Aryl substituted tricyclic compound and its preparation method and use

Abstract

The present invention discloses an aromatic formyl-substituted tricyclic compound, a preparation method and a use thereof. Specifically, the aromatic formyl-substituted tricyclic compound of the present invention has a structure of formula (C), and as a BTK inhibitor, it has the advantages of high activity, good selectivity and low toxicity and side effects. #imgabs0#

Description

[0001] This application claims priority to Chinese Patent Application No. 2020110094513, filed on September 23, 2020, Chinese Patent Application No. 2021101506608, filed on February 3, 2021, and Chinese Patent Application No. 202111038855X, filed on September 6, 2021. This application incorporates the entirety of the aforementioned Chinese patent applications. Technical Field

[0002] The present invention belongs to the field of medicine, and in particular relates to an aromatic formyl-substituted tricyclic compound, a preparation method and an application thereof. Background Art

[0003] Bruton's tyrosine kinase (BTK), a member of the Tec family of non-receptor tyrosine kinases, is a key kinase in the B cell antigen receptor (BCR) signaling pathway. Signaling via the BCR controls a range of effector responses, including the activation, proliferation, and differentiation of cells that produce mature antibodies. Aberrant BCR-mediated signaling can lead to misregulated B cell activation and / or the formation of pathogenic autoantibodies, contributing to a variety of human diseases, including cancer, autoimmune diseases, and xenoimmune diseases. Ibrutinib (trade name Imbmvica), the first BTK inhibitor to enter the market, has achieved tremendous success. However, like many other anticancer drugs, some patients develop resistance to the drug. Studies have identified the C481S mutation in BTK kinase as a major cause of resistance. Ibrutinib exerts its pharmacodynamic activity through irreversible covalent binding to the tryptophan residue C481 of BTK kinase. The C481S mutation converts the tryptophan to a serine, thereby eliminating the ability of ibrutinib to covalently bind to ibrutinib. Against this backdrop, there remains a need for the development of more potent inhibitors targeting BTK. Summary of the Invention

[0004] The present invention provides an aromatic formyl-substituted tricyclic compound, which, as a BTK inhibitor, has the advantages of high activity, good selectivity, and low toxic and side effects.

[0005] In one aspect, the present invention provides a compound of formula (C) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:

[0006]

[0007] Where,

[0008] R1 and R2 are each independently selected from: H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-20 Cycloalkyl, 3 to 20 membered heterocyclic group, C1-6 Alkoxy and C 1-6 Alkylthio; or R1 and R2 together with the carbon atom to which they are attached constitute: C 3-20 Cycloalkyl, 3 to 20-membered heterocyclyl, carbonyl (C=O) or C=S; the C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-20 Cycloalkyl, the 3 to 20 membered heterocyclic group, the C 1-6 Alkoxy and the C 1-6 Each alkylthio group is independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S1;

[0009] R3 and R4 are each independently selected from: H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-20 Cycloalkyl and 3 to 20 membered heterocyclic group; or R3 and R4 together with the carbon atom to which they are attached constitute: C 3-20 Cycloalkyl, 3 to 20-membered heterocyclic group or carbonyl (C=O); the C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-20 The cycloalkyl group and the 3- to 20-membered heterocyclic group are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S1;

[0010] n is 0, 1, 2, or 3;

[0011] E is NR5, O or N; wherein R5 is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-deuterated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-deuterated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-4 Alkylene-NR a R b 、-C 1-4 Alkylene-C(O)NR a R b 、-C 1-4 Alkylene-C(O)OC 1-6 Alkyl, -C 1-4 Alkylene-SO2C 1-3 Alkyl, -C 1-4 Alkylene-carboxyl or C 3-6 Monocyclic cycloalkyl; wherein the -C 1-4 Alkylene- is unsubstituted, or the -C 1-4 One or two hydrogen atoms on the alkylene group are independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl and deuterated C 1-6 substituted with an alkyl group, or the -C 1-4 The two hydrogen atoms on the same carbon atom of the alkylene group are simultaneously replaced by -(CH2) j -substituted to form a cycloalkyl group, wherein j is 2, 3, 4, 5 or 6; said C 3-6 The monocyclic cycloalkyl and the 3 to 6 membered monocyclic heterocyclic groups are optionally substituted by 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and deuterated C 1-6 alkoxy;

[0012] When E is NR5 or O, the " ” indicates a single bond;

[0013] When E is N, the " ” indicates a double bond and R2 is none;

[0014] A is CR6 or N; wherein R6 is H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl or -C 3-6 Cycloalkyl;

[0015] B is CR7 or N; wherein R7 is H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl or -C3-6 Cycloalkyl;

[0016] G1 is C 6-14 aryl, 5- or 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl; and said C 6-14 The aryl group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from Group S2;

[0017] G2 is C 6-14 aryl, 5- or 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl; and said C 6-14 The aryl group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from Group S2;

[0018] L is a key, CR 8 R 9 、O、NH、NHC(O)、C 1-2 Alkylene-NHC(O) or NHC(O)-C 1-2 Alkylene-; wherein R 8 and R 9 are independently H, halogen, hydroxy, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-NR a R b 、-C 1-4 Alkylene-C(O)NR a R b 、-C 1-4 Alkylene-SO2C 1-3 Alkyl or -C 1-4 Alkylene-carboxyl;

[0019] i is 0 or 1;

[0020] The groups of S1 and S2 are independently selected from: deuterium, halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 3-20 Cycloalkyl (e.g. -C 3-6 Monocyclic cycloalkyl), halogenated C 3-20 Cycloalkyl (e.g. -haloC 3-6 Monocyclic cycloalkyl), -OC 3-20 Cycloalkyl (e.g. -OC 3-6 monocyclic cycloalkyl), 3- to 20-membered heterocyclyl (e.g., 3- to 6-membered monocyclic heterocyclyl), -O-3- to 20-membered heterocyclyl (e.g., -O-3- to 6-membered monocyclic heterocyclyl), C 6-14 Aryl (e.g. phenyl), -OC 6-14 Aryl (e.g., -O-phenyl), 5- or 6-membered monocyclic heteroaryl, -O-5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, -O-8- to 10-membered bicyclic heteroaryl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-deuterated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-deuterated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-20 Cycloalkyl (e.g. -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl), -C 1-4 Alkylene-OC 3-20 Cycloalkyl (e.g. -C 1-4 Alkylene-OC 3-6 Monocyclic cycloalkyl), -C 1-4 Alkylene-3 to 20 membered heterocyclic group (e.g. -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group), -C 1-4 Alkylene-O-3 to 20-membered heterocyclic group (e.g. -C 1-4 Alkylene-O-3 to 6-membered monocyclic heterocyclic group), -C 1-4 Alkylene-C6-14 Aryl (e.g. -C 1-4 Alkylene-phenyl), -C 1-4 Alkylene-OC 6-14 Aryl (e.g. -C 1-4 Alkylene-O-phenyl), -C 1-4 Alkylene-5 or 6-membered monocyclic heteroaryl, -C 1-4 Alkylene-O-5 or 6-membered monocyclic heteroaryl, -C 1-4 Alkylene-8 to 10-membered bicyclic heteroaryl, -C 1-4 Alkylene-O-8 to 10-membered bicyclic heteroaryl, -C 1-4 Alkylene-NR a R b 、-C 1-4 Alkylene-C(O)NR a R b 、-C 1-4 Alkylene-NR d C(O)R c 、-C 1-4 Alkylene-NR d C(O)NR a R b 、-C 1-4 Alkylene-SO2R c 、-C 1-4 Alkylene-NR d SO2R c 、-C 1-4 Alkylene-SO2NR a R b 、-C 1-4 Alkylene-NR d SO2NR a R b 、-C 1-4 Alkylene-carboxyl, -C(O)C 1-6 Alkyl, -C(O)halogenated C 1-6 Alkyl, -C(O) deuterated C 1-6 Alkyl, -C(O)C 3-20 Cycloalkyl (e.g. -C(O)C 3-6 monocyclic cycloalkyl), -C(O)3 to 20-membered heterocyclyl (e.g., -C(O)3 to 6-membered monocyclic heterocyclyl), -C(O)C 6-14 Aryl (e.g., -C(O)phenyl), -C(O)5- or 6-membered monocyclic heteroaryl, -C(O)8- to 10-membered bicyclic heteroaryl, -C(O)NR a R b 、-NR d C(O)R c 、-NR d C(O)NR aR b 、-SO2R c 、-NR d SO2R c 、-SO2NR a R b 、-NR d SO2NR a R b 、-NR a R b AND-OR c ; said-C 1-4 Alkylene- is unsubstituted, or the -C 1-4 The hydrogen atoms on the alkylene group are independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl and deuterated C 1-6 substituted with an alkyl group, or the -C 1-4 The two hydrogen atoms on the same carbon atom of the alkylene group are simultaneously replaced by -(CH2) j -substituted to form a cycloalkyl group, wherein j is 2, 3, 4, 5 or 6; said C 3-20 Cycloalkyl, the 3 to 20 membered heterocyclic group, the C 6-14 The aryl group, the 5- or 6-membered monocyclic heteroaryl group and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally substituted by 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and deuterated C 1-6 alkoxy;

[0021] In the above groups, R a and R b Each independently is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-deuterated C 1-6 Alkoxy, 3 to 6 membered monocyclic heterocyclic group, -C 1-4 Alkylene-3 to 6 membered monocyclic heterocyclic group, C 6-14Aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, -C 1-4 Alkylene-C 6-14 Aryl, -C 1-4 Alkylene-5 or 6-membered monocyclic heteroaryl, -C 1-4 Alkylene-8 to 10 membered bicyclic heteroaryl or C(O)C 1-6 Alkyl; the C 3-6 Monocyclic cycloalkyl, the 3 to 6 membered monocyclic heterocyclic group, the C 6-14 The aryl group, the 5- or 6-membered monocyclic heteroaryl group and the 8- to 10-membered bicyclic heteroaryl group are optionally substituted by 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and deuterated C 1-6 alkoxy; or

[0022] In the above groups, R a 、R b Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group; and the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and deuterated C 1-6 alkoxy;

[0023] In the above groups, R c Each independently is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-deuterated C 1-6 Alkyl, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-deuterated C 1-6 Alkoxy, C 3-6 Monocyclic cycloalkyl, -C 1-4Alkylene-C 3-6 Monocyclic cycloalkyl, 3 to 6 membered monocyclic heterocyclic group, -C 1-4 Alkylene-3 to 6 membered monocyclic heterocyclic group, C 6-14 Aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, -C 1-4 Alkylene-C 6-14 Aryl, -C 1-4 Alkylene-5 or 6 membered monocyclic heteroaryl or -C 1-4 Alkylene-8 to 10 membered bicyclic heteroaryl; said C 3-6 Monocyclic cycloalkyl, the 3 to 6 membered monocyclic heterocyclic group, the C 6-14 The aryl group, the 5- or 6-membered monocyclic heteroaryl group and the 8- to 10-membered bicyclic heteroaryl group are optionally substituted by 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and deuterated C 1-6 alkoxy;

[0024] In the above groups, R d Each independently is H, C 1-6 Alkyl or deuterated C 1-6 alkyl;

[0025] The carbon atom marked with “*” is a chiral carbon atom (eg, R configuration, S configuration, or a mixture thereof) or an achiral carbon atom.

[0026] In one embodiment, in the above-mentioned compound of formula (C) or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, certain groups have the following definitions, and the definitions of the unmentioned groups are as described in any embodiment of the present invention (hereinafter referred to as "in one embodiment" or "in a preferred embodiment").

[0027] In one embodiment, the compound of formula (C) has the structure shown in formula (D):

[0028]

[0029] wherein A, B, R1, R3, R4, L, G1, G2, n, i and “*” are the same as those defined in the present invention.

[0030] In one embodiment, the compound of formula (C) has a structure shown in formula (E) or formula (F):

[0031]

[0032] wherein A, B, R1, R3, R4, L, G1, G2, n and “*” are the same as those defined in the present invention.

[0033] In one embodiment, the compound of formula (C) has a structure represented by formula (II'), formula (B1'), formula (B2'), formula (C1), formula (C2) or formula (C3):

[0034]

[0035] wherein A, B, R1, R3, R4, R5, L, G1, G2 and “*” are the same as those defined in the present invention.

[0036] In one embodiment, the compound of formula (C) has a structure represented by formula (IIb'), formula (B1a'), formula (B2a'), formula (C1a), formula (C2a) or formula (C3a):

[0037]

[0038] wherein R1, R3, R4, R5, G1, G2 and “*” are the same as those defined in the present invention.

[0039] In one embodiment, the compound of formula (C) has a structure represented by formula (C1a-1), formula (C1a-2), formula (C2a-1), formula (C2a-2), formula (C3a-1) or formula (C3a-2):

[0040]

[0041] wherein R1, R3, R4, R5, G1, and G2 are the same as those defined in the present invention.

[0042] In one embodiment, in Formula C, Formula D, Formula E, Formula F, Formula C1, Formula C2, Formula C1a, Formula C2a, Formula C1a-1, Formula C1a-2, Formula C2a-1 or Formula C2a-2, R1 is C 1-6 Alkoxy (such as methoxy) or C 1-6 Alkylthio (eg, methylthio or ethylthio).

[0043] In another aspect, the present invention provides a compound of formula (A) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:

[0044]

[0045] Where,

[0046] R1 and R2 are each independently selected from: H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-20 Cycloalkyl and 3 to 20 membered heterocyclic group; or R1 and R2 together with the carbon atom to which they are attached constitute: C 3-20 Cycloalkyl, 3 to 20-membered heterocyclic group or carbonyl (C=O); the C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-20 The cycloalkyl group and the 3- to 20-membered heterocyclic group are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S1;

[0047] R3 and R4 are each independently selected from: H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-20 Cycloalkyl and 3 to 20 membered heterocyclic group; or R3 and R4 together with the carbon atom to which they are attached constitute: C 3-20 Cycloalkyl, 3 to 20-membered heterocyclic group or carbonyl (C=O); the C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-20 The cycloalkyl group and the 3- to 20-membered heterocyclic group are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S1;

[0048] n is 0, 1, 2, or 3;

[0049] E is NR5 or O; wherein R5 is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-deuterated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-deuterated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-4 Alkylene-NR aR b 、-C 1-4 Alkylene-C(O)NR a R b 、-C 1-4 Alkylene-C(O)OC 1-6 Alkyl, -C 1-4 Alkylene-SO2C 1-3 Alkyl, -C 1-4 Alkylene-carboxyl or C 3-6 Monocyclic cycloalkyl; wherein the -C 1-4 Alkylene- is unsubstituted, or the -C 1-4 One or two hydrogen atoms on the alkylene group are independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl and deuterated C 1-6 substituted with an alkyl group, or the -C 1-4 The two hydrogen atoms on the same carbon atom of the alkylene group are simultaneously replaced by -(CH2) j -substituted to form a cycloalkyl group, wherein j is 2, 3, 4, 5 or 6; said C 3-6 The monocyclic cycloalkyl and the 3 to 6 membered monocyclic heterocyclic groups are optionally substituted by 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and deuterated C 1-6 alkoxy;

[0050] A is CR6 or N; wherein R6 is H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl or -C 3-6 Cycloalkyl;

[0051] B is CR7 or N; wherein R7 is H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl or -C 3-6 Cycloalkyl;

[0052] G1 is C 6-14 aryl, 5- or 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl; and said C 6-14 The aryl group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from Group S2;

[0053] G2 is C6-14 aryl, 5- or 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl; and said C 6-14 The aryl group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from Group S2;

[0054] L is a key, CR 8 R 9 、O、NH、NHC(O)、C 1-2 Alkylene-NHC(O) or NHC(O)-C 1-2 Alkyl; wherein R 8 、R 9 are independently H, halogen, hydroxy, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-NR a R b 、-C 1-4 Alkylene-C(O)NR a R b 、-C 1-4 Alkylene-SO2C 1-3 Alkyl or -C 1-4 Alkylene-carboxyl;

[0055] i is 0 or 1;

[0056] The groups of group S1 or S2 are independently selected from: deuterium, halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 3-20Cycloalkyl (e.g. -C 3-6 Monocyclic cycloalkyl), halogenated C 3-20 Cycloalkyl (e.g. -haloC 3-6 Monocyclic cycloalkyl), -OC 3-20 Cycloalkyl (e.g. -OC 3-6 monocyclic cycloalkyl), 3- to 20-membered heterocyclyl (e.g., 3- to 6-membered monocyclic heterocyclyl), -O-3- to 20-membered heterocyclyl (e.g., -O-3- to 6-membered monocyclic heterocyclyl), C 6-14 Aryl (e.g. phenyl), -OC 6-14 Aryl (e.g., -O-phenyl), 5- or 6-membered monocyclic heteroaryl, -O-5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, -O-8- to 10-membered bicyclic heteroaryl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-deuterated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-deuterated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-20 Cycloalkyl (e.g. -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl), -C 1-4 Alkylene-OC 3-20 Cycloalkyl (e.g. -C 1-4 Alkylene-OC 3-6 Monocyclic cycloalkyl), -C 1-4 Alkylene-3 to 20 membered heterocyclic group (e.g. -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group), -C 1-4 Alkylene-O-3 to 20-membered heterocyclic group (e.g. -C 1-4 Alkylene-O-3 to 6-membered monocyclic heterocyclic group), -C 1-4 Alkylene-C 6-14 Aryl (e.g. -C 1-4 Alkylene-phenyl), -C 1-4 Alkylene-OC 6-14 Aryl (e.g. -C 1-4 Alkylene-O-phenyl), -C 1-4 Alkylene-5 or 6-membered monocyclic heteroaryl, -C 1-4 Alkylene-O-5 or 6-membered monocyclic heteroaryl, -C 1-4Alkylene-8 to 10-membered bicyclic heteroaryl, -C 1-4 Alkylene-O-8 to 10-membered bicyclic heteroaryl, -C 1-4 Alkylene-NR a R b 、-C 1-4 Alkylene-C(O)NR a R b 、-C 1-4 Alkylene-NR d C(O)R c 、-C 1-4 Alkylene-NR d C(O)NR a R b 、-C 1-4 Alkylene-SO2R c 、-C 1-4 Alkylene-NR d SO2R c 、-C 1-4 Alkylene-SO2NR a R b 、-C 1-4 Alkylene-NR d SO2NR a R b 、-C 1-4 Alkylene-carboxyl, -C(O)C 1-6 Alkyl, -C(O)halogenated C 1-6 Alkyl, -C(O) deuterated C 1-6 Alkyl, -C(O)C 3-20 Cycloalkyl (e.g. -C(O)C 3-6 monocyclic cycloalkyl), -C(O)3 to 20-membered heterocyclyl (e.g., -C(O)3 to 6-membered monocyclic heterocyclyl), -C(O)C 6-14 Aryl (e.g., -C(O)phenyl), -C(O)5- or 6-membered monocyclic heteroaryl, -C(O)8- to 10-membered bicyclic heteroaryl, -C(O)NR a R b 、-NR d C(O)R c 、-NR d C(O)NR a R b 、-SO2R c 、-NR d SO2R c 、-SO2NR a R b 、-NR d SO2NR a R b 、-NR a R bAND-OR c ; said-C 1-4 Alkylene- is unsubstituted, or the -C 1-4 The hydrogen atoms on the alkylene group are independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl and deuterated C 1-6 substituted with an alkyl group, or the -C 1-4 The two hydrogen atoms on the same carbon atom of the alkylene group are simultaneously replaced by -(CH2) j -substituted to form a cycloalkyl group, wherein j is 2, 3, 4, 5 or 6; said C 3-20 Cycloalkyl, the 3 to 20 membered heterocyclic group, the C 6-14 The aryl group, the 5- or 6-membered monocyclic heteroaryl group and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally substituted by 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and deuterated C 1-6 alkoxy;

[0057] In the above groups, R a and R b Each independently is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-deuterated C 1-6 Alkoxy, 3 to 6 membered monocyclic heterocyclic group, -C 1-4 Alkylene-3 to 6 membered monocyclic heterocyclic group, C 6-14 Aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, -C 1-4 Alkylene-C 6-14 Aryl, -C 1-4 Alkylene-5 or 6-membered monocyclic heteroaryl, -C 1-4 Alkylene-8 to 10 membered bicyclic heteroaryl or C(O)C 1-6 Alkyl; the C 3-6 Monocyclic cycloalkyl, the 3 to 6 membered monocyclic heterocyclic group, the C 6-14The aryl group, the 5- or 6-membered monocyclic heteroaryl group and the 8- to 10-membered bicyclic heteroaryl group are optionally substituted by 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and deuterated C 1-6 alkoxy; or

[0058] In the above groups, R a 、R b Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group; and the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and deuterated C 1-6 alkoxy;

[0059] In the above groups, R c Each independently is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-deuterated C 1-6 Alkyl, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-deuterated C 1-6 Alkoxy, C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, 3 to 6 membered monocyclic heterocyclic group, -C 1-4 Alkylene-3 to 6 membered monocyclic heterocyclic group, C 6-14 Aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, -C 1-4 Alkylene-C 6-14 Aryl, -C 1-4 Alkylene-5 or 6 membered monocyclic heteroaryl or -C 1-4Alkylene-8 to 10 membered bicyclic heteroaryl; said C 3-6 Monocyclic cycloalkyl, the 3 to 6 membered monocyclic heterocyclic group, the C 6-14 The aryl group, the 5- or 6-membered monocyclic heteroaryl group and the 8- to 10-membered bicyclic heteroaryl group are optionally substituted by 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and deuterated C 1-6 alkoxy;

[0060] In the above groups, R d Each independently is H, C 1-6 Alkyl or deuterated C 1-6 alkyl.

[0061] Herein, the 3- to 20-membered heterocyclic group has 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring atoms.

[0062] Herein, the 3- to 6-membered monocyclic heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms.

[0063] Herein, the 5- or 6-membered monocyclic heteroaryl group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms.

[0064] Herein, the 8- to 10-membered bicyclic heteroaryl group has 1, 2, 3, 4 or 5 heteroatoms selected from N, O and S as ring atoms.

[0065] Herein, the 3- to 6-membered nitrogen-containing heterocyclic group has 1 nitrogen atom and optionally 1 or 2 heteroatoms selected from N, O and S as ring atoms.

[0066] In another aspect, the present invention provides a compound of formula (B) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:

[0067] Where,

[0068] R1 and R2 are each independently selected from: H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-20 Cycloalkyl and 3 to 20 membered heterocyclic group; or R1 and R2 together with the carbon atom to which they are attached constitute: C 3-20 cycloalkyl, 3- to 20-membered heterocyclyl or carbonyl (C=O); the 3- to 20-membered heterocyclyl has 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring atoms; the C1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-20 The cycloalkyl group and the 3- to 20-membered heterocyclic group are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S1;

[0069] R3 and R4 are each independently selected from: H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-20 Cycloalkyl and 3 to 20 membered heterocyclic group; or R3 and R4 together with the carbon atom to which they are attached constitute: C 3-20 cycloalkyl, 3- to 20-membered heterocyclyl or carbonyl (C=O); the 3- to 20-membered heterocyclyl has 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring atoms; the C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-20 The cycloalkyl group and the 3- to 20-membered heterocyclic group are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S1;

[0070] n is 0, 1, 2, or 3;

[0071] E is NR5 or O; wherein R5 is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-deuterated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-deuterated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-4 Alkylene-NR a R b 、-C 1-4 Alkylene-C(O)NRa R b 、-C 1-4 Alkylene-C(O)OC 1-6 Alkyl, -C 1-4 Alkylene-SO2C 1-3 Alkyl, -C 1-4 Alkylene-carboxyl or C 3-6 Monocyclic cycloalkyl; wherein the -C 1-4 Alkylene- is unsubstituted, or the -C 1-4 One or two hydrogen atoms on the alkylene group are independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl and deuterated C 1-6 substituted with an alkyl group, or the -C 1-4 The two hydrogen atoms on the same carbon atom of the alkylene group are simultaneously replaced by -(CH2) j -substituted to form a cycloalkyl group, wherein j is 2, 3, 4, 5 or 6; the 3 to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3 to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and deuterated C 1-6 alkoxy;

[0072] A is CR6 or N; wherein R6 is H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl or -C 3-6 Cycloalkyl;

[0073] B is CR7 or N; wherein R7 is H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl or -C 3-6 Cycloalkyl;

[0074] G1 is C 6-14 aryl, 5- or 6-membered monocyclic heteroaryl or 8- to 10-membered bicyclic heteroaryl; wherein the 5- or 6-membered monocyclic heteroaryl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 8- to 10-membered bicyclic heteroaryl has 1, 2, 3, 4 or 5 heteroatoms selected from N, O and S as ring atoms; and the C 6-14The aryl group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from Group S2;

[0075] The groups of group S1 or S2 are independently selected from: deuterium, halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 3-20 Cycloalkyl (e.g. -C 3-6 Monocyclic cycloalkyl), halogenated C 3-20 Cycloalkyl (e.g. -haloC 3-6 Monocyclic cycloalkyl), -OC 3-20 Cycloalkyl (e.g. -OC 3-6 monocyclic cycloalkyl), 3- to 20-membered heterocyclyl (e.g., 3- to 6-membered monocyclic heterocyclyl), -O-3- to 20-membered heterocyclyl (e.g., -O-3- to 6-membered monocyclic heterocyclyl), C 6-14 Aryl (e.g. phenyl), -OC 6-14 Aryl (e.g., -O-phenyl), 5- or 6-membered monocyclic heteroaryl, -O-5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, -O-8- to 10-membered bicyclic heteroaryl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-deuterated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-deuterated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-20 Cycloalkyl (e.g. -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl), -C 1-4 Alkylene-OC 3-20 Cycloalkyl (e.g. -C 1-4 Alkylene-OC 3-6 Monocyclic cycloalkyl), -C 1-4 Alkylene-3 to 20 membered heterocyclic group (e.g. -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group), -C 1-4Alkylene-O-3 to 20-membered heterocyclic group (e.g. -C 1-4 Alkylene-O-3 to 6-membered monocyclic heterocyclic group), -C 1-4 Alkylene-C 6-14 Aryl (e.g. -C 1-4 Alkylene-phenyl), -C 1-4 Alkylene-OC 6-14 Aryl (e.g. -C 1-4 Alkylene-O-phenyl), -C 1-4 Alkylene-5 or 6-membered monocyclic heteroaryl, -C 1-4 Alkylene-O-5 or 6-membered monocyclic heteroaryl, -C 1-4 Alkylene-8 to 10-membered bicyclic heteroaryl, -C 1-4 Alkylene-O-8 to 10-membered bicyclic heteroaryl, -C 1-4 Alkylene-NR a R b 、-C 1-4 Alkylene-C(O)NR a R b 、-C 1-4 Alkylene-NHC(O)R c 、-C 1-4 Alkylene-SO2C 1-3 Alkyl, -C 1-4 Alkylene-SO2-halogenated C 1-3 Alkyl, -C 1-4 Alkylene-SO2-deuterated C 1-3 Alkyl, -C 1-4 Alkylene-5O2C 6-14 Aryl, -C 1-4 Alkylene-SO2-5 or 6-membered monocyclic heteroaryl, -C 1-4 Alkylene-SO2-8 to 10-membered bicyclic heteroaryl, -C 1-4 Alkylene-carboxyl, -C(O)C 1-6 Alkyl, -C(O)halogenated C 1-6 Alkyl, -C(O) deuterated C 1-6 Alkyl, -C(O)C 3-20 Cycloalkyl (e.g. -C(O)C 3-6 monocyclic cycloalkyl), -C(O)3 to 20-membered heterocyclyl (e.g., -C(O)3 to 6-membered monocyclic heterocyclyl), -C(O)C 6-14 Aryl (e.g., -C(O)phenyl), -C(O)5- or 6-membered monocyclic heteroaryl, -C(O)8- to 10-membered bicyclic heteroaryl, -C(O)NR a R b 、-NHC(O)R c 、-NR a R b AND-ORc The 3- to 20-membered heterocyclyl has 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring atoms (e.g., the 3- to 6-membered monocyclic heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms); the -C 1-4 Alkylene- is unsubstituted, or the -C 1-4 The hydrogen atoms on the alkylene group are independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl and deuterated C 1-6 substituted with an alkyl group, or the -C 1-4 The two hydrogen atoms on the same carbon atom of the alkylene group are simultaneously replaced by -(CH2) j -substituted to form a cycloalkyl group, wherein j is 2, 3, 4, 5 or 6; said C 3-20 Cycloalkyl, the 3 to 20 membered heterocyclic group, the C 6-14 The aryl group, the 5- or 6-membered monocyclic heteroaryl group and the 8- to 10-membered bicyclic heteroaryl group are each independently optionally substituted by 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and deuterated C 1-6 alkoxy;

[0076] In the above groups, R a and R b Each independently is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-deuterated C 1-6 Alkoxy, 3 to 6 membered monocyclic heterocyclic group, -C 1-4 Alkylene-3 to 6 membered monocyclic heterocyclic group, C 6-14 Aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, -C 1-4 Alkylene-C 6-14 Aryl, -C 1-4 Alkylene-5 or 6-membered monocyclic heteroaryl, -C 1-4Alkylene-8 to 10 membered bicyclic heteroaryl or C(O)C 1-6 wherein the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; 3-6 Monocyclic cycloalkyl, the 3 to 6 membered monocyclic heterocyclic group, the C 6-14 The aryl group, the 5- or 6-membered monocyclic heteroaryl group and the 8- to 10-membered bicyclic heteroaryl group are optionally substituted by 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and deuterated C 1-6 alkoxy; or

[0077] In the above groups, R a 、R b Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group; wherein the 3- to 6-membered nitrogen-containing heterocyclic group has 1 nitrogen atom and optionally 1 or 2 heteroatoms selected from N, O and S as ring atoms; and the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and deuterated C 1-6 alkoxy;

[0078] In the above groups, R c H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-deuterated C 1-6 Alkyl, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-deuterated C 1-6 Alkoxy, C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-C 3-6Monocyclic cycloalkyl, 3 to 6 membered monocyclic heterocyclic group, -C 1-4 Alkylene-3 to 6 membered monocyclic heterocyclic group, C 6-14 Aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, -C 1-4 Alkylene-C 6-14 Aryl, -C 1-4 Alkylene-5 or 6 membered monocyclic heteroaryl or -C 1-4 Alkylene-8 to 10 membered bicyclic heteroaryl; said C 3-6 Monocyclic cycloalkyl, the 3 to 6 membered monocyclic heterocyclic group, the C 6-14 The aryl group, the 5- or 6-membered monocyclic heteroaryl group and the 8- to 10-membered bicyclic heteroaryl group are optionally substituted by 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and deuterated C 1-6 Alkoxy.

[0079] In one embodiment, the compound of formula (B) has the structure shown in formula B1:

[0080]

[0081] In each formula, A, B, R3, R4, R5, and G1 are the same as those defined in formula B.

[0082] In one embodiment, the compound of formula (B) has the structure shown in formula B1a:

[0083]

[0084] In each formula, R3, R4, R5, and G1 are the same as those defined in Formula B.

[0085] In one embodiment, the compound of formula (B) has the structure shown in formula B1a-1 or formula B1a-2:

[0086]

[0087] In each formula, R3, R4, R5, and G1 are the same as those defined in Formula B.

[0088] In one embodiment, in Formula B1, Formula B1a, Formula B1a-1 or Formula B1a-2, R5 is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 1-4 Alkylene-hydroxyl, -C 1-4Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-deuterated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-deuterated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-4 Alkylene-NR a R b 、-C 1-4 Alkylene-C(O)NR a R b 、-C 1-4 Alkylene-C(O)OC 1-6 Alkyl, -C 1-4 Alkylene-SO2C 1-3 Alkyl, -C 1-4 Alkylene-carboxyl, 3 to 6 membered monocyclic heterocyclic group or C 3-6 Monocyclic cycloalkyl; wherein the "-C 1-4 One or two hydrogen atoms on the "alkylene-" group may be optionally replaced by C 1-6 Alkyl substituted or the "-C 1-4 Two hydrogen atoms on the same carbon of the alkylene-" are simultaneously replaced by -CH2CH2- to form a cycloalkyl group; the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the following groups: C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl; R a and R b Each is defined the same as in formula (B).

[0089] In one embodiment, in Formula B1, Formula B1a, Formula B1a-1 or Formula B1a-2, R5 is H, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 1-2 Alkylene-hydroxyl, -C 1-2 Alkylene-cyano, -C 1-2 Alkylene-C 1-4 Alkoxy, -C 1-2 Alkylene-halogenated C1-4 Base, -C 1-2 Alkylene-deuterated C 1-4 Alkyl, -C 1-2 Alkylene-halogenated C 1-4 Alkoxy, -C 1-2 Alkylene-deuterated C 1-4 Alkoxy, -C 1-2 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-2 Alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-2 Alkylene-NR a R b 、-C 1-2 Alkylene-C(O)NR a R b 、-C 1-2 Alkylene-C(O)OC 1-4 Alkyl, -C 1-2 Alkylene-SO2C 1-3 Alkyl, -C 1-2 Alkylene-carboxyl, 3 to 6 membered monocyclic heterocyclic group or C 3-6 Monocyclic cycloalkyl; wherein the "-C 1-2 One or two hydrogen atoms on the "alkylene-" group may be optionally replaced by C 1-4 Alkyl substituted, or the "-C 1-2 Two hydrogen atoms on the same carbon of the alkylene-" are simultaneously replaced by -CH2CH2- to form a cycloalkyl group; the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the following groups: C 1-4 Alkyl, halogenated C 1-4 Alkyl and deuterated C 1-4 Alkyl; R a and R b Each is defined the same as in formula (B).

[0090] In one embodiment, in Formula B1, Formula B1a, Formula B1a-1 or Formula B1a-2, R3 and R4 are each independently selected from: H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 monocyclic cycloalkyl and 3- to 6-membered monocyclic heterocyclyl; said 3- to 6-membered monocyclic heterocyclyl having 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; said C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-6The monocyclic cycloalkyl group and the 3- to 6-membered monocyclic heterocyclic group are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S1.

[0091] In one embodiment, in Formula B1, Formula B1a, Formula B1a-1 or Formula B1a-2, R3 and R4 are each independently selected from: C 1-6 Alkyl, C 3-6 monocyclic cycloalkyl and 3- to 6-membered monocyclic heterocyclyl; said 3- to 6-membered monocyclic heterocyclyl having 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; said C 1-6 Alkyl, the C 3-6 The monocyclic cycloalkyl group and the 3- to 6-membered monocyclic heterocyclic group are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S1.

[0092] In one embodiment, in Formula B1, Formula B1a, Formula B1a-1 or Formula B1a-2, R3 and R4 are each independently selected from: C 1-6 Alkyl; the C 1-6 The alkyl group is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from the S1 group; wherein the groups of the S1 group are selected from: halogen, hydroxyl, -C 1-3 Alkoxy, -deuterated C 1-3 Alkoxy, -halogenated C 1-3 Alkoxy, -C 3-6 Monocyclic cycloalkyl, -OC 3-6 Monocyclic cycloalkyl and -NR a R b ; Among them, R a and R b Each independently is H, C 1-3 Alkyl, deuterated C 1-3 Alkyl or cyclopropyl; or R a 、R b Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group; wherein the 3- to 6-membered nitrogen-containing heterocyclic group has 1 nitrogen atom and optionally 1 or 2 heteroatoms selected from N, O and S as ring atoms.

[0093] In one embodiment, in Formula B1, Formula B1a, Formula B1a-1 or Formula B1a-2, R3 is selected from: C 1-6 Alkyl and C 3-6 Monocyclic cycloalkyl; said C 1-6 Alkyl is unsubstituted or substituted by deuterium or halogen; R4 is selected from: C 1-6 Alkyl; the C 1-6 The alkyl group is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from the group S1; the groups of the group S1 are selected from: hydroxyl, C 1-6 Alkoxy, halogenated C1-6 Alkoxy, deuterated C 1-6 Alkoxy, -C 3-6 Monocyclic cycloalkyl, -OC 3-6 Monocyclic cycloalkyl and -NR a R b ; Among them, R a and R b Each independently is H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-C 1-6 Alkoxy, 3 to 6 membered monocyclic heterocyclic group, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group or C(O)C 1-6 wherein the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; and the 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the group consisting of: C 1-6 Alkyl; or R a 、R b Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group; wherein the 3- to 6-membered nitrogen-containing heterocyclic group has 1 nitrogen atom and optionally 1 or 2 heteroatoms selected from N, O and S as ring atoms; and the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from the group consisting of: C 1-6 alkyl.

