Spiro derivative serving as WRN inhibitor and use of spiro derivative

Abstract

Disclosed in the present invention are a spiro derivative serving as a WRN helicase inhibitor and a use of the spiro derivative. The spiro derivative has good WRN helicase inhibitory activity, can be used for inhibiting the growth of microsatellite-instable (MSI) tumor cells by inhibiting the occurrence of a high level of DNA double-strand breaks (DSBs) in MSI cells caused by WRN and is used for preventing and / or treating related cancers, especially colorectal cancer, gastric cancer, ovarian cancer, endometrial tumors, and the like, can compensate for the lack of specific MSI subtype cancer targeting drugs, and has extremely good prospects for application and values in the field of medicine.

Description

Spirocyclic derivatives as WRN inhibitors and their applications Technical Field

[0001] The present invention relates to the field of chemical medicine technology, and specifically to a spirocyclic derivative as a WRN helicase inhibitor and its application, in particular in the treatment of cancer (especially cancers with microsatellite instability (MSI), such as colorectal cancer, gastric cancer, ovarian cancer and endometrial tumors). Background Art

[0002] Microsatellite instability (MSI) is a common feature associated with various cancers, most commonly in colon, gastric, ovarian, and endometrial cancers. It is characterized by small expansions and contractions of short repetitive DNA elements (microsatellites) distributed throughout the genome. MSI results from mutations in one or more core components of the mismatch repair mechanism (MMR), and MMR defects may contribute to the development of MSI (Nat Rev Clin Oncol, 7 (2010), pp. 153-162).

[0003] Overall, MSI tumors have a better prognosis and are less likely to metastasize than microsatellite stable (MSS) tumors derived from the same tissue. However, there is some evidence that chemotherapy efficacy differs between MSS and MSI cancers, with MSI cancers responding less well to current chemotherapy regimens (J Clin Oncol, 28 (2010), pp. 3219-3226).

[0004] WRN is one of the five human RecQ-like helicases. WRN plays an important role in HR-mediated replication fork restart and prevention of replication fork collapse. In 2019, multiple research groups demonstrated that the survival of MSI cancer cells selectively depends on WRN helicase (Nature, 568 (2019), pp. 551-556; Nature, 568 (2019), pp. 511-516). Depletion of WRN leads to high levels of DNA double-strand breaks (DSBs) in MSI cells, leading to cell death. However, microsatellite stable (MSS) cells are insensitive to WRN depletion. These studies clearly identify WRN as a therapeutic target for MSI cancers.

[0005] By developing novel WRN inhibitors, it is possible to selectively inhibit the growth of MSI cancer cells while maintaining a good safety profile in normal adjacent tissues of MSS. Therefore, further development of WRN inhibitors is needed in the field of MSI cancer treatment to accelerate the development of precision medicine for cancer patients characterized by MSI. Summary of the Invention

[0006] In a first aspect of the present invention, a compound or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof is provided, wherein the compound has the following structure:

[0007] in,

[0008] represents a single bond or a double bond, and two Not a double bond at the same time;

[0009] Ring A is a 4-6 membered heterocyclic ring;

[0010] The J ring is a 6-18 membered spiro ring;

[0011] X1, X2, X3, X4 are independently selected from: C(R5), N; R5 is selected from: H, D, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -O(C3-C 10 Cycloalkyl), -S(C 0-10 Alkyl), -S(C3-C 10 Cycloalkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2(C3-C 10 Cycloalkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10Alkyl)(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -CO(C 0-10 alkyl);

[0012] A1, A2, A3 are independently selected from: single bond, C1-C 10 Alkylene, wherein the C1-C 10 0-6 methylene units in the alkylene group are independently substituted by the following groups: -Cy-, -O-, -S-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OS(O)2-, -OC(O)N(R a )-、-C(O)N(R a )-、-N(R a )C(O)-、-N(R a )C(O)O-、-N(R a )C(O)N(R b )-、-N(R a )-、-S(O)2-、-S(O)2N(R a )-、-N(R a )S(O)2-、-S(O)-、-S(O)N(R a )-、-N(R a )S(O)-、-Si-、 Among them, R a and R b Independently selected from: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl); each -Cy- is independently an optionally substituted divalent ring selected from the following: arylene, cycloalkylene, heterocyclyl; wherein the C1-C 10 The H in the alkylene group is optionally substituted with one or more R0;

[0013] R1 is one or more independent substituents on ring A, selected from: H, D, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -O(C3-C 10 Cycloalkyl), -S(C 0-10 Alkyl), -S(C3-C 10 Cycloalkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2(C3-C 10 Cycloalkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -CO(C 0-10 Alkyl), -Si(C 0-10 Alkyl)(C 0-10 Alkyl)(C 0-10 Alkyl); wherein, C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C 0-10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 4-10 membered heterocyclic group may be optionally substituted by one or more R0;

[0014] R2, R3, R4 are independently selected from: H, D, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -O(C3-C 10 Cycloalkyl), -S(C 0-10 Alkyl), -S(C3-C 10 Cycloalkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2(C3-C 10 Cycloalkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -CO(C 0-10 Alkyl), -Si(C 0-10 Alkyl)(C 0-10 Alkyl)(C 0-10 Alkyl); wherein, C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C 0-10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10H in the aryl group or the 4-10 membered heterocyclic group may be optionally substituted by one or more R0; or, R3 and A1 and the atoms to which they are connected together form a carbocyclic ring or a heterocyclic ring, and H in the carbocyclic ring or the heterocyclic ring may be optionally substituted by one or more R0;

[0015] R5 is one or more independent substituents on the J ring selected from: H, D, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -O(C3-C 10 Cycloalkyl), -S(C 0-10 Alkyl), -S(C3-C 10 Cycloalkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2(C3-C 10 Cycloalkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -CO(C 0-10 Alkyl), -Si(C 0-10 Alkyl)(C 0-10 Alkyl)(C 0-10 Alkyl); wherein, C0-C6 alkylene, C1-C 10Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C 0-10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 4-10 membered heterocyclic group may be optionally substituted by one or more R0;

[0016] R0 is selected from: D, =O, halogen, cyano, nitro, azido, -SF5, -OR', -C(O)R', -C(S)R', -C(O)OR', -C(S)SR', -OC(O)R', -OC(S)R', -OC(S)SR', -C(O)NR'R", -OC(O)NR'R", -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -OSO2NR'R", -NR'C(O)R", -NR'R", -SR', -SOR', -SO2R', -OSO2R', -SO3H, -SiR'R'R", C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl);

[0017] Each R' and R" is independently selected from: H, D, Cl-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group); wherein the C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -O(C3-C 10 Cycloalkyl), -S(C 0-10 Alkyl), -S(C3-C 10 Cycloalkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2(C3-C 10 Cycloalkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -CO(C 0-10 Alkyl), -Si(C 0-10 Alkyl)(C 0-10 Alkyl)(C 0-10 alkyl).

[0018] Specifically, each -CY- is independently selected from the following optionally substituted bivalent rings: phenylene, bicyclic arylene, tricyclic arylene, monocyclic cycloalkylene, bicyclic cycloalkylene, tricyclic cycloalkylene, monocyclic heteroarylene, bicyclic heteroarylene, tricyclic heteroarylene, monocyclic heterocycloalkylene, bicyclic heterocycloalkylene, tricyclic heterocycloalkylene.

[0019] In some embodiments of the present invention, each -CY- is independently an optionally substituted bivalent ring selected from the group consisting of monocyclic cycloalkylene, bicyclic cycloalkylene, monocyclic saturated heterocyclylene, and bicyclic saturated heterocyclylene.

[0020] Specifically, each -CY- is optionally substituted with halogen, cyano, nitro, azido, C1-C 10 Alkyl, -N(C0-C 10 Alkyl)(C0-C 10 alkyl), -O(C0-C 10 alkyl), -CON(C0-C 10 Alkyl)(C0-C 10 Alkyl), -N(C0-C 10 alkyl)CO(C0-C 10 Alkyl), -SO2N(C0-C 10 Alkyl)(C0-C 10 Alkyl), -N(C0-C 10 Alkyl)SO2(C0-C 10 alkyl), -OCH2F, -OCHF2, -OCF3, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 4-10 membered heterocyclic group.

[0021] In some embodiments of the present invention, ring A is a 4-6 membered nitrogen-containing heterocyclic ring, particularly a 5 membered nitrogen-containing heteroaromatic ring, for example, in particular

[0022] In some embodiments of the present invention, Ring in particular

[0023] In some embodiments of the present invention, Ring Wherein, X5 and X6 are independently selected from: C(H), N, for example, in particular

[0024] Specifically, A1 is C1-C 10 Alkylene, wherein 1-3 methylene units are independently substituted by: -O-, -S-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -N(R a )-、-C(O)N(R a )-、-N(R a )C(O)-、-S(O)-、-S(O)2-、 In some embodiments of the present invention, A1 is -(C0-C3 alkylene)-N(C 0-6 alkyl)-(C0-C3 alkylene)-, -(C0-C3 alkylene)-C(O)N(C 0-6alkyl)-(C0-C3 alkylene)-, -(C0-C3 alkylene)-N(C 0-6 -(C0-C3 alkylene)-, -(C0-C3 alkylene)-O-(C0-C3 alkylene)-, -(C0-C3 alkylene)-S-(C0-C3 alkylene)-.

[0025] In some embodiments of the present invention, A1 is C1-C6 alkylene, wherein H is optionally substituted by one or more groups selected from the group consisting of H, D, halogen, -(C0-C3 alkylene)-(C3-C6 cycloalkyl), -(C0-C3 alkylene)-(phenyl), and -(C0-C3 alkylene)-(4-6 membered saturated heterocyclyl).

[0026] In some embodiments of the present invention, A1 is Wherein, R6 and R7 are independently selected from: H, D, C1-C 10 Alkyl, C1-C 10 Haloalkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl).

[0027] Specifically, R6 and R7 are independently selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -OH, -NH2, -COOH; more specifically, R6 and R7 are independently selected from: H, D, C1-C3 alkyl.

[0028] In some embodiments of the present invention, R3 and R7, together with the atoms to which they are attached, form a 4-8 membered (e.g., 4, 5, 6, 7, 8 membered) carbocyclic or heterocyclic ring, wherein H in the carbocyclic or heterocyclic ring may be optionally substituted by one or more R0; specifically, the carbocyclic or heterocyclic ring is optionally substituted by one or more groups selected from the group consisting of H, D, halogen, cyano, hydroxyl, thiol, amino, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -(C0-C6 alkylene)-(phenyl), -O(C1-C6 alkyl), -S(C1-C6 alkyl), -N(H)(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -CON(C0-C6 alkyl)(C0-C6 alkyl), -N(C0-C6 alkyl)CO(C C0-C6 alkyl), -SO2N(C0-C6 alkyl)(C0-C6 alkyl), -N(C0-C6 alkyl)SO2(C0-C6 alkyl), wherein the H in the C0-C6 alkylene, C0-C6 alkyl, C1-C6 alkyl, C3-C6 cycloalkyl, and phenyl group may be optionally substituted by a group selected from the group consisting of D, halogen, cyano, hydroxyl, mercapto, amino, C1-C3 alkyl, and C1-C3 alkoxy; more specifically, the carbocyclic or heterocyclic ring is optionally substituted by one or more groups selected from the group consisting of H, D, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -OH, -NH2, and -COOH; wherein the C1-C6 alkyl is optionally substituted by one or more groups selected from the group consisting of H, D, halogen, cyano, -OH, -NH2, and -COOH.

[0029] In some embodiments of the present invention, R3 and R7, together with the atoms to which they are connected, form a 4-8 membered heterocyclic ring, wherein H in the heterocyclic ring may be optionally replaced by one or more R0; the heterocyclic ring may contain one or more heteroatoms selected from: N, O, and S.

[0030] In some embodiments of the present invention, R7 is H.

[0031] In some embodiments of the present invention, A1 is Among them, R6': H, D, C1-C 10 Alkyl, C1-C 10 Haloalkyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl).

[0032] Specifically, R6′: H, D, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl); more specifically, R6′ is H.

[0033] Specifically, A2 is C1-C 10Alkylene, wherein 1-3 methylene units are independently substituted by the following groups: -C(O)-, -C(S)-, -C(O)O-, -N(R a )-、-C(O)N(R a )-、-N(R a )C(O)-、-S(O)N(R a )-、-S(O)2N(R a )-; In some embodiments of the present invention, A2 is -(C0-C3 alkylene)-C(O)N(C 0-6 alkyl)-(C0-C3 alkylene)-, -(C0-C3 alkylene)-N(C 0-6 alkyl)C(O)-(C0-C3 alkylene)-, -(C0-C3 alkylene)-S(O)2N(C 0-6 alkyl)-(C0-C3 alkylene)-, -(C0-C3 alkylene)-S(O)N(C 0-6 alkyl)-(C0-C3 alkylene)-.

[0034] In some embodiments of the present invention, A2 is -C(O)N(R8)- or -S(O)2N(R8)-, and R8 is selected from: H, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C6 cycloalkyl).

[0035] Specifically, R8 is selected from: H, C1-C3 alkyl, -(C0-C3 alkylene)-(C3-C4 cycloalkyl); in some embodiments of the present invention, R8 is H.

[0036] In some embodiments of the present invention, the compound has the following structure:

[0037] In some embodiments of the present invention, the compound has the following structure:

[0038] in,

[0039] Ring Y is a 5-7 membered heterocyclic ring;

[0040] R9 is one or more independent substituents on the Y ring, which have the same meaning as R0 as described above.

[0041] Specifically, the Y ring is a 5-7 membered saturated heterocyclic ring, which, in addition to the nitrogen atom shown in the above formula, optionally further comprises one or more heteroatoms selected from: N, O, S, for example

[0042] Specifically, each R9 is independently selected from: H, D, halogen, cyano, hydroxyl, thiol, amino, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -(C0-C6 alkylene)-(phenyl), -O(C1-C6 alkyl), -S(C1-C6 alkyl), -N(H)(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -CON(C0-C6 alkyl)(C0-C6 alkyl), -N(C0-C6 alkyl)CO(C0-C6 alkyl), -SO2N(C0-C6 alkyl)(C0-C6 alkyl), -N(C0-C6 alkyl)SO2(C0-C6 alkyl), wherein the H in the C0-C6 alkylene, C0-C6 alkyl, C1-C6 alkyl, C3-C6 cycloalkyl, and phenyl group may be optionally substituted by a group selected from the group consisting of: D, halogen, cyano, hydroxyl, mercapto, amino, C1-C3 alkyl, and C1-C3 alkoxy; more specifically, each R9 is independently selected from the group consisting of: H, D, halogen, cyano, hydroxyl, mercapto, amino, and C1-C6 alkyl; wherein the C1-C6 alkyl group is optionally substituted by one or more groups selected from the group consisting of: D, halogen, cyano, hydroxyl, amino, and C1-C3 alkoxy.

[0043] In some embodiments of the present invention, the J ring is a 6-12 membered (e.g., 6, 7, 8, 9, 10, 11 membered) saturated or partially unsaturated spiro heterocycle; more specifically, at least one ring atom of the J ring is N; in some embodiments of the present invention, two ring atoms of the J ring are N.

[0044] Specifically, R5 is selected from the group consisting of: H, halogen, hydroxy, mercapto, amino, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -O(C 1-6 Alkyl), -S(C 1-6 alkyl), -N(H)(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 wherein the H in the C0-C6 alkylene, C1-C6 alkyl, C3-C6 cycloalkyl group may be optionally substituted by a group selected from the following: halogen, hydroxyl, C1-C3 alkoxy; more specifically, R5 is selected from the group consisting of: H, halogen (such as F, Cl), hydroxyl, mercapto, amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxy-substituted alkyl, -(C0-C3 alkylene)-(C3-C5 cycloalkyl), -O(C 1-3 Alkyl), -S(C 1-3 alkyl), -N(H)(C 1-3 Alkyl), -N(C 1-3 Alkyl)(C 1-3 alkyl).

[0045] In some embodiments of the present invention, R5 is selected from the group consisting of: H, F, Cl, -OH, -NH2, methyl, ethyl.

[0046] Specifically, The section has the following structure: in,

[0047] J1 ring is a 3-8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic carbocyclic ring or heterocyclic ring;

[0048] J2 ring is a 3-8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic carbocyclic ring or heterocyclic ring;

[0049] R 51 、R 52 are one or more independent substituents on the J1 and J2 rings, respectively, having the same definition as R5.

[0050] Specifically, the J1 ring is a 3-6 membered saturated or partially unsaturated carbocyclic or heterocyclic ring, for example, In some embodiments of the present invention, the J1 ring is a 3-6 membered partially unsaturated carbocyclic ring; In some embodiments of the present invention, the J1 ring is a 3-6 membered saturated heterocyclic ring, at least one of the ring atoms of which is N.

[0051] Specifically, the J2 ring is a 3-6 membered saturated or partially unsaturated carbocyclic or heterocyclic ring, for example, In some embodiments of the present invention, the J2 ring is a 3-6 membered saturated heterocyclic ring, at least one of which is N, for example

[0052] Specifically, The section has the following structure:

[0053] In some embodiments of the present invention, The section has the following structure:

[0054] Specifically, R 51 Selected from: H, halogen, hydroxyl, mercapto, amino, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -O(C 1-6 Alkyl), -S(C 1-6 alkyl), -N(H)(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6wherein the H in the C0-C6 alkylene, C1-C6 alkyl, C3-C6 cycloalkyl group may be optionally substituted by a group selected from the following: halogen, hydroxyl, C1-C3 alkoxy; more specifically, R 51 Selected from: H, halogen (such as F, Cl), hydroxyl, mercapto, amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxy substituted alkyl, -(C0-C3 alkylene)-(C3-C5 cycloalkyl), -O(C 1-3 Alkyl), -S(C 1-3 alkyl), -N(H)(C 1-3 Alkyl), -N(C 1-3 Alkyl)(C 1-3 alkyl); in some embodiments of the present invention, R 51 For H.

[0055] Specifically, R 52 Selected from: H, halogen, hydroxyl, mercapto, amino, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -O(C 1-6 Alkyl), -S(C 1-6 alkyl), -N(H)(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 wherein the H in the C0-C6 alkylene, C1-C6 alkyl, C3-C6 cycloalkyl group may be optionally substituted by a group selected from the following: halogen, hydroxyl, C1-C3 alkoxy; more specifically, R 52 Selected from: H, halogen (such as F, Cl), hydroxyl, mercapto, amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxy substituted alkyl, -(C0-C3 alkylene)-(C3-C5 cycloalkyl), -O(C 1-3 Alkyl), -S(C 1-3 alkyl), -N(H)(C 1-3 Alkyl), -N(C 1-3 Alkyl)(C 1-3 alkyl); in some embodiments of the present invention, R 52 Selected from: H, F, Cl, -OH, -NH2, methyl, ethyl.

