METTL3 inhibitor as well as preparation method and application thereof

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to an METTL3 inhibitor as well as a preparation method and application thereof. The METTL3 inhibitor is characterized in that the METTL3 inhibitor has a structure as shown in a formula I which is described in the specification. Researches show that the METTL3 inhibitor with the structure as shown in the formula I provided by the invention has METTL3 inhibitory activity. And the formula I of the # imgabs0 # is shown in the specification.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to a class of METTL3 inhibitors, a preparation method thereof and an application thereof. Background Art

[0002] As biological genetic material, RNA not only expresses genetic information as protein, but also has many chemical modifications. 6 -methyladenosine (m 6 A) is the most common and abundant type of chemical modification in eukaryotic RNA. 6 The A modification is dynamically reversible and is installed on mRNA under the action of a methyltransferase complex composed of METTL3, METTL14, and WTAP. 6 A mark; it is cleared by the demethylases FTO and ALKBH5. Among them, METTL3 is the core catalytic subunit of the methyltransferase complex. METTL3 can transfer the -CH3 of S-adenosyl-methionine to the target RNA, METTL14 promotes the binding of -CH3 to the substrate, and WTAP locates the substrate RNA in the complex. These enzymes are important for maintaining the stability, splicing and translation of mRNA, and changes in their levels may affect m 6 A modification, thereby affecting a variety of biological processes in the body and even causing the occurrence of autoimmune diseases, neurological diseases, inflammatory diseases, cancer or infectious diseases.

[0003] At present, a series of studies have shown that METTL3 plays an important role in human cancer and can affect the progression of cancer. METTL3 can regulate the occurrence and development of cancer through various mechanisms and regulate the methylation level of tumor cells. Studies have found that METTL3-mediated m 6 A modification can promote the progression of acute myeloid leukemia (AML). Its expression is upregulated in AML, inhibiting the differentiation of AML cells. Knocking down METTL3 can cause cell cycle arrest in AML cells. In addition, studies have found that knocking down METTL3 can activate the apoptosis pathway of gastric cancer cells and inhibit the proliferation, migration and invasion of gastric cancer cells. Knocking down METTL3 can inhibit the occurrence and development of cancers such as colorectal cancer cells, lung cancer and breast cancer.

[0004] In recent years, researchers have begun to explore the development of METTL3 inhibitors. The British company STORM has conducted clinical studies on the latest generation of METTL3 inhibitors STC-15, which is indicated for advanced solid tumors and AML. Recent news reports show that STC-15 is a highly selective METTL3 inhibitor that blocks tumor growth and induces tumor regression by activating anti-tumor immune responses. Combining it with immune checkpoint blockade can further enhance the efficacy and induce lasting anti-tumor immunity. At present, no METTL3 inhibitors have entered clinical research in China. METTL3 inhibitors are still in the early stages, so finding highly selective and potent METTL3 inhibitors is one of the important directions of current research. Summary of the invention

[0005] The object of the present invention is to provide a METTL3 inhibitor, which has a compound described in Formula I. The compound provided by the present invention has the effect of inhibiting the activity of METTL3.

[0006] The present invention provides a compound represented by formula I or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates and preparation methods thereof.

[0007] Another object of the present invention is to provide the use of the compound of formula I or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals for the preparation of drugs for treating METTL3-mediated diseases.

[0008] To achieve the above object, the present invention adopts the following technical solution:

[0009] The compounds provided by the present invention or their stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals have the following general structural formula:

[0010]

[0011] Wherein: the A ring is selected from a 5-12 membered aromatic ring, a 5-12 membered aromatic heterocyclic ring, a 5-12 membered bridged ring, a 5-12 membered bridged heterocyclic ring, a 5-12 membered spiro ring, and a 5-12 membered spiro heterocyclic ring;

[0012] R a is selected from hydrogen, halogen, =O, cyano, trifluoromethyl, hydroxyl, nitro, -C 1～6 Alkyl, -O(C 1～6 Alkyl), halogen-substituted-C 1～6 Alkyl, -O(halogen substituted C 1～6 Alkyl), -C 2～6 Alkenyl, -C 2～6 Alkynyl, -C3～6 Cycloalkyl, hydroxy-substituted-C 1～6 Alkyl, cyano-substituted -C 1～6 Alkyl, -NR a1 C(=O)R a2 、-C(=O)NR a1 R a2 、-NR a1 R a2 、-S(=O)R a1 、-S(=O)2R a1 、-C(=O)R a1 , 3-12 membered heterocycloalkyl, 5-12 membered aryl, 5-12 membered heteroaryl, 4-12 membered bridged ring, 4-12 membered bridged heterocyclic ring, -C 0～6 Alkyl-3- to 12-membered heterocycloalkyl, wherein the heterocycloalkyl, heteroaryl or bridged heterocyclic ring contains 1 to 4 heteroatoms selected from O, S and N; the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, bridged ring or bridged heterocyclic ring may be further substituted by 1 to 5 atoms selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～6 Alkyl, -O(C 1～6 Alkyl), halogen-substituted-C 1～6 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～6 Alkyl, cyano-substituted -C 1～6 Alkyl is substituted by a substituent; R a1 , R a2 Each independently selected from hydrogen, halogen, amino, hydroxyl, -C 1～6 Alkyl; the A ring and R a The 5-membered and 6-membered heteroaryl groups or the 6-membered and 6-membered heteroaryl groups may be connected together to form a 5-membered and 6-membered heteroaryl group, wherein the 5-membered and 6-membered heteroaryl group or the 6-membered and 6-membered heteroaryl group may be further selected from hydrogen, halogen, =O, cyano, trifluoromethyl, hydroxyl, amino, nitro, -C 1～6 Alkyl, -O(C 1～6 Alkyl), -C 2～6 Alkenyl, -C 2～6 Alkynyl, -C 3～6 Substitution of cycloalkyl groups;

[0013] m is selected from 0, 1, 2, 3, 4 or 5;

[0014] Y is selected from O, S, -CR Y1 R Y2 -、-NR Y2 -, -S(=O)-, -S(=O)2-, -NR Y1 C(=O)NR Y2 -、-NR Y1 C(=O)O-

[0015] or -S(=O)2NR Y1 -; said R Y1 and R Y2 Each independently selected from hydrogen, deuterium, -C 1～6 Alkyl, halogen, hydroxyl, amino, -NO;

[0016] n is selected from 0, 1, 2, 3, 4 or 5;

[0017] X1 is selected from CRx1 or N;

[0018] X2 is selected from CRx2 or N;

[0019] X3 is selected from CRx3 or N;

[0020] X4 is selected from CRx4 or N;

[0021] The Rx1, Rx2, Rx3, and Rx4 are each independently selected from hydrogen, amino, halogen, cyano, nitro, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, -S(=O)2R X5 、-NR X5 C(=O)CR X6 , -C 0～4 Alkyl-NR X5 R X6 , 5- to 12-membered aromatic ring, 5- to 12-membered aromatic heterocyclic ring; R X5 , R X6 Each independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;

[0022] The L is selected from:

[0023] The right side of the L substituent is connected to the ring B; the R L may be further substituted by 1 to 3 groups selected from hydrogen, halogen, hydroxy, cyano, amino, -C 1～6 Alkyl, -O(C 1～6 Alkyl), halogen-substituted-C 1～6 Alkyl, hydroxy substituted -C 1～6 Alkyl, cyano-substituted -C 1～6 substituted by an alkyl substituent;

[0024] p is selected from 0, 1, 2 or 3;

[0025] R L1 and R L2 Each independently selected from hydrogen, halogen, hydroxyl, =O, cyano, -C 1～6 Alkyl, -O(C 1～6 Alkyl), -C 3～6 Cycloalkyl, the alkyl, cycloalkyl may be further substituted by 1 to 4 groups selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～6 Alkyl, -O(C 1～6 Alkyl), halogen-substituted-C 1～6 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～6 Alkyl, cyano-substituted -C 1～6 substituted by an alkyl substituent;

[0026] Ring B is selected from a 5- to 10-membered heterocyclic group containing 1 to 5 heteroatoms selected from O, S, and N;

[0027] q is selected from 0, 1, 2, 3, 4, 5, 6 or 7;

[0028] The R b Selected from hydrogen, halogen, cyano, hydroxyl, =O, -C 1～6 Alkyl, -O(C 1～6 Alkyl), -C 3～6 Cycloalkyl, the alkyl, cycloalkyl may be further substituted by 1 to 4 groups selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～6 Alkyl, -O(C 1～6 Alkyl), halogen-substituted-C 1～6 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～6 Alkyl, cyano-substituted -C 1～6 substituted by an alkyl substituent;

[0029] R c1 and R c2 Each independently selected from hydrogen, halogen, cyano, hydroxyl, =O, -C 1～6 Alkyl, -O(C 1～6 Alkyl), -C 3～6 Cycloalkyl, the alkyl, cycloalkyl may be further substituted by 1 to 4 groups selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～6 Alkyl, -O(C 1～6 Alkyl), halogen-substituted-C 1～6 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～6 Alkyl, cyano-substituted -C1～6 substituted by an alkyl substituent;

[0030] s is selected from 0, 1, 2, or 3;

[0031] Z is selected from hydrogen, halogen, cyano, hydroxyl, -NR Z1 R Z2 , -C 3～12 Heterocycloalkyl, -C 5～10 Aromatic ring, -C 5～10 Aromatic heterocycle, -C 5～12 Bridge ring, -C 5～12 Bridged heterocycle, -C 5～12 Spirocyclic, -C 5～12 Spiro heterocycle; the heterocycloalkyl, aromatic heterocycle, bridged heterocycle, spiro heterocycle contain 1 to 3 heteroatoms selected from O, S, N; the heterocycloalkyl, aromatic ring, aromatic heterocycle, bridged ring, bridged heterocycle, spiro ring, spiro heterocycle may be further substituted by 1 to 4 heteroatoms selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～6 Alkyl, -O(C 1～6 alkyl) is substituted with a substituent;

[0032] The R Z1 and R Z2 Each independently selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkyl-(3-12 membered cycloalkyl), -C 0～2 Alkyl-(3- to 12-membered heterocycloalkyl), -C 0～2 Alkyl-(5-10 membered aromatic ring), -C 0～2 Alkyl-(5-10 membered aromatic heterocyclic ring), -C 0～2 Alkyl-(4-12 membered bridge ring), -C 0～2 Alkyl-(4-12 membered heterocyclic ring), -C 0～2 Alkyl-(5- to 12-membered spirocyclic ring), -C 0～2 Alkyl-(5- to 12-membered spiro heterocycle); wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, bridged ring, bridged heterocycle, spiro ring, spiro heterocycle may be further substituted by 1 to 3 groups selected from hydrogen, halogen, cyano, =O, hydroxyl, trifluoromethyl, amino, -C 1～6 Alkyl, -O(C 1～6 Alkyl), -C 3～12 The alkyl, cycloalkyl, and heterocyclic group may be substituted by 1 to 4 substituents selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～6 Alkyl, -O(C 1～6 alkyl), halogen-substituted-C 1～6 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～6Alkyl, cyano-substituted -C 1～6 The heterocyclic group is substituted by a substituent of an alkyl group, and the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N.

[0033] Furthermore, the A ring is selected from a 5- to 10-membered aromatic ring, a 5- to 10-membered aromatic heterocyclic ring, a 5- to 10-membered bridged ring, a 5- to 10-membered bridged heterocyclic ring, a 5- to 10-membered spiro ring, and a 5- to 10-membered spiro heterocyclic ring;

[0034] R a is selected from hydrogen, halogen, =O, cyano, trifluoromethyl, hydroxyl, nitro, -C 1～4 Alkyl, -O(C 1～4 Alkyl), halogen-substituted-C 1～4 Alkyl, -O(halogen substituted C 1～4 Alkyl), -C 2～4 Alkenyl, -C 2～4 Alkynyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～4 Alkyl, cyano-substituted -C 1～4 Alkyl, -NR a1 C(=O)R a2 、-C(=O)NR a1 R a2 、-NR a1 R a2 、-S(=O)R a1 、-S(=O)2R a1 、-C(=O)R a1 , 3-10 membered heterocycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered bridged ring, 4-10 membered bridged heterocyclic ring, -C 0～6 Alkyl-3- to 10-membered heterocycloalkyl, wherein the heterocycloalkyl, heteroaryl or bridged heterocyclic ring contains 1 to 4 heteroatoms selected from O, S and N; the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or bridged heterocyclic ring may be further substituted by 1 to 4 heteroatoms selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～4 Alkyl, -O(C 1～4 Alkyl), halogen-substituted-C 1～4 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～4 Alkyl, cyano-substituted -C 1～4 Alkyl is substituted by a substituent; R a1 , R a2 Each independently selected from hydrogen, halogen, amino, hydroxyl, -C 1～4 Alkyl; the A ring and R aThe 5-membered and 6-membered heteroaryl groups or the 6-membered and 6-membered heteroaryl groups may be connected together to form a 5-membered and 6-membered heteroaryl group, wherein the 5-membered and 6-membered heteroaryl group or the 6-membered and 6-membered heteroaryl group may be further selected from hydrogen, halogen, =O, cyano, trifluoromethyl, hydroxyl, amino, nitro, -C 1～4 Alkyl, -O(C 1～4 Alkyl), -C 2～4 Alkenyl, -C 2～4 Alkynyl, -C 3～6 Substitution of cycloalkyl groups;

[0035] m is selected from 0, 1, 2, 3 or 4;

[0036] Y is selected from O, S, -CR Y1 R Y2 -、-NR Y2 -, -S(=O)-, -S(=O)2-, -NR Y1 C(=O)NR Y2 -、-NR Y1 C(=O)O-

[0037] or -S(=O)2NR Y1 -; said R Y1 and R Y2 Each independently selected from hydrogen, deuterium, -C 1～4 Alkyl, halogen, hydroxyl, amino, -NO;

[0038] n is selected from 0, 1, 2, 3 or 4;

[0039] X1 is selected from CRx1 or N;

[0040] X2 is selected from CRx2 or N;

[0041] X3 is selected from CRx3 or N;

[0042] X4 is selected from CRx4 or N;

[0043] The Rx1, Rx2, Rx3, and Rx4 are each independently selected from hydrogen, amino, halogen, cyano, nitro, -C 1～4 Alkyl, -C 2～4 Alkenyl, -C 2～4 Alkynyl, -S(=O)2R X5 、-NR X5 C(=O)CR X6 , -C 0～2 Alkyl-NR X5 R X6 , 5- to 10-membered aromatic ring, 5- to 10-membered aromatic heterocyclic ring; R X5 , R X6 Each independently selected from hydrogen, -C 1～4 Alkyl, -C2～4 Alkenyl, -C 2～4 Alkynyl, halogen-substituted-C 1～4 Alkyl, halogen-substituted -C 2～4 Alkenyl, halogen-substituted-C 2～4 Alkynyl;

[0044] The L is selected from: The right side of the L substituent is connected to the ring B; the R L may be further substituted by 1 to 2 groups selected from hydrogen, halogen, hydroxy, cyano, amino, -C 1～4 Alkyl, -O(C 1～4 alkyl), halogen-substituted-C 1～4 Alkyl, hydroxy substituted -C 1～4 Alkyl, cyano-substituted -C 1～4 substituted by an alkyl substituent;

[0045] p is selected from 0, 1 or 2;

[0046] R L1 and R L2 Each independently selected from hydrogen, halogen, hydroxyl, =O, cyano, -C 1～4 Alkyl, -O(C 1～4 Alkyl), -C 3～6 Cycloalkyl, the alkyl, cycloalkyl may be further substituted by 1 to 4 groups selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～4 Alkyl, -O(C 1～4 alkyl), halogen-substituted-C 1～4 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～4 Alkyl, cyano-substituted -C 1～4 substituted by an alkyl substituent;

[0047] Ring B is selected from 5-and-5-membered biheteroaryl, 5-and-6-membered heteroaryl or 6-and-6-membered heteroaryl, wherein the heteroaryl contains 1 to 5 heteroatoms selected from O, S and N;

[0048] q is selected from 0, 1, or 2;

[0049] The R b Selected from hydrogen, halogen, cyano, hydroxyl, =O, -C 1～4 Alkyl, -O(C 1～4 Alkyl), -C 3～6 Cycloalkyl, the alkyl, cycloalkyl may be further substituted by 1 to 4 groups selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～4 Alkyl, -O(C 1～4 alkyl), halogen-substituted-C 1～4 Alkyl, -C3～6 Cycloalkyl, hydroxy-substituted-C 1～4 Alkyl, cyano-substituted -C 1～4 substituted by an alkyl substituent;

[0050] R c1 and R c2 Each independently selected from hydrogen, halogen, cyano, hydroxyl, =O, -C 1～4 Alkyl, -O(C 1～4 Alkyl), -C 3～6 Cycloalkyl, the alkyl, cycloalkyl may be further substituted by 1 to 4 groups selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～4 Alkyl, -O(C 1～4 Alkyl), halogen-substituted-C 1～4 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～4 Alkyl, cyano-substituted -C 1～4 substituted by an alkyl substituent;

[0051] s is selected from 0, 1, or 2;

[0052] Z is selected from hydrogen, halogen, cyano, hydroxyl, -NR Z1 R Z2 , -C 4～9 Heterocycloalkyl, 6-membered aromatic ring, 10-membered aromatic ring, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle, 10-membered aromatic heterocycle, -C 6～9 Bridge ring, -C 6～9 Bridged heterocycle, -C 6～9 Spirocyclic, -C 6～9 Spiro heterocycle; the heterocycloalkyl, aromatic heterocycle, bridged heterocycle, spiro heterocycle contain 1 to 3 heteroatoms selected from O, S, N; the heterocycloalkyl, aromatic ring, aromatic heterocycle, bridged ring, bridged heterocycle, spiro ring, spiro heterocycle may be further substituted by 1 to 4 heteroatoms selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～4 Alkyl, -O(C 1～4 alkyl) is substituted with a substituent;

[0053] The R Z1 and R Z2 Each independently selected from hydrogen, -C 1～4 Alkyl, -C 0～2 Alkyl-(3- to 6-membered cycloalkyl), -C 0～2 Alkyl-(4- to 9-membered heterocycloalkyl), -C 0～2 Alkyl-(6-10 membered aromatic ring), -C 0～2 Alkyl-(5-10 membered aromatic heterocyclic ring), -C 0～2 Alkyl-(4-9 membered bridge ring), -C 0～2 Alkyl-(4-9 membered heterocyclic ring), -C0～2 Alkyl-(6- to 9-membered spirocyclic ring), -C 0～2 Alkyl-(6- to 9-membered spiro heterocycle); wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, bridged ring, bridged heterocycle, spiro ring, spiro heterocycle may be further substituted by 1 to 3 groups selected from hydrogen, halogen, cyano, =O, hydroxyl, trifluoromethyl, amino, -C 1～4 Alkyl, -O(C 1～4 Alkyl), -C 3～6 The alkyl, cycloalkyl, and heterocyclic group may be substituted by 1 to 4 substituents selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～4 Alkyl, -O(C 1～4 Alkyl), halogen-substituted-C 1～4 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～4 Alkyl, cyano-substituted -C 1～4 The heterocyclic group is substituted by a substituent of an alkyl group, and the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N.