[0094] In one embodiment, in Formula B1, Formula B1a, Formula B1a-1 or Formula B1a-2, R3 is methyl, trifluoromethyl, ethyl, n-propyl or cyclopropyl; R4 is methyl or ethyl; the methyl and ethyl are unsubstituted or substituted by one group selected from Group S1; the group of Group S1 is selected from: hydroxy, methoxy, deuterated methoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, -O-cyclopropyl, -O-cyclobutyl, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH3)(CH3), -N(CH2CH2CH3)(CH3) and -N(CH2CH2CH3)(CH2CH3).

[0095] In one embodiment, in Formula B1, Formula B1a, Formula B1a-1 or Formula B1a-2, R3 is methyl or ethyl; R4 is methyl or ethyl; the methyl and ethyl are unsubstituted or substituted by one group selected from Group S1; the group of Group S1 is selected from: hydroxy, methoxy, deuterated methoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, -O-cyclopropyl, -O-cyclobutyl, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH3)(CH3), -N(CH2CH2CH3)(CH3) and -N(CH2CH2CH3)(CH2CH3); R5 is H.

[0096] In one embodiment, in Formula B1, Formula B1a, Formula B1a-1 or Formula B1a-2, R3 is methyl and the methyl group is unsubstituted or substituted with deuterium or halogen; R4 is methyl and the methyl group is unsubstituted or substituted with methoxy, deuterated methoxy, halogenated methoxy, ethoxy, deuterated ethoxy or halogenated ethoxy; R5 is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C 3-6 Monocyclic cycloalkyl, -halogenated C 3-6 Monocyclic cycloalkyl, -deuterated C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-4 Alkylene-NR a R b 、-C 1-4 Alkylene-C(O)NR a R b 、-C 1-4 Alkylene-C(O)OC 1-6 Alkyl, -C 1-4 Alkylene-SO2C 1-3 Alkyl, -C 1-4 Alkylene-carboxyl, 3 to 6 membered monocyclic heterocyclic group or C 3-6 Monocyclic cycloalkyl; wherein the "-C 1-4 One or two hydrogen atoms on the "alkylene-" group may be optionally replaced by C 1-6Alkyl substituted, or the "-C 1-4 Two hydrogen atoms on the same carbon of the alkylene-" are simultaneously replaced by -CH2CH2- to form a cycloalkyl group; the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the following groups: C 1-6 Alkyl; R a and R b Each is defined the same as in formula (B).

[0097] In one embodiment, in Formula B1, Formula B1a, Formula B1a-1 or Formula B1a-2, R3 and R4 are each independently methyl; the methyl groups are each independently unsubstituted or substituted with deuterium, halogen, hydroxyl, methoxy, deuterated methoxy, halogenated methoxy, ethoxy, deuterated ethoxy or halogenated ethoxy.

[0098] In one embodiment, in Formula B1, Formula B1a, Formula B1a-1 or Formula B1a-2, R3 and R4 together with the carbon atom to which they are attached constitute: 3-6 monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclyl or carbonyl (C=O); the 3- to 6-membered monocyclic heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the C 3-6 The monocyclic cycloalkyl group and the 3- to 6-membered monocyclic heterocyclic group are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S1.

[0099] In one embodiment, in Formula B1, Formula B1a, Formula B1a-1 or Formula B1a-2, R3 and R4 together with the carbon atoms to which they are attached constitute: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran, piperidine or carbonyl (C=O); the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the oxetanyl, the azetidinyl, the tetrahydropyrrole, the tetrahydrofuran, the tetrahydropyran and the piperidine are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S1.

[0100] In one embodiment, in Formula B1, Formula B1a, Formula B1a-1 or Formula B1a-2, R3 and R4 together with the carbon atom to which they are attached constitute: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran, piperidine or carbonyl (C=O); the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran and piperidine are each independently unsubstituted or substituted. , 2, 3 or 4 groups independently selected from S1 group are substituted; wherein the groups of S1 group are selected from: cyano, hydroxy, methyl, ethyl, propyl, halomethyl, methoxy, ethoxy, -C(O)CH3, -C(O)cyclopropyl, -C(O)NH2, -C(O)N(CH3)2, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3-CH2N(CH3)2, -CH2CH2N(CH3)2, -NHC(O)CH3 and -N(CH3)2.

[0101] In one embodiment, the compound of formula (B) has the structure shown in formula B2:

[0102]

[0103] In each formula, A, B, R3, R4, R5, and G1 are the same as those defined in formula B.

[0104] In one embodiment, the compound of formula (B) has the structure shown in formula B2a:

[0105]

[0106] In each formula, R3, R4, R5, and G1 are the same as those defined in Formula B.

[0107] In one embodiment, the compound of formula (B) has the structure shown in formula B2a-1 or formula B2a-2:

[0108]

[0109] In each formula, R3, R4, R5, and G1 are the same as those defined in Formula B.

[0110] In one embodiment, in Formula B2, Formula B2a, Formula B2a-1 or Formula B2a-2, R3 and R4 are each independently selected from: H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6monocyclic cycloalkyl and 3- to 6-membered monocyclic heterocyclyl; said 3- to 6-membered monocyclic heterocyclyl having 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; said C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-6 The monocyclic cycloalkyl group and the 3- to 6-membered monocyclic heterocyclic group are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S1.

[0111] In one embodiment, in Formula B2, Formula B2a, Formula B2a-1 or Formula B2a-2, R3 and R4 are each independently selected from: C 1-6 Alkyl, C 3-6 monocyclic cycloalkyl and 3- to 6-membered monocyclic heterocyclyl; said 3- to 6-membered monocyclic heterocyclyl having 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; said C 1-6 Alkyl, the C 3-6 The monocyclic cycloalkyl group and the 3- to 6-membered monocyclic heterocyclic group are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S1.

[0112] In one embodiment, in Formula B2, Formula B2a, Formula B2a-1 or Formula B2a-2, R3 and R4 are each independently selected from: C 1-6 Alkyl; the C 1-6 The alkyl group is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from the S1 group; wherein the groups of the S1 group are selected from: halogen, hydroxyl, -C 1-3 Alkoxy, -deuterated C 1-3 Alkoxy, -halogenated C 1-3 Alkoxy, -C 3-6 Monocyclic cycloalkyl, -OC 3-6 Monocyclic cycloalkyl and -NR a R b ; Among them, R a and R b Each independently is H, C 1-3 Alkyl, deuterated C 1-3 Alkyl or cyclopropyl; or R a 、R b Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group; wherein the 3- to 6-membered nitrogen-containing heterocyclic group has 1 nitrogen atom and optionally 1 or 2 heteroatoms selected from N, O and S as ring atoms.

[0113] In one embodiment, in Formula B2, Formula B2a, Formula B2a-1 or Formula B2a-2, R3 and R4 are each independently methyl; and the methyl groups are each independently unsubstituted or substituted with deuterium, halogen, hydroxyl, methoxy, deuterated methoxy, halogenated methoxy, ethoxy, deuterated ethoxy or halogenated ethoxy.

[0114] In one embodiment, in Formula B2, Formula B2a, Formula B2a-1 or Formula B2a-2, R3 and R4 together with the carbon atom to which they are attached constitute: 3-6 monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclyl or carbonyl (C=O); the 3- to 6-membered monocyclic heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the C 3-6 The monocyclic cycloalkyl group and the 3- to 6-membered monocyclic heterocyclic group are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S1.

[0115] In one embodiment, in formula B2, formula B2a, formula B2a-1 or formula B2a-2, R3 and R4 together with the carbon atoms to which they are attached constitute: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran, piperidine or carbonyl (C=O); the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the oxetanyl, the azetidinyl, the tetrahydropyrrole, the tetrahydrofuran, the tetrahydropyran and the piperidine are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from group S1.

[0116] In one embodiment, in Formula B2, Formula B2a, Formula B2a-1 or Formula B2a-2, R3 and R4 together with the carbon atom to which they are attached constitute: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran, piperidine or carbonyl (C=O); the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran and piperidine are each independently unsubstituted or substituted. , 2, 3 or 4 groups independently selected from S1 group are substituted; wherein the groups of S1 group are selected from: cyano, hydroxy, methyl, ethyl, propyl, halomethyl, methoxy, ethoxy, -C(O)CH3, -C(O)cyclopropyl, -C(O)NH2, -C(O)N(CH3)2, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3-CH2N(CH3)2, -CH2CH2N(CH3)2, -NHC(O)CH3 and -N(CH3)2.

[0117] In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:

[0118] Where,

[0119] R1 and R2 are each independently selected from: H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-20 Cycloalkyl and 3 to 20 membered heterocyclic group; or R1 and R2 together with the carbon atom to which they are attached constitute: C 3-20 cycloalkyl, 3- to 20-membered heterocyclyl or carbonyl (C=O); the 3- to 20-membered heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-20 The cycloalkyl group and the 3- to 20-membered heterocyclic group are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S1;

[0120] R3 and R4 are each independently selected from: H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-20 Cycloalkyl and 3 to 20 membered heterocyclic group; or R3 and R4 together with the carbon atom to which they are attached constitute: C 3-20 cycloalkyl, 3- to 20-membered heterocyclyl or carbonyl (C=O); the 3- to 20-membered heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-20 The cycloalkyl group and the 3- to 20-membered heterocyclic group are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S1;

[0121] n is 0, 1, 2, or 3;

[0122] E is NR5 or O; wherein R5 is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-deuterated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-deuterated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-4 Alkylene-NR a R b 、-C 1-4 Alkylene-C(O)NR a R b 、-C 1-4 Alkylene-C(O)OC 1-6 Alkyl, -C 1-4 Alkylene-SO2C 1-3 Alkyl, -C 1-4 Alkylene-carboxyl or C 3-6 Monocyclic cycloalkyl; wherein the "-C 1-4 One or two hydrogen atoms on the "alkylene-" group may be optionally replaced by C 1-6 Alkyl substituted, or the "-C 1-4 Two hydrogen atoms on the same carbon of the alkylene-" are simultaneously replaced by -CH2CH2- to form a cycloalkyl group; the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the following groups: C 1-6 alkyl;

[0123] A is CR6 or N; wherein R6 is H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl or -C 3-6 Cycloalkyl;

[0124] B is CR7 or N; wherein R7 is H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl or -C 3-6 Cycloalkyl;

[0125] G1 is C 6-14aryl, 5- or 6-membered monocyclic heteroaryl or 8- to 10-membered bicyclic heteroaryl; wherein the 5- or 6-membered monocyclic heteroaryl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 8- to 10-membered bicyclic heteroaryl has 1, 2, 3, 4 or 5 heteroatoms selected from N, O and S as ring atoms; and the C 6-14 The aryl group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from Group S2;

[0126] G2 is C 6-14 aryl, 5- or 6-membered monocyclic heteroaryl or 8- to 10-membered bicyclic heteroaryl; wherein the 5- or 6-membered monocyclic heteroaryl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 8- to 10-membered bicyclic heteroaryl has 1, 2, 3, 4 or 5 heteroatoms selected from N, O and S as ring atoms; and the C 6-14 The aryl group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from Group S2;

[0127] L is a key, CR 8 R 9 、O、NH、NHC(O)、C 1-2 Alkylene-NHC(O) or NHC(O)-C 1-2 Alkylene; wherein R 8 、R 9 are independently H, halogen, hydroxy, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-NR a R b 、-C 1-4 Alkylene-C(O)NR a R b、-C 1-4 Alkylene-SO2C 1-3 Alkyl or -C 1-4 Alkylene-carboxyl;

[0128] The groups of group S1 or S2 are independently selected from: deuterium, halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -C 3-6 Monocyclic cycloalkyl, -halogenated C 3-6 Monocyclic cycloalkyl, -OC 3-6 Monocyclic cycloalkyl, 3 to 6 membered monocyclic heterocyclic group, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-4 Alkylene-NR a R b 、-C 1-4 Alkylene-C(O)NR a R b 、-C 1-4 Alkylene-SO2C 1-3 Alkyl, -C 1-4 Alkylene-carboxyl, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Monocyclic cycloalkyl, -C(O)NR a R b 、-NHC(O)R c and -NR a R b ; The 3- to 6-membered monocyclic heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

[0129] In the above groups, R a and R b Each independently is H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6Monocyclic cycloalkyl, -C 1-4 Alkylene-C 1-6 Alkoxy, 3 to 6 membered monocyclic heterocyclic group, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group or C(O)C 1-6 wherein the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; and the 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the group consisting of: C 1-6 alkyl; or

[0130] In the above groups, R a 、R b Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group; wherein the 3- to 6-membered nitrogen-containing heterocyclic group has 1 nitrogen atom and optionally 1 or 2 heteroatoms selected from N, O and S as ring atoms; and the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from the group consisting of: C 1-6 alkyl;

[0131] In the above groups, R c For hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl.

[0132] In one embodiment, the compound of formula (I) has the structure shown in formula II:

[0133]

[0134] In the formula, A, B, R3, R4, R5, L, G1, and G2 have the same definitions as those of the groups in formula (I).

[0135] In one embodiment, the compound of formula (I) has the structure shown in formula IIa:

[0136]

[0137] In the formula, R3, R4, R5, L, G1, and G2 have the same definitions as those of the groups in formula (I).

[0138] In one embodiment, the compound of formula (I) has a structure shown in formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIg, formula IIh, formula III, formula IIj or formula IIk:

[0139]

[0140]

[0141] In each formula, R3, R4, R5, R7, R8, G1, and G2 are defined the same as those of the groups in formula (I); and m is independently 1 or 2.

[0142] In one embodiment, the compound of formula (I) has a structure represented by formula IIb-1, formula IIc-1, formula IId-1, formula IIe-1, formula IIf-1, formula IIg-1, formula IIh-1, formula IIi-1, formula IIj-1, formula IIk-1, formula IIb-2, formula IIc-2, formula IId-2, formula IIe-2, formula IIf-2, formula IIg-2, formula IIh-2, formula IIi-2, formula IIj-2 or formula IIk-2:

[0143]

[0144]

[0145] In each formula, R3, R4, R5, R7, R8, G1, and G2 are defined the same as those of the groups in formula (I); and m is independently 1 or 2.

[0146] In one embodiment, in Formula IIk, R7 and R8 are each independently selected from: H.

[0147] In one embodiment, in Formula II, Formula IIa, Formula IIb, Formula IIc, Formula IId, Formula IIe, Formula IIf, Formula IIg, Formula IIh, Formula IIi, Formula IIj, Formula IIk, Formula IIb-1, Formula IIc-1, Formula IId-1, Formula IIe-1, Formula IIf-1, Formula IIg-1, Formula IIh-1, Formula IIi-1, Formula IIj-1, Formula IIk-1, Formula IIb-2, Formula IIc-2, Formula IId-2, Formula IIe-2, Formula IIf-2, Formula IIg-2, Formula IIh-2, Formula IIi-2, Formula IIj-2 or Formula IIk-2, R3 and R4 are each independently selected from: methyl, ethyl, n-propyl, n-butyl, n-pentyl; the methyl, ethyl, n-propyl, n-butyl, and n-pentyl are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S1.

[0148] In one embodiment, in Formula II, Formula IIa, Formula IIb, Formula IIc, Formula IId, Formula IIe, Formula IIf, Formula IIg, Formula IIh, Formula IIi, Formula IIj, Formula IIk, Formula IIb-1, Formula IIc-1, Formula IId-1, Formula IIe-1, Formula IIf-1, Formula IIg-1, Formula IIh-1, Formula IIi-1, Formula IIj-1, Formula IIk-1, Formula IIb-2, Formula IIc-2, Formula IId-2, Formula IIe-2, Formula IIf-2, Formula IIg-2, Formula IIh-2, Formula IIi-2, Formula IIj-2 or Formula IIk-2, R5 is H, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 1-2 Alkylene-hydroxyl, -C 1-2 Alkylene-cyano, -C 1-2 Alkylene-C 1-2 Alkoxy, -C 1-2 Alkylene-halogenated C 1-2 Alkyl, -C 1-2 Alkylene-deuterated C 1-2 Alkyl, -C 1-2 Alkylene-halogenated C 1-2 Alkoxy, -C 1-2 Alkylene-deuterated C 1-2 Alkoxy, -C 1-2 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-2 Alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-2 Alkylene-NR a R b 、-C 1-2 Alkylene-C(O)NR a R b 、-C 1-2 Alkylene-C(O)OC 1-4 Alkyl, -C 1-2 Alkylene-SO2C 1-3 Alkyl, -C 1-2 Alkylene-carboxyl, 3 to 6 membered monocyclic heterocyclic group or C 3-6 Monocyclic cycloalkyl; wherein the -C 1-2 Alkylene- is unsubstituted, or -C 1-2 One or two hydrogen atoms on the alkylene group are independently selected from halogen, cyano, hydroxyl, -C 1-2 Alkyl, -halogenated C 1-2 Alkyl and deuterated C 1-2 substituted with an alkyl group, or the -C 1-2The two hydrogen atoms on the same carbon atom of the alkylene group are simultaneously replaced by -(CH2) j -substituted to form a cycloalkyl group, wherein j is 2 or 3; the 3 to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3 to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxyl, nitro, C 1-4 Alkyl, -halogenated C 1-4 Alkyl, -deuterated C 1-4 Alkyl, -C 1-4 Alkoxy, -halogenated C 1-4 Alkoxy and -deuterated C 1-4 Alkoxy.

[0149] In one embodiment, in Formula II, Formula IIa, Formula IIb, Formula IIc, Formula IId, Formula IIe, Formula IIf, Formula IIg, Formula IIh, Formula III, Formula IIj, Formula IIk, Formula IIb-1, Formula IIc-1, Formula IId-1, Formula IIe-1, Formula IIf-1, Formula IIg-1, Formula IIh-1, Formula III-1, Formula IIj-1, Formula IIk-1, Formula IIb-2, Formula IIc-2, Formula IId-2, Formula IIe-2, Formula IIf-2, Formula IIg-2, Formula IIh-2, Formula III-2, Formula IIj-2 or Formula IIk-2, R3 and R4 are each independently selected from: H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 monocyclic cycloalkyl and 3- to 6-membered monocyclic heterocyclyl; said 3- to 6-membered monocyclic heterocyclyl having 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; said C 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 Alkynyl, the C 3-6 The monocyclic cycloalkyl group and the 3- to 6-membered monocyclic heterocyclic group are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S1;

[0150] R5 is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1- 4-alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-4 Alkylene-NR a R b 、-C 1-4 Alkylene-C(O)NR a R b 、-C 1-4 Alkylene-C(O)OC 1-6 Alkyl, -C 1-4 Alkylene-SO2C 1-3 Alkyl, -C 1-4 Alkylene-carboxyl or C 3-6 Monocyclic cycloalkyl; wherein the "-C 1-4 One or two hydrogen atoms on the "alkylene-" group may be optionally replaced by C 1-6 Alkyl substituted, or the "-C 1-4 Two hydrogen atoms on the same carbon of the alkylene-" are simultaneously replaced by -CH2CH2- to form a cycloalkyl group; the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the following groups: C 1-6 Alkyl; R a and R b Each is defined the same as in formula (I).

[0151] In one embodiment, in Formula II, Formula IIa, Formula IIb, Formula IIc, Formula IId, Formula IIe, Formula IIf, Formula IIg, Formula IIh, Formula III, Formula IIj, Formula IIk, Formula IIb-1, Formula IIc-1, Formula IId-1, Formula IIe-1, Formula IIf-1, Formula IIg-1, Formula IIh-1, Formula III-1, Formula IIj-1, Formula IIk-1, Formula IIb-2, Formula IIc-2, Formula IId-2, Formula IIe-2, Formula IIf-2, Formula IIg-2, Formula IIh-2, Formula III-2, Formula IIj-2 or Formula IIk-2, R3 and R4 are each independently selected from: C 1-6 Alkyl, C 3-6 monocyclic cycloalkyl and 3- to 6-membered monocyclic heterocyclyl; said 3- to 6-membered monocyclic heterocyclyl having 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; said C 1-6 Alkyl, the C 3-6 The monocyclic cycloalkyl group and the 3- to 6-membered monocyclic heterocyclic group are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S1;

[0152] R5 is H, C 1-6 Alkyl, -C 1-4Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-4 Alkylene-NR a R b 、-C 1-4 Alkylene-C(O)NR a R b 、-C 1-4 Alkylene-C(O)OC 1-6 Alkyl, -C 1-4 Alkylene-SO2C 1-3 Alkyl, -C 1-4 Alkylene-carboxyl or C 3-6 Monocyclic cycloalkyl; wherein the "-C 1-4 One or two hydrogen atoms on the "alkylene-" group may be optionally replaced by C 1-6 Alkyl substituted, or the "-C 1-4 Two hydrogen atoms on the same carbon of the alkylene-" are simultaneously replaced by -CH2CH2- to form a cycloalkyl group; the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the following groups: C 1-6 Alkyl; R a and R b Each is defined the same as in formula (I).

[0153] In one embodiment, in Formula II, Formula IIa, Formula IIb, Formula IIc, Formula IId, Formula IIe, Formula IIf, Formula IIg, Formula IIh, Formula III, Formula IIj, Formula IIk, Formula IIb-1, Formula IIc-1, Formula IId-1, Formula IIe-1, Formula IIf-1, Formula IIg-1, Formula IIh-1, Formula III-1, Formula IIj-1, Formula IIk-1, Formula IIb-2, Formula IIc-2, Formula IId-2, Formula IIe-2, Formula IIf-2, Formula IIg-2, Formula IIh-2, Formula III-2, Formula IIj-2 or Formula IIk-2, R3 and R4 are each independently selected from: C 1-6 Alkyl; the C 1-6The alkyl group is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from the S1 group; wherein the groups of the S1 group are selected from: hydroxyl, -C 1-3 Alkoxy, -OC 3-6 Monocyclic cycloalkyl and -NR a R b ; Among them, R a and R b Each independently is H, C 1-3 Alkyl, deuterated C 1-3 Alkyl or cyclopropyl; or R a 、R b Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group; wherein the 3- to 6-membered nitrogen-containing heterocyclic group has 1 nitrogen atom and optionally 1 or 2 heteroatoms selected from N, O and S as ring atoms;

[0154] R5 is H, C 1-6 Alkyl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-4 Alkylene-NR a R b 、-C 1-4 Alkylene-C(O)NR a R b 、-C 1-4 Alkylene-C(O)OC 1-6 Alkyl, -C 1-4 Alkylene-SO2C 1-3 Alkyl, -C 1-4 Alkylene-carboxyl or C 3-6 Monocyclic cycloalkyl; wherein the "-C 1-4 One or two hydrogen atoms on the "alkylene-" group may be optionally replaced by C 1-6 Alkyl substituted, or the "-C 1-4 Two hydrogen atoms on the same carbon of the alkylene-" are simultaneously replaced by -CH2CH2- to form a cycloalkyl group; the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the following groups: C 1-6 Alkyl; Ra and R b Each is defined the same as in formula (I).

[0155] In one embodiment, in Formula II, Formula IIa, Formula IIb, Formula IIc, Formula IId, Formula IIe, Formula IIf, Formula IIg, Formula IIh, Formula IIi, Formula IIj, Formula IIk, Formula IIb-1, Formula IIc-1, Formula IId-1, Formula IIe-1, Formula IIf-1, Formula IIg-1, Formula IIh-1, Formula IIi-1, Formula IIj-1, Formula IIk-1, Formula IIb-2, Formula IIc-2, Formula IId-2, Formula IIe-2, Formula IIf-2, Formula IIg-2, Formula IIh-2, Formula IIi-2, Formula IIj-2 or Formula IIk-2, R3 is selected from: C 1-6 Alkyl and C 3-6 Monocyclic cycloalkyl; said C 1-6 Alkyl is unsubstituted or substituted by halogen; R4 is selected from: C 1-6 Alkyl; the C 1-6 The alkyl group is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from the group S1; the groups of the group S1 are selected from: hydroxyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -OC 3-6 Monocyclic cycloalkyl and -NR a R b ; Among them, R a and R b Each independently is H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-C 1-6 Alkoxy, 3 to 6 membered monocyclic heterocyclic group, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group and C(O)C 1-6 wherein the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; and the 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the group consisting of: C 1-6 Alkyl; or R a 、R b Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group; wherein the 3- to 6-membered nitrogen-containing heterocyclic group has 1 nitrogen atom and optionally 1 or 2 heteroatoms selected from N, O and S as ring atoms; and the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from the group consisting of: C 1-6 alkyl;

[0156] R5 is H, C1-6 Alkyl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-4 Alkylene-NR a R b 、-C 1-4 Alkylene-C(O)NR a R b 、-C 1-4 Alkylene-C(O)OC 1-6 Alkyl, -C 1-4 Alkylene-SO2C 1-3 Alkyl, -C 1-4 Alkylene-carboxyl or C 3-6 Monocyclic cycloalkyl; wherein the "-C 1-4 One or two hydrogen atoms on the "alkylene-" group may be optionally replaced by C 1-6 Alkyl substituted, or the "-C 1-4 Two hydrogen atoms on the same carbon of the alkylene-" are simultaneously replaced by -CH2CH2- to form a cycloalkyl group; the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the following groups: C 1-6 Alkyl; R a and R b Each is defined the same as in formula (I).

[0157] In one embodiment, in Formula II, Formula IIa, Formula IIb, Formula IIc, Formula IId, Formula IIe, Formula IIf, Formula IIg, Formula IIh, Formula IIi, Formula IIj, Formula IIk, Formula IIb-1, Formula IIc-1, Formula IId-1, Formula IIe-1, Formula IIf-1, Formula IIg-1, Formula IIh-1, Formula III-1, Formula IIj-1, Formula IIk-1, Formula IIb-2, Formula IIc-2, Formula IId-2, Formula IIe-2, Formula IIf-2, Formula IIg-2, Formula IIh-2, Formula IIi-2, Formula IIj-2 or Formula IIk-2 , R3 is methyl, trifluoromethyl, ethyl, n-propyl or cyclopropyl; R4 is methyl or ethyl; the methyl and ethyl groups are unsubstituted or substituted by one group selected from Group S1; the groups of Group S1 are selected from the group consisting of hydroxy, methoxy, deuterated methoxy, trifluoromethoxy, deuterated methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, -O-cyclopropyl, -O-cyclobutyl, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH3)(CH3), -N(CH2CH2CH3)(CH3) and -N(CH2CH2CH3)(CH2CH3);

[0158] R5 is H, C 1-6 Alkyl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-4 Alkylene-NR a R b 、-C 1-4 Alkylene-C(O)NR a R b 、-C 1-4 Alkylene-C(O)OC 1-6 Alkyl, -C 1-4 Alkylene-SO2C 1-3 Alkyl, -C 1-4 Alkylene-carboxyl or C 3-6 Monocyclic cycloalkyl; wherein the "-C 1-4 One or two hydrogen atoms on the "alkylene-" group may be optionally replaced by C 1-6 Alkyl substituted, or the "-C 1-4Two hydrogen atoms on the same carbon of the alkylene-" are simultaneously replaced by -CH2CH2- to form a cycloalkyl group; the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the following groups: C 1-6 Alkyl; R a and R b Each is defined the same as in formula (I).

[0159] In one embodiment, in Formula II, Formula IIa, Formula IIb, Formula IIc, Formula IId, Formula IIe, Formula IIf, Formula IIg, Formula IIh, Formula III, Formula IIj, Formula IIk, Formula IIb-1, Formula IIc-1, Formula IId-1, Formula IIe-1, Formula IIf-1, Formula IIg-1, Formula IIh-1, Formula III-1, Formula IIj-1, Formula IIk-1, Formula IIb-2, Formula IIc-2, Formula IId-2, Formula IIe-2, Formula IIf-2, Formula IIg-2, Formula IIh-2, Formula III-2, Formula IIj-2 or Formula IIk-2, R3 and R4 together with the carbon atom to which they are attached constitute: C 3-6 monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclyl or carbonyl (C=O); the 3- to 6-membered monocyclic heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the C 3-6 The monocyclic cycloalkyl group and the 3- to 6-membered monocyclic heterocyclic group are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S1;

[0160] R5 is H, C 1-6 Alkyl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-4 Alkylene-NR a R b 、-C 1-4 Alkylene-C(O)NR a R b 、-C 1-4 Alkylene-C(O)OC 1-6 Alkyl, -C 1-4 Alkylene-SO2C1-3 Alkyl, -C 1-4 Alkylene-carboxyl or C 3-6 Monocyclic cycloalkyl; wherein the "-C 1-4 One or two hydrogen atoms on the "alkylene-" group may be optionally replaced by C 1-6 Alkyl substituted, or the "-C 1-4 Two hydrogen atoms on the same carbon of the alkylene-" are simultaneously replaced by -CH2CH2- to form a cycloalkyl group; the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the following groups: C 1-6 Alkyl; R a and R b Each is defined the same as in formula (I).

[0161] In one embodiment, Formula II, Formula IIa, Formula IIb, Formula IIc, Formula IId, Formula IIe, Formula IIf, Formula IIg, Formula IIh, Formula IIi, Formula IIj, Formula IIk, Formula IIb-1, Formula IIc-1, Formula IId-1, Formula IIe-1, Formula IIf-1, Formula IIg-1, Formula IIh-1, Formula IIi-1, Formula IIj-1, Formula IIk-1, Formula IIb-2, Formula IIc-2, Formula IId-2, Formula IIe-2, Formula IIf-2, Formula IIg-2, Formula IIh-2, Formula IIi -2, in formula IIj-2 or formula IIk-2, R3 and R4 together with the carbon atom to which they are attached constitute: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran, piperidine or carbonyl (C=O); the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran and piperidine are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S1;

[0162] R5 is H, C 1-6 Alkyl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-4 Alkylene-NRa R b 、-C 1-4 Alkylene-C(O)NR a R b 、-C 1-4 Alkylene-C(O)OC 1-6 Alkyl, -C 1-4 Alkylene-SO2C 1-3 Alkyl, -C 1-4 Alkylene-carboxyl or C 3-6 Monocyclic cycloalkyl; wherein the "-C 1-4 One or two hydrogen atoms on the "alkylene-" group may be optionally replaced by C 1-6 Alkyl substituted, or the "-C 1-4 Two hydrogen atoms on the same carbon of the alkylene-" are simultaneously replaced by -CH2CH2- to form a cycloalkyl group; the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the following groups: C 1-6 Alkyl; R a and R b Each is defined the same as in formula (I).

[0163] In one embodiment, in Formula II, Formula IIa, Formula IIb, Formula IIc, Formula IId, Formula IIe, Formula IIf, Formula IIg, Formula IIh, Formula IIi, Formula IIj, Formula IIk, Formula IIb-1, Formula IIc-1, Formula IId-1, Formula IIe-1, Formula IIf-1, Formula IIg-1, Formula IIh-1, Formula IIi-1, Formula IIj-1, Formula IIk-1, Formula IIb-2, Formula IIc-2, Formula IId-2, Formula IIe-2, Formula IIf-2, Formula IIg-2, Formula IIh-2, Formula IIi-2, Formula IIj-2 or Formula IIk-2, R3 and R4 together with the carbon atom to which they are attached constitute: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran, piperidine or carbonyl (C=O); the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the oxetanyl, the azetidinyl, the tetrahydropyrrole, the tetrahydrofuran, the tetrahydropyran and the piperidine are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S1; wherein the groups of Group S1 are selected from: cyano, hydroxyl, methyl, ethyl, propyl, halomethyl, methoxy, ethoxy, -C(O)CH3, -C(O)cyclopropyl, -C(O)NH2, -C(O)N(CH3)2, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, -CH2N(CH3)2, -CH2CH2N(CH3)2, -NHC(O)CH3 and -N(CH3)2;

[0164] R5 is H, C 1-6 Alkyl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C1 -6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-4 Alkylene-NR a R b 、-C 1-4 Alkylene-C(O)NR a R b 、-C 1-4 Alkylene-C(O)OC 1-6 Alkyl, -C 1-4 Alkylene-SO2C 1-3Alkyl, -C 1-4 Alkylene-carboxyl or C 3-6 Monocyclic cycloalkyl; wherein the "-C 1-4 One or two hydrogen atoms on the "alkylene-" group may be optionally replaced by C 1-6 Alkyl substituted, or the "-C 1-4 Two hydrogen atoms on the same carbon of the alkylene-" are simultaneously replaced by -CH2CH2- to form a cycloalkyl group; the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the following groups: C 1-6 Alkyl; R a and R b Each is defined the same as in formula (I).

[0165] In one embodiment, in Formula II, Formula IIa, Formula IIb, Formula IIc, Formula IId, Formula IIe, Formula IIf, Formula IIg, Formula IIh, Formula IIi, Formula IIj, Formula IIk, Formula IIb-1, Formula IIc-1, Formula IId-1, Formula IIe-1, Formula IIf-1, Formula IIg-1, Formula IIh-1, Formula IIi-1, Formula IIj-1, Formula IIk-1, Formula IIb-2, Formula IIc-2, Formula IId-2, Formula IIe-2, Formula IIf-2, Formula IIg-2, Formula IIh-2, Formula IIi-2, Formula IIj-2 or Formula IIk-2, R3 and R4 are each independently methyl; the methyl groups are each independently unsubstituted or substituted with deuterium, halogen, hydroxy, methoxy, deuterated methoxy, halogenated methoxy, ethoxy, deuterated ethoxy or halogenated ethoxy; R5 is H, C 1-6 Alkyl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-4 Alkylene-NR a R b 、-C 1-4 Alkylene-C(O)NR a R b 、-C 1-4 Alkylene-C(O)OC 1-6 Alkyl, -C 1-4Alkylene-SO2C 1-3 Alkyl, -C 1-4 Alkylene-carboxyl or C 3-6 Monocyclic cycloalkyl; wherein the "-C 1-4 One or two hydrogen atoms on the "alkylene-" group may be optionally replaced by C 1-6 Alkyl substituted, or the "-C 1-4 Two hydrogen atoms on the same carbon of the alkylene-" are simultaneously replaced by -CH2CH2- to form a cycloalkyl group; the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the following groups: C 1-6 Alkyl; R a and R b Each is defined the same as in formula (I).

[0166] In one embodiment, the compound of formula (I) has a structure shown in formula IIb', formula IIc', formula IId', formula IIe', formula IIf', formula IIg', formula IIh', formula IIi', formula IIj' or formula IIk':

[0167]

[0168]

[0169] In each formula, R5, R7, R8, G1, and G2 are defined as the same as those of the groups in formula (I); m is independently 1 or 2; C 3-20 Cycloalkyl or 3- to 20-membered heterocyclic group; the 3- to 20-membered heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the C 3-20 The cycloalkyl group and the 3- to 20-membered heterocyclic group are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S1.

[0170] In one embodiment, in Formula IIk', R7 and R8 are each independently selected from: H.

[0171] In one embodiment, in Formula IIb', Formula IIc', Formula IId', Formula IIe', Formula IIf', Formula IIg', Formula IIh', Formula IIi', Formula IIj' or Formula IIk', C 3-6 monocyclic cycloalkyl or 3- to 6-membered monocyclic heterocyclic group; said 3- to 6-membered monocyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; said C 3-6The monocyclic cycloalkyl and the 3 to 6 membered monocyclic heterocyclic groups are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from S1 group; R5 is H, C 1-6 Alkyl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-4 Alkylene-NR a R b 、-C 1-4 Alkylene-C(O)NR a R b 、-C 1-4 Alkylene-C(O)OC 1-6 Alkyl, -C 1-4 Alkylene-SO2C 1-3 Alkyl, -C 1-4 Alkylene-carboxyl or C 3-6 Monocyclic cycloalkyl; wherein the "-C 1-4 One or two hydrogen atoms on the "alkylene-" group may be optionally replaced by C 1-6 Alkyl substituted, or the "-C 1-4 Two hydrogen atoms on the same carbon of the alkylene-" are simultaneously replaced by -CH2CH2- to form a cycloalkyl group; the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the following groups: C 1-6 Alkyl; R a and R b Each is defined the same as in formula (I).

[0172] In one embodiment, in Formula IIb', Formula IIc', Formula IId', Formula IIe', Formula IIf', Formula IIg', Formula IIh', Formula IIi', Formula IIj' or Formula IIk', is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran or piperidine; the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran and piperidine are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S1; R5 is H, C 1-6 Alkyl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-4 Alkylene-NR a R b 、-C 1-4 Alkylene-C(O)NR a R b 、-C 1-4 Alkylene-C(O)OC 1-6 Alkyl, -C 1-4 Alkylene-SO2C 1-3 Alkyl, -C 1-4 Alkylene-carboxyl or C 3-6 Monocyclic cycloalkyl; wherein the "-C 1-4 One or two hydrogen atoms on the "alkylene-" group may be optionally replaced by C 1-6 Alkyl substituted, or the "-C 1-4 Two hydrogen atoms on the same carbon of the alkylene-" are simultaneously replaced by -CH2CH2- to form a cycloalkyl group; the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the following groups: C 1-6 Alkyl; R a and R b Each is defined the same as in formula (I).

