Spiro derivative as WRN inhibitor and application thereof

Abstract

The invention discloses a spiro derivative serving as a WRN helicase inhibitor and application of the spiro derivative. The spiro derivative has better WRN helicase inhibitory activity, can be used for inhibiting growth of microsatellite unstable (MSI) tumor cells by inhibiting high-level DNA double-strand breakage (DSB) in microsatellite unstable (MSI) cells caused by WRN, is used for preventing and / or treating related cancers, especially colorectal cancer, gastric cancer, ovarian cancer, endometrial tumor and the like, and has a good application prospect. The vacancy of specific MSI type cancer targeting drugs can be filled, and the application prospect and value in the field of medicines are very good.

Description

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]

[0008] wherein,

[0009] represents a single bond or a double bond, and the two are not both double bonds at the same time;

[0010] Ring A is a 4- to 6-membered heterocyclic ring;

[0011] Ring J is a 6- to 18-membered spiro ring;

[0012] X1, X2, X3, and 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- to 10-membered heterocyclic group), halogen, cyano, nitro, azide, C1-C 10 haloalkyl, 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(C0-10 (alkyl)(C3-C 10 cycloalkyl), -CO(C 0-10 alkyl);

[0013] A1, A2, A3 are independently selected from: a single bond, C1-C 10 alkylene, wherein 0-6 methylene units in the C1-C 10 alkylene are independently substituted by the following groups: -Cy-, -O-, -S-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -OC(O)O-, -O-S(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-, wherein, R a and R b are 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 heterocyclic group); each -Cy- is independently an optionally substituted divalent ring selected from: arylene, cycloalkylene, heterocyclene; wherein the H in the C1-C 10 alkylene is optionally substituted by one or more R0;

[0014] R1 is one or more independent substituents on the A 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, azide, C1-C 10Halogenated alkyl, C1-C 10 halogenated alkoxy, -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, the H in 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 aryl, 4-10 membered heterocyclic group may optionally be substituted by one or more R0;

[0015] 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 10aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), halogen, cyano, nitro, azide, C1-C 10 haloalkyl, 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, the H in 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 aryl, 4-10 membered heterocyclic group may optionally be substituted by one or more R0; or, R3 and A1 together with the atoms to which they are attached form a carbocyclic or heterocyclic ring, and the H in the carbocyclic or heterocyclic ring may optionally be substituted by one or more R0;

[0016] 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, azide, C1-C 10 haloalkyl, 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 10The H in aryl or 4- to 10-membered heterocyclic group may optionally be substituted by one or more R0;

[0017] R0 is selected from: D, =O, halogen, cyano, nitro, azide, -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 haloalkyl, C1-C 10 haloalkoxy, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4- to 10-membered heterocyclic group);

[0018] Each R' and R” independently is 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- to 10-membered heterocyclic group); wherein the H in the C0-C6 alkylene, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 4- to 10-membered heterocyclic group may optionally be substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C 10 alkyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4- to 10-membered heterocyclic group), C1-C 10 haloalkyl, 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).

[0019] Specifically, each -CY- is independently selected from the following optionally substituted divalent rings: phenylene, bicyclic arylene, tricyclic arylene, monocyclic cycloalkylene, bicyclic cycloalkylene, tricyclic cycloalkylene, monocyclic heteroarylene, bicyclic heteroarylene, tricyclic heteroarylene, monocyclic heterocycloalkylene, bicyclic heterocycloalkylene, tricyclic heterocycloalkylene.

[0020] In some embodiments of the present invention, each -CY- is independently selected from the following optionally substituted divalent rings: monocyclic cycloalkylene, bicyclic cycloalkylene, monocyclic saturated heterocycloalkylene, bicyclic saturated heterocycloalkylene.

[0021] Specifically, each -CY- is optionally substituted with the following groups: halogen, cyano, nitro, azide, C1-C 10 (alkyl), -N(C0-C 10 (alkyl)(C0-C10 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- to 10-membered heterocyclic group.