[0054] Furthermore, the A ring is selected from a 5- to 10-membered aromatic ring, a 5- to 10-membered aromatic heterocyclic ring, a 6- to 9-membered bridged ring, a 6- to 9-membered bridged heterocyclic ring, a 6- to 9-membered spiro ring, and a 6- to 9-membered spiro heterocyclic ring;

[0055] R a is selected from hydrogen, halogen, =0, cyano, trifluoromethyl, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, -C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, 4-9 membered bridged ring, 4-9 membered bridged heterocyclic ring, -NR a1 R a2 , -C 0～6 Alkyl-3-6 membered heterocycloalkyl, wherein the heterocycloalkyl, heteroaryl or bridged heterocyclic ring contains 1 to 4 heteroatoms selected from O, S and N; the methyl, ethyl, propyl, isopropyl, cycloalkyl, heterocycloalkyl, heteroaryl or bridged heterocyclic ring may be further substituted by 1 to 3 substituents selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, methyl, ethyl, propyl, isopropyl, methoxy and ethoxy; R a1 , R a2 Each independently selected from hydrogen, halogen, amino, hydroxyl, methyl, ethyl, propyl, isopropyl; the A ring and R a The 5-membered and 6-membered heteroaryl groups or the 6-membered and 6-membered heteroaryl groups may be connected together to form a 5-membered and 6-membered heteroaryl group, wherein the 5-membered and 6-membered heteroaryl group or the 6-membered and 6-membered heteroaryl group may be further selected from hydrogen, halogen, =O, cyano, trifluoromethyl, hydroxyl, amino, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, -C3～6 Substitution of cycloalkyl groups;

[0056] m is selected from 0, 1, 2 or 3;

[0057] Y is selected from O, S, -CR Y1 R Y2 -、-NR Y2 -、-S(=O)2-、-NR Y1 C(=O)NR Y2 -; said R Y1 and R Y2 Each is independently selected from hydrogen, deuterium, methyl, halogen, -NO;

[0058] n is selected from 0, 1, 2 or 3;

[0059] X1 is selected from CRx1 or N;

[0060] X2 is selected from CRx2 or N;

[0061] X3 is selected from CRx3 or N;

[0062] X4 is selected from CRx4 or N;

[0063] The Rx1, Rx2, Rx3, and Rx4 are each independently selected from hydrogen, amino, halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, -C 0～2 Alkyl-NR X5 R X6 , 5- to 10-membered aromatic ring, 5- to 10-membered aromatic heterocyclic ring; R X5 , R X6 Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl;

[0064] The L is selected from: The right side of the L substituent is connected to the ring B; the R L may be further substituted by 1 to 2 substituents selected from hydrogen, halogen, hydroxy, cyano, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy;

[0065] p is selected from 0, 1 or 2;

[0066] R L1 and R L2 Each is independently selected from hydrogen, halogen, hydroxy, =O, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, -C 3～6 Cycloalkyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and cycloalkyl groups may be further substituted by 1 to 4 substituents selected from hydrogen, halogen, amino, cyano, and hydroxyl groups;

[0067] Ring B is selected from the group consisting of pyrrolopyrrolyl, pyrrolopyrazolyl, pyrroloimidazolyl, thienopyrrolyl, pyrazolopyrazolyl, pyrazoloimidazolyl, imidazoimidazolyl, imidazothiazolyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, pyridopyrrolyl, pyridopyrazolyl, pyridoimidazolyl, thiazolopyridinyl, thienopyridinyl, pyrimidopyrrolyl, pyrimidin ... pyridazinyl, pyridopyridyl, pyrimidoimidazolyl, thiazolopyrimidyl, thienopyrimidinyl, pyrazinopyrrolyl, pyrazinopyrazolyl, pyrazinoimidazolyl, thienopyrazinyl, pyridazinopyrrolyl, pyridazinopyrazolyl, pyridazinoimidazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, benzopyridazinyl, pyridopyridyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, imidazopyridinyl;

[0068] q is selected from 0, 1, or 2;

[0069] The R b is selected from hydrogen, halogen, cyano, hydroxy, =O, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, -C 3～6 Cycloalkyl, the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cycloalkyl may be further substituted by 1 to 4 groups selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～4 Alkyl, -O(C 1～4 Alkyl), halogen-substituted-C 1～4 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～4 Alkyl, cyano-substituted -C 1～4 substituted by an alkyl substituent;

[0070] R c1 and R c2 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, =O, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl may be further substituted by 1 to 4 groups selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～4 Alkyl, -O(C 1～4 Alkyl), halogen-substituted-C 1～4 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～4 Alkyl, cyano-substituted -C 1～4 substituted by an alkyl substituent;

[0071] s is selected from 0, 1, or 2;

[0072] Z is selected from hydrogen, halogen, cyano, hydroxyl, -NR Z1 R Z2 , -C4～9 Heterocycloalkyl, 6-membered aromatic ring, 10-membered aromatic ring, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle, 10-membered aromatic heterocycle, -C 6～9 Bridge ring, -C 6～9 Bridged heterocycle, -C 6～9 Spirocyclic, -C 6～9 Spiro heterocycle; the heterocycloalkyl, aromatic heterocycle, bridged heterocycle, spiro heterocycle contain 1 to 3 heteroatoms selected from O, S, and N; the heterocycloalkyl, aromatic ring, aromatic heterocycle, bridged ring, bridged heterocycle, spiro ring, and spiro heterocycle may be further substituted by 1 to 4 substituents selected from hydrogen, halogen, methyl, and methoxy;

[0073] The R Z1 and R Z2 Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, -C 0～2 Alkyl-(3- to 6-membered cycloalkyl), -C 0～2 Alkyl-(4- to 9-membered heterocycloalkyl), -C 0～2 Alkyl-(6-membered aromatic ring), -C 0～2 Alkyl-(5-6 membered aromatic heterocyclic ring), -C 0～2 Alkyl-(4-6 membered bridge ring), -C 0～2 Alkyl-(4- to 6-membered heterocyclic ring), -C 0～2 Alkyl-(6- to 9-membered spirocyclic ring), -C 0～2 Alkyl-(6- to 9-membered spiro heterocycle); wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, bridged ring, bridged heterocycle, spiro ring, spiro heterocycle may be further substituted by 1 to 3 groups selected from hydrogen, halogen, cyano, =O, hydroxyl, trifluoromethyl, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, -C 3～6 The methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cycloalkyl, heterocyclic group may be further substituted by 1 to 4 substituents selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～4 Alkyl, -O(C 1～4 Alkyl), halogen-substituted-C 1～4 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～4 Alkyl, cyano-substituted -C 1～4 The heterocyclic group is substituted by a substituent of an alkyl group, and the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N.

[0074] Furthermore, the A ring is selected from a 5- to 10-membered aromatic ring and a 5- to 10-membered aromatic heterocyclic ring;

[0075] R a is selected from hydrogen, halogen, =0, cyano, trifluoromethyl, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethynyl, cyclopropyl, -NRa1 R a2 , 5-10 membered aryl, 5-10 membered heteroaryl, 4-7 membered bridged ring, 4-7 membered bridged heterocyclic ring, -C 0～6 Alkyl-3-6 membered heterocycloalkyl, wherein the heterocycloalkyl, heteroaryl or bridged heterocycle contains 1 to 4 heteroatoms selected from O, S and N; the methyl, ethyl, propyl, isopropyl, methoxy, ethynyl, cyclopropyl, heterocycloalkyl, heteroaryl or bridged heterocycle is further substituted by 1 to 3 substituents selected from hydrogen, halogen, amino, cyano and hydroxyl; R a1 , R a2 Each independently selected from hydrogen, halogen, amino, hydroxyl, methyl, ethyl, propyl, isopropyl; the A ring and R a The 5-membered and 6-membered heteroaryl groups or the 6-membered and 6-membered heteroaryl groups may be connected together to form a 5-membered and 6-membered heteroaryl group, wherein the 5-membered and 6-membered heteroaryl group or the 6-membered and 6-membered heteroaryl group may be further selected from hydrogen, halogen, =O, cyano, trifluoromethyl, hydroxyl, amino, nitro, methyl, ethyl, isopropyl, methoxy, ethynyl, -C 3～4 Substitution of cycloalkyl groups;

[0076] m is selected from 0, 1 or 2;

[0077] Y is selected from O, S, -CR Y1 R Y2 -、-NR Y2 -、-S(=O)2-、-NR Y1 C(=O)NR Y2 -; said R Y1 and R Y2 Each is independently selected from hydrogen, deuterium, methyl, -NO;

[0078] n is selected from 0, 1, 2 or 3;

[0079] X1 is selected from CRx1 or N;

[0080] X2 is selected from CRx2 or N;

[0081] X3 is selected from CRx3 or N;

[0082] X4 is selected from CRx4 or N;

[0083] The Rx1, Rx2, Rx3, and Rx4 are each independently selected from hydrogen, amino, halogen, cyano, methyl, ethyl, propyl, isopropyl, 5-10 membered aromatic ring, and 5-10 membered aromatic heterocycle;

[0084] The L is selected from: The right side of the L substituent is connected to ring B;

[0085] p is selected from 0 or 1;

[0086] R L1 and R L2 Each is independently selected from hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, and cyclopropyl, and the methyl, ethyl, propyl, isopropyl, and cyclopropyl may be further substituted by 1 to 3 substituents selected from hydrogen, halogen, amino, cyano, and hydroxy;

[0087] Ring B is selected from thienopyrrolyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, pyridopyrrolyl, pyridopyrazolyl, pyridoimidazolyl, pyrimidopyrrolyl, pyrimidopyrazolyl, pyrimidoimidazolyl, pyrazinopyrrolyl, pyrazinopyrazolyl, pyrazinoimidazolyl, pyridazinopyrrolyl, pyridazinopyrazolyl, pyridazinoimidazolyl, imidazopyridinyl;

[0088] q is selected from 0, 1, or 2;

[0089] The R b Selected from hydrogen, halogen, cyano, =0, methyl, ethyl, propyl, isopropyl, cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl may be further substituted by 1 to 4 substituents selected from hydrogen, halogen, amino, cyano, hydroxyl;

[0090] R c1 and R c2 Each is independently selected from hydrogen, halogen, cyano, hydroxy, =O, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl;

[0091] s is selected from 0, 1, or 2;

[0092] Z is selected from hydrogen, halogen, cyano, hydroxyl, -NR Z1 R Z2 , -C 4～6 Heterocycloalkyl, 6-membered aromatic ring, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle, -C 6～9 Bridge ring, -C 6～9 Bridged heterocycle, -C 7～9 Spirocyclic, -C 7～9 Spiro heterocycle; the heterocycloalkyl, aromatic heterocycle, bridged heterocycle, spiro heterocycle contain 1 to 3 heteroatoms selected from O, S, and N; the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, bridged ring, bridged heterocycle, spiro ring, and spiro heterocycle may be further substituted by 1 to 4 substituents selected from hydrogen, fluorine, methyl, and methoxy;

[0093] The R Z1 and R Z2 Each independently selected from hydrogen, -C 0～2 Alkyl-(3- to 6-membered cycloalkyl), -C 0～2 Alkyl-(4- to 9-membered heterocycloalkyl), -C 0～2 Alkyl-(6-membered aromatic ring), -C0～2 Alkyl-(6-membered aromatic heterocycle), -C 0～2 Alkyl-(4-6 membered bridge ring), -C 0～2 Alkyl-(4- to 6-membered heterocyclic ring), -C 0～2 Alkyl-(6- to 9-membered spirocyclic ring), -C 0～2 Alkyl-(6- to 9-membered spiroheterocycle); wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, bridged ring, bridged heterocycle, spiro ring, spiroheterocycle may be further substituted by 1 to 3 substituents selected from hydrogen, halogen, cyano, hydroxyl, methyl, isopropyl, methoxy, and trifluoromethyl.

[0094] Preferably, the A ring is selected from

[0095] R a is selected from hydrogen, halogen, cyano, trifluoromethyl, hydroxy, methyl, methoxy, ethynyl, cyclopropyl, -NR a1 R a2 、-C(=O)NR a1 R a2 、-S(=O)2R a1 , 5-membered heterocycloalkyl, 5-membered heteroaryl or 6-membered bridged heterocycle; R a1 , R a2 Each independently selected from hydrogen, halogen, amino, hydroxyl, methyl, isopropyl; the A ring and R a may be connected together to form a 5-membered ring and a 6-membered heteroaryl or a 6-membered ring and a 6-membered heteroaryl, and the 5-membered ring and a 6-membered heteroaryl or the 6-membered ring and a 6-membered heteroaryl may be further substituted by a substituent selected from hydrogen, halogen, cyano, trifluoromethyl, hydroxyl, amino, methyl, methoxy, ethynyl, and cyclopropyl;

[0096] m is selected from 0, 1 or 2;

[0097] Y is selected from -CH2-, -CD2-, -CHCH3-, -NH-;

[0098] n is selected from 0, 1, 2 or 3;

[0099] X1 is selected from CRx1 or N;

[0100] X2 is selected from CRx2 or N;

[0101] X3 is selected from CRx3 or N;

[0102] X4 is selected from CRx4 or N;

[0103] The Rx1, Rx2, Rx3, and Rx4 are independently selected from hydrogen, methyl, halogen, benzene ring, and indole;

[0104] The L is selected from: The right side of the L substituent is connected to ring B;

[0105] p is selected from 1;

[0106] R L1 and R L2 Each independently selected from hydrogen and halogen;

[0107] Ring B is selected from thienopyrrolyl, benzopyrrolyl, pyridoimidazolyl, imidazopyridinyl;

[0108] q is selected from 0, 1, or 2;

[0109] The R b Selected from hydrogen, halogen, =0, methyl, ethyl, propyl, isopropyl, cyano, cyclopropyl, trifluoromethyl, hydroxyl;

[0110] R c1 and R c2 are each independently selected from hydrogen;

[0111] s is selected from 0, 1, or 2;

[0112] Z is selected from

[0113]

[0114] The present invention relates to the following compound or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, characterized in that the compound is selected from any of the following structures:

[0115]

[0116]

[0117]

[0118] The present invention also provides a method for preparing the above-mentioned METTL3 inhibitor (compound or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal).

[0119] The present invention also provides the use of the above-mentioned METTL3 inhibitor (compound or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal) in the preparation of a drug for treating METTL3-mediated diseases.

[0120] Furthermore, the above-mentioned treatment of METTL3-mediated diseases is used for one or more of autoimmune diseases, nervous system diseases, inflammatory diseases, cancer, and infectious diseases.

[0121] Further preferably, the disease mediated by METTL3 is treated for one or more of leukemia, ovarian cancer, etc.

[0122] The present invention provides a pharmaceutical composition, comprising the above-mentioned compound or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a preparation prepared by adding pharmaceutically acceptable excipients.

[0123] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, the meaning that a person skilled in the art would give them should be given based on the context of the disclosure.

[0124] "Alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 10 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof. The alkyl groups appearing herein are defined in accordance with this definition. Alkyl groups may be monovalent, divalent, trivalent, or tetravalent.

[0125] The alkyl group may be substituted with one or more substituents. When substituted, the substituents may be substituted at any available point of attachment. The substituents are independently selected from the group consisting of halogen, hydroxy, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0126] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 20 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, etc. Cycloalkyl groups appearing herein are defined as above. Cycloalkyl groups may be monovalent, divalent, trivalent or tetravalent.

[0127] "Alkenyl" refers to a straight or branched chain hydrocarbon group having the specified number of carbon atoms and in some embodiments 2 to 6 carbon atoms or 2 to 4 carbon atoms and having at least 1 site of vinyl unsaturation (>C=C<). a-b Alkenyl refers to an alkenyl group having from a to b carbon atoms and is intended to include, for example, ethenyl, propenyl, isopropenyl, 1,3-butadienyl, and the like.

[0128] "Alkynyl" refers to a straight chain monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" is also intended to include hydrocarbon groups having one triple bond and one double bond. For example, (C2-C6)alkynyl is intended to include ethynyl, propynyl, and the like.

[0129] "Halogen" refers to F, Cl, Br or I.

[0130] "Halogen substituted" refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, and substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen substituted" is abbreviated as "halo".

[0131] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. For example, -O(C 1～6 Alkyl) is intended to include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and the like.

[0132] “Heterocyclyl” refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which may be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring or a 10-15 membered tricyclic ring system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S.

[0133] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O or S.

[0134] "Spirocyclyl" and "spirocycle" are used interchangeably, and both refer to polycyclic saturated rings or non-aromatic unsaturated hydrocarbon rings in which the monocyclic rings share a carbon atom (called spiro atom). For example, "5- to 12-membered spirocycle" refers to a spirocycle with 5 to 12 ring atoms. According to the number of rings, the spirocycle is divided into a bispirocycle or a polyspirocycle, preferably a bispirocycle.

[0135] "Spiroheterocyclyl" and "spiroheterocycle" are used interchangeably and refer to a non-aromatic saturated ring or a non-aromatic unsaturated ring system having two monocyclic rings sharing one carbon atom. It is composed of carbon atoms and heteroatoms selected from N, O, S or P. For example, "5- to 12-membered spiroheterocycle" refers to a spiroheterocycle having 5 to 12 ring atoms, of which 1, 2 or 3 ring atoms are heteroatoms.

[0136] "Aryl" and "aromatic ring" are used interchangeably and refer to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent carbon atoms) group having a conjugated π electron system, such as "C 6-10The term "aryl" refers to a monocyclic or bicyclic aromatic group having 6 to 10 carbon atoms, and non-limiting examples of aryl include phenyl, naphthyl, and the like.

[0137] "Heteroaryl" and "aromatic heterocycle" are used interchangeably and refer to substituted or unsubstituted aromatic hydrocarbon groups containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O or S(=O), n is 0, 1, 2), and the number of heteroatoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6.

[0138] "Bridged ring group" and "bridged ring" are used interchangeably and refer to a saturated or unsaturated cyclic group formed by two or more cyclic structures sharing two non-adjacent atoms. Specific examples thereof include but are not limited to:

[0139] "Bridged heterocyclic group" and "bridged heterocycle" are used interchangeably and refer to a saturated or unsaturated cyclic group formed by two or more cyclic structures sharing two non-adjacent atoms, which is composed of carbon atoms and heteroatoms selected from N, O, S or P. Specific examples include, but are not limited to:

[0140] "5-membered ring and 5-membered heteroaryl" and "5-membered ring and 5-membered heteroaromatic ring" are used interchangeably, referring to a 5-membered fused heteroaromatic ring, wherein at least one of the two fused rings contains one or more heteroatoms (including but not limited to O, S or N), and the entire group is aromatic. Non-limiting examples include pyrrolopyrrole ring, pyrazolopyrrole ring, pyrazolopyrazole ring, pyrrolofuran ring, pyrazolofuran ring, pyrrolothiophene ring, and pyrazolothiophene ring.

[0141] "5-membered ring and 6-membered heteroaryl" and "5-membered ring and 6-membered heteroaromatic ring" can be used interchangeably, referring to a 5- and 6-membered fused heteroaromatic ring, at least one of the two rings contains one or more heteroatoms (including but not limited to O, S or N), and the entire group is aromatic. Non-limiting examples include benzo 5-membered heteroaromatic ring, 6-membered heteroaromatic ring and 5-membered heteroaromatic ring.

[0142] "6-membered ring and 6-membered heteroaryl" and "6-membered ring and 6-membered heteroaromatic ring" can be used interchangeably, referring to a 6-and-6-membered fused heteroaromatic ring, where at least one of the two rings contains one or more heteroatoms (including but not limited to O, S or N), and the entire group is aromatic. Non-limiting examples include benzopyrrole ring, benzopyrazole ring, benzopyridine ring, benzopyrimidine ring, and pyridopyrimidine ring.

[0143] "Fused" refers to structures in which two or more rings share one or more bonds.

[0144] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, and include enantiomers and diastereomers.

[0145] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism, amide-imidic acid isomerism, etc.

[0146] "Pharmaceutically acceptable salt" refers to a salt of the compound of the present invention which retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0147] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention or their stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0148] "Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

[0149] "Co-crystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components. Co-crystal is a multi-component crystal, including both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between neutral solids and salts or solvates.

[0150] “IC 50 ” is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of the process such as an enzyme, receptor, cell, etc.) by half. DETAILED DESCRIPTION

[0151] The technical solution of the present invention is further described in detail below in conjunction with examples, but the protection scope of the present invention is not limited thereto.

[0152] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). -6The unit of (ppm) is given. NMR measurements were performed using AVII 400MHz and BRUKER AVII 100MHz nuclear magnetic spectrometers, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the measurement solvent, and tetramethylsilane (TMS) as the internal standard.

[0153] MS was measured (AB Sciex TripleTOF 6600).

[0154] The thin layer chromatography silica gel plate used was Shanxi Nuotai GF254, the specification used for thin layer chromatography separation and purification products was 1mm, and column chromatography generally used Qingdao Ocean Silica Gel 200-300 mesh silica gel as the carrier.

[0155] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Bidex Pharmaceuticals, Jiangsu Aikon, Leyan, Aladdin, Dibai, and Xiens.

[0156] Synthesis of intermediate A1

[0157]

[0158] Under nitrogen protection, 6-aminonicotinic acid ethyl ester (5g, 30.1mmol) was added to 40ml of anhydrous tetrahydrofuran to dissolve, and then the reaction system was placed in an ice-water bath, and 50ml of lithium aluminum hydride (49g, 1.29mol) was slowly added dropwise. The reaction solution was reacted at room temperature (25±5℃, the same below) overnight (12h, the same below). After the reaction was completed by TLC monitoring, the reaction system was placed in an ice-water bath, 3ml of ice water was added dropwise to quench, and then 3ml of saturated sodium hydroxide solution was added and stirred until solid-liquid separation. Then, a Buchner funnel was used for suction filtration, the filtrate was collected, the solvent was evaporated under reduced pressure, and the product was separated and purified by silica gel column chromatography (dichloromethane: methanol = 20: 1, volume ratio) to obtain a yellow solid A1-1 (2.5g, yield: 67%), MS m / z = 125 [M+1] + .

[0159] 1,3-Dichloroacetone (4 g, 32 mmol) was added to a mixture of A1-1 (2 g, 16.1 mmol) and anhydrous dioxane (20 ml). After reacting at 100°C for 2 h, the pH was adjusted to 8-9 with saturated sodium bicarbonate. The solvent was evaporated under reduced pressure, and the product was separated and purified by silica gel column chromatography (dichloromethane: methanol = 20: 1, volume ratio) to obtain a yellow-brown solid A1-2 (1 g, yield: 32%), MS m / z = 197 [M+1] + .

[0160] A1-2 (500 mg, 2.54 mmol) was added to a mixture of sodium azide (413 mg, 6.35 mmol), sodium iodide (38 g, 0.25 mmol) and anhydrous N, N-dimethylformamide (5 ml), and the mixture was reacted overnight at 0°C under nitrogen protection. The next day, the solvent in the reaction system was evaporated under reduced pressure, saturated sodium bicarbonate (10 ml) was added, and the mixture was extracted with dichloromethane (20 ml × 3). The organic phases were combined and dried by adding anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (dichloromethane: methanol = 20: 1, volume ratio) to obtain a yellow-white solid A1-3 (460 g, yield: 89%), MS m / z = 204 [M+1] + .

[0161] Under nitrogen protection and ice bath, Dessmartin (760 mg, 1.79 mmol) was added to a mixture of A1-3 (243 mg, 1.20 mmol) and anhydrous dichloromethane (20 ml) and allowed to react overnight. After TLC monitoring, the reaction was completed, and saturated sodium bicarbonate (10 ml × 3) was added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phases were concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (dichloromethane: ethyl acetate = 10: 1, volume ratio) to obtain a pink solid A1-4 (210 mg, yield: 88%), MSm / z = 202 [M+1] + .

[0162] A1-4 (262 mg, 1.30 mmol) was dissolved in 2 ml of anhydrous ethanol, followed by the addition of cyclobutylmethylamine (222 mg, 2.60 mmol), and the reaction was carried out at 60 ° C for 2 h. The reaction system was then transferred to ice water, and sodium borohydride (99 mg, 2.60 mmol) was added under an ice bath. After the addition, the reaction was carried out at room temperature for 1.5 h. TLC monitoring showed that the reaction was complete, and the solvent was evaporated under reduced pressure, saturated sodium chloride (5 ml) was added, and the mixture was extracted with dichloromethane (20 ml × 3). The organic phases were combined and dried with anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (dichloromethane: methanol = 50: 1, volume ratio) to obtain a yellow oil A1-5 (190 mg, yield: 54%), MS m / z = 271 [M+1] + .

[0163] Add di-tert-butyl dicarbonate (789 mg, 3.62 mmol) to a mixture of A1-5 (489 mg, 1.81 mmol), triethylamine (366 mg, 3.62 mmol) and anhydrous dichloromethane (10 ml) and react at room temperature for 1.5 h. After the reaction, add saturated sodium chloride (5 ml) to the reaction solution, extract with dichloromethane (20 ml × 2), combine the organic phases, add anhydrous sodium sulfate and dry. The organic phase is concentrated to obtain a crude product, which is separated and purified by silica gel column chromatography (dichloromethane: methanol = 40: 1, volume ratio) to obtain a yellow oil A1-6 (728 mg, yield: 108%), MS m / z = 371 [M+1] + .

[0164] A1-6 (209 mg, 0.56 mmol) was added to a hydrogenation reaction bottle containing 5 ml of methanol, and Pd / C catalyst (10%, 20 mg) was added. The reaction was carried out at room temperature under hydrogen for 1 h. TLC monitoring showed that the reaction was complete. Celite was added for filtration, and the filtrate was collected and concentrated under reduced pressure to obtain the target crude product A1 (184 mg, yield: 95%), MS m / z=345[M+1] + .

[0165] Synthesis of intermediate A2

[0166]

[0167] A1-3 (209 mg, 1.03 mmol) was added to a hydrogenation reaction bottle containing 5 ml of methanol, and Pd / C catalyst (10%, 20 mg) was added. The reaction was carried out at room temperature under hydrogen for 1 h. TLC monitoring showed that the reaction was complete. Celite was added for filtration, and the filtrate was collected and concentrated under reduced pressure to obtain the target crude product A2 (184 mg, yield: 95%), MS m / z = 178 [M+1] + .

[0168] Synthesis of intermediate B1

[0169]

[0170] Benzyl bromide (740 μl, 5.19 mmol) was added to a mixture of methyl 6-hydroxypyrimidine-4-carboxylate (800 mg, 6.23 mmol) and potassium carbonate (1.435 g, 10.38 mmol) in anhydrous N,N-dimethylformamide (20 ml), and the reaction solution was reacted at room temperature overnight. After the reaction was completed by TLC monitoring, the solvent in the reaction system was evaporated under reduced pressure, saturated sodium chloride (5 ml) was added, and the mixture was extracted with dichloromethane (20 ml × 3), the organic phases were combined, and anhydrous sodium sulfate was added to dry. The organic phase was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (dichloromethane: methanol = 40: 1, volume ratio) to obtain a white solid B1-1 (1.2 g, yield: 94.4%), MS m / z = 245 [M+1] + .

[0171] Dissolve B1-1 (1.5559 g, 5.7 mmol) in 10 ml methanol, add 2 mol / L sodium hydroxide solution (8.5 ml, 17 mmol), and react at room temperature overnight. The next day, the reaction was completed by TLC monitoring. Slowly add concentrated hydrochloric acid to the reaction system to adjust the pH to 2-3. A precipitate is precipitated, filtered, and dried to obtain a white solid B1 (1.40 g, yield: 95.2%), MS m / z = 231 [M+1] + .

[0172] Synthesis of intermediate A3

[0173]

[0174] 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATu, 1 g, 2.708 mmol) and N,N-diisopropylethylamine (DIEA, 583.4 mg, 4.514 mmol) were added to a mixture of anhydrous N,N-dimethylformamide (10 ml) containing B1 (519.2 mg, 2.257 mmol) and A2 (479.6 mg, 2.708 mmol) and reacted at room temperature overnight. TLC monitoring showed that the reaction was complete. The solvent in the reaction system was evaporated, saturated sodium chloride (10 ml) was added, and the mixture was extracted with dichloromethane (20 ml × 3). The organic phases were combined and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the mixture was separated and purified by silica gel column chromatography (dichloromethane: methanol = 15: 1, volume ratio) to obtain a yellow foamy solid A3-1 (337 mg, yield: 38%), MS m / z = 390 [M+1] + .

[0175] Under nitrogen protection and ice bath, Dessmartin (652 mg, 1.53 mmol) was added to a mixture of A3-1 (300 mg, 0.76 mmol) and anhydrous dichloromethane (20 ml) and allowed to react overnight. After TLC monitoring, the reaction was completed, and saturated sodium bicarbonate (10 ml × 3) was added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phases were concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (dichloromethane: tetrahydrofuran = 5:1, volume ratio) to obtain a pink solid A3 (160 mg, yield: 41%), MS m / z = 388 [M+1] + .

[0176] Synthesis of intermediate B2

[0177]

[0178] 2-Chloromethylpyridine hydrochloride (234 mg, 1.43 mmol) and N,N-diisopropylethylamine (283 μl, 1.72 mmol) were added to a mixture of 6-carbonyl-1,6-dihydropyrimidine-4-carboxylic acid ethyl ester (200 mg, 1.19 mmol) and potassium carbonate (329 mg, 2.38 mmol) in anhydrous N,N-dimethylformamide (5 ml), and the reaction solution was reacted at room temperature overnight. After the reaction was completed by TLC monitoring, the solvent in the reaction system was evaporated, saturated sodium chloride (5 ml) was added, and the mixture was extracted with dichloromethane (20 ml × 3), the organic phases were combined, and anhydrous sodium sulfate was added to dry. The organic phase was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (dichloromethane: methanol = 40: 1, volume ratio) to obtain a white solid B2-1 (279 mg, yield: 91%), MS m / z = 260 [M+1] + .

[0179] Lithium hydroxide (22 mg, 0.926 mmol) was added to a solution of B2-1 (240 mg, 0.926 mmol) in methanol (5 ml) and reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, the pH was adjusted to 2-3 and the mixture was concentrated under reduced pressure to obtain the target crude product B2 (245 mg, yield: 114%), MS m / z = 232 [M+1] + .

[0180] Referring to the synthetic route of intermediate B2, 2-chloromethylpyridine hydrochloride is replaced with the corresponding compound in the following table in step 1, and the other operating reagents are the same, to obtain the corresponding intermediates in the following Table 1.

[0181] Table 1 Intermediates B3-B5

[0182]

[0183] Synthesis of intermediate B6

[0184]

[0185] 2-(Chloromethyl)benzonitrile (541 mg, 3.57 mmol) was added to a mixture of ethyl 6-carbonyl-1,6-dihydropyrimidine-4-carboxylate (500 mg, 2.97 mmol) and potassium carbonate (822 mg, 5.95 mmol) in anhydrous N,N-dimethylformamide (10 ml), and the reaction solution was reacted at room temperature overnight. After the reaction was completed by TLC monitoring, the solvent in the reaction system was evaporated, saturated sodium chloride (5 ml) was added, and the mixture was extracted with dichloromethane (20 ml × 3), the organic phases were combined, and anhydrous sodium sulfate was added to dry. The organic phase was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (dichloromethane: ethyl acetate = 20: 1, volume ratio) to obtain a white solid B6-1 (653 mg, yield: 72%), MS m / z = 284 [M+1] + .

[0186] Lithium hydroxide (63 mg, 2.65 mmol) was added to a tetrahydrofuran (5 ml) solution of B6-1 (500 mg, 1.76 mmol), and the mixture was reacted at room temperature for 1 h. The reaction was monitored by TLC and the pH was adjusted to 2-3. The mixture was concentrated under reduced pressure to obtain the crude target product B6 (245 mg, yield: 100%), MS m / z = 256 [M+1] + .

[0187] Referring to the synthetic route of intermediate B6, 2-(chloromethyl)benzonitrile is replaced with the corresponding compound in the following table in step 1, and the remaining operating reagents are the same, to obtain the corresponding intermediates in the following Table 2.

[0188] Table 2 Intermediates B7-B25 and B40-B44

[0189]

[0190]

[0191] Synthesis of intermediate B26

[0192]

[0193] Di-tert-butyl dicarbonate (3.14 g, 14.37 mmol) was added to a mixture of o-aminobenzyl alcohol (1 g, 7.18 mmol), triethylamine (2.2 ml, 14.37 mmol) and anhydrous dichloromethane (10 ml) and reacted at room temperature for 2 h. After the reaction, saturated sodium chloride (5 ml) was added to the reaction solution, extracted with dichloromethane (20 ml × 2), the organic phases were combined, and anhydrous sodium sulfate was added to dry. The organic phase was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1, volume ratio) to obtain a yellow oil B26-1 (598 mg, yield: 35%), MS m / z = 240 [M+1] + .

[0194] Under nitrogen protection, add thionyl chloride (3ml, 5.04mmol) to a mixture of B26-1 (498g, 2.08mmol) and anhydrous dichloromethane (5ml), and react at 0℃ for 1h. After the reaction, evaporate the solvent under reduced pressure, add saturated sodium bicarbonate (5ml) to the reaction solution, extract with dichloromethane (20ml×2), combine the organic phases, add anhydrous sodium sulfate and dry. The organic phase is concentrated to obtain a crude product, which is separated and purified by silica gel column chromatography (dichloromethane: ethyl acetate = 20:1, volume ratio) to obtain a yellow oil B26-2 (263mg, yield: 50%), MS m / z = 258 [M+1] + .

[0195] B26-2 (250 mg, 0.97 mmol) was added to a mixture of ethyl 6-carbonyl-1,6-dihydropyrimidine-4-carboxylate (135 mg, 0.8 mmol) and potassium carbonate (223 mg, 1.62 mmol) in anhydrous N,N-dimethylformamide (5 ml), and the reaction solution was reacted at room temperature overnight. After the reaction was completed by TLC monitoring, the solvent in the reaction system was evaporated, saturated sodium chloride (5 ml) was added, and the mixture was extracted with dichloromethane (20 ml × 3), the organic phases were combined, and anhydrous sodium sulfate was added to dry. The organic phase was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (dichloromethane: ethyl acetate = 30: 1, volume ratio) to obtain a white solid B26-3 (255 mg, yield: 81%), MS m / z = 390 [M+1] + .

[0196] Lithium hydroxide (22 mg, 0.926 mmol) was added to a tetrahydrofuran (5 ml) solution of B26-3 (222 mg, 0.59 mmol), and the mixture was reacted at room temperature for 1 h. The reaction was completed after TLC monitoring. The pH was adjusted to 2-3, and the mixture was concentrated under reduced pressure to obtain the crude target product B26 (205 mg, yield: 100%), MS m / z=362[M+1] + .

[0197] Synthesis of intermediate B27

[0198]

[0199] Referring to the synthetic route of intermediate B26, 2-fluoro-6-methylbenzyl alcohol was used to replace B26-1 tert-butyl (2-(hydroxymethyl)phenyl)carbamate in step 2, and the other operating reagents were the same to obtain intermediate B27, MS m / z = 263 [M+1] + .

[0200] Synthesis of intermediate B28

[0201]

[0202] Under nitrogen protection, add thionyl chloride (1.5ml, 21.4mmol) to a mixture of 2-hydroxybenzyl alcohol (1g, 7.13mmol) and anhydrous N,N-dimethylformamide (5ml), and react at 0℃ for 1.5h. After the reaction, evaporate the solvent under reduced pressure, add saturated sodium bicarbonate (5ml) to the reaction solution, extract with dichloromethane (20ml×2), combine the organic phases, add anhydrous sodium sulfate and dry. The organic phase is concentrated to obtain a crude product, which is separated and purified by silica gel column chromatography (dichloromethane: methanol = 20: 1, volume ratio) to obtain a yellow solid B28-1 (580mg, yield: 51%), MS m / z = 159 [M+1] + .

[0203] B28-1 (250 mg, 1.58 mmol) was added to a mixture of ethyl 6-carbonyl-1,6-dihydropyrimidine-4-carboxylate (220 mg, 1.31 mmol) and potassium carbonate (362 mg, 2.62 mmol) in anhydrous N,N-dimethylformamide (5 ml), and the reaction solution was reacted at room temperature overnight. After the reaction was completed by TLC monitoring, the solvent in the reaction system was evaporated, saturated sodium chloride (5 ml) was added, and the mixture was extracted with dichloromethane (20 ml × 3), the organic phases were combined, and anhydrous sodium sulfate was added to dry. The organic phase was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (dichloromethane: methanol = 20: 1, volume ratio) to obtain a white solid B28-2 (273 mg, yield: 76%), MS m / z = 275 [M+1] + .

[0204] Tert-butyldiphenylsilyl chloride (252 mg, 0.92 mmol), imidazole (104 mg, 1.53 mmol), 4-dimethylaminopyridine (94 mg, 1.53 mmol) were added to a mixture of B28-2 (210 mg, 0.77 mmol) in anhydrous dichloromethane (5 ml), and the reaction solution was reacted at room temperature overnight. After the reaction was completed by TLC monitoring, the solvent in the reaction system was evaporated and purified by silica gel column chromatography (dichloromethane: ethyl acetate = 20: 1, volume ratio) to obtain an oil B28-3 (275 mg, yield: 70%), MS m / z = 513 [M+1] + .

[0205] Lithium hydroxide (23 mg, 0.98 mmol) was added to a tetrahydrofuran (5 ml) solution of B28-3 (250 mg, 0.49 mmol), and the mixture was reacted at room temperature for 1 h. After the reaction was completed by TLC monitoring, the pH was adjusted to 2-3. The solvent in the reaction system was evaporated and the mixture was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1, volume ratio) to obtain a yellow solid B28 (92 mg, yield: 39%), MS m / z = 485 [M+1] + .

[0206] Synthesis of intermediate B29

[0207]

[0208] Benzyl bromide (300 mg, 1.96 mmol) was added to a mixture of methyl 6-oxo-3,6-dihydropyridine-4-carboxylate (503 mg, 2.94 mmol) and potassium carbonate (542 mg, 3.92 mmol) in anhydrous N,N-dimethylformamide (8 ml), and the reaction solution was reacted at room temperature overnight. After the reaction was completed by TLC monitoring, the solvent in the reaction system was evaporated, saturated sodium chloride (5 ml) was added, and the mixture was extracted with dichloromethane (20 ml × 3), the organic phases were combined, and anhydrous sodium sulfate was added to dry. The organic phase was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (dichloromethane: methanol = 30: 1, volume ratio) to obtain pure white solid B29-1 (427 mg, yield: 90%), MS m / z = 244 [M+1] + .

[0209] Lithium hydroxide (79 mg, 3.29 mmol) was added to a tetrahydrofuran (5 ml) solution of B29-1 (400 mg, 1.64 mmol), and the mixture was reacted at room temperature for 1 h. After the reaction was completed, the pH was adjusted to 2-3 after TLC monitoring. The crude target product B29 (481 mg, yield: 127%) was obtained by concentration under reduced pressure. MS m / z = 230 [M+1] + .

[0210] Synthesis of intermediate B30

[0211]

[0212] N-bromosuccinimide (801 mg, 0.82 mmol) and azobisisobutyronitrile (134 mg, 4.50 mmol) were added to carbon tetrachloride (15 ml), and then o-methylanisole (500 mg, 4.09 mmol) was added to the reaction system. The reaction was carried out at 80°C for 30 min. The reaction was completed after TLC monitoring. The solvent in the reaction system was evaporated, water (5 ml) was added, and the mixture was extracted with dichloromethane (20 ml × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain crude product B30-1 (359 mg, yield: 44%), MS m / z = 202 [M+1] + .

[0213] Referring to the synthesis method of intermediate B6, intermediate B30-1 was used to replace 2-(chloromethyl)benzonitrile to obtain intermediate B30, MS m / z=261[M+1] + .

[0214] Synthesis of intermediate B31

[0215]

[0216] 4-iodo-3-nitrobenzonitrile (3g, 10.95mmol) and reduced iron powder (6.1g, 109.48mmol) were added to a mixed solution of ethanol (100ml) and water (30ml), and ammonium chloride (1.76g, 32.84mmol) was added. The reaction solution was heated at 80℃ for 2h. The reaction was completed after TLC monitoring, filtered through diatomaceous earth, and the filtrate was concentrated and 10ml of 2M ammonium chloride solution was added. The mixture was extracted with ethyl acetate (20ml×3), and the organic phases were combined and dried with anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 7:1, volume ratio) to obtain pure yellow solid B31-1 (2.464g, yield: 92%), MS m / z = 244 [M+1] + .

[0217] B31-1 (2.464 g, 10.1 mmol), Pd(PPh3)2Cl2 (82 mg, 0.1 mmol), triphenylphosphine (53 mg, 0.2 mmol) and triethylamine (18 mg, 0.18 mmol) were added to anhydrous tetrahydrofuran (13 ml) solution at room temperature, and the solution was replaced with nitrogen three times by vacuum, and then cuprous iodide (38 mg, 0.2 mmol) and 3,3-diethoxyprop-1-yne (1.55 g, 12.1 mmol) were added, and the reaction was carried out at room temperature overnight under nitrogen protection. After the reaction was completed, the solid was removed by filtration, and the filtrate was collected to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain a pure brown oil B31-2 (2.358 g, yield: 95%), MS m / z = 245 [M+1] + .

[0218] B31-2 (1.5 g, 6.14 mmol) and potassium tert-butoxide (1.38 g, 12.28 mmol) were added to 1-methyl-2-pyrrolidone (19 ml) solution at 0°C, and then transferred to room temperature for overnight reaction. After the reaction was completed by TLC monitoring, 10 ml of saturated ammonium chloride solution, 25 ml of ethyl acetate and 25 ml of water were added to the reaction system for extraction and separation. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1, volume ratio) to obtain pure yellow oily solid B31-3 (949 mg, yield: 63%), MS m / z = 245 [M+1] + .

[0219] B31-3 (949 mg, 3.88 mmol) was dissolved in ethanol, ammonia (7M, 3.3 ml, 0.016 mmol) was added, and Raney nickel (1.32 g, 15 mmol) was added. The mixture was replaced with hydrogen in vacuum three times and reacted at room temperature for 3 h. After the reaction was completed by TLC monitoring, nickel was recovered by filtration with diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the target crude product B31 (979 mg, yield: 102%), MS m / z = 249 [M+1] + .

[0220] Synthesis of intermediate B32

[0221]

[0222] Referring to the synthesis method of intermediate B31, intermediate B32-1 was used to replace B31-1 to obtain intermediate B32, MS m / z=267[M+1] + .

[0223] Synthesis of intermediate B33

[0224]

[0225] Tert-butyl p-chloromethylbenzoate (850 mg, 3.75 mmol) was added to a mixture of ethyl 6-carbonyl-1,6-dihydropyrimidine-4-carboxylate (522 mg, 3.12 mmol) and potassium carbonate (863 mg, 6.25 mmol) in anhydrous N,N-dimethylformamide (10 ml), and the reaction solution was reacted at room temperature overnight. After the reaction was completed by TLC monitoring, the solvent in the reaction system was evaporated, saturated sodium chloride (10 ml) was added, and the mixture was extracted with dichloromethane (20 ml × 3), the organic phases were combined, and anhydrous sodium sulfate was added to dry. The organic phase was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (100% dichloromethane) to obtain a white solid B33-1 (468 mg, yield: 41%), MS m / z = 359 [M+1] + .

[0226] Lithium hydroxide (35 mg, 1.5 mmol) was added to a tetrahydrofuran (5 ml) solution of B33-1 (448 mg, 1.25 mmol), and the mixture was reacted at room temperature for 1 h. After the reaction was completed, the pH was adjusted to 2-3, and the mixture was concentrated under reduced pressure to obtain the crude target product B33 (390 mg, yield: 95%), MS m / z=331[M+1] + .

[0227] Synthesis of intermediate B34

[0228]

[0229] Benzyl bromide (1.03 g, 6 mmol) and 4-hydroxy-6-bromopyrimidine (700 mg, 4 mmol) were dissolved in anhydrous N,N-dimethylformamide (10 ml), potassium carbonate (1.11 g, 8 mmol) was added, and the reaction solution was heated at 80°C for 1.5 h. The reaction was completed by TLC monitoring, and the solvent in the reaction system was evaporated, and water (10 ml) was added. The mixture was extracted with dichloromethane (20 ml × 3), and the organic phases were combined and dried by adding anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (dichloromethane: ethyl acetate = 20: 1, volume ratio) to obtain pure white solid B34-1 (850 mg, yield: 80%), MS m / z = 264 [M+1] + .

[0230] B34-1 (800 mg, 3 mmol), Pd(PPh3)2Cl2 (10 mg, 0.015 mmol), triphenylphosphine (8 mg, 0.03 mmol), cuprous iodide (5.7 mg, 0.03 mmol) and triethylamine (6 ml) were added to anhydrous tetrahydrofuran (4 ml) solution, and the solution was replaced with nitrogen three times by vacuum evacuation. Then trimethylacetylene silicon (444.5 mg, 4.5 mmol) was added, and the reaction was carried out at 60 ° C under nitrogen protection for 5 h. After the reaction was completed by TLC monitoring, the solvent in the reaction system was evaporated, sodium chloride (10 ml) was added, and the mixture was extracted with dichloromethane (20 ml × 3), the organic phases were combined, and anhydrous sodium sulfate was added for drying. The organic phases were concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 3, volume ratio) to obtain pure yellow solid B34-2 (687 mg, yield: 81%), MS m / z = 283 [M+1] + .

[0231] B34-2 (200 mg, 0.7 mmol) was dissolved in 10 ml methanol, potassium hydroxide (47 mg, 0.8 mmol) was added, and the mixture was reacted at room temperature for 1 h. The reaction was monitored by TLC. The solvent in the reaction system was evaporated, sodium chloride (10 ml) was added, and the mixture was extracted with dichloromethane (20 ml × 3). The organic phases were combined and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (dichloromethane: ethyl acetate = 20: 1, volume ratio) to obtain pure yellow oily solid B34 (89 mg, yield: 60%), MS m / z = 211 [M+1] + .

[0232] Referring to the synthetic route of intermediate B6, in step 1, 6-carbonyl-1,6-dihydropyrimidine-4-carboxylic acid ethyl ester is replaced with the corresponding compound in the table below, and 2-(chloromethyl)benzonitrile is replaced with B27-1. The other operating reagents are the same, and the corresponding intermediates in Table 3 below can be obtained.

[0233] Table 3 Intermediates B35-B36

[0234]

[0235] Synthesis of intermediate B37

[0236]

[0237] Dissolve lithium aluminum hydride deuteride (210 mg, 4.99 mmol) in 10 ml of anhydrous tetrahydrofuran in an ice bath, then slowly dropwise add methyl 3-methylbenzoate (750 mg, 4.99 mmol) in tetrahydrofuran under nitrogen protection, and let the reaction solution react overnight at room temperature. TLC monitors the reaction to be complete, add D2O and 40% NaOD solution dropwise, and stir until solid-liquid separation. Then add diatomaceous earth for suction filtration, collect the filtrate, evaporate the solvent under reduced pressure, and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1, volume ratio) to obtain a colorless oil B37-1 (72 mg, yield: 116%), MS m / z = 125 [M+1] + .

[0238] Dissolve B37-1 (200 mg, 1.61 mmol) in 10 ml of anhydrous dichloromethane, place in an ice bath, then add thionyl chloride (350 μL, 4.83 mmol) dropwise and react for 3 h. After the reaction, add water (5 ml) to the reaction solution, extract with dichloromethane (20 ml × 2), combine the organic phases, add anhydrous sodium sulfate and dry. The organic phase is concentrated to obtain a crude product, which is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 9: 1, volume ratio) to obtain a colorless oil B37-2 (102 mg, yield: 45%), MS m / z = 143 [M+1] + .

[0239] B37-2 (102 mg, 0.72 mmol) was added to a mixture of ethyl 6-carbonyl-1,6-dihydropyrimidine-4-carboxylate (80 mg, 0.48 mmol) and potassium carbonate (132 mg, 0.95 mmol) in anhydrous N,N-dimethylformamide (5 ml), and the reaction solution was reacted at room temperature overnight. After the reaction was completed by TLC monitoring, the solvent in the reaction system was evaporated, saturated sodium chloride (5 ml) was added, and the mixture was extracted with dichloromethane (10 ml × 3), the organic phases were combined, and anhydrous sodium sulfate was added to dry. The organic phase was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (dichloromethane: ethyl acetate = 40: 1, volume ratio) to obtain a white oil B37-3 (80 mg, yield: 62%), MS m / z = 275 [M+1] + .

[0240] Lithium hydroxide (38 mg, 1.58 mmol) was added to a tetrahydrofuran (8 ml) solution of B37-3 (361 mg, 1.32 mmol), and the mixture was reacted at room temperature for 1 h. After the reaction was completed, the pH was adjusted to 2-3, and the mixture was concentrated under reduced pressure to obtain the crude target product B37 (180 mg, yield: 56%), MS m / z=247[M+1] + .

[0241] Synthesis of intermediate B38

[0242]

[0243] Dissolve 3-methylphenylboronic acid (300 mg, 2.21 mmol) and ethyl 6-carbonyl-1,6-dihydropyrimidine-4-carboxylate (360 mg, 2.21 mmol) in anhydrous N,N-dimethylformamide (6 ml), then add copper acetate (330 mg, 1.65 mmol) and pyridine (360 μL, 4.41 mmol) and react at room temperature overnight. TLC monitors the reaction to be complete, add saturated sodium chloride (5 ml), extract with dichloromethane (10 ml × 3), combine the organic phases, add anhydrous sodium sulfate and dry. The organic phase is concentrated to obtain a crude product, which is separated and purified by silica gel column chromatography (dichloromethane: ethyl acetate = 40: 1, volume ratio) to obtain a yellow oil B38-1 (323 mg, yield: 57%), MSm / z = 259 [M+1] + .

[0244] Lithium hydroxide (33 mg, 1.39 mmol) was added to a tetrahydrofuran (6 ml) solution of B38-1 (300 mg, 1.16 mmol), and the mixture was reacted at room temperature for 1 h. The reaction was completed after monitoring by TLC. The pH was adjusted to 2-3, and the mixture was concentrated under reduced pressure to obtain the crude target product B38 (200 mg, yield: 75%), MS m / z=231[M+1] + .

[0245] Synthesis of intermediate B39

[0246]

[0247] Referring to the synthetic route of intermediate B6, 1-(1-bromoethyl)-2-fluorobenzene was used to replace 2-(chloromethyl)benzonitrile, and the rest of the operations were the same to obtain B39, MS m / z=263[M+1] + .

[0248] Preparation of compounds from Examples 1 to 2

[0249] Example 1: Preparation of 1-benzyl-N-((6-(((cyclohexylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 1)

[0250]

[0251] The intermediate A3 (164.9 mg, 0.425 mmol) was dissolved in 3 ml of anhydrous ethanol, followed by the addition of cyclohexylmethylamine (96 mg, 0.851 mmol), and the reaction was carried out at 60 ° C for 2 h. The reaction system was then transferred to ice water, and sodium borohydride (32.2 mg, 0.851 mmol) was added under an ice bath. After the addition, the reaction was carried out at room temperature for 1.5 h. TLC monitoring showed that the reaction was complete. The solvent in the reaction system was evaporated, saturated sodium chloride (5 ml) was added, and the mixture was extracted with dichloromethane (20 ml × 3). The organic phases were combined and dried with anhydrous sodium sulfate. The organic phases were concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (dichloromethane: methanol: triethylamine = 70: 1: 15, volume ratio) to obtain compound 1 as a yellow-green solid (91 mg, yield: 46%), MS m / z = 485 [M+1] + . 1 H NMR (400MHz, MeOD) δ8.60(s,1H),8.32(s,1H),7.73(s,1H),7.47(d,J=9.3Hz,1H),7.41-7.30(m,5H),7.14(d,J=0.5Hz,1H),5.21(s,2H),4.71( s,2H),3.76(s,2H),2.44(d,J=6.8Hz,2H),1.84-1.66(m,5H),1.52(m,J =10.3, 6.9, 3.4Hz, 1H), 1.29-1.13 (m, 2H), 0.93 (m, J = 12.3, 6.1Hz, 2H).

[0252] Example 2: Preparation of 1-benzyl-N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 2)

[0253]

[0254] The preparation method is similar to that of Example 1, wherein cyclohexylmethylamine is replaced by cyclobutylmethylamine. Compound 2 is obtained as a yellow solid (50 mg, yield: 42%), MS m / z=457[M+1] + . 1H NMR (400MHz, MeOD) δ8.47(s,1H),8.18(s,1H),7.60(s,1H),7.34(d,J=9.3Hz,1H),7.23(ddd,J=9.3,4.6,2.2Hz,6H),7.00(d,J=0.5Hz,1H),5.08 (s,2H),4.58(s,2H),3.63(s,2H),2.51(d,J=7.3Hz,2H),2.40(dp,J=14 .9,7.5Hz,1H),2.05-1.89(m,2H),1.89-1.65(m,2H),1.65-1.49(m,2H).

[0255] Example 3: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-6-oxo-1-((pyridin-2-yl)methyl)-1,6-dihydropyrimidine-4-carboxamide (Compound 3)

[0256]

[0257] 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATu, 167 mg, 0.438 mmol) and N,N-diisopropylethylamine (DIEA, 87 mg, 0.674 mmol) were added to a mixture of anhydrous dimethylformamide (5 ml) containing B2 (78 mg, 0.337 mmol) and A1 (140 mg, 0.404 mmol) and reacted at room temperature overnight. TLC monitoring showed that the reaction was complete, the solvent in the reaction system was evaporated, saturated sodium chloride (10 ml) was added, and the mixture was extracted with dichloromethane (20 ml×3), the organic phases were combined, and anhydrous sodium sulfate was added to dry. The organic phase was concentrated to obtain a crude product, and anhydrous dichloromethane (4 ml) was added after drying. Trifluoroacetic acid (1 ml) was added under ice bath conditions. After reacting for 2 h, TLC monitoring showed that the reaction was complete. The solvent in the reaction system was evaporated, saturated sodium bicarbonate (5 ml) was added, and extracted with dichloromethane (20 ml×3). The organic phase was collected, dried, and the solvent was evaporated under reduced pressure. The product was separated and purified by silica gel column chromatography (dichloromethane: methanol = 10: 1, volume ratio) to obtain compound 3 as a white foamy solid (49 mg, yield: 32%), MS m / z = 458 [M+1] + . 1H NMR (400MHz, CDCl3) δ8.44(d,J=4.3Hz,1H),8.38(s,1H),8.33(s,1H),8.07(s,1H),7.61(td ,J=7.7,1.7Hz,1H),7.45(d,J=2.1Hz,1H),7.36(t,J=8.2Hz,2H),7.18-7.12(m,2H),7.04(d ,J=9.1Hz,1H),5.11(s,2H),4.62(d,J=5.7Hz,2H),3.77(s,2H),2.72(d,J=7.4Hz,2H),2.46 (dt,J=15.4,7.7Hz,1H),1.97-1.90(m,2H),1.86-1.66(m,2H),1.59(dd,J=19.4,8.9Hz,2H).

[0258] Example 4: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-6-oxo-1-((pyridin-3-yl)methyl)-1,6-dihydropyrimidine-4-carboxamide (Compound 4)

[0259]

[0260] The preparation method is similar to that of Example 3, wherein B2 is replaced by B3. Compound 4 is obtained as a yellow solid with a yield of 23%. MS m / z=458[M+1] + . 1 H NMR (400MHz, DMSO) δ9.11(t,J=5.6Hz,1H),8.90(s,1H),8.64(s,1H),8.51(d,J=3.9Hz,1 H),8.43(s,1H),7.78(s,2H),7.48(d,J=9.2Hz,1H),7.38(dd,J=7.8,4.7Hz,1H),7.26(d ,J=9.2Hz,1H),6.92(s,1H),5.19(s,2H),4.57(d,J=5.7Hz,2H),3.80(s,2H),2.65(d,J= 7.2Hz,2H),2.49-2.40(m,1H),2.05-1.94(m,2H),1.89-1.72(m,2H),1.71-1.60(m,2H).

[0261] Example 5: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-6-oxo-1-((pyridin-4-yl)methyl)-1,6-dihydropyrimidine-4-carboxamide (Compound 5)

[0262]

[0263] The preparation method is similar to that of Example 3, wherein B2 is replaced by B4. Compound 5 is obtained as a yellow-green solid with a yield of 30%, MS m / z = 458 [M+1] + . 1 H NMR(400MHz,DMSO)δ9.12(t,J=5.9Hz,1H),8.81(s,1H),8.53(dd,J=4.5,1.5Hz,2H),8.3 6(s,1H),7.75(s,1H),7.44(d,J=9.2Hz,1H),7.26(d,J=5.9Hz,2H),7.23(dd,J=9.3,1.4H z,1H),6.95(s,1H),5.20(s,2H),4.57(d,J=5.9Hz,2H),3.66(s,2H),2.50(d,J=2.3Hz,2H ), 2.39 (dt, J = 15.0, 7.5Hz, 1H), 2.02-1.91 (m, 2H), 1.87-1.70 (m, 2H), 1.66-1.55 (m, 2H).

[0264] Example 6: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-6-oxo-1-((thiazol-4-yl)methyl)-1,6-dihydropyrimidine-4-carboxamide (Compound 6)

[0265]

[0266] The preparation method is similar to that of Example 3, wherein B2 is replaced by B5. Compound 6 is obtained as a yellow-white solid with a yield of 39% and MS m / z = 464 [M+1] + . 1 H NMR (400MHz, DMSO) δ9.13(t,J=6.0Hz,1H),9.05(d,J=1.9Hz,1H),8.78(d,J=0.6Hz,1H),8 .34(s,1H),7.73(s,1H),7.65(d,J=1.9Hz,1H),7.43(d,J=9.2Hz,1H),7.23(dd,J=9.3,1. 6Hz,1H),6.91(d,J=0.6Hz,1H),5.29(s,2H),4.56(d,J=5.9Hz,2H),3.63(s,2H),2.48(d, J=7.3Hz,2H),2.44-2.32(m,1H),2.03-1.90(m,2H),1.88-1.70(m,2H),1.67-1.54(m,2H).

[0267] Example 7: Preparation of 1-(2-cyanobenzyl)-N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 7)

[0268]

[0269] The preparation method is similar to that of Example 3, wherein B2 is replaced by B6. Compound 7 is obtained as a yellow foamy solid with a yield of 46% and MS m / z=482[M+1] + . 1 H NMR (400MHz, DMSO) δ9.14(t,J=5.9Hz,1H),8.84(s,1H),8.38(s,1H),7.89(d,J=7.2Hz,1H),7. 76(s,1H),7.67(t,J=7.3Hz,1H),7.51(t,J=7.5Hz,1H),7.45(d,J=9.2Hz,1H),7.30(d,J=7.9Hz ,1H),7.22(d,J=9.2Hz,1H),6.94(s,1H),5.36(s,2H),4.58(d,J=5.8Hz,2H),3.67(s,2H),2.53 (s,2H),2.40(dt,J=15.0,7.5Hz,1H),2.03-1.91(m,2H),1.88-1.71(m,2H),1.68-1.56(m,2H).

[0270] Example 8: Preparation of 1-(3-cyanobenzyl)-N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 8)

[0271]

[0272] The preparation method was similar to that of Example 3, wherein B2 was replaced by B7. Compound 8 was obtained as a yellow foamy solid with a yield of 38% and MS m / z=482[M+1] + . 1H NMR (400MHz, DMSO) δ9.13(t,J=5.9Hz,1H),8.85(s,1H),8.48(s,1H),7.85(s,1H),7.78( d,J=6.8Hz,2H),7.69(d,J=7.9Hz,1H),7.57(t,J=7.8Hz,1H),7.50(d,J=9.3Hz,1H),7.29 (d,J=9.3Hz,1H),6.92(s,1H),5.20(s,2H),4.58(d,J=5.9Hz,2H),3.92(s,2H),2.77(d, J=7.2Hz,2H),2.06-1.93(m,2H),1.80(ddd,J=12.8,11.7,6.1Hz,2H),1.74-1.62(m,3H).

[0273] Example 9: Preparation of 1-(4-cyanobenzyl)-N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 9)

[0274]

[0275] The preparation method is similar to that of Example 3, wherein B2 is replaced by B8. Compound 9 is obtained as a yellow-white solid with a yield of 30%, MS m / z = 482 [M+1] + . 1 H NMR(400MHz,DMSO)δ9.15(t,J=5.8Hz,1H),8.85(s,1H),8.55(s,1H),7.87-7.78(m ,3H),7.52(t,J=9.6Hz,3H),7.33(d,J=9.3Hz,1H),6.93(s,1H),5.24(s,2H),4.58 (d,J=5.8Hz,2H),4.02(s,2H),2.91-2.79(m,2H),2.57(dt,J=12.5,6.3Hz,1H),2. 02(dd,J=18.0,9.4Hz,2H),1.82(ddd,J=16.3,14.6,7.6Hz,2H),1.75-1.63(m,2H).

[0276] Example 10: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-6-oxo-1-(2-(trifluoromethyl)benzyl)-1,6-dihydropyrimidine-4-carboxamide (Compound 10)

[0277]

[0278] The preparation method was similar to that of Example 3, wherein B2 was replaced by B9. Compound 10 was obtained as a yellow solid with a yield of 48% and MS m / z = 525 [M+1] + . 1 H NMR(400MHz,DMSO)δ9.18(t,J=5.9Hz,1H),8.77(s,1H),8.47(s,1H),7.81(d,J=6.0Hz, 2H),7.62(t,J=7.5Hz,1H),7.52(dd,J=15.0,8.4Hz,2H),7.27(d,J=9.3Hz,1H),7.06-6. 95(m,2H),5.38(s,2H),4.60(d,J=5.8Hz,2H),3.83(s,2H),2.68(d,J=7.2Hz,2H),2.49 -2.43(m,1H),2.06-1.94(m,2H),1.80(tdd,J=15.2,7.6,2.8Hz,2H),1.73-1.61(m,2H).

[0279] Example 11: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-6-oxo-1-(3-(trifluoromethyl)benzyl)-1,6-dihydropyrimidine-4-carboxamide (Compound 11)

[0280]

[0281] The preparation method is similar to that of Example 3, wherein B2 is replaced by B10. Compound 11 is obtained as a yellow foamy solid with a yield of 42% and MS m / z=525[M+1] + . 1 H NMR (400MHz, DMSO) δ9.12(t,J=5.8Hz,1H),8.92(s,1H),8.42(s,1H),7.79(d,J=6.9Hz ,2H),7.72-7.64(m,2H),7.63-7.56(m,1H),7.48(d,J=9.2Hz,1H),7.26(d,J=9.2Hz,1H ),6.94(s,1H),5.26(s,2H),4.58(d,J=5.8Hz,2H),3.77(s,2H),2.62(d,J=7.2Hz,2H), 2.44(td,J=15.0,7.5Hz,1H),2.05-1.93(m,2H),1.89-1.72(m,2H),1.70-1.59(m,2H).

[0282] Example 12: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(2-methoxybenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 12)

[0283]

[0284] The preparation method is similar to that of Example 3, wherein B2 is replaced by B30. Compound 12 is obtained as a yellow solid with a yield of 40%, MS m / z = 487 [M+1] + . 1 H NMR (400MHz, DMSO) δ9.07(t,J=5.7Hz,1H),8.67(s,1H),8.36(s,1H),7.75(s,1H),7.44(d,J=9.2 Hz,1H),7.31(t,J=7.7Hz,1H),7.22(d,J=9.2Hz,1H),7.13(d,J=7.3Hz,1H),7.03(d,J=8.3Hz,1H ),6.96-6.85(m,2H),5.07(s,2H),4.56(d,J=5.8Hz,2H),3.83(s,3H),3.65(s,2H),2.52(s,2H), 2.39(dt,J=15.0,7.5Hz,1H),1.97(m,J=11.7,5.8Hz,2H),1.88-1.71(m,2H),1.68-1.56(m,2H).

[0285] Example 13: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(3-methoxybenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 13)

[0286]

[0287] The preparation method is the same as that of Example 3, wherein B2 is replaced by B11. Compound 13 is obtained as a yellow solid with a yield of 38%, MS m / z = 487 [M+1] + . 1H NMR(400MHz,DMSO)δ9.10(t,J=5.9Hz,1H),8.83(s,1H),8.44(s,1H),7.78(s,1H),7.49( d,J=9.2Hz,1H),7.27(t,J=7.9Hz,2H),6.94(d,J=6.3Hz,2H),6.89(d,J=8.0Hz,2H),5.13 (s,2H),4.57(d,J=5.8Hz,2H),3.82(s,2H),3.74(s,3H),2.67(d,J=7.2Hz,2H),2.46(dd ,J=15.2,7.7Hz,1H),2.05-1.93(m,2H),1.89-1.73(m,2H),1.66(dt,J=16.8,8.3Hz,2H).

[0288] Example 14: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 14)

[0289]

[0290] The preparation method is similar to that of Example 3, wherein B2 is replaced by B12. Compound 14 is obtained as a yellow solid with a yield of 45%, MS m / z = 487 [M+1] + . 1 H NMR(400MHz, CDCl3)δ8.40(t,J=5.4Hz,1H),8.10(s,1H),8.03(s,1H),7.49(s,1H),7 .45(d,J=9.2Hz,1H),7.26(d,J=6.1Hz,3H),7.15(d,J=9.3Hz,1H),6.92-6.82(m,2H) ,5.04(s,2H),4.71(d,J=5.8Hz,2H),3.78(d,J=5.7Hz,5H),2.67(d,J=7.2Hz,2H),2. 51(dp,J=15.1,7.5Hz,1H),2.13-2.02(m,2H),1.97-1.79(m,2H),1.74-1.60(m,2H).

[0291] Example 15: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(2-methylbenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 15)

[0292]

[0293] The preparation method is similar to that of Example 3, wherein B2 is replaced by B13. Compound 15 is obtained as a yellow solid with a yield of 31%, MS m / z = 471 [M+1] + . 1 H NMR (400MHz, DMSO) δ9.12(t,J=5.9Hz,1H),8.69(s,1H),8.46(s,1H),7.80(s,1H),7.49(d,J=9.2H z,1H),7.28(d,J=9.3Hz,1H),7.21(q,J=7.4Hz,2H),7.15(t,J=7.2Hz,1H),6.96(s,1H),6.86(d,J= 7.5Hz,1H),5.16(s,2H),4.59(d,J=5.8Hz,2H),3.81(s,2H),2.66(d,J=7.2Hz,2H),2.49-2.42(m,1 H), 2.36 (s, 3H), 2.00 (m, J = 11.7, 8.1, 3.9Hz, 2H), 1.89-1.74 (m, 2H), 1.66 (dt, J = 16.6, 8.2Hz, 3H).

[0294] Example 16: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(3-methylbenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 16)

[0295]

[0296] The preparation method is similar to that of Example 3, wherein B2 is replaced by B14. Compound 16 is obtained as a yellow solid with a yield of 30%. MS m / z = 471 [M+1] + . 1 H NMR (400MHz, DMSO) δ9.08 (t, J = 5.8Hz, 1H), 8.82 (s, 1H), 8.39 (s, 1H), 7.76 (s, 1H), 7. 45(d,J=9.2Hz,1H),7.28-7.19(m,2H),7.13(dd,J=12.9,7.5Hz,3H),6.93(s,1H),5. 12(s,2H),4.57(d,J=5.8Hz,2H),3.70(s,2H),2.56(d,J=7.1Hz,2H),2.42(dt,J=15. 0,7.5Hz,1H),2.28(s,3H),2.03-1.91(m,2H),1.89-1.71(m,2H),1.68-1.56(m,2H).

[0297] Example 17: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(4-methylbenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 17)

[0298]

[0299] The preparation method is similar to that of Example 3, wherein B2 is replaced by B15. Compound 17 is obtained as a yellow solid with a yield of 39% and MS m / z = 471 [M+1] + . 1 H NMR (400MHz, DMSO) δ9.03 (t, J = 5.8Hz, 1H), 8.80 (s, 1H), 8.34 (s, 1H), 7.73 (s, 1H) ),7.43(d,J=9.2Hz,1H),7.27-7.18(m,3H),7.16(d,J=7.9Hz,2H),6.91(s,1H),5 .11(s,2H),4.56(d,J=5.9Hz,2H),3.64(s,2H),2.49(s,2H),2.39(dt,J=14.9,7 .5Hz,1H),2.27(s,3H),2.02-1.89(m,2H),1.86-1.71(m,2H),1.66-1.55(m,2H).

[0300] Example 18: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(2-fluorobenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 18)

[0301]

[0302] The preparation method is similar to that of Example 3, wherein B2 is replaced by B16. Compound 18 is obtained as a yellow solid with a yield of 46% and MS m / z = 475 [M+1] + . 1H NMR(400MHz, CDCl3)δ8.40(t,J=5.5Hz,1H),8.23(s,1H),8.03(s,1H),7.52-7.42( m,3H),7.31(m,J=7.4,5.5,1.7Hz,1H),7.24(d,J=0.5Hz,1H),7.16-7.10(m,2H),7 .09-7.02(m,1H),5.11(s,2H),4.70(d,J=5.8Hz,2H),3.76(s,2H),2.65(d,J=7.3H z,2H),2.53-2.47(m,1H),2.10-1.97(m,3H),1.93-1.77(m,2H),1.69-1.58(m,2H).

[0303] Example 19: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(3-fluorobenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 19)

[0304]

[0305] The preparation method is similar to that of Example 3, wherein B2 is replaced by B17. Compound 19 is obtained as a yellow solid with a yield of 34% and MS m / z = 475 [M+1] + . 1 H NMR(400MHz,DMSO)δ9.11(t,J=5.9Hz,1H),8.85(s,1H),8.43(s,1H),7.78(s,1H),7 .48(d,J=9.2Hz,1H),7.44-7.36(m,1H),7.29-7.20(m,2H),7.20-7.11(m,2H),6.94 (s,1H),5.18(s,2H),4.58(d,J=5.8Hz,2H),3.78(s,2H),2.63(d,J=7.2Hz,2H),2.4 5(td,J=15.0,7.6Hz,1H),2.05-1.92(m,2H),1.90-1.71(m,2H),1.71-1.57(m,2H).

[0306] Example 20: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(4-fluorobenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 20)

[0307]

[0308] The preparation method is similar to that of Example 3, wherein B2 is replaced by B18. Compound 20 is obtained as a yellow solid with a yield of 32%, MS m / z = 475 [M+1] + . 1 H NMR(400MHz,DMSO)δ9.10(t,J=5.9Hz,1H),8.86(s,1H),8.45(s,1H),7.78(s,1H),7.49( d,J=9.3Hz,1H),7.44(dd,J=8.6,5.6Hz,2H),7.28(dd,J=9.3,1.4Hz,1H),7.19(t,J=8.9H z,2H),6.92(s,1H),5.15(s,2H),4.57(d,J=5.9Hz,2H),3.82(s,2H),2.67(d,J=7.2Hz,2H ), 2.45 (dd, J = 14.9, 7.4Hz, 1H), 2.05-1.93 (m, 2H), 1.90-1.74 (m, 2H), 1.72-1.61 (m, 2H).

[0309] Example 21: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(2,6-difluorobenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 21)

[0310]

[0311] The preparation method is similar to that of Example 3, wherein B2 is replaced by B19. Compound 21 is obtained as a yellow solid with a yield of 36%. MS m / z = 493 [M+1] + . 1 H NMR(400MHz,DMSO)δ9.11(t,J=5.9Hz,1H),8.82(s,1H),8.39(s,1H),7.76(s,1H), 7.50-7.37(m,2H),7.23(d,J=9.2Hz,1H),7.11(t,J=8.2Hz,2H),6.85(s,1H),5.22( s,2H),4.56(d,J=5.9Hz,2H),3.72(s,2H),2.57(d,J=7.2Hz,2H),2.42(dt,J=15.0, 7.5Hz,1H),2.04-1.92(m,2H),1.80(m,J=12.6,6.2,2.2Hz,2H),1.69-1.58(m,2H).

[0312] Example 22: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(2,4-difluorobenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 22)

[0313]

[0314] The preparation method is similar to that of Example 3, wherein B2 is replaced by B20. Compound 22 is obtained as a yellow solid with a yield of 26%. MS m / z = 493 [M+1] + . 1 H NMR (400MHz, DMSO) δ9.08(t,J=5.9Hz,1H),8.77(s,1H),8.35(s,1H),7.74(s,1H),7.43( d,J=9.4Hz,1H),7.41-7.34(m,1H),7.28(t,J=10.0Hz,1H),7.21(d,J=9.2Hz,1H),7.07(t ,J=8.5Hz,1H),6.90(s,1H),5.17(s,2H),4.56(d,J=5.9Hz,2H),3.64(s,2H),2.48(s,2H ), 2.37(td,J=14.7,7.3Hz,1H),2.03-1.89(m,2H),1.87-1.70(m,2H),1.67-1.54(m,2H).

[0315] Example 23: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(2,5-difluorobenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 23)

[0316]

[0317] The preparation method is similar to that of Example 3, wherein B2 is replaced by B21. Compound 23 is obtained as a yellow solid with a yield of 48% and MS m / z = 493 [M+1] + . 1H NMR (400MHz, DMSO) δ9.14(t,J=5.9Hz,1H),8.82(s,1H),8.50(s,1H),7.82(s,1H),7.53(d,J=9 .3Hz,1H),7.44(dt,J=15.0,7.5Hz,1H),7.29(d,J=9.3Hz,1H),7.11(t,J=8.2Hz,2H),6.85(s,1 H),5.23(s,2H),4.57(d,J=5.9Hz,2H),3.95(s,2H),2.80(d,J=7.2Hz,2H),2.58-2.52(m,1H), 2.01(dt,J=8.4,6.1Hz,2H), 1.81(ddd,J=12.7,11.8,6.1Hz,2H), 1.71(dd,J=17.6,8.7Hz,2H).

[0318] Example 24: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(2-fluoro-6-methylbenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 24)

[0319]

[0320] The preparation method was similar to that of Example 3, wherein B2 was replaced by B27. Compound 24 was obtained as a yellow solid with a yield of 36%. MS m / z = 489 [M+1] + . 1 H NMR (400MHz, DMSO) δ9.05(t,J=5.9Hz,1H),8.67(d,J=2.7Hz,1H),8.39(s,1H),7.76(s,1H),7 .45(d,J=9.2Hz,1H),7.31-7.20(m,2H),7.07(d,J=7.6Hz,1H),7.04-6.97(m,1H),6.86(s,1H ),5.17(s,2H),4.56(d,J=5.9Hz,2H),3.70(s,2H),2.56(d,J=7.2Hz,2H),2.48(s,3H),2.41( dd,J=14.9,7.5Hz,1H),1.97(m,J=7.3,6.5,3.0Hz,2H),1.86-1.72(m,2H),1.69-1.57(m,2H).

[0321] Example 25: Preparation of 1-(2-aminobenzyl)-N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 25)

[0322]

[0323] The preparation method was similar to that of Example 3, wherein B2 was replaced by B26. Compound 25 was obtained as a yellow-white solid with a yield of 30%. MS m / z = 472 [M+1] + . 1 H NMR(400MHz,DMSO)δ9.08(s,1H),8.66(s,1H),8.35(s,1H),7.74(s,1H),7.43(d,J =8.9Hz,1H),7.21(d,J=8.7Hz,1H),7.09-6.97(m,2H),6.95(s,1H),6.69(d,J=7.6 Hz,1H),6.54(t,J=6.8Hz,1H),5.30(s,2H),5.02(s,2H),4.57(s,2H),3.65(s,2H) ,2.45-2.31(m,1H),1.96(s,2H),1.79(dd,J=16.4,7.8Hz,2H),1.68-1.51(m,2H).

[0324] Example 26: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(2-hydroxybenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 26)

[0325]

[0326] 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATu, 172 mg, 0.447 mmol) and N,N-diisopropylethylamine (DIEA, 90 mg, 0.696 mmol) were added to a mixture of anhydrous dimethylformamide (5 ml) containing B28 (203 mg, 0.418 mmol) and A1 (120 mg, 0.348 mmol) and reacted at room temperature overnight. TLC monitoring showed that the reaction was complete, the solvent in the reaction system was evaporated, saturated sodium chloride (10 ml) was added, and the mixture was extracted with dichloromethane (20 ml×3), the organic phases were combined, and anhydrous sodium sulfate was added to dry. The organic phase was concentrated to obtain a crude product 26-1. After drying, anhydrous tetrahydrofuran (6 ml) was added, and tetrabutylammonium fluoride (180 μl) was added. After reacting for 30 minutes, TLC monitoring showed that the reaction was complete. The solvent in the reaction system was evaporated and purified by silica gel column chromatography (dichloromethane: methanol = 20: 1, volume ratio) to obtain 26-2 as a yellow foamy solid (92 mg, yield: 76%).

[0327] Dissolve 26-2 in anhydrous dichloromethane (2 ml), add trifluoroacetic acid (500 μl) under ice bath conditions, react for 2 h, TLC monitoring shows that the reaction is complete, evaporate the solvent in the reaction system, add saturated sodium bicarbonate (5 ml), extract with dichloromethane (20 ml × 3), collect the organic phase, dry, evaporate the solvent under reduced pressure, separate and purify by silica gel column chromatography (dichloromethane: methanol = 10: 1, volume ratio), and obtain compound 26 as a yellow-white solid (35 mg, yield: 36%), MS m / z = 473 [M+1] + . 1 H NMR (400MHz, DMSO) δ9.09 (t, J=5.9Hz, 1H), 8.68 (s, 1H), 8.37 (s, 1H), 7.75 (s, 1H), 7.45 (d, J= 9.2Hz,1H),7.23(d,J=9.2Hz,1H),7.13(dd,J=12.9,7.1Hz,2H),6.89(s,1H),6.85(d,J=8.0Hz ,1H),6.77(t,J=7.4Hz,1H),5.05(s,2H),4.56(d,J=5.8Hz,2H),3.69(s,2H),2.54(d,J=7.1H z,2H),2.41(dt,J=15.0,7.5Hz,1H),2.04-1.91(m,2H),1.86-1.71(m,2H),1.69-1.55(m,2H).

[0328] Example 27: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-6-oxo-1-phenethyl-1,6-dihydropyrimidine-4-carboxamide (Compound 27)

[0329]

[0330] The preparation method was similar to that of Example 3, wherein B2 was replaced by B22. Compound 27 was obtained as a yellow oil with a yield of 37%, MS m / z = 471 [M+1] + . 1 H NMR (400MHz, DMSO) δ9.01(t,J=5.9Hz,1H),8.44(s,1H),8.30(s,1H),7.75(s,1H),7.47(d,J =9.3Hz,1H),7.33-7.24(m,3H),7.21(dd,J=13.2,7.1Hz,3H),6.90(s,1H),4.54(d,J=5.9Hz ,2H),4.18(t,J=7.2Hz,2H),3.80(s,2H),2.98(t,J=7.2Hz,2H),2.65(d,J=7.2Hz,2H),2.44 (dd,J=15.0,7.5Hz,1H),2.04-1.92(m,2H),1.86-1.71(m,2H),1.65(dt,J=16.9,8.3Hz,2H).

[0331] Example 28: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-6-oxo-1-(3-phenylpropyl)-1,6-dihydropyrimidine-4-carboxamide (Compound 28)

[0332]

[0333] The preparation method was similar to that of Example 3, wherein B2 was replaced by B23. Compound 28 was obtained as a yellow solid with a yield of 20%. MS m / z = 485 [M+1] + . 1H NMR (400MHz, CDCl3) δ8.32(t,J=5.5Hz,1H),7.98(s,1H),7.89(s,1H),7.45(s,1H),7.41(d,J= 9.2Hz,1H),7.22(t,J=7.4Hz,2H),7.18(s,1H),7.14(d,J=7.4Hz,1H),7.09(t,J=7.9Hz,3H),4 .66(d,J=5.8Hz,2H),3.91-3.81(m,2H),3.70(s,2H),2.65-2.57(m,4H),2.43(dt,J=15.2,7.6 Hz, 1H), 1.98 (ddd, J=7.6, 4.3, 2.1Hz, 2H), 1.80 (m, J=15.5, 7.7, 3.4Hz, 2H), 1.64-1.53 ​​(m, 2H).

[0334] Example 29: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(2-fluorophenethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 29)

[0335]

[0336] The preparation method is similar to that of Example 3, wherein B2 is replaced by B25. Compound 29 is obtained as a yellow solid with a yield of 43% and MS m / z = 489 [M+1] + . 1 H NMR(400MHz,DMSO)δ9.03(t,J=5.9Hz,1H),8.44(s,1H),8.29(s,1H),7.76(s,1H),7.47(d ,J=9.3Hz,1H),7.27(t,J=7.5Hz,3H),7.14(dd,J=12.9,5.5Hz,2H),6.88(s,1H),4.54(d,J =5.8Hz,2H),4.18(t,J=6.8Hz,2H),3.80(s,2H),3.04(t,J=6.8Hz,2H),2.65(d,J=7.2Hz,2 H), 2.49-2.40 (m, 1H), 2.05-1.92 (m, 2H), 1.89-1.71 (m, 2H), 1.65 (dt, J = 16.6, 8.4Hz, 2H).

[0337] Example 30: Preparation of 1-benzyl-N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxamide (Compound 30)

[0338]

[0339] The preparation method was similar to that of Example 3, wherein B2 was replaced by B29. Compound 30 was obtained as a yellow foamy solid with a yield of 45%. MS m / z = 456 [M+1] + . 1 H NMR (400MHz, DMSO) δ9.20(t,J=5.6Hz,1H),8.41(s,1H),7.89(d,J=7.0Hz,1H),7.78(s,1H ),7.45(d,J=9.2Hz,1H),7.37-7.31(m,2H),7.26(dd,J=14.0,8.3Hz,4H),6.90(s,1H),6. 61(d,J=7.0Hz,1H),5.12(s,2H),4.52(d,J=5.6Hz,2H),3.78(s,2H),2.63(d,J=7.2Hz,2H ), 2.44(dt,J=15.1,7.7Hz,1H),2.04-1.91(m,2H),1.85-1.71(m,2H),1.69-1.58(m,2H).

[0340] Example 31: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-(4-ethynylbenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 31)

[0341]

[0342] The preparation method is similar to that of Example 3, wherein B2 is replaced by B24. Compound 31 is obtained as a white solid with a yield of 45%, MS m / z = 481 [M+1] + . 1 H NMR(400MHz,DMSO)δ9.11(t,J=5.9Hz,1H),8.84(s,1H),8.42(s,1H),7.77(s,1H) ,7.50-7.43(m,3H),7.34(d,J=8.2Hz,2H),7.26(dd,J=9.3,1.4Hz,1H),6.92(s,1H ),5.17(s,2H),4.57(d,J=5.8Hz,2H),4.20(s,1H),3.77(s,2H),2.62(d,J=7.2Hz ,2H),2.48-2.39(m,1H),2.04-1.94(m,2H),1.87-1.72(m,2H),1.70-1.59(m,2H).

[0343] Example 32: Preparation of N-((2-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-1-(2-fluorobenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 32)

[0344]

[0345] 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATu, 367 mg, 0.97 mmol) and N,N-diisopropylethylamine (DIEA, 312 mg, 2.42 mmol) were added to a mixture of anhydrous N,N-dimethylformamide (5 ml) containing B16 (240 mg, 0.97 mmol) and B31 (200 mg, 0.81 mmol) and reacted at room temperature overnight. TLC monitoring showed that the reaction was complete, the solvent in the reaction system was evaporated, saturated sodium chloride (10 ml) was added, and the mixture was extracted with dichloromethane (20 ml×3), the organic phases were combined, and anhydrous sodium sulfate was added to dry. The organic phase was concentrated to obtain a crude product 32A. 32A (150 mg, 0.37 mmol) was dissolved in tetrahydrofuran (10 ml), and water (1 ml) and acetic acid (1 ml) were added. The mixture was reacted at room temperature for 2 h. After concentration under reduced pressure, the mixture was separated and purified by silica gel column chromatography (dichloromethane: methanol = 40: 1, volume ratio) to obtain 32B (167 mg, yield: 70%).

[0346] 32B (150 mg, 0.37 mmol) was dissolved in 1,2-dichloroethane (5 ml), and cyclobutylmethylamine hydrochloride (90 mg, 0.74 mmol) and N,N-diisopropylethylamine (DIEA, 115 mg, 0.89 mmol) were added at 65°C. The reaction was allowed to react for 2 h, and then the reaction system was transferred to ice water. Sodium cyanoborohydride (79 mg, 1.26 mmol) was added in an ice bath. After the addition, the temperature was moved to 65°C. TLC monitoring showed that the reaction was complete. The solvent in the reaction system was evaporated, saturated sodium chloride (5 ml) was added, and the mixture was extracted with dichloromethane (20 ml × 3). The organic phases were combined and dried with anhydrous sodium sulfate. The organic phases were concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (dichloromethane: methanol = 30: 1, volume ratio) to obtain compound 32 as a yellow-white solid (56 mg, yield: 49%), MS m / z = 474 [M+1] + . 1H NMR (400MHz, DMSO) δ10.81(s,1H),9.13(t,J=6.2Hz,1H),8.65(s,1H),7.25(t,J=8.7 Hz,2H),7.19-7.13(m,2H),7.13-7.02(m,2H),6.84(d,J=8.1Hz,1H),6.80(s,1H),6. 14(s,1H),5.09(s,2H),4.40(d,J=6.2Hz,2H),3.74(s,2H),2.47(d,J=7.1Hz,2H),2. 32(dt,J=15.0,7.6Hz,1H),1.94-1.81(m,2H),1.77-1.60(m,2H),1.59-1.47(m,2H).

[0347] Example 33: Preparation of N-((2-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-1-(2-fluoro-6-methylbenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 33)

[0348]

[0349] The preparation method was similar to that of Example 32, wherein B16 was replaced by B27. Compound 33 was obtained as a yellow solid with a yield of 56%. MS m / z = 488 [M+1] + . 1 H NMR (400MHz, DMSO) δ10.88(s,1H),9.19(t,J=6.2Hz,1H),8.67(d,J=2.6Hz,1H),7.36(d,J=8.0Hz ,1H),7.26(q,J=8.0Hz,2H),7.06(d,J=7.5Hz,1H),7.04-6.97(m,1H),6.93(d,J=8.1Hz,1H),6.8 5(s,1H),6.21(s,1H),5.16(s,2H),4.50(d,J=6.2Hz,2H),3.79(s,2H),2.53(d,J=7.3Hz,2H),2. 47(s,3H),2.39(dd,J=15.0,7.5Hz,1H),2.03-1.92(m,2H),1.86-1.72(m,2H),1.69-1.57(m,2H).

[0350] Example 34: Preparation of N-((2-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-6-oxo-1-(3-(trifluoromethyl)benzyl)-1,6-dihydropyrimidine-4-carboxamide (Compound 34)

[0351]

[0352] The preparation method was similar to that of Example 32, wherein B16 was replaced by B10. Compound 34 was obtained as a yellow-white solid with a yield of 36%. MS m / z = 524 [M+1] + . 1 H NMR (400MHz, CDCl3) δ9.74 (s, 1H), 8.14-8.04 (m, 2H), 7.54 (d, J = 6.2Hz, 2H), 7 .50-7.39(m,3H),7.23(s,2H),6.96(d,J=8.1Hz,1H),6.34(s,1H),5.06(s,2H) ,4.57(d,J=5.7Hz,2H),4.02(s,2H),2.71(d,J=7.3Hz,2H),2.55(dt,J=15.3,7 .6Hz,1H),2.08-1.97(m,2H),1.88-1.74(m,2H),1.66(dd,J=18.5,8.9Hz,2H).

[0353] Example 35: Preparation of N-((2-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-1-(3-methoxybenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 35)

[0354]

[0355] The preparation method was similar to that of Example 32, wherein B16 was replaced by B11. Compound 35 was obtained as a yellow-white solid with a yield of 34%. MS m / z=486[M+1] + . 1 H NMR (400MHz, DMSO) δ10.89(s,1H),9.18(t,J=6.3Hz,1H),8.79(s,1H),7.36(d,J=8.1 Hz,1H),7.26(t,J=7.9Hz,2H),6.96-6.90(m,3H),6.90-6.84(m,2H),6.21(s,1H),5. 11(s,2H),4.50(d,J=6.3Hz,2H),3.79(s,2H),3.73(s,3H),2.53(d,J=7.1Hz,2H),2. 40(dt,J=14.9,7.5Hz,1H),2.02-1.91(m,2H),1.87-1.72(m,2H),1.68-1.57(m,2H).

[0356] Example 36: Preparation of N-((2-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-1-(3-methylbenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 36)

[0357]

[0358] The preparation method was similar to that of Example 32, wherein B16 was replaced by B14. Compound 36 was obtained as a yellow solid with a yield of 26%. MS m / z = 470 [M+1] + . 1 H NMR (400MHz, DMSO) δ10.93 (s, 1H), 9.19 (s, 1H), 8.79 (s, 1H), 7.38 (d, J = 8.0Hz, 1H), 7.28(s,1H),7.23(t,J=7.4Hz,1H),7.17-7.05(m,3H),6.99-6.87(m,2H),6.25(s,1H ),5.11(s,2H),4.51(d,J=5.8Hz,2H),3.85(s,2H),2.58(d,J=7.0Hz,2H),2.48-2.3 8(m,1H),2.28(s,3H),1.97(s,2H),1.87-1.72(m,2H),1.65(dd,J=17.4,8.4Hz,2H).

[0359] Example 37: Preparation of N-((2-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-1-(2-fluoro-6-methylbenzyl)-6-oxo-1,6-dihydropyridazine-4-carboxamide (Compound 37)

[0360]

[0361] The preparation method was similar to that of Example 32, wherein B16 was replaced by B35. Compound 37 was obtained as a yellow solid with a yield of 56%. MS m / z = 488 [M+1] + . 1H NMR (400MHz, DMSO) δ11.16(s,1H),9.41(t,J=5.9Hz,1H),8.15(d,J=2.1Hz,1H),7.45(d, J=8.1Hz,1H),7.36-7.30(m,2H),7.30-7.23(m,1H),7.08-6.94(m,3H),6.43(s,1H),5.33 (s,2H),4.52(d,J=5.8Hz,2H),4.06(s,2H),2.77(d,J=7.3Hz,2H),2.56(dd,J=15.1,7.6 Hz, 1H), 2.29 (s, 3H), 2.07-1.97 (m, 2H), 1.91-1.75 (m, 2H), 1.69 (dd, J = 17.6, 9.0Hz, 2H).

[0362] Example 38: Preparation of 1-benzyl-N-((2-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 38)

[0363]

[0364] The preparation method was similar to that of Example 32, wherein B16 was replaced by B1. Compound 38 was obtained as a yellow solid with a yield of 55%. MS m / z = 456 [M+1] + . 1 H NMR (400MHz, DMSO) δ11.01 (s, 1H), 9.12 (t, J = 6.2Hz, 1H), 8.70 (s, 1H), 7.33 ( d,J=8.1Hz,1H),7.26-7.16(m,6H),6.88(d,J=8.1Hz,1H),6.80(s,1H),6.33( s,1H),5.04(s,2H),4.40(d,J=6.2Hz,2H),3.98(s,2H),2.70(d,J=7.3Hz,2H) ,2.50-2.41(m,1H),1.95-1.85(m,2H),1.77-1.64(m,2H),1.64-1.54(m,2H).

[0365] Example 39: Preparation of 1-(2-cyanobenzyl)-N-((2-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 39)

[0366]

[0367] The preparation method is similar to that of Example 32, wherein B16 is replaced by B6. Compound 39 is obtained as a yellow solid with a yield of 35%, MS m / z = 481 [M+1] + . 1 H NMR (400MHz, DMSO) δ10.89(s,1H),9.25(t,J=6.3Hz,1H),8.81(s,1H),7.88(d,J=7.7Hz,1H),7. 65(t,J=7.7Hz,1H),7.50(t,J=7.3Hz,1H),7.37(d,J=8.1Hz,1H),7.28(d,J=10.5Hz,2H),6.94(d d,J=7.0,5.7Hz,2H),6.22(s,1H),5.34(s,2H),4.51(d,J=6.3Hz,2H),3.81(s,2H),2.54(d,J=7. 1Hz,2H),2.41(dt,J=15.0,7.5Hz,1H),2.03-1.91(m,2H),1.87-1.71(m,2H),1.69-1.57(m,2H).

[0368] Example 40: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-1-(2,6-difluorobenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 40)

[0369]

[0370] The preparation method was similar to that of Example 32, wherein B16 was replaced by B19. Compound 40 was obtained as a yellow solid with a yield of 26%. MS m / z = 492 [M+1] + . 1 H NMR (400MHz, DMSO) δ10.98 (s, 1H), 9.22 (t, J = 6.3Hz, 1H), 8.80 (s, 1H), 7.49-7.36 (m, 2H),7.29(s,1H),7.10(t,J=8.2Hz,2H),6.96(dd,J=8.1,1.1Hz,1H),6.85(s,1H),6. 30(s,1H),5.22(s,2H),4.51(d,J=6.3Hz,2H),3.91(s,2H),2.64(d,J=7.2Hz,2H),2. 46(dd,J=15.0,7.5Hz,1H),2.04-1.94(m,2H),1.87-1.72(m,2H),1.71-1.60(m,2H).

[0371] Example 41: Preparation of N-((2-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-1-(2-fluoro-6-methylbenzyl)-2-oxo-1,2-dihydropyrimidine-4-carboxamide (Compound 41)

[0372]

[0373] The preparation method was similar to that of Example 32, wherein B16 was replaced by B36. Compound 41 was obtained as a yellow solid with a yield of 15%. MS m / z = 488 [M+1] + . 1 H NMR (400MHz, DMSO) δ10.87(s,1H),9.27(t,J=6.4Hz,1H),8.28(dd,J=6.7,2. 1Hz,1H),7.38-7.22(m,3H),7.13-7.01(m,2H),6.93(t,J=7.4Hz,2H),6.21(s ,1H),5.15(s,2H),4.46(d,J=6.3Hz,2H),3.79(s,2H),2.53(d,J=7.2Hz,2H) ,2.45-2.37(m,4H),2.01-1.92(m,2H),1.86-1.71(m,2H),1.67-1.57(m,2H).

[0374] Example 42: Preparation of N-((2-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-1-(3-fluorobenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 42)

[0375]

[0376] The preparation method was similar to that of Example 32, wherein B16 was replaced by B17. Compound 42 was obtained as a yellow-white solid with a yield of 32%. MS m / z=474[M+1] + . 1H NMR (400MHz, DMSO) δ10.99 (s, 1H), 9.21 (t, J = 6.3Hz, 1H), 8.82 (s, 1H), 7.43-7.35 (m, 2H) ,7.29(s,1H),7.24-7.18(m,1H),7.18-7.10(m,2H),6.96(dd,J=8.1,1.2Hz,1H),6.92(s ,1H),6.31(s,1H),5.16(s,2H),4.51(d,J=6.3Hz,2H),3.92(s,2H),2.64(d,J=7.2Hz,2H ), 2.44 (dd, J = 14.9, 7.4Hz, 1H), 2.05-1.93 (m, 2H), 1.87-1.73 (m, 2H), 1.71-1.61 (m, 2H).

[0377] Example 43: Preparation of N-((2-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-1-(2-methylbenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 43)

[0378] The preparation method was similar to that of Example 32, wherein B16 was replaced by B13. Compound 43 was obtained as a yellow-white solid with a yield of 20%. MS m / z = 470 [M+1] + . 1 H NMR (400MHz, CDCl3) δ9.49 (s, 1H), 8.01 (t, J = 5.8Hz, 1H), 7.77 (s, 1H), 7.38 (d, J = 8.1Hz, 1H),7.20(s,1H),7.19-7.08(m,5H),6.96(d,J=7.4Hz,1H),6.92(d,J=8.1Hz,1H),6.30(s ,1H),4.99(s,2H),4.52(d,J=5.8Hz,2H),3.97(s,2H),2.67(d,J=7.4Hz,2H),2.50(dt,J =15.3,7.7Hz,1H),2.20(s,3H),2.04-1.93(m,2H),1.85-1.67(m,2H),1.66-1.55(m,2H).

[0379] Example 44: Preparation of N-((2-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 44)

[0380]

[0381] The preparation method was similar to that of Example 32, wherein B16 was replaced by B12. Compound 44 was obtained as a yellow solid with a yield of 24%. MS m / z = 486 [M+1] + . 1 H NMR (400MHz, DMSO) δ10.93(s,1H),9.16(t,J=6.3Hz,1H),8.79(s,1H),7.37(d,J=8.1Hz,1H) ,7.32(d,J=8.7Hz,2H),7.27(s,1H),6.94(dd,J=8.1,1.2Hz,1H),6.91(s,1H),6.89(s,2H), 6.26(s,1H),5.07(s,2H),4.50(d,J=6.3Hz,2H),3.87(s,2H),3.72(s,3H),2.60(d,J=7.2Hz ,2H),2.44(dt,J=15.0,7.6Hz,1H),1.98(m,2H),1.80(m,2H),1.65(dd,J=18.2,8.5Hz,2H).

[0382] Example 45: Preparation of 1-benzyl-N-((2-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxamide (Compound 45)

[0383]

[0384] The preparation method was similar to that of Example 32, wherein B16 was replaced by B29. Compound 45 was obtained as a yellow solid with a yield of 40%. MS m / z = 455 [M+1] + . 1 H NMR (400MHz, CDCl3) δ9.25(s,1H),7.71(s,1H),7.30(d,J=8.1Hz,1H),7.22(d,J=6.7Hz,3H),7.13- 7.09(m,2H),7.09-7.02(m,2H),6.93(d,J=8.2Hz,1H),6.88(d,J=1.1Hz,1H),6.44(dd,J=7.0,1.6Hz ,1H),6.09(s,1H),4.87(s,2H),4.44(d,J=5.5Hz,2H),3.85(s,2H),2.65(d,J=7.3Hz,2H),2.46(dt, J=15.2,7.6Hz,1H),1.99(dt,J=11.2,5.3Hz,2H),1.86-1.71(m,2H),1.61(dd,J=17.8,10.1Hz,2H).

[0385] Example 46: Preparation of N-((2-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-1-(4-fluorobenzyl)-6-oxo-1,2-dihydropyrimidine-4-carboxamide (Compound 46)

[0386]

[0387] The preparation method was similar to that of Example 32, wherein B16 was replaced by B18. Compound 46 was obtained as a yellow solid with a yield of 40%. MS m / z = 474 [M+1] + . 1 H NMR (400MHz, DMSO) δ11.02 (s, 1H), 9.21 (t, J = 6.3Hz, 1H), 8.84 (s, 1H), 7.46-7.36 (m, 3H),7.29(s,1H),7.18(t,J=8.8Hz,2H),6.96(dd,J=8.1,0.7Hz,1H),6.92(s,1H),6. 30(s,1H),5.14(s,2H),4.52(d,J=6.3Hz,2H),3.91(s,2H),2.63(d,J=7.2Hz,2H),2. 46(dd,J=15.0,7.5Hz,1H),2.05-1.93(m,2H),1.86-1.73(m,2H),1.71-1.60(m,2H).

[0388] Example 47: Preparation of N-((2-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-1-(4-methylbenzyl)-6-oxo-1,2-dihydropyrimidine-4-carboxamide (Compound 47)

[0389]

[0390] The preparation method was similar to that of Example 32, wherein B16 was replaced by B15. Compound 47 was obtained as a yellow solid with a yield of 36%. MS m / z = 470 [M+1] + . 1H NMR (400MHz, DMSO) δ10.92(s,1H),9.18(t,J=6.3Hz,1H),8.78(s,1H),7.38(d,J=8.1Hz,1H), 7.29-7.20(m,3H),7.15(d,J=7.9Hz,2H),6.94(d,J=8.1Hz,1H),6.89(s,1H),6.28(s,1H),5. 10(s,2H),4.50(d,J=6.3Hz,2H),3.88(s,2H),2.62(d,J=7.2Hz,2H),2.44(dd,J=15.1,7.5Hz ,1H),2.26(s,3H),2.05-1.93(m,2H),1.81(ddd,J=13.6,9.5,3.2Hz,2H),1.71-1.60(m,2H).

[0391] Example 48: Preparation of N-((2-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-1-(2,6-dimethylbenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 48)

[0392]

[0393] The preparation method was similar to that of Example 32, wherein B16 was replaced by B40. Compound 48 was obtained as a yellow solid with a yield of 36%. MS m / z = 484 [M+1] + . 1 H NMR (400MHz, DMSO) δ11.02(s,1H),9.10(t,J=6.3Hz,1H),7.97(s,1H),7.40(d,J=8.1Hz,1H) ,7.29(s,1H),7.22-7.16(m,1H),7.10(d,J=7.5Hz,2H),6.98-6.90(m,2H),6.34(s,1H),5.1 4(s,2H),4.50(d,J=6.3Hz,2H),3.96(s,2H),2.69(d,J=7.2Hz,2H),2.50-2.42(m,1H),2.27 (s, 6H), 2.00 (tdd, J = 8.5, 6.1, 2.6Hz, 2H), 1.89-1.74 (m, 2H), 1.68 (dt, J = 16.8, 8.5Hz, 2H).

[0394] Example 49: Preparation of 1-(2-chlorobenzyl)-N-((2-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 49)

[0395]

[0396] The preparation method was similar to that of Example 32, wherein B16 was replaced by B41. Compound 49 was obtained as a yellow solid with a yield of 26%. MS m / z = 490 [M+1] + . 1 H NMR (400MHz, DMSO) δ10.87(s,1H),9.24(t,J=6.3Hz,1H),8.73(s,1H),7.51(d,J =7.7Hz,1H),7.39-7.26(m,4H),7.04(d,J=7.4Hz,1H),6.94(t,J=3.4Hz,2H),6. 21(s,1H),5.22(s,2H),4.51(d,J=6.3Hz,2H),3.78(s,2H),2.53(s,2H),2.40(d t,J=15.0,7.3Hz,1H),2.03-1.92(m,2H),1.86-1.71(m,2H),1.67-1.57(m,2H).

[0397] Example 50: Preparation of N-((2-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-1-(2,6-dichlorobenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 50)

[0398]

[0399] The preparation method was similar to that of Example 32, wherein B16 was replaced by B42. Compound 50 was obtained as a yellow solid with a yield of 11%. MS m / z = 524 [M+1] + . 1 H NMR (400MHz, DMSO) δ10.91(s,1H),9.23(t,J=6.3Hz,1H),8.73(s,1H),7.68(d,J=2.1Hz ,1H),7.37(dd,J=8.3,2.4Hz,2H),7.29(s,1H),7.11(d,J=8.4Hz,1H),6.95(d,J=8.0Hz, 2H),6.23(s,1H),5.19(s,2H),4.51(d,J=6.3Hz,2H),3.82(s,2H),2.56(d,J=7.1Hz,2H) ,2.42(dt,J=15.0,7.5Hz,1H),2.03-1.92(m,2H),1.87-1.71(m,2H),1.69-1.57(m,2H).

[0400] Example 51: Preparation of 1-(2-fluorobenzyl)-N-((2-((((3-fluorobicyclo[1.1.1]pentan-1yl)methyl)amino)methyl)-1hydro-indol-6-yl)methyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 51)

[0401]

[0402] The preparation method is similar to that of Example 32, wherein cyclobutylmethylamine hydrochloride is replaced by (3-fluorobicyclo[1.1.1]pentane-1-yl)methylamine hydrochloride. Compound 51 is obtained as a yellow-white solid with a yield of 54%. MS m / z=504[M+1] + . 1 H NMR (400MHz, DMSO) δ10.86(s,1H),9.22(t,J=6.2Hz,1H),8.76(s,1H),7.37(t,J=8.2Hz,2H),7.28(s,1H),7.26-7.14(m, 3H), 6.99-6.85 (m, 2H), 6.21 (s, 1H), 5.20 (s, 2H), 4.51 (d, J = 6.2Hz, 2H), 3.81 (s, 2H), 2.76 (s, 2H), 1.93 (d, J = 2.6Hz, 6H).

[0403] Example 52: Preparation of 1-benzyl-N-((2-((((3-fluorobicyclo[1.1.1]pentan-1yl)methyl)amino)methyl)-1hydro-indol-6-yl)methyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 52)

[0404]

[0405] The preparation method is similar to Example 38, wherein cyclobutylmethylamine hydrochloride is replaced by (3-fluorobicyclo[1.1.1]pentan-1-yl)methylamine hydrochloride. Compound 52 is obtained as a white solid with a yield of 13%. MS m / z=486[M+1] + . 1 H NMR (400MHz, DMSO) δ10.84(s,1H),9.18(t,J=6.2Hz,1H),8.81(s,1H),7.31(ddd,J=13.9,10.3,5.8Hz,7H),6.92(d ,J=11.5Hz,2H),6.20(s,1H),5.15(s,2H),4.50(d,J=6.2Hz,2H),3.80(s,2H),2.75(s,2H),1.93(d,J=2.4Hz,6H).

[0406] Example 53: Preparation of N-((2-((((3-fluorobicyclo[1.1.1]pentan-1yl)methyl)amino)methyl)-1hydro-indol-6-yl)methyl)-1-(3-methylbenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 53)

[0407]

[0408] The preparation method is similar to that of Example 36, wherein cyclobutylmethylamine hydrochloride is replaced by (3-fluorobicyclo[1.1.1]pentane-1-yl)methylamine hydrochloride. Compound 53 is obtained as a yellow solid with a yield of 57%. MS m / z=500[M+1] + . 1 H NMR (400MHz, DMSO) δ10.85(s,1H),9.18(t,J=6.1Hz,1H),8.79(s,1H),7.36(d,J=8.0Hz,1H),7.24(dd,J=15.6,8.0Hz,2H),7.16-7.07(m ,3H),6.98-6.88(m,2H),6.21(s,1H),5.11(s,2H),4.50(d,J=6.2Hz,2H),3.81(s,2H),2.76(s,2H),2.27(s,3H),1.93(d,J=2.4Hz,6H).

[0409] Example 54: Preparation of N-((2-((((3-fluorobicyclo[1.1.1]pentan-1yl)methyl)amino)methyl)-1hydro-indol-6-yl)methyl)-6-oxo-1-(3-(trifluoromethyl)benzyl)-1,6-dihydropyrimidine-4-carboxamide (Compound 54)

[0410]

[0411] The preparation method is similar to Example 34, wherein cyclobutylmethylamine hydrochloride is replaced by (3-fluorobicyclo[1.1.1]pentane-1-yl)methylamine hydrochloride. Compound 54 is obtained as a yellow solid with a yield of 45%. MS m / z=554[M+1] + . 1H NMR (400MHz, DMSO) δ10.85(s,1H),9.20(t,J=6.1Hz,1H),8.87(s,1H),7.78(s,1H),7.63(dq,J=22.8,7.5Hz,3H),7.36(d,J=8.0Hz,1H) ,7.27(s,1H),6.93(d,J=9.1Hz,2H),6.20(s,1H),5.24(s,2H),4.51(d,J=6.1Hz,2H),3.81(s,2H),2.75(s,2H),1.93(d,J=2.4Hz,6H).

[0412] Example 55: Preparation of N-((2-((((3-fluorobicyclo[1.1.1]pentan-1yl)methyl)amino)methyl)-1hydro-indol-6-yl)methyl)-1-(3-methoxybenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 55)

[0413]

[0414] The preparation method is similar to that of Example 35, wherein cyclobutylmethylamine hydrochloride is replaced by (3-fluorobicyclo[1.1.1]pentane-1-yl)methylamine hydrochloride. Compound 55 is obtained as a yellow solid with a yield of 46%. MS m / z=516[M+1] + . 1 H NMR (400MHz, DMSO) δ10.85(s,1H),9.18(t,J=6.3Hz,1H),8.79(s,1H),7.36(d,J=8.1Hz,1H),7.26(t,J=7.9Hz,2H),6.93(d,J=8.6H z,3H),6.87(m,2H),6.20(s,1H),5.12(s,2H),4.51(d,J=6.3Hz,2H),3.80(s,2H),3.73(s,3H),2.75(s,2H),1.93(d,J=2.6Hz,6H).

[0415] Example 56: Preparation of N-((2-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-1-(2-hydroxybenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 56)

[0416]

[0417] The preparation method is as described in Example 32, wherein B16 is replaced by B28 to obtain compound 56-3 as a yellow solid. 56-3 is dissolved in anhydrous tetrahydrofuran (6 ml), tetrabutylammonium fluoride (180 μl) is added, and after reacting for 30 minutes, TLC monitoring shows that the reaction is complete, and the solvent in the reaction system is evaporated and purified by silica gel column chromatography (dichloromethane: methanol = 10: 1, volume ratio) to obtain compound 56 as a yellow-white solid (43 mg, yield: 30%), MS m / z = 472 [M+1] + . 1 H NMR (400MHz, DMSO) δ10.92(s,1H),9.19(t,J=6.3Hz,1H),8.65(s,1H),7.37(d,J=8.1Hz,1H),7.27(s, 1H),7.17-7.05(m,2H),6.93(d,J=8.0Hz,1H),6.88(s,1H),6.83(d,J=8.0Hz,1H),6.75(t,J=7.4Hz,1 H),6.24(s,1H),5.03(s,2H),4.50(d,J=6.2Hz,2H),3.83(s,2H),2.57(d,J=7.1Hz,2H),2.42(dt,J=1 5.0,7.6Hz,1H),1.98(tt,J=15.3,7.6Hz,2H),1.80(ddd,J=21.9,9.4,3.3Hz,2H),1.69-1.58(m,2H).

[0418] Example 57: Preparation of N-((2-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-6-oxo-1-((tetrahydropyran-4-yl)methyl)-1,6-dihydropyrimidine-4-carboxamide (Compound 57)

[0419]

[0420] The preparation method was similar to that of Example 32, wherein B16 was replaced by B43. Compound 57 was obtained as a yellow solid with a yield of 30%. MS m / z=464[M+1] + . 1H NMR (400MHz, DMSO) δ10.94(s,1H),9.19(t,J=6.3Hz,1H),8.56(s,1H),7.40(d,J=8.1Hz,1H),7.29( s,1H),6.96(dd,J=8.1,1.2Hz,1H),6.89(m,1H),6.31(s,1H),4.51(d,J=6.3Hz,2H),3.92(s,2H),3 .82(dd,J=11.0,5.2Hz,4H),3.22(t,J=10.8Hz,2H),2.65(d,J=7.2Hz,2H),2.45(dd,J=15.1,7.6Hz ,1H),2.00(m,2H),1.81(m,2H),1.65(m,2H),1.42(d,J=12.5Hz,3H),1.28(dd,J=12.0,4.2Hz,2H).

[0421] Example 58: Preparation of N-((2-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-1-(2,4-difluorobenzyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 58)

[0422]

[0423] The preparation method was similar to that of Example 32, wherein B16 was replaced by B20. Compound 58 was obtained as a yellow solid with a yield of 36%. MS m / z = 492 [M+1] + . 1 H NMR (400MHz, DMSO) δ10.93(s,1H),9.13(t,J=6.3Hz,1H),8.65(s,1H),7.31(d,J=8.0Hz,1H),7.29 -7.23(m,1H),7.20(s,1H),7.19-7.13(m,1H),6.96(td,J=8.5,2.0Hz,1H),6.86(dd,J=8.1,1.2Hz, 1H),6.79(s,1H),6.25(s,1H),5.06(s,2H),4.41(d,J=6.3Hz,2H),3.88(s,2H),2.60(d,J=7.2Hz,2 H), 2.37 (d, J = 7.5Hz, 1H), 1.89 (tdd, J = 8.5, 6.0, 2.5Hz, 2H), 1.77-1.63 (m, 2H), 1.62-1.52 (m, 2H).

[0424] Example 59: Preparation of N-((2-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-1-(cyclohexylmethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 59)

[0425]

[0426] The preparation method was similar to that of Example 32, wherein B16 was replaced by B44. Compound 59 was obtained as a yellow solid with a yield of 46%. MS m / z = 462 [M+1] + . 1 H NMR (400MHz, CDCl3) δ9.06 (s, 1H), 8.00 (t, J = 5.7Hz, 1H), 7.82 (s, 1H), 7.41 (d, J = 8.1Hz, 1H), 7. 17(s,2H),6.94(d,J=8.1Hz,1H),6.27(s,1H),4.55(d,J=5.8Hz,2H),3.93(s,2H),3.63(d,J=7. 2Hz,2H),2.65(d,J=7.3Hz,2H),2.45(dt,J=15.3,7.6Hz,1H),1.98(dtd,J=11.5,8.0,3.8Hz,2H ), 1.88-1.69 (m, 3H), 1.66 (s, 7H), 1.10 (dd, J = 23.3, 15.1Hz, 3H), 0.86 (dt, J = 18.2, 9.0Hz, 2H).

[0427] Example 60: Preparation of N-((2-(((cyclobutylmethyl)amino)methyl)-1hydro-indol-6-yl)methyl)-1-(4-benzoic acid)-6-oxo-1,2-dihydropyrimidine-4-carboxamide (Compound 60)

[0428]

[0429] The preparation method is as in Example 32, wherein B16 is replaced by B33. Compound 60-3 is obtained as a yellow solid. After drying, anhydrous dichloromethane (4 ml) is added, and trifluoroacetic acid (1 ml) is added under ice bath conditions. After reacting for 2 hours, TLC monitoring shows that the reaction is complete. The solvent in the reaction system is evaporated, saturated sodium bicarbonate (5 ml) is added, and extracted with dichloromethane (20 ml×3), the organic phase is collected, dried, and the solvent is evaporated under reduced pressure. The compound 60 is separated and purified by silica gel column chromatography (dichloromethane: methanol = 20: 3) to obtain a yellow-white solid (30 mg, yield: 22%) of compound 60, MS m / z = 500 [M+1] + . 1H NMR (400MHz, DMSO) δ11.27(s,1H),9.29(t,J=6.3Hz,1H),8.83(s,1H),7.92(d,J=8.2H z,2H),7.48(d,J=8.1Hz,1H),7.41(d,J=8.2Hz,2H),7.36(s,1H),7.03(d,J=8.3Hz,1H ),6.93(s,1H),6.54(s,1H),5.23(s,2H),4.53(d,J=6.2Hz,2H),4.25(s,2H),2.95(d, J=7.4Hz,2H),2.61(dt,J=14.7,7.5Hz,1H),2.04(q,J=7.4Hz,2H),1.92-1.68(m,4H).

[0430] Example 61: Preparation of 1-benzyl-N-((2-(((cyclobutylmethyl)amino)methyl)-5-fluoro-1 hydrogen-indol-6-yl)methyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 61)

[0431]

[0432] The preparation method is the same as that of Example 32, wherein B16 is replaced by B1, and B31 is replaced by B32, to obtain compound 61 as a yellow solid with a yield of 30%, MS m / z=474[M+1] + . 1 H NMR (400MHz, DMSO) δ10.95 (s, 1H), 9.14 (t, J = 6.0Hz, 1H), 8.84 (s, 1H), 7.34 (m, 5H),7.24(d,J=6.7Hz,1H),7.19(d,J=11.1Hz,1H),6.91(s,1H),6.25(s,1H),5 .17(s,2H),4.55(d,J=5.9Hz,2H),3.81(s,2H),2.55(d,J=7.2Hz,2H),2.40(dd ,J=15.0,7.6Hz,1H),1.98(d,J=4.1Hz,2H),1.79(m,2H),1.64(d,J=9.6Hz,2H).

[0433] Example 62: Preparation of N-((6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1-benzyl-6-oxo-1,6-dihydropyrimidine-4-(1,2,3-triazole) (Compound 62)

[0434]

[0435] B34 (89 mg, 0.42 mmol) and A1-5 (101 mg, 0.35 mmol) were added to tetrahydrofuran (3 ml) and stirred at room temperature. 18mg, 0.07mmol) and sodium ascorbate (28mg, 0.14mmol) were dissolved in water (0.5ml), and the solution was added to the above stirring system to react for half an hour. The solvent in the reaction system was evaporated, dichloromethane (10ml) was added, and the mixture was extracted with water three times. The organic phases were combined, and anhydrous sodium sulfate was added to dry the organic phases. The crude product was concentrated and purified by silica gel column chromatography (dichloromethane: methanol = 20: 4, volume ratio) to obtain pure compound 62 as a yellow solid with a yield of 32%, MS m / z = 481 [M+1] + . 1 H NMR (400MHz, DMSO) δ8.70(d,J=35.5Hz,2H),8.44(s,1H),7.96(s,1H),7.47(d,J=9.3Hz,1H),7.36-7.25(m,6H),6.91(s,1H),5.78(s,2H) ,5.14(s,2H),3.70(s,2H),2.54(d,J=7.0Hz,2H),2.41(dt,J=14.8,7.5Hz,1H),2.04-1.90(m,2H),1.86-1.72(m,2H),1.69-1.57(m,2H).

[0436] Example 63: Preparation of N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-6-oxo-1-(m-methylbenzene)-1,6-dihydropyrimidine-4-carboxamide (Compound 63)

[0437]

[0438] The preparation method was similar to that of Example 32, wherein B16 was replaced by B38. Compound 63 was obtained as a yellow solid with a yield of 40%. MS m / z = 456 [M+1] + . 1H NMR (400MHz, DMSO) δ10.96(s,1H),9.26(t,J=6.3Hz,1H),8.55(s,1H),7.42(m,2H),7.31(m,4H),6.97(m,2H),6.29(s,1H),4.53(d,J=6.3Hz,2H ), 3.90 (s, 2H), 2.63 (d, J = 7.2Hz, 2H), 2.44 (dd, J = 15.1, 7.5Hz, 1H), 2.37 (s, 3H), 1.98 (m, 2H), 1.79 (tdd, J = 14.8, 7.6, 2.9Hz, 2H), 1.65 (m, 2H).

[0439] Example 64: Preparation of N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1-(1-(2-fluorophenyl)ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Compound 64)

[0440]

[0441] The preparation method was similar to that of Example 32, wherein B16 was replaced by B39. Compound 64 was obtained as a yellow solid with a yield of 40%. MS m / z = 488 [M+1] + . 1 H NMR (400MHz, DMSO) δ10.87(s,1H),9.10(t,J=6.3Hz,1H),8.55(s,1H),7.51(t,J=7.3Hz,1H) ,7.41(dd,J=10.5,4.5Hz,1H),7.35(d,J=8.1Hz,1H),7.25(d,J=4.2Hz,2H),7.20(m,1H),6.9 2(d,J=8.1Hz,1H),6.88(s,1H),6.20(s,1H),6.07(q,J=7.1Hz,1H),4.51(d,J=6.3Hz,2H),3. 78(s,2H),2.53(s,2H),2.40(dt,J=15.0,7.5Hz,1H),1.96(m,2H),1.78(m,5H),1.62(m,2H).

[0442] Example 65: Preparation of N-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-6-oxo-1-(m-methylbenzyl-deuterium 2)-1,6-dihydropyrimidine-4-carboxamide (Compound 65)

[0443]

[0444] The preparation method was similar to that of Example 32, wherein B16 was replaced by B37. Compound 65 was obtained as a yellow solid with a yield of 30%. MS m / z = 472 [M+1] + . 1 H NMR (400MHz, DMSO) δ10.87 (s, 1H), 9.18 (t, J = 6.3Hz, 1H), 8.79 (s, 1H), 7.36 (d, J=8.1Hz,1H),7.24(dd,J=15.9,8.3Hz,2H),7.12(dd,J=9.8,7.9Hz,3H),6.93(m ,2H),6.21(s,1H),4.51(d,J=6.3Hz,2H),3.79(s,2H),2.52(d,J=7.2Hz,2H),2. 40(dt,J=15.0,7.5Hz,1H),2.27(s,3H),1.96(m,2H),1.78(m,2H),1.62(m,2H).

[0445] Embodiment 66

[0446] A tablet containing a METTL3 inhibitor, each tablet having the following specific formula: containing METTL3 inhibitor: 15 mg; microcrystalline cellulose: 80 mg; pregelatinized starch: 40 mg; polyvinyl pyrrolidone: 8 mg; sodium carboxymethyl starch: 6 mg; magnesium stearate: 1.5 mg; talc: 2.5 mg; ethanol: appropriate amount.

[0447] According to the above formula, the mixture containing METTL3 inhibitor, pregelatinized starch and microcrystalline cellulose is sieved and fully mixed, polyvinyl pyrrolidone is added, mixed, and a soft material is prepared (the above formula is mixed to form a soft material), sieved, and wet granules are prepared, and the granules are dried at 50-60°C. Sodium carboxymethyl starch, magnesium stearate and talc are sieved, added to the above granules, mixed with an appropriate amount of ethanol, and pressed into tablets.

[0448] Experimental verification demonstrated that the above-mentioned composition also has the activity of inhibiting METTL3.

[0449] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the essence and scope of the technical solution of the present invention.

[0450] The beneficial effects of the present invention are demonstrated below through specific test examples.

[0451] Test Example 1: METTL3 Enzyme Test

[0452] Enzyme experiments were performed using a radiometric assay to detect the inhibition of RNA methyltransferase activity of METTL3 by small molecule inhibitors. The experiment was performed in a 384-well plate (Corning, Cat. No. 3657) and the reaction buffer (20 mM HEPES pH 7.5 (Gibco, Cat. No. 11344-041), 50 mM KCl (Sigma, Cat. No. P5405 ), 250 μM MgCl2 (Sigma, Cat. No. M9272 ), 1mM DTT (Sigma, Cat. No. D0632-10G), 0.01% Tween-20 (Sigma, Cat. No. P2287-100ML), 0.01% bovine skin gelatin (BSG), 0.004U / μL RNAseOUT (Thermo Fisher Scientific, Cat. No. 10777019,)), dimethyl sulfoxide was used to dilute the test compound, and then each compound dilution was added to a 384-well plate. RecombiNaNt METTL3 / METTL14 complex (Activemotif, Cat. No. 31570) was added to the reaction buffer to form an enzyme solution with a final enzyme concentration of 10nM; ssRNA-Radio (GenScript, Customized) and 3 H-SAM (Revvity, Cat. No. NET155V001MC) was added to the reaction buffer to form a substrate solution, ssRNA-Radio and 3 The final concentrations of H-SAM were 0.1 μM and 0.136 μM, respectively. Add 10 μL of enzyme solution to the wells of the 384-well reaction plate. Centrifuge at 1000 rpm for 1 minute and incubate at room temperature for 15 minutes. Add 10 μL of substrate solution to each well of the 384-well reaction plate. Centrifuge at 1000 rpm for 1 minute and react at room temperature for 30 minutes; terminate the reaction and centrifuge at 1000 rpm for 1 minute; transfer 25 μL from the 384-well reaction plate to the 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at room temperature for at least 60 minutes; use MicroBeta2 to read the CPM value. The experimental data were analyzed and processed by GraphPad Prism 8 software to obtain IC 50 value.

[0453] The compounds prepared in the examples were tested for their RNA methyltransferase inhibitory activity against METTL3 protein according to the above method. The test results are shown in Table 5. The IC 50 According to the description classification, in Table 5:

[0454] "+" indicates IC 50 The measured value is less than 100 μM and greater than or equal to 2 μM;

[0455] "++" indicates IC 50 The measured value is less than 2 μM and greater than or equal to 100 nM;

[0456] "+++" indicates IC 50 The measured value was less than 100 nM and greater than or equal to 0.1 nM.

[0457] Test Example 2: CCK-8 Cell Proliferation Test

[0458] The cell proliferation assay was performed by quantitatively detecting the inhibition of MOLM-13 cell proliferation activity by small molecule inhibitors using CCK-8 reagent (APE×BIO). The experiment was performed in a 96-well plate (Corning, REF 3599), with 8,000 MOLM-13 cells (human acute myeloid leukemia cells) or 5,000 SKOV3 cells (human ovarian cancer cells) inoculated in each well and cultured for 72 or 96 hours (MOLM-13 cells were cultured for 72 hours, and SKOV3 cells were cultured for 96 hours) in a medium containing different concentrations of the test compound (RPMI-1640 + 10% FBS + 1% P / S for MOLM-13 cells and DMEM + 10% FBS + 1% P / S for SKOV3 cells). After the culture was completed, 10 μL of CCK-8 detection reagent was added, and after incubation at 37°C for 1.5 hours, the absorbance value of the 450 nM channel was recorded using an enzyme reader (SpectraMax i3x). The experimental data were analyzed and processed by GraphPad Prism 8 software to obtain IC 50 value.

[0459] The compounds prepared in the examples were subjected to METTL3 CCK-8 cell proliferation test according to the above method. The test results are shown in Table 5, wherein the IC 50 According to the description classification, in Table 5:

[0460] "+" indicates IC 50 The measured value is greater than or equal to 100 μM;

[0461] "++" indicates IC 50 The measured value is less than 100 μM and greater than or equal to 20 μM;

[0462] "+++" indicates IC 50 The measured value was less than 20 μM and greater than or equal to 1 μM.

[0463] Table 5 Inhibitory activity of compounds on METTL3 enzyme, MOLM-13 and SKOV3 cells

[0464]

[0465]

[0466]

[0467] In summary, the compounds of the present invention have significant inhibitory activity on METTL3. As METTL3 inhibitors, they provide candidate drugs for the treatment of METTL3-mediated autoimmune diseases, nervous system diseases, inflammatory diseases, cancer or infectious diseases. They are particularly suitable for use as METTL3 inhibitors, and for the treatment of leukemia, ovarian cancer, etc.

Claims

1. A compound of formula I, or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof: in, The A ring is selected from a 5- to 12-membered aromatic ring, a 5- to 12-membered aromatic heterocyclic ring, a 5- to 12-membered bridged ring, a 5- to 12-membered bridged heterocyclic ring, a 5- to 12-membered spiro ring, and a 5- to 12-membered spiro heterocyclic ring; R a is selected from hydrogen, halogen, =O, cyano, trifluoromethyl, hydroxyl, nitro, -C 1～6 Alkyl, -O(C 1～6 alkyl), halogen-substituted-C 1～6 Alkyl, -O(halogen substituted C 1～6 Alkyl), -C 2～6 Alkenyl, -C 2～6 Alkynyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～6 Alkyl, cyano-substituted -C 1～6 Alkyl, -NR a1 C(=O)R a2 、-C(=O)NR a1 R a2 、-NR a1 R a2 、-S(=O)R a1 、-S(=O)2R a1 、-C(=O)R a1 , 3-12 membered heterocycloalkyl, 5-12 membered aryl, 5-12 membered heteroaryl, 4-12 membered bridged ring, 4-12 membered bridged heterocyclic ring, -C 0～6 Alkyl-3- to 12-membered heterocycloalkyl, wherein the heterocycloalkyl, heteroaryl or bridged heterocyclic ring contains 1 to 4 heteroatoms selected from O, S and N; the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, bridged ring or bridged heterocyclic ring may be further substituted by 1 to 5 atoms selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～6 Alkyl, -O(C 1～6 alkyl), halogen-substituted-C 1～6 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～6 Alkyl, cyano-substituted -C 1～6 Alkyl is substituted by a substituent; R a1 , R a2 Each independently selected from hydrogen, halogen, amino, hydroxyl, -C 1～6 Alkyl; the A ring and R a The 5-membered and 6-membered heteroaryl groups or the 6-membered and 6-membered heteroaryl groups may be connected together to form a 5-membered and 6-membered heteroaryl group, wherein the 5-membered and 6-membered heteroaryl group or the 6-membered and 6-membered heteroaryl group may be further selected from hydrogen, halogen, =O, cyano, trifluoromethyl, hydroxyl, amino, nitro, -C 1～6 Alkyl, -O(C 1～6 Alkyl), -C 2～6 Alkenyl, -C 2～6 Alkynyl, -C 3～6 Substitution of cycloalkyl groups; m is selected from 0, 1, 2, 3, 4 or 5; Y is selected from O, S, -CR Y1 R Y2 -, -NR Y2 -, -S(=O)-, -S(=O)2-, -NR Y1 C(=O)NR Y2 -, - NR Y1 C(=O)O- or -S(=O)2NR Y1 -; said R Y1 and R Y2 Each independently selected from hydrogen, deuterium, -C 1～6 Alkyl, halogen, hydroxyl, amino, -NO; n is selected from 0, 1, 2, 3, 4 or 5; X1 is selected from CRx1 or N; X2 is selected from CRx2 or N; X3 is selected from CRx3 or N; X4 is selected from CRx4 or N; The Rx1, Rx2, Rx3, and Rx4 are each independently selected from hydrogen, amino, halogen, cyano, nitro, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, -S(=O)2R X5 、-NR X5 C(=O)CR X6 , -C 0～4 Alkyl-NR X5 R X6 , 5- to 12-membered aromatic ring, 5- to 12-membered aromatic heterocyclic ring; R X5 , R X6 Each independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl; The L is selected from: The right side of the L substituent is connected to the ring B; the R L may be further substituted by 1 to 3 groups selected from hydrogen, halogen, hydroxy, cyano, amino, -C 1～6 Alkyl, -O(C 1～6 alkyl), halogen-substituted-C 1～6 Alkyl, hydroxy substituted -C 1～6 Alkyl, cyano-substituted -C 1～6 substituted by an alkyl substituent; p is selected from 0, 1, 2 or 3; R L1 and R L2 Each independently selected from hydrogen, halogen, hydroxyl, =O, cyano, -C 1～6 Alkyl, -O(C 1～6 Alkyl), -C 3～6 Cycloalkyl, the alkyl, cycloalkyl may be further substituted by 1 to 4 groups selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～6 Alkyl, -O(C 1～6 alkyl), halogen-substituted-C 1～6 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～6 Alkyl, cyano-substituted -C 1～6 substituted by an alkyl substituent; Ring B is selected from a 5- to 10-membered heterocyclic group containing 1 to 5 heteroatoms selected from O, S, and N; q is selected from 0, 1, 2, 3, 4, 5, 6 or 7; The R b Selected from hydrogen, halogen, cyano, hydroxyl, =O, -C 1～6 Alkyl, -O(C 1～6 Alkyl), -C 3～6 Cycloalkyl, the alkyl, cycloalkyl may be further substituted by 1 to 4 groups selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～6 Alkyl, -O(C 1～6 alkyl), halogen-substituted-C 1～6 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～6 Alkyl, cyano-substituted -C 1～6 substituted by an alkyl substituent; R c1 and R c2 Each independently selected from hydrogen, halogen, cyano, hydroxyl, =O, -C 1～6 Alkyl, -O(C 1～6 Alkyl), -C 3～6 Cycloalkyl, the alkyl, cycloalkyl may be further substituted by 1 to 4 groups selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～6 Alkyl, -O(C 1～6 alkyl), halogen-substituted-C 1～6 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～6 Alkyl, cyano-substituted -C 1～6 substituted by an alkyl substituent; s is selected from 0, 1, 2, or 3; Z is selected from hydrogen, halogen, cyano, hydroxyl, -NR Z1 R Z2 , -C 3～12 Heterocycloalkyl, -C 5～10 Aromatic ring, -C 5～10 Aromatic heterocycle, -C 5～12 Bridge ring, -C 5～12 Bridged heterocycle, -C 5～12 Spirocyclic, -C 5～12 Spiro heterocycle; the heterocycloalkyl, aromatic heterocycle, bridged heterocycle, spiro heterocycle contain 1 to 3 heteroatoms selected from O, S, N; the heterocycloalkyl, aromatic ring, aromatic heterocycle, bridged ring, bridged heterocycle, spiro ring, spiro heterocycle may be further substituted by 1 to 4 heteroatoms selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～6 Alkyl, -O(C 1～6 alkyl) is substituted with a substituent; The R Z1 and R Z2 Each independently selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkyl-(3-12 membered cycloalkyl), -C 0～2 Alkyl-(3- to 12-membered heterocycloalkyl), -C 0～2 Alkyl-(5-10 membered aromatic ring), -C 0～2 Alkyl-(5-10 membered aromatic heterocycle), -C 0～2 Alkyl-(4-12 membered bridge ring), -C 0～2 Alkyl-(4-12 membered heterocyclic ring), -C 0～2 Alkyl-(5- to 12-membered spirocyclic ring), -C 0～2 Alkyl-(5- to 12-membered spiro heterocycle); wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, bridged ring, bridged heterocycle, spiro ring, spiro heterocycle may be further substituted by 1 to 3 groups selected from hydrogen, halogen, cyano, =O, hydroxyl, trifluoromethyl, amino, -C 1～6 Alkyl, -O(C 1～6 Alkyl), -C 3～12 The alkyl, cycloalkyl, and heterocyclic group may be substituted by 1 to 4 substituents selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～6 Alkyl, -O(C 1～6 alkyl), halogen-substituted-C 1～6 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～6 Alkyl, cyano-substituted -C 1～6 The heterocyclic group is substituted by a substituent of an alkyl group, and the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N.

2. The compound according to claim 1 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, characterized in that: The A ring is selected from a 5- to 10-membered aromatic ring, a 5- to 10-membered aromatic heterocyclic ring, a 5- to 10-membered bridged ring, a 5- to 10-membered bridged heterocyclic ring, a 5- to 10-membered spiro ring, and a 5- to 10-membered spiro heterocyclic ring; R a is selected from hydrogen, halogen, =O, cyano, trifluoromethyl, hydroxyl, nitro, -C 1～4 Alkyl, -O(C 1～4 alkyl), halogen-substituted-C 1～4 Alkyl, -O(halogen substituted C 1～4 Alkyl), -C 2～4 Alkenyl, -C 2～4 Alkynyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～4 Alkyl, cyano-substituted -C 1～4 Alkyl, -NR a1 C(=O)R a2 、-C(=O)NR a1 R a2 、-NR a1 R a2 、-S(=O)R a1 、-S(=O)2R a1 、-C(=O)R a1 , 3-10 membered heterocycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered bridged ring, 4-10 membered bridged heterocyclic ring, -C 0～6 Alkyl-3- to 10-membered heterocycloalkyl, wherein the heterocycloalkyl, heteroaryl or bridged heterocyclic ring contains 1 to 4 heteroatoms selected from O, S and N; the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or bridged heterocyclic ring may be further substituted by 1 to 4 heteroatoms selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～4 Alkyl, -O(C 1～4 alkyl), halogen-substituted-C 1～4 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～4 Alkyl, cyano-substituted -C 1～4 Alkyl is substituted by a substituent; R a1 , R a2 Each independently selected from hydrogen, halogen, amino, hydroxyl, -C 1～4 Alkyl; the A ring and R a The 5-membered and 6-membered heteroaryl groups or the 6-membered and 6-membered heteroaryl groups may be connected together to form a 5-membered and 6-membered heteroaryl group, wherein the 5-membered and 6-membered heteroaryl group or the 6-membered and 6-membered heteroaryl group may be further selected from hydrogen, halogen, =O, cyano, trifluoromethyl, hydroxyl, amino, nitro, -C 1～4 Alkyl, -O(C 1～4 Alkyl), -C 2～4 Alkenyl, -C 2～4 Alkynyl, -C 3～6 Substitution of cycloalkyl groups; m is selected from 0, 1, 2, 3 or 4; Y is selected from O, S, -CR Y1 R Y2 -, -NR Y2 -, -S(=O)-, -S(=O)2-, -NR Y1 C(=O)NR Y2 -, - NR Y1 C(=O)O- or -S(=O)2NR Y1 -; said R Y1 and R Y2 Each independently selected from hydrogen, deuterium, -C 1～4 Alkyl, halogen, hydroxyl, amino, -NO; n is selected from 0, 1, 2, 3 or 4; X1 is selected from CRx1 or N; X2 is selected from CRx2 or N; X3 is selected from CRx3 or N; X4 is selected from CRx4 or N; The Rx1, Rx2, Rx3, and Rx4 are each independently selected from hydrogen, amino, halogen, cyano, nitro, -C 1～4 Alkyl, -C 2～4 Alkenyl, -C 2～4 Alkynyl, -S(=O)2R X5 、-NR X5 C(=O)CR X6 , -C 0～2 Alkyl-NR X5 R X6 , 5- to 10-membered aromatic ring, 5- to 10-membered aromatic heterocyclic ring; R X5 , R X6 Each independently selected from hydrogen, -C 1～4 Alkyl, -C 2～4 Alkenyl, -C 2～4 Alkynyl, halogen-substituted-C 1～4 Alkyl, halogen-substituted -C 2～4 Alkenyl, halogen-substituted-C 2～4 Alkynyl; The L is selected from: The right side of the L substituent is connected to the ring B; the R L may be further substituted by 1 to 2 groups selected from hydrogen, halogen, hydroxy, cyano, amino, -C 1～4 Alkyl, -O(C 1～4 alkyl), halogen-substituted-C 1～4 Alkyl, hydroxy substituted -C 1～4 Alkyl, cyano-substituted -C 1～4 substituted by an alkyl substituent; p is selected from 0, 1 or 2; R L1 and R L2 Each independently selected from hydrogen, halogen, hydroxyl, =O, cyano, -C 1～4 Alkyl, -O(C 1～4 Alkyl), -C 3～6 Cycloalkyl, the alkyl, cycloalkyl may be further substituted by 1 to 4 groups selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～4 Alkyl, -O(C 1～4 alkyl), halogen-substituted-C 1～4 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～4 Alkyl, cyano-substituted -C 1～4 substituted by an alkyl substituent; Ring B is selected from 5-and-5-membered biheteroaryl, 5-and-6-membered heteroaryl or 6-and-6-membered heteroaryl, wherein the heteroaryl contains 1 to 5 heteroatoms selected from O, S and N; q is selected from 0, 1, or 2; The R b Selected from hydrogen, halogen, cyano, hydroxyl, =O, -C 1～4 Alkyl, -O(C 1～4 Alkyl), -C 3～6 Cycloalkyl, the alkyl, cycloalkyl may be further substituted by 1 to 4 groups selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～4 Alkyl, -O(C 1～4 alkyl), halogen-substituted-C 1～4 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～4 Alkyl, cyano-substituted -C 1～4 substituted by an alkyl substituent; R c1 and R c2 Each independently selected from hydrogen, halogen, cyano, hydroxyl, =O, -C 1～4 Alkyl, -O(C 1～4 Alkyl), -C 3～6 Cycloalkyl, the alkyl, cycloalkyl may be further substituted by 1 to 4 groups selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～4 Alkyl, -O(C 1～4 alkyl), halogen-substituted-C 1～4 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～4 Alkyl, cyano-substituted -C 1～4 substituted by an alkyl substituent; s is selected from 0, 1, or 2; Z is selected from hydrogen, halogen, cyano, hydroxyl, -NR Z1 R Z2 , -C 4～9 Heterocycloalkyl, 6-membered aromatic ring, 10-membered aromatic ring, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle, 10-membered aromatic heterocycle, -C 6～9 Bridge ring, -C 6～9 Bridged heterocycle, -C 6～9 Spirocyclic, -C 6～9 Spiro heterocycle; the heterocycloalkyl, aromatic heterocycle, bridged heterocycle, spiro heterocycle contain 1 to 3 heteroatoms selected from O, S, N; the heterocycloalkyl, aromatic ring, aromatic heterocycle, bridged ring, bridged heterocycle, spiro ring, spiro heterocycle may be further substituted by 1 to 4 heteroatoms selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～4 Alkyl, -O(C 1～4 alkyl) is substituted with a substituent; The R Z1 and R Z2 Each independently selected from hydrogen, -C 1～4 Alkyl, -C 0～2 Alkyl-(3- to 6-membered cycloalkyl), -C 0～2 Alkyl-(4- to 9-membered heterocycloalkyl), -C 0～2 Alkyl-(6-10 membered aromatic ring), -C 0～2 Alkyl-(5-10 membered aromatic heterocycle), -C 0～2 Alkyl-(4-9 membered bridge ring), -C 0～2 Alkyl-(4-9 membered heterocyclic ring), -C 0～2 Alkyl-(6- to 9-membered spirocyclic ring), -C 0～2 Alkyl-(6- to 9-membered spiro heterocycle); wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, bridged ring, bridged heterocycle, spiro ring, spiro heterocycle may be further substituted by 1 to 3 groups selected from hydrogen, halogen, cyano, =O, hydroxyl, trifluoromethyl, amino, -C 1～4 Alkyl, -O(C 1～4 Alkyl), -C 3～6 The alkyl, cycloalkyl, and heterocyclic group may be substituted by 1 to 4 substituents selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～4 Alkyl, -O(C 1～4 alkyl), halogen-substituted-C 1～4 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～4 Alkyl, cyano-substituted -C 1～4 The heterocyclic group is substituted by a substituent of an alkyl group, and the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N.

3. The compound according to claim 2 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, characterized in that: The A ring is selected from a 5- to 10-membered aromatic ring, a 5- to 10-membered aromatic heterocyclic ring, a 6- to 9-membered bridged ring, a 6- to 9-membered bridged heterocyclic ring, a 6- to 9-membered spiro ring, and a 6- to 9-membered spiro heterocyclic ring; R a is selected from hydrogen, halogen, =0, cyano, trifluoromethyl, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, -C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, 4-9 membered bridged ring, 4-9 membered bridged heterocyclic ring, -NR a1 R a2 , -C 0～6 Alkyl-3-6 membered heterocycloalkyl, wherein the heterocycloalkyl, heteroaryl or bridged heterocyclic ring contains 1 to 4 heteroatoms selected from O, S and N; the methyl, ethyl, propyl, isopropyl, cycloalkyl, heterocycloalkyl, heteroaryl or bridged heterocyclic ring may be further substituted by 1 to 3 substituents selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, methyl, ethyl, propyl, isopropyl, methoxy and ethoxy; R a1 , R a2 Each independently selected from hydrogen, halogen, amino, hydroxyl, methyl, ethyl, propyl, isopropyl; the A ring and R a The 5-membered and 6-membered heteroaryl groups or the 6-membered and 6-membered heteroaryl groups may be connected together to form a 5-membered and 6-membered heteroaryl group, wherein the 5-membered and 6-membered heteroaryl group or the 6-membered and 6-membered heteroaryl group may be further selected from hydrogen, halogen, =O, cyano, trifluoromethyl, hydroxyl, amino, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, -C 3～6 Substitution of cycloalkyl groups; m is selected from 0, 1, 2 or 3; Y is selected from O, S, -CR Y1 R Y2 -、-NR Y2 -、-S(=O)2-、-NR Y1 C(=O)NR Y2 -; said R Y1 and R Y2 Each is independently selected from hydrogen, deuterium, methyl, halogen, -NO; n is selected from 0, 1, 2 or 3; X1 is selected from CRx1 or N; X2 is selected from CRx2 or N; X3 is selected from CRx3 or N; X4 is selected from CRx4 or N; The Rx1, Rx2, Rx3, and Rx4 are each independently selected from hydrogen, amino, halogen, cyano, nitro, methyl, ethyl, propyl, isopropyl, -C 0～2 Alkyl-NR X5 R X6 , 5- to 10-membered aromatic ring, 5- to 10-membered aromatic heterocyclic ring; R X5 , R X6 Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl; The L is selected from: The right side of the L substituent is connected to the ring B; the R L may be further substituted by 1 to 2 substituents selected from hydrogen, halogen, hydroxy, cyano, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy; p is selected from 0, 1 or 2; R L1 and R L2 Each is independently selected from hydrogen, halogen, hydroxy, =O, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, -C 3～6 Cycloalkyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and cycloalkyl groups may be further substituted by 1 to 4 substituents selected from hydrogen, halogen, amino, cyano, and hydroxyl groups; Ring B is selected from the group consisting of pyrrolopyrrolyl, pyrrolopyrazolyl, pyrroloimidazolyl, thienopyrrolyl, pyrazolopyrazolyl, pyrazoloimidazolyl, imidazoimidazolyl, imidazothiazolyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, pyridopyrrolyl, pyridopyrazolyl, pyridoimidazolyl, thiazolopyridinyl, thienopyridinyl, pyrimidopyrrolyl, pyrimidin ... pyridazinyl, pyridopyridyl, pyrimidoimidazolyl, thiazolopyrimidyl, thienopyrimidinyl, pyrazinopyrrolyl, pyrazinopyrazolyl, pyrazinoimidazolyl, thienopyrazinyl, pyridazinopyrrolyl, pyridazinopyrazolyl, pyridazinoimidazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, benzopyridazinyl, pyridopyridyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, imidazopyridinyl; q is selected from 0, 1, or 2; The R b is selected from hydrogen, halogen, cyano, hydroxy, =O, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, -C 3～6 Cycloalkyl, the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cycloalkyl may be further substituted by 1 to 4 groups selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～4 Alkyl, -O(C 1～4 alkyl), halogen-substituted-C 1～4 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～4 Alkyl, cyano-substituted -C 1～4 substituted by an alkyl substituent; R c1 and R c2 Each is independently selected from hydrogen, halogen, cyano, hydroxyl, =O, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl may be further substituted by 1 to 4 groups selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～4 Alkyl, -O(C 1～4 alkyl), halogen-substituted-C 1～4 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～4 Alkyl, cyano-substituted -C 1～4 substituted by an alkyl substituent; s is selected from 0, 1, or 2; Z is selected from hydrogen, halogen, cyano, hydroxyl, -NR Z1 R Z2 , -C 4～9 Heterocycloalkyl, 6-membered aromatic ring, 10-membered aromatic ring, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle, 10-membered aromatic heterocycle, -C 6～9 Bridge ring, -C 6～9 Bridged heterocycle, -C 6～9 Spirocyclic, -C 6～9 Spiro heterocycle; the heterocycloalkyl, aromatic heterocycle, bridged heterocycle, spiro heterocycle contain 1 to 3 heteroatoms selected from O, S, and N; the heterocycloalkyl, aromatic ring, aromatic heterocycle, bridged ring, bridged heterocycle, spiro ring, and spiro heterocycle may be further substituted by 1 to 4 substituents selected from hydrogen, halogen, methyl, and methoxy; The R Z1 and R Z2 Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, -C 0～2 Alkyl-(3- to 6-membered cycloalkyl), -C 0～2 Alkyl-(4- to 9-membered heterocycloalkyl), -C 0～2 Alkyl-(6-membered aromatic ring), -C 0～2 Alkyl-(5-6 membered aromatic heterocyclic ring), -C 0～2 Alkyl-(4-6 membered bridge ring), -C 0～2 Alkyl-(4- to 6-membered heterocyclic ring), -C 0～2 Alkyl-(6- to 9-membered spirocyclic ring), -C 0～2 Alkyl-(6- to 9-membered spiro heterocycle); wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, bridged ring, bridged heterocycle, spiro ring, spiro heterocycle may be further substituted by 1 to 3 groups selected from hydrogen, halogen, cyano, =O, hydroxyl, trifluoromethyl, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, -C 3～6 The methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cycloalkyl, heterocyclic group may be further substituted by 1 to 4 substituents selected from hydrogen, halogen, amino, cyano, hydroxyl, =O, -C 1～4 Alkyl, -O(C 1～4 alkyl), halogen-substituted-C 1～4 Alkyl, -C 3～6 Cycloalkyl, hydroxy-substituted-C 1～4 Alkyl, cyano-substituted -C 1～4 The heterocyclic group is substituted by a substituent of an alkyl group, and the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N.

4. The compound according to claim 3 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, characterized in that: The A ring is selected from a 5- to 10-membered aromatic ring and a 5- to 10-membered aromatic heterocyclic ring; R a is selected from hydrogen, halogen, =0, cyano, trifluoromethyl, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethynyl, cyclopropyl, -NR a1 R a2 , 5-10 membered aryl, 5-10 membered heteroaryl, 4-7 membered bridged ring, 4-7 membered bridged heterocyclic ring, -C 0～6 Alkyl-3-6 membered heterocycloalkyl, wherein the heterocycloalkyl, heteroaryl or bridged heterocycle contains 1 to 4 heteroatoms selected from O, S and N; the methyl, ethyl, propyl, isopropyl, methoxy, ethynyl, cyclopropyl, heterocycloalkyl, heteroaryl or bridged heterocycle is further substituted by 1 to 3 substituents selected from hydrogen, halogen, amino, cyano and hydroxyl; R a1 , R a2 Each independently selected from hydrogen, halogen, amino, hydroxyl, methyl, ethyl, propyl, isopropyl; the A ring and R a The 5-membered and 6-membered heteroaryl groups or the 6-membered and 6-membered heteroaryl groups may be connected together to form a 5-membered and 6-membered heteroaryl group, wherein the 5-membered and 6-membered heteroaryl group or the 6-membered and 6-membered heteroaryl group may be further selected from hydrogen, halogen, =O, cyano, trifluoromethyl, hydroxyl, amino, nitro, methyl, ethyl, isopropyl, methoxy, ethynyl, -C 3～4 Substitution of cycloalkyl groups; m is selected from 0, 1 or 2; Y is selected from O, S, -CR Y1 R Y2 -、-NR Y2 -、-S(=O)2-、-NR Y1 C(=O)NR Y2 -; said R Y1 and R Y2 Each independently selected from hydrogen, deuterium, methyl, -NO; n is selected from 0, 1, 2 or 3; X1 is selected from CRx1 or N; X2 is selected from CRx2 or N; X3 is selected from CRx3 or N; X4 is selected from CRx4 or N; The Rx1, Rx2, Rx3, and Rx4 are each independently selected from hydrogen, amino, halogen, cyano, methyl, ethyl, propyl, isopropyl, 5-10 membered aromatic ring, and 5-10 membered aromatic heterocycle; The L is selected from: The right side of the L substituent is connected to ring B; p is selected from 0 or 1; R L1 and R L2 Each is independently selected from hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, and cyclopropyl, and the methyl, ethyl, propyl, isopropyl, and cyclopropyl may be further substituted by 1 to 3 substituents selected from hydrogen, halogen, amino, cyano, and hydroxy; Ring B is selected from thienopyrrolyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, pyridopyrrolyl, pyridopyrazolyl, pyridoimidazolyl, pyrimidopyrrolyl, pyrimidopyrazolyl, pyrimidoimidazolyl, pyrazinopyrrolyl, pyrazinopyrazolyl, pyrazinoimidazolyl, pyridazinopyrrolyl, pyridazinopyrazolyl, pyridazinoimidazolyl, imidazopyridinyl; q is selected from 0, 1, or 2; The R b Selected from hydrogen, halogen, cyano, =0, methyl, ethyl, propyl, isopropyl, cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl may be further substituted by 1 to 4 substituents selected from hydrogen, halogen, amino, cyano, hydroxyl; R c1 and R c2 Each is independently selected from hydrogen, halogen, cyano, hydroxy, =O, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl; s is selected from 0, 1, or 2; Z is selected from hydrogen, halogen, cyano, hydroxyl, -NR Z1 R Z2 , -C 4～6 Heterocycloalkyl, 6-membered aromatic ring, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle, -C 6～9 Bridge ring, -C 6～9 Bridged heterocycle, -C 7～9 Spirocyclic, -C 7～9 Spiro heterocycle; the heterocycloalkyl, aromatic heterocycle, bridged heterocycle, spiro heterocycle contain 1 to 3 heteroatoms selected from O, S, and N; the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, bridged ring, bridged heterocycle, spiro ring, and spiro heterocycle may be further substituted by 1 to 4 substituents selected from hydrogen, fluorine, methyl, and methoxy; The R Z1 and R Z2 Each independently selected from hydrogen, -C 0～2 Alkyl-(3- to 6-membered cycloalkyl), -C 0～2 Alkyl-(4- to 9-membered heterocycloalkyl), -C 0～2 Alkyl-(6-membered aromatic ring), -C 0～2 Alkyl-(6-membered aromatic heterocycle), -C 0～2 Alkyl-(4-6 membered bridge ring), -C 0～2 Alkyl-(4- to 6-membered heterocyclic ring), -C 0～2 Alkyl-(6- to 9-membered spirocyclic ring), -C 0～2 Alkyl-(6- to 9-membered spiroheterocycle); wherein the alkyl, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle, bridged ring, bridged heterocycle, spiro ring, spiroheterocycle may be further substituted by 1 to 3 substituents selected from hydrogen, halogen, cyano, hydroxyl, methyl, isopropyl, methoxy, and trifluoromethyl.

5. The compound according to claim 4 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, characterized in that: The A ring is selected from R a is selected from hydrogen, halogen, cyano, trifluoromethyl, hydroxy, methyl, methoxy, ethynyl, cyclopropyl, -NR a1 R a2 、-C(=O)NR a1 R a2 、-S(=O)2R a1 , 5-membered heterocycloalkyl, 5-membered heteroaryl or 6-membered bridged heterocycle; R a1 , R a2 Each independently selected from hydrogen, halogen, amino, hydroxyl, methyl, isopropyl; the A ring and R a may be connected together to form a 5-membered ring and a 6-membered heteroaryl or a 6-membered ring and a 6-membered heteroaryl, and the 5-membered ring and a 6-membered heteroaryl or the 6-membered ring and a 6-membered heteroaryl may be further substituted by a substituent selected from hydrogen, halogen, cyano, trifluoromethyl, hydroxyl, amino, methyl, methoxy, ethynyl, and cyclopropyl; m is selected from 0, 1 or 2; Y is selected from -CH2-, -CD2-, -CHCH3-, -NH-; n is selected from 0, 1, 2 or 3; X1 is selected from CRx1 or N; X2 is selected from CRx2 or N; X3 is selected from CRx3 or N; X4 is selected from CRx4 or N; The Rx1, Rx2, Rx3, and Rx4 are independently selected from hydrogen, methyl, halogen, benzene ring, and indole; The L is selected from: The right side of the L substituent is connected to ring B; p is selected from 1; R L1 and R L2 Each independently selected from hydrogen and halogen; Ring B is selected from thienopyrrolyl, benzopyrrolyl, pyridoimidazolyl, imidazopyridinyl; q is selected from 0, 1, or 2; The R b Selected from hydrogen, halogen, =0, methyl, ethyl, propyl, isopropyl, cyano, cyclopropyl, trifluoromethyl, hydroxyl; R c1 and R c2 are each independently selected from hydrogen; s is selected from 0, 1, or 2; Z is selected from 6. The compound according to claim 1 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, characterized in that: The compound is selected from any of the following structures:

7. A method for preparing the compound of any one of claims 1 to 6 or its stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals.

8. Use of the compound according to any one of claims 1 to 7 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the preparation of a medicament for treating a METTL3-mediated disease.

9. The use according to claim 8, characterized in that: The treatment of METTL3-mediated diseases is for one or more of autoimmune diseases, nervous system diseases, inflammatory diseases, cancer, and infectious diseases.

10. A pharmaceutical composition, characterized in that: A preparation prepared from the compound according to any one of claims 1 to 6 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, plus a pharmaceutically acceptable excipient.

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