[0173] In one embodiment, in Formula IIb', Formula IIc', Formula IId', Formula IIe', Formula IIf', Formula IIg', Formula IIh', Formula IIi', Formula IIj' or Formula IIk', is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran or piperidine; the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran and piperidine are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from S1 group; wherein the groups of S1 group are selected from : cyano, hydroxy, methyl, ethyl, propyl, halomethyl, methoxy, ethoxy, -C(O)CH3, -C(O)cyclopropyl, -C(O)NH2, -C(O)N(CH3)2, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3-CH2N(CH3)2, -CH2CH2N(CH3)2, -NHC(O)CH3 and -N(CH3)2; R5 is H, C 1-6 Alkyl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-4 Alkylene-NR a R b 、-C 1-4 Alkylene-C(O)NR a R b 、-C 1-4 Alkylene-C(O)OC 1-6 Alkyl, -C 1-4 Alkylene-SO2C 1-3 Alkyl, -C 1-4 Alkylene-carboxyl or C 3-6 Monocyclic cycloalkyl; wherein the "-C 1-4 One or two hydrogen atoms on the "alkylene-" group may be optionally replaced by C 1-6 Alkyl substituted, or the "-C 1-4 Two hydrogen atoms on the same carbon of the alkylene-" are simultaneously replaced by -CH2CH2- to form a cycloalkyl group; the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the following groups: C 1-6 Alkyl; R a and Rb Each is defined the same as in formula (I).

[0174] In one embodiment, the compound of formula (I) has the structure shown in formula III:

[0175]

[0176] In the formula, A, B, R3, R4, L, G1, and G2 have the same definitions as those of the groups in formula (I).

[0177] In one embodiment, the compound of formula (I) has the structure shown in formula IIIa:

[0178]

[0179] In the formula, R3, R4, L, G1, and G2 have the same definitions as those of the groups in formula (I).

[0180] In one embodiment, the compound of formula (I) has a structure shown in formula IIIb, formula IIIc, formula IIId, formula IIIe, formula IIIf, formula IIIg, formula IIIh, formula IIIi, formula IIIj or formula IIIk:

[0181]

[0182] In each formula, R3, R4, R7, R8, G1, and G2 are defined the same as those of the groups in formula (I); and m is independently 1 or 2.

[0183] In one embodiment, the compound of formula (I) has a structure represented by formula IIIb-1, formula IIIc-1, formula IIId-1, formula IIIe-1, formula IIIf-1, formula IIIg-1, formula IIIh-1, formula IIIi-1, formula IIIj-1, formula IIIk-1, formula IIIb-2, formula IIIc-2, formula IIId-2, formula IIIe-2, formula IIIf-2, formula IIIg-2, formula IIIh-2, formula IIIi-2, formula IIIj-2 or formula IIIk-2:

[0184]

[0185] In each formula, R3, R4, R7, R8, G1, and G2 are defined the same as those of the groups in formula (I); and m is independently 1 or 2.

[0186] In one embodiment, in Formula III, Formula IIIa, Formula IIIb, Formula IIIc, Formula IIId, Formula IIIe, Formula IIIf, Formula IIIg, Formula IIIh, Formula IIIi, Formula IIIj, Formula IIIk, Formula IIIb-1, Formula IIIc-1, Formula IIId-1, Formula IIIe-1, Formula IIIf-1, Formula IIIg-1, Formula IIIh-1, Formula IIIi-1, Formula IIIj-1, Formula IIIk-1, Formula IIIb-2, Formula IIIc-2, Formula IIId-2, Formula IIIe-2, Formula IIIf-2, Formula IIIg-2, Formula IIIh-2, Formula IIIi-2, Formula IIIj-2 or Formula IIIk-2, R3 and R4 are each independently selected from: H, C 1-6 Alkyl, C 3-6 monocyclic cycloalkyl and 3- to 6-membered monocyclic heterocyclyl; said 3- to 6-membered monocyclic heterocyclyl having 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; said C 1-6 Alkyl, the C 3-6 The monocyclic cycloalkyl group and the 3- to 6-membered monocyclic heterocyclic group are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S1.

[0187] In one embodiment, in Formula III, Formula IIIa, Formula IIIb, Formula IIIc, Formula IIId, Formula IIIe, Formula IIIf, Formula IIIg, Formula IIIh, Formula IIIi, Formula IIIj, Formula IIIk, Formula IIIb-1, Formula IIIc-1, Formula IIId-1, Formula IIIe-1, Formula IIIf-1, Formula IIIg-1, Formula IIIh-1, Formula IIIi-1, Formula IIIj-1, Formula IIIk-1, Formula IIIb-2, Formula IIIc-2, Formula IIId-2, Formula IIIe-2, Formula IIIf-2, Formula IIIg-2, Formula IIIh-2, Formula IIIi-2, Formula IIIj-2 or Formula IIIk-2, R3 and R4 are each independently selected from: C 1-6 Alkyl, C 3-6 monocyclic cycloalkyl and 3- to 6-membered monocyclic heterocyclyl; said 3- to 6-membered monocyclic heterocyclyl having 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; said C 1-6 Alkyl, the C 3-6 The monocyclic cycloalkyl group and the 3- to 6-membered monocyclic heterocyclic group are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S1.

[0188] In one embodiment, in Formula III, Formula IIIa, Formula IIIb, Formula IIIc, Formula IIId, Formula IIIe, Formula IIIf, Formula IIIg, Formula IIIh, Formula IIIi, Formula IIIj, Formula IIIk, Formula IIIb-1, Formula IIIc-1, Formula IIId-1, Formula IIIe-1, Formula IIIf-1, Formula IIIg-1, Formula IIIh-1, Formula IIIi-1, Formula IIIj-1, Formula IIIk-1, Formula IIIb-2, Formula IIIc-2, Formula IIId-2, Formula IIIe-2, Formula IIIf-2, Formula IIIg-2, Formula IIIh-2, Formula IIIi-2, Formula IIIj-2 or Formula IIIk-2, R3 and R4 are each independently selected from: C 1-6 Alkyl; the C 1-6 The alkyl group is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from the S1 group; wherein the groups of the S1 group are selected from: hydroxyl, -C 1-3 Alkoxy, -OC 3-6 Monocyclic cycloalkyl and -NR a R b ; Among them, R a and R b Each independently is H, C 1-3 Alkyl, deuterated C 1-3 Alkyl or cyclopropyl; or R a 、R b Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group; wherein the 3- to 6-membered nitrogen-containing heterocyclic group has 1 nitrogen atom and optionally 1 or 2 heteroatoms selected from N, O and S as ring atoms.

[0189] In one embodiment, in Formula III, Formula IIIa, Formula IIIb, Formula IIIc, Formula IIId, Formula IIIe, Formula IIIf, Formula IIIg, Formula IIIh, Formula IIIi, Formula IIIj, Formula IIIk, Formula IIIb-1, Formula IIIc-1, Formula IIId-1, Formula IIIe-1, Formula IIIf-1, Formula IIIg-1, Formula IIIh-1, Formula IIIi-1, Formula IIIj-1, Formula IIIk-1, Formula IIIb-2, Formula IIIc-2, Formula IIId-2, Formula IIIe-2, Formula IIIf-2, Formula IIIg-2, Formula IIIh-2, Formula IIIi-2, Formula IIIj-2 or Formula IIIk-2, R3 and R4 together with the carbon atom to which they are attached form: C 3-6 monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclyl or carbonyl (C=O); the 3- to 6-membered monocyclic heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the C 3-6The monocyclic cycloalkyl group and the 3- to 6-membered monocyclic heterocyclic group are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S1.

[0190] In one embodiment, formula III, formula IIIa, formula IIIb, formula IIIc, formula IIId, formula IIIe, formula IIIf, formula IIIg, formula IIIh, formula IIIi, formula IIIj, formula IIIk, formula IIIb-1, formula IIIc-1, formula IIId-1, formula IIIe-1, formula IIIf-1, formula IIIg-1, formula IIIh-1, formula IIIi-1, formula IIIj-1, formula IIIk-1, formula IIIb-2, formula IIIc-2, formula IIId-2, formula IIIe-2, formula IIIf-2, formula IIIg-2 , Formula IIIh-2, Formula IIIi-2, Formula IIIj-2 or Formula IIIk-2, R3 and R4 together with the carbon atoms to which they are connected constitute: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran, piperidine or carbonyl (C=O); the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the oxetanyl, the azetidinyl, the tetrahydropyrrole, the tetrahydrofuran, the tetrahydropyran and the piperidine are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S1.

[0191] In one embodiment, in Formula III, Formula IIIa, Formula IIIb, Formula IIIc, Formula IIId, Formula IIIe, Formula IIIf, Formula IIIg, Formula IIIh, Formula IIIi, Formula IIIj, Formula IIIk, Formula IIIb-1, Formula IIIc-1, Formula IIId-1, Formula IIIe-1, Formula IIIf-1, Formula IIIg-1, Formula IIIh-1, Formula IIIi-1, Formula IIIj-1, Formula IIIk-1, Formula IIIb-2, Formula IIIc-2, Formula IIId-2, Formula IIIe-2, Formula IIIf-2, Formula IIIg-2, Formula IIIh-2, Formula IIIi-2, Formula IIIj-2 or Formula IIIk-2, R3 and R4 together with the carbon atoms to which they are attached constitute: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrakis The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran and piperidine are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from S1 group; wherein the groups of S1 group are selected from: cyano, hydroxyl, methyl, ethyl, propyl, halomethyl, methoxy, ethoxy, -C(O)CH3, -C(O)cyclopropyl, -C(O)NH2, -C(O)N(CH3)2, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3-CH2N(CH3)2, -CH2CH2N(CH3)2, -NHC(O)CH3 and -N(CH3)2.

[0192] In one embodiment, in Formula III, Formula IIIa, Formula IIIb, Formula IIIc, Formula IIId, Formula IIIe, Formula IIIf, Formula IIIg, Formula IIIh, Formula IIIi, Formula IIIj, Formula IIIk, Formula IIIb-1, Formula IIIc-1, Formula IIId-1, Formula IIIe-1, Formula IIIf-1, Formula IIIg-1, Formula IIIh-1, Formula IIIi-1, Formula IIIj-1, Formula IIIk-1, Formula IIIb-2, Formula IIIc-2, Formula IIId-2, Formula IIIe-2, Formula IIIf-2, Formula IIIg-2, Formula IIIh-2, Formula IIIi-2, Formula IIIj-2 or Formula IIIk-2, R3 and R4 are each independently methyl; the methyl group is each independently unsubstituted or substituted with deuterium, halogen, hydroxyl, methoxy, deuterated methoxy, halogenated methoxy, ethoxy, deuterated ethoxy or halogenated ethoxy.

[0193] In one embodiment, G1 and G2 are both unsubstituted.

[0194] In one embodiment, G1 is unsubstituted and G2 is substituted; the substituents are as described above.

[0195] In one embodiment, G1 is substituted; the substituents are as described above; and G2 is unsubstituted.

[0196] In one embodiment, G1 and G2 are both substituted; the substituents are as described above.

[0197] In a preferred embodiment, R a and R b Each independently is C 1-6 Alkyl groups, such as C 1-4 Alkyl, such as methyl.

[0198] In a preferred embodiment, R c -C 1-4 Alkylene-C 1-6 Alkoxy (e.g. -C 1-2 Alkylene-C 1-3 Alkoxy, for example -CH2CH2OCH3 or -CH2CH2OCH2CH3) or a 3- to 6-membered monocyclic heterocyclic group substituted by 1 or 2 halogens (for example, the halogen in the 3- to 6-membered monocyclic heterocyclic group substituted by 1 or 2 halogens is fluorine, chlorine or bromine; for example, the 3- to 6-membered monocyclic heterocyclic group in the 3- to 6-membered monocyclic heterocyclic group substituted by 1 or 2 halogens is cyclopropyl).

[0199] In one embodiment, the group S1 is selected from the group consisting of: deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -C 3-6 Monocyclic cycloalkyl, -halogenated C 3-6 Monocyclic cycloalkyl, -OC 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Monocyclic cycloalkyl, -C(O)NR a R b 、-NHC(O)R c and -NR a R b ; Among them, R a and R b Each independently is H, C1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-C 1-6 Alkoxy, 3 to 6 membered monocyclic heterocyclic group, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group or C(O)C 1- wherein the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; and the 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the group consisting of: C 1-6 Alkyl; or R a 、R b Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group; wherein the 3- to 6-membered nitrogen-containing heterocyclic group has 1 nitrogen atom and optionally 1 or 2 heteroatoms selected from N, O and S as ring atoms; and the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from the group consisting of: C 1-6 Alkyl; R c For hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl.

[0200] In one embodiment, the group S1 is selected from the group consisting of: deuterium, halogen, cyano, hydroxyl, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -deuterated C 1-3 Alkyl, -C 1-3 Alkoxy, -halogenated C 1-3 Alkoxy, -deuterated C 1-3 Alkoxy, -cyclopropyl, -halocyclopropyl, -O-cyclopropyl, -C 1-2 Alkylene-hydroxyl, -C 1-2 Alkylene-cyano, -C 1-2 Alkylene-C 1-3 Alkoxy, -C(O)C 1-3 Alkyl, -C(O)cyclopropyl, -C(O)NR a R b 、-NHC(O)R c and -NR a R b ; Among them, R a and R b Each independently is H, C 1-3 Alkyl, deuterated C 1-3 Alkyl or cyclopropyl; or R a 、R bTogether with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group; wherein the 3- to 6-membered nitrogen-containing heterocyclic group has 1 nitrogen atom and optionally 1 or 2 heteroatoms selected from N, O and S as ring atoms; R c For hydrogen, C 1-3 Alkyl or halogenated C 1-3 alkyl.

[0201] In one embodiment, the groups of group S1 are selected from the group consisting of: deuterium, halogen, cyano, hydroxyl, methyl, ethyl, propyl, halomethyl, deuterated methyl, methoxy, ethoxy, halomethoxy, deuterated methoxy, -C(O)CH3, -C(O)cyclopropyl, -C(O)NH2, -C(O)N(CH3)2, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, -CH2N(CH3)2, -CH2CH2N(CH3)2, -NHC(O)CH3 and -N(CH3)2.

[0202] In one embodiment, the group S1 is selected from the group consisting of: deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl (e.g. C 1- 3 alkyl), C 1-6 Alkoxy (e.g. C 1-3 Alkyl), halogenated C 1-6 Alkoxy (e.g., halo-C 1-3 alkyl, such as difluoromethoxy or trifluoromethoxy), deuterated C 1-6 Alkoxy (e.g. deuterated C 1-3 Alkyl), -C 1-4 Alkylene-hydroxy (e.g. -C 1- 2-alkylene-hydroxyl), -C(O)C 1-6 Alkyl (e.g. -C(O)C 1-3 alkyl), -C(O)C 3-20 Cycloalkyl (e.g. -C(O)C 3-6 monocyclic cycloalkyl), 3- to 20-membered heterocyclyl (e.g., 3- to 6-membered monocyclic heterocyclyl, wherein the 3- to 6-membered monocyclic heterocyclyl has 1 or 2 heteroatoms selected from N and O as ring atoms), -OC 3-6 Monocyclic cycloalkyl, -NR a R b AND-OR c (For example -OC 1-4 Alkylene-C 1-6 alkoxy), wherein the 3- to 20-membered heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms.

[0203] In one embodiment, the group of S1 is selected from the group consisting of deuterium, fluorine, cyano, hydroxyl, methyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, deuterated methoxy (-OCD3), -CH2OH, -C(O)CH3, -C(O)-cyclopropyl, morpholinyl -O-cyclopropyl, -N(CH3)2, -OCH2CH2OCH3 and -CH2CH2OCH2CH3.

[0204] In one embodiment, the group of S2 is selected from the group consisting of fluorine, chlorine, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl and -C 3- 6-monocyclic cycloalkyl.

[0205] In one embodiment, the group S2 is selected from the group consisting of fluorine, chlorine, methyl, trifluoromethyl and cyclopropyl.

[0206] In one embodiment, the group of S2 is selected from the group consisting of: halogen, cyano, -C 1-6 Alkyl (e.g. -C 1-3 Alkyl), halogenated C 1-6 Alkyl (e.g. halo-C 1-3 Alkyl), deuterated C 1-6 Alkyl (e.g. deuterated C 1-3 Alkyl, such as deuterated methyl), C 1-6 Alkoxy (e.g. C 1-3 Alkoxy), halogenated C 1-6 Alkoxy (e.g., halo-C 1-3 Alkoxy), deuterated C 1-6 Alkoxy (e.g. deuterated C 1-3 Alkoxy), C 3-20 Cycloalkyl (e.g. C 3-6 Monocyclic cycloalkyl), halogenated C 3-20 Cycloalkyl (e.g., halo-C 3-6 Monocyclic cycloalkyl, such as halocyclopropyl), -OC 3-20 Cycloalkyl (e.g. -OC 3-6 Monocyclic cycloalkyl), -NR a R b AND-OR c .

[0207] In one embodiment, the groups of group S2 are selected from fluorine, chlorine, bromine, iodine, cyano, methyl, isopropyl, trifluoromethyl, methoxy, trifluoromethoxy, deuterated methoxy, cyclopropyl, -O-cyclopropyl, -O-cyclopentyl, -N(CH3)2 and -OCH2CH2OCH3.

[0208] In one embodiment, R1 and R2 are each independently selected from: H, C 1-6Alkyl, C 3-6 Monocyclic cycloalkyl and 3 to 6 membered monocyclic heterocyclic group; or R1 and R2 together with the carbon atom to which they are attached constitute: C 3-6 monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclyl or carbonyl (C=O); the 3- to 6-membered monocyclic heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the C 1-6 Alkyl, the C 3-6 The monocyclic cycloalkyl group and the 3- to 6-membered monocyclic heterocyclic group are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S1.

[0209] In one embodiment, R1 and R2 are each independently selected from: H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl and cyclobutyl; or R1 and R2 together with the carbon atoms to which they are attached constitute: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran, piperidine or carbonyl (C=O); the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran and piperidine are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from S1 group.

[0210] In one embodiment, R1 and R2 are each independently H.

[0211] In one embodiment, R1 and R2 together with the carbon atom to which they are attached form a carbonyl group (C=O).

[0212] In one embodiment, R1 and R2 are each independently selected from: H, C 1-6 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl), C 3-6 Monocyclic cycloalkyl (e.g., cyclopropyl, cyclobutyl), 3- to 6-membered monocyclic heterocyclic group, C 1-6 Alkoxy (such as methoxy) and C 1-6 Alkylthio (e.g., methylthio, ethylthio); or R1 and R2 together with the carbon atom to which they are attached constitute: C 3-6 monocyclic cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), 3- to 6-membered monocyclic heterocyclic group (e.g., oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran, piperidine), carbonyl (C═O) or C═S; the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the C 1-6 Alkyl, the C 3-6 Monocyclic cycloalkyl, the 3 to 6 membered monocyclic heterocyclic group, C 1-6Alkoxy, C 1-6 Each alkylthio group is independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S1.

[0213] In one embodiment, R1 and R2 are each independently selected from: H, C 1-6 Alkoxy (e.g. C 1-3 Alkoxy, such as methoxy) and C 1-6 Alkylthio (e.g. C 1-3 Alkylthio, for example methylthio, ethylthio); or R1 and R2 together with the carbon atom to which they are attached constitute: carbonyl (C=O) or C=S, wherein the C 1-6 Alkoxy and the C 1-6 Each alkylthio group is independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S1.

[0214] In one embodiment, R1 and R2 are each independently selected from the group consisting of: methoxy, methylthio, and ethylthio.

[0215] In one embodiment, R1 and R2 together with the carbon atom to which they are attached form a carbonyl group (C=O) or C=S.

[0216] In one embodiment, R1 and R2 together with the carbon atom to which they are attached form C=S.

[0217] In one embodiment, R3 and R4 are each independently selected from: H, C 1-6 Alkyl, C 3-6 Monocyclic cycloalkyl and 3 to 6 membered monocyclic heterocyclic group; or R3 and R4 together with the carbon atom to which they are attached constitute: C 3-6 monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclyl or carbonyl (C=O); the 3- to 6-membered monocyclic heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the C 1-6 Alkyl, the C 3-6 The monocyclic cycloalkyl group and the 3- to 6-membered monocyclic heterocyclic group are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S1.

[0218] In one embodiment, R3 and R4 are each independently selected from: H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl and cyclobutyl; or R3 and R4 together with the carbon atoms to which they are attached constitute: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran, piperidine or carbonyl (C=O); the methyl, the ethyl, the n-propyl, the isopropyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the oxetanyl, the azetidinyl, the tetrahydropyrrole, the tetrahydrofuran, the tetrahydropyran and the piperidine are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S1.

[0219] In one embodiment, R3 and R4 are each independently selected from: methyl, ethyl, n-propyl, isopropyl, cyclopropyl and cyclobutyl; the methyl, ethyl, n-propyl, isopropyl, cyclopropyl and cyclobutyl are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from S1 group.

[0220] In one embodiment, R3 and R4 are each independently selected from: C 1-6 Alkyl (e.g. C 1-3 Alkyl, such as methyl or ethyl) and C 3-20 Cycloalkyl (e.g. C 3-6 Monocyclic cycloalkyl, for example cyclopropyl); or R3 and R4 together with the carbon atom to which they are attached constitute: C 3-20 Cycloalkyl (e.g. C 3-6 monocyclic cycloalkyl, for example cyclopropyl, cyclopentyl, cyclohexyl) or 3 to 20-membered heterocyclyl, the 3 to 20-membered heterocyclyl having 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms (for example 3 to 6-membered monocyclic heterocyclyl, wherein the 3 to 6-membered monocyclic heterocyclyl has 1 or 2 heteroatoms selected from N and O as ring atoms, for example oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran or piperidine); the C 1-6 Alkyl, the C 3-6 The monocyclic cycloalkyl and the 3- to 6-membered monocyclic heterocycle are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S1. In a preferred embodiment, the groups of Group S1 are selected from: deuterium, halogen (e.g., F), cyano, hydroxyl, C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (such as methoxy, ethoxy), deuterated C 1-6 Alkoxy (e.g., deuterated methoxy), -C 1-4 Alkylene-hydroxy (e.g. -CH2OH), -C(O)C 1-6 Alkyl (e.g. -C(O)CH3), -C(O)C3-20 Cycloalkyl (e.g. -C(O)-cyclopropyl), 3- to 20-membered heterocyclic (e.g. morpholinyl), ),-OC 3-6 Monocyclic cycloalkyl (e.g., -O-cyclopropyl), -NR a R b (e.g. -N(CH3)2) and -OR c (For example -OC 1-4 Alkylene-C 1-6 Alkoxy, for example -CH2OCH2CH2OCH3).

[0221] In one embodiment, R3 and R4 are each independently selected from: -CH3, -CH2CH3, cyclopropyl, trifluoromethyl, deuterated methyl, -CH2OH, -CH2OCH3, -CH2OCF3, -CH2OCHF2, -CH2OCD3, -CH2OCH2CH3, -CH2OCH2CH2OCH3, -CH2CH2OCH2CH3, -CH2O-cyclopropyl, -CH2N(CH3)2, -CH(OH)CH3 and -CH2CH3OCH3.

[0222] In one embodiment, R3 is selected from: C 1-6 Alkyl and C 3-6 Monocyclic cycloalkyl; said C 1-6 Alkyl and the C 3-6 Each monocyclic cycloalkyl group is independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S1.

[0223] In one embodiment, R3 is selected from: C 1-6 Alkyl and C 3-6 Monocyclic cycloalkyl; said C 1-6 Alkyl and the C 3-6 Monocyclic cycloalkyl groups are unsubstituted or substituted with halogen.

[0224] In one embodiment, R3 is selected from the group consisting of: methyl, trifluoromethyl, ethyl, n-propyl, and cyclopropyl.

[0225] In one embodiment, R3 is selected from: C 1-6 Alkyl (such as methyl or ethyl) and C 3-6 Monocyclic cycloalkyl (eg cyclopropyl); said C 1-6 Alkyl and the C 3-6 Each monocyclic cycloalkyl group is independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S1. In a preferred embodiment, the groups in Group S1 are selected from: deuterium and halogen (e.g., F). In one embodiment, R3 is selected from: -CH3, -CH2CH3, trifluoromethyl, deuterated methyl and cyclopropyl.

[0226] In one embodiment, R4 is selected from: C 1-6 Alkyl; the C 1-6 The alkyl group is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from the group S1; the groups of the group S1 are selected from: hydroxyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -OC 3-6 Monocyclic cycloalkyl and -NR a R b ; Among them, R a and R b Each independently is H, C 1- 6-alkyl, deuterated C 1-6 Alkyl, C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-C 1-6 Alkoxy, 3 to 6 membered monocyclic heterocyclic group, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group or C(O)C 1-6 wherein the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; and the 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the group consisting of: C 1-6 Alkyl; or R a 、R b Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group; wherein the 3- to 6-membered nitrogen-containing heterocyclic group has 1 nitrogen atom and optionally 1 or 2 heteroatoms selected from N, O and S as ring atoms; and the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from the group consisting of: C 1-6 alkyl.

[0227] In one embodiment, R4 is selected from: methyl and ethyl; the methyl and ethyl are each independently unsubstituted or substituted by one group selected from S1 group; the group of S1 group is selected from: hydroxy, methoxy, deuterated methoxy, trifluoromethoxy, ethoxy, deuterated ethoxy, haloethoxy, n-propoxy, isopropoxy, n-butoxy, -O-cyclopropyl, -O-cyclobutyl, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH3)(CH3), -N(CH2CH2CH3)(CH3) and -N(CH2CH2CH3)(CH2CH3).

[0228] In one embodiment, R4 is selected from: C 1-6 Alkyl (eg methyl, ethyl); the C 1-6 The alkyl group is unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from the group S1; the groups of the group S1 are selected from: hydroxyl, C1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -OC 3-6 Monocyclic cycloalkyl, -NR a R b AND-OR c (For example -OC 1-4 Alkylene-C 1-6 alkoxy); wherein R a and R b Each independently is H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-C 1-6 Alkoxy, 3 to 6 membered monocyclic heterocyclic group, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group or C(O)C 1-6 wherein the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; and the 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the group consisting of: C 1-6 Alkyl; or R a 、R b Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group; wherein the 3- to 6-membered nitrogen-containing heterocyclic group has 1 nitrogen atom and optionally 1 or 2 heteroatoms selected from N, O and S as ring atoms; and the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from the group consisting of: C 1-6 alkyl.

[0229] In one embodiment, R4 is selected from the group consisting of methyl and ethyl; the methyl and ethyl groups are unsubstituted or substituted with one group selected from the group S1; the groups of the group S1 are selected from the group consisting of hydroxy, methoxy, deuterated methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, deuterated ethoxy, haloethoxy, n-propoxy, isopropoxy, n-butoxy, -OCH2CH2OCH3, -OCH2CH2OCH2CH3, -O-cyclopropyl, -O-cyclobutyl, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH3)(CH3), -N(CH2CH2CH3)(CH3) and -N(CH2CH2CH3)(CH2CH3). In a preferred embodiment, the groups of the group S1 are selected from the group consisting of hydroxy, methoxy, deuterated methoxy, ethoxy, -OCH2CH2OCH3, -O-cyclopropyl and -N(CH3)2. In one embodiment, R4 is selected from: -CH3, -CH2OH, -CH2OCH3, -CH2OCF3, -CH2OCHF2, -CH2OCF3, -CH2OCHF2, -CH2OCD3, -CH2OCH2CH3, -CH2OCH2CH2OCH3, -CH2CH2OCH2CH3, -CH2O-cyclopropyl, -CH2N(CH3)2, -CH(OH)CH3 and -CH2CH3OCH3.

[0230] In one embodiment, R3 and R4 together with the carbon atoms to which they are attached constitute: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran, piperidine or carbonyl (C=O); the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran and piperidine are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from S1 group. In a preferred embodiment, the groups of S1 group are selected from: cyano, hydroxyl, C 1-6 Alkyl (such as methyl), C 1-6 Alkoxy (such as methoxy), -C 1-4 Alkylene-hydroxy (e.g. -CH2OH), -C(O)C 1-6 Alkyl (e.g. -C(O)CH3), -C(O)C 3-20 Cycloalkyl (e.g. -C(O)-cyclopropyl) and 3- to 20-membered heterocyclic groups (e.g. morpholinyl ).

[0231] In one embodiment, R3 and R4 together with the carbon atom to which they are attached form:

[0232] The cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the oxetanyl (e.g. ), the azetidinyl group (e.g. ), the tetrahydropyrrole (e.g. ), the tetrahydrofuran (e.g. ), the tetrahydropyran (e.g. ), the piperidine (e.g. ) is spiro-attached to the rest of the molecule through any one of the ring atoms.

[0233] In one embodiment, R5 is H, C 1-3 Alkyl, -C 1-2 Alkylene-hydroxyl, -C 1-2 Alkylene-cyano, -C 1-2 Alkylene-C 1-3 Alkoxy, -C 1-2 Alkylene-halogenated C 1-3 Alkyl, -C 1-2 Alkylene-halogenated C 1-3 Alkoxy, -C 1-2 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-2 Alkylene-3 to 6-membered monocyclic heterocyclic group, -C 1-2 Alkylene-NR a R b 、-C 1-2 Alkylene-C(O)NR a R b 、-C 1-2 Alkylene-C(O)OC 1-3 Alkyl, -C 1-2 Alkylene-SO2C 1-3 Alkyl, -C 1-2 Alkylene-carboxyl or C 3-6 Monocyclic cycloalkyl; wherein the "-C 1-2 One or two hydrogen atoms on the "alkylene-" group may be optionally replaced by C 1-3 Alkyl substituted or the "-C 1-2 Two hydrogen atoms on the same carbon of the alkylene-" are simultaneously replaced by -CH2CH2- to form a cycloalkyl group; the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 3- to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the following groups: C 1-6 Alkyl; R a and R b Each is defined the same as in formula (I).

[0234] In one embodiment, R5 is H, C1-6 Alkyl, -C 1-4 Alkylene-NR a R b or C 3-6 Monocyclic cycloalkyl; R a and R b Each is defined the same as in formula (I).

[0235] In one embodiment, R5 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or -CH2CH2N(CH3)2.

[0236] In one embodiment, R5 is H, C 1-6 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and also methyl, ethyl), deuterated C 1-6 Alkyl (e.g. deuterated C 1-3 Alkyl, such as deuterated methyl), -C 1-4 Alkylene-hydroxy (e.g. -C 1-2 Alkylene-hydroxyl, for example -CH2CH2OH), -C 1-4 Alkylene-C 1-6 Alkoxy (e.g. -C 1-2 Alkylene-C 1-3 Alkoxy, for example -CH2CH2OCH3) or -C 1-4 Alkylene-NR a R b (e.g. -C 1-2 Alkylene-NR a R b , for example -CH2CH2N(CH3)2).

[0237] In one embodiment, L is a bond.

[0238] In one embodiment, L is CR 8 R 9 ; Among them, R 8 、R 9 Each independently is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-cyano, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C1-4 Alkylene-halogenated C 1-6 Alkoxy.

[0239] In one embodiment, L is CH2.

[0240] In one embodiment, L is O.

[0241] In one embodiment, L is NH.

[0242] In one embodiment, L is NHC(O).

[0243] In one embodiment, L is CH2NHC(O).

[0244] In one embodiment, L is NHC(O)CH2.

[0245] In one embodiment, n is 0 or 1.

[0246] In one embodiment, E is NR5.

[0247] In one embodiment, E is O.

[0248] In one embodiment, E is N.

[0249] In one embodiment, A is CR6; wherein R6 is H.

[0250] In one embodiment, A is N.

[0251] In one embodiment, B is N.

[0252] In one embodiment, B is CR7; wherein R7 is H.

[0253] In one embodiment, G1 is phenyl, pyridyl, pyrimidinyl, furanyl, pyrrolyl, thiazolyl or pyrazolyl; the phenyl, pyridyl, pyrimidinyl, furanyl, pyrrolyl, thiazolyl or pyrazolyl are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S2.

[0254] In one embodiment, G1 is phenyl or pyridyl; said phenyl or said pyridyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S2.

[0255] In one embodiment, G1 is phenyl or pyridyl; said phenyl or said pyridyl are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from S2 group; wherein said S2 group is selected from: fluorine, chlorine, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 3-6Monocyclic cycloalkyl.

[0256] In one embodiment, G1 is C 6-14 Aryl or 5- or 6-membered monocyclic heteroaryl; said 5- or 6-membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms, and said C 6-14 The aryl group and the 5- or 6-membered monocyclic heteroaryl group are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S2.

[0257] In one embodiment, G1 is phenyl or pyridyl; the phenyl and pyridyl are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from S2 group; wherein the groups of S2 group are selected from the following groups: fluorine, chlorine, bromine, cyano, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -deuterated C 1-3 Alkyl, -C 3-6 Monocyclic cycloalkyl, -halogenated C 3-6 Monocyclic cycloalkyl, -OC 3-6 Monocyclic cycloalkyl, -O-halogenated C 3-6 Monocyclic cycloalkyl.

[0258] In one embodiment, G1 is phenyl, pyridyl, pyrimidinyl, furanyl, pyrrolyl, thiazolyl, pyrazolyl or thienyl; the phenyl, pyridyl, pyrimidinyl, furanyl, pyrrolyl, thiazolyl, pyrazolyl and thienyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S2.

[0259] In one embodiment, G1 is phenyl, pyridyl, furyl or thienyl; the phenyl, pyridyl, furyl and thienyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S2.

[0260] In one embodiment, in G1, the group of S2 is selected from: halogen, cyano, -C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-20 Cycloalkyl, -OC 3-20 Cycloalkyl, -NR a R b AND-OR c ; for example, fluorine, chlorine, bromine, iodine, cyano, methyl, isopropyl, trifluoromethyl, methoxy, trifluoromethoxy, cyclopropyl, -O-cyclopropyl, -O-cyclopentyl, -N(CH3)2 and -OCH2CH2OCH3.

[0261] In one embodiment, G1 is phenyl, 2-chlorophenyl, 2-fluorophenyl, 2-trifluoromethylphenyl, 2-chloro-6-fluorophenyl, 2-chloro-3,4-difluorophenyl, 2-chloro-3-fluoro-4-methoxyphenyl, 2-chloro-4-cyclopentyloxyphenyl, 2-chloro-4-(2-methoxyethyl)phenyl, 2-chloro-4-dimethylaminophenyl, 2-chloro-4-cyclopropyloxyphenyl, 2-chloro-4-methoxyphenyl, 2-chloro-4- isopropylphenyl, 2-chloro-4-cyclopropylphenyl, 2-chloro-4-methylphenyl, 2-chlorofuryl, furyl, thienyl, 2-bromothienyl, 2-chlorothienyl, pyridyl, 3-chloropyridyl, 2-methylphenyl, 2-chloro-4-cyanophenyl, 2-chloro-4-fluorophenyl, 2-iodophenyl, 2-chloro-5-fluorophenyl, 2-chloro-3-fluorophenyl, 2-chloro-trifluoromethoxyphenyl, 2-chloro-4-bromophenyl or 2,4-dichlorophenyl.

[0262] In one embodiment, G2 is C 6-14 Aryl or 5- or 6-membered monocyclic heteroaryl; said 5- or 6-membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms, and said C 6-14 The aryl group and the 5- or 6-membered monocyclic heteroaryl group are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S2.

[0263] In one embodiment, G2 is phenyl, pyridyl, pyrimidinyl, furanyl, pyrrolyl, thiazolyl or pyrazolyl; the phenyl, pyridyl, pyrimidinyl, furanyl, pyrrolyl, thiazolyl or pyrazolyl are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S2.

[0264] In one embodiment, G2 is phenyl, pyridyl or pyrazolyl; said phenyl, said pyridyl and said pyrazolyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S2.

[0265] In one embodiment, G2 is phenyl or pyridyl; said phenyl or said pyridyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S2.

[0266] In one embodiment, G2 is phenyl or pyridyl; said phenyl or said pyridyl are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from S2 group; wherein said S2 group is selected from: fluorine, chlorine, -C 1-3 Alkyl, -halogenated C 1-3 Alkyl, -C 3-6 Monocyclic cycloalkyl.