[0022] In some embodiments of the present invention, ring A is a 4- to 6-membered nitrogen-containing heterocycle, particularly a 5-membered nitrogen-containing heteroaromatic ring, for example, particularly

[0023] In some embodiments of the present invention, ring is particularly

[0024] In some embodiments of the present invention, ring is wherein X5 and X6 are independently selected from: C(H), N, for example, particularly

[0025] Specifically, A1 is C1-C 10 alkylene, wherein 1 to 3 methylene units are independently substituted by the following groups: -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 0-6 alkyl)-(C0-C3 alkylene)-, -(C0-C3 alkylene)-N(C 0-6alkyl)C(O)-(C0-C3 alkylene)-, -(C0-C3 alkylene)-O-(C0-C3 alkylene)-, -(C0-C3 alkylene)-S-(C0-C3 alkylene)-.

[0026] In some embodiments of the present invention, A1 is C1-C6 alkylene, wherein the H is optionally substituted by one or more groups selected from: H, D, halogen, -(C0-C3 alkylene)-(C3-C6 cycloalkyl), -(C0-C3 alkylene)-(phenyl), -(C0-C3 alkylene)-(4-6 membered saturated heterocyclic group).

[0027] 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).

[0028] 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.

[0029] In some embodiments of the present invention, R3 and R7 together with the atoms to which they are attached form a 4- to 8-membered (e.g., 4, 5, 6, 7, 8-membered) carbocyclic or heterocyclic ring, and the H in the carbocyclic or heterocyclic ring may optionally be substituted by one or more R0; specifically, the carbocyclic or heterocyclic ring is optionally substituted by one or more groups selected from the following: H, D, halogen, cyano, hydroxy, mercapto, 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, phenyl may optionally be substituted by a group selected from the following: D, halogen, cyano, hydroxy, mercapto, amino, C1-C3 alkyl, C1-C3 alkoxy; more specifically, the carbocyclic or heterocyclic ring is optionally substituted by one or more groups selected from the following: H, D, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -OH, -NH2, -COOH; wherein the C1-C6 alkyl is optionally substituted by one or more groups selected from the following: H, D, halogen, cyano, -OH, -NH2, -COOH.

[0030] In some embodiments of the present invention, R3 and R7 together with the atoms to which they are attached form a 4- to 8-membered heterocyclic ring, and the H in the heterocyclic ring may optionally be substituted by one or more R0; the heterocyclic ring may contain one or more heteroatoms selected from: N, O, S.

[0031] In some embodiments of the present invention, R7 is H.

[0032] In some embodiments of the present invention, A1 is wherein, R6': H, D, C1-C 10 alkyl, C1-C 10 haloalkyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl).

[0033] Specifically, R6': H, D, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl); more specifically, R6' is H.

[0034] Specifically, A2 is C1-C 10An alkylene group, wherein 1 to 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)-.

[0035] 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).

[0036] 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.

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

[0038]

[0039] In some embodiments of the present invention, the compound has the following structure:

[0040]

[0041] Wherein,

[0042] The Y ring is a 5-7 membered heterocyclic ring;

[0043] R9 is one or more independent substituents on the Y ring, which has the definition of R0 as described above.

[0044] Specifically, the Y ring is a 5-7 membered saturated heterocyclic ring. In addition to the nitrogen atom shown in the above formula, optionally, it may further contain one or more heteroatoms, and the heteroatoms are selected from: N, O, S. For example

[0045] Specifically, each R9 is independently selected from: H, D, halogen, cyano, hydroxy, mercapto, 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, phenyl may optionally be substituted with a group selected from: D, halogen, cyano, hydroxy, mercapto, amino, C1-C3 alkyl, C1-C3 alkoxy; more specifically, each R9 is independently selected from: H, D, halogen, cyano, hydroxy, mercapto, amino, C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with one or more groups selected from: D, halogen, cyano, hydroxy, amino, C1-C3 alkoxy.

[0046] 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 spiroheterocyclic ring; 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.

[0047] Specifically, R5 is selected from: 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 may optionally be substituted with a group selected from: halogen, hydroxy, C1-C3 alkoxy; more specifically, R5 is selected from: H, halogen (such as F, Cl), 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).

[0048] In some embodiments of the present invention, R5 is selected from: H, F, Cl, -OH, -NH2, methyl, ethyl.

[0049] Specifically, Part has the following structure: Wherein,

[0050] The J1 ring is a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic carbocyclic or heterocyclic ring;

[0051] The J2 ring is a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic carbocyclic or heterocyclic ring;

[0052] R 51 、R 52 Are each one or more independent substituents on the J1 and J2 rings, which have the definition of R5.

[0053] Specifically, the J1 ring is a 3- to 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- to 6-membered partially unsaturated carbocyclic ring; In some embodiments of the present invention, a 3- to 6-membered saturated heterocyclic ring having at least one ring atom as N.

[0054] Specifically, the J2 ring is a 3- to 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- to 6-membered saturated heterocyclic ring having at least one ring atom as N, for example

[0055] Specifically, Part has the following structure:

[0056]

[0057]

[0058]

[0059]

[0060]

[0061] In some embodiments of the present invention, Part has the following structure:

[0062] Specifically, R 51 Is selected from: H, halogen, hydroxyl, mercapto, amino, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -O(C 1-6alkyl), -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 may optionally be substituted with a group selected from: halogen, hydroxy, C1-C3 alkoxy; more specifically, R 51 is selected from: H, halogen (such as F, Cl), 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); in some embodiments of the present invention, R 51 is H.

[0063] Specifically, R 52 is selected from: 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 may optionally be substituted with a group selected from: halogen, hydroxy, C1-C3 alkoxy; more specifically, R 52 is selected from: H, halogen (such as F, Cl), 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); in some embodiments of the present invention, R 52 is selected from: H, F, Cl, -OH, -NH2, methyl, ethyl.

[0064] In some embodiments of the present invention, part has the following structure: Especially wherein, R 52a , R52b Having R 52 of the definition.

[0065] In some embodiments of the present invention, a part has the following structure:

[0066]

[0067] In other embodiments of the present invention, a part has the following structure:

[0068]

[0069] In some embodiments of the present invention, R1 has the following structure: Wherein:

[0070] A4 is selected from: a single bond, a C1-C6 alkylene group, wherein 0-3 methylene units in the C1-C6 alkylene group are independently substituted by the following groups: -O-, -S-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -C(O)N(H)-, -N(H)C(O)-, -N(H)-, -S(O)2-;

[0071] Ring B is a 4-10 membered carbocyclic or heterocyclic ring;

[0072] R 11 is one or more independent substituents on ring B, 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, azide, C1-C 10 haloalkyl, 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(C0-10 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, the 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 aryl, and the H in the 4-10 membered heterocyclic group may optionally be substituted by one or more R0.

[0073] Specifically, ring B is a 5-8 membered (saturated, partially saturated or aromatic) carbocyclic or heterocyclic ring, such as:

[0074]

[0075] Specifically, Part has the following structure:

[0076]

[0077]

[0078] Wherein, R 12 is 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 haloalkyl, C1-C 10 haloalkoxy, -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, the C0-C6 alkylene, C1-C 10 alkyl, C2-C 10Alkenyl, C2-C 10 Alkynyl, C 0-10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 In aryl, 4- to 10-membered heterocyclic group, H may optionally be substituted by one or more R0.

[0079] Specifically, R 12 is selected from: H, C1-C6 alkyl, -C(O)OH, -C(O)O(C 1-6 alkyl), -C(O)H, -C(O)(C 1-6 alkyl), wherein H in C1-C6 alkyl may optionally be substituted by a group selected from: 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 is 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). In some embodiments of the present invention, R 12 is H,

[0080] Specifically, each R 11 is independently selected from: H, halogen, hydroxy, mercapto, 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 H in C1-C6 alkyl may optionally be substituted by a group selected from: 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 11Independently 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). In some embodiments of the present invention, R 11 is H, F, methyl, ethyl,

[0081] In some embodiments of the present invention, part has the following structure:

[0082]

[0083]

[0084] Especially

[0085] In some embodiments of the present invention, A4 is a single bond, that is, R1 is

[0086] In some embodiments of the present