (preferably a compound represented by formula (IV-1)), a compound represented by formula (V) (e.g., a compound represented by formula (V-1) or a compound represented by formula (V-2)), or a compound represented by formula (VI): (preferred) )、 (For example )or Wherein, in the compound shown in formula (IV) (preferably the compound shown in formula (IV-1), the compound shown in formula (V), or the compound shown in formula (VI), X, U, V, R, R1, R2, R3, R3', R 5-1 R6, R 6-1 R 6-4 The definitions of R8 and n are as described in any one of claims 1-7; in the compound shown in formula (V-1) or the compound shown in formula (V-2), X, R2, R3, R... 6- 1 is defined as described in any one of claims 1-7, R 5-1 Halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; Preferably, the compound represented by formula (III) is any of the following schemes: (1) In the compound shown in formula (IV), X is N or CH (preferably CH); U is either O or S; R is hydrogen; R1 is hydrogen, halogen, cyano, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl thio, pentafluoride thio, C 3-6 Monocyclic cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted C 3-6 Monocyclic cycloalkyl; R2 is hydrogen or halogen; R3 represents hydrogen, hydroxyl group, and C. 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl, C 1-6 Alkyl, 5-10 heteroaryl, or with 1-3 halogens or C 1-3 Alkyl-substituted 5-10-membered heteroaryl groups; R3' is hydrogen; R6 is hydrogen or deuterium; R8 is deuterium; n can be 0, 1, 2, 3, or 4; (2) In the compound shown in formula (IV-1), X is N or CH (preferably CH); R1 is hydrogen, halogen, cyano, or C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl thiols, halogenated C 1-6 Alkyl thio, pentafluoride thio, C 3-6 Monocyclic cycloalkyl groups or those with 1 to 3 halogens or C 1-3 Alkyl-substituted C 3-6 Monocyclic cycloalkyl; R2 is hydrogen or halogen; R3 represents hydrogen, hydroxyl group, and C. 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl, C 1-6 Alkyl, 5-10 heteroaryl, or with 1-3 halogens or C 1-3 Alkyl-substituted 5-10-membered heteroaryl groups; R6 is hydrogen or deuterium; R8 is deuterium; n can be 0, 1, 2, 3, or 4; (3) In the compound shown in formula (V), X is N or CH (preferably CH); R2 is hydrogen or halogen; R3 is hydrogen, methyl, or deuterated methyl; R 5-1 It is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; R 6-1 It is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; (4) Among the compounds shown in formula (V-1) and formula (V-2), X is N or CH (preferably CH); R2 is hydrogen or halogen; R3 is hydrogen, methyl, or deuterated methyl; R 5-1 Halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; R 6-1 It is hydrogen, deuterium, halogen or C 1-6 alkyl; (5) In the compound shown in formula (VI), X is N or CH (preferably CH); V is O, S, or NH; R2 is hydrogen or halogen; R3 is hydrogen, methyl, or deuterated methyl; R 6-4 It can be hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 1-6 Alkoxy C 1-3 Alkyl, Halogenated C 1-6 Alkoxy C 1-3 Alkyl, C 1-6 Alkylamino, C 1-6 Alkylamino C 1-3 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; More preferably, the compound is any of the following schemes: (1) In the compound shown in formula (IV-1), X is N or CH (preferably CH); R1 is a halogen or halogenated C. 1-6 Alkyl, pentafluoride sulfide or C 3-6 Monocyclic cycloalkyl; R2 is hydrogen or halogen; R3 is hydrogen, C 1-6 Alkyl, deuterated methyl, halogenated C 1-6 Alkyl or C 1-3 Alkyl-substituted 5-10-membered heteroaryl groups (with 1 C) 1-3 Alkyl-substituted 5-10-membered heteroaryl groups; R6 is hydrogen or deuterium; R8 is deuterium; n is 0 or 4; (2) In the compound shown in formula (V), X is CH; R2 is hydrogen; R3 is hydrogen; R 5-1 Halogen, C 1-6 Alkyl (e.g., methyl) or halogenated C 1-6 Alkyl groups (e.g., CHF2); R 6-1 It is hydrogen or deuterium; (3) Among the compounds shown in formula (V-1) and formula (V-2), X is CH; R2 is hydrogen; R3 is hydrogen; R 5-1 Halogen, C 1-6 Alkyl (e.g., methyl) or halogenated C 1-6 Alkyl groups (e.g., CHF2); R 6-1 It is hydrogen or deuterium; (4) In the compound shown in formula (VI), X is CH; V is either O or S; R2 is hydrogen; R3 is hydrogen; R 6-4 Halogen or C 1-6 Alkyl (e.g., methyl).