[0056] In some embodiments of the present invention, The section has the following structure: in particular Among them, R 52a 、R 52b With R 52 Definition of .

[0057] In some embodiments of the present invention, The section has the following structure:

[0058] In other embodiments of the present invention, The section has the following structure:

[0059] In some embodiments of the present invention, R1 has the following structure: in:

[0060] A4 is selected from the group consisting of: a single bond, C1-C6 alkylene, wherein 0-3 methylene units in the C1-C6 alkylene are independently substituted by: -O-, -S-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -C(O)N(H)-, -N(H)C(O)-, -N(H)-, -S(O)2-;

[0061] Ring B is a 4-10 membered carbocyclic or heterocyclic ring;

[0062] R 11 is one or more independent substituents on the B ring selected from: H, D, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -S(C 0-10 Alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl); wherein, C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C 0-10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 4-10 membered heterocyclic group may be optionally substituted by one or more R0.

[0063] Specifically, Ring B is a 5-8 membered (saturated, partially saturated or aromatic) carbocyclic or heterocyclic ring, for example:

[0064] Specifically, The section has the following structure:

[0065] Among them, R 12 Selected from: H, D, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl); wherein, C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C 0-10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 4-10 membered heterocyclic group may be optionally substituted by one or more R0.

[0066] Specifically, R 12 Selected from: H, C1-C6 alkyl, -C(O)OH, -C(O)O(C 1-6alkyl), -C(O)H, -C(O)(C 1-6 alkyl), wherein the H in the C1-C6 alkyl may be optionally substituted by a group selected from the group consisting of halogen, -O(C 0-6 Alkyl), -COO(C 0-6 alkyl), -OCO(C 0-6 alkyl), -CON(C 0-6 Alkyl)(C 0-6 alkyl), -CO(C 0-6 alkyl); more specifically, R 12 Selected from: H, C1-C4 alkyl, C1-C4 haloalkyl, -(C1-C4 alkylene)-C(O)OH, -(C1-C4 alkylene)-C(O)-(C 0-4 alkyl), -(C1-C4 alkylene)-C(O)O-(C 0-4 alkyl), -CO(C 1-4 In some embodiments of the present invention, R 12 For H,

[0067] Specifically, each R 11 Independently selected from: H, halogen, hydroxy, thiol, amino, C1-C6 alkyl, -N(H)(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -O(C 1-6 Alkyl), -S(C 1-6 alkyl), -C(O)OH, -C(O)O(C 1-6 alkyl), wherein the H in the C1-C6 alkyl may be optionally substituted by a group selected from the group consisting of halogen, -O(C 0-6 Alkyl), -COO(C 0-6 alkyl), -OCO(C 0-6 alkyl), -CON(C 0-6 Alkyl)(C 0-6 alkyl), -CO(C 0-6 alkyl); specifically, each R 11 independently selected from: H, halogen (such as F), C1-C4 alkyl, C1-C4 haloalkyl, -OH, C1-C4 alkoxy, C1-C4 haloalkoxy, -NH2, -N(H)(C 1-4 alkyl), -N(H)(C 1-4 Haloalkyl), -N(C 1-4 Alkyl)(C 1-4 haloalkyl), -(C1-C4 alkylene)-C(O)OH, -(C1-C4 alkylene)-C(O)-(C 0-4alkyl), -(C1-C4 alkylene)-C(O)O-(C 0-4 alkyl), -CO(C 1-4 In some embodiments of the present invention, R 11 For H, F, methyl, ethyl,

[0068] In some embodiments of the present invention, The section has the following structure:

[0069] in particular

[0070] In some embodiments of the present invention, A4 is a single bond, that is, R1 is

[0071] In some embodiments of the present invention, R2 has the following structure: in:

[0072] The E ring is a 4-12 membered carbocyclic or heterocyclic ring;

[0073] R 21 is one or more independent substituents on the E ring selected from: H, D, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), halogen, cyano, nitro, azido, -SF5, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -S(C 0-10 Alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl); wherein, C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C 0-10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group or the 4-10 membered heterocyclic group may be optionally substituted by one or more R0; or, two R 21 Together with the ring atoms to which they are attached, they form a carbocyclic or heterocyclic ring, wherein H in the carbocyclic or heterocyclic ring may be optionally substituted by one or more R0.

[0074] Specifically, the E ring is a 5-10 membered aromatic ring or heteroaromatic ring, for example:

[0075] in particular

[0076] In some embodiments of the present invention, The section has the following structure:

[0077] in particular

[0078] Specifically, R 21 Selected from: H, halogen, cyano, -SF5, hydroxyl, mercapto, -C(O)H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -O(C 1-6 Alkyl), -S(C 1-6 alkyl), -CO(C 1-6 alkyl), wherein H in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 alkylene, C3-C6 cycloalkyl may be optionally substituted by a group selected from the following: halogen, hydroxyl, C1-C3 alkoxy; or, two R 21 Together with the ring atoms to which they are attached, they form a carbocyclic or heterocyclic ring, wherein H in the carbocyclic or heterocyclic ring may be optionally substituted by a group selected from the group consisting of halogen, hydroxy, and C1-C3 alkoxy.

[0079] In some embodiments of the present invention, R2 has the following structure: Wherein, X7 is selected from: C(R 23 ), N, R 22 to R26 With R 21 Definition, or R 23 With R 24 or R 22 Together with the atoms to which it is attached, it forms a 4-6 membered saturated carbon ring, wherein the H in the carbon ring may be optionally substituted by a group selected from the following: halogen, hydroxyl, C1-C3 alkoxy.

[0080] Specifically, R 22 Selected from: H, halogen, cyano, hydroxy, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -O(C 1-6 alkyl), wherein the H in the C1-C6 alkyl and C3-C6 cycloalkyl groups may be optionally substituted by a group selected from the group consisting of halogen, hydroxy, and C1-C3 alkoxy; more specifically, R 22 Selected from: H, halogen (e.g. F, Cl, Br), cyano, hydroxy, C1-C4 alkyl (e.g. methyl, ethyl), C1-C4 haloalkyl (e.g. -CF3, -CHF2, -CH2F), C1-C4 alkoxy (e.g. methoxy), C1-C4 haloalkoxy (e.g. -OCF3, -OCHF2, -OCH2F).

[0081] Specifically, R 23 is selected from: H, halogen (such as F, Cl, Br); more specifically, R 23 H or F.

[0082] Specifically, R 24 Selected from: H, halogen, cyano, -SF5, hydroxyl, -C(O)H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -CO(C 1-6 alkyl), -O(C 1-6 alkyl), wherein the H in the C1-C6 alkyl and C3-C6 cycloalkyl groups may be optionally substituted by a group selected from the group consisting of halogen, hydroxy, and C1-C3 alkoxy; more specifically, R 24 Selected from: H, halogen (e.g. F, Cl, Br), cyano, -SF5, C1-C4 alkyl (e.g. methyl, ethyl), C1-C4 haloalkyl (e.g. -CF3, -CHF2, -CH2F), C1-C4 haloalkyl (e.g. -CF3, -CHF2, -CH2F), C1-C4 alkoxy (e.g. methoxy), C1-C4 haloalkoxy (e.g. -OCF3, -OCHF2, -OCH2F), -C(O)H.

[0083] Specifically, R 25 is selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl; more specifically, R 25Selected from: H, halogen (such as F, Cl, Br), C1-C4 alkyl (such as methyl, ethyl), C1-C4 haloalkyl (such as -CF3, -CHF2, -CH2F).

[0084] Specifically, R 26 Selected from: H, halogen, cyano, hydroxyl, C1-C6 alkyl, -O(C 1-6 alkyl); more specifically, R 26 Selected from: H, halogen (such as F, Cl, Br), cyano, hydroxy, C1-C4 alkoxy (such as methoxy).

[0085] In some embodiments of the present invention, The section has the following structure:

[0086] in particular In some embodiments of the present invention, The section has the following structure:

[0087] Specifically, R0 is selected from: H, halogen, hydroxyl, C1-C3 alkoxy.

[0088] More specifically, The section has the following structure:

[0089] In some embodiments of the present invention, A3 is selected from: -C(O)-, -S(O)-, -S(O)2-, Especially -C(O)-.

[0090] In some embodiments of the present invention, R4 has the following structure: in:

[0091] Ring G is a 4-10 membered carbocyclic or heterocyclic ring;

[0092] R 41 is one or more independent substituents on the G ring selected from: H, D, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -S(C 0-10 Alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl); wherein, C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C 0-10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 4-10 membered heterocyclic group may be optionally substituted by one or more R0.

[0093] Specifically, the G ring is a 5-10 membered aromatic ring or heteroaromatic ring, for example:

[0094] in particular

[0095] In some embodiments of the present invention, The section has the following structure:

[0096] Among them, R 43 to R 49 With R 41 Definition of R 42 Selected from: H, hydroxyl, protected hydroxyl.

[0097] Specifically, R 42 is selected from the group consisting of: H, -OH, -O(C1-C6 alkyl), -O(benzyl), -O(p-methoxybenzyl), -O(C1-C6 silyl); in some embodiments of the present invention, R 42is -OH; in some embodiments of the present invention, R 42 For H.

[0098] Specifically, R 43 to R 49 independently selected from: H, halogen, cyano, hydroxyl, mercapto, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -O(C 1-6 alkyl), -O(C3-C6 cycloalkyl), -S(C 1-6 alkyl), -C(O)H, -CO(C 1-6 Alkyl), -NR 401 R 402 wherein the H in the C0-C6 alkylene, C1-C6 alkyl, C3-C6 cycloalkyl group may be optionally substituted by a group selected from the following: halogen, hydroxyl, C1-C3 alkoxy; R 401 and R 402 Independently selected from: H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, or R 401 and R 402 Together with the nitrogen atom to which it is attached, it forms a 4-8 membered heterocyclic ring (especially a 4-6 membered saturated heterocyclic ring, such as ), wherein the heterocyclic ring is optionally substituted by a group selected from the group consisting of halogen, hydroxy, and C1-C3 alkoxy.

[0099] More specifically, R 43 is selected from the group consisting of: H, halogen (e.g., F, Cl, Br), C1-C4 alkyl (e.g., methyl, ethyl), C1-C4 haloalkyl (e.g., -CF3, -CHF2, -CH2F), C1-C4 alkoxy (e.g., methoxy), C1-C4 haloalkoxy (e.g., -OCF3, -OCHF2, -OCH2F); in some embodiments of the present invention, R 43 Selected from: H, F, Cl, methyl, -OCF3.

[0100] More specifically, R 44 is selected from the group consisting of: H, halogen (e.g., F, Cl, Br), C1-C4 alkyl (e.g., methyl, ethyl), C1-C4 haloalkyl (e.g., -CF3, -CHF2, -CH2F); in some embodiments of the present invention, R 44 Selected from: H, F, Cl, methyl.

[0101] More specifically, R 45 is selected from the group consisting of: H, halogen (e.g., F, Cl, Br), C1-C4 alkyl (e.g., methyl, ethyl), C1-C4 haloalkyl (e.g., -CF3, -CHF2, -CH2F); in some embodiments of the present invention, R45 Selected from: H, Cl, methyl.

[0102] More specifically, R 46 Selected from: H, halogen (e.g., F, Cl, Br), C1-C4 alkyl (e.g., methyl, ethyl), C1-C4 haloalkyl (e.g., -CF3, -CHF2, -CH2F), -S(C1-C4 alkyl) (e.g., -S-CH3), -NH2, -N(H)(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl); in some embodiments of the present invention, R 46 Selected from: H, -S-CH3, methyl, -NH2.

[0103] More specifically, R 47 is selected from the group consisting of: H, halogen (e.g., F, Cl, Br), C1-C4 alkyl (e.g., methyl, ethyl), C1-C4 haloalkyl (e.g., -CF3, -CHF2, -CH2F), C1-C4 alkoxy (e.g., methoxy), C1-C4 haloalkoxy (e.g., -OCF3, -OCHF2, -OCH2F), C3-C4 cycloalkyl (e.g., cyclopropyl); in some embodiments of the present invention, R 47 Selected from: H, Cl, methyl, ethyl, cyclopropyl, -OCF3, -OCHF2.

[0104] Specifically, R 48 and R 49 Independently selected from: H, halogen (e.g. F, Cl, Br), C1-C4 alkyl (e.g. methyl, ethyl), C1-C4 haloalkyl (e.g. -CF3, -CHF2, -CH2F), C1-C4 alkoxy (e.g. methoxy), C1-C4 haloalkoxy (e.g. -OCF3, -OCHF2, -OCH2F).

[0105] In some embodiments of the present invention, The section has the following structure:

[0106] in particular

[0107] Specifically, R3 is selected from the group consisting of: H, halogen, hydroxy, mercapto, amino, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -O(C 1-6 Alkyl), -S(C 1-6 alkyl), -N(H)(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6wherein the H in the C0-C6 alkylene, C1-C6 alkyl, C3-C6 cycloalkyl group may be optionally substituted by a group selected from the following: D, halogen, hydroxyl, C1-C3 alkoxy; more specifically, R3 is selected from the group consisting of: H, halogen, hydroxyl, mercapto, amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 deuterated alkyl, C1-C4 hydroxy-substituted alkyl, -(C0-C3 alkylene)-(C3-C4 cycloalkyl), -O(C 1-3 Alkyl), -S(C 1-3 alkyl), -N(H)(C 1-3 Alkyl), -N(C 1-3 Alkyl)(C 1-3 alkyl).

[0108] In some embodiments of the present invention, R3 is selected from: H,

[0109] In some embodiments of the present invention, the compound has the following structure:

[0110] In some embodiments of the present invention, the compound has the following structure:

[0111] In some embodiments of the present invention, the compound has the following structure:

[0112] In some embodiments of the present invention, the compound has the following structure:

[0113] In some embodiments of the present invention, the compound has the following structure:

[0114] In some embodiments of the present invention, the compound has the following structure:

[0115] In some embodiments of the present invention, the stereoisomers of the compound have the following structures:

[0116] In some embodiments of the present invention, the stereoisomers of the compound have the following structures:

[0117] In some embodiments of the present invention, the stereoisomers of the compound have the following structures:

[0118] In some embodiments of the present invention, the compound has the following structure:

[0119] In some embodiments of the present invention, the compound has the following structure:

[0120] The second aspect of the present invention provides an intermediate compound and its stereoisomers, which have the following structure:

[0121] wherein Ring A, Ring J, X1, X2, X3, X4, A1, A2, R1, R2, R3, and R5 have the same definitions as those in the first aspect of the present invention;

[0122] R L For the reactive group.

[0123] In some embodiments of the present invention, Part of R L is H or an amino protecting group (such as a Boc group).

[0124] In some embodiments of the present invention, the intermediate compound has the following structure:

[0125] like

[0126] Among them, R L It can be H or an amino protecting group (such as a Boc group).

[0127] In some embodiments of the present invention, the intermediate compound has the following structure:

[0128] like

[0129] In some embodiments of the present invention, R L For H.

[0130] In some embodiments of the present invention, the intermediate compound has the following structure:

[0131] In some embodiments of the present invention, the intermediate compound has the following structure:

[0132] In some embodiments of the present invention, the intermediate compound has the following structure:

[0133] In some embodiments of the present invention, an intermediate compound is also provided, which has the following structure:

[0134] wherein Ring A, Ring J, X1, X2, X3, X4, A1, A2, R1, R2, R3, and R5 have the same definitions as those in the first aspect of the present invention;

[0135] R L 、R L '、R L " is an independent reactive group.

[0136] In some embodiments of the present invention, the compound represented by formula IM-2 has the following structure:

[0137] like In some embodiments of the present invention, the compound represented by formula IM-3 has the following structure:

[0138] like

[0139] In some embodiments of the present invention, the compound represented by formula IM-3 has the following structure:

[0140] like

[0141] In some embodiments of the present invention, R L ' is a leaving group, such as halogen (eg F, Cl, Br or I), alkanesulfonyloxy, arylsulfonyloxy, etc., especially halogen.

[0142] In some embodiments of the present invention, R L "" is H or an amino protecting group (such as a Boc group).

[0143] In the third aspect of the present invention, a method for preparing the compound of the first aspect of the present invention is provided, which comprises the compound represented by formula IM-1 and The reaction connection step, wherein A3 and R4 have the definitions of the first aspect of the present invention, R L1 For the leaving group.

[0144] In some embodiments of the present invention, R L1 Halogen (such as Cl, Br) or

[0145] In some embodiments of the present invention, the method further comprises the step of preparing the compound of formula IM-1, for example, by reacting the compound of formula IM-2 with R L2 -R1 reaction, or by reacting the compound represented by formula IM-3 with Reaction, where R L2 、R L3 For the leaving group.

[0146] In some embodiments of the present invention, the method further comprises the step of preparing the compound of formula IM-2, for example, by and Reaction, where R L ″'、R L0 For the reactive group.

[0147] In some embodiments of the present invention, the method further comprises the step of preparing the compound of formula IM-3, for example, by and Reaction, where R L ″'、R L0 For the reactive group.

[0148] In other embodiments of the present invention, the method further comprises the step of preparing the compound of formula IM-1, for example, by and Reaction, where R L ″'、R L0 In some embodiments of the present invention, R L "' is a leaving group, such as halogen (eg, F, Cl, Br or I), alkanesulfonyloxy, arylsulfonyloxy, etc., such as Br.

[0149] In some embodiments of the present invention, for For example

[0150] The fourth aspect of the present invention provides a combination comprising the compound of the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, deuterated compound thereof, and one or more other therapeutically active agents.

[0151] In particular, the other therapeutically active agent may be an anticancer agent or a chemotherapeutic agent.

[0152] Specifically, chemotherapeutic agents include, for example, anastrozole, bicalutamide, bleomycin sulfate, busulfan, capecitabine, N4-pentyloxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, cyclophosphamide, cytarabine, cytosine arabinoside, cytarabine liposome injection, dacarbazine, dactinomycin (actinomycin D, Cosmegan), daunorubicin hydrochloride, daunorubicin citrate liposome injection, dexamethasone, docetaxel, doxorubicin hydrochloride, etoposide. glycosides, fludarabine 5-fluorouracil phosphate, flutamide tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea, idarubicin, ifosfamide, irinotecan, L-asparaginase, leucovorin calcium, melphalan, 6-mercaptopurine, methotrexate, mitoxantrone, gemtuzumab tuzumab (mylotarg), paclitaxel, phoenix (Yttrium 90 / MX-DTPA), pentostatin, polifeprosan 20 cocarmustine implant, tamoxifen citrate, teniposide, 6-thioguanine, thiotepa, tirapazamine, topotecan hydrochloride for injection, vinblastine, vincristine, and vinorelbine, particularly irinotecan.