[0267] In one embodiment, G2 is phenyl or pyridyl; said phenyl or said pyridyl are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from S2 group; wherein said S2 group is selected from the following groups: fluorine, chlorine, bromine, cyano, -C 1-3 Alkyl, -C 1-3 Alkoxy, -halogenated C 1-3 Alkyl, -deuterated C 1-3 Alkyl, -halogenated C 1-3 Alkoxy, -deuterated C 1-3 Alkoxy, -C 3-6 Monocyclic cycloalkyl, -OC 3-6 Monocyclic cycloalkyl, -halogenated C 3-6 Monocyclic cycloalkyl and -O-halogenated C 3-6 Monocyclic cycloalkyl.

[0268] In one embodiment, in G2, the group of S2 is selected from: halogen, cyano, -C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy and C 3-20 Cycloalkyl groups such as fluoro, chloro, cyano, methyl, trifluoromethyl, methoxy, deuterated methoxy and cyclopropyl.

[0269] In one embodiment, G2 is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-trifluoromethylpyridinyl, 3-methylpyridinyl, 3-trifluoromethylpyridinyl, 4-methylpyridinyl, 4-cyclopropylpyridinyl, 4,6-dimethylpyridinyl, 4-chloro-6-methylpyridinyl, 2-methyl-6-chloropyridinyl, 3-cyanophenyl, 3-fluoro-4-methylpyridinyl, pyridinyl, 3-fluoropyridinyl, 2-methoxyphenyl, 2-chlorophenyl, 3-methoxyphenyl, 2-fluoro-6-methoxyphenyl, pyrazolyl, 3-methylpyrazolyl, 2-methoxy-3-fluorophenyl, 2-fluoro-3-deuteromethoxyphenyl, 2,4-dimethylpyridinyl, 2-chloropyridinyl, 2-methoxy-3-fluorophenyl, 2-deuteromethoxy-3-fluorophenyl.

[0270] In one embodiment, G1 is phenyl and said phenyl is substituted by fluoro or chloro; G2 is phenyl or pyridyl and said phenyl or said pyridyl are each independently unsubstituted or substituted by fluoro, chloro, methyl, trifluoromethyl or cyclopropyl.

[0271] In one embodiment, G1 is phenyl and the phenyl is substituted by fluorine or chlorine; G2 is phenyl or pyridyl and the phenyl or the pyridyl are each independently unsubstituted or substituted by one, two or three selected from fluorine, chlorine, bromine, cyano, methyl, deuterated methyl, methoxy, deuterated methoxy, trifluoromethyl, trifluoromethoxy, cyclopropyl, halogenated cyclopropyl, -O-cyclopropyl, -O-halogenated cyclopropyl.

[0272] In one embodiment, G1 is phenyl and said phenyl is substituted by fluoro or chloro; G2 is phenyl and said phenyl is unsubstituted or substituted by fluoro, chloro, methyl, trifluoromethyl or cyclopropyl.

[0273] In one embodiment, G1 is phenyl and said phenyl is substituted by fluorine or chlorine; G2 is pyridyl and said pyridyl is unsubstituted or substituted by fluorine, chlorine, methyl, trifluoromethyl or cyclopropyl.

[0274] In one embodiment, in Formula B, Formula B1, Formula B1a, Formula B1a-1, Formula B1a-2, Formula B2, Formula B2a, Formula B2a-1 or Formula B2a-2, G1 is selected from the following group:

[0275]

[0276] In each formula, Rg1 and Rg2 are each independently hydrogen or a group selected from Group S2.

[0277] In one embodiment, i, G1, L, and G2 have any of the following definitions:

[0278] (1) i is 0, G1 is phenyl, pyridyl, furyl or thienyl; the phenyl, pyridyl, furyl and thienyl are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S2;

[0279] (2) i is 1, L is CR 8 R 9 or O, G1 is phenyl or pyridyl, G2 is phenyl, pyridyl or pyrazolyl; the phenyl, the pyridyl and the pyrazolyl are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S2;

[0280] (3) i is 1, L is CR 8 R 9 , G1 is phenyl, G2 is pyrazolyl; the phenyl and the pyrazolyl are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S2;

[0281] (4) i is 1, L is O, G1 is phenyl or pyridyl, G2 is phenyl or pyridyl; the phenyl and pyridyl are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S2.

[0282] In a preferred embodiment, i is 0 and G1 is selected from:

[0283]

[0284] Rg1 and Rg2 are each independently hydrogen or a group selected from Group S2.

[0285] In one embodiment, Rg2 is hydrogen or selected from the group consisting of deuterium, halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C 3-6 Monocyclic cycloalkyl, -halogenated C 3-6 Monocyclic cycloalkyl.

[0286] In one embodiment, Rg1 is hydrogen or selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -C 3-6 Monocyclic cycloalkyl, -halogenated C 3-6 Monocyclic cycloalkyl, -OC 3-6 monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclic group, -O-3- to 6-membered monocyclic heterocyclic group, -NR a R b AND-OR c The 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the C 3-6 The monocyclic cycloalkyl and the 3 to 6 membered monocyclic heterocyclic groups are each independently optionally substituted by 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and deuterated C 1-6 alkoxy;

[0287] In the above groups, R a and R b Each independently is H, C 1-6 Alkyl, halogenated C1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-G 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-deuterated C 1-6 Alkoxy, 3 to 6 membered monocyclic heterocyclic group, -C 1-4 Alkylene-3 to 6-membered monocyclic heterocyclic group or C(O)C 1-6 wherein the 3- to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; 3-6 Monocyclic cycloalkyl, the 3 to 6 membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and deuterated C 1-6 alkoxy; or

[0288] In the above groups, R a 、R b Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic group; wherein the 3- to 6-membered nitrogen-containing heterocyclic group has 1 nitrogen atom and optionally 1 or 2 heteroatoms selected from N, O and S as ring atoms; and the 3- to 6-membered nitrogen-containing heterocyclic group is optionally substituted by 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and deuterated C 1-6 alkoxy;

[0289] In the above groups, R c H, -C 1-4 Alkylene-halogenated C 1-6 Alkyl, -C 1-4 Alkylene-deuterated C 1-6 Alkyl, -C 1-4 Alkylene-C 1-6 Alkoxy, -C 1-4 Alkylene-halogenated C 1-6 Alkoxy, -C 1-4 Alkylene-deuterated C1-6 Alkoxy, -C 1-4 Alkylene-C 3-6 Monocyclic cycloalkyl, -C 1-4 Alkylene-3 to 6 membered monocyclic heterocyclic group; said C 3-6 Monocyclic cycloalkyl, the 3 to 6 membered monocyclic heterocyclic group is optionally substituted by 1 or 2 groups selected from the group consisting of halogen, hydroxy, carboxyl, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and deuterated C 1-6 Alkoxy.

[0290] In a preferred embodiment, Rg1 is hydrogen or selected from the group consisting of halogen (e.g., fluorine, chlorine, bromine, iodine), cyano, C 1-6 Alkyl (such as methyl), halogenated C 1-6 Alkyl (such as trifluoromethyl), deuterated C 1-6 Alkyl (e.g. deuterated methyl), C 1-6 Alkoxy (such as methoxy), halogenated C 1-6 Alkoxy (such as trifluoromethoxy), deuterated C 1-6 Alkoxy (eg, deuterated methoxy), -OC 3-6 Monocyclic cycloalkyl (e.g., -O-cyclopropyl, -O-cyclopentyl), -NR a R b (e.g. -N(CH3)2) or -OR c (e.g. -O-CH2CH2OCH3).

[0291] In a preferred embodiment, Rg2 is halogen (eg, fluorine, chlorine, bromine, iodine), cyano, C 1-6 Alkyl (such as methyl), halogenated C 1-6 Alkyl (such as trifluoromethyl), deuterated C 1-6 Alkyl (e.g. deuterated methyl), C 1-6 Alkoxy (such as methoxy), halogenated C 1-6 Alkoxy (such as trifluoromethoxy), deuterated C 1-6 Alkoxy (eg, deuterated methoxy), -OC 3-6 Monocyclic cycloalkyl (e.g., -O-cyclopropyl, -O-cyclopentyl), -NR a R b (e.g. -N(CH3)2) or -OR c (e.g. -O-CH2CH2OCH3).

[0292] In one embodiment, the structural unit Selected from:

[0293] In one embodiment, in each formula, R1, R2, R3, R4, n, E, A, B, G1, L, G2, and i are each independently a corresponding group in each specific compound in the examples.

[0294] In one embodiment, R1, R2, R3, R4, n, E, A, B, G1, L, G, i are defined as follows:

[0295] R1 and R2 are each independently selected from: H, C 1-6 Alkoxy, C 1-6 Alkylthio; or R1 and R2 together with the carbon atom to which they are attached constitute: carbonyl (C=O) or C=S; the C 1-6 Alkoxy and the C 1-6 Each alkylthio group is independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S1;

[0296] R3 and R4 are each independently selected from: C 1-6 Alkyl and C 3-20 Cycloalkyl; or R3 and R4 together with the carbon atom to which they are attached constitute: C 3-20 Cycloalkyl and 3 to 20 membered heterocyclic group; said C 1-6 Alkyl, the C 3-20 The cycloalkyl group and the 3- to 20-membered heterocyclic group are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S1;

[0297] n is 0;

[0298] E is NR5, O or N; wherein R5 is H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-C 1-6 Alkoxy or -C 1-4 Alkylene-NR a R b ;

[0299] When E is NR5 or O, the represents a single bond;

[0300] When E is N, the represents a double bond and R2 is none;

[0301] A is CR6;

[0302] B is CR7;

[0303] G1 is C 6-14 Aryl or 5 or 6-membered monocyclic heteroaryl; and said C 6-14 Aryl and 5- or 6-membered monocyclic heteroaryl are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from Group S2;

[0304] G2 is C 6-14 Aryl or 5 or 6-membered monocyclic heteroaryl; and said C 6-14 Aryl and the 5- or 6-membered monocyclic heteroaryl are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S2;

[0305] L is CR 8 R 9 or O;

[0306] i is 0 or 1.

[0307] In one embodiment, the compound of the present invention is selected from the compounds prepared in the examples of this application. For example,

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316] In another aspect, the present invention provides a pharmaceutical composition comprising the compound described in the above aspects or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof; and a pharmaceutically acceptable carrier.

[0317] As used herein, the term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or subject. Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, etc. Their preparation is well known to those skilled in the field of cosmetics or topical medicine.

[0318] In an embodiment of the present invention, the pharmaceutical composition can be administered in any of the following ways: orally, by spray inhalation, rectally, nasally, buccally, topically, parenterally, such as by subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, and intracranial injection or infusion, or by means of an explanted reservoir. Among these, oral, intraperitoneal, or intravenous administration is preferred. When administered orally, the compounds of the present invention can be prepared into any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions, or aqueous suspensions. Carriers used in tablets generally include lactose and corn starch, and lubricants such as magnesium stearate may also be added. Diluents used in capsule formulations generally include lactose and dried corn starch. Aqueous suspension formulations are typically prepared by mixing the active ingredient with a suitable emulsifier and suspending agent. If desired, sweeteners, flavorings, or coloring agents may also be added to the above oral formulations. For topical administration, particularly for the treatment of affected areas or organs readily accessible by topical application, such as the eyes, skin, or lower intestinal neurological disorders, the compounds of the present invention can be formulated into different topical formulations depending on the affected area or organ. For topical ophthalmic administration, the compounds of the present invention can be formulated into a micronized suspension or solution in an isotonic, sterile saline solution at a specific pH, with or without a preservative such as benzyl chloride. For ophthalmic administration, the compounds can also be formulated into an ointment such as vaseline. For topical skin administration, the compounds of the present invention can be formulated into a suitable ointment, lotion, or cream formulation, wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers that can be used for ointment preparations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax, and water; carriers that can be used for lotions or creams include, but are not limited to, mineral oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The compounds of the present invention can also be administered in the form of sterile injectable preparations, including sterile water for injection or oil suspensions or sterile injectable solutions. Useful carriers and solvents include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils such as monoglycerides or diglycerides can also be used as solvents or suspending media.

[0319] In another aspect, the present invention provides the compound described in the above aspects or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof as a drug.

[0320] On the other hand, the present invention provides the use of the compound described in the above aspects or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug or the pharmaceutical composition described in the above aspects in the preparation of a medicament for preventing and / or treating a disease or condition; the disease or condition is related to BTK and / or related to abnormal B cell activation.

[0321] In one embodiment, the disease or disorder is selected from the group consisting of heteroimmune diseases, autoimmune diseases, inflammatory diseases, and cancer.

[0322] In one embodiment, the heteroimmune disease, autoimmune disease, inflammatory disease can be selected from the group consisting of rheumatic diseases, glomerulonephritis, Goodpasture syndrome, atherosclerosis, autoimmune blood diseases, autoimmune gastritis, autoimmune inflammatory bowel disease, irritable bowel syndrome, allogeneic transplant rejection, chronic thyroiditis, Graves' disease, Sjögren's disease, scleroderma, diabetes, hepatitis, pancreatitis, primary cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, psoriasis, atopic dermatitis, Dermatomyositis, contact dermatitis, eczema, vasculitis, chronic renal insufficiency, Stevens-Johnson syndrome, inflammatory pain, idiopathic diarrhea, cachexia, sarcoidosis, Guillain-Barre syndrome, uveitis, conjunctivitis, otitis media, periodontal disease, Parkinson's disease, Alzheimer's disease, septic shock, pulmonary fibrosis, asthma, bronchitis, rhinitis, sinusitis, pneumoconiosis, pulmonary insufficiency syndrome, emphysema, pulmonary fibrosis, chronic inflammatory lung disease and other inflammatory or obstructive diseases of the airways.

[0323] In one embodiment, the cancer is leukemia or lymphoma.

[0324] In one embodiment, the cancer can be selected from the group consisting of small lymphocytic lymphoma (SLL), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute promyelocytic leukemia, chronic myeloid leukemia, diffuse large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Waldenstrom's macroglobulinemia, follicular lymphoma, multiple myeloma, mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and non-Hodgkin's lymphoma.

[0325] On the other hand, the present invention provides use of the compound described in the above aspects or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, or the pharmaceutical composition described in the above aspects in the preparation of a BTK inhibitor.

[0326] On the other hand, the present invention provides a method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound described in the above aspects or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, or any combination thereof, or the step of administering the pharmaceutical composition described in the above aspects.

[0327] As used herein, the term "subject" refers to an animal, particularly a mammal, preferably a human.

[0328] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic but sufficient amount of a drug or medicament that achieves the desired effect. In embodiments of the present invention, when treating a patient according to the present invention, the amount of a given drug depends on many factors, such as a specific dosing regimen, the type of disease or condition and its severity, the uniqueness of the subject or host to be treated (e.g., body weight), but, depending on specific surrounding circumstances, including, for example, the specific drug, route of administration, the condition to be treated, and the subject or host to be treated, the dosage can be routinely determined by methods known in the art. Typically, with respect to the dosage used for adult treatment, the dosage is typically in the range of 0.02-5000 mg / day, such as about 1-1500 mg / day. The desired dosage can be conveniently expressed as one dose, or simultaneously administered (or in a short period of time) or in divided doses at appropriate intervals, such as two, three, four, or more divided doses per day. It will be appreciated by those skilled in the art that, although the above-mentioned dosage range has been given, the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.

[0329] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is pharmaceutically acceptable and possesses the pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic or organic acids, such as nitric, phosphoric, and carbonic acids; organic acids, such as propionic, hexanoic, cyclopentylpropionic, glycolic, pyruvic, gluconic, stearic, and muconic acids; salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal or alkaline earth metal ion; or coordination compounds formed with an organic base, such as ethanolamine. Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid or base groups by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water, an organic solvent, or a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. In addition to salt forms, the compounds provided herein also exist in prodrug form. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the invention. Additionally, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo environment.

[0330] As used herein, the terms "solvate" and "solvate" refer to compounds of the present invention combined with a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents include acetic acid, etc. Solvates include stoichiometric and non-stoichiometric solvents. Certain compounds of the present invention may exist in unsolvated or solvated forms. Generally speaking, solvated forms are equivalent to unsolvated forms and are encompassed by the present invention.

[0331] As used herein, the term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers. The compounds of the present invention may exist in the form of stereoisomers, and therefore encompass all possible stereoisomeric forms, including but not limited to cis-trans isomers, tautomers, enantiomers, diastereomers, atropisomers, etc. The compounds of the present invention may also exist in the form of any combination or any mixture of the aforementioned stereoisomers, such as mesomorphs, racemates, equal mixtures of atropisomers, etc. For example, a single enantiomer, a single diastereomer or a mixture thereof, or a single atropisomer or a mixture thereof. When the compound of the present invention contains an olefin double bond, unless otherwise specified, it includes cis-isomers and trans-isomers, and any combination thereof. The atropisomers of the present invention are stereoisomers with axial or planar chirality based on restricted intramolecular rotation. And as a drug, stereoisomers with excellent activity are preferred. The compounds of the present invention have optical isomers arising from asymmetric carbon atoms, etc., and individual isomers can be resolved and obtained, if necessary, by methods known in the art, such as crystallization or chiral chromatography.

[0332] As used herein, the term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group. 1-20 "Alkyl" refers to a straight or branched chain alkyl group having 1 to 20 carbon atoms. Preferably, C 1-10 Alkyl. More preferably C 1-6 Alkyl (i.e., linear or branched alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms). More preferably, C 1-4 Alkyl. More preferably C 1-3Alkyl. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched chain isomers thereof.

[0333] As used herein, the term "alkoxy" refers to a group having the structure -O-alkyl, wherein alkyl is as defined above. 1-10 "Alkoxy" refers to an alkoxy group having 1 to 10 carbon atoms. Preferably, C 1-6 Alkoxy. More preferably C 1-4 Alkoxy. More preferably C 1-3 Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, n-pentoxy, and the like.

[0334] As used herein, the term "alkylthio" refers to a group having the structure -S-alkyl, wherein alkyl is as defined above. 1-10 "Alkylthio" refers to an alkylthio group having 1 to 10 carbon atoms. Preferably, C 1-6 More preferably, C 1-4 More preferably C 1-3 Specific examples include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, isobutylthio, n-pentylthio, and the like.

[0335] As used herein, the term "alkenyl" refers to an alkyl group as defined above having one or more carbon-carbon double bonds at any position of the chain. 2-8 "Alkenyl" refers to an alkenyl group having 2 to 8 carbon atoms and at least one (e.g., 1 to 2) carbon-carbon double bond. Preferably, C 2-6 Alkenyl (ie, alkenyl having 2 to 6 carbon atoms and 1 to 2 carbon-carbon double bonds). More preferably C 2-4 Alkenyl (i.e., alkenyl having 2 to 4 carbon atoms and 1 to 2 carbon-carbon double bonds). Specific examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, pentenyl, hexenyl, butadienyl, and the like.

[0336] As used herein, the term "alkynyl" refers to an alkyl group as defined above having one or more carbon-carbon triple bonds at any position of the chain. 2-8"Alkynyl" refers to an alkynyl group having 2 to 8 carbon atoms and at least one (e.g., 1 to 2) carbon-carbon triple bond. Preferably, C 2-6 Alkynyl (ie, an alkynyl group having 2 to 6 carbon atoms and 1 to 2 carbon-carbon triple bonds). More preferably, C 2-4 Alkynyl (i.e., an alkynyl group having 2 to 4 carbon atoms and 1 to 2 carbon-carbon triple bonds). Specific examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.

[0337] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0338] As used herein, the term "halo" refers to fluoro, chloro, bromo, or iodo.

[0339] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms are replaced by halogen, wherein alkyl is as defined above. 1-10 "Alkyl" refers to a halogenated alkyl group having 1 to 10 carbon atoms. Preferably, the halogenated C 1-6 Alkyl. More preferably halogenated C 1-4 Alkyl. More preferably halogenated C 1-3 Specific examples include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, and the like.

[0340] As used herein, the term "haloalkoxy" refers to an alkoxy group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms are replaced by halogen, wherein the definition of alkoxy is as described above. 1-10 "Alkoxy" refers to a halogenated alkoxy group having 1 to 10 carbon atoms. Preferably, the halogenated C 1-6 Alkoxy. More preferably halogenated C 1-4 Alkoxy. More preferably halogenated C 1-3 Specific examples include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.

[0341] As used herein, the term "deuterated" refers to a group in which one or more hydrogen atoms are replaced by deuterium atoms.

[0342] As used herein, the term "deuterated alkyl" refers to an alkyl group in which one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms are replaced by deuterium atoms, wherein the definition of alkyl is as described above. 1-10 "Alkyl" refers to a deuterated alkyl group having 1 to 10 carbon atoms. Preferably, it is a deuterated C 1-6 More preferably, deuterated C 1-4More preferably, deuterated C 1-3 Specific examples include, but are not limited to, monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, monodeuterioethyl, 1,2-dideuterioethyl, trideuterioethyl, and the like.

[0343] As used herein, the term "deuterated alkoxy" refers to an alkoxy group in which one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms are replaced by deuterium atoms, wherein the definition of alkoxy is as described above. 1-10 "Alkoxy" refers to a deuterated alkoxy group having 1 to 10 carbon atoms. Preferably, it is a deuterated C 1-6 Alkoxy. More preferably deuterated C 1-4 Alkoxy. More preferably deuterated C 1-3 Specific examples include, but are not limited to, trideutermethoxy, trideuterethoxy, monodeutermethoxy, monodeuterethoxy, dialdeutermethoxy, dialdeuterethoxy, and the like.

[0344] As used herein, the terms "cycloalkyl" and "cycloalkyl ring" are used interchangeably to refer to saturated monocyclic or polycyclic cyclic hydrocarbon groups, including, for example, monocyclic cycloalkyl, spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl. The ring carbon atoms of the cycloalkyl group described in the present invention may be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone structure. The terms "3 to 20 membered cycloalkyl" or "C 3-20 "Cycloalkyl" refers to a cycloalkyl group having 3 to 20 ring carbon atoms, including monocyclic cycloalkyl, spirocyclic alkyl, fused cycloalkyl and bridged cycloalkyl. Preferably, C 3-12 Cycloalkyl, C 5-20 Spiroalkyl, C 5-20 Fused cycloalkyl or C 5-20 More preferably C 3-8 Monocyclic cycloalkyl.

[0345] The term "C 3-8 "Monocyclic cycloalkyl" and "3 to 8 membered monocyclic cycloalkyl" refer to saturated monocyclic hydrocarbon groups having 3 to 8 ring carbon atoms. Preferably, C 3-6 Monocyclic cycloalkyl (i.e., 3 to 6-membered monocyclic cycloalkyl) or C 4-6 Monocyclic cycloalkyl (i.e., 4- to 6-membered monocyclic cycloalkyl). More preferably, it is a C3, C4, C5, or C6 monocyclic cycloalkyl. Specific examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0346] As used herein, the terms "spiroalkyl" and "spiroalkyl ring" refer to a polycyclic hydrocarbon group formed by two or more monocyclic rings sharing a carbon atom (called a spiro atom). Spiroalkyl groups are divided into monospiroalkyl, dispiroalkyl and polyspiroalkyl groups according to the number of spiro atoms shared between the rings. The terms "5- to 20-membered spiroalkyl" or "C 5-20Spiroalkyl refers to a polycyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein the monocyclic ring sharing the spiro atom is a 3 to 8-membered monocyclic cycloalkyl ring. Preferably, the ring is a 6 to 14-membered (i.e., C 6-14 ) spirocycloalkyl. More preferably, it is a 6- to 14-membered monospirocycloalkyl. More preferably, it is a 7- to 11-membered (i.e., C 7-11 ) spirocycloalkyl. More preferably, it is a 7- to 11-membered monospirocycloalkyl. Most preferably, it is a 7-membered (4-membered monocyclic cycloalkyl ring / 4-membered monocyclic cycloalkyl ring), an 8-membered (4-membered monocyclic cycloalkyl ring / 5-membered monocyclic cycloalkyl ring), a 9-membered (4-membered monocyclic cycloalkyl ring / 6-membered monocyclic cycloalkyl ring, a 5-membered monocyclic cycloalkyl ring / 5-membered monocyclic cycloalkyl ring), a 10-membered (5-membered monocyclic cycloalkyl ring / 6-membered monocyclic cycloalkyl ring) or an 11-membered (6-membered monocyclic cycloalkyl ring / 6-membered monocyclic cycloalkyl ring) monospirocycloalkyl. Specific examples of spirocycloalkyl include, but are not limited to:

[0347]

[0348] These spirocycloalkyl groups may be attached to the rest of the molecule via any of the ring atoms.

[0349] As used herein, the terms "fused cycloalkyl" and "fused cycloalkyl ring" refer to a polycyclic hydrocarbon group formed by two or more monocyclic rings sharing a pair of adjacent carbon atoms. Depending on the number of rings formed, fused cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic or polycyclic. The terms "5- to 20-membered fused cycloalkyl" or "C 5-20 "Fused cycloalkyl" refers to a polycyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein the monocyclic ring sharing adjacent carbon atom pairs is a 3- to 8-membered monocyclic cycloalkyl ring. Preferably, the monocyclic ring is a 6- to 14-membered (i.e., C 6-14 ) fused cycloalkyl. More preferably, it is a 6- to 14-membered difused cycloalkyl. More preferably, it is a 7- to 10-membered (i.e., C 7-10 ) fused cycloalkyl. More preferably, it is a 7- to 10-membered di-fused cycloalkyl. Most preferably, it is an 8-membered (5-membered monocyclic cycloalkyl ring fused to a 5-membered monocyclic cycloalkyl ring), 9-membered (5-membered monocyclic cycloalkyl ring fused to a 6-membered monocyclic cycloalkyl ring), or 10-membered (6-membered monocyclic cycloalkyl ring fused to a 6-membered monocyclic cycloalkyl ring) di-fused cycloalkyl. Specific examples of fused cycloalkyl groups include, but are not limited to:

[0350]

[0351] These fused cycloalkyl groups may be attached to the rest of the molecule via any one of the ring atoms.

[0352] As used herein, the terms "bridged cycloalkyl" and "bridged cycloalkyl ring" refer to a polycyclic hydrocarbon group formed by sharing two carbon atoms that are not directly connected between two or more monocyclic rings. Depending on the number of rings formed, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. The terms "5- to 20-membered bridged cycloalkyl" and "C 5-20"Bridged cycloalkyl" refers to a polycyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein any two rings share two carbon atoms that are not directly connected. Preferably, the cycloalkyl group is 6 to 14 members (i.e., C 6-14 ) bridged cycloalkyl. More preferably 7 to 10 members (ie C 7-10 ) bridged cycloalkyl. Specific examples of bridged cycloalkyl include, but are not limited to:

[0353]

[0354] These bridged cycloalkyl groups can be attached to the rest of the molecule via any ring atom.

[0355] As used herein, the term "halocycloalkyl" refers to a cycloalkyl group in which one or more (eg, 1, 2, 3, 4, or 5) hydrogen atoms are replaced by a halogen, wherein cycloalkyl is as defined above.

[0356] As used herein, the term "halogenated C 3-8 "Monocyclic cycloalkyl" refers to a halogenated monocyclic cycloalkyl group having 3 to 8 ring carbon atoms. Preferably, the halogenated C 3-6 Monocyclic cycloalkyl. More preferably, it is a halogenated C3, halogenated C4, halogenated C5 or halogenated C6 monocyclic cycloalkyl. Specific examples include, but are not limited to, trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, etc.

[0357] As used herein, the terms "heterocyclyl" and "heterocyclyl ring" are used interchangeably to refer to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon groups, including, for example, monocyclic heterocyclyls, spiro heterocyclyls, fused heterocyclyls, and bridged heterocyclyls. The ring carbon atoms of the heterocyclyl group described in the present invention may be optionally substituted with 1, 2, or 3 oxo groups to form a cyclic ketone, cyclic lactone, or cyclic lactam structure. The term "3- to 20-membered heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group having 3 to 20 ring atoms, wherein one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, or S(=O). m The heterocyclic groups of the present invention include 3- to 20-membered heterocyclic groups, ...

[0358] As used herein, the terms "3- to 8-membered monocyclic heterocyclyl" and "3- to 8-membered monocyclic heterocyclyl ring" refer to a group having 3 to 8 ring atoms, wherein 1, 2 or 3 ring atoms are selected from nitrogen, oxygen or S(=O). m' (wherein m' is an integer from 0 to 2) is a saturated or partially unsaturated monocyclic hydrocarbon group containing a heteroatom. Preferably, it is a 3- to 6-membered monocyclic heterocyclic group having 3 to 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms. More preferably, it is a 4- to 6-membered monocyclic heterocyclic group having 4 to 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms. More preferably, it is a 5- or 6-membered monocyclic heterocyclic group having 5 or 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (i.e., N or NR, R is hydrogen or other substituents as defined herein). When the heteroatom is a sulfur atom, the sulfur atom may be optionally oxidized (i.e., S(=O) mm' is an integer from 0 to 2). The ring carbon atoms of the monocyclic heterocyclic group may be optionally substituted by 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure. Specific examples of monocyclic heterocyclic groups include, but are not limited to, aziridine, oxirane, azetidine, azetidine-2-one, oxetane, oxetane-2-one, oxazolidine, pyrrolidone, pyrrolidine-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2,5-dione, piperidine-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3-dioxolane-2-one, oxazolidin-2-one, imidazolidin-2-one, piperidine, piperazine, piperazin-2-one, morpholine, morpholin-3-one, morpholin-2-one, thiophene ... Morpholin-3-one 1,1-dioxide, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetadiene, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydropyridine, 1,3-oxazinane, hexahydropyrimidine, 1,4-dioxane, tetrahydropyrimidin-2(1H)-one, 1,4-dioxane-2-one, 5,6-dihydro-2H-pyran-2-one, 5,6-dihydropyrimidin-4(3H)-one, 3,4-dihydropyridin-2(1H)-one, 5,6-dihydropyridin-2(1H)-one, 5,6-dihydropyrimidin-4(1H)-one, pyrimidin-4(3H)-one, pyrimidin-4(1H)-one, 4,5-dihydro-1H-imidazole, 2,3-dihydro-1H-imidazole, 2,3-dihydrooxazole, 1,3-dioxole, 2,3-dihydrothiophene, 2,5-dihydrothiophene, 3,4-dihydro-2H-1,4-oxazine, 3,4-dihydro-2H-1,4-thiazine 1,1-dioxide, 1,2,3,4-tetrahydropyrazine, 1,3-dihydro-2H-pyrrole-2- ketone, 1,5-dihydro-2H-pyrrol-2-one, 1H-pyrrole-2,5-dione, furan-2(3H)-one, furan-2(5H)-one, 1,3-dioxol-2-one, oxazole-2(3H)-one, 1,3-dihydro-2H-imidazole-2-one, furan-2,5-dione, 3,6-dihydropyridine-2(1H)-one, pyridine-2,6-(1H,3H)-dione, 5,6-dihydro-2H-pyran-2-one, 3,6-dihydro-2H-pyran-2-one, 3,4-dihydro-2H-1,3-oxazine, 3,6-dihydro-2H-1,3-oxazine, 1,2,3,4-tetrahydropyrimidine, etc.

[0359] As used herein, the term "3- to 6-membered nitrogen-containing heterocyclic group" refers to a group having 3 to 6 ring atoms, wherein one ring atom is a nitrogen atom and the other one or two ring atoms are selected from nitrogen, oxygen or S(=O). m m' is an integer from 0 to 2. Specific examples include, but are not limited to, aziridine, azetidinyl, azopentyl (i.e., tetrahydropyrrole), azohexyl (i.e., hexahydropyridine), morpholinyl, piperazinyl, and oxazolidine.

[0360] As used herein, the term "3 to 8-membered monocyclic heterocycloalkyl" refers to a saturated monocyclic hydrocarbon group having 3 to 8 ring atoms, 1 or 2 of which are heteroatoms. Preferably, it is a 3 to 6-membered monocyclic heterocycloalkyl group, i.e., a saturated monocyclic hydrocarbon group having 3 to 6 ring atoms, 1 or 2 of which are heteroatoms. Specific examples of heterocycloalkyl include, but are not limited to, aziridine, oxiranyl, azetidinyl, oxetane, oxazolidinyl, 1,3-dioxolane, dioxane, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine-1,1-dioxide, tetrahydropyranyl, 1,4-oxazepanyl, 1,3-oxazinyl, hexahydropyrimidinyl, 1,4-dioxanyl.

[0361] The two ring atoms connected to the monocyclic heterocyclyl ring, including C—C and C—N, can be optionally fused with a cycloalkyl, heterocyclyl, aryl, or heteroaryl group, such as a monocyclic cycloalkyl ring, a monocyclic heterocyclyl ring, a monoaryl ring, a 5- or 6-membered monocyclic heteroaryl ring, as defined herein, to form a fused polycyclic ring. The two ring atoms connected to the monocyclic heterocyclyl ring forming a fused ring with another ring are preferably C—C.

[0362] As used herein, the terms "spiroheterocyclyl" and "spiroheterocyclyl ring" refer to a polycyclic heterocyclic group formed by two or more saturated or partially unsaturated monocyclic rings sharing a carbon atom (called a spiro atom), wherein one or more (e.g., 1, 2, or 3) ring atoms are selected from nitrogen, oxygen, or S(=O). mIn some embodiments, the heteroatom of the present invention is a 5- to 2-membered spiro heterocyclic group, wherein m' is a heteroatom (wherein m' is an integer from 0 to 2), and the remaining ring atoms are carbon. When the heteroatom is a nitrogen atom, the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, R is hydrogen or other substituents defined herein). Each monocycle can contain one or more double bonds, but no ring has a completely conjugated π electron system. Spiro heterocyclic groups are divided into monospiro heterocyclic groups, dispiro heterocyclic groups or polyspiro heterocyclic groups according to the number of shared spiro atoms between the rings. The term "5 to 20 membered spiro heterocyclic groups" refers to spiro heterocyclic groups with 5 to 20 ring atoms, wherein one monocycle in the monocycle sharing spiro atoms is a 3 to 8-membered monocyclic heterocyclic ring, and the other monocycle is a 3 to 8-membered monocyclic heterocyclic ring or a 3 to 8-membered monocyclic cycloalkyl ring. Preferably, there are 6 to 14 ring atoms, wherein 1 or 2 ring atoms are 6 to 14 membered spiro heterocyclic groups with heteroatoms. More preferably, it is a 7 to 11-membered spiro heterocyclic radical having 7 to 11 ring atoms, wherein 1 or 2 ring atoms are heteroatoms. Most preferably, it is a 7-membered (4-membered monocyclic heterocyclic radical ring / 4-membered monocyclic heterocyclic radical ring or 4-membered monocyclic heterocyclic radical ring / 4-membered monocyclic cycloalkyl or 4-membered monocyclic cycloalkyl ring / 4-membered monocyclic heterocyclic radical ring), an 8-membered (4-membered monocyclic heterocyclic radical ring / 5-membered monocyclic heterocyclic radical ring), a 9-membered (4-membered monocyclic heterocyclic radical ring / 6-membered monocyclic heterocyclic radical ring, a 5-membered monocyclic heterocyclic radical ring / 5-membered monocyclic heterocyclic radical ring), a 10-membered (5-membered monocyclic heterocyclic radical ring / 6-membered monocyclic heterocyclic radical ring) or an 11-membered (6-membered monocyclic heterocyclic radical ring / 6-membered monocyclic heterocyclic radical ring) monospiro heterocyclic radical. Specific examples of spiro heterocyclic radicals include, but are not limited to:

[0363]

[0364]

[0365] These spiroheterocyclyl groups may be attached to the rest of the molecule via any suitable ring atom.

[0366] As used herein, the terms "fused heterocyclyl" and "fused heterocyclyl ring" refer to a polycyclic heterocyclyl formed by two or more saturated or partially unsaturated monocyclic rings sharing a pair of adjacent ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are selected from nitrogen, oxygen, or S(=O). m' (wherein m' is an integer from 0 to 2) heteroatom, and the remaining ring atoms are carbon. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (i.e., N or NR, R is hydrogen or other substituents defined herein). Each monocyclic ring may contain one or more double bonds, but no ring has a completely conjugated π electron system. The shared adjacent ring atom pairs may be CC or NC. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups. The term "5 to 20 membered fused heterocyclic group" refers to a fused heterocyclic group having 5 to 20 ring atoms, wherein the monocyclic ring sharing adjacent ring atom pairs is a 3 to 8 membered monocyclic heterocyclic ring. Preferably, it is a 6 to 14 membered fused heterocyclic group having 6 to 14 ring atoms, wherein 1 or 2 ring atoms are heteroatoms. More preferably, it is a 6 to 10 membered fused heterocyclic group having 6 to 10 ring atoms, wherein 1 or 2 ring atoms are heteroatoms. More preferably, it is an 8- to 10-membered fused heterocyclic group having 8 to 10 ring atoms, of which 1 or 2 ring atoms are heteroatoms. Most preferably, it is an 8-membered (5-membered monocyclic heterocyclic ring fused to a 5-membered monocyclic heterocyclic ring), a 9-membered (5-membered monocyclic heterocyclic ring fused to a 6-membered monocyclic heterocyclic ring) or a 10-membered (6-membered monocyclic heterocyclic ring fused to a 6-membered monocyclic heterocyclic ring) bicyclic fused heterocyclic group. Specific examples of fused heterocyclic groups include, but are not limited to:

[0367]

[0368]

[0369] These fused heterocyclic groups may be attached to the rest of the molecule through any suitable ring atom.

[0370] As used herein, the terms "bridged heterocyclyl" and "bridged heterocyclyl ring" refer to a polycyclic heterocyclyl formed by two or more saturated or partially unsaturated monocyclic rings sharing two ring atoms that are not directly connected, wherein one or more (e.g., 1, 2, or 3) ring atoms are selected from nitrogen, oxygen, or S(=O). m ' (wherein m' is an integer from 0 to 2) heteroatom, and the remaining ring atoms are carbon. According to the number of rings formed, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl. The term "5 to 20 membered bridged heterocyclic group" refers to a saturated or partially unsaturated polycyclic heterocyclic group having 5 to 20 ring atoms, wherein any two rings share two ring atoms that are not directly connected, each monocyclic ring may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably it is a 6 to 14 membered bridged heterocyclic group. More preferably it is a 7 to 10 membered bridged heterocyclic group. Specific examples of bridged heterocyclic groups include, but are not limited to:

[0371]

[0372] These bridged heterocyclic groups may be attached to the rest of the molecule via any suitable ring atom.

[0373] In the present invention, the various heterocyclic groups mentioned above may be optionally substituted. When substituted, the substituents are preferably one or more substituent groups described in this application.

[0374] As used herein, the terms "aryl", "aryl ring" and "aromatic ring" are used interchangeably to refer to an all-carbon monocyclic, all-carbon non-fused polycyclic (rings are connected by covalent bonds and are not fused) or all-carbon fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group, wherein at least one ring in the group is aromatic, i.e., has a conjugated π electron system. The term "C 6-14 "Aryl" refers to an aromatic group having 6 to 14 ring atoms. Preferably, C 6-10 Aryl. In the present invention, C 6-14 The aryl group includes a monocyclic aryl group, a non-condensed polycyclic aryl group, and an aromatic condensed polycyclic group. Examples of the monocyclic aryl group include a phenyl group, and examples of the non-condensed polycyclic aryl group include a biphenyl group.

[0375] In the present invention, when C 6-14 When the aryl group is an aromatic fused polycyclic ring, the aromatic fused polycyclic ring may be a polycyclic group formed by condensing a single aryl ring with one or more single aryl rings, and non-limiting examples thereof include naphthyl, anthracenyl, and the like.

[0376] In some embodiments of the present invention, when C 6-14 When the aromatic group is an aromatic fused polycyclic ring, the aromatic fused polycyclic ring may also be a polycyclic group formed by the fusion of a single aromatic ring (such as a phenyl group) and one or more non-aromatic rings, wherein the ring connected to the parent structure is an aromatic ring or a non-aromatic ring. The non-aromatic ring includes but is not limited to a 3- to 6-membered monocyclic heterocyclic ring (preferably a 5- or 6-membered monocyclic heterocyclic ring, the ring carbon atoms of which may be substituted by 1 to 2 oxo groups to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered monocyclic cycloalkyl ring (preferably a 5- or 6-membered monocyclic cycloalkyl ring, the ring carbon atoms of which may be substituted by 1 or 2 oxo groups to form a cyclic ketone structure). The polycyclic group in which the above-mentioned single aromatic ring is fused to one or more non-aromatic rings may be connected to other groups or the parent structure through nitrogen atoms or carbon atoms, and the ring connected to the parent structure is a single aromatic ring or a non-aromatic ring.

[0377] In the present invention, the above-mentioned various aryl groups may be substituted or unsubstituted. When substituted, the substituent is preferably one or more substituent groups described in this application.

[0378] As used herein, the terms "heteroaryl", "heteroaryl ring" and "heteroaromatic ring" are used interchangeably and refer to monocyclic or fused polycyclic (i.e., sharing adjacent pairs of ring atoms, where the shared adjacent pairs of ring atoms can be CC or NC) groups in which the ring atoms are substituted by at least one heteroatom independently selected from nitrogen, oxygen or sulfur, wherein the nitrogen and sulfur atoms can be optionally oxidized and the nitrogen atom can be optionally quaternized. The heteroaryl group has 6, 10 or 14 shared π electrons, and at least one ring in the group is aromatic. The term "5- to 14-membered heteroaryl" refers to a group having 5 to 14 ring atoms, wherein 1, 2, 3 or 4 ring atoms are selected from nitrogen, oxygen or S(=O) m The heteroaryl group is preferably a 5- to 10-membered heteroaryl group having 5 to 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms. The 5- to 14-membered heteroaryl group of the present invention may be a monocyclic heteroaryl group, a fused bicyclic heteroaryl group, or a fused tricyclic heteroaryl group.

[0379] As used herein, the term "5- or 6-membered monocyclic heteroaryl" refers to a group having 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are selected from nitrogen, oxygen or S(=O). m m′ is an integer from 0 to 2. Specific examples of monocyclic heteroaryl groups include, but are not limited to, thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and the like.

[0380] As used herein, the term "8- to 10-membered bicyclic heteroaryl" refers to a bicyclic heteroaryl group having 8 to 10 ring atoms, wherein 1, 2, 3, 4 or 5 ring atoms are selected from nitrogen, oxygen or S(=O). m The fused bicyclic heteroaryl group may be a bicyclic group (preferably a 9- or 10-membered bicyclic heteroaryl ring) formed by the fusion of a monocyclic heteroaryl ring (such as a phenyl group) and a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring), or a bicyclic group (preferably a 5- or 6-membered monocyclic heteroaryl ring) and a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring).

[0381] Any two connected ring atoms on the monocyclic heteroaryl ring, including CC, NC, and NN, can be fused with a cycloalkyl, heterocyclyl, aryl, or heteroaryl group, such as a monocyclic cycloalkyl ring, a monocyclic heterocyclyl ring, a monoaryl ring, a 5- or 6-membered monocyclic heteroaryl ring, to form a fused polycyclic ring. The two connected ring atoms on the monocyclic heteroaryl ring forming a fused ring with another ring are preferably CC, including, but not limited to, the following forms:

[0382]

[0383]

[0384] In the above groups The labeled ring atoms are attached to the rest of the molecule.

[0385] Non-limiting examples of 8- to 10-membered bicyclic heteroaryls include benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzo[d]thiazole, indazole, benzofuran, benzo[b]thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, pyrazolo[1,5-a]pyrimidine, imidazo[1,2-b]pyridazine, and the like.

[0386] Specific examples of bicyclic heteroaryl groups include, but are not limited to:

[0387]

[0388] These groups may be attached to the rest of the molecule via any suitable ring atom. The ring attached to the parent structure may be a monocyclic heteroaryl ring or a benzene ring.

[0389] In some embodiments of the present invention, the fused bicyclic heteroaryl or fused tricyclic heteroaryl can be a polycyclic group formed by the fusion of a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) and one or more non-aromatic rings, wherein the ring connected to the parent structure is a monocyclic heteroaryl ring or a non-aromatic ring. The non-aromatic ring includes but is not limited to a 3- to 6-membered monocyclic heterocyclyl ring (preferably a 5- or 6-membered monocyclic heterocyclyl ring, the ring carbon atoms of the monocyclic heterocyclyl ring may be substituted by 1 to 2 oxo groups to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered monocyclic cycloalkyl ring (preferably a 5- or 6-membered monocyclic cycloalkyl ring, the ring carbon atoms of the monocyclic cycloalkyl ring may be substituted by 1 or 2 oxo groups to form a cyclic ketone structure), etc. The polycyclic group formed by the fusion of the above-mentioned monocyclic heteroaryl ring and one or more non-aromatic rings can be connected to other groups or the parent structure through nitrogen atoms or carbon atoms, and the ring connected to the parent structure is a monocyclic heteroaryl ring or a non-aromatic ring.

[0390] In the present invention, the various heteroaryl groups mentioned above may be substituted or unsubstituted. When substituted, the substituents are preferably one or more substituent groups described in this application.

[0391] As used herein, the term "hydroxy" refers to -OH.

[0392] As used herein, the term "hydroxymethyl" refers to -CH2OH, and "hydroxyethyl" refers to -CH2CH2OH or -CH(OH)CH3.

[0393] As used herein, the term "cyanomethyl" refers to -CH2CN, and "cyanoethyl" refers to -CH2CH2CN or -CHCNCH3.

[0394] As used herein, the term "amino" refers to -NH2.

[0395] As used herein, the term "cyano" refers to -CN.

[0396] As used herein, the term "nitro" refers to -NO2.

[0397] As used herein, the term "benzyl" refers to -CH2-benzene.

[0398] As used herein, the term "oxo" refers to =0.

[0399] As used herein, the term "carboxy" refers to -C(O)OH.

[0400] As used herein, the term "carboxylate" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl).

[0401] As used herein, the term "acetyl" refers to -COCH3.

[0402] As used herein, the term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo group (i.e., =O), it means that two hydrogen atoms are replaced. Oxo substitution does not occur on aromatic groups. The term "optionally substituted" or "optionally substituted" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of substituents can be arbitrary based on chemical achievable conditions.

[0403] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0404] In any embodiment, any or all hydrogens present in the compound, or hydrogens in a specific group or moiety within the compound, may be replaced by deuterium or tritium. From one to the maximum number of hydrogens present in the compound may be replaced by deuterium. From one to the maximum number of hydrogens present in any group in the general compound or in the specific compound may be deuterated. For example, when describing a group as ethyl, the ethyl group may be C2H5 or C2H5 in which x (1 to 5) hydrogens are replaced by deuterium, such as C2D x H 5-x When describing a group as a deuterated ethyl group, the deuterated ethyl group may be C2H5 in which x (1 to 5) hydrogen atoms are replaced by deuterium, for example, C2D x H 5-x . DETAILED DESCRIPTION

[0405] The compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining the same with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0406] The present invention is described in detail below by way of examples, but this is not intended to limit the present invention in any way. The present invention has been described in detail herein, and specific embodiments thereof are disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. Where specific conditions are not specified in the examples, the experiments were carried out under conventional conditions or the conditions recommended by the manufacturer. Where the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be obtained commercially.

[0407] The reagents used in the following examples are abbreviated as follows: DMSO: dimethyl sulfoxide; DDQ: 2,3-dichloro-5,6-dicyano-p-benzoquinone; NH4HCO3: ammonium bicarbonate; CAN: acetonitrile.

[0408] The preparative HPLC conditions used in the following examples, unless otherwise specified, were as follows: column type: Waters XBridge C18, 190*250 mm, 5 μm; mobile phase system: A: 0.1% ammonium bicarbonate aqueous solution; B: preparative-grade acetonitrile; flow rate: 15 ml / min; B% = 20%-100%; column temperature: room temperature.

[0409] Preparation Example 1: Synthesis of 4-chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine

[0410]

[0411] Step 1: 4-chloro-1H-pyrrolo[2,3-b]pyridine (5.0 g, 32.89 mmol) was suspended in dichloromethane (100 mL). Triethylamine (6.9 mL, 49.34 mmol), 4-dimethylaminopyridine (400 mg, 3.29 mmol) and benzenesulfonyl chloride (4.6 mL, 36.18 mmol) were added in sequence. The reaction was stirred at room temperature for 18 hours. 200 mL of dichloromethane was added to the reaction solution, which was washed with 1.0 M 60 mL of dilute hydrochloric acid twice, 80 mL of saturated sodium bicarbonate, 50 mL of water, and 60 mL of saturated brine. The solution was dried and concentrated to give 4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (9.5 g, yield 99%) as a brown solid. ES-API: [M+H] + =293.0.

[0412] Step 2: Dissolve 4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (5.0 g, 17.12 mmol) in dichloromethane (75 mL), cool to -10°C under nitrogen, and add tetramethylammonium nitrate (3.49 g, 25.68 mmol). Slowly add trifluoroacetic anhydride (3.74 mL, 26.54 mmol) dropwise. After addition, stir the reaction at -5°C-0°C for 30 minutes, then slowly warm to room temperature and react for 18 hours. 200 mL of dichloromethane was added to the reaction solution, and the mixture was washed with 100 mL of water twice, 100 mL of saturated sodium carbonate, 100 mL of saturated sodium bicarbonate, 100 mL of water, and 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered through silica gel, and the filtrate was concentrated to obtain 4-chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (4.05 g, yield 70%) as a white solid. ES-API: [M+H] + =338.0.

[0413] Preparation Example 2 Synthesis of (S)-2-(methoxymethyl)-2-methyl-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazin-3-one

[0414]

[0415] Step 1: (S)-2-Amino-3-hydroxy-2-methylpropionic acid methyl ester hydrochloride (10.0 g, 58.96 mmol) and 4-chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (19.0 g, 56.26 mmol) were dissolved in N,N-dimethylacetamide (250 mL), and anhydrous N,N-diisopropylethylamine (36.36 g, 281.29 mmol) was added, and the reaction was stirred at 110 ° C for 17 hours. 1000 mL of ethyl acetate was added to the reaction solution, and the mixture was washed twice with 500 mL of water and three times with 500 mL of saturated brine. The mixture was then dried and concentrated, and the crude product was purified on a flash silica gel column (ethyl acetate / petroleum ether: 0-50%) to obtain (S)-methyl 3-hydroxy-2-methyl-2-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)propanoate (16.0 g, yield 65.5%) as a yellow solid. ES-API: [M+H] + =435.1.

[0416] Step 2: Methyl (S)-3-hydroxy-2-methyl-2-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)propanoate (5.0 g, 11.51 mmol) was dissolved in acetonitrile (150 mL), and silver (II) oxide (26.67 g, 115.10 mmol) and iodomethane (16.34 g, 115.10 mmol) were added. The reaction was stirred at 35°C for 48 hours. The reaction solution was cooled to room temperature and filtered through celite. The filter cake was washed with ethyl acetate (200 mL). The filtrate was concentrated in vacuo to afford methyl (S)-3-methoxy-2-methyl-2-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)propanoate (5 g, 97% yield) as a yellow solid. ES-API: [M+H] + =449.1.

[0417] Step 3: Methyl (S)-3-methoxy-2-methyl-2-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)propanoate (5 g, 11.15 mmol) was dissolved in acetic acid (100 mL) and iron powder (6.23 g, 111.5 mmol) was added. The reaction was stirred at 90°C for 2 hours. The reaction solution was cooled to room temperature and filtered through celite. The filter cake was washed with ethyl acetate (200 mL). The filtrate was concentrated in vacuo, and the crude product was purified on a flash silica gel column (ethyl acetate / petroleum ether: 0-100%) to provide (S)-2-(methoxymethyl)-2-methyl-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazin-3-one (4 g, 93% yield) as a light yellow solid. ES-API: [M+H] + =387.2.

[0418] Preparation Example 3 Synthesis of (S)-2-((methoxy-d3)methyl)-2-methyl-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazin-3-one

[0419]

[0420] Step 1: Methyl (S)-3-hydroxy-2-methyl-2-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)propanoate (5.0 g, 11.51 mmol) was dissolved in acetonitrile (150 mL). Silver (II) oxide (26.67 g, 115.10 mmol) and deuterated iodomethane (16.34 g, 115.10 mmol) were added. The reaction mixture was heated to 35°C and stirred for 48 hours in the dark. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with ethyl acetate (200 mL). The resulting filtrate was concentrated in vacuo to afford methyl (S)-3-(methoxy-d3)-2-methyl-2-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)propanoate (5 g, 96% yield) as a yellow solid. ES-API: [M+H] + =452.1.

[0421] Step 2: Methyl (S)-3-(methoxy-d3)-2-methyl-2-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)propanoate (5 g, 11.07 mmol) was dissolved in acetic acid (100 mL). Iron powder (6.23 g, 111.5 mmol) was added and the reaction was stirred at 90°C for 2 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with ethyl acetate (200 mL). The filtrate was concentrated in vacuo, and the resulting crude product was purified on a flash silica gel column (ethyl acetate / petroleum ether: 0-100%) to afford (S)-2-((methoxy-d3)methyl)-2-methyl-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazin-3-one (4 g, 93% yield) as a light yellow solid. ES-API: [M+H] + =390.2.

[0422] Preparation Example 4 Synthesis of (S)-2-amino-2 (hydroxymethyl) propionic acid methyl ester-3,3,3-d3 hydrochloride

[0423]

[0424] Step 1: (S)-Methyl 2-amino-3-hydroxypropionate (10 g, 64.3 mmol) was dissolved in tetrahydrofuran (100 mL), and p-valeraldehyde (6.63 g, 77.1 mmol) and triethylamine (7.14 g, 70.7 mmol) were added. The mixture was reacted at 70°C for 4 hours, cooled to room temperature, and the reaction solution was directly used for the next step reaction without treatment.

[0425] Step 2: To the reaction mixture from the previous step, potassium carbonate solution (133 g, 96.5 mmol) and di-tert-butyl dicarbonate (15.4 g, 70.7 mmol) were added and reacted at room temperature for 16 hours. Water and ethyl acetate were added for separation. The organic phase was washed with brine, dried, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain 3-(tert-butyl)-4-methyl (2R,4S)-2-(tert-butyl)oxazolidine-3,4-dicarboxylate (7.5 g, yield: 40.7%). ES-API: [M-55] + =232.2.

[0426] Step 3: 3-(tert-Butyl)-4-methyl (2R, 4S)-2-(tert-butyl)oxazolidine-3,4-dicarboxylate (5.1 g, 17.7 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to -78 ° C, and 1 M lithium bistrimethylsilylamine tetrahydrofuran solution (53 mL) was added and reacted for 0.5 hours. Deuterated iodomethane (12.83 g, 88.5 mmol) was added and reacted at -78 ° C for 1 hour. The reaction was quenched with ammonium chloride (50 mL), extracted with ethyl acetate (50 mL x 1), and the organic phase was washed with brine (50 mL x 1), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 3-(tert-butyl)-4-methyl (2R,4S)-2-(tert-butyl)-4-(methyl-d3)oxazolidine-3,4-dicarboxylate (4.5 g, yield: 80.6%). ES-API: [M-55] + =260.2.

[0427] Step 4: 3-(tert-Butyl)-4-methyl (2R,4S)-2-(tert-butyl)-4-(methyl-d3)oxazolidine-3,4-dicarboxylate (4.5 g, 14.8 mmol) was dissolved in dioxane (25 mL), 6N hydrochloric acid (25 mL) was added, and the reaction was carried out at 50°C for 2 hours. The solvent was concentrated to dryness, and the crude product was dissolved in 1M hydrochloric acid (25 mL), back-extracted with ethyl acetate (25 mL x 3), and the aqueous phase was concentrated to dryness to obtain (S)-methyl 2-amino-2(hydroxymethyl)propanoate-3,3,3-d3 hydrochloride (2.55 g, yield: 100%). ES-API: [M+H] + =137.1. 1 H NMR (400MHz, CDCl3) δ8.68 (s, 2H), 7.53-7.27 (m, 1H), 3.7 (s, 3H), 3.63-3.60 (m, 1H).

[0428] Example 1: Synthesis of Z1, Z1-1, and Z1-2

[0429]

[0430] Step 1: 4-Chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.0 g, 2.97 mmol) and 3-aminotetrahydrofuran-3-carboxylic acid methyl ester hydrochloride (806 mg, 4.45 mmol) were dissolved in N,N-dimethylformamide (15 mL), and N,N-diisopropylethylamine (1.34 g, 10.40 mmol) was added. The reaction was stirred at 95 ° C for 16 hours. 100 mL of ethyl acetate was added to the reaction solution, and the mixture was washed twice with 60 mL of water and three times with 30 mL of saturated brine. The mixture was dried and concentrated, and the crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether: 0-50%) to obtain methyl (3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)tetrahydrofuran-3-carboxylate (660 mg, yield: 50%) as a yellow solid. ES-API: [M+H] + =447.1.

[0431] Step 2: Methyl (3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)tetrahydrofuran-3-carboxylate (635 mg, 1.42 mmol) was dissolved in acetic acid (15 mL), iron powder (558 mg, 9.97 mmol) was added, and the reaction was stirred at 85 ° C for 3 hours. 100 mL of ethyl acetate was added to the reaction solution, and it was washed twice with 60 mL of water, and 40 mL of saturated carbon was added. The product was washed twice with sodium hydroxide, twice with 40 mL of saturated sodium bicarbonate, and then dried and concentrated with 40 mL of saturated brine. The crude product was slurried with ethyl acetate to give 7′-(phenylsulfonyl)-4,4′,5,7′-tetrahydro-2H-spiro[furan-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (530 mg, yield 97%) as a yellow solid. ES-API: [M+H] + =385.1

[0432] Step 3: (7′-(phenylsulfonyl)-4,4′,5,7′-tetrahydro-2H-spiro[furan-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (200 mg, 0.52 mmol) was dissolved in 10 mL of methanol, 5 mL of tetrahydrofuran and 2 mL of water, and sodium hydroxide (146 mg, 3.64 mmol) was added. The reaction was stirred at 65° C. for 7 hours. 15% HCl was added to the reaction mixture. The mixture was added with 1 mL of water and 4 mL of saturated ammonium chloride solution, and extracted with 100 mL of ethyl acetate. The organic phase was washed sequentially with 20 mL of saturated sodium bicarbonate solution and 20 mL of saturated brine, dried, and concentrated to yield 4,4′,5,7′-tetrahydro-2H-spiro[furan-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (105 mg, 82% yield) as an off-white solid. ES-API: [M+H] + =245.1.

[0433] Step 4: Dissolve 4,4′,5,7′-tetrahydro-2H-spiro[furan-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (105 mg, 0.43 mmol) and 2-chloro-4-phenoxybenzaldehyde (100 mg, 0.43 mmol) in methanol (8 mL). Cool the reaction mixture to 0°C and add potassium hydroxide (168 mg, 3.01 mmol). Stir the reaction mixture at room temperature for 48 hours. Pour the reaction mixture into 60 mL of water, adjust the pH to 8 with 1.0 M dilute hydrochloric acid, and extract with 80 mL of ethyl acetate. The organic phase was washed with 25 mL of saturated brine, dried, and concentrated. The crude product was purified using a thin layer preparation plate (dichloromethane / 7 M ammonia methanol = 100:7.5) to afford 9′-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-4,4′,5,7′-tetrahydro-2H-spiro[furan-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (70 mg, 34% yield) as a pale yellow solid. ES-API: [M+H] + =477.1.

[0434] Step 5: 9'-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-4,4',5,7'-tetrahydro-2H-spiro[furan-3,2'-pyrrolo[3',2':5,6]pyridin[3,4-b]pyrazin]-3'(1'H)-one (70 mg, 0.15 mmol) was dissolved in 6 mL of tetrahydrofuran, and Dess-Martin periodinane (94 mg, 0.22 mmol) was added. The reaction was stirred at room temperature for 4 hours. Dess-Martin periodinane (94 mg, 0.22 mmol) was then added, and the reaction was stirred at room temperature for 18 hours. 5 mL of saturated sodium thiosulfate solution and 20 mL of saturated sodium bicarbonate solution were added to the reaction solution, and the mixture was extracted with 60 mL of ethyl acetate. The organic phase was washed with 15 mL of saturated brine, dried and concentrated, and the crude product was purified by preparative HPLC to give 9′-(2-chloro-4-phenoxybenzoyl)-4,4′,5,7′-tetrahydro-2H-spiro[furan-3,2′-pyrrole[3′,2′:5,6]pyridin[3,4-b]pyrazine]-3′(1′H)-one (Z1, 27 mg, yield 39%) as a light yellow solid. 1 H NMR (500MHz, DMSO-d6) δ12.56 (s, 1H), 10.70 (s, 1H), 8.51 (s, 1H), 7.78 (s, 1H), 7.67 (s, 1H), 7.57 (d, J=8.5Hz, 1H), 7.5 1-7.43 (m, 2H), 7.26 (t, J=7.5Hz, 1H), 7.21-7.15 (m, 3H), 7.02 (dd, J=8.5, 2.0Hz, 1H), 4.06-3.96 (m, 2H), 3.94-3.89 (m 1H), 3.80 (d, J=9.0Hz, 1H), 2.55-2.50 (m, 2H), 2.11-1.98 (m, 1H).ES-API: [M+H] + =475.0.

[0435] Step 6: Compound Z1 (14 mg, 0.03 mmol) obtained in the above step was subjected to chiral preparative separation (AB column, 250 mm x 4.6 mm x 5 μm; mobile phase: hexane: EtOH = 50:50; flow rate: 1 ml / min; column temperature: 30°C) to afford two single isomers. One isomer, arbitrarily designated as Z1-1 (4 mg, peak 1, retention time: 7.186 min, yield 28%), ES-API: [M+H] + =475.1, as a white solid. Another isomer, arbitrarily designated as Z1-2 (4 mg, peak 2, retention time: 8.731 min, yield 28%), ES-API: [M+H] + =475.1, off-white solid.

[0436] Example 2: Synthesis of Z2

[0437]

[0438] Step 1: 4-Chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.0 g, 2.97 mmol) and 1-tert-butyl 3-methyl-3-aminopyrrolidine-1,3-dicarboxylate (1.01 g, 4.16 mmol) were dissolved in 15 mL of N,N-dimethylacetamide, and N,N-diisopropylethylamine (958 mg, 7.42 mmol) was added. The reaction was stirred at 95 ° C for 16 hours. 100 mL of ethyl acetate was added to the reaction mixture, which was then washed three times with 30 mL of dilute brine and then with 30 mL of saturated brine. The mixture was dried and concentrated, and the crude product was purified on a flash silica gel column (ethyl acetate / petroleum ether: 0-50%) to obtain 1-(tert-butyl)-3-methyl-3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1,3-dicarboxylate (660 mg, 40% yield) as a yellow solid. ES-API: [M+H] + =546.1.

[0439] Step 2: 1-(tert-Butyl) 3-methyl 3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1,3-dicarboxylate (270 mg, 0.50 mmol) was dissolved in 3 mL of dichloromethane, 1.5 mL of trifluoroacetic acid was added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated, 15 mL of saturated sodium bicarbonate solution was added, and extracted with 60 mL of ethyl acetate. The organic phase was washed with 15 mL of saturated brine, dried, and concentrated to give methyl 3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-3-carboxylate (220 mg, yield 100%) as a yellow solid. ES-API: [M+H] + =446.2.

[0440] Step 3: 3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-3-carboxylic acid methyl ester (220 mg, 0.49 mmol) was dissolved in 10 mL of acetonitrile, and sodium triacetoxyborohydride (416 mg, 1.96 mmol) and 37% formaldehyde aqueous solution (159 mg, 1.96 mmol) were added in sequence under ice bath, and the reaction was stirred at room temperature for 2 hours. 20 mL of saturated sodium bicarbonate solution was added to the reaction solution and extracted with 90 mL of ethyl acetate. The organic phase was washed with 30 mL of saturated brine, dried and concentrated to give 1-methyl-3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-3-carboxylic acid methyl ester (225 mg, yield 99%) as a yellow solid. ES-API: [M+H] + =460.1.

[0441] Step 4: 1-Methyl-3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-3-carboxylate (225 mg, 0.49 mmol) was dissolved in acetic acid (7 mL), iron powder (192 mg, 3.43 mmol) was added, and the reaction was stirred at 85 °C for 2 hours. The reaction mixture was concentrated, and 20 mL of saturated sodium bicarbonate solution and 100 mL of dichloromethane / methanol (10:1) were added. The suspension was filtered through celite, and the filter cake was washed with dichloromethane / methanol (10:1). The organic phase was separated, washed with 25 mL of saturated brine, and dried and concentrated to yield 1-methyl-7′-(phenylsulfonyl)-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (195 mg, 100% yield) as an off-white solid. ES-API: [M+H] + =398.1

[0442] Step 5: 1-Methyl-7′-(phenylsulfonyl)-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazine]-3′(1′H)-one (195 mg, 0.49 mmol) was dissolved in 10 mL of methanol, 5 mL of tetrahydrofuran and 2 mL of water, and sodium hydroxide (98 mg, 2.45 mmol) was added. The reaction was stirred at 65°C for 16 hours. The reaction solution was adjusted to pH 8 with 1.0 M dilute hydrochloric acid, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried, and concentrated to yield 1-methyl-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolidin-3,2′-pyrrolidin-3,4-b]pyrazin-3′(1′H)-one (80 mg, 63% yield) as a light brown solid. ES-API: [M+H] + =258.1.

[0443] Step 6: Dissolve 1-methyl-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (80 mg, 0.31 mmol) and 2-chloro-4-phenoxybenzaldehyde (108 mg, 0.46 mmol) in methanol (8 mL). Cool the reaction mixture to 0°C and add potassium hydroxide (122 mg, 2.17 mmol). Stir the reaction mixture at room temperature for 18 hours. Pour the reaction mixture into 30 mL of water, adjust the pH to 8 with 1.0 M dilute hydrochloric acid, and extract with 80 mL of ethyl acetate. The organic phase was washed with 25 mL of saturated brine, dried, and concentrated. The crude product was purified using a thin layer preparation plate (dichloromethane / 7M ammonia methanol = 10:1) to afford 9′-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-1-methyl-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (53 mg, 35% yield) as a yellow solid. ES-API: [M+H] + =490.1.

[0444] Step 7: 9′-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-1-methyl-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (53 mg, 0.11 mmol) was dissolved in 6 mL of tetrahydrofuran and cooled to 0°C. Dess-Martin periodinane (92 mg, 0.22 mmol) was added and the reaction was stirred at room temperature for 18 hours. 3 mL of saturated sodium thiosulfate solution and 10 mL of saturated sodium bicarbonate solution were added to the reaction solution, and the solution was extracted with 40 mL of ethyl acetate. The organic phase was washed with 10 mL of saturated brine, dried, and concentrated. The crude product was purified by preparative HPLC to yield the desired product (Z2, 11 mg, 20% yield) as a light yellow solid. ES-API: [M+H] + =488.1.

[0445]

[0446] Step 8: Compound Z2 (17 mg, 0.035 mmol) prepared in the above step was subjected to chiral preparative separation (IF column, 250 mm x 4.6 mm x 5 μm, mobile phase: n-hexane: ethanol: diethylamine = 70:30:2, flow rate: 1 ml / min, column temperature: 30°C) to afford two single isomers. One single isomer, arbitrarily designated Z2-1 (7.0 mg, peak 1, retention time 10.161 min, yield 41%), was obtained as a white solid. ES-API: [M+H] + = 488.0. Another single isomer, whose structure was arbitrarily designated as Z2-2 (6.8 mg, peak 2, retention time 13.023 min, yield 40%), was obtained as an off-white solid. 1 H NMR (500MHz, DMSO-d6) δ12.65 (s, 1H), 10.74 (s, 1H), 8.67 (s, 1H), 7.77 (s, 1H), 7 .68(s, 1H), 7.57(d, J=8.5Hz, 1H), 7.48(t, J=7.5Hz, 2H), 7.25(t, J=7.5Hz, 1H), 7.21-7.15(m, 3H), 7.02(dd, J=8.5, 2.5Hz, 1H), 4.05-3.97(m, 2H), 3.95-3.88(m , 1H), 3.82 (d, J=9.0Hz, 1H), 2.58-2.52 (m, 1H), 2.11-2.01 (m, 1H).ES-API: [M+H] + =488.0.

[0447] Example 3: Synthesis of Z3

[0448]

[0449] Step 1: 7′-(phenylsulfonyl)-4,4′,5,7′-tetrahydro-2H-spiro[furan-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (prepared as described in Steps 1 and 2 of Example 1) (150 mg, 0.39 mmol) was dissolved in 6 mL of acetone. Anhydrous potassium carbonate (118 mg, 0.86 mmol) and iodomethane (72 mg, 0.51 mmol) were added sequentially. The reaction was stirred at room temperature for 18 hours. Anhydrous potassium carbonate (118 mg, 0.86 mmol) and iodomethane (72 mg, 0.51 mmol) were further added, and the reaction was stirred at room temperature for 96 hours. The reaction solution was poured into 15 mL of water and extracted with 60 mL of ethyl acetate. The organic phase was washed with 15 mL of saturated brine, dried, and concentrated to yield 4′-methyl-7′-(phenylsulfonyl)-4,4′,5,7′-tetrahydro-2H-spiro[furan-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (155 mg, 100% yield) as a yellow solid. ES-API: [M+H] + =399.1.

[0450] Step 2: 4′-Methyl-7′-(phenylsulfonyl)-4,4′,5,7′-tetrahydro-2H-spiro[furan-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazine]-3′(1′H)-one (155 mg, 0.39 mmol) was dissolved in 10 mL of methanol, 5 mL of tetrahydrofuran and 2 mL of water. Sodium hydroxide (78 mg, 1.95 mmol) was added and the reaction was stirred at 65°C for 16 hours. The reaction solution was adjusted to pH 8 with 1.0 M dilute hydrochloric acid, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried, and concentrated to yield 4′-methyl-4,4′,5,7′-tetrahydro-2H-spiro[furan-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (95 mg, 94% yield) as a light brown solid. ES-API: [M+H] + =259.1.

[0451] Step 3: Dissolve 4′-methyl-4,4′,5,7′-tetrahydro-2H-spiro[furan-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (80 mg, 0.31 mmol) and 2-chloro-4-phenoxybenzaldehyde (108 mg, 0.47 mmol) in methanol (8 mL). Cool the reaction mixture to 0°C and add potassium hydroxide (122 mg, 2.17 mmol). Stir the reaction mixture at room temperature for 24 hours. Pour the reaction mixture into 30 mL of water, adjust the pH to 8 with 1.0 M dilute hydrochloric acid, and extract with 80 mL of ethyl acetate. The organic phase was washed with 25 mL of saturated brine, dried, and concentrated. The crude product was purified using a thin layer preparation plate (dichloromethane / methanol = 10:1) to give 9'-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-4'-methyl-4,4',5,7'-tetrahydro-2H-spiro[furan-3,2'-pyrrolo[3',2':5,6]pyridin[3,4-b]pyrazin]-3'(1'H)-one (80 mg, 52% yield) as an off-white solid. ES-API: [M+H] + =491.1.

[0452] Step 4: 9′-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-4′-methyl-4,4′,5,7′-tetrahydro-2H-spiro[furan-3,2′-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazin]-3′(1′H)-one (75 mg, 0.15 mmol) was dissolved in 6 mL of tetrahydrofuran and cooled to 0°C. Dess-Martin periodinane (130 mg, 0.30 mmol) was added and the reaction was stirred at room temperature for 2 hours. 4 mL of saturated sodium thiosulfate solution and 15 mL of saturated sodium bicarbonate solution were added to the reaction solution, and the solution was extracted with 40 mL of ethyl acetate. The organic phase was washed with 15 mL of saturated brine, dried, and concentrated. The crude product was purified by preparative HPLC to yield the desired product (Z3, 48 mg, 64% yield) as a pale yellow solid. 1 H NMR (500MHz, DMSO-d6) δ8.74 (s, 1H), 8.03 (s, 1H), 7.70 (s, 1H), 7.56 (d, J=8. 5Hz, 1H), 7.48 (t, J=8.0Hz, 2H), 7.25 (t, J=7.5Hz, 1H), 7.22-7.14 (m, 3H), 7. 02 (dd, J=8.5, 2.5Hz, 1H), 4.04-4.00 (m, 2H), 3.94-3.89 (m, 1H), 3.78 (d, J=9 .0Hz, 1H), 3.42(s, 3H), 2.54-2.48(m, 1H), 2.07-1.98(m, 1H).ES-API: [M+H] + =489.1.

[0453] Example 4: Synthesis of Z4, Z4-1 and Z4-2

[0454]

[0455] Step 1: Dissolve 1-(tert-Butyl)-3-methyl-3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1,3-dicarboxylate (220 mg, 0.40 mmol) in acetic acid (8 mL). Add iron powder (224 mg, 4.0 mmol) and stir at 85°C for 1 hour. Cool the reaction mixture to room temperature, pour into 30 mL of water, and extract twice with 30 mL of ethyl acetate. The combined organic phases were washed sequentially with 25 mL of water, three times with 30 mL of saturated sodium bicarbonate solution, and then washed with 30 mL of saturated brine, dried, and concentrated to yield tert-butyl 3′-oxo-7′-(phenylsulfonyl)-1′,3′,4′,7′-tetrahydrospiro[pyrrolidine-3,2′-pyrrole[3′,2′:5,6]pyridine[3,4-b]pyrazine]-1-carboxylate (195 mg, 100% yield) as a light brown solid. ES-API: [M+H] + =484.1

[0456] Step 2: Tert-butyl 3′-oxo-7′-(phenylsulfonyl)-1′,3′,4′,7′-tetrahydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridine[3,4-b]pyrazine]-1-carboxylate (195 mg, 0.40 mmol) was dissolved in 10 mL of methanol, 5 mL of tetrahydrofuran and 2 mL of water. Sodium hydroxide (80 mg, 2.00 mmol) and triethylamine (202 mg, 2.0 mmol) were added, and the reaction was stirred at 65°C for 16 hours. The reaction solution was adjusted to pH 8 with 1.0 M dilute hydrochloric acid, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried, and concentrated to yield tert-butyl 3′-oxo-1′,3′,4′,7′-tetrahydrospiro[pyrrolidine-3,2′-pyrrole[3′,2′:5,6]pyridine[3,4-b]pyrazine]-1-carboxylate (130 mg, 94% yield) as a light brown solid. ES-API: [M+H] + =344.2.

[0457] Step 3: tert-Butyl 3′-oxo-1′,3′,4′,7′-tetrahydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazine]-1-carboxylate (130 mg, 0.38 mmol) was dissolved in 2 mL of methanol and 4.0 M methanolic hydrogen chloride (5 mL, 20.0 mmol) was added. The reaction was stirred at room temperature for 4 hours. The reaction solution was concentrated to give 4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazine]-3′(1′H)-one hydrochloride (110 mg, 92% yield) as a light green solid. ES-API: [M+H] + =244.1(free base).

[0458] Step 4: 4′,7′-Dihydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazine]-3′(1′H)-one hydrochloride (110 mg, 0.35 mmol) was suspended in dichloromethane (15 mL), cooled to 0°C, and triethylamine (177 mg, 1.75 mmol) and acetyl chloride (68 mg, 0.87 mmol) in 0.5 mL of dichloromethane were added sequentially, and the reaction was stirred in an ice bath for 2 hours. The reaction mixture was added with 2 mL of methanol, and the crude product was concentrated and purified using a thin layer preparation plate (dichloromethane / methanol = 8:1) to afford 1-acetyl-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolidin-3,2′-pyrrolo[3′,2′:5,6]pyridin-3,4-b]pyrazin-3′(1′H)-one (50 mg, 50% yield) as a light brown solid. ES-API: [M+H] + =286.1

[0459] Step 5: 1-Acetyl-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolidinone[3′,2′:5,6]pyridinone[3,4-b]pyrazine]-3′(1′H)-one (45 mg, 0.16 mmol) and 2-chloro-4-phenoxybenzaldehyde (74 mg, 0.32 mmol) were dissolved in methanol (6 mL), the reaction was cooled to 0°C, potassium hydroxide (63 mg, 1.12 mmol) was added, and the reaction was stirred at room temperature for 18 hours. The reaction mixture was adjusted to pH 8 with 1.0 M dilute hydrochloric acid, and the crude product was concentrated and purified using a thin layer preparation plate (dichloromethane / methanol = 10:1) to afford 1-acetyl-9′-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolidin[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (48 mg, 58% yield) as an off-white solid. ES-API: [M+H] + =518.2.

[0460] Step 6: 1-Acetyl-9′-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (43 mg, 0.083 mmol) was dissolved in 6 mL of tetrahydrofuran and cooled to 0°C. Dess-Martin periodinane (70 mg, 0.166 mmol) was added and the reaction was stirred at room temperature for 16 hours. 3 mL of saturated sodium thiosulfate solution and 10 mL of saturated sodium bicarbonate solution were added to the reaction solution, and the solution was extracted with 60 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried, and concentrated. The crude product was purified by preparative HPLC to obtain the desired product (Z4, 20 mg, 51% yield) as a white solid. ES-API: [M+H] + =516.0.

[0461] Step 7: Compound Z4 (19 mg, 0.037 mmol) prepared in the above step was subjected to chiral preparative separation (column: IC 250 mm x 4.6 mm x 5 μm, mobile phase: methanol:ethanol = 50:50, flow rate: 1 ml / min, column temperature: 30°C) to afford two single isomers. One single isomer, arbitrarily designated Z4-1 (5 mg, peak 1, retention time 5.370 min, yield 26%), was obtained as a white solid. ES-API: [M+H] + =516.0. Another single isomer, whose structure was arbitrarily designated as Z4-2 (7 mg, peak 2, retention time 8.524 min, yield 37%), was obtained as a white solid. ES-API: [M+H] + =516.0.

[0462] Example 5: Synthesis of Z5

[0463]

[0464] Step 1: 2,4-Difluorobenzaldehyde (2.84 g, 20.0 mmol) and phenol (1.69 g, 18.0 mmol) were dissolved in 50 mL of N,N-dimethylformamide, and cesium carbonate (8.80 g, 30.0 mmol) was added. The reaction was stirred at 75°C for 16 hours. The reaction solution was poured into 100 mL of water and extracted with 80 mL of ethyl acetate. The organic phase was washed four times with 40 mL of saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (ethyl acetate / petroleum ether: 0-3%) to obtain 2-fluoro-4-phenoxybenzaldehyde (1.4 g, 36% yield) as a colorless liquid. 1H NMR (500MHz, DMSO-d6) δ10.11 (s, 1H), 7.85 (t, J=8.5Hz, 1H), 7.54-7.44 (m, 2H), 7.34-7.29 (m, 1 H), 7.22-7.16 (m, 2H), 6.95 (dd, J=12.5, 2.5Hz, 1H), 6.89 (dd, J=8.5, 2.5Hz, 1H). ES-API: [M+H] + =217.1.

[0465] Step 2: 1-Methyl-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolidinone[3′,2′:5,6]pyridinone[3,4-b]pyrazine]-3′(1′H)-one (50 mg, 0.19 mmol) and 2-fluoro-4-phenoxybenzaldehyde (123 mg, 0.57 mmol) were dissolved in methanol (6 mL). The reaction was cooled to 0°C and potassium hydroxide (74 mg, 1.33 mmol) was added. The reaction was stirred at room temperature for 18 hours. The reaction mixture was adjusted to pH 8 with 1.0 M dilute hydrochloric acid, and the crude product was concentrated and purified using a thin layer preparative plate (dichloromethane / 7 M ammonia methanol = 10:1) to afford 9′-((2-fluoro-4-phenoxyphenyl)(hydroxy)methyl)-1-methyl-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (37 mg, 40% yield) as a pale yellow solid. ES-API: [M+H] + =474.1.

[0466] Step 3: 9′-((2-fluoro-4-phenoxyphenyl)(hydroxy)methyl)-1-methyl-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (37 mg, 0.078 mmol) was dissolved in 8 mL of tetrahydrofuran and cooled to 0°C. Dess-Martin periodinane (99 mg, 0.23 mmol) was added and the reaction was stirred at room temperature for 18 hours. 2 mL of saturated sodium thiosulfate solution and 8 mL of saturated sodium bicarbonate solution were added to the reaction solution, and the solution was extracted with 40 mL of ethyl acetate. The organic phase was washed with 15 mL of saturated brine, dried, and concentrated. The crude product was purified by preparative HPLC to yield the desired product (Z5, 6 mg, 16% yield) as a white solid. 1H NMR (500MHz, CDCl3) δ13.13 (s, 1H), 12.13 (s, 1H), 7.89 (s, 1H), 7.52-7.46 (m, 2H), 7.43 (t, J=8.0Hz, 2H), 7.23 (t, J=7.5Hz, 1H), 7.12 (d, J=7.5H z, 2H), 6.86 (dd, J=8.5, 2.5Hz, 1H), 6.79 (dd, J=11.0, 2.0Hz, 1H), 3.37 (s, 1H), 2.96-2.63 (m, 4H), 2.46 (s, 3H), 2.20-2.11 (m, 1H). ES-API: [M+H] + =472.1.

[0467] Example 6: Synthesis of Z6

[0468]

[0469] Step 1: 2-chloro-4-fluorobenzaldehyde (1.0 g, 6.33 mmol) and 2-fluorophenol (744 mg, 6.65 mmol) were dissolved in 15 mL of N,N-dimethylformamide, and cesium carbonate (2.47 g, 7.60 mmol) was added. The reaction was stirred at 75 ° C for 16 hours. The reaction solution was poured into 30 mL of water and extracted with 100 mL of ethyl acetate. The organic phase was washed three times with 30 mL of saturated brine, dried and concentrated, and the crude product was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-4%) to obtain 2-chloro-4-(2-fluorophenoxy)benzaldehyde (1.15 g, yield 72%) as a white solid. ES-API: [M+H] + =251.1.

[0470] Step 2: 1-Methyl-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolidinone[3′,2′:5,6]pyridinone[3,4-b]pyrazine]-3′(1′H)-one (50 mg, 0.19 mmol) and 2-chloro-4-(2-fluorophenoxy)benzaldehyde (143 mg, 0.57 mmol) were dissolved in methanol (6 mL). The reaction was cooled to 0°C and potassium hydroxide (75 mg, 1.33 mmol) was added. The reaction was stirred at room temperature for 18 hours. The reaction mixture was adjusted to pH 8 with 1.0 M dilute hydrochloric acid, and the crude product was concentrated and purified using a thin layer preparation plate (dichloromethane / 7 M ammonia methanol = 10:1) to afford 9′-((2-chloro-4-(2-fluorophenoxy)phenyl)(hydroxy)methyl)-1-methyl-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (41 mg, 41% yield) as a yellow solid. ES-API: [M+H] + =508.1.

[0471] Step 3: 9′-((2-chloro-4-(2-fluorophenoxy)phenyl)(hydroxy)methyl)-1-methyl-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (41 mg, 0.08 mmol) was dissolved in 6 mL of tetrahydrofuran and cooled to 0°C. Dess-Martin periodinane (51 mg, 0.12 mmol) was added and the reaction was stirred at room temperature for 3 hours. An additional Dess-Martin periodinane (51 mg, 0.12 mmol) was added and the reaction was stirred at room temperature for 16 hours. 2 mL of saturated sodium thiosulfate solution and 10 mL of saturated sodium bicarbonate solution were added to the reaction solution, and the solution was extracted with 40 mL of ethyl acetate. The organic phase was washed with 15 mL of saturated brine, dried, and concentrated. The crude product was purified by preparative HPLC to yield the desired product (Z6, 2.5 mg, 6% yield) as a pale yellow solid. ES-API: [M+H] + =506.0.

[0472] Example 7: Synthesis of Z7

[0473]

[0474] Step 1: 2-chloro-4-fluorobenzaldehyde (1.0 g, 6.33 mmol) and 3-fluorophenol (744 mg, 6.65 mmol) were dissolved in 15 mL of N,N-dimethylformamide, and cesium carbonate (2.47 g, 7.60 mmol) was added. The reaction was stirred at 75°C for 16 hours. The reaction solution was poured into 30 mL of water and extracted with 100 mL of ethyl acetate. The organic phase was washed three times with 30 mL of saturated brine, dried and concentrated, and the crude product was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-4%) to obtain 2-chloro-4-(3-fluorophenoxy)benzaldehyde (930 mg, yield 59%) as a white solid. ES-API: [M+H] + =251.1.

[0475] Step 2: 1-Methyl-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolidinone[3′,2′:5,6]pyridinone[3,4-b]pyrazine]-3′(1H)-one (50 mg, 0.19 mmol) and 2-chloro-4-(3-fluorophenoxy)benzaldehyde (143 mg, 0.57 mmol) were dissolved in methanol (6 mL). The reaction was cooled to 0°C and potassium hydroxide (75 mg, 1.33 mmol) was added. The reaction was stirred at room temperature for 18 hours. The reaction mixture was adjusted to pH 8 with 1.0 M dilute hydrochloric acid, and the crude product was concentrated and purified using a thin layer preparative plate (dichloromethane / 7 M ammonia methanol = 10:1) to afford 9′-((2-chloro-4-(3-fluorophenoxy)phenyl)(hydroxy)methyl)-1-methyl-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (50 mg, 50% yield) as a yellow solid. ES-API: [M+H] + =508.0.

[0476] Step 3: 9′-((2-chloro-4-(3-fluorophenoxy)phenyl)(hydroxy)methyl)-1-methyl-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (50 mg, 0.10 mmol) was dissolved in 6 mL of tetrahydrofuran and cooled to 0°C. Dess-Martin periodinane (64 mg, 0.15 mmol) was added and the reaction was stirred at room temperature for 3 hours. An additional Dess-Martin periodinane (64 mg, 0.15 mmol) was added and the reaction was stirred at room temperature for 16 hours. 2 mL of saturated sodium thiosulfate solution and 10 mL of saturated sodium bicarbonate solution were added to the reaction solution, and the solution was extracted with 40 mL of ethyl acetate. The organic phase was washed with 15 mL of saturated brine, dried, and concentrated. The crude product was purified by preparative HPLC to yield the desired product (Z7, 5 mg, 10% yield) as a pale yellow solid. 1 HNMR (500MHz, CDCl3) δ13.12 (s, 1H), 12.15 (s, 1H), 7.42-7.35 (m, 2H), 7.30 (dd, J=15.0, 8.0Hz, 1H), 7.06 (d, J=2.5Hz, 1H), 6 .93(dd, J=8.5, 2.5Hz, 1H), 6.88-6.71(m, 3H), 3.37(s, 1H), 3.05-2.58(m, 4H), 2.48(s, 3H), 2.20-2.10(m, 1H).ES-API: [M+H] + =506.0.

[0477] Example 8: Synthesis of Z8

[0478]

[0479] Step 1: Dissolve tert-butyl 3′-oxo-7′-(phenylsulfonyl)-1′,3′,4′,7′-tetrahydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazine]-1-carboxylate (225 mg, 0.47 mmol) in 12 mL of acetone. Add anhydrous potassium carbonate (324 mg, 2.35 mmol) and iodomethane (267 mg, 1.88 mmol) sequentially. Stir the reaction at room temperature for 72 hours. Pour the reaction mixture into 15 mL of water and extract with 60 mL of ethyl acetate. The organic phase was washed with 15 mL of saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (ethyl acetate / petroleum ether: 0-50%) to afford tert-butyl 4′-methyl-3′-oxo-7′-(phenylsulfonyl)-1′,3′,4′,7′-tetrahydrospiro[pyrrolidine-3,2′-pyrrole[3′,2′:5,6]pyridine[3,4-b]pyrazine]-1-carboxylate (180 mg, 78% yield) as a light yellow solid. ES-API: [M+H] + =498.1.

[0480] Step 2: Tert-butyl 4′-methyl-3′-oxo-7′-(phenylsulfonyl)-1′,3′,4′,7′-tetrahydrospiro[pyrrolidine-3,2′-pyrrole[3′,2′:5,6]pyridine[3,4-b]pyrazine]-1-carboxylate (180 mg, 0.36 mmol) was dissolved in 10 mL of methanol, 5 mL of tetrahydrofuran and 2 mL of water. Sodium hydroxide (72 mg, 1.80 mmol) was added and the reaction was stirred at 65°C for 16 hours. The reaction solution was adjusted to pH 8 with 1.0 M dilute hydrochloric acid, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was washed with 25 mL of saturated brine, dried, and concentrated to yield tert-butyl 4′-methyl-3′-oxo-1′,3′,4′,7′-tetrahydrospiro[pyrrolidine-3,2′-pyrrole[3′,2′:5,6]pyridine[3,4-b]pyrazine]-1-carboxylate (125 mg, 97% yield) as a light brown solid. ES-API: [M+H] + =358.2.

[0481] Step 3: Dissolve tert-butyl 4′-methyl-3′-oxo-1′,3′,4′,7′-tetrahydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazine]-1-carboxylate (125 mg, 0.35 mmol) and 2-chloro-4-phenoxybenzaldehyde (244 mg, 1.05 mmol) in methanol (12 mL). Cool the reaction mixture to 0°C and add potassium hydroxide (137 mg, 2.45 mmol). Stir the reaction mixture at room temperature for 18 hours. Adjust the pH of the reaction mixture to 8 with 1.0 M dilute hydrochloric acid and add 80 mL of ethyl acetate. The organic phase was washed with 25 mL of saturated brine, dried, and concentrated. The crude product was purified using a thin layer preparation plate (dichloromethane / methanol = 10:1) to yield tert-butyl 9′-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-4′-methyl-3′-oxo-1′,3′,4′,7′-tetrahydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridinium[3,4-b]pyrazine]-1-carboxylate (168 mg, 81% yield) as a white solid. ES-API: [M+H] + =590.2.

[0482] Step 4: tert-Butyl 9′-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-4′-methyl-3′-oxo-1′,3′,4′,7′-tetrahydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazine]-1-carboxylate (153 mg, 0.26 mmol) was dissolved in 20 mL of tetrahydrofuran, cooled to 0°C, and Dess-Martin periodinane (165 mg, 0.39 mmol) was added. The reaction was stirred at room temperature for 16 hours. 4 mL of saturated sodium thiosulfate solution and 10 mL of saturated sodium bicarbonate solution were added to the reaction solution, and the mixture was extracted with 60 mL of ethyl acetate. The organic phase was washed sequentially with 20 mL of saturated sodium bicarbonate solution and 20 mL of saturated brine, dried, and concentrated to yield tert-butyl 9′-(2-chloro-4-phenoxybenzoyl)-4′-methyl-3′-oxo-1′,3′,4′,7′-tetrahydrospiro[pyrrolidine-3,2′-pyrrole[3′,2′:5,6]pyridine[3,4-b]pyrazine]-1-carboxylate (150 mg, 100% yield) as a yellow solid. ES-API: [M+H] + =588.1.

[0483] Step 5: tert-Butyl 9′-(2-chloro-4-phenoxybenzoyl)-4′-methyl-3′-oxo-1′,3′,4′,7′-tetrahydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazine]-1-carboxylate (150 mg, 0.25 mmol) was dissolved in 4.5 mL of dichloromethane, cooled to 0°C, and 1.5 mL of trifluoroacetic acid was added. The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted twice with 40 mL of ethyl acetate. The organic phase was washed with 25 mL of saturated brine, dried, and concentrated to yield 9′-(2-chloro-4-phenoxybenzoyl)-4′-methyl-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolidin[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (124 mg, 100% yield) as a light brown solid. ES-API: [M+H] + =488.0.

[0484] Step 6: 9'-(2-chloro-4-phenoxybenzoyl)-4'-methyl-4',7'-dihydrospiro[pyrrolidine-3,2'-pyrrolo[3',2':5,6]pyridin[3,4-b]pyrazin]-3'(1'H)-one (104 mg, 0.21 mmol) was dissolved in 10 mL of methanol and 2 mL of dichloromethane. 37% aqueous formaldehyde (85 mg, 1.05 mmol) and 1 drop of acetic acid were added sequentially at room temperature. The reaction was stirred at room temperature for 30 minutes, and then sodium cyanoborohydride (26 mg, 0.42 mmol) was added. The reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the crude product was purified by TLC plate (dichloromethane / 7M ammonia methanol = 10:1) to give 58 mg of crude product. The desired product (Z8, 8 mg, 7% yield) was then purified by preparative HPLC to give the desired product (Z8, 8 mg, 7% yield) as a yellow solid. ES-API: [M+H] + =502.1.

[0485] Example 9: Synthesis of Z9, Z9-1 and Z9-2

[0486]

[0487] Step 1: 4-Chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.9 g, 2.671 mmol) and methyl 2-amino-3-hydroxy-2-methylpropanoate hydrochloride (1.0 g, 5.915 mmol) were dissolved in N,N-dimethylformamide (30 mL), and N,N-diisopropylethylamine (7.64 g, 59.15 mmol) was added. The reaction was stirred at 95 ° C for 16 hours. 100 mL of ethyl acetate was added to the reaction solution, and the mixture was washed twice with 60 mL of water and three times with 30 mL of saturated brine. The mixture was dried and concentrated, and the crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether: 0-50%) to give 3-hydroxy-2-methyl-2-methyl (((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)propanoate (620 mg, yield 53%) as a light yellow solid. ES-API: [M+H] + =435.1.

[0488] Step 2: 3-Hydroxy-2-methyl-2-methyl (((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) propanoate (550 mg, 1.267 mmol) was dissolved in acetic acid (15 mL), iron powder (1.40 g, 25.00 mmol) was added, and the reaction was stirred at 80 ° C for 1 hour. The solvent was dried under reduced pressure and then 200 mL of ethyl acetate was added, and the mixture was washed twice with 80 mL of water. The product was washed twice with 60 mL of saturated sodium carbonate, twice with 80 mL of saturated sodium bicarbonate, and then dried and concentrated with 80 mL of saturated brine. The crude product was slurried with ethyl acetate to obtain 2-(hydroxymethyl)-2-methyl-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazin-3-one (380 mg, yield 80.6%) as a yellow solid. ES-API: [M+H] + =373.1

[0489] Step 3: 2-(Hydroxymethyl)-2-methyl-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazin-3-one (200 mg, 0.5376 mmol) was dissolved in 12 mL of methanol, 2 mL of tetrahydrofuran, and 2 mL of water. Sodium hydroxide (215 mg, 5.376 mmol) was added and the reaction was stirred at 65°C for 7 hours. 20 mL of water and 5 mL of saturated ammonium chloride solution were added to the reaction solution, and the mixture was extracted with 150 mL of ethyl acetate. The organic phase was washed sequentially with 30 mL of saturated sodium bicarbonate solution and 80 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield 2-(hydroxymethyl)-2-methyl-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazin-3-one (300 mg, crude) as an off-white solid. ES-API: [M+H] + =233.0.

[0490] Step 4: Dissolve 2-(Hydroxymethyl)-2-methyl-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazin-3-one (300 mg, 1.293 mmol) and 2-chloro-4-phenoxybenzaldehyde (350 mg, 1.510 mmol) in methanol (12.0 mL). Cool the reaction mixture to 0°C and add potassium hydroxide (300 mg, 5.375 mmol). Stir the reaction mixture at room temperature for 6 hours. Pour the reaction mixture into 30 mL of saturated aqueous ammonium chloride, adjust the pH to 8, and extract with 100 mL of ethyl acetate. The organic phase was washed with 60 mL of saturated brine, dried, and concentrated to give the crude target product, 9-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-2-(hydroxymethyl)-2-methyl-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3-one (320 mg, crude), as a pale yellow solid. ES-API: [M+H] + =465.1.

[0491] Step 5: 9-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-2-(hydroxymethyl)-2-methyl-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazin]-3-one (320 mg, 0.6896 mmol) was dissolved in 30 mL of dichloromethane. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (320 mg, 1.410 mmol) was added and the reaction was stirred at room temperature for 2 hours. 60 mL of saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with 80 mL of ethyl acetate. The organic phase was washed with 60 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative HPLC to give 9-(2-chloro-4-phenoxybenzoyl)-2-(hydroxymethyl)-2-methyl-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin-3-one (Z9, 26 mg, yield 8%) as a light yellow solid. ES-API: [M+H] + =463.0. 1 H NMR (500MHz, DMSO-d6) δ12.39 (s, 1H), 10.39 (s, 1H), 8.23 ​​(s, 1H), 7.67 (s, 1 H), 7.57 (s, 1H), 7.54 (d, J=8.4Hz, 1H), 7.48 (t, J=8.0Hz, 2H), 7.25 (t, J=7.4 Hz, 1H), 7.22-7.13 (m, 3H), 7.02 (dd, J=8.4, 2.4Hz, 1H), 5.21 (t, J=5.4Hz, 1 H), 3.69 (dd, J=10.6, 6.0Hz, 1H), 3.48 (dd, J=10.7, 4.8Hz, 1H), 1.36 (s, 3H).

[0492] Step 6: Compound Z9 (20 mg, 0.0433 mmol) prepared in the above step was subjected to chiral preparative separation (column: IC150 mm x 4.6 mm x 5 μm, mobile phase: n-hexane: ethanol: diethylamine = 70:30:0.2, flow rate: 1 ml / min, column temperature: 30°C) to afford two single isomers. One single isomer, arbitrarily designated Z9-1 (7 mg, peak 1, retention time 10.019 min, yield 35%), was obtained as a pale white solid. ES-API: [M+H] + =463.0. Another single isomer, whose structure was arbitrarily designated as Z9-2 (6.5 mg, peak 2, retention time 11.323 min, yield 34%), was obtained as a pale white solid. ES-API: [M+H] + =463.0.

[0493] Example 10: Synthesis of Z10

[0494]

[0495] Step 1: Tert-butyl 3′-oxo-7′-(phenylsulfonyl)-1′,3′,4′,7′-tetrahydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridine[3,4-b]pyrazine]-1-carboxylate (300 mg, 0.62 mmol) was dissolved in 10 mL of methanol, 5 mL of tetrahydrofuran and 2 mL of water. Sodium hydroxide (124 mg, 3.10 mmol) was added and the reaction was stirred at 60°C for 16 hours. The reaction solution was adjusted to pH 8 with 1.0 M dilute hydrochloric acid, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was washed with 25 mL of saturated brine, dried, and concentrated to yield tert-butyl 3′-oxo-1′,3′,4′,7′-tetrahydrospiro[pyrrolidine-3,2′-pyrrole[3′,2′:5,6]pyridine[3,4-b]pyrazine]-1-carboxylate (170 mg, 80% yield) as a light brown solid. ES-API: [M+H] + =344.2.

[0496] Step 2: Dissolve tert-butyl 3′-oxo-1′,3′,4′,7′-tetrahydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazine]-1-carboxylate (170 mg, 0.50 mmol) and 2-chloro-4-phenoxybenzaldehyde (345 mg, 1.50 mmol) in methanol (15 mL). Cool the reaction mixture to 0°C and add potassium hydroxide (196 mg, 3.50 mmol). Stir the reaction at room temperature for 18 hours. The reaction mixture was adjusted to pH 8 with 1.0 M dilute hydrochloric acid, and the crude product was concentrated and purified using a thin layer preparation plate (dichloromethane / methanol = 10:1) to afford tert-butyl 9′-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-3′-oxo-1′,3′,4′,7′-tetrahydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridinium[3,4-b]pyrazine]-1-carboxylate (145 mg, 51% yield) as a yellow solid. ES-API: [M+H] + =576.1.

[0497] Step 3: tert-Butyl 9′-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-3′-oxo-1′,3′,4′,7′-tetrahydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazine]-1-carboxylate (130 mg, 0.26 mmol) was dissolved in 10 mL of tetrahydrofuran and cooled to 0°C. Dess-Martin periodinane (146 mg, 0.34 mmol) was added and the reaction was stirred at room temperature for 18 hours. 4 mL of saturated sodium thiosulfate solution and 10 mL of saturated sodium bicarbonate solution were added to the reaction solution, and the mixture was extracted with 40 mL of ethyl acetate. The organic phase was washed sequentially with 10 mL of saturated sodium bicarbonate solution and 10 mL of saturated brine, dried, and concentrated to afford tert-butyl 9′-(2-chloro-4-phenoxybenzoyl)-3′-oxo-1′,3′,4′,7′-tetrahydrospiro[pyrrolidine-3,2′-pyrrole[3′,2′:5,6]pyridine[3,4-b]pyrazine]-1-carboxylate (129 mg, 100% yield) as a yellow solid. S-API: [M+H] + =574.2.

[0498] Step 5: Dissolve tert-butyl 9′-(2-chloro-4-phenoxybenzoyl)-3′-oxo-1′,3′,4′,7′-tetrahydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazine]-1-carboxylate (30 mg, 0.25 mmol) in 2 mL of methanol, add 2 mL of 4.0 M hydrogen chloride solution in dioxane, and stir at room temperature for 2 hours. The reaction solution is concentrated to give 9′-(2-chloro-4-phenoxybenzoyl)-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazine]-3′(1′H)-one hydrochloride (30 mg, 100% yield) as a yellow solid. ES-API: [M+H] + =474.0 (free base).

[0499] Step 6: 9′-(2-chloro-4-phenoxybenzoyl)-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one hydrochloride (30 mg, 0.05 mmol) was dissolved in 5 mL of dichloromethane. Triethylamine (27 mg, 0.26 mmol) and a solution of cyclopropanecarboxylic acid chloride (7 mg, 0.06 mmol) in 0.5 mL of dichloromethane were added sequentially under ice-cooling. The reaction was stirred under ice-cooling for 15 minutes. 2 mL of methanol was added to the reaction mixture, which was concentrated. The crude product was purified by preparative HPLC to yield the desired product (Z10, 15 mg, 54% yield) as a white solid. 1H NMR (500MHz, DMSO-d6) δ12.58 (s, 1H), 10.78-10.74 (m, 1H), 8.58-8.51 (m, 1H), 7.83-7.8 0 (m, 1H), 7.70-7.66 (m, 1H), 7.58-7.52 (m, 1H), 7.50-7.42 (m, 2H), 7.25 (t, J=6.9Hz, 1H) , 7.21-7.13 (m, 3H), 7.02 (dd, J=8.5, 1.5Hz, 1H), 4.17-3.80 (m, 2H), 3.75-3.48 (m, 2H), 2 .57-2.33(m, 1H), 2.21-2.00(m, 1H), 1.85-1.72(m, 1H), 0.80-0.60(m, 4H).ES-API: [M+H] + =542.1.

[0500] Example 11: Synthesis of Z11

[0501]

[0502] Step 1: 4-Chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (950 mg, 2.819 mmol) and 1-(tert-butyl) 3-ethyl 3-aminoazetidine-1,3-dicarboxylate (1.0 g, 4.096 mmol) were dissolved in N,N-dimethylformamide (30 mL), and N,N-diisopropylethylamine (3.643 g, 28.19 mmol) was added. The reaction was stirred at 95 ° C for 16 hours. After the reaction mixture was cooled to room temperature, 100 mL of ethyl acetate was added, and the mixture was washed twice with 80 mL of water and three times with 60 mL of saturated brine. The mixture was then dried and concentrated. The crude product was purified on a flash silica gel column (ethyl acetate / petroleum ether: 0-50%) to afford 1-(tert-butyl)-3-ethyl-3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)azetidine-1,3-dicarboxylate (860 mg, 56% yield) as a pale yellow solid. ES-API: [M+H] + =546.1.

[0503] Step 2: 1-(tert-Butyl)3-ethyl 3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)azetidine-1,3-dicarboxylate (700 mg, 1.284 mmol) was dissolved in acetic acid (50 mL), iron powder (700 mg, 12.50 mmol) was added, and the reaction was stirred at 80°C for 1 hour. After the solvent was evaporated under reduced pressure, 200 mL of ethyl acetate was added, and the mixture was washed with 80 mL of water twice, 60 mL of saturated sodium carbonate twice, 60 mL of saturated sodium bicarbonate twice, and 60 mL of saturated brine, dried and concentrated. The crude product was slurried with ethyl acetate to obtain tert-butyl 3′-oxo-7′-(phenylsulfonyl)-1′,3′,4′,7′-tetrahydrospiro[azetidine-3,2′-pyrrole[3′,2′:5,6]pyridine[3,4-b]pyrazine]-1-carboxylate (530 mg, yield 88%) as a light yellow solid. ES-API: [M+H] + =470.1

[0504] Step 3: Tert-butyl 3′-oxo-7′-(phenylsulfonyl)-1′,3′,4′,7′-tetrahydrospiro[azetidine-3,2′-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazine]-1-carboxylate (330 mg, 0.7035 mmol) was dissolved in 12 mL of methanol, 2 mL of tetrahydrofuran, and 2 mL of water. Sodium hydroxide (300 mg, 7.50 mmol) was added and the reaction was stirred at 65°C for 6 hours. 15 mL of water and 10 mL of saturated ammonium chloride solution were added to the reaction solution, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was washed sequentially with 40 mL of saturated sodium bicarbonate solution and 60 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield tert-butyl 3′-oxo-1′,3′,4′,7′-tetrahydrospiro[azetidine-3,2′-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazine]-1-carboxylate (200 mg, 86% yield) as an off-white solid. ES-API: [M+H] + =330.1.

[0505] Step 4: Dissolve tert-butyl 3′-oxo-1′, 3′, 4′, 7′-tetrahydrospiro[azetidine-3, 2′-pyrrolo[3′, 2′: 5, 6]pyrido[3, 4-b]pyrazine]-1-carboxylate (200 mg, 0.6079 mmol) and 2-chloro-4-phenoxybenzaldehyde (300 mg, 1.293 mmol) in methanol (12 mL). Cool the reaction mixture to 0°C and add potassium hydroxide (240 mg, 4.285 mmol). Stir the reaction at room temperature for 6 hours. Pour the reaction mixture into 30 mL of saturated aqueous ammonium chloride solution, adjust the pH to 8, and extract with 100 mL of ethyl acetate. The organic phase was washed with 60 mL of saturated brine, dried, and concentrated to give the crude target product, tert-butyl 9′-(((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-3′-oxo-1′,3′,4′,7′-tetrahydrospiro[azetidine-3,2′-pyrrolo[3′,2′:5,6]pyridine[3,4-b]pyrazine]-1-carboxylate (412 mg, crude) as a light yellow solid. ES-API: [M+H] + =562.2.

[0506] Step 5: tert-Butyl 9′-(((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-3′-oxo-1′, 3′, 4′, 7′-tetrahydrospiro[azetidine-3, 2′-pyrrolo[3′, 2′: 5, 6]pyridine[3, 4-b]pyrazine]-1-carboxylate (412 mg, 0.7341 mmol) was dissolved in 30 mL of dichloromethane, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (400 mg, 1.762 mmol) was added, and the reaction was stirred at room temperature for 3 hours. The reaction solution was added with 60 mL of saturated and sodium bicarbonate solution, extracted with 150 mL of ethyl acetate. The organic phase was washed with 60 mL of saturated brine, dried, and concentrated. The crude product was purified by flash silica gel column chromatography (methanol / dichloromethane: 0-20%) to obtain tert-butyl 9′-(2-chloro-4-phenoxybenzoyl)-3′-oxo-1′, 3′, 4′, 7′-tetrahydrospiro[azetidine-3, 2′-pyrrolo[3′, 2′: 5, 6]pyrido[3, 4-b]pyrazine]-1-carboxylate (230 mg, yield 67%) as a light yellow solid. ES-API: [M+H] + =560.2.

[0507] Step 6: Dissolve tert-butyl 9′-(2-chloro-4-phenoxybenzoyl)-3′-oxo-1′,3′,4′,7′-tetrahydrospiro[azetidine-3,2′-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazine]-1-carboxylate (230 mg, 0.4113 mmol) in 8 mL of dichloromethane, and add trifluoroacetic acid (469.0 mg, 4.113 mmol). The reaction was allowed to react at room temperature for 2 hours. Upon completion, the solvent was evaporated under reduced pressure to afford the crude target compound, 9′-(2-chloro-4-phenoxybenzoyl)-4′,7′-dihydrospiro[azetidine-3,2′-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazine]-3′(1′H)-one (330 mg, crude). The product was a brown oily liquid. ES-API: [M+H] + =460.1.

[0508] Step 7: 9′-(2-chloro-4-phenoxybenzoyl)-4′,7′-dihydrospiro[azetidine-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (330 mg, 0.7189 mmol) was added to 30 mL of acetonitrile. After cooling the mixture to 0-5°C in an ice-water bath, formaldehyde (333 mg, 4.11 mmol) was added, followed by sodium cyanoborohydride (260 mg, 4.110 mmol). After reacting at room temperature for 2 hours, 50 mL of saturated sodium bicarbonate and 80 mL of ethyl acetate were added. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. The crude product was purified by preparative HPLC to yield 9′-(2-chloro-4-phenoxybenzoyl)-1-methyl-4′,7′-dihydrospiro[azetidine-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (Z11, 10.0 mg, 5% yield). A pale yellow solid was obtained. ES-API: [M+H] + =474.1.

[0509] Example 12: Synthesis of Z12

[0510]

[0511] Step 1: 2-Chloro-4-hydroxybenzaldehyde (500 mg, 3.20 mmol) and 2-fluoro-4-(trifluoromethyl)pyridine (686 mg, 4.16 mmol) were dissolved in 12 mL of N,N-dimethylformamide, potassium carbonate (883 mg, 6.40 mmol) was added, and the reaction was stirred at 95°C for 20 hours. The reaction solution was poured into 40 mL of water and extracted with 60 mL of ethyl acetate. The organic phase was washed three times with 25 mL of saturated brine, dried and concentrated, and the crude product was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-5%) to obtain 2-chloro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)benzaldehyde (720 mg, yield 75%) as a colorless liquid. ES-API: [M+H] + =302.0.

[0512] Step 2: Tert-butyl 3′-oxo-1′,3′,4′,7′-tetrahydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazine]-1-carboxylate (130 mg, 0.38 mmol) and 2-chloro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)benzaldehyde (343 mg, 1.14 mmol) were dissolved in methanol (10 mL). The reaction mixture was cooled to 0°C and potassium hydroxide (149 mg, 2.66 mmol) was added. The reaction was stirred at room temperature for 18 hours. The reaction mixture was adjusted to pH 8 with 1.0 M dilute hydrochloric acid, and the crude product was concentrated and purified using a thin layer preparation plate (dichloromethane / methanol = 10:1) to afford tert-butyl 9′-((2-chloro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(hydroxy)methyl)-3′-oxo-1′,3′,4′,7′-tetrahydrospiro[3,2′-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazine]-1-carboxylate (135 mg, 55% yield) as a light brown solid. ES-API: [M+H] + =645.1.

[0513] Step 3: tert-Butyl 9′-((2-chloro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(hydroxy)methyl)-3′-oxo-1′,3′,4′,7′-tetrahydrospiro[3,2′-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazine]-1-carboxylate (122 mg, 0.19 mmol) was dissolved in 10 mL of tetrahydrofuran, cooled to 0°C, and Dess-Martin periodinane (104 mg, 0.25 mmol) was added. The reaction was stirred at room temperature for 18 hours. 4 mL of saturated sodium thiosulfate solution and 10 mL of saturated sodium bicarbonate solution were added to the reaction solution, and the mixture was extracted with 40 mL of ethyl acetate. The organic phase was washed sequentially with 10 mL of saturated sodium bicarbonate solution and 10 mL of saturated brine, dried, and concentrated to yield tert-butyl 9′-(2-chloro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)benzoyl)-3′-oxo-1′,3′,4′,7′-tetrahydrospiro[pyrrolidine-3,2′-pyrrole[3′,2′:5,6]pyridine[3,4-b]pyrazine]-1-carboxylate (121 mg, 100% yield) as a yellow solid. ES-API: [M+H] + =643.2.

[0514] Step 4: Tert-butyl 9′-(2-chloro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)benzoyl)-3′-oxo-1′,3′,4′,7′-tetrahydrospiro[pyrrolidine-3,2′-pyrrole[3′,2′:5,6]pyridine[3,4-b]pyrazine]-1-carboxylate (60 mg, 0.093 mmol) was dissolved in 2 mL of dichloromethane, cooled to 0°C, and 0.5 mL of trifluoroacetic acid was added. The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give 9′-(2-chloro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)benzoyl)-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolidin[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one trifluoroacetate (75 mg, crude). ES-API: [M+H] + =543.1 (free base).

[0515] Step 5: 9′-(2-chloro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)benzoyl)-4′,7′-dihydrospiro[pyrrolidine-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one trifluoroacetate (70 mg, crude) was dissolved in 3 mL of acetonitrile. 37% aqueous formaldehyde solution (50 mg, 0.61 mmol) was added sequentially at room temperature. The reaction was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (19 mg, 0.31 mmol) was then added and the reaction was stirred at room temperature for 30 minutes. The reaction solution was concentrated and the crude product was purified by preparative HPLC to give the desired product (Z12, 8 mg, 15% yield) as a white solid. 1 H NMR (500MHz, DMSO-d6) δ12.56 (s, 1H), 10.58 (s, 1H), 8.48 (d, J=5.0Hz, 1H), 8.45 (s, 1H) ), 8.33 (s, 1H), 7.76 (s, 1H), 7.64 (d, J = 8.5Hz, 1H), 7.62-7.56 (m, 3H), 7.54 (d, J = 2.0H z, 1H), 7.31 (dd, J=8.5, 2.0Hz, 1H), 2.99-2.91 (m, 1H), 2.82 (d, J=9.5Hz, 1H), 2.70 (d, J=9.5Hz, 1H), 2.55-2.50(m, 1H), 2.34-2.22(m, 4H), 1.90-1.80(m, 1H).ES-API: [M+H] + =557.0.

[0516] Example 13: Synthesis of Z13, Z13-1 and Z13-2

[0517]

[0518] Step 1: 4-Chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.9 g, 2.671 mmol) and methyl 2-amino-3-hydroxy-2-methylpropanoate hydrochloride (1.0 g, 5.915 mmol) were dissolved in N,N-dimethylformamide (30 mL), and N,N-diisopropylethylamine (7.64 g, 59.15 mmol) was added. The reaction was stirred at 95 ° C for 16 hours. 100 mL of ethyl acetate was added to the reaction solution, and the mixture was washed twice with 60 mL of water and three times with 30 mL of saturated brine. The mixture was dried and concentrated, and the crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether: 0-50%) to give 3-hydroxy-2-methyl-2-methyl (((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)propanoate (620 mg, yield 53%) as a light yellow solid. ES-API: [M+H]+ =435.1.

[0519] Step 2: 3-Hydroxy-2-methyl-2-methyl-(((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)propanoate (700 mg, 1.613 mmol) was dissolved in acetonitrile (30 mL), and silver oxide (1.87 g, 8.065 mmol) and iodomethane (2.29 g, 16.13 mmol) were added sequentially. The mixture was stirred at room temperature in the dark under nitrogen protection for 48 hours. After the reaction was completed, celite was added and the filtrate was dried under reduced pressure. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether: 0-50%) to give methyl 3-methoxy-2-methyl-2-(((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)propanoate (570 mg, yield 78%) as a yellow solid. ES-API: [M+H] + =449.0.

[0520] Step 3: 3-methoxy-2-methyl-2-(((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)propionic acid methyl ester (700 mg, 1.613 mmol) was dissolved in acetic acid (30 mL) and iron powder (1.80 g, 32.26 mmol) was added. The temperature was gradually raised to 80° C. and stirred for 1 hour. After the reaction was completed, the solvent was dried under reduced pressure and 200 mL of ethyl acetate was added, followed by 80 mL of The product was washed twice with water, twice with 60 mL of saturated sodium carbonate, twice with 80 mL of saturated sodium bicarbonate, and then dried and concentrated with 80 mL of saturated brine. The crude product was slurried with ethyl acetate to obtain 2-(methoxymethyl)-2-methyl-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazin-3-one (400 mg, yield 64%) as a yellow solid. ES-API: [M+H] + =387.1

[0521] Step 4: 2-(Methoxymethyl)-2-methyl-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazin-3-one (400 mg, 1.0362 mmol) was dissolved in 12 mL of methanol, 3 mL of tetrahydrofuran, and 2 mL of water. Sodium hydroxide (290 mg, 7.264 mmol) was added and the reaction was stirred at 65°C for 7 hours. 20 mL of water and 15 mL of saturated ammonium chloride solution were added to the reaction solution, and the mixture was extracted with 150 mL of ethyl acetate. The organic phase was washed sequentially with 30 mL of saturated sodium bicarbonate solution and 80 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield 2-(methoxymethyl)-2-methyl-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazin-3-one (480 mg, crude) as a pale white solid. ES-API: [M+H] + =247.1.

[0522] Step 5: Dissolve 2-(Methoxymethyl)-2-methyl-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazin-3-one (480 mg, crude) and 2-chloro-4-phenoxybenzaldehyde (480 mg, 2.0724 mmol) in methanol (20.0 mL). Cool the reaction mixture to 0°C and add potassium hydroxide (406 mg, 7.253 mmol). Stir the reaction mixture at room temperature for 6 hours. Pour the reaction mixture into 30 mL of saturated aqueous ammonium chloride, adjust the pH to 8, and extract with 100 mL of ethyl acetate. The organic phase was washed with 60 mL of saturated brine, dried, and concentrated to give the crude target product, 9-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-2-(methoxymethyl)-2-methyl-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazin]-3-one (620 mg, crude), as a pale yellow solid. ES-API: [M+H] + =479.0.

[0523] Step 6: 9-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-2-(methoxymethyl)-2-methyl-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazin]-3-one (620 mg, crude) was dissolved in 30 mL of dichloromethane. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (470 mg, 2.0724 mmol) was added and the reaction was stirred at room temperature for 2 hours. 60 mL of saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with 80 mL of ethyl acetate. The organic phase was washed with 60 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative HPLC to give 9-(2-chloro-4-phenoxybenzoyl)-2-(methoxymethyl)-2-methyl-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin-3-one (Z13, 126 mg, three-step yield 25%) as a light yellow solid. ES-API: [M+H] + =477.1. 1 H NMR (500MHz, DMSO-d6) δ12.45 (s, 1H), 10.48 (s, 1H), 8.27 (s, 1H), 7.69 (s, 1H), 7.60 (s, 1H), 7.56 (d, J=8.5Hz, 1H), 7.48 (dd, J=8.5, 7.5Hz, 2H) , 7.25 (t, J=7.5Hz, 1H), 7.22-7.11 (m, 3H), 7.02 (dd, J=8.5, 2.5Hz, 1H), 3.64 (d, J=9.5Hz, 1H), 3.47 (d, J=9.5Hz, 1H), 3.29 (s, 3H), 1.39 (s, 3H).

[0524] Step 7: Compound Z13 (126 mg, 0.2646 mmol) prepared in the above step was subjected to chiral preparative separation (column: IC 150 mm x 4.6 mm x 5 μm, mobile phase: n-hexane: ethanol: diethylamine = 70:30:0.2, flow rate: 1 ml / min, column temperature: 30°C) to afford two single isomers. One single isomer (51.45 mg, peak 1, retention time 8.881 min, 40% yield) was obtained as a pale white solid. ES-API: [M+H] + =477.1. 1H NMR (500MHz, DMSO-d6) δ12.46 (s, 1H), 10.49 (s, 1H), 8.28 (s, 1H), 7.69 (s, 1H), 7.60 (s, 1H), 7.56 (d, J = 8.5Hz, 1H), 7.48 (t, J = 8.0Hz, 2H), 7. 25 (t, J=7.5Hz, 1H), 7.21-7.16 (m, 3H), 7.02 (dd, J=8.5, 2.5Hz, 1H), 3.65 (d, J=9.5Hz, 1H), 3.47 (d, J=9.5Hz, 1H), 3.29 (s, 3H), 1.39 (s, 3H). Another single isomer (53.0 mg, peak 2, retention time 11.86 min, yield 42%), pale white solid. ES-API: [M+H] + =477.1. 1 H NMR (400MHz, DMSO-d6) δ12.46 (s, 1H), 10.49 (s, 1H), 8.28 (s, 1H), 7.69 (s, 1H), 7.60 (s, 1H), 7.56 (d, J=8.4Hz, 1H), 7.52-7.44 (m, 2H), 7. 29-7.23 (m, 1H), 7.22-7.16 (m, 3H), 7.02 (dd, J=8.4, 2.4Hz, 1H), 3.65 (d, J=9.6Hz, 1H), 3.47 (d, J=9.6Hz, 1H), 3.29 (s, 3H), 1.39 (s, 3H).

[0525] Example 13A: Synthesis of Z13-1

[0526]

[0527] This embodiment refers to the steps of embodiment 13, except that the first step of this embodiment uses Instead of step 1 of Example 13 Chiral analysis of the resulting final product (column: IC 150mm*4.6mm*5um, mobile phase: n-hexane:ethanol:diethylamine = 70:30:0.2, flow rate: 1ml / min, column temperature: 30°C) confirmed that no racemization occurred, and thus the final product was identified as Z13-1. Comparison of the two single isomers resolved in step 7 of Example 13 with the product Z13-1 prepared in Example 13A confirmed that the structure of the isomer with a retention time of 8.881min was compound Z13-1, and the structure of the isomer with a retention time of 11.86min was compound Z13-2.

[0528] Example 14: Synthesis of Z14

[0529]

[0530] Step 1: 4-Chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.48 mmol) and methyl 4-aminotetrahydro-2H-pyran-4-carboxylate (260 mg, 1.63 mmol) were dissolved in 5 mL of N,N-dimethylacetamide, and N,N-diisopropylethylamine (480 mg, 3.71 mmol) was added. The reaction was stirred in a microwave at 120°C for 1 hour. 100 mL of ethyl acetate was added to the reaction solution, which was then washed three times with 30 mL of dilute brine and then with 30 mL of saturated brine. The mixture was dried and concentrated, and the crude product was purified on a flash silica gel column (ethyl acetate / petroleum ether: 0-50%) to afford 4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)methyl)tetrahydro-2H-pyran-4-carboxylate (300 mg, 44% yield) as a yellow solid. ES-API: [M+H] + =461.0.

[0531] Step 2: 4-((5-Nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)methyl)tetrahydro-2H-pyran-4-carboxylate (300 mg, 0.65 mmol) was dissolved in 10 mL of acetic acid, and iron powder (182 mg, 3.26 mmol) was added. The mixture was stirred at 80°C for 3 hours. The reaction mixture was concentrated, 60 mL of ethyl acetate was added, and the mixture was filtered and concentrated. The residue was purified on a flash silica gel column (0-100% ethyl acetate / petroleum ether) to afford 7′-(phenylsulfonyl)-2,3,4′,5,6,7′-hexahydrospiro[pyran-4,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (200 mg, 77% yield) as a yellow solid. ES-API: [M+H] + =399.1.

[0532] Step 3: 7′-(phenylsulfonyl)-2,3,4′,5,6,7′-hexahydrospiro[pyran-4,2′-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazin]-3′(1′H)-one (200 mg, 0.50 mmol) was dissolved in 2 mL of methanol and 0.4 mL of water. Sodium hydroxide (100 mg, 2.50 mmol) was added and the reaction was stirred in a microwave at 120°C for 1 hour. The reaction solution was dried and concentrated to give crude 2,3,4′,5,6,7′-hexahydrospiro[pyran-4,2′-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazin]-3′(1′H)-one (200 mg) as a black solid. ES-API: [M+H] + =259.1.

[0533] Step 6: Dissolve 2,3,4′,5,6,7′-hexahydrospiro[pyran-4,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (200 mg, 0.77 mmol) and 2-chloro-4-phenoxybenzaldehyde (360 mg, 1.55 mmol) in methanol (10 mL). Cool the reaction mixture to 0°C and add potassium hydroxide (304 mg, 5.42 mmol). Stir the reaction mixture at room temperature for 5 hours. Pour the reaction mixture into 30 mL of water, adjust the pH to 8 with 1.0 M dilute hydrochloric acid, and extract with 80 mL of ethyl acetate. The organic phase was washed with 25 mL of saturated brine, dried, and concentrated. The crude product was purified by flash silica gel column chromatography (0-20% methanol / dichloromethane) to give 9′-(((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-2,3,4′,5,6,7′-hexahydrospiro[pyran-4,2′-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazine]-3′(1′H)-one (70 mg, 18% yield) as a yellow solid. ES-API: [M+H] + =491.0.

[0534] Step 7: 9′-(((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-2,3,4′,5,6,7′-hexahydrospiro[pyran-4,2′-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazine]-3′(1′H)-one (70 mg, 0.14 mmol) was dissolved in 2 mL of 1,4-dioxane and 0.2 mL of water, cooled to 0°C, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (49 mg, 0.21 mmol) was added. The reaction was stirred at room temperature for 2 hours. 3 mL of saturated sodium thiosulfate solution and 10 mL of saturated sodium bicarbonate solution were added to the reaction solution, and the solution was extracted with 40 mL of ethyl acetate. The organic phase was washed with 10 mL of saturated brine, dried, and concentrated. The crude product was purified by preparative HPLC to give the desired product (Z14, 24 mg, 34% yield) as a light yellow solid. 1 H NMR (400MHz, DMSO-d6) δ12.58 (s, 1H), 10.54 (s, 1H), 8.86 (s, 1H), 7.78 (s, 1H), 7.70 (s, 1H), 7.60 (d, J=8.4Hz, 1H), 7.53-7.44 (m, 2H), 7.29-7.23 (m, 1H), 7.21 -7.19 (m, 2H), 7.19-7.17 (m, 1H), 7.04 (dd, J=8.4, 2.0Hz, 1H), 3.89-3.80 (m, 2H ), 3.80-3.69(m, 2H), 2.14-2.02(m, 2H), 1.61(d, J=12.8Hz, 2H).ES-API: [M+H] +=489.1.

[0535] Example 15: Synthesis of Z15

[0536]

[0537] Step 1: 4-chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.0 g, 2.97 mmol) and methyl 2-amino-2-methylpropanoate hydrochloride (908 mg, 5.94 mmol) were dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (2.3 mL, 13.36 mmol) was added. The reaction was stirred at 80° C. for 16 hours. 100 mL of ethyl acetate was added to the reaction solution, washed twice with 40 mL of water and three times with 30 mL of saturated brine, dried and concentrated, and the crude product was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-40%) to obtain methyl 2-methyl-2-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)propanoate (870 mg, yield 70%) as a yellow solid. ES-API: [M+H] + =419.0.

[0538] Step 2: Methyl 2-methyl-2-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)propanoate (870 mg, 2.08 mmol) was dissolved in acetic acid (15 mL), and iron powder (466 mg, 8.32 mmol) was added. The reaction was stirred at 85°C for 4 hours. The reaction solution was poured into 45 mL of water, the insoluble solid was filtered, and the filter cake was washed with a small amount of water and dried in vacuo to obtain 2,2-dimethyl-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin-3-one (670 mg, 90% yield) as an off-white solid. ES-API: [M+H] + =357.1

[0539] Step 3: 2,2-Dimethyl-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazin-3-one (300 mg, 0.84 mmol) was dissolved in 12 mL of N,N-dimethylformamide. Anhydrous potassium carbonate (464 mg, 3.36 mmol) and tert-butyl(2-iodomethoxy)dimethylsilane (721 mg, 2.52 mmol) were added sequentially. The reaction was stirred at 60°C for 24 hours. The reaction mixture was poured into 40 mL of water and extracted with 80 mL of ethyl acetate. The organic phase was washed three times with 30 mL of saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (ethyl acetate / petroleum ether: 0-40%) to afford 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2,2-dimethyl-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazin-3-one (400 mg, 92% yield) as a white solid. ES-API: [M+H] + =515.2.

[0540] Step 4: 4-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-2,2-dimethyl-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin-3-one (350 mg, 0.68 mmol) was dissolved in 15 mL of methanol, 5 mL of tetrahydrofuran and 3 mL of water. Sodium hydroxide (136 mg, 3.40 mmol) was added and the reaction was stirred at 60°C for 16 hours. The reaction solution was adjusted to pH 8 with 1.0 M dilute hydrochloric acid, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was washed sequentially with 20 mL of saturated sodium bicarbonate solution and 20 mL of saturated brine, dried, and concentrated to yield 4-(2-hydroxyethyl)-2,2-dimethyl-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin-3-one (177 mg, 100% yield) as a white solid. ES-API: [M+H] + =261.1.

[0541] Step 5: Dissolve 4-(2-hydroxyethyl)-2,2-dimethyl-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazin-3-one (75 mg, 0.29 mmol) and 2-chloro-4-phenoxybenzaldehyde (135 mg, 0.58 mmol) in methanol (7 mL). Cool the reaction mixture to 0°C and add potassium hydroxide (114 mg, 2.03 mmol). Stir the reaction mixture at room temperature for 16 hours. Adjust the pH to 8 with 1.0 M dilute hydrochloric acid and extract with 60 mL of ethyl acetate. The organic phase was washed with 15 mL of saturated brine, dried, and concentrated. The crude product was purified using a thin layer preparation plate (dichloromethane / methanol = 10:1) to afford 9-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-4-(2-hydroxyethyl)-2,2-dimethyl-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin-3-one (95 mg, 67% yield) as a pale yellow solid. ES-API: [M+H] + =493.1.

[0542] Step 6: 9-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-4-(2-hydroxyethyl)-2,2-dimethyl-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazin-3-one (90 mg, 0.18 mmol) was dissolved in 6 mL of dichloromethane. 2,3-Dichloro-5,6-dicyano-p-benzoquinone (83 mg, 0.36 mmol) was added at room temperature. The reaction was stirred at room temperature for 16 hours. 5 mL of saturated sodium thiosulfate solution and 10 mL of saturated sodium bicarbonate solution were added to the reaction solution, and the solution was extracted with 50 mL of ethyl acetate. The organic phase was washed sequentially with 15 mL of saturated sodium bicarbonate solution and 15 mL of saturated brine, dried, and concentrated. The crude product was purified by preparative HPLC to obtain the desired product (Z15, 70 mg, 78% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ12.61 (s, 1H), 8.33 (s, 1H), 8.15 (s, 1H), 7.68 (s, 1H), 7.57 (d, J = 8.4Hz, 1H), 7.51-7.44 (m, 2H), 7.28-7.22 (m, 1H) ), 7.21-7.15 (m, 3H), 7.02 (dd, J=8.4, 2.4Hz, 1H), 4.89 (s, 1H), 4.04 (t, J=6.0Hz, 2H), 3.59 (t, J=6.0Hz, 2H), 1.38 (s, 6H). ES-API: [M+H] + =491.1.

[0543] Example 16: Synthesis of Z16, Z16-1 and Z16-2

[0544]

[0545] Step 1: 4-Chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.60 g, 1.7804 mmol) and 3-aminotetrahydro-2H-pyran-3-carboxylic acid methyl ester (351.23 mg, 2.209 mmol) were dissolved in N,N-dimethylformamide (30 mL), and N,N-diisopropylethylamine (7.64 g, 59.15 mmol) was added. The reaction was stirred at 95 ° C for 12 hours. 100 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed twice with 60 mL of water and three times with 30 mL of saturated brine. The mixture was then dried and concentrated. The crude product was purified on a flash silica gel column (ethyl acetate / petroleum ether: 0-50%) to obtain methyl 3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)tetrahydro-2H-pyran-3-carboxylate (320 mg, 39% yield) as a light yellow solid. ES-API: [M+H] + =461.0.

[0546] Step 2: Methyl 3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)tetrahydro-2H-pyran-3-carboxylate (320 mg, 0.6956 mmol) was dissolved in acetic acid (20 mL), iron powder (0.780 g, 13.91 mmol) was added, and the reaction was stirred at 80°C for 1 hour. The solvent was dried under reduced pressure and then added with 200 mL of ethyl acetate. The mixture was washed with 80 mL of water twice, 60 mL of saturated sodium carbonate twice, 80 mL of saturated sodium bicarbonate twice, and 80 mL of saturated brine, dried, concentrated, and the crude product was slurried with ethyl acetate to obtain 7′-(phenylsulfonyl)-4′,5,6,7′-tetrahydro-2H,4H-spiro[pyran-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (240 mg, yield 85.0%) as a light yellow solid. ES-API: [M+H] + =399.1

[0547] Step 3: 7′-(Phenylsulfonyl)-4′,5,6,7′-tetrahydro-2H,4H-spiro[pyran-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (240 mg, 0.6030 mmol) was dissolved in 12 mL of methanol, 3 mL of tetrahydrofuran, and 2 mL of water. Sodium hydroxide (170 mg, 4.221 mmol) was added and the reaction was stirred at 65°C for 7 hours. 20 mL of water and 5 mL of saturated ammonium chloride solution were added to the reaction solution, and the mixture was extracted with 160 mL of ethyl acetate. The organic phase was washed sequentially with 40 mL of saturated sodium bicarbonate solution and 60 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield 4′,5,6,7′-tetrahydro-2H,4H-spiro[pyran-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (340 mg, crude) as an off-white solid. ES-API: [M+H] + =259.1.

[0548] Step 4: Dissolve 4′,5,6,7′-tetrahydro-2H,4H-spiro[pyran-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (340 mg, crude) and 2-chloro-4-phenoxybenzaldehyde (280 mg, 1.206 mmol) in methanol (12.0 mL). Cool the reaction mixture to 0°C and add potassium hydroxide (236 mg, 4.221 mmol). Stir the reaction mixture at room temperature for 6 hours. Pour the reaction mixture into 30 mL of saturated aqueous ammonium chloride solution, adjust the pH to 8, and extract with 120 mL of ethyl acetate. The organic phase was washed with 63 mL of saturated brine, dried, and concentrated to afford the crude target product, 9′-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-4′,5,6,7′-tetrahydro-2H,4H-spiro[pyran-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (400 mg, crude), as a pale yellow solid. ES-API: [M+H] + =491.2.

[0549] Step 5: 9′-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-4′,5,6,7′-tetrahydro-2H,4H-spiro[pyran-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (400 mg, crude) was dissolved in 20 mL of dichloromethane. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (400 mg, 1.762 mmol) was added and the reaction was stirred at room temperature for 2 hours. 60 mL of saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with 80 mL of ethyl acetate. The organic phase was washed with 60 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative HPLC to give 9′-(2-chloro-4-phenoxybenzoyl)-4′,5,6,7′-tetrahydro-2H,4H-spiro[pyran-3,2′-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazine]-3′(1′H)-one (Z16, 65 mg, total yield for three steps 20%) as a light yellow solid. ES-API: [M+H] + =489.1.

[0550] Step 6: Compound Z16 (65 mg, 0.1332 mmol), prepared in the above step, was subjected to chiral preparative separation (IC column: 150 mm x 4.6 mm x 5 μm, mobile phase: n-hexane:ethanol = 50:50, flow rate: 1 ml / min, column temperature: 30°C) to afford two single isomers. One single isomer, arbitrarily designated Z16-1 (15.15 mg, peak 1, retention time 8.132 min, yield 23%), was obtained as a pale white solid. ES-API: [M+H] + =489.1; 1 H NMR (400MHz, DMSO-d6) δ12.52 (s, 1H), 10.54 (s, 1H), 8.79 (s, 1H), 7.75 (s, 1 H), 7.66 (s, 1H), 7.58 (d, J = 8.4Hz, 1H), 7.52-7.43 (m, 2H), 7.22 (dt, J = 9.4, 7.4Hz, 4H), 7.03 (dd, J=8.4, 2.3Hz, 1H), 3.92 (d, J=9.2Hz, 1H), 3.80 (q, J=1 1.6Hz, 2H), 3.40 (d, J=8.4Hz, 1H), 1.97-1.80 (m, 3H), 1.51 (d, J=6.7Hz, 1H). Another single isomer, whose structure was arbitrarily designated as Z16-2 (15.30 mg, peak 2, retention time 11.960 min, yield 23.5%), was obtained as a pale white solid. ES-API: [M+H] = 489.1; 1H NMR (400MHz, DMSO-d6) δ12.52(s, 1H), 10.54(s, 1H), 8.79(s, 1H), 7.75(s, 1H ), 7.66 (s, 1H), 7.58 (d, J = 8.4Hz, 1H), 7.52-7.43 (m, 2H), 7.21 (ddd, J = 11.6, 9 .7, 4.1Hz, 4H), 7.03 (dd, J=8.4, 2.4Hz, 1H), 3.92 (d, J=8.3Hz, 1H), 3.80 (q, J= 11.4Hz, 2H), 3.42 (t, J=9.8Hz, 1H), 1.98-1.81 (m, 3H), 1.51 (d, J=7.1Hz, 1H).

[0551] Example 17: Synthesis of Z17

[0552]

[0553] Step 1: 4-chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.49 mmol) and 4-amino-1-methylpiperidine-4-carboxylic acid methyl ester (333 g, 1.94 mmol) were dissolved in 15 mL of N, N-dimethylacetamide, and N, N-diisopropylethylamine (577 mg, 4.47 mmol) was added. The reaction was stirred at 95 ° C for 16 hours. 100 mL of ethyl acetate was added to the reaction solution, which was washed three times with 30 mL of dilute brine and 30 mL of saturated brine, dried and concentrated, and the crude product was purified by flash silica gel column (ethyl acetate / petroleum ether: 0-50%) to obtain 1-methyl-4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-4-carboxylate (296 mg, yield 42%) as a yellow solid. ES-API: [M+H] + =474.1.

[0554] Step 2: 1-Methyl-4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-4-carboxylate (296 mg, 0.63 mmol) was dissolved in acetic acid (7 mL), iron powder (247 mg, 4.41 mmol) was added, and the reaction was stirred at 85 °C for 2 hours. The reaction mixture was concentrated, and 20 mL of saturated sodium bicarbonate solution and 100 mL of dichloromethane / methanol (10:1) were added. The suspension was filtered through celite, and the filter cake was washed with dichloromethane / methanol (10:1). The organic phase was separated, washed with 25 mL of saturated brine, and dried and concentrated to afford 1-methyl-7′-(phenylsulfonyl)-4′,7′-dihydrospiro[piperidine-4,2′-pyrrolo[3′,2′:5,6]pyridinyl[3,4-b]pyrazine]-3′(1′1H)-one (258 mg, 100% yield, crude product) as an off-white solid, which was directly used in the next reaction. ES-API: [M+H] + =412.3.

[0555] Step 3: 1-Methyl-7′-(phenylsulfonyl)-4′,7′-dihydrospiro[piperidine-4,2′-pyrrolo[3′,2′:5,6]pyridinyl[3,4-b]pyrazine]-3′(1′1H)-one (258 mg, 0.63 mmol) was dissolved in 10 mL of methanol, 5 mL of tetrahydrofuran and 2 mL of water. Sodium hydroxide (176 mg, 4.41 mmol) was added and the reaction was stirred at 65°C for 16 hours. The reaction solution was adjusted to pH 8 with 1.0 M dilute hydrochloric acid, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried, and concentrated to yield 1-methyl-4′,7′-dihydrospiro[piperidin-4,2′-pyrrolo[3′,2′:5,6]pyridinyl[3,4-b]pyrazin]-3′(1H)-one (76 mg, 45% yield) as a light brown solid. ES-API: [M+H] + =272.2.

[0556] Step 4: 1-Methyl-4′,7′-dihydrospiro[piperidine-4,2′-pyrrolo[3′,2′:5,6]pyridinyl[3,4-b]pyrazine]-3′(1′H)-one (76 mg, 0.28 mmol) and 2-chloro-4-phenoxybenzaldehyde (79 mg, 0.34 mmol) were dissolved in methanol (8 mL), the reaction was cooled to 0°C, potassium hydroxide (110 mg, 1.96 mmol) was added, and the reaction was stirred at room temperature for 18 hours. The reaction mixture was adjusted to pH 8 with 1.0 M dilute hydrochloric acid and concentrated directly. The crude product was purified using a thin layer preparation plate (dichloromethane / 7 M ammonia methanol = 10:1) to afford 9′-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-1-methyl-4′,7′-dihydrospiro[piperidin-4,2′-pyrrolidino[3′,2′:5,6]pyrido[3,4-b]pyrazin]-3′(1′H)-one (56 mg, 33% yield) as a yellow solid. ES-API: [M+H] + =504.2.

[0557] Step 5: 9′-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-1-methyl-4′,7′-dihydrospiro[piperidin-4,2′-pyrrolidino[3′,2′:5,6]pyrido[3,4-b]pyrazin]-3′(1′H)-one (56 mg, 0.11 mmol) was dissolved in 6 mL of tetrahydrofuran and cooled to 0°C. Dess-Martin periodinane (92 mg, 0.22 mmol) was added and the reaction was stirred at room temperature for 2 hours. 3 mL of saturated sodium thiosulfate solution and 10 mL of saturated sodium bicarbonate solution were added to the reaction solution, and the mixture was extracted with 40 mL of ethyl acetate. The organic phase was washed with 10 mL of saturated brine, dried, and concentrated. The crude product was purified by preparative HPLC to yield 9′-(2-chloro-4-phenoxybenzoyl)-1-methyl-4′,7′-dihydrospiro[piperidin-4,2′-pyrrolo[3′,2′:5,6]pyridinyl[3,4-b]pyrazin]-3′(1′H)-one (Z17, 0.61 mg, 1.1% yield) as a light yellow solid. ES-API: [M+H] + =502.2.

[0558] Example 18: Synthesis of Z63

[0559]

[0560] Step 1: 2,2-Dimethyl-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazin-3-one (400 mg, 1.12 mmol) was dissolved in 12 mL of N,N-dimethylformamide. Anhydrous potassium carbonate (773 mg, 5.60 mmol) and 2-chloro-N,N-dimethylethane-1-amine hydrochloride (323 mg, 2.24 mmol) were added sequentially. The reaction was stirred at 60°C for 16 hours. The reaction solution was cooled to room temperature, and anhydrous potassium carbonate (309 mg, 2.24 mmol) and 2-chloro-N,N-dimethylethane-1-amine hydrochloride (161 mg, 1.12 mmol) were added. The reaction was stirred at 60°C for 8 hours. The reaction solution was poured into 40 mL of water and extracted twice with 40 mL of ethyl acetate. The combined organic phases were washed three times with 25 mL of saturated brine, dried and concentrated, and the crude product was purified by flash silica gel column purification (methanol / dichloromethane: 0-7%) to give 4-(2-(dimethylamino)ethyl)-2,2-dimethyl-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin-3-one (300 mg, yield 62%) as a light yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.10-8.05(m, 2H), 7.94(s, 1H), 7.74-7.69(m 1H), 7.65-7.58 (m, 3H), 7.34 (s, 1H), 6.93 (d, J=4.0Hz, 1H), 4.00 (t, J=7.2Hz, 2H), 2.41 (t, J=7.2Hz, 2H), 2.20 (s, 6H), 1.29 (s, 6H). ES-API: [M+H] + =428.1.

[0561] Step 2: 4-(2-(Dimethylamino)ethyl)-2,2-dimethyl-7-(phenylsulfonyl)-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin-3-one (250 mg, 0.58 mmol) was dissolved in 10 mL of methanol, 3 mL of tetrahydrofuran and 2 mL of water. Sodium hydroxide (94 mg, 2.32 mmol) and triethylamine (1.17 g, 11.60 mmol) were added and the reaction was stirred at 60°C for 16 hours. The reaction mixture was adjusted to pH 8 with 1.0 M dilute hydrochloric acid, 100 mL of ethyl acetate was added, and the mixture was washed twice with 30 mL of saturated sodium bicarbonate solution and then with 30 mL of saturated brine. After drying, the mixture was concentrated to obtain 4-(2-(dimethylamino)ethyl)-2,2-dimethyl-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin-3-one (150 mg, 89% yield) as a white solid. ES-API: [M+H] + =288.3.

[0562] Step 3: Dissolve 4-(2-(Dimethylamino)ethyl)-2,2-dimethyl-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazin-3-one (75 mg, 0.26 mmol) and 2-chloro-4-phenoxybenzaldehyde (151 mg, 0.65 mmol) in methanol (6 mL). Cool the reaction mixture to 0°C and add potassium hydroxide (102 mg, 1.82 mmol). Stir the reaction at room temperature for 16 hours. The reaction mixture was adjusted to pH 8 with 1.0 M dilute hydrochloric acid, and the crude product was concentrated and purified using a thin layer preparation plate (dichloromethane / 7.0 M methanolic ammonia solution = 10:1) to afford 9-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-4-(2-(dimethylamino)ethyl)-2,2-dimethyl-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin-3-one (100 mg, 74% yield) as a pale yellow solid. ES-API: [M+H] + =520.2.

[0563] Step 4: 9-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-4-(2-(dimethylamino)ethyl)-2,2-dimethyl-1,2,4,7-tetrahydro-3H-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazin-3-one (95 mg, 0.18 mmol) was dissolved in 1,4-dioxane (5 mL) and water (0.5 mL). 2,3-Dichloro-5,6-dicyano-p-benzoquinone (82 mg, 0.36 mmol) was added at room temperature and the reaction was stirred at room temperature for 2 hours. 6 mL of saturated sodium thiosulfate solution and 10 mL of saturated sodium bicarbonate solution were added to the reaction solution, and the solution was extracted with 80 mL of ethyl acetate. The organic phase was washed sequentially with 20 mL of saturated sodium bicarbonate solution and 20 mL of saturated brine, dried, and concentrated. The crude product was purified by preparative HPLC to yield the desired product (Z63, 70 mg, 74% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ12.60 (s, 1H), 8.33 (s, 1H), 8.03 (s, 1H), 7.68 (s, 1H), 7.57 (d, J = 8.4Hz, 1H), 7.52-7.43 (m, 2H), 7.25 (t, J = 7.2Hz, 1H), 7.23-7.14 (m, 3H), 7.02 (dd, J=8.4, 2.4Hz, 1H), 4.09 (t, J=7.2Hz, 2H), 2.44 (t, J=7.2Hz, 2H), 2.21 (s, 6H), 1.38 (s, 6H). ES-API: [M+H] + =518.2.

[0564] Example 19: Synthesis of Z18

[0565]

[0566] Step 1: 5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine (950 mg, 4.42 mmol) was dissolved in 25 mL of tetrahydrofuran and cooled to 0°C under nitrogen. Sodium hydride (1.01 g, 5.75 mmol, 60% dispersion in mineral oil) was added and the reaction was stirred at room temperature for 30 minutes. The mixture was cooled to 0°C again and a solution of benzenesulfonyl chloride (1.01 g, 5.75 mmol) in tetrahydrofuran (2 mL) was slowly added dropwise. The reaction was stirred at room temperature for 16 hours. 40 mL of water was added to the reaction solution, and the mixture was extracted with 80 mL of ethyl acetate. The organic phase was washed with 30 mL of saturated brine, dried, and concentrated. The crude product was purified on a flash silica gel column (ethyl acetate / petroleum ether: 0-100%) to afford 5-bromo-4-fluoro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.5 g, 95% yield) as a white solid. ES-API: [M+H] + =355.0,357.0.

[0567] Step 2: To a 20 mL microwave tube, 5-bromo-4-fluoro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.41 mmol), (3-aminotetrahydrofuran-3-yl)methanol (330 mg, 2.82 mmol), N,N-dimethylacetamide (7 mL), and N,N-diisopropylethylamine (546 mg, 13.36 mmol) were added in sequence and the mixture was reacted at 160 ° C in a microwave reactor for 8 hours. 100 mL of ethyl acetate was added to the reaction solution, washed three times with 30 mL of dilute brine and then with 30 mL of saturated brine, dried and concentrated, and the crude product was slurried with ethyl acetate / petroleum ether = 1:1 to give (3-((5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)tetrahydrofuran-3-yl)methanol (240 mg, yield 38%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.16 (s, 1H), 8.08 (d, J=7.6Hz, 2H), 7.77-7.69 (m, 2H), 7.62 (t, J=7.6Hz, 2H), 6.81 (d, J=4.0Hz, 1H), 5.67 (s, 1H), 5.44 (t, J=5.2Hz, 1H), 3.95-3.59 (m, 6H), 2.30-2.10 (m, 2H).ES-API: [M+H] + =452.0,454.0.

[0568] Step 3: 3-((5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)tetrahydrofuran-3-yl)methanol (115 mg, 0.25 mmol), palladium acetate (12 mg, 0.05 mmol), [1,1″-binaphthyl]-2-yldi-tert-butylphosphine (30 mg, 0.075 mmol), cesium carbonate (122 mg, 0.375 mmol) and toluene (4 mL) were added to a 5 mL microwave tube in sequence, and nitrogen was added. The reaction mixture was replaced for 2 minutes and then reacted in a microwave reactor at 115°C for 1 hour. The reaction mixture was filtered and washed with dichloromethane. The filtrate was concentrated and the crude product was purified on a flash silica gel column (methanol / dichloromethane: 0-3%) to give 7'-(phenylsulfonyl)-1',4,5,7'-tetrahydro-2H,3'H-spiro[furan-3,2'-pyrrolo[3',2':5,6]pyridin[3,4-b][1,4]oxazine] (105 mg, crude) as a light yellow solid. ES-API: [M+H] + =372.1

[0569] Step 4: 7′-(Benzenesulfonyl)-1′,4,5,7′-tetrahydro-2H,3′H-spiro[furan-3,2′-pyrrolo[3′,2′:5,6]pyridinium[3,4-b][1,4]oxazine] (180 mg, crude) was dissolved in 8 mL of methanol, 2 mL of tetrahydrofuran and 2 mL of water. Sodium hydroxide (78 mg, 1.94 mmol) was added and the reaction was stirred at 65°C for 16 hours. The reaction solution was adjusted to pH 8 with 1.0 M dilute hydrochloric acid, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with 80 mL of ethyl acetate. The organic phase was washed sequentially with 20 mL of saturated sodium bicarbonate solution and 20 mL of saturated brine, dried, and concentrated. The crude product was purified by thin-layer preparation on a plate (dichloromethane / methanol = 10:1) to afford 1′,4,5,7′-tetrahydro-2H,3′H-spiro[furan-3,2′-pyrrolo[3′,2′:5,6]pyridinium[3,4-b][1,4]oxazine] (90 mg, 82% yield over two steps) as a pale yellow solid. ES-API: [M+H] + =232.1.

[0570] Step 5: Dissolve 1′,4,5,7′-tetrahydro-2H,3′H-spiro[furan-3,2′-pyrrolo[3′,2′:5,6]pyridino[3,4-b][1,4]oxazine] (85 mg, 0.37 mmol) and 2-chloro-4-phenoxybenzaldehyde (256 mg, 1.10 mmol) in methanol (8 mL). Cool the reaction mixture to 0°C and add potassium hydroxide (145 mg, 2.59 mmol). Stir the reaction mixture at room temperature for 16 hours. Adjust the pH to 8 with 1.0 M dilute hydrochloric acid and extract with 60 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried, and concentrated. The crude product was purified using a thin layer preparation plate (dichloromethane / methanol = 10:1) to give (2-chloro-4-phenoxyphenyl)(1′,4,5,7′-tetrahydro-2H,3′H-spiro[furan-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b][1,4]oxazin]-9′-yl)methanol (120 mg, 70% yield) as a light yellow solid. ES-API: [M+H] + =464.1.

[0571] Step 6: (2-Chloro-4-phenoxyphenyl)(1′,4,5,7′-tetrahydro-2H,3′H-spiro[furan-3,2′-pyrrolo[3′,2′:5,6]pyridino[3,4-b][1,4]oxazin]-9′-yl)methanol (120 mg, 0.26 mmol) was dissolved in 1,4-dioxane (5 mL) and water (0.5 mL). 2,3-Dichloro-5,6-dicyano-p-benzoquinone (83 mg, 0.36 mmol) was added at room temperature. The reaction was stirred at room temperature for 1 hour. 5 mL of saturated sodium thiosulfate solution and 10 mL of saturated sodium bicarbonate solution were added to the reaction solution, and the solution was extracted with 50 mL of ethyl acetate. The organic phase was washed sequentially with 15 mL of saturated sodium bicarbonate solution and 15 mL of saturated brine, dried, and concentrated. The crude product was purified by preparative HPLC to yield the desired product (Z18, 40 mg, 33% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.39 (s, 1H), 7.75 (s, 1H), 7.57-7.52 (m, 2H), 7.47 (t, J =8.0Hz, 2H), 7.25 (t, J = 7.6Hz, 1H), 7.21-7.15 (m, 3H), 7.01 (dd, J = 8.4, 2.4Hz, 1H), 6.06 (s, 1H), 4.11 (d, J = 10.6Hz, 1H), 4.04-3.89 (m, 3H), 3.76 (d, J = 8.8Hz, 1H), 3.56(d, J=8.8Hz, 1H), 2.18-2.08(m, 1H), 1.99-1.89(m, 1H).ES-API: [M+H] + =462.0.

[0572] Example 20: Synthesis of Z19

[0573]

[0574] Step 1: 4-Chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.60 g, 1.7804 mmol) and 1-(tert-butyl) 3-methyl 3-aminopiperidine-1,3-dicarboxylate (450 mg, 1.540 mmol) were dissolved in N,N-dimethylformamide (20 mL), and N,N-diisopropylethylamine (7.64 g, 59.15 mmol) was added. The reaction was stirred at 95 ° C for 12 hours. 120 mL of ethyl acetate was added to the reaction mixture, which was washed twice with 80 mL of water and three times with 60 mL of saturated brine. The mixture was dried and concentrated, and the crude product was purified on a flash silica gel column (ethyl acetate / petroleum ether: 0-50%) to afford 1-(tert-butyl)-3-methyl-3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1,3-dicarboxylic acid (367 mg, 36% yield) as a light yellow solid. ES-API: [M+H] + =560.2.

[0575] Step 2: 1-(tert-Butyl)3-methyl 3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1,3-dicarboxylic acid (320 mg, 0.6563 mmol) was dissolved in acetic acid (20 mL), iron powder (0.672 g, 12.0 mmol) was added, and the reaction was stirred at 80°C for 1 hour. The solvent was dried under reduced pressure and then added with 200 mL of ethyl acetate. The mixture was washed with 80 mL of water twice, 60 mL of saturated sodium carbonate twice, 80 mL of saturated sodium bicarbonate twice, and 80 mL of saturated brine, dried, concentrated, and the crude product was slurried with ethyl acetate to obtain tert-butyl 3′-oxo-7′-(phenylsulfonyl)-1′,3′,4′,7′-tetrahydrospiro[piperidine-3,2′-pyrrolo[3′,2′:5,6]pyridine[3,4-b]pyrazine]-1-carboxylate (230 mg, 70% yield) as a light yellow solid. ES-API: [M+H] + =498.2.

[0576] Step 3: Tert-butyl 3′-oxo-7′-(phenylsulfonyl)-1′,3′,4′,7′-tetrahydrospiro[piperidine-3,2′-pyrrolo[3′,2′:5,6]pyridino[3,4-b]pyrazine]-1-carboxylate (230 mg, 0.4626 mmol) was dissolved in 12 mL of methanol, 3 mL of tetrahydrofuran, and 2 mL of water. Sodium hydroxide (129 mg, 3.2381 mmol) was added and the reaction was stirred at 65°C for 7 hours. 20 mL of water and 5 mL of saturated ammonium chloride solution were added to the reaction solution, and the mixture was extracted with 160 mL of ethyl acetate. The organic phase was washed sequentially with 40 mL of saturated sodium bicarbonate solution and 60 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield tert-butyl 3′-oxo-1′,3′,4′,7′-tetrahydrospiro[piperidine-3,2′-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazine]-1-carboxylate (382 mg, crude) as an off-white solid. ES-API: [M+H] + =358.3.

[0577] Step 4: Dissolve tert-butyl 3′-oxo-1′,3′,4′,7′-tetrahydrospiro[piperidine-3,2′-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazine]-1-carboxylate (382 mg, crude) and 2-chloro-4-phenoxybenzaldehyde (215 mg, 0.9252 mmol) in methanol (12.0 mL). Cool the reaction mixture to 0°C and add potassium hydroxide (181 mg, 3.238 mmol). Stir the reaction mixture at room temperature for 6 hours. Pour the reaction mixture into 30 mL of saturated aqueous ammonium chloride solution, adjust the pH to 8, and extract with 120 mL of ethyl acetate. The organic phase was washed with 63 mL of saturated brine, dried, and concentrated to give the crude target product, tert-butyl 9′-(((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-3′-oxo-1′,3′,4′,7′-tetrahydrospiro[piperidine-3,2′-pyrrolo[3′,2′:5,6]pyridine[3,4-b]pyrazine]-1-carboxylate (500 mg, crude) as a pale yellow solid. ES-API: [M+H] + =590.2.

[0578] Step 5: tert-Butyl 9′-(((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-3′-oxo-1′, 3′, 4′, 7′-tetrahydrospiro[piperidine-3, 2′-pyrrolo[3′, 2′: 5, 6]pyridine[3, 4-b]pyrazine]-1-carboxylate (500 mg, crude) was dissolved in 20 mL of dichloromethane, 2,3-dichloro-5,6-dicyano-1, 4-benzoquinone (210 mg, 0.9252 mmol) was added, and the reaction was stirred at room temperature for 2 hours. 60 mL of saturated sodium bicarbonate solution was added to the reaction solution. , extracted with 80 mL of ethyl acetate. The organic phase was washed with 60 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash silica gel column chromatography (methanol / dichloromethane: 0-30%) to give tert-butyl 9′-(2-chloro-4-phenoxybenzoyl)-3′-oxo-1′,3′,4′,7′-tetrahydrospiro[piperidine-3,2′-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazine]-1-carboxylate (260 mg, total yield over three steps 95%) as a light yellow solid. ES-API: [M+H] + =588.2.

[0579] Step 6: tert-Butyl 9′-(2-chloro-4-phenoxybenzoyl)-3′-oxo-1′,3′,4′,7′-tetrahydrospiro[piperidine-3,2′-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazine]-1-carboxylate (260 mg, 0.4429 mmol) was dissolved in dichloromethane (12 mL), and trifluoroacetic acid (3.0 mL) was added. After reacting at room temperature for 3 hours, the solvent was evaporated under reduced pressure to give crude 9′-(2-chloro-4-phenoxybenzoyl)-4′,7′-dihydrospiro[piperidine-3,2′-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazine]-3′(1′H)-one (300 mg, crude). ES-API: [M+H] + =488.1. The crude product was used directly in the next reaction.

[0580] Step 7: Under ice-water bath conditions, tert-butyl 9′-(2-chloro-4-phenoxybenzoyl)-3′-oxo-1′,3′,4′,7′-tetrahydrospiro[piperidine-3,2′-pyrrolo[3′,2′:5,6]pyrido[3,4-b]pyrazine]-1-carboxylate (300 mg, crude) was dissolved in acetonitrile (20 mL), sodium cyanoborohydride (139 mg, 2.21 mmol) was added, and then formaldehyde solution (180 mg, 2.21 mmol, 37% aq.) was added dropwise. The system was slowly warmed to room temperature and stirred for 2 hours. After the reaction was complete, saturated sodium bicarbonate (30 mL) and ethyl acetate (60 mL) were added to the system. The ethyl acetate phase was dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was purified by preparative HPLC to give 9′-(2-chloro-4-phenoxybenzoyl)-1-methyl-4′,7′-dihydrospiro[piperidin-3,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (Z19, 13 mg, 6% total yield over 2 steps). ES-API: [M+H] + =502.2.

[0581] Example 21: Synthesis of Z22

[0582]

[0583] Step 1: 4-Chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.48 mmol) and 4-aminotetrahydro-2H-pyran-4-carboxylic acid methyl ester (283 mg, 1.78 mmol) were dissolved in N,N-dimethylacetamide (5 mL), and N,N-diisopropylethylamine (573 g, 4.44 mmol) was added. The reaction was stirred at 120 ° C. for 1.5 hours under microwave reaction. 100 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed twice with 60 mL of water and three times with 30 mL of saturated brine. The mixture was then dried and concentrated. The crude product was purified on a flash silica gel column (ethyl acetate / petroleum ether: 0-50%) to obtain methyl 4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)tetrahydro-2H-pyran-4-carboxylate (374 mg, 55% yield) as a yellow solid. ES-API: [M+H] + =461.1.

[0584] Step 2: Methyl 4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)tetrahydro-2H-pyran-4-carboxylate (374 mg, 0.813 mmol) was dissolved in acetic acid (10 mL), iron powder (455 mg, 8.13 mmol) was added, and the reaction was stirred at 80°C for 3 hours. The reaction mixture was added with 100 mL of ethyl acetate and washed with 60 mL of water twice, 40 mL of saturated sodium carbonate twice, 40 mL of saturated sodium bicarbonate twice, and 40 mL of saturated brine, dried and concentrated. The crude product was slurried with ethyl acetate to obtain 7′-(phenylsulfonyl)-2,3,4′,5,6,7′-hexahydrospiro[pyran-4,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (200 mg, yield 61%) as a yellow solid. ES-API: [M+H] + =399.1

[0585] Step 3: 7′-(phenylsulfonyl)-2,3,4′,5,6,7′-hexahydrospiro[pyran-4,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (200 mg, 0.50 mmol) was dissolved in 10 mL of N,N-dimethylformamide. Anhydrous potassium carbonate (414 mg, 3.0 mmol) and iodomethane (352 mg, 2.5 mmol) were added. The reaction mixture was stirred at 40°C for 3 hours in a sealed tube. 100 mL of ethyl acetate was added to the reaction mixture for extraction. The organic phase was washed sequentially with water and saturated brine, dried, and concentrated to yield 4′-methyl-7′-(phenylsulfonyl)-2,3,4′,5,6,7′-hexahydrospiro[pyran-4,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (180 mg, 87% yield) as an off-white solid. ES-API: [M+H] + =413.1.

[0586] Step 4: 4′-Methyl-7′-(phenylsulfonyl)-2,3,4′,5,6,7′-hexahydrospiro[pyran-4,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (180 mg, 0.43 mmol) was dissolved in 10 mL of methanol, 5 mL of tetrahydrofuran, and 2 mL of water. Sodium hydroxide (86 mg, 2.15 mmol) was added and the reaction was stirred at 65°C for 15 hours. 15 mL of water and 4 mL of saturated ammonium chloride solution were added to the reaction solution, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was washed sequentially with 20 mL of saturated sodium bicarbonate solution and 20 mL of saturated brine, dried, and concentrated to yield 4′-methyl-2,3,4′,5,6,7′-hexahydrospiro[pyran-4,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (92 mg, 42% yield) as an off-white solid. ES-API: [M+H] + =273.1.

[0587] Step 6: Dissolve 4′-methyl-2,3,4′,5,6,7′-hexahydrospiro[pyran-4,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazin]-3′(1′H)-one (92 mg, 0.34 mmol) and 2-chloro-4-phenoxybenzaldehyde (157 mg, 0.68 mmol) in methanol (5 mL). Cool the reaction mixture to 0°C and add potassium hydroxide (95 mg, 1.70 mmol). Stir the reaction mixture at room temperature for 3 hours. Pour the reaction mixture into 60 mL of water, adjust the pH to 8 with 1.0 M dilute hydrochloric acid, and extract with 80 mL of ethyl acetate. The organic phase was washed with 25 mL of saturated brine, dried, and concentrated. The crude product was purified using a thin layer preparation plate (dichloromethane / methanol = 10:1) to afford 9′-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-4′-methyl-2,3,4′,5,6,7′-hexahydrospiro[pyran-4,2′-pyrrolo[3′,2′:5,6]pyrrolo[3,4-b]pyrazin]-3′(1′H)-one (110 mg, 65% yield) as a pale yellow solid. ES-API: [M+H] + =505.1.

[0588] Step 7: 9′-((2-chloro-4-phenoxyphenyl)(hydroxy)methyl)-4′-methyl-2,3,4′,5,6,7′-hexahydrospiro[pyran-4,2′-pyrrolo[3′,2′:5,6]pyrrolo[3,4-b]pyrazine]-3′(1′H)-one (110 mg, 0.218 mmol) was dissolved in 5 mL of 1,4-dioxane and 1 ml of water, and DDQ (99 mg, 0.436 mmol) was added. The reaction was stirred at room temperature for 30 minutes. 5 mL of saturated sodium thiosulfate solution and 20 mL of saturated sodium bicarbonate solution were added to the reaction solution, and the mixture was extracted with 60 mL of ethyl acetate. The crude product was concentrated and purified by preparative HPLC to give 9′-(2-chloro-4-phenoxybenzoyl)-4′-methyl-2,3,4′,5,6,7′-hexahydrospiro[pyran-4,2′-pyrrolo[3′,2′:5,6]pyridin[3,4-b]pyrazine]-3′(1′H)-one (Z22, 28 mg, 25% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ12.78 (s, 1H), 9.06 (s, 1H), 8.05 (s, 1H), 7.76 (s, 1H), 7.60 (d, J=8.5Hz, 1H), 7.53-7.44...

Claims

1. A compound of formula (C) or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that: In the formula, R1 and R2 are each independently selected from: H, C 1-6 Alkoxy and C 1-6 Alkylthio; or R1 and R2 together with the carbon atom to which they are attached constitute: C=O or C=S; the C 1-6 The alkoxy group and the C 1-6 Each alkylthio group is independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S1; R3 and R4 are each independently selected from: 1-6 Alkyl and C 3-6 Monocyclic cycloalkyl; or R3 and R4 together with the carbon atom to which they are attached constitute: C 3-6 monocyclic cycloalkyl or 3- to 6-membered monocyclic heterocyclic radical having 1 or 2 heteroatoms selected from N and O as ring atoms; 1-6 Alkyl, the C 3-6 The monocyclic cycloalkyl and the 3- to 6-membered monocyclic heterocyclic group are each independently unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S1; n is 0; E is NR5, O or N; R5 is H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C 1-4 Alkylene-hydroxyl, -C 1-4 Alkylene-C 1-6 Alkoxy or -C 1-4 Alkylene-NR a R b ; When E is NR5 or O, the "" connected to E represents a single bond; When E is N, the "" connected to E represents a double bond and R2 is none; A is CR6 or N; wherein R6 is H; B is CR7; wherein R7 is H; G1 is C 6-14 aryl or 5- or 6-membered monocyclic heteroaryl; the 5- or 6-membered monocyclic heteroaryl has 1 or 2 heteroatoms selected from N, O and S as ring atoms, and the C 6-14 The aryl group and the 5- or 6-membered monocyclic heteroaryl group are unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S2; G2 is C 6-14 aryl or 5- or 6-membered monocyclic heteroaryl; the 5- or 6-membered monocyclic heteroaryl has 1 or 2 heteroatoms selected from N, O and S as ring atoms, and the C 6-14 The aryl group and the 5- or 6-membered monocyclic heteroaryl group are unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S2; L is CR 8 R 9 or O; where R 8 and R 9 Each independently is H; i is 0 or 1; The group of S1 is selected from: deuterium, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -C 1-4 Alkylene-hydroxy, -C(O)C 1-6 Alkyl, -C(O)C 3-6 Monocyclic cycloalkyl, 3- to 6-membered monocyclic heterocyclic group, -OC 3-6 Monocyclic cycloalkyl, -NR a R b AND-OR c , wherein the 3- to 6-membered monocyclic heterocyclyl has 1 or 2 heteroatoms selected from N and O as ring atoms; The group of S2 is selected from: halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 3-6 Monocyclic cycloalkyl, halogenated C 3-6 Monocyclic cycloalkyl, -OC 3-6 Monocyclic cycloalkyl, -NR a R b AND-OR c ; R a and R b Each independently is C 1-6 alkyl; R c For -C 1-4 Alkylene-C 1-6 Alkoxy or C substituted by 1 or 2 halogens 3-6 monocyclic cycloalkyl; The carbon atom marked with "*" is a chiral carbon atom or an achiral carbon atom.

2. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that: R1 and R2, the C 1-6 The alkoxy groups are each independently C 1-3 Alkoxy; and / or, among R1 and R2, the C 1-6 The alkylthio groups are each independently C 1-3 Alkylthio; and / or, among R1 and R2, the C 1-6 The alkoxy group and the C 1-6 Each alkylthio group is independently unsubstituted; and / or, among R3 and R4, the C 1-6 The alkyl groups are each independently C 1-3 alkyl; and / or, among R3 and R4, the C 3-6 The monocyclic cycloalkyl groups are each independently cyclopropyl; and / or, when R3 and R4 together with the carbon atom to which they are attached form C 3-6 When the monocyclic cycloalkyl group is 3-6 Monocyclic cycloalkyl is cyclopropyl, cyclopentyl, cyclohexyl; and / or, when R3 and R4 together with the carbon atom to which they are attached form a 3- to 6-membered monocyclic heterocyclic group, the 3- to 6-membered monocyclic heterocyclic group is oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuran, tetrahydropyran or piperidine; and / or, among R3 and R4, the C 1-6 Alkyl, the C 3-6 The monocyclic cycloalkyl group and the 3- to 6-membered monocyclic heterocyclic group are each independently unsubstituted or substituted by 1 or 2 groups selected from Group S1; and / or, in R5, the C 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl; and / or, in R5, the deuterated C 1-6 Alkyl is deuterated C 1-3 alkyl; and / or, in R5, the -C 1-4 Alkylene-hydroxy is -C 1-2 Alkylene-hydroxyl; and / or, in R5, the -C 1-4 Alkylene-C 1-6 Alkoxy is -C 1-2 Alkylene-C 1-3 Alkoxy; and / or, R5, -C 1-4 Alkylene-NR a R b For -C 1-2 Alkylene-NR a R b ; and / or, A is CH; and / or, B is CH; and / or, G1, the C 6-14 Aryl is phenyl; and / or, in G1, the 5- or 6-membered monocyclic heteroaryl group is pyridyl, pyrimidinyl, furanyl, pyrrolyl, thiazolyl, pyrazolyl or thienyl; and / or, G1, the C 6-14 The aryl group and the 5- or 6-membered monocyclic heteroaryl group are unsubstituted or substituted by 1, 2 or 3 groups independently selected from Group S2; And / or, in G1, the group of S2 is selected from: halogen, cyano, -C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 3-6 Monocyclic cycloalkyl, halogenated C 3-6 Monocyclic cycloalkyl, -OC 3-6 Monocyclic cycloalkyl, -NR a R b AND-OR c ; and / or, G2, the C 6-14 Aryl is phenyl; and / or, in G2, the 5- or 6-membered monocyclic heteroaryl group is pyridyl, pyrimidinyl, furanyl, pyrrolyl, thiazolyl or pyrazolyl; and / or, G2, the C 6-14 The aryl group and the 5- or 6-membered monocyclic heteroaryl group are unsubstituted or substituted by 1, 2 or 3 groups independently selected from Group S2; And / or, in G2, the group of S2 is selected from: halogen, cyano, -C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy and C 3-6 monocyclic cycloalkyl; and / or, L, the CR 8 R 9 is CH2; and / or, in the group of group S1, the halogen is independently fluorine or chlorine; And / or, in the group of the S1 group, the C 1-6 The alkyl groups are each independently C 1-3 alkyl; And / or, in the group of the S1 group, the C 1-6 The alkoxy groups are each independently C 1-3 Alkoxy; And / or, in the group of the S1 group, the halogenated C 1-6 The alkoxy groups are each independently halogenated C 1-3 Alkoxy; and / or, in the group of group S1, the deuterated C 1-6 The alkoxy groups are each independently deuterated C 1-3 Alkoxy; And / or, in the group of the S1 group, the C 1-4 The alkylene-hydroxyl groups are each independently C 1-2 Alkylene-hydroxyl; And / or, in the group of the S1 group, the -C(O)C 1-6 The alkyl groups are each independently -C(O)C 1-3 alkyl; And / or, in the group of the S1 group, the -C(O)C 3-6 Each monocyclic cycloalkyl group is independently -C(O)-cyclopropyl; and / or, in the group of group S1, the 3- to 6-membered monocyclic heterocyclic groups are each independently morpholinyl; And / or, in the group of the S1 group, the -NR a R b Each independently is -N(CH3)2; And / or, in the group of the S1 group, the -OR c Each is independently -OCH2CH2OCH3 or -CH2CH2OCH2CH3; and / or, in the group of group S2, the halogen is independently fluorine, chlorine, bromine or iodine; And / or, in the group of the S2 group, the C 1-6 The alkyl groups are each independently C 1-3 alkyl; And / or, in the group of the S2 group, the halogenated C 1-6 The alkyl groups are each independently halogenated C 1-3 alkyl; And / or, in the group of S2, the deuterated C 1-6 The alkyl groups are each independently deuterated C 1-3 alkyl; And / or, in the group of the S2 group, the C 1-6 The alkoxy groups are each independently C 1-3 Alkoxy; And / or, in the group of the S2 group, the halogenated C 1-6 The alkoxy groups are each independently halogenated C 1-3 Alkoxy; And / or, in the group of S2, the deuterated C 1-6 The alkoxy groups are each independently deuterated C 1-3 Alkoxy; And / or, in the group of the S2 group, the C 3-6 The monocyclic cycloalkyl groups are each independently cyclopropyl; And / or, in the group of the S2 group, the halogenated C 3-6 The monocyclic cycloalkyl groups are each independently halocyclopropyl; And / or, in the group of the S2 group, the -OC 3-6 The monocyclic cycloalkyl groups are each independently -O-cyclopropyl or -O-cyclopentyl; And / or, in the group of the S2 group, the -NR a R b Each independently is -N(CH3)2; And / or, in the group of the S2 group, the -OR c Each is independently -OCH2CH2OCH3 or -OCH2CH2OCH2CH3; and / or, R a and R b Each independently is C 1-3 alkyl; and / or, R c In the -C 1-4 Alkylene-C 1-6 The alkoxy groups are each independently -C 1-2 Alkylene-C 1-3 Alkoxy; and / or, R c wherein the C 3-6 The halogen in the monocyclic cycloalkyl is fluorine, chlorine or bromine; and / or, R c wherein the C 3-6 C in monocyclic cycloalkyl 3-6 The monocyclic cycloalkyl group is cyclopropyl; And / or, when the carbon atom marked at "*" is a chiral carbon atom, the carbon atom is in R configuration, S configuration or a mixture thereof.

3. The compound according to claim 2 or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that: R1 and R2, the C 1-6 The alkoxy groups are each independently methoxy; and / or, among R1 and R2, the C 1-6 Each alkylthio group is independently methylthio or ethylthio; and / or, among R3 and R4, the C 1-6 The alkyl groups are each independently methyl or ethyl; and / or, in R5, the C 1-6 Alkyl is methyl or ethyl; and / or, in R5, the deuterated C 1-6 The alkyl group is a deuterated methyl group; and / or, in R5, the -C 1-4 Alkylene-hydroxy is -CH2CH2OH; and / or, in R5, the -C 1-4 Alkylene-C 1-6 Alkoxy is -CH2CH2OCH3; and / or, R5, -C 1-4 Alkylene-NR a R b is -CH2CH2N(CH3)2; and / or, in G1, the 5- or 6-membered monocyclic heteroaryl group is pyridyl, furyl or thienyl; and / or, in G1, the group of group S2 is selected from: fluorine, chlorine, bromine, iodine, cyano, methyl, isopropyl, trifluoromethyl, methoxy, trifluoromethoxy, cyclopropyl, -O-cyclopropyl, -O-cyclopentyl, -N(CH3)2 and -OCH2CH2OCH3; and / or, in G2, the 5- or 6-membered monocyclic heteroaryl group is pyridyl or pyrazolyl; and / or, in G2, the group of S2 is selected from the group consisting of fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy, deuterated methoxy and cyclopropyl; And / or, in the group of the S1 group, the C 1-6 The alkyl groups are each independently methyl; And / or, in the group of the S1 group, the C 1-6 The alkoxy groups are each independently methoxy or ethoxy; And / or, in the group of the S1 group, the halogenated C 1-6 The alkoxy groups are each independently difluoromethoxy or trifluoromethoxy; and / or, in the group of group S1, the deuterated C 1-6 The alkoxy groups are each independently deuterated methoxy; And / or, in the group of the S1 group, the C 1-4 Each alkylene-hydroxyl group is independently -CH2OH; And / or, in the group of the S1 group, the -C(O)C 1-6 The alkyl groups are each independently -C(O)CH3; And / or, in the group of the S2 group, the C 1-6 The alkyl groups are each independently methyl or isopropyl; And / or, in the group of the S2 group, the halogenated C 1-6 The alkyl groups are each independently trifluoromethyl; And / or, in the group of S2, the deuterated C 1-6 The alkyl groups are each independently deuterated methyl; And / or, in the group of the S2 group, the C 1-6 The alkoxy groups are each independently methoxy; And / or, in the group of the S2 group, the halogenated C 1-6 The alkoxy groups are each independently difluoromethoxy or trifluoromethoxy; And / or, in the group of S2, the deuterated C 1-6 The alkoxy groups are each independently deuterated methoxy; and / or, R a and R b are each independently methyl; and / or, R c In the -C 1-4 Alkylene-C 1-6 Each alkoxy group is independently -CH2CH2OCH3 or -CH2CH2OCH2CH3.

4. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 3, characterized in that: R1 and R2 are each independently selected from: H, methoxy, methylthio and ethylthio; or R1 and R2 together with the carbon atom to which they are attached constitute: C=O or C=S; And / or, R3 and R4 are each independently selected from: -CH3, -CH2CH3, cyclopropyl, trifluoromethyl (CF3), deuterated methyl (CD3), -CH2OH, -CH2OCH3, -CH2OCF3, -CH2OCHF2, -CH2OCD3, -CH2OCH2CH3, -CH2OCH2CH2OCH3, -CH2CH2OCH2CH3, -CH2O-cyclopropyl, -CH2N(CH3)2, -CH(OH)CH3 and -CH2CH3OCH3; and / or, R5 is H, methyl, ethyl, deuterated methyl, -CH2CH2OH, -CH2CH2OCH3 or -CH2CH2N(CH3)2; and / or G1 is phenyl, 2-chlorophenyl, 2-fluorophenyl, 2-trifluoromethylphenyl, 2-chloro-6-fluorophenyl, 2-chloro-3,4-difluorophenyl, 2-chloro-3-fluoro-4-methoxyphenyl, 2-chloro-4-cyclopentyloxyphenyl, 2-chloro-4-(2-methoxyethyl)phenyl, 2-chloro-4-dimethylaminophenyl, 2-chloro-4-cyclopropyloxyphenyl, 2-chloro-4-methoxyphenyl, 2-chloro-4-isopropyl phenyl, 2-chloro-4-cyclopropylphenyl, 2-chloro-4-methylphenyl, 2-chlorofuranyl, furanyl, thienyl, 2-bromothienyl, 2-chlorothienyl, pyridyl, 3-chloropyridyl, 2-methylphenyl, 2-chloro-4-cyanophenyl, 2-chloro-4-fluorophenyl, 2-iodophenyl, 2-chloro-5-fluorophenyl, 2-chloro-3-fluorophenyl, 2-chloro-trifluoromethoxyphenyl, 2-chloro-4-bromophenyl or 2,4-dichlorophenyl; and / or, G2 is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-trifluoromethylpyridyl, 3-methylpyridyl, 3-trifluoromethylpyridyl, 4-methylpyridyl, 4-cyclopropylpyridyl, 4,6-dimethylpyridyl, 4-chloro-6-methylpyridyl, 2-methyl-6-chloropyridyl, 3-cyanophenyl, 3-fluoro-4-methylpyridyl, pyridyl, 3-fluoropyridyl, 2-methoxyphenyl, 2-chlorophenyl, 3-methoxyphenyl, 2-fluoro-6-methoxyphenyl, pyrazolyl, 3-methylpyrazolyl, 2-methoxy-3-fluorophenyl, 2-fluoro-3-deuterated methoxyphenyl, 2,4-dimethylpyridyl, 2-chloropyridyl, 2-methoxy-3-fluorophenyl or 2-deuterated methoxy-3-fluorophenyl; and / or, L is CH2 or O; and / or, the group of group S1 is selected from: deuterium, fluorine, cyano, hydroxyl, methyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, deuterated methoxy, -CH2OH, -C(O)CH3, -C(O)-cyclopropyl, morpholinyl, -O-cyclopropyl, -N(CH3)2, -OCH2CH2OCH3 and -CH2CH2OCH2CH3; And / or, the groups in group S2 are selected from: fluorine, chlorine, bromine, iodine, cyano, methyl, deuterated methyl, isopropyl, trifluoromethyl, methoxy, trifluoromethoxy, deuterated methoxy, cyclopropyl, -O-cyclopropyl, -O-cyclopentyl, -N(CH3)2 and -OCH2CH2OCH3.

5. The compound according to claim 4 or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that: R3 is selected from: -CH3, -CH2CH3, trifluoromethyl, deuterated methyl and cyclopropyl, R4 is selected from: -CH3, -CH2OH, -CH2OCH3, -CH2OCF3, -CH2OCHF2, -CH2OCF3, -CH2OCHF2, -CH2OCD3, -CH2OCH2CH3, -CH2OCH2CH2OCH3, -CH2CH2OCH2CH3, -CH2O-cyclopropyl, -CH2N(CH3)2, -CH(OH)CH3 and -CH2CH3OCH3; or R3 and R4 together with the carbon atom to which they are attached constitute:

6. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 3, characterized in that: i, G1, L, G2 have any of the following definitions: (1) i is 0, G1 is phenyl, pyridyl, furyl or thienyl; the phenyl, pyridyl, furyl and thienyl are unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S2; (2) i is 1, L is CR 8 R 9 or O, G1 is phenyl or pyridyl, G2 is phenyl, pyridyl or pyrazolyl; the phenyl, pyridyl and pyrazolyl are unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S2; (3) i is 1, L is CR 8 R 9 , G1 is phenyl, G2 is pyrazolyl; the phenyl and pyrazolyl are unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S2; (4) i is 1, L is O, G1 is phenyl or pyridyl, G2 is phenyl or pyridyl; the phenyl and pyridyl are unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from Group S2.

7. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 3, characterized in that: Structural unit Selected from:

8. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that: The compound has any of the following structures: In each formula, A, B, R1, R3, R4, R5, L, G1, G2, and "*" are as defined in any one of claims 1 to 7.

9. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that: The compound has any of the following structures: In each formula, R1, R3, R4, R5, G1, G2, and "*" are as defined in any one of claims 1 to 8.

10. The compound according to claim 8 or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that: R1 is C 1-6 Alkoxy or C 1-6 Alkylthio.

11. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that: The compound has any of the following structures:

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt or stereoisomer thereof; and a pharmaceutically acceptable carrier.

13. Use of the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt or stereoisomer thereof in the preparation of a medicament for preventing and / or treating a disease or condition; the disease or condition is associated with BTK and / or associated with abnormal B cell activation; the disease or condition is lymphoma.

14. The use according to claim 13, characterized in that The lymphoma is diffuse large B-cell lymphoma.

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