9. The compound of formula (III) as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts, characterized in that, The compound represented by formula (III) is any of the following compounds: (For example ), (For example ), 10. The compound of formula (III) as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts, characterized in that, The compound is any of the following schemes: Option 1: The compound shown in formula (III) is a single transisomer of the compound of the following formula. The UPCC retention time of the single isomer is relatively short: analytical column: (R,R)WHELK-O1 25*250mm, 5um (Regis), flow rate: 3.0mL / min; column temperature: 40℃; detection wavelength: 214 and / or 254nM; mobile phase: CO2 / [MeOH(0.2% NH3(7M in MeOH)]=70 / 30; preferably, the retention time of the compound with the short retention time is about 0.75-0.90min, for example, about 0.821min; The single isomer is: Option 2: The compound shown in formula (III) is a single transisomer of the compound of the following formula. The UPCC retention time of the single isomer with longer retention time is as follows: analytical column: (R,R)WHELK-O1 25*250mm, 5um (Regis), flow rate: 3.0mL / min; column temperature: 40℃, detection wavelength: 214 and / or 254nM; mobile phase: CO2 / [MeOH(0.2% NH3(7M in MeOH)]=70 / 30; preferably, the retention time of the compound with longer retention time is about 1.60-1.70min, for example, about 1.687min; The single isomer is: Option 3: The compound shown in formula (III) is a single transisomer of the compound of the following formula. The UPCC retention time of the single isomer is relatively short: analytical column: (R,R)WHELK-O1 25*250mm, 5um (Regis), flow rate: 3.0mL / min; column temperature: 40℃; detection wavelength: 214 and / or 254nM; mobile phase: CO2 / [MeOH(0.2%NH3(7M in MeOH)]=70 / 30; preferably, the retention time of the compound with the short retention time is about 0.75-0.90min, for example, about 0.822min; The single isomer is: Option 4: The compound shown in formula (III) is a single transisomer of the compound of the following formula. The UPCC retention time of the single isomer is relatively long: analytical column: (R,R)WHELK-O1 25*250mm, 5um (Regis), flow rate: 3.0mL / min; column temperature: 40℃; detection wavelength: 214 and / or 254nM; mobile phase: CO2 / [MeOH(0.2% NH3(7M in MeOH)]=70 / 30; preferably, the retention time of the compound with the long retention time is about 1.85-1.95min, for example, about 1.903min; The single isomer is:

11. A pharmaceutical composition, characterized in that, It comprises (i) a compound of formula (III) as described in any one of claims 1 to 10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutical excipient.

12. The use of a compound of formula (III) as claimed in any one of claims 1 to 10, its stereoisomer or pharmaceutically acceptable salt, or a pharmaceutical composition as claimed in claim 11, the use comprising: (1) as a medicament; (2) as a MAT2A inhibitor; (3) in the preparation of a MAT2A inhibitor medicament; (4) in the preparation of a medicament for treating and / or preventing a disease, preferably cancer.

13. A compound as shown in Formula X-1, its stereoisomer, or a pharmaceutically acceptable salt thereof. in, The definitions of R, R1, R2, X, A, and U are as described in any one of claims 1-10.

14. The compound of formula X-1 as claimed in claim 13, its stereoisomers, or pharmaceutically acceptable salts, characterized in that, The compound shown in formula X-1 is any one of the following compounds: (For example )、 (For example )、

Images