[0153] In some embodiments of the present invention, the other therapeutic agent is an inhibitor of PD-1 (e.g., human PD-1). In some embodiments of the present invention, the other therapeutic agent is an inhibitor of PD-L1 (e.g., human PD-L1). Specifically, the inhibitor of PD-1 or PD-L1 can be an antibody molecule to PD-1 or PD-L1.

[0154] Specifically, PD-1 inhibitors include, for example, PDR001 (Novartis AG), nivolumab (Bristol-Myers Squibb Co. Squibb), pembrolizumab (Merck & Co), pidilizumab (CureTech), MEDI0680 (Medimmune), cemiplizumab (REGN2810, Regeneron), dotalimumab (TSR-042, Tesaro), PF-06801591 (Pfizer), tislelizumab (BGB-A317, BeiGene), BGB-108 (BeiGene), INCSHR1210 (Incyte), batilizumab (AGEN2035, Agenus), sintilimab (InnoVent), toripalimab (Shanghai Junshi Biosciences). Bioscience), camrelizumab (Jiangsu Hengrui Medicine Co.), and AMP-224 (Amplimmune), penpulimab (Akeso Biopharma Inc), sepalizumab (Arcus Biosciences), and prolgolimab (Biocad Ltd), in particular PDR001, and more particularly tislelizumab (BGB-A317, BeiGene).

[0155] The fifth aspect of the present invention provides a pharmaceutical composition comprising the compound of the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

[0156] Specifically, the pharmaceutically acceptable excipients may be selected from one or more of fillers, binders, lubricants, disintegrants, antioxidants, buffers, antibacterial agents, suspending agents, solubilizers, thickeners, stabilizers, preservatives, and the like.

[0157] Specifically, the pharmaceutical composition can be administered by any suitable route, such as enteral administration (e.g., oral, sublingual, rectal) or parenteral administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory tract administration, etc.).

[0158] In some embodiments of the present invention, the pharmaceutical composition is an oral preparation, including, but not limited to, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (including soft capsules, microcapsules), lozenges, syrups, liquids, emulsions, suspensions, controlled-release preparations (e.g., instant-release preparations, sustained-release preparations, sustained-release microcapsules).

[0159] In some embodiments of the present invention, the pharmaceutical composition is an injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection).

[0160] In other embodiments of the present invention, the pharmaceutical composition is an intravenous drip, a transdermal absorption preparation, a lotion, a suppository (eg, a rectal suppository, a vaginal suppository), a nasal preparation, a pulmonary preparation (inhalation), an eye drop, and the like.

[0161] Specifically, the pharmaceutical composition is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form can be a capsule, tablet, or any other dosage form; in addition, the unit dosage form can also be a packaged preparation, such as tablets, capsules, and powders packaged in vials or ampoules.

[0162] Specifically, in the pharmaceutical composition, the compound or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound can be used alone or in combination with other therapeutically active agents (as described in the fourth aspect of the present invention).

[0163] Specifically, the various dosage forms of the pharmaceutical composition can be prepared according to conventional production methods in the pharmaceutical field, such as mixing the active ingredient with one or more carriers and then preparing the mixture into the desired dosage form.

[0164] Specifically, the pharmaceutical composition contains an active ingredient (the compound of the first aspect or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound, or a combination thereof with other types of active ingredients) in a weight ratio of 0.1-99.5% (e.g., 0.1%, 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%).

[0165] Specifically, the pharmaceutical composition contains pharmaceutically acceptable excipients in a weight ratio of 0.5%-99.9% (e.g., 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%).

[0166] In a sixth aspect, the present invention provides the compound described in the first aspect or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, deuterated compound as a WRN helicase inhibitor, for example, in the preparation of a drug for preventing and / or treating WRN-mediated diseases.

[0167] In particular, the disease is a disease the prevention and / or treatment of which may be beneficial by inhibiting WRN.

[0168] In some preferred embodiments of the present invention, the disease is a tumor, for example, acute myeloid leukemia, juvenile cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem cell glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoid tumor, embryonal tumor, blastoma, primary lymphoma, cervical cancer, childhood cancer, chordoma, heart tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumor, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, nasal glioma, Ewing sarcoma, extracranial ectodermal cell tumor, gonadal ectodermal cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, stomach cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), blastoma, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, Kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasms, mycosis fungoides, myelodysplastic syndrome, myelodysplasia / myeloproliferative neoplasms, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), mouth cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer , papillomavirus, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (stomach / gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastoma, rare childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virally induced cancers.

[0169] In particular, the tumor is a cancer with microsatellite instability (MSI), such as colorectal cancer, gastric cancer, ovarian cancer, endometrial tumor, ovarian cancer, etc.

[0170] In some embodiments of the invention, the disease is a non-cancerous hyperproliferative disorder, such as benign hyperplasia of the skin (eg, psoriasis), restenosis, or prostate enlargement (eg, benign prostatic hypertrophy (BPH)).

[0171] In the seventh aspect of the present invention, a method for inhibiting WRN helicase is provided, comprising the step of using the compound of the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof.

[0172] In some embodiments of the invention, the method is performed in vivo.

[0173] In some embodiments of the invention, the method is performed in vitro.

[0174] In the eighth aspect of the present invention, a method for preventing and / or treating WRN-mediated diseases is provided, comprising the step of administering to a subject in need thereof an effective amount of the compound of the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, deuterated compound thereof, or the combination of the fourth aspect, or the pharmaceutical composition of the fifth aspect.

[0175] Specifically, the disease is as described in the sixth aspect of the present invention.

[0176] Specifically, the subject is a mammal, such as a human.

[0177] The present invention provides a novel WRN helicase inhibitor with excellent inhibitory activity. It can be used to inhibit WRN to cause high levels of DNA double-strand breaks (DSBs) in microsatellite instability (MSI) cells, thereby inhibiting the growth of microsatellite instability (MSI) tumor cells. It is used to prevent and / or treat related cancers, especially colorectal cancer, gastric cancer, ovarian cancer and endometrial tumors. It can fill the gap in specific MSI-type cancer targeted drugs and has very good application prospects and value in the medical field. BRIEF DESCRIPTION OF THE DRAWINGS

[0178] Figure 1 shows the IC50 curve of compound T074 inhibiting WRN helicase activity.

[0179] FIG2 shows the IC50 curve of compound T074 inhibiting ATPase activity.

[0180] FIG3 shows the EC50 curve of compound T074 for inhibiting the growth of SW48 tumor cells. DETAILED DESCRIPTION

[0181] Unless otherwise defined, all scientific and technical terms used in the present invention have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention relates.

[0182] In the present invention, the term "aliphatic group" refers to a straight or branched hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a cyclic hydrocarbon group that is fully saturated or contains one or more unsaturated units (also referred to herein as "aliphatic ring"), which is connected to the rest of the molecule by a single bond. Suitable aliphatic groups include, but are not limited to, straight or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (cycloalkyl)alkenyl, etc. Typical aliphatic groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms.

[0183] The term "carbocycle" is composed entirely of carbon atoms and can be divided into aliphatic rings and aromatic rings.

[0184] The term "alkyl" refers to a straight or branched hydrocarbon chain radical that does not contain unsaturated bonds and is connected to the rest of the molecule by a single bond. Typical alkyl groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc. If the alkyl group is substituted by a cycloalkyl group, it is correspondingly a "cycloalkylalkyl" group, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc. If the alkyl group is substituted by an aryl group, it is correspondingly an "aralkyl" group, such as benzyl, diphenylmethyl, or phenethyl. If the alkyl group is substituted by a heterocyclic group, it is correspondingly a "heterocyclylalkyl" group. In the present invention, a C0 alkyl group refers to H, i.e., C 0-10 Alkyl (or C0-C 10 Alkyl) includes H and C 1-10 Alkyl (or C1-C 10 alkyl).

[0185] The term "alkylene" refers to a hydrocarbon group (divalent alkyl) formed by losing two hydrogen atoms from an alkane molecule, which can be a straight chain or branched chain and is connected to the rest of the molecule by a single bond. In this context, a typical alkylene group has 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methylene (-CH2-), ethylene, propylene, butylene, etc. In the present invention, a C0 alkylene group refers to a single bond, i.e., C 0-10 Alkylene (or C0-C 10 Alkylene) includes single bonds and C 1-10 Alkylene (or C1-C 10 alkylene).

[0186] The term "cycloalkyl" refers to alicyclic hydrocarbons, such as those containing 1 to 4 single rings and / or condensed rings, containing 3-18 carbon atoms, preferably 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl, etc.

[0187] The term "alkoxy" refers to a substituent formed by replacing the hydrogen of a hydroxy group with an alkyl group, such as an alkoxy group containing 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, and the like.

[0188] The term "aryl" refers to a monocyclic or polycyclic radical, including a polycyclic radical containing a monocyclic aromatic group and / or a fused aromatic group, such as a radical containing 1-3 monocyclic or fused rings and 6-18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms. Typical aryl groups are those containing 6-12 carbon ring atoms, such as phenyl, naphthyl, biphenyl, indenyl, etc. "Arylene" refers to a divalent radical derived from an aromatic hydrocarbon by removing two hydrogen atoms.

[0189] The term "heterocyclyl" includes heteroaromatic and heteroalicyclic groups containing 1 to 3 monocyclic and / or fused rings and 3 to about 18 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18) ring atoms. Preferred heteroaromatic and heteroalicyclic groups contain 4 to about 10 (e.g., 4, 5, 6, 7, 8, 9, 10) ring atoms. Suitable heteroaryl groups in the compounds of the present invention contain 1, 2, or 3 heteroatoms selected from N, O, or S atoms. Examples of heteroaryl groups include, but are not limited to, coumarin, including 8-coumarin, quinolinyl, including 8-quinolinyl, isoquinolinyl, pyridinyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazolyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofurazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl, etc. Suitable heteroalicyclic groups in the compounds of the present invention contain 1, 2 or 3 heteroatoms selected from N, O or S atoms. Examples of heteroalicyclic groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, oxathianyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxirane, thiirane, azepinyl, oxazepanyl, diazepinyl, triazepinyl, 1,2,3,6-tetrahydro- ... 1-Hydroxy-1-pyridyl, 2-Hydroxy-1-pyridyl, 3-Hydroxy-1-pyridyl, 4-Hydroxy-1-pyridyl, 2-Hydroxy-1-pyridyl, 3 ...

[0190] The above groups may be substituted at one or more available positions by one or more suitable groups, such as OR', =O, SR', SOR', SO2R', OSO2R', OSO3R', NO2, NHR', N(R')2, =NR', N(R')COR', N(COR')2, N(R')SO2R', N(R')C(=NR')N(R')R', N3, CN, halogen, COR', COOR', OCOR', OCOOR', OCONHR', OCON(R')2, CONHR', CON(R')2, CON(R')OR', CON(R')SO2R', PO(OR')2, PO(OR')R', PO(OR')(N(R')R'), C1-C 12 Alkyl, C3-C 10 Cycloalkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, aryl and heterocyclic groups, wherein each R' group is independently selected from hydrogen, OH, NO2, NH2, SH, CN, halogen, COH, CO alkyl, COOH, C1-C 12 Alkyl, C3-C 10 Cycloalkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, aryl and heterocyclyl. Where these groups themselves are substituted, the substituents may be selected from the aforementioned list.

[0191] "Halogen" refers to bromine, chlorine, iodine, or fluorine. A haloalkyl group is an alkyl group in which a hydrogen atom is replaced by a halogen atom (F, Cl, Br, I), such as -CH2Rh, -CHRh2, -CRh3, where Rh is F, Cl, Br, or I; for example, -CF3.

[0192] The term "pharmaceutically acceptable salt" refers to an acidic or basic salt that is theoretically non-toxic, non-irritating, and non-allergenic, and that can achieve or provide clinically acceptable pharmacokinetic properties, absorption, distribution, and metabolic properties of the drug molecule, thereby achieving the intended purpose. The salts described herein include pharmaceutically acceptable acidic or basic salts of the acidic, basic, or amphiphilic groups of the compound. A list of suitable salts can be found in SM Birge, et al., J. Pharm. Sci., 66, 1-19 (1977).

[0193] The pharmaceutically acceptable salts of the present invention include acid addition salts and base addition salts.

[0194] Such acid addition salts include, but are not limited to, salts from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic and phosphonic acids, and salts from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids and aliphatic and aromatic sulfonic acids. The present invention relates to the preparation of the present invention and the like.Therefore, these salts include but are not limited to sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, iodate, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate and mesylate, also comprise amino acid whose salt such as arginate, gluconate, galacturonate etc.Acid addition salts can be prepared by making free alkali form contact with sufficient amount of required acid in a conventional manner.Free alkali form can be regenerated by making salt form contact with alkali, and separate this free alkali in a conventional manner.

[0195] Base addition salts of the present invention refer to salts formed with metals or amines, such as hydroxides of alkali metals and alkaline earth metals, or with organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucamine, and procaine. Base addition salts can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form the salt. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.

[0196] The term "solvate" is understood to mean any form of a compound of the invention in which the compound is linked to another molecule (usually a polar solvent) by a non-covalent bond, and particularly includes hydrates and alcoholates, such as methanolates. Preferred solvates are hydrates.

[0197] The term "prodrug" is used in its broad sense and encompasses derivatives that can be converted into compounds of the invention in vivo. Examples of prodrugs include, but are not limited to, derivatives and metabolites of compounds, including biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Preferably, the prodrug with a carboxyl functional group is a lower alkyl ester of a carboxylic acid. The carboxylic acid ester is readily obtained by esterification of any carboxylic acid moiety present in the molecule. Prodrugs can generally be prepared by known methods, such as those described in Burger "Medicinal Chemistry and Drug Discovery, 6th Edition" (Donald J. Abraham ed., 2001, Wiley) and "Design and Applications of Prodrugs" (H. Bundgaard ed., 1985, Harwood Academic Publishers).

[0198] The term "absent" indicates that the linking group is a bond.

[0199] Any compound involved herein is intended to represent such a specific compound and some deformation or some form thereof. In particular, the compound involved herein may have an asymmetric center, and therefore there are different enantiomers or diastereomeric forms. Thus, any given compound involved herein represents any one of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof. Similarly, there may also be stereoisomers or geometric isomers of double bonds, whereby in some cases, molecules may exist as (E)-isomers or (Z)-isomers (trans and cis isomers). If a molecule comprises multiple double bonds, each double bond will have its own stereoisomerism, which may be the same or different from the stereoisomerism of other double bonds of the molecule. In addition, the compound involved herein may have atropisomers. All stereoisomers of the compound involved herein, including enantiomers, diastereoisomers, geometric isomers and atropisomers, and mixtures thereof, are within the scope of the present invention.

[0200] The term "leaving group" is given its common meaning in the field of synthetic organic chemistry and refers to an atom or group that can be replaced by a nucleophilic reagent. For example, referring to Smith, March Advanced Organic Chemistry the 6th edition, (501-502). The example of a suitable leaving group includes but is not limited to halogen (for example F, Cl, Br or I), alkanesulfonyloxy, arylsulfonyloxy etc.

[0201] The disclosures of various publications, patents, and published patent specifications cited herein are incorporated by reference in their entirety.

[0202] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts shall fall within the scope of protection of the present invention.

[0203] Compound Synthesis Examples

[0204] Example 1

[0205] The synthetic route is as follows:

[0206] The specific steps are:

[0207] 1.1 Synthesis of Intermediate A-1

[0208] Under nitrogen, 3,5-diamino-1,2,4-triazole (1.0 eq) was added to a 48% aqueous solution of hydrobromic acid (1 mmol: 0.4 mL). An aqueous solution of sodium nitrite (1.1 eq) was then added dropwise at 0°C. The mixture was then reacted at 100°C for 16 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was cooled to 0°C, the pH was adjusted to 4 with 10% sodium hydroxide solution, and the mixture was extracted four times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Intermediate A-1.

[0209] 1.2 Synthesis of intermediate B-1

[0210] 3-Chloro-4-aminobenzotrifluoride (1.0 eq) was added to dichloromethane (1 mmol: 2 mL), and chloroacetyl chloride (1.05 eq) was added dropwise at 0°C. The mixture was then allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was then slurried with petroleum ether to obtain Intermediate B-1.

[0211] 1.3 Synthesis of intermediate C-1

[0212] Under nitrogen, 3-hydroxy-2-pyridinecarboxylic acid (1.0 eq) and pentafluorophenol (1.05 eq) were added to dichloromethane (1 mmol:2 mL). N,N'-diisopropylcarbodiimide (1.05 eq) was added dropwise at 0°C, and the mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by column chromatography to yield Intermediate C-1.

[0213] 1.4 Synthesis of Intermediate A-2

[0214] Ethyl propionyl acetate (1.1 eq) and Intermediate A-1 (1.0 eq) were added to acetic acid (1 mmol: 0.5 mL) at room temperature, then heated to 80°C for 16 hours. After completion of the reaction, monitored by LC-MS, the reaction solution was cooled to 0°C and stirred for one hour. The resulting solid was filtered, washed with a small amount of ethanol, and dried to obtain Intermediate A-2.

[0215] 1.5 Synthesis of Intermediate A-3

[0216] Intermediate A-2 (1.0 eq), intermediate B-1 (1.2 eq), and N,N-diisopropylethylamine (2.5 eq) were added to N,N-dimethylformamide (1 mmol:2 mL) at room temperature, and the temperature was then raised to 80°C for 16 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to yield intermediate A-3.

[0217] 1.6 Synthesis of Intermediate A-4

[0218] Intermediate A-3 (1.0 eq), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.2 eq), XPhos Pd G3 (0.05 eq), and potassium phosphate (2.5 eq) were added to N,N-dimethylformamide and water (7:1, 1 mmol:5 mL). The atmosphere was replaced with nitrogen three times, and the temperature was then raised to 80°C for 16 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain Intermediate A-4.

[0219] 1.7 Synthesis of Intermediate A-5

[0220] Intermediate A-4 (1.0 eq) was dissolved in N,N-dimethylformamide (1 mmol:10 mL) at room temperature, followed by the addition of N-bromosuccinimide (1.5 eq) in portions, and the reaction was allowed to proceed for 4 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed once with saturated sodium bicarbonate, twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to yield Intermediate A-5.

[0221] 1.8 Synthesis of Intermediate A-6 or A-6'

[0222] A-5 (1.0 eq), N,N-diisopropylethylamine (3.0 eq), and a commercially available tert-butyloxycarbonyl-protected spiroamine (S-1 or S-1') (2.5 eq) were dissolved in dimethyl sulfoxide (1 mmol / 5 mL) and reacted at 120°C for 16 hours under nitrogen. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to yield intermediate A-6 or A-6'.

[0223] 1.9 Synthesis of Intermediate A-7 or A-7'

[0224] Intermediates A-6 and A-6' (1.0 eq) were dissolved in dichloromethane (1 mmol:5 mL) at room temperature. Trifluoroacetic acid (1 mmol:1 mL) was then added at 0°C and the mixture was allowed to warm to room temperature for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was concentrated to near dryness under reduced pressure, diluted with dichloromethane, and the aqueous phase was adjusted to pH 8-9 with saturated sodium bicarbonate. The mixture was extracted twice with dichloromethane, and the organic phase was washed with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield Intermediate A-7 or A-7'.

[0225] 1.10 Synthesis of Compound A-8 or A-8'

[0226] Intermediate A-7 or A-7' (1.0 eq), triethylamine (3.0 eq), and intermediate C-1 (1.2 eq) were dissolved in N,N-dimethylformamide (1 mmol:10 mL) and reacted at 80°C for 2 hours under nitrogen. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to high-pressure reverse transpiration to produce compound A-8 or A-8'.

[0227] When Y is CH2, n=1, and m=1, A-8 obtained according to the above synthetic steps is compound T001.

[0228] When Y does not exist, n=2, and m=1, A-8 obtained according to the above synthetic steps is compound T004.

[0229] When Y is CH2, n=1, and m=1, A-8' obtained according to the above synthetic steps is compound T005.

[0230] When Y is CH2, n=1, and m=0, A-8' obtained according to the above synthetic steps is compound T006.

[0231] When Y is CH2, n=1, and m=3, A-8 obtained according to the above synthetic steps is compound T007.

[0232] When Y is CH2, n=1, and m=2, A-8 obtained according to the above synthetic steps is compound T008.

[0233] When Y is CH2, n=1, and m=2, A-8' obtained according to the above synthetic steps is compound T009.

[0234] When Y is CH2, n=2, and m=1, A-8 obtained according to the above synthetic steps is compound T010.

[0235] When Y is CH2, n=2, and m=2, A-8 obtained according to the above synthetic steps is compound T011.

[0236] When Y is CH2, n=2, and m=2, A-8' obtained according to the above synthetic steps, particularly when the configuration of the spiro atom is S-type, is compound T12.

[0237] When Y is CH2, n=0, and m=2, A-8' obtained according to the above synthetic steps is compound T013.

[0238] When Y is CH2, n=1, and m=3, A-8' obtained according to the above synthetic steps is compound T014.

[0239] When Y is CH2, n=2, and m=2, A-8' obtained according to the above synthetic steps, particularly when the configuration of the spiro atom is R-type, is compound T015.

[0240] The structures and general analytical data of the target compounds are shown in Table 1.

[0241] Example 2

[0242] The specific steps are:

[0243] 2.1 Synthesis of intermediate C-2

[0244] 2.1.1 Synthesis of intermediate C-2

[0245] 3-Hydroxy-4-methylpyridine (1.0 eq) and sodium carbonate (2.3 eq) were dissolved in water (1 mmol:5 mL), followed by the addition of iodine (1.0 eq) and the reaction mixture was allowed to react at room temperature for 4 hours. After completion of the reaction, the pH of the reaction mixture was adjusted to 4-5 with 2 mol / L hydrochloric acid at 0°C. The mixture was extracted three times with ethyl acetate, and the organic phase was washed with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to yield intermediate C-2-1.

[0246] 2.1.2 Synthesis of intermediate C-2-2

[0247] Intermediate C-2-1 (1.0 eq) and cuprous cyanide (4.0 eq) were added to N,N-dimethylformamide (1 mmol:2 mL) at room temperature. The atmosphere was replaced with nitrogen three times, and the temperature was then raised to 100°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and diluted with ethyl acetate and water. The organic phase was separated by filtration and washed once with water and once with brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain intermediate C-2-2.

[0248] 2.1.3 Synthesis of intermediate C-2

[0249] Potassium hydroxide (6.0 eq) was dissolved in water (1 mmol:2 mL), followed by the addition of intermediate C-2-2 (1.0 eq). The temperature was raised to 90°C and the reaction was allowed to react for 16 hours. After completion of the reaction, as monitored by LC-MS, the mixture was cooled to 0°C and the pH adjusted to approximately 3 with 2 mol / L hydrochloric acid. The filtered solid was washed twice with a small amount of water, collected, and dried to yield intermediate C-2.

[0250] 2.2 Synthesis of compound T002

[0251] Compound T002 was synthesized by condensing intermediate A-7 (Y is CH2, n=1, m=1) obtained in the synthetic implementation steps of Example 1 with C-2.

[0252] Intermediate A-7 (1.0 eq), C-2 (2.0 eq), and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol:5 mL) at room temperature. 1H-Benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (2.0 eq) was then added at 0°C, and the mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to high pressure reverse transpiration to yield compound T002, whose structure and general analytical data are shown in Table 1.

[0253] Example 3

[0254] 3.1 Synthesis of intermediate C-3

[0255] 3.1.1 Synthesis of intermediate C-3-1

[0256] Intermediate C2-1-1 (1.0 eq) and potassium carbonate (1.5 eq) were added to N,N-dimethylformamide (1 mmol:3 mL) at room temperature, followed by benzyl bromide (1.05 eq). The reaction temperature was then raised to 40°C for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with a large amount of water and extracted twice with ethyl acetate. The resulting organic phase was washed once with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield Intermediate C-3-1.

[0257] 3.1.2 Synthesis of intermediate C-3-2

[0258] Intermediate C-3-1 (1.0 eq), benzyl mercaptan (2.0 eq), XanPhos (0.15 eq), Pd2(dba)3 (0.075 eq), and N,N-diisopropylethylamine (3.0 eq) were added to 1,4-dioxane (1 mmol:4 mL) at room temperature. The atmosphere was purged with nitrogen three times and then heated to 100°C for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain intermediate C-3-2.

[0259] 3.1.3 Synthesis of intermediate C-3

[0260] Intermediate C-3-2 (1.0 eq) was dissolved in acetonitrile (1 mmol:4 mL) and water (1 mmol:0.5 mL), cooled to 0°C, and acetic acid (6.0 eq) and 1,3-dichloro-5,5-dimethylhydantoin (1.0 eq) were added. The mixture was then allowed to warm to room temperature and react for 2 hours. After completion of the reaction, the pH of the reaction solution was adjusted to 7 with saturated sodium bicarbonate and extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain intermediate C-3.

[0261] 3.2 Synthesis of compound T003

[0262] Compound T003 was synthesized by condensing intermediate A-7 (Y is CH2, n=1, m=1) obtained in the synthetic implementation steps of Example 1 with C-3.

[0263] Intermediate A-7 (1.0 eq) and triethylamine (5 e.q.) were dissolved in dichloromethane (1 mmol:10 mL). The reaction solution was then cooled to 0°C, and Intermediate C-3 (2.5 eq) was added. The reaction mixture was then warmed to room temperature and reacted for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with water and extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to high-pressure reverse transpiration to produce compound T003. Its structure and general analytical data are shown in Table 1.

[0264] Example 4

[0265] The synthetic route is as follows:

[0266] The specific steps are:

[0267] 4.1 Synthesis of Intermediate A-9

[0268] Ethyl acetoacetate (1.0 eq) and ammonium acetate (0.3 eq) were added to anhydrous ether (1 mmol:5 mL), followed by the addition of NBS (1.08 eq) in batches, and the solution was stirred at room temperature for 4 hours. The reaction was monitored by TLC, and the ether was dried, diluted with ethyl acetate, and washed three times with brine. The organic phase was collected and dried over anhydrous sodium sulfate to obtain crude product A-9. It was used directly in the next step without purification.

[0269] 4.2 Synthesis of Intermediate A-10

[0270] Intermediate A-9 (1.0 eq), (R)-1-BOC-1,7-diazaspiro[4.4]nonane (0.8 eq), and potassium carbonate (3.0 eq) were weighed and dissolved in acetonitrile (1 mmol:2 mL). The reaction was stirred at room temperature for 2-3 hours. After completion of the reaction, the acetonitrile was removed by swirl, the mixture was diluted with ethyl acetate, washed three times with brine, and dried over anhydrous sodium sulfate. The organic phase was retained and swirl-dried to obtain the crude product. Finally, the product was purified by column chromatography to obtain A-10.

[0271] 4.3 Synthesis of Intermediate A-11

[0272] Under nitrogen, WRI-INT-1 (1.5 eq) and 85% aqueous phosphoric acid (1.0 eq) were added to an ethanol solution (1 mmol: 0.5 mL) of intermediate A-10 (1.0 eq), followed by stirring at 90°C for 16 hours. After completion of the reaction, which was monitored by LC-MS, the solution was cooled to room temperature, the ethanol was dried, diluted with ethyl acetate, and washed with ammonium chloride. The organic phase was collected, dried over anhydrous sodium sulfate, and dried to give the crude product. Finally, product A-11 was obtained by column chromatography.

[0273] 4.4 Synthesis of Intermediate A-12

[0274] Intermediate A-11 (1.0 eq), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.2 eq), XPhos Pd G3 (0.05 eq), and potassium phosphate (2.5 eq) were added to 1,4-dioxane and water (5:1, 1 mmol:5 mL). The atmosphere was purged with nitrogen three times, and the temperature was then raised to 80°C for 4 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate and washed with brine. The organic phase was collected, dried over anhydrous sodium sulfate, and spin-dried. The product was then purified by column chromatography to yield Intermediate A-12.

[0275] 4.5 Synthesis of Intermediate A-13-1

[0276] Intermediate A-12 (1.0 eq), intermediate B-1 (1.2 eq), and N,N-diisopropylethylamine (2.5 eq) were added to N,N-dimethylformamide (1 mmol:2 mL) at room temperature, and the temperature was then raised to 80°C for 16 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to yield intermediate A-13-1.

[0277] 4.6 Synthesis of Intermediate A-14-1

[0278] Intermediate A-13-1 (1.0 eq) was dissolved in dichloromethane (1 mmol:5 mL) at room temperature, followed by the addition of trifluoroacetic acid (1 mmol:3 mL) at 0°C. The temperature was then raised to 40°C and allowed to react for 16 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was concentrated to near dryness under reduced pressure, diluted with dichloromethane, and the pH of the aqueous phase was adjusted to 8-9 with saturated sodium bicarbonate. The reaction mixture was extracted twice with dichloromethane, and the organic phase was washed with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford Intermediate A-14-1.

[0279] 4.7 Synthesis of target product

[0280] 4.7.1 Synthesis of target product T016

[0281] Intermediate A-14-1 (1.0 eq), C-4 (2.0 eq), and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol:5 mL) at room temperature. 1H-Benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (2.0 eq) was then added at 0°C, and the reaction temperature was raised to 40°C for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to high-pressure reverse transpiration to yield compound T016, whose structure and general analytical data are shown in Table 1.

[0282] 4.7.2 Synthesis of target product T017

[0283] Intermediate A-14-1 (1.0 eq), C-5 (2.0 eq), and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol:5 mL) at room temperature. 1H-Benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (2.0 eq) was then added at 0°C, and the reaction temperature was raised to 40°C for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to high-pressure reverse transpiration to yield compound T017, whose structure and general analytical data are shown in Table 1.

[0284] 4.7.3 Synthesis of target product T018

[0285] Intermediate A-14-1 (1.0 eq), C-6 (2.0 eq), and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol:5 mL) at room temperature. 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.5 eq) was then added at 0°C. The reaction temperature was then raised to 40°C for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to high-pressure reverse transpiration to yield compound T018, whose structure and general analytical data are shown in Table 1.

[0286] 4.7.4 Synthesis of target product T019

[0287] Intermediate A-14-1 (1.0 eq), C-7 (2.0 eq), and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol:5 mL) at room temperature. 1H-Benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (2.0 eq) was then added at 0°C, and the reaction temperature was raised to 40°C for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to high-pressure reverse transpiration to yield compound T019, whose structure and general analytical data are shown in Table 1.

[0288] 4.7.5 Synthesis of target product T020

[0289] Intermediate A-14-1 (1.0 eq), C-8 (2.0 eq), and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol:5 mL) at room temperature. 1H-Benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (2.0 eq) was then added at 0°C, and the reaction temperature was raised to 40°C for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to high-pressure reverse transpiration to yield compound T020, whose structure and general analytical data are shown in Table 1.

[0290] 4.7.6 Synthesis of target product T021

[0291] Intermediate A-14-1 (1.0 eq), C-2 (2.0 eq), and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol:5 mL) at room temperature. 1H-Benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (2.0 eq) was then added at 0°C, and the reaction temperature was raised to 40°C for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to high-pressure reverse transpiration to yield compound T021, whose structure and general analytical data are shown in Table 1.

[0292] 4.7.7 Synthesis of target product T006

[0293] 4.7.7.1 Synthesis of Intermediate A-15-1

[0294] Intermediate A-14-1 (1.0 eq), C-9 (2.0 eq), and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol:5 mL) at room temperature. 1H-Benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (2.0 eq) was then added at 0°C, and the reaction temperature was raised to 40°C for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield intermediate A-15-1.

[0295] 4.7.7.2 Synthesis of target product T006

[0296] Intermediate A-15-1 (1.0 eq) was dissolved in trifluoroacetic acid (1 mmol:1 mL) at room temperature, and the reaction mixture was heated to 40°C for 12 hours. After completion of the reaction, the trifluoroacetic acid was evaporated, and the concentrate was diluted with ethyl acetate, washed once with a saturated sodium bicarbonate solution and once with saturated brine. The organic phase was evaporated and then subjected to high-pressure reverse osmosis to produce compound T006, whose structure and general analytical data are shown in Table 1.

[0297] 4.7.8 Synthesis of target product T013

[0298] 4.7.8.1 Synthesis of Intermediate A-15-2

[0299] Intermediate A-14-1 (1.0 eq), C-10 (2.0 eq), and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol:5 mL) at room temperature. 1H-Benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (2.0 eq) was then added at 0°C, and the reaction temperature was raised to 40°C for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield Intermediate A-15-1.

[0300] 4.7.8.2 Synthesis of target product T013

[0301] Intermediate A-15-2 (1.0 eq) was dissolved in trifluoroacetic acid (1 mmol:1 mL) at room temperature, and the reaction mixture was heated to 40°C for 12 hours. After completion of the reaction, the trifluoroacetic acid was evaporated, and the concentrate was diluted with ethyl acetate, washed once with a saturated sodium bicarbonate solution and once with saturated brine. The organic phase was evaporated and then subjected to high-pressure reverse osmosis to produce compound T013, whose structure and general analytical data are shown in Table 1.

[0302] 4.7.9 Synthesis of target product T014

[0303] Intermediate A-14-1 (1.0 eq), C-11 (2.0 eq), and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol:5 mL) at room temperature. 1H-Benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (2.0 eq) was then added at 0°C, and the reaction temperature was raised to 40°C for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to high-pressure reverse transpiration to yield compound T014, whose structure and general analytical data are shown in Table 1.

[0304] Example 5

[0305] The synthetic route is as follows:

[0306] The specific steps are:

[0307] 5.1 The synthetic route of intermediate B-2 is as follows:

[0308] 5.1.1 Synthesis of Intermediate B-2-1

[0309] 4-Amino-2-chlorobenzotrifluoride (1.0 eq) was dissolved in CH3OH:DCM = 3:2 mL (1.0 mmol:5 mL) at room temperature. Iodine monochloride (1.5 eq) was added at 0°C and the mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, diluted with ethyl acetate, and slowly added to a saturated sodium thiosulfate solution, stirring for 5-10 minutes. Finally, the organic phase was washed twice with water and then with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate B-2-1. The crude product was purified by column chromatography to obtain pure intermediate B-2-1.

[0310] 5.1.2 Synthesis of Intermediate B-2-2

[0311] Intermediate B-2-1 (1.0 eq), trimethylcyclotriboroxane (2.5 eq), DPPF palladium dichloride methane complex (0.05 eq), and potassium carbonate (2.5 eq) were added to 1,4-dioxane (1 mmol:2 mL). The atmosphere was replaced with nitrogen three times, and the temperature was then raised to 100°C for 16 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed with brine, and the organic phase was collected, dried over anhydrous sodium sulfate, and spin-dried. Intermediate B-2-2 was obtained by column chromatography.

[0312] 5.1.3 Synthesis of Intermediate B-2

[0313] Intermediate B-2-2 (1.0 eq) was added to dichloromethane (1 mmol: 2 mL), and chloroacetyl chloride (1.05 eq) was added dropwise at 0°C. The mixture was then reacted at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then slurried with petroleum ether to obtain intermediate B-2.

[0314] 5.2 Synthesis of Intermediate A-3b

[0315] Intermediate A-2 (1.0 eq), intermediate B-2 (1.2 eq), and N,N-diisopropylethylamine (2.5 eq) were added to N,N-dimethylformamide (1 mmol:2 mL) at room temperature, and the reaction temperature was raised to 80°C for 16 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield intermediate A-3b.

[0316] 5.3 Synthesis of Intermediate A-4b

[0317] Intermediate A-3b (1.0 eq), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.2 eq), XPhos Pd G3 (0.05 eq), and potassium phosphate (2.5 eq) were added to N,N-dimethylformamide and water (7:1, 1 mmol:5 mL). The atmosphere was replaced with nitrogen three times, and the temperature was then raised to 80°C for 16 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain intermediate A-4b.

[0318] 5.4 Synthesis of Intermediate A-5b

[0319] Intermediate A-4b (1.0 eq) was dissolved in N,N-dimethylformamide (1 mmol:10 mL) at room temperature, followed by the addition of N-bromosuccinimide (1.5 eq) in portions. The reaction was allowed to react for 4 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed once with saturated sodium bicarbonate, twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to yield Intermediate A-5b.

[0320] 5.5 Synthesis of Intermediate A-6b

[0321] Intermediate A-5b (1.0 eq), N,N-diisopropylethylamine (3.0 eq), and commercially available (R)-1-BOC-1,7-diazaspiro[4.4]nonane (2.5 eq) were dissolved in dimethyl sulfoxide (1 mmol:5 mL) and reacted at 120°C for 16 hours under nitrogen. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to afford Intermediate A-6b.

[0322] 5.6 Synthesis of Intermediate A-7b

[0323] Intermediate A-6b (1.0 eq) was dissolved in dichloromethane (1 mmol:5 mL) at room temperature, followed by the addition of trifluoroacetic acid (1 mmol:1 mL) at 0°C. The reaction mixture was then allowed to warm to room temperature for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was concentrated to near dryness under reduced pressure, diluted with dichloromethane, and the aqueous phase was adjusted to pH 8-9 with saturated sodium bicarbonate. The mixture was extracted twice with dichloromethane, and the organic phase was washed with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield Intermediate A-7b.

[0324] 5.7 Synthesis of target product

[0325] 5.7.1 The synthesis steps of the target product T022 are based on the synthesis of A-8. Its structure and general analytical data are shown in Table 1.

[0326] 5.7.2 The synthesis steps of the target product T023 are based on the synthesis of T016. Its structure and general analytical data are shown in Table 1.

[0327] 5.7.3 The synthesis steps of the target product T024 are based on the synthesis of T017. Its structure and general analytical data are shown in Table 1.

[0328] 5.7.4 The synthesis steps of the target product T025 are based on the synthesis of T018. Its structure and general analytical data are shown in Table 1.

[0329] 5.7.5 The synthesis steps of the target product T026 are based on the synthesis of T019. Its structure and general analytical data are shown in Table 1.

[0330] 5.7.6 The synthesis steps of the target product T027 are based on the synthesis of T020. Its structure and general analytical data are shown in Table 1.

[0331] 5.7.7 The synthesis steps of the target product T028 are based on the synthesis of T021. Its structure and general analytical data are shown in Table 1.

[0332] 5.7.8 The synthesis steps of the target product T029 are based on the synthesis of T006. Its structure and general analytical data are shown in Table 1.

[0333] 5.7.9 The synthesis steps of the target product T030 are based on the synthesis of T013. Its structure and general analytical data are shown in Table 1.

[0334] 5.7.10 The synthesis steps of target product T031 are based on the synthesis of T014. Its structure and general analytical data are shown in Table 1.

[0335] Example 6

[0336] The synthetic route is as follows:

[0337] 6.1 Synthesis of Intermediate B-3

[0338] 6.1.1 Synthesis of Intermediate B-3-1

[0339] 3-Fluoro-2-methylaniline was dissolved in acetic acid (1 mmol:1 mL) at room temperature, followed by the addition of N-iodosuccinimide (1.0 eq). The reaction mixture was then heated to 95°C and allowed to react for 2.5 hours. After completion of the reaction, as monitored by LC-MS, the reaction mixture was concentrated to near dryness, diluted with ethyl acetate, and poured into a saturated sodium thiosulfate solution, stirring for 5-10 minutes. The mixture was then washed twice with water and once with saturated brine. The resulting organic phase was concentrated under reduced pressure over anhydrous sodium sulfate and subjected to column chromatography to yield intermediate B-3-1.

[0340] 6.1.2 Synthesis of Intermediate B-3-2

[0341] Intermediate B-3-1 (1.0 eq) and triethylamine (2.0 eq) were dissolved in DCM (1 mmol:3 mL) at room temperature. The reaction solution was then cooled to 0°C, acetyl chloride (1.5 eq) was added, and the reaction solution was slowly warmed to room temperature for 4 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain Intermediate B-3-2.

[0342] 6.1.3 Synthesis of Intermediate B-3-3

[0343] Intermediate B-3-2 (1.0 eq), hexamethylphosphoric triamide (5.0 eq), methyl fluorosulfonyldifluoroacetate (5.0 eq), and cuprous iodide (2.0 eq) were dissolved in DMF (1 mmol:2 mL). The atmosphere was replaced with nitrogen three times, and the reaction solution was heated to 80°C and reacted for 16 hours. After completion of the reaction, as monitored by LCMS, the reaction solution was diluted with ethyl acetate, washed three times with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain intermediate B-3-3.

[0344] 6.1.4 Synthesis of Intermediate B-3-4

[0345] Intermediate B-3-3 (1.0 eq) was dissolved in ethanol (1 mmol:2 mL) at room temperature, and 2N HCl in dioxane (5.0 eq) was added. The reaction mixture was then heated under reflux for 2 hours. After completion of the reaction, as monitored by LCMS, the reaction mixture was concentrated to near dryness and slurried with ethyl acetate and petroleum ether (1:2) to obtain pure intermediate B-3-4.

[0346] 6.1.5 Synthesis of Intermediate B-3

[0347] Intermediate B-3-4 (1.0 eq) and sodium bicarbonate (3.0 eq) were added to dichloromethane (1 mmol: 2 mL). Chloroacetyl chloride (1.05 eq) was added dropwise at 0°C, and the mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then slurried with petroleum ether to obtain Intermediate B-3.

[0348] 6.2 Synthesis of Intermediate A-3c was carried out according to the synthesis steps of Reaction Example A-3b.

[0349] 6.3 Synthesis of Intermediate A-4c was carried out according to the synthesis steps of Reaction Example A-4b.

[0350] 6.4 Synthesis of Intermediate A-5c was carried out according to the synthesis steps of Reaction Example A-5b.

[0351] 6.5 Synthesis of Intermediate A-6c was carried out according to the synthesis steps of Reaction Example A-6b.

[0352] 6.6 The synthesis of intermediate A-7c was carried out according to the synthesis steps of reaction example A-7b.

[0353] 6.7 Synthesis of target product

[0354] 6.7.1 The synthesis steps of the target product T032 are based on the synthesis of A-8. Its structure and general analytical data are shown in Table 1.

[0355] 6.7.2 The synthesis steps of the target product T033 are based on the synthesis of T016. Its structure and general analytical data are shown in Table 1.

[0356] 6.7.3 The synthesis steps of the target product T034 are based on the synthesis of T017. Its structure and general analytical data are shown in Table 1.

[0357] 6.7.4 The synthesis steps of the target product T035 are based on the synthesis of T018. Its structure and general analytical data are shown in Table 1.

[0358] 6.7.5 The synthesis steps of the target product T036 are based on the synthesis of T019. Its structure and general analytical data are shown in Table 1.

[0359] 6.7.6 The synthesis steps of the target product T037 are based on the synthesis of T020. Its structure and general analytical data are shown in Table 1.

[0360] 6.7.7 The synthesis steps of the target product T038 are based on the synthesis of T021. Its structure and general analytical data are shown in Table 1.

[0361] 6.7.8 The synthesis steps of the target product T039 are based on the synthesis of T006. Its structure and general analytical data are shown in Table 1.

[0362] 6.7.9 The synthesis steps of the target product T040 are based on the synthesis of T013. Its structure and general analytical data are shown in Table 1.

[0363] 6.7.10 The synthesis steps of target product T041 are based on the synthesis of T014. Its structure and general analytical data are shown in Table 1.

[0364] Example 7

[0365] The synthetic route is as follows:

[0366] 7.1 Synthesis of Intermediate B-4

[0367] 7.1.1 Synthesis of Intermediate B-4-1

[0368] The intermediate 4-amino-2-fluorotrifluorotoluene (1.0 eq) and boron trifluoride etherate (1.0 eq) were dissolved in dichloromethane (1 mmol: 3 mL) at room temperature. The reaction solution was then cooled to 0°C and NIS (1.0 eq) was added dropwise. The reaction solution was warmed to room temperature and reacted for 2 hours. After the reaction was completed as monitored by LCMS, the reaction solution was concentrated to dryness, diluted with ethyl acetate, poured into a saturated sodium thiosulfate solution, and stirred at room temperature for 5-10 minutes. The organic phase was then retained and washed twice with water and once with saturated brine. The organic phase was spin-dried and purified by column chromatography to obtain intermediate B-4-1.

[0369] 7.1.2 Synthesis of Intermediate B-4-2

[0370] Intermediate B-4-1 (1.0 eq), trimethylcyclotriboroxane (3.2 eq), Pd(PPh3)4 (0.05 eq), and potassium carbonate (4.6 eq) were dissolved in 1,4-dioxane (1 mmol:3 mL). The reaction mixture was heated to 80°C for 16 hours. After completion of the reaction, as monitored by LCMS, the mixture was cooled to room temperature and diluted with ethyl acetate, washed twice with water, and once with saturated brine. The organic phase was then dried and purified by column chromatography to yield intermediate B-4-2.

[0371] 7.1.3 Synthesis of Intermediate B-4

[0372] Intermediate B-4-2 (1.0 eq) and sodium bicarbonate (3.0 eq) were added to dichloromethane (1 mmol:2 mL). Chloroacetyl chloride (1.05 eq) was added dropwise at 0°C, and the mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then slurried with petroleum ether to obtain intermediate B-4.

[0373] 7.2 The synthesis of intermediate A-3d was carried out according to the synthesis steps of Reaction Example A-3b.

[0374] 7.3 Synthesis of Intermediate A-4d was carried out according to the synthesis steps of Reaction Example A-4b.

[0375] 7.4 Synthesis of Intermediate A-5d was carried out according to the synthesis steps of Reaction Example A-5b.

[0376] 7.5 Synthesis of Intermediate A-6d was carried out according to the synthesis steps of Reaction Example A-6b.

[0377] 7.6 The synthesis of intermediate A-7d was carried out according to the synthesis steps of Reaction Example A-7b.

[0378] 7.7 Synthesis of target product

[0379] 7.7.1 The synthesis steps of the target product T042 are based on the synthesis of A-8. Its structure and general analytical data are shown in Table 1.

[0380] 7.7.2 The synthesis steps of the target product T043 are based on the synthesis of T016. Its structure and general analytical data are shown in Table 1.

[0381] 7.7.3 The synthesis steps of the target product T044 are based on the synthesis of T017. Its structure and general analytical data are shown in Table 1.

[0382] 7.7.4 The synthesis steps of the target product T045 are based on the synthesis of T018. Its structure and general analytical data are shown in Table 1.

[0383] 7.7.5 The synthesis steps of the target product T046 are based on the synthesis of T019. Its structure and general analytical data are shown in Table 1.

[0384] 7.7.6 The synthesis steps of the target product T047 are based on the synthesis of T020. Its structure and general analytical data are shown in Table 1.

[0385] 7.7.7 The synthesis steps of the target product T048 are based on the synthesis of T021. Its structure and general analytical data are shown in Table 1.

[0386] 7.7.8 The synthesis steps of the target product T049 are based on the synthesis of T006. Its structure and general analytical data are shown in Table 1.

[0387] 7.7.9 The synthesis steps of the target product T050 are based on the synthesis of T013. Its structure and general analytical data are shown in Table 1.

[0388] 7.7.10 The synthesis steps of target product T051 are based on the synthesis of T014. Its structure and general analytical data are shown in Table 1.

[0389] Example 8

[0390] The synthetic route is as follows:

[0391] 8.1 Synthesis of Intermediate B-5

[0392] p-Trifluoromethylaniline (1.0 eq) was added to dichloromethane (1 mmol: 2 mL), and chloroacetyl chloride (1.05 eq) was added dropwise at 0°C. The mixture was then allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was then slurried with petroleum ether to obtain Intermediate B-5.

[0393] 8.2 The synthesis of intermediate A-3e was carried out according to the synthesis steps of reaction example A-3b.

[0394] 8.3 Synthesis of Intermediate A-4e was carried out according to the synthesis steps of Reaction Example A-4b.

[0395] 8.4 Synthesis of Intermediate A-5e was carried out according to the synthesis steps of Reaction Example A-5b.

[0396] 8.5 Synthesis of Intermediate A-6e was carried out according to the synthesis steps of Reaction Example A-6b.

[0397] 8.6 The synthesis of intermediate A-7e was carried out according to the synthesis steps of Reaction Example A-7b.

[0398] 8.7 Synthesis of target product

[0399] 8.7.1 The synthesis steps of the target product T052 are based on the synthesis of A-8. Its structure and general analytical data are shown in Table 1.

[0400] 8.7.2 The synthesis steps of the target product T053 are based on the synthesis of T016. Its structure and general analytical data are shown in Table 1.

[0401] 8.7.3 The synthesis steps of the target product T054 are based on the synthesis of T017. Its structure and general analytical data are shown in Table 1.

[0402] 8.7.4 The synthesis steps of the target product T055 are based on the synthesis of T018. Its structure and general analytical data are shown in Table 1.

[0403] 8.7.5 The synthesis steps of the target product T056 are based on the synthesis of T019. Its structure and general analytical data are shown in Table 1.

[0404] 8.7.6 The synthesis steps of the target product T057 are based on the synthesis of T020. Its structure and general analytical data are shown in Table 1.

[0405] 8.7.7 The synthesis steps of the target product T058 are based on the synthesis of T021. Its structure and general analytical data are shown in Table 1.

[0406] 8.7.8 The synthesis steps of target product T059 are based on the synthesis of T006. Its structure and general analytical data are shown in Table 1.

[0407] 8.7.9 The synthesis steps of the target product T060 are based on the synthesis of T013. Its structure and general analytical data are shown in Table 1.

[0408] 8.7.10 The synthesis steps of target product T061 are based on the synthesis of T014. Its structure and general analytical data are shown in Table 1.

[0409] Example 9

[0410] The synthetic route is as follows:

[0411] 9.1 Synthesis of Intermediate B-6

[0412] 4-(2-Methyl-4-trifluoromethyl)aniline (1.0 eq) was added to dichloromethane (1 mmol: 2 mL). Chloroacetyl chloride (1.05 eq) was added dropwise at 0°C, and the mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then slurried with petroleum ether to obtain Intermediate B-6.

[0413] 9.2 The synthesis of intermediate A-3f was carried out according to the synthesis steps of reaction example A-3b.

[0414] 9.3 Synthesis of Intermediate A-4f was carried out according to the synthesis steps of Reaction Example A-4b.

[0415] 9.4 Synthesis of Intermediate A-5f was carried out according to the synthesis steps of Reaction Example A-5b.

[0416] 9.5 Synthesis of Intermediate A-6f was carried out according to the synthesis steps of Reaction Example A-6b.

[0417] 9.6 The synthesis of intermediate A-7f was carried out according to the synthesis steps of reaction example A-7b.

[0418] 9.7 Synthesis of target product

[0419] 9.7.1 The synthesis steps of target product T062 are based on the synthesis of A-8. Its structure and general analytical data are shown in Table 1.

[0420] 9.7.2 The synthesis steps of the target product T063 are based on the synthesis of T016. Its structure and general analytical data are shown in Table 1.

[0421] 9.7.3 The synthesis steps of the target product T064 are based on the synthesis of T017. Its structure and general analytical data are shown in Table 1.

[0422] 9.7.4 The synthesis steps of the target product T065 are based on the synthesis of T018. Its structure and general analytical data are shown in Table 1.

[0423] 9.7.5 The synthesis steps of the target product T066 are based on the synthesis of T019. Its structure and general analytical data are shown in Table 1.

[0424] 9.7.6 The synthesis steps of the target product T067 are based on the synthesis of T020. Its structure and general analytical data are shown in Table 1.

[0425] 9.7.7 The synthesis steps of the target product T068 are based on the synthesis of T021. Its structure and general analytical data are shown in Table 1.

[0426] 9.7.8 The synthesis steps of the target product T069 are based on the synthesis of T006. Its structure and general analytical data are shown in Table 1.

[0427] 9.7.9 The synthesis steps of the target product T070 are based on the synthesis of T013. Its structure and general analytical data are shown in Table 1.

[0428] 9.7.10 The synthesis steps of target product T071 are based on the synthesis of T014. Its structure and general analytical data are shown in Table 1.

[0429] Example 10

[0430] The synthetic route is as follows:

[0431] 10.1 Synthesis of Intermediate B-7

[0432] 2-Fluoro-4-(trifluoromethyl)aniline (1.0 eq) was added to dichloromethane (1 mmol: 2 mL). Chloroacetyl chloride (1.05 eq) was added dropwise at 0°C, and the mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then slurried with petroleum ether to obtain Intermediate B-7.

[0433] 10.2 Synthesis of intermediate A-3g was carried out according to the synthetic procedure of A-3b.

[0434] 10.3 Synthesis of intermediate A-4g was carried out according to the synthetic procedure of A-4b.

[0435] 10.4 Synthesis of intermediate A-5g was carried out according to the synthetic procedure of A-5b.

[0436] 10.5 Synthesis of intermediate A-6g was carried out according to the synthesis procedure of A-6b.

[0437] 10.6 Synthesis of intermediate A-7g was carried out according to the synthetic procedure of A-7b.

[0438] 10.7 Synthesis of target product

[0439] 10.7.1 The synthesis steps of target product T072 are based on the synthesis of A-8. Its structure and general analytical data are shown in Table 1.

[0440] 10.7.2 The synthesis steps of the target product T073 are based on the synthesis of T016. Its structure and general analytical data are shown in Table 1.

[0441] 10.7.3 The synthesis steps of the target product T074 are based on the synthesis of T017. Its structure and general analytical data are shown in Table 1.

[0442] 10.7.4 The synthesis steps of the target product T075 are based on the synthesis of T018. Its structure and general analytical data are shown in Table 1.

[0443] 10.7.5 The synthesis steps of the target product T076 are based on the synthesis of T019. Its structure and general analytical data are shown in Table 1.

[0444] 10.7.6 The synthesis steps of the target product T077 are based on the synthesis of T020. Its structure and general analytical data are shown in Table 1.

[0445] 10.7.7 The synthesis steps of the target product T078 are based on the synthesis of T021. Its structure and general analytical data are shown in Table 1.

[0446] 10.7.8 The synthesis steps of target product T079 are based on the synthesis of T006. Its structure and general analytical data are shown in Table 1.

[0447] 10.7.9 The synthesis steps of the target product T080 are based on the synthesis of T013. Its structure and general analytical data are shown in Table 1.

[0448] 10.7.10 The synthesis steps of target product T081 are based on the synthesis of T014. Its structure and general analytical data are shown in Table 1.

[0449] 10.7.11 Synthesis of Target Product T094

[0450] Intermediate A-7g (1.0 eq), PyBOP (2.5 eq), and DIEA (3 e.q.) were dissolved in DMF (1 mmol:10 mL). 3-Hydroxy-2-pyrazinecarboxylic acid (2.5 eq) was added, and the reaction temperature was raised to 50°C for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with water and extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to high-pressure reverse transpiration to yield compound T094. Its structure and general analytical data are shown in Table 1.

[0451] 10.7.12 Synthesis of Target Product T095

[0452] Intermediate A-7g (1.0 eq), PyBOP (2.5 eq), and DIEA (3 e.q.) were dissolved in DMF (1 mmol:10 mL). 6-methylpyrimidine-4-carboxylic acid (2.5 eq) was then added, and the reaction temperature was raised to 50°C for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with water and extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to high-pressure reverse transpiration to yield compound T095. Its structure and general analytical data are shown in Table 1.

[0453] 10.7.13 Synthesis of Target Product T096

[0454] Intermediate A-7g (1.0 eq), PyBOP (2.5 eq), and DIEA (3 e.q.) were dissolved in DMF (1 mmol:10 mL). 2-Aminopyrimidine-4-carboxylic acid (2.5 eq) was added, and the reaction temperature was raised to 50°C for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with water and extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to high-pressure reverse transpiration to produce compound T096. Its structure and general analytical data are shown in Table 1.

[0455] 10.7.14 Synthesis of Target Product T099

[0456] Intermediate A-7g (1.0 eq), PyBOP (2.5 eq), and DIEA (3 e.q.) were dissolved in DMF (1 mmol:10 mL). 3-Carboxypyridazine (2.5 eq) was added, and the reaction temperature was raised to 50°C for 2 hours. After completion of the reaction, monitored by LC-MS, the reaction solution was diluted with water and extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to high-pressure reverse transpiration to yield compound T099. Its structure and general analytical data are shown in Table 1.

[0457] 10.7.15 Synthesis of Target Product T100

[0458] Intermediate A-7g (1.0 eq), PyBOP (2.5 eq), and DIEA (3 e.q.) were dissolved in DMF (1 mmol:10 mL). 4-Pyrimidinecarboxylic acid (2.5 eq) was then added, and the reaction temperature was raised to 50°C for two hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with water and extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to high-pressure reverse transpiration to yield Compound T100, whose structure and general analytical data are shown in Table 1.

[0459] 10.7.16 Synthesis of Target Product T101

[0460] Intermediate A-7g (1.0 eq), PyBOP (2.5 eq), and DIEA (3 e.q.) were dissolved in DMF (1 mmol / 10 mL). 2,6-Dimethylpyrimidine-4-carboxylic acid (2.5 eq) was added, and the reaction temperature was raised to 50°C for 2 hours. After completion of the reaction, monitored by LC-MS, the reaction solution was diluted with water and extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to high-pressure reverse transpiration to yield compound T101. Its structure and general analytical data are shown in Table 1.

[0461] 10.7.17 Synthesis of Target Product T102

[0462] Intermediate A-7g (1.0 eq), PyBOP (2.5 eq), and DIEA (3 e.q.) were dissolved in DMF (1 mmol:10 mL). 5-Fluoro-2-pyridinecarboxylic acid (2.5 eq) was added, and the reaction temperature was raised to 50°C for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with water and extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to high-pressure reverse transpiration to yield compound T102, whose structure and general analytical data are shown in Table 1.

[0463] 10.7.18 Synthesis of Target Product T103

[0464] Intermediate A-7g (1.0 eq), PyBOP (2.5 eq), and DIEA (3 e.q.) were dissolved in DMF (1 mmol:10 mL). 3-Fluoropyridine-2-carboxylic acid (2.5 eq) was added, and the reaction temperature was raised to 50°C for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with water and extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to high-pressure reverse transpiration to yield compound T103, whose structure and general analytical data are shown in Table 1.

[0465] 10.7.19 Synthesis of Target Product T104

[0466] Intermediate A-7g (1.0 eq), PyBOP (2.5 eq), and DIEA (3 e.q.) were dissolved in DMF (1 mmol:10 mL). 3,5-Difluoro-2-pyridinecarboxylic acid (2.5 eq) was added, and the reaction temperature was raised to 50°C for 2 hours. After completion of the reaction, monitored by LC-MS, the reaction solution was diluted with water and extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to high-pressure reverse transpiration to yield compound T104. Its structure and general analytical data are shown in Table 1.

[0467] 10.7.20 Synthesis of Target Product T105

[0468] Intermediate A-7g (1.0 eq), PyBOP (2.5 eq), and DIEA (3 e.q.) were dissolved in DMF (1 mmol:10 mL). 5-Fluoro-6-methylpyridine-2-carboxylic acid (2.5 eq) was added, and the reaction temperature was raised to 50°C for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with water and extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to high pressure reverse reaction to yield compound T105. Its structure and general analytical data are shown in Table 1.

[0469] 10.7.21 Synthesis of Target Product T106

[0470] Intermediate A-7g (1.0 eq), PyBOP (2.5 eq), and DIEA (3 e.q.) were dissolved in DMF (1 mmol:10 mL). 5-Fluoro-3-methylpicolinic acid (2.5 eq) was added, and the reaction temperature was raised to 50°C for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with water and extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to high-pressure reverse transpiration to yield Compound T106, whose structure and general analytical data are shown in Table 1.

[0471] Example 11

[0472] The synthetic route is as follows:

[0473] 11.1 Synthesis of Intermediate B-8

[0474] 11.1.1 Synthesis of Intermediate B-8-1

[0475] The intermediate 4-amino-2-fluorobenzotrifluoride (1.0 eq) was dissolved in acetonitrile (1 mmol: 2 mL) at room temperature. N-chlorosuccinimide (1.05 eq) was added in batches, and the reaction mixture was heated to 50°C for 6 hours. After completion of the reaction, the acetonitrile was removed by spin drying, the concentrate was diluted with ethyl acetate, and the organic phase was washed twice with water and once with saturated brine. The organic phase was then dried and purified by column chromatography to obtain pure intermediate B-8-1.

[0476] 11.1.2 Synthesis of Intermediate B-8

[0477] Intermediate B-8-1 (1.0 eq) was added to dichloromethane (1 mmol: 2 mL), and chloroacetyl chloride (1.05 eq) was added dropwise at 0°C. The mixture was then reacted at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then slurried with petroleum ether to obtain intermediate B-8.

[0478] 11.2 Synthesis of intermediate A-3h was based on the synthetic procedure of A-3b.

[0479] 11.3 Synthesis of intermediate A-4h was based on the synthetic procedure of A-4b.

[0480] 11.4 Synthesis of intermediate A-5h was carried out according to the synthetic procedure of A-5b.

[0481] 11.5 Synthesis of intermediate A-6h was based on the synthetic procedure of A-6b.

[0482] 11.6 Synthesis of intermediate A-7h was based on the synthetic procedure of A-7b.

[0483] 11.7 Synthesis of target product

[0484] 11.7.1 The synthesis steps of target product T082 are based on the synthesis of A-8. Its structure and general analytical data are shown in Table 1.

[0485] 11.7.2 The synthesis steps of the target product T083 are based on the synthesis of T016. Its structure and general analytical data are shown in Table 1.

[0486] 11.7.3 The synthesis steps of the target product T084 are based on the synthesis of T017. Its structure and general analytical data are shown in Table 1.

[0487] 11.7.4 The synthesis steps of the target product T085 are based on the synthesis of T018. Its structure and general analytical data are shown in Table 1.

[0488] 11.7.5 The synthesis steps of the target product T086 are based on the synthesis of T019. Its structure and general analytical data are shown in Table 1.

[0489] 11.7.6 The synthesis steps of the target product T087 are based on the synthesis of T020. Its structure and general analytical data are shown in Table 1.

[0490] 11.7.7 The synthesis steps of the target product T088 are based on the synthesis of T021. Its structure and general analytical data are shown in Table 1.

[0491] 11.7.8 The synthesis steps of the target product T089 are based on the synthesis of T006. Its structure and general analytical data are shown in Table 1.

[0492] 11.7.9 The synthesis steps of the target product T090 are based on the synthesis of T013. Its structure and general analytical data are shown in Table 1.

[0493] 11.7.10 The synthesis steps of the target product T091 are based on the synthesis of T014. Its structure and general analytical data are shown in Table 1.

[0494] Example 12

[0495] The synthetic route is as follows:

[0496] 12.1 Synthesis of Intermediate A-3i The synthesis procedure of A-3b was followed.

[0497] 12.2 Synthesis of intermediate A-4i was based on the synthetic procedure of A-4b.

[0498] 12.3 Synthesis of intermediate A-5i was based on the synthetic procedure of A-5b.

[0499] 12.4 Synthesis of intermediate A-6i was based on the synthetic procedure of A-6b.

[0500] 12.5 Synthesis of intermediate A-7i was carried out according to the synthetic procedure of A-7b.

[0501] 12.6 Synthesis of intermediate 8i was carried out according to the synthetic procedure of A-8h.

[0502] 12.7 Synthesis of target product

[0503] 12.7.1 Synthesis of target products T097 and T098, where BX = B-7.

[0504] Intermediate A-7i (1.0 eq), C-5 (2.0 eq), and N,N-diisopropylethylamine (3 e.q.) were dissolved in N,N-dimethylformamide (1 mmol:5 mL) at room temperature. 1H-Benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (2.0 eq) was then added at 0°C, and the reaction temperature was raised to 40°C for 2 hours. After completion of the reaction, monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The purified product was purified by column chromatography, and then chiral separation by SFC afforded the target products T097 and T098, respectively, according to the order of peak elution. Their structures and general analytical data are shown in Table 1.

[0505] The chiral separation conditions are as follows:

[0506] Prep-HPLC conditions:

[0507] Chromatographic column: CHIRALPAK IG, 2 cm × 25 cm, 5 μm;

[0508] Mobile phase: A: hexane (0.1% FA); B: MeOH:DCM;

[0509] Flow rate: 20 mL / min;

[0510] Wavelength: UV 220nm;

[0511] Column temperature: 25°C;

[0512] Prep-HPLC chromatograph: Prep-HPLC-Gilson.

[0513] 12.7.2 Synthesis of Target Products T113 and T114 Based on the synthesis of T111, target products T113 and T114 were obtained in the order of peak elution by SFC chiral resolution. Their structures and general analytical data are shown in Table 1. The chiral resolution conditions were the same as those for T097 and T098.

[0514] 12.7.3 Synthesis of target products T115 and T116, where BX = B-5.

[0515] Intermediate P-10 (1.0 eq) was dissolved in trifluoroacetic acid (1 mmol / 5 mL) at room temperature and then heated to 60°C for 12 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The target products T115 and T116 were then separated by SFC in the order of peak elution. The chiral separation conditions were the same as for T097 and T098. Their structures and general analytical data are shown in Table 1.

[0516] Example 13

[0517] The synthetic route is as follows:

[0518] 13.1 Synthesis of Intermediate A-2-1 was carried out according to the synthesis procedure of A-2.

[0519] 13.2 Synthesis of intermediate A-4j was carried out according to the synthesis steps of A-3.

[0520] 13.3 Synthesis of intermediate A-5j was based on the synthetic procedure of A-5b.

[0521] 13.4 Synthesis of intermediate A-6j was based on the synthetic procedure of A-6b.

[0522] 13.5 Synthesis of intermediate A-7j was based on the synthetic procedure of A-7b.

[0523] 13.6 The synthesis of intermediate A-8j was based on the synthesis steps of A-8i.

[0524] 13.7 Synthesis of target product

[0525] 13.7.1 Synthesis of target product T093, where BX = B-5.

[0526] Intermediate A-71 (1.0 eq), C-5 (2.0 eq), and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol:5 mL) at room temperature. 1H-Benzotriazol-1-yloxytripyrrolidinoyl hexafluorophosphate (2.0 eq) was then added at 0°C, and the reaction temperature was raised to 40°C for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to high-pressure reverse transpiration to yield compound T093. Its structure and general analytical data are shown in Table 1.

[0527] 13.7.2 Synthesis of target product T111, where BX = B-7.

[0528] Its synthesis was based on that of T093, and its structure and general analytical data are shown in Table 1.

[0529] 13.7.3 The synthesis of target product T112 was based on the synthesis of T019, where BX = B-5. Its structure and general analytical data are shown in Table 1.

[0530] 2-Fluoro-4-(pentafluorothio)aniline (1.0 eq) was added to dichloromethane (1 mmol:2 mL). Chloroacetyl chloride (1.05 eq) was added dropwise at 0°C, and the mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product, which was then slurried with petroleum ether to obtain Intermediate B-9.

[0531] 13.7.4 The synthesis of target product T121 was based on the synthesis of T019, where BX = B-9. Its structure and general analytical data are shown in Table 1.

[0532] Example 14

[0533] The synthetic route is as follows:

[0534] 14.1 Synthesis of Intermediate C-12-1

[0535] 3-Hydroxy-2-iodopyridine (1.0 eq), benzyl bromide (1.05 eq), and potassium carbonate (1.5 eq) were dissolved in DMF (1 mmol:5 mL) at room temperature. The reaction mixture was heated to 50°C and stirred for two hours. After completion of the reaction, as monitored by LC-MS, the reaction mixture was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield product C-12-1.

[0536] 14.2 Synthesis of Intermediate C-12-2

[0537] C-12-1 (1.0 eq), benzyl mercaptan (1.2 eq), PD2DBA3 (0.02 eq), and Xantphos (0.06 eq) were dissolved in 1,4-dioxane (1 mmol:10 mL) at room temperature. The atmosphere was replaced with nitrogen, and the reaction mixture was heated to 100°C and stirred for two hours. After completion of the reaction, as monitored by LC-MS, the reaction mixture was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield product C-12-2.

[0538] 14.3 Synthesis of Intermediate C-12

[0539] Intermediate C-12-2 (1.0 eq) was dissolved in acetonitrile (1 mmol:4 mL) and water (1 mmol:0.5 mL), cooled to 0°C, and acetic acid (6.0 eq) and 1,3-dichloro-5,5-dimethylhydantoin (1.0 eq) were added. The mixture was then allowed to warm to room temperature and react for 5 hours. After completion of the reaction, the pH of the reaction solution was adjusted to 7 with saturated sodium bicarbonate and extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain Intermediate C-12.

[0540] 14.4 Synthesis of Intermediate P-12

[0541] Compound P-12 is synthesized by condensing intermediate A-7g (Y is CH2, n=1, m=1) obtained in the synthetic implementation steps of Example 10 with C-12.

[0542] Intermediate A-7 (1.0 eq) and triethylamine (5 e.q.) were dissolved in dichloromethane (1 mmol:10 mL). The reaction solution was then cooled to 0°C and added with Intermediate C-3 (2.5 eq). The mixture was then allowed to warm to room temperature and allowed to react for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with water and extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain pure intermediate P-12.

[0543] 14.5 Synthesis of target product T092

[0544] Intermediate P-12 was dissolved in trifluoroacetic acid (1 mmol:5 mL) and the reaction mixture was heated to 80°C overnight. After completion of the reaction, as monitored by LC-MS, the reaction mixture was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound T092 was then prepared by high-pressure reverse transpiration. Its structure and general analytical data are shown in Table 1.

[0545] Example 15

[0546] 15.1 Synthesis of Intermediate A-3k

[0547] Intermediate A-3k is prepared by carrying out the steps of Example 1 to obtain intermediate A-2.

[0548] A-2 (1.0 eq) was weighed and dissolved in a 1:1 ratio of DMF:THF (1 mmol:15 mL) at room temperature. The reaction solution was cooled to 0°C and NaH (1.5 eq) was added portionwise. After reacting in an ice bath for two hours, the air in the reaction flask was replaced with a nitrogen atmosphere. SEMCl (2.0 eq) was added dropwise at 0°C. The reaction solution was slowly warmed to room temperature and stirred overnight. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain pure intermediate A-3k.

[0549] 15.2 Synthesis of Intermediate A-4k

[0550] A-3k (1.0 eq) was weighed and dissolved in anhydrous THF at room temperature. The air in the reaction flask was replaced with nitrogen. After cooling to -78°C, NaHMDS (1.5 eq) was added dropwise. After stirring at -78°C for two hours, allyl iodide (1.5 eq) was added dropwise. The reaction solution was slowly warmed to room temperature and stirred overnight. After completion of the reaction, monitored by LC-MS, the reaction was quenched with aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic phases were washed once with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain pure A-4k.

[0551] 15.3 Synthesis of Intermediate A-5k

[0552] A-4k (1.0 eq) and m-CPBA (2.5 eq) were dissolved in DCM (1 mmol:10 mL) at room temperature and allowed to react overnight. After completion of the reaction, as monitored by LC-MS, the mixture was diluted with water and extracted twice with dichloromethane. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain pure intermediate A-5k.

[0553] 15.4 Synthesis of Intermediate A-6k

[0554] A-5k (1.0 eq) and DIEA (3.0 eq) were dissolved in DMSO (1 mmol:10 mL) at room temperature under nitrogen. The reaction mixture was heated to 120°C and stirred overnight. After completion of the reaction, as monitored by LC-MS, the reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain intermediate A-6k.

[0555] 15.5 Synthesis of Intermediate A-7k

[0556] First, prepare fresh Jones reagent. Dissolve chromium trioxide (5 g, 0.25 mol) in water (15 mL) in a 100 mL beaker. Slowly add concentrated sulfuric acid (25 mL) dropwise with stirring under an ice bath. Maintain the solution at 0-5°C. The prepared reagent has a solubility of 2.5 M. Weigh A-6k (1.0 eq) and dissolve it in acetone (1 mmol, 10 mL). Cool the reaction mixture to 0°C and add freshly prepared Kone reagent (2.5 eq, 2.5 M) dropwise. Stir at room temperature for two hours. After completion of the reaction, monitor the reaction using LC-MS. Dilute the reaction mixture with water and extract twice with ethyl acetate. Combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain intermediate A-7k.

[0557] 15.5 Synthesis of Intermediate A-8k

[0558] Intermediate A-7k (1.0 eq), 2-fluoro-4-(trifluoromethyl)aniline (1.2 eq), 50% T3P in EA (4.5 eq), and triethylamine (15 e.q.) were dissolved in ethyl acetate (1 mmol, 10 mL). The reaction mixture was then heated to 50°C and stirred for one hour. After completion of the reaction, as monitored by LC-MS, the reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain Intermediate A-8k.

[0559] 15.6 Synthesis of Intermediate A-9k

[0560] Intermediate A-8k (1.0 eq), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.2 eq), Pd(dppf)Cl2 (0.05 eq), and potassium phosphate (2.5 eq) were added to 1,4-dioxane and water (2.5:1, 1 mmol:5 mL). The atmosphere was purged with nitrogen three times, and the temperature was then raised to 80°C for 4 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate and washed with brine. The organic phase was collected, dried over anhydrous sodium sulfate, and spin-dried. The resulting product was then purified by column chromatography to yield intermediate A-9k.

[0561] 15.7 Synthesis of Intermediate A-10k

[0562] Intermediate A-9k (1.0 eq) was dissolved in N,N-dimethylformamide (1 mmol:10 mL) at room temperature, followed by the addition of N-bromosuccinimide (1.5 eq) in portions. The reaction was allowed to react for 4 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed once with saturated sodium bicarbonate, twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to yield Intermediate A-10k.

[0563] 15.8 Synthesis of Intermediate A-11k

[0564] Intermediate A-9 (1.0 eq), (R)-1-BOC-1,7-diazaspiro[4.4]nonane (0.8 eq), and DIEA (3.0 eq) were weighed and dissolved in DMSO (1 mmol:2 mL). The mixture was then heated to 120°C and stirred overnight. After completion of the reaction, as monitored by LC-MS, the reaction mixture was diluted with ethyl acetate, washed once with saturated sodium bicarbonate, twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain Intermediate A-11k.

[0565] 15.9 Synthesis of Intermediate A-12k

[0566] Intermediate A-11k (1.0 eq) was dissolved in CF3COOH:DCM (1:1; 1 mmol:10 mL) at room temperature. The reaction mixture was heated to 40°C for 12 hours. After completion of the reaction, monitored by LC-MS, the solution was evaporated to dryness. The concentrate was diluted with ethyl acetate, washed once with saturated sodium bicarbonate solution and once with saturated brine, and the organic phase was evaporated to dryness to obtain product A-12k.

[0567] 15.10 Synthesis of Intermediate P-13

[0568] Intermediate A-12k (1.0 eq), 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (2.0 eq), and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol:5 mL) at room temperature. 1H-Benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (2.0 eq) was then added at 0°C. The reaction temperature was then raised to 40°C for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield pure P-13.

[0569] 15.11 Target products T107, T108, T109 and T110.

[0570] Intermediate A-11k (1.0 eq) was dissolved in trifluoroacetic acid at room temperature, and the reaction mixture was heated to 60°C for 12 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The purified product was purified by column chromatography and then chiral separation by SFC. The target products T107, T108, T109, and T110 were obtained in the order of peak elution. Their structures and general analytical data are shown in Table 1.

[0571] The chiral resolution conditions used were as follows:

[0572] First Prep-HPLC conditions:

[0573] Chromatographic column: CHIRALPAK IBN, 2 cm × 25 cm, 5 μm;

[0574] Mobile phase: A: MTBE (0.1% FA); B: MeOH:DCM;

[0575] Flow rate: 20 mL / min;

[0576] Wavelength: UV 220nm;

[0577] Column temperature: 25°C;

[0578] Chromatograph: Prep-HPLC-Gilson.

[0579] Second Prep-HPLC conditions:

[0580] Chromatographic column: CHIRALPAK IC, 2 cm × 25 cm, 5 μm;

[0581] Mobile phase: A: MTBE (0.1% FA); B: MEOH;

[0582] Flow rate: 20 mL / min;

[0583] Wavelength: UV 220nm;

[0584] Column temperature: 25°C;

[0585] Chromatograph: Prep-HPLC-Gilson.

[0586] Example 16

[0587] The synthetic route is as follows:

[0588] 16.1 Synthesis of Intermediate D-1

[0589] 16.1.1 Synthesis of Intermediate D-1-1

[0590] The intermediate thiophene-2,3-dicarboxylic acid (1.0 eq) was dissolved in tetrahydrofuran (1 mmol:2 mL) at 0°C, and a 1 mol / L solution of lithium aluminum tetrahydride in tetrahydrofuran (4.0 eq) was slowly added dropwise. The reaction mixture was then heated to 70°C and reacted for 16 hours. After completion of the reaction, as monitored by LCMS, the reaction mixture was cooled to 0°C and quenched by the addition of water and 10% sodium hydroxide solution. The mixture was dried over anhydrous sodium sulfate overnight, and the purified intermediate D-1-1 was filtered and concentrated.

[0591] 16.1.2 Synthesis of Intermediate D-1-2

[0592] Intermediate D-1-1 (1.0 eq) was added to tetrahydrofuran (1 mmol: 2 mL). N-bromosuccinimide (1.05 eq) was added portionwise at 0°C, followed by reaction at room temperature for 4 hours. After completion of the reaction, as monitored by TLC, the reaction solution was diluted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate solution and saturated brine. The organic phase was concentrated under reduced pressure at low temperature to obtain Intermediate D-1-2.

[0593] 16.1.3 Synthesis of Intermediate D-1-3

[0594] Intermediate D-1-2 (1.0 eq) was added to dimethyl carbonate (1 mmol:1 mL), and sodium methoxide (1.5 eq) was added portionwise. The mixture was then reacted at 120°C for 4 hours. After completion of the reaction, as monitored by LCMS, the reaction solution was cooled to room temperature and diluted with ethyl acetate and water. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to afford Intermediate D-1-3.

[0595] 16.1.4 Synthesis of Intermediate D-1

[0596] Intermediate D-1-3 (1.0 eq) was added to tetrahydrofuran (1 mmol:2 mL), and a solution of n-butyllithium in n-hexane (1.5 eq) was added dropwise at -78°C. After reacting at -78°C for half an hour, isopropyl pinacol borate (1.2 eq) was added dropwise, and the reaction was continued at -78°C for two hours. After completion of the reaction, as monitored by LCMS, the reaction solution was cooled, quenched with saturated ammonium chloride, and extracted twice with ethyl acetate. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain Intermediate D-1.

[0597] 16.2 Synthesis of Intermediate A-31 The synthesis procedure of A-3b was followed.

[0598] 16.3 Synthesis of Intermediate A-41 The synthesis procedure of A-4b was followed.

[0599] 16.4 Synthesis of Intermediate A-51 The synthesis procedure of A-5b was followed.

[0600] 16.5 The synthesis of intermediate A-61 was based on the synthesis procedure of A-6b.

[0601] 16.6 The synthesis of intermediate A-71 was based on the synthetic procedure of A-7b.

[0602] 16.6 Synthesis of target product

[0603] 16.6.1 When BX = B-5, the synthesis steps of the target product T117 are based on the synthesis of T019. Its structure and general analytical data are shown in Table 1.

[0604] 16.6.2 When BX = B-7, the synthesis of the target product T-118 is based on the synthesis of T019. Its structure and general analytical data are shown in Table 1.

[0605] 16.6.3 When BX = B-1, the synthesis of the target product T-119 is based on the synthesis of T019. Its structure and general analytical data are shown in Table 1.

[0606] The intermediate D-1 in Synthesis Example 16 was replaced by 4-dimethylaminopiperidine (Cas No.: 50533-97-6). The same steps as Synthesis Examples 16.2 to 16.6 were followed, except that BX = B-7. Following the synthesis of T019, the target product T120 was obtained. Its structure and general analytical data are shown in Table 1.

[0607] Intermediate D-1 in Synthesis Example 16 was replaced with tetrahydropyrrole (Cas No.: 123-75-1). Following the same steps as Synthesis Examples 16.2 to 16.6, with BX=B-7, the target product T122 was obtained according to the synthesis method of T019. Its structure and general analytical data are shown in Table 1.

[0608] The intermediate D-1 in Synthesis Example 16 was replaced by N-BOC-piperazine (Cas No.: 57260-71-6), and the corresponding intermediate A-6m was obtained through the same steps as Synthesis Examples 16.2 to 16.5 when BX=B-7.

[0609] Intermediate A-6m (1.0 eq) was dissolved in dichloromethane (1 mmol:5 mL) at room temperature, followed by the addition of trifluoroacetic acid (1 mmol:1 mL) at 0°C. The reaction mixture was then allowed to warm to room temperature for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was concentrated to near dryness under reduced pressure, diluted with dichloromethane, and the aqueous phase was adjusted to pH 8-9 with saturated sodium bicarbonate. The mixture was extracted twice with dichloromethane, and the organic phase was washed with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield Intermediate A-7m.

[0610] Intermediate A-7m (1.0 eq) was dissolved in tetrahydrofuran (1 mmol: 5 mL) at 0°C, and di-tert-butyl dicarbonate (1.0 eq) and sodium bicarbonate (1.0 eq) were added. The reaction mixture was allowed to slowly warm to room temperature and stirred for 1.5 hours. The reaction solution was concentrated, and the obtained organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound A-8m was then separated by column chromatography.

[0611] Intermediate A-8m (1.0 eq), C-7 (2.0 eq), and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol:5 mL) at room temperature. 1H-Benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (2.0 eq) was then added at 0°C, and the reaction temperature was raised to 40°C for 2 hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then isolated by column chromatography to yield compound A-9m.

[0612] Intermediate A-9m (1.0 eq) was dissolved in dichloromethane (1 mmol:5 mL) at room temperature, followed by the addition of trifluoroacetic acid (1 mmol:1 mL) at 0°C. The reaction mixture was then allowed to warm to room temperature for two hours. After completion of the reaction, as monitored by LC-MS, the reaction solution was concentrated to near dryness under reduced pressure, diluted with dichloromethane, and the aqueous phase was adjusted to pH 8-9 with saturated sodium bicarbonate. The reaction mixture was extracted twice with dichloromethane, and the organic phase was washed with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to high-pressure reverse transpiration to yield the target product, T123. Its structure and general analytical data are shown in Table 1.

[0613] Table 1 Example compounds and general analytical data

[0614] Activity test example:

[0615] Example 1: Determination of the inhibitory effect of the test substance on tumor cell growth

[0616] Taking SW48 cells as an example, the inhibitory activity of the compounds of the present invention on tumor growth was tested.

[0617] 1.1 Cell seeding

[0618] Human colon cancer SW48 cells (ZQ0793) were cultured in DMEM (C3113-0500) containing a mixture of 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin (C3421-0100) at 37°C and 5% CO2. The culture medium in the T25 flask was discarded, and 1 mL of PBS solution was added to rinse twice. Then, 1 mL of trypsin (C3530-0500) was added to the digestion solution and the cells were incubated in a 37°C incubator for 2 minutes to digest the cells. When the cell edges became round, 1 mL of culture medium containing 10% FBS was added to terminate the cell digestion and the cells were pipetted into a cell suspension. The cells were counted and then diluted to a cell density of 5×10 using complete culture medium. 4 100 μL of cell suspension was added to each well of a white transparent bottom 96-well plate (Coring, CLS3903) (PBS solution was added to the edge of the well plate), and the cell plate was placed in an incubator at 37°C and 5% CO2 for overnight culture.

[0619] 1.2 Compound preparation

[0620] The compound stock solution (100 mM DMSO stock solution) was diluted with DMSO to a 1 or 10 mM secondary stock solution. 1 μL of the secondary stock solution was added to 1 mL of DMEM complete medium and vortexed on a shaker to dissolve. A maximum dosing concentration of 1 or 10 μM was prepared. 8 to 10 dosing concentrations were prepared at a 3-fold dilution ratio and mixed thoroughly. 0.1% DMSO vehicle was added to the control group.

[0621] 1.3 Drug treatment

[0622] After the cells adhere, carefully aspirate the culture medium and add 100 μL of DMEM complete medium containing different concentrations of the drug to the corresponding wells of a 96-well plate. Set up three replicates for each concentration. Incubate the cell plates after drug administration in a 37°C, 5% CO2 incubator for 4 days.

[0623] 1.4 Bioanalytical methods

[0624] After 4 days of incubation, 50 μL of The detection reagent (Promega, G7572) was added, mixed and incubated with shaking, and the reaction was allowed to react at room temperature for 10 min. The chemiluminescence value RLU (Relative Luminescence Unit) was detected using a microplate reader. The cell viability at different drug concentrations was calculated according to the following formula, and the IC50 was fitted using Prism.

[0625] Cell viability (%) = ((As-Ab)) / ((Ac-Ab)*100)

[0626] As: RLU of experimental group (including cells, culture medium and drug molecules)

[0627] Ac: RLU of control group (containing cells, culture medium and DMSO solvent)

[0628] Ab: Zero well RLU (containing only culture medium)

[0629] 2 Experimental results

[0630] The experimental results are shown in Table 2.

[0631] Example 2: Enzyme activity experiment

[0632] 2.1 Determination of the inhibition of WRN helicase activity by the test substances

[0633] The helicase activity assay established in the literature was used to evaluate the effects of compounds on DNA-dependent WRN helicase activity (PMC6326523 DOI:10.1371 / journal.pone.0210525).

[0634] The protein used was WRN (500-1229) (Sino Biological, 17475-HNCB), expressed in baculovirus-insect cells. The assay was performed in a 384-well black microtiter plate (Loctite, M38-3111). The double-stranded fluorescent DNA fork substrate sequences were fork-F (TAMRA-5'-GCACTGGCCGTCGTTTTACGGTCGTGACT-3') and fork-R (5'-TTTTTTCCAAGTAAAACGACGGCCAGTGC-3'-BHQ2). The fluorescent DNA substrate fork was obtained by heating to 96°C followed by a gradient cooling (annealing buffer: 25 mM Tris, 2 mM MgCl2, 5 mM NaCl, pH 8.0). The reaction system was 50 μL, and the buffer solution was 25 mM Tris, 2 mM MgCl2, 5 mM NaCl, 1 mM DTT, 2.5 μg / mL calf thymus DNA, pH 8.0.

[0635] The IC50 value of the test compound's inhibition of WRN protein helicase activity was determined in two replicates. In the first, WRN protein and the test compound were incubated. A three-fold serial dilution of the compound solution in DMSO was prepared. 44 μL of WRN protein (at a final concentration of 50 nM) and 1 μL of the compound (at a final concentration of 1 μM, three-fold dilution) were added to a 384-well plate, shaken, and incubated for 1 hour. In the second, ATP and a fluorescent DNA substrate were added to a 5 μL volume, with a final ATP concentration of 2 mM and a fluorescent DNA substrate concentration of 200 nM. After the incubation of the small molecule and protein, the reaction system was added and incubated for 1 hour. RFU values ​​were measured using a microplate reader with excitation wavelengths of 544 nm and emission wavelengths of 590 nm. A high control group containing only the protein and the corresponding DMSO solvent was designated, while a low control group containing only the buffer without the protein was designated. The inhibition rate of the compound in inhibiting helicase activity was calculated as Inhibition = (high control-sample) / (high control-low control), and the IC50 value was obtained using GraphPad prism four-parameter fitting.

[0636] 2.2 Determination of the inhibition of WRN ATPase activity by the test substances

[0637] The protein used was WRN (500-1229) (Sino biological, 17475-HNCB). The assay was performed in a 384-well, white-bottomed ELISA plate (LABSELECT, 31432). The double-stranded DNA fork substrate sequences were fork-F (5'-GCACTGGCCGTCGTTTTACGGTCGTGACT-3') and fork-R (5'-TTTTTTCCAAGTAAAACGACGGCCAGTGC-3'). The assay buffer consisted of 25 mM Tris, 2 mM MgCl2, 5 mM NaCl, 1 mM DTT, and 2.5 μg / mL calf thymus DNA, pH 8.0.

[0638] Compound preparation: The compound stock solution (10 mM DMSO stock solution) was diluted with DMSO to a 500 μM secondary stock solution, which was then three-fold diluted with DMSO (6 + 12 μL) to prepare 10 gradients of drug molecules. This was then uniformly diluted with Assay Buffer (1 μL secondary stock solution + 11.5 μL Assay Buffer) to prepare a compound solution with a maximum concentration of 40 μM and three-fold dilutions containing 10 gradients (diluted and prepared using a 96-well non-skirted PCR plate).

[0639] Enzyme activity system reaction (3.75μL pro + 3.75μL cpds + 7.5μL DNA / ATP mix): According to the protein concentration (final: 25nM) determined by the WRN protease activity assay, a sufficient amount of protein solution was prepared and added to a 96-well skirtless PCR plate to carry out the enzyme activity reaction. 3.75μL of protein solution was dispensed into each well, followed by the addition of 3.75μL of the pre-prepared compound solution, centrifuged, and incubated for 30min. After the incubation, 7.5μL of DNA (final: 200nM) and ATP (final: 300μM) mixture was added to the plate and incubated for 30min. After the enzyme activity reaction, the solution was dispensed into a 384-well plate, 5μL per well, and two replicates were set up. In addition, the experimental group containing only the corresponding DMSO solvent was set as the high control, and the group containing only ATP buffer solution without protein was set as the blank control (low control).

[0640] ADP-Glo™ System Reaction (5+5+10μL): Immediately after the enzyme activity reaction is complete and aliquoted, add 5μL of ATP Depletion Reagent and incubate for 60 minutes. After the Regeant reaction is complete, add 10μL of Kinase Detection Reagent and incubate for 60 minutes. Chemiluminescence (RLU) values ​​were measured using a microplate reader. Data analysis and IC50 fitting were performed using the same methods as described for the helicase activity assay.

[0641] 3 Experimental results

[0642] The experimental results are shown in Table 2.

[0643] Table 2. Biochemical and cellular activities of the compounds

[0644] Note: ++++: IC50 < 100 nM; +++: 100 nM ≤ IC50 < 1 μM; ++: 1 μM ≤ IC50 < 10 μM; +: 10 μM ≤ IC50.

[0645] The IC50 curve of compound T074 inhibiting WRN helicase activity, the IC50 curve of inhibiting ATPase activity, and the EC50 curve of inhibiting tumor cell (SW48) growth are shown in Figures 1-3, respectively.

[0646] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

[0647] The aforementioned embodiments and methods described in the present invention may be varied based on the ability, experience, and preference of those skilled in the art.

[0648] In the present invention, merely listing the steps of the method in a certain order does not constitute any limitation on the order of the method steps.

Claims

1. A compound or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, wherein the compound has the following structure: in, represents a single bond or a double bond, and two Not a double bond at the same time; Ring A is a 4-6 membered heterocyclic ring; The J ring is a 6-18 membered spiro ring; X1, X2, X3, X4 are independently selected from: C(R5), N; R5 is selected from: H, D, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -O(C3-C 10 Cycloalkyl), -S(C 0-10 Alkyl), -S(C3-C 10 Cycloalkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2(C3-C 10 Cycloalkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -CO(C 0-10 alkyl); A1, A2, A3 are independently selected from: single bond, C1-C 10 Alkylene, wherein the C1-C 10 0-6 methylene units in the alkylene group are independently substituted by the following groups: -Cy-, -O-, -S-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OS(O)2-, -OC(O)N(R a )-、-C(O)N(R a )-、-N(R a )C(O)-、-N(R a )C(O)O-、-N(R a )C(O)N(R b )-、-N(R a )-、-S(O)2-、-S(O)2N(R a )-、-N(R a )S(O)2-、-S(O)-、-S(O)N(R a )-、-N(R a )S(O)-、-Si-、 Among them, R a and R b Independently selected from: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl); each -Cy- is independently an optionally substituted divalent ring selected from the following: arylene, cycloalkylene, heterocyclyl; wherein the C1-C 10 The H in the alkylene group is optionally substituted by one or more R0; R1 is one or more independent substituents on ring A, selected from: H, D, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -O(C3-C 10 Cycloalkyl), -S(C 0-10 Alkyl), -S(C3-C 10 Cycloalkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2(C3-C 10 Cycloalkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -CO(C 0-10 Alkyl), -Si(C 0-10 Alkyl)(C 0-10 Alkyl)(C 0-10 Alkyl); wherein, C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C 0-10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 4-10 membered heterocyclic group may be optionally substituted by one or more R0; R2, R3, R4 are independently selected from: H, D, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -O(C3-C 10 Cycloalkyl), -S(C 0-10 Alkyl), -S(C3-C 10 Cycloalkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2(C3-C 10 Cycloalkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -CO(C 0-10 Alkyl), -Si(C 0-10 Alkyl)(C 0-10 Alkyl)(C 0-10 Alkyl); wherein, C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C 0-10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 H in the aryl group or the 4-10 membered heterocyclic group may be optionally substituted by one or more R0; or, R3 and A1 and the atoms to which they are connected together form a carbocyclic ring or a heterocyclic ring, and H in the carbocyclic ring or the heterocyclic ring may be optionally substituted by one or more R0; R5 is one or more independent substituents on the J ring selected from: H, D, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -O(C3-C 10 Cycloalkyl), -S(C 0-10 Alkyl), -S(C3-C 10 Cycloalkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2(C3-C 10 Cycloalkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -CO(C 0-10 Alkyl), -Si(C 0-10 Alkyl)(C 0-10 Alkyl)(C 0-10 Alkyl); wherein, C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C 0-10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 4-10 membered heterocyclic group may be optionally substituted by one or more R0; R0 is selected from: D, =O, halogen, cyano, nitro, azido, -SF5, -OR', -C(O)R', -C(S)R', -C(O)OR', -C(S)SR', -OC(O)R', -OC(S)R', -OC(S)SR', -C(O)NR'R", -OC(O)NR'R", -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -OSO2NR'R", -NR'C(O)R", -NR'R", -SR', -SOR', -SO2R', -OSO2R', -SO3H, -SiR'R'R", C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl); Each R' and R" is independently selected from: H, D, Cl-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group); wherein the C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -O(C3-C 10 Cycloalkyl), -S(C 0-10 Alkyl), -S(C3-C 10 Cycloalkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2(C3-C 10 Cycloalkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -CO(C 0-10 Alkyl), -Si(C 0-10 Alkyl)(C 0-10 Alkyl)(C 0-10 alkyl); Preferably, the J ring is a 6-12 membered saturated or partially unsaturated spiro heterocycle, at least one of the ring atoms of which is nitrogen.

2. The compound according to claim 1, wherein Has the following structure: in, J1 ring is a 3-8 membered monocyclic carbocyclic ring or heterocyclic ring; J2 ring is a 3-8 membered monocyclic carbocyclic ring or heterocyclic ring; R 51 、R 52 One or more independent substituents on J1 and J2 rings, independently selected from: H, D, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -O(C3-C 10 Cycloalkyl), -S(C 0-10 Alkyl), -S(C3-C 10 Cycloalkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2(C3-C 10 Cycloalkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C3-C 10 Cycloalkyl), -CO(C 0-10 Alkyl), -Si(C 0-10 Alkyl)(C 0-10 Alkyl)(C 0-10 Alkyl); wherein, C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C 0-10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 4-10 membered heterocyclic group may be optionally substituted by one or more R0; Preferably, Partially selected from the following structures: Preferably, R 51 Selected from: H, halogen, hydroxy, mercapto, amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxy-substituted alkyl, -(C0-C3 alkylene)-(C3-C5 cycloalkyl), -O(C 1-3 Alkyl), -S(C 1-3 alkyl), -N(H)(C 1-3 Alkyl), -N(C 1-3 Alkyl)(C 1-3 alkyl); Preferably, R 52 Selected from: H, halogen, hydroxy, mercapto, amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxy-substituted alkyl, -(C0-C3 alkylene)-(C3-C5 cycloalkyl), -O(C 1-3 Alkyl), -S(C 1-3 alkyl), -N(H)(C 1-3 Alkyl), -N(C 1-3 Alkyl)(C 1-3 alkyl); More preferably, Has the following structure:

3. The compound according to claim 1 or 2, characterized in that Ring Wherein, X5 and X6 are independently selected from: C(H), N; Preferably, Ring in particular 4. The compound according to any one of claims 1 to 3, wherein A1 is Wherein, R6 and R7 are independently selected from: H, D, C1-C 10 Alkyl, C1-C 10 Haloalkyl, -O(C 0-10 Alkyl), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl); Preferably, R6 and R7 are independently selected from: H, D, C1-C3 alkyl; Preferably, R3 and R7 and the atoms to which they are connected together form a 4-8 membered carbocyclic ring or heterocyclic ring (e.g., a 5-7 membered saturated heterocyclic ring), wherein H in the carbocyclic ring or heterocyclic ring may be optionally substituted by one or more R0; more preferably, the carbocyclic ring or heterocyclic ring is optionally substituted by one or more groups selected from the following: H, D, halogen, cyano, hydroxyl, thiol, amino, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -(C0-C6 alkylene)-(phenyl), -O(C1-C6 alkyl), -S(C1-C6 alkyl), -N(H)(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -CON(C0-C6 alkyl)(C0-C6 alkyl), -N(C0-C6 alkyl)CO(C0-C6 alkyl), -SO2N(C0-C6 alkyl)(C0-C6 alkyl), -N(C0-C6 alkyl)SO2(C0-C6 alkyl), wherein the H in the C0-C6 alkylene, C0-C6 alkyl, C1-C6 alkyl, C3-C6 cycloalkyl, and phenyl group may be optionally substituted by a group selected from the group consisting of D, halogen, cyano, hydroxyl, mercapto, amino, C1-C3 alkyl, and C1-C3 alkoxy.

5. The compound according to any one of claims 1 to 4, characterized in that A2 is -C(O)N(R8)- or -S(O)2N(R8)-, R8 is selected from: H, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C6 cycloalkyl); Preferably, R8 is H.

6. The compound according to any one of claims 1 to 5, characterized in that R1 has the following structure: in: A4 is selected from the group consisting of: a single bond, C1-C6 alkylene, wherein 0-3 methylene units in the C1-C6 alkylene are independently substituted by: -O-, -S-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -C(O)N(H)-, -N(H)C(O)-, -N(H)-, -S(O)2-; Ring B is a 4-10 membered carbocyclic or heterocyclic ring; R 11 is one or more independent substituents on the B ring selected from: H, D, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -S(C 0-10 Alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl); wherein, C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C 0-10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 4-10 membered heterocyclic group may be optionally substituted by one or more R0; Preferably, A4 is a single bond; Preferably, Partially selected from the following structures: Among them, R 12 Selected from: H, D, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl); wherein, C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C 0-10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 4-10 membered heterocyclic group may be optionally substituted by one or more R0.

7. The compound according to claim 6, characterized in that R 12 Selected from: H, C1-C4 alkyl, C1-C4 haloalkyl, -(C1-C4 alkylene)-C(O)OH, -(C1-C4 alkylene)-C(O)-(C 0-4 alkyl), -(C1-C4 alkylene)-C(O)O-(C 0-4 alkyl), -CO(C 1-4 alkyl); Preferably, R 12 For H, 8. The compound according to claim 6, wherein Each R 11 independently selected from: H, halogen (such as F), C1-C4 alkyl, C1-C4 haloalkyl, -OH, C1-C4 alkoxy, C1-C4 haloalkoxy, -NH2, -N(H)(C 1-4 alkyl), -N(H)(C 1-4 Haloalkyl), -N(C 1-4 Alkyl)(C 1-4 haloalkyl), -(C1-C4 alkylene)-C(O)OH, -(C1-C4 alkylene)-C(O)-(C 0-4 alkyl), -(C1-C4 alkylene)-C(O)O-(C 0-4 alkyl), -CO(C 1-4 alkyl); Preferably, R 11 For H, F, methyl, ethyl, 9. The compound according to claim 6, wherein Partially selected from the following structures: in particular 10. The compound according to any one of claims 1 to 9, characterized in that R2 has the following structure: in: The E ring is a 4-12 membered carbocyclic or heterocyclic ring; R 21 is one or more independent substituents on the E ring selected from: H, D, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), halogen, cyano, nitro, azido, -SF5, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -S(C 0-10 Alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl); wherein, C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C 0-10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group or the 4-10 membered heterocyclic group may be optionally substituted by one or more R0; or, two R 21 Together with the ring atoms to which they are attached, they form a carbocyclic or heterocyclic ring, wherein H in the carbocyclic or heterocyclic ring may be optionally substituted with one or more R0; Preferably, Has the following structure: in particular More preferably, R2 has the following structure: in, X7 is selected from: C(R 23 ), N; R 22 to R 26 independently selected from: H, halogen, cyano, -SF5, hydroxyl, mercapto, -C(O)H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -O(C 1-6 Alkyl), -S(C 1-6 alkyl), -CO(C 1-6 alkyl), wherein H in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 alkylene, C3-C6 cycloalkyl may be optionally substituted by a group selected from the following: halogen, hydroxyl, C1-C3 alkoxy; or, two R 21 Together with the ring atoms to which they are attached, they form a carbocyclic or heterocyclic ring, wherein H in the carbocyclic or heterocyclic ring may be optionally substituted by a group selected from the group consisting of halogen, hydroxy, and C1-C3 alkoxy.

11. The compound according to claim 10, characterized in that R 22 Selected from: H, halogen, cyano, hydroxy, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -O(C 1-6 Alkyl), wherein the H in C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted by a group selected from the following: halogen, hydroxy, C1-C3 alkoxy; Preferably, R 23 Selected from: H, halogen; Preferably, R 24 Selected from: H, halogen, cyano, -SF5, hydroxyl, -C(O)H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -CO(C 1-6 alkyl), -O(C 1-6 Alkyl), wherein the H in C1-C6 alkyl and C3-C6 cycloalkyl may be optionally substituted by a group selected from the following: halogen, hydroxy, C1-C3 alkoxy; Preferably, R 25 Selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl; Preferably, R 26 Selected from: H, halogen, cyano, hydroxyl, C1-C6 alkyl, -O(C 1-6 alkyl).

12. The compound according to claim 10, characterized in that Has the following structure: in particular 13. The compound according to any one of claims 1 to 12, characterized in that A3 is selected from: -C(O)-, -S(O)-, -S(O)2-, Especially -C(O)-.

14. The compound according to any one of claims 1 to 13, characterized in that R4 has the following structure: in: Ring G is a 4-10 membered carbocyclic or heterocyclic ring; R 41 is one or more independent substituents on the G ring selected from: H, D, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -S(C 0-10 Alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl); wherein, C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C 0-10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 4-10 membered heterocyclic group may be optionally substituted by one or more R0; Preferably, Partially selected from the following structures: Among them, R 43 to R 47 independently selected from: H, halogen, cyano, hydroxyl, mercapto, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -O(C 1-6 alkyl), -O(C3-C6 cycloalkyl), -S(C 1-6 alkyl), -C(O)H, -CO(C 1-6 Alkyl), -NR 401 R 402 wherein the H in the C0-C6 alkylene, C1-C6 alkyl, C3-C6 cycloalkyl group may be optionally substituted by a group selected from the following: halogen, hydroxyl, C1-C3 alkoxy; R 401 and R 402 Independently selected from: H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, or R 401 and R 402 Together with the nitrogen atom to which it is attached, it forms a 4-8 membered heterocyclic ring, which is optionally substituted by a group selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy; R 42 Selected from: H, hydroxyl, protected hydroxyl.

15. The compound according to claim 14, characterized in that R 42 Selected from: H, -OH, -O(C1-C6 alkyl), -O(benzyl), -O(p-methoxybenzyl), -O(C1-C6 silyl), preferably -OH or H; Preferably, R 43 Selected from: H, halogen (e.g., F, Cl, Br), C1-C4 alkyl (e.g., methyl, ethyl), C1-C4 haloalkyl (e.g., -CF3, -CHF2, -CH2F), C1-C4 alkoxy (e.g., methoxy), C1-C4 haloalkoxy (e.g., -OCF3, -OCHF2, -OCH2F); Preferably, R 44 Selected from: H, halogen (e.g., F, Cl, Br), C1-C4 alkyl (e.g., methyl, ethyl), C1-C4 haloalkyl (e.g., -CF3, -CHF2, -CH2F); Preferably, R 45 Selected from: H, halogen (e.g., F, Cl, Br), C1-C4 alkyl (e.g., methyl, ethyl), C1-C4 haloalkyl (e.g., -CF3, -CHF2, -CH2F); Preferably, R 46 Selected from: H, halogen (e.g., F, Cl, Br), C1-C4 alkyl (e.g., methyl, ethyl), C1-C4 haloalkyl (e.g., -CF3, -CHF2, -CH2F), -S(C1-C4 alkyl) (e.g., -S-CH3), -NH2, -N(H)(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl); Preferably, R 47 Selected from: H, halogen (e.g., F, Cl, Br), C1-C4 alkyl (e.g., methyl, ethyl), C1-C4 haloalkyl (e.g., -CF3, -CHF2, -CH2F), C1-C4 alkoxy (e.g., methoxy), C1-C4 haloalkoxy (e.g., -OCF3, -OCHF2, -OCH2F), C3-C4 cycloalkyl (e.g., cyclopropyl); Preferably, R 48 and R 49 Independently selected from: H, halogen (e.g. F, Cl, Br), C1-C4 alkyl (e.g. methyl, ethyl), C1-C4 haloalkyl (e.g. -CF3, -CHF2, -CH2F), C1-C4 alkoxy (e.g. methoxy), C1-C4 haloalkoxy (e.g. -OCF3, -OCHF2, -OCH2F).

16. The compound according to claim 14, characterized in that Has the following structure: in particular 17. The compound according to any one of claims 1 to 16, characterized in that R3 is selected from the group consisting of: H, halogen, hydroxy, mercapto, amino, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -O(C 1-6 Alkyl), -S(C 1-6 alkyl), -N(H)(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl); wherein the H in the C0-C6 alkylene, C1-C6 alkyl, C3-C6 cycloalkyl group may be optionally substituted by a group selected from the following: D, halogen, hydroxyl, C1-C3 alkoxy; Preferably, R3 is selected from: H, 18. The compound according to any one of claims 1 to 17, characterized in that The compound has the following structure: Preferably, Wherein, R9 is one or more independent substituents on the Y ring selected from: H, D, halogen, cyano, hydroxyl, thiol, amino, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -(C0-C6 alkylene)-(phenyl), -O(C1-C6 alkyl), -S(C1-C6 alkyl), -N(H)(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -CON(C0-C6 alkyl)(C0- C0-C6 alkyl), -N(C0-C6 alkyl)CO(C0-C6 alkyl), -SO2N(C0-C6 alkyl)(C0-C6 alkyl), -N(C0-C6 alkyl)SO2(C0-C6 alkyl), wherein the H in the C0-C6 alkylene, C0-C6 alkyl, C1-C6 alkyl, C3-C6 cycloalkyl, and phenyl group may be optionally substituted with a group selected from the group consisting of D, halogen, cyano, hydroxyl, thiol, amino, C1-C3 alkyl, and C1-C3 alkoxy; Preferably, each R9 is independently selected from: H, D, halogen, cyano, hydroxyl, thiol, amino, C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted by one or more groups selected from the following: D, halogen, cyano, hydroxyl, amino, C1-C3 alkoxy.

19. The compound according to any one of claims 1 to 18, characterized in that The stereoisomers of the compound have the following structures: Preferably, the stereoisomers of the compound are selected from the following structures:

20. The compound according to claim 1, characterized in that The compound is selected from the following structures:

21. An intermediate of the compound according to any one of claims 1 to 20, having the following structure: in, R L is a reactive group; Preferably, the intermediate is selected from the following structures: Among them, R L is H or an amino protecting group; More preferably, the intermediate is selected from the following structures:

22. An intermediate of the compound according to any one of claims 1 to 20, having the following structure: in, R L 、R L '、R L ” is an independent reactive group; Preferably, the intermediate has the following structure: Among them, R L is H or an amino protecting group, R L ' is a leaving group, R L " is H or an amino protecting group.

23. A method for preparing a compound according to any one of claims 1 to 20, comprising: A reaction ligation step, wherein R L1 is a leaving group, Among them, R L For the reactive group.

24. A combination comprising a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, deuterated compound thereof, and one or more other therapeutically active agents; Preferably, the other therapeutically active agent is an anticancer agent or a chemotherapeutic agent; More preferably, the chemotherapy agent is selected from the group consisting of anastrozole, bicalutamide, bleomycin sulfate, busulfan, capecitabine, N4-pentyloxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, cyclophosphamide, cytarabine, cytosine arabinoside, cytarabine liposome injection, dacarbazine, dactinomycin, daunorubicin hydrochloride, daunorubicin citrate liposome injection, dexamethasone, cytosine arabinoside, cytosine arabinoside, cytarabine liposome injection, dactinomycin, daunorubicin hydrochloride, daunorubicin citrate liposome injection, dexamethasone, cytosine arabinoside, cytosine arabinoside, cytosine arabinoside, cytosine arabinoside liposome injection, dexamethasone ... methotrexate, docetaxel, doxorubicin hydrochloride, etoposide, fludarabine 5-fluorouracil phosphate, flutamide tezacitibine, gemcitabine, hydroxyurea, idarubicin, ifosfamide, irinotecan, L-asparaginase, leucovorin calcium, melphalan, 6-mercaptopurine, methotrexate, mitoxantrone, gemtuzumab ozogamicin, paclitaxel, phoenix, pentostatin, polifeprosan 20 cocarmustine implant, tamoxifen citrate, teniposide, 6-thioguanine, thiotepa, tirapazamine, topotecan hydrochloride for injection, vinblastine, vincristine, and vinorelbine, especially irinotecan; More preferably, the other therapeutically active agent is a PD-1 inhibitor; More preferably, the PD-1 inhibitor is selected from the group consisting of: PDR001, nivolumab, pembrolizumab, pidilizumab, MEDI0680, cemiplizumab, dotalizumab, PF-06801591, tilelizumab, BGB-108, INCSHR1210, batilizumab, sintilimab, toripalimab, carrelizumab, AMP-224, penampalimumab, sepalimumab and prolgolimab, in particular PDR001, more in particular tilelizumab.

25. A pharmaceutical composition comprising the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

26. Use of the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof in the preparation of a medicament for preventing and / or treating WRN-mediated diseases; Preferably, the disease is a tumor, in particular a cancer with microsatellite instability (MSI); More preferably, the tumor is selected from the group consisting of acute myeloid leukemia, juvenile cancer, childhood adrenocortical carcinoma, AIDS-related cancer, anal cancer, appendix cancer, astrocytoma, atypical teratoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem cell glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoid tumor, embryonal tumor, blastoma, primary lymphoma, cervical cancer, childhood cancer, chordoma, heart tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, Carcinoma, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumor, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, nasal glioma, Ewing sarcoma, extracranial ectodermal tumor, gonadal ectodermal tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, stomach cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), blastoma, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cancer, liver cancer, lobular Carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasms, mycosis fungoides, myelodysplastic syndrome, myelodysplasia / myeloproliferative neoplasms, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), mouth cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, paranasal sinus cancer sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, rare childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancers, especially colorectal cancer, gastric cancer, ovarian cancer, endometrial cancer, and ovarian cancer; Preferably, the disease is a non-cancerous hyperproliferative disorder, such as benign hyperplasia of the skin, restenosis, or prostatic hyperplasia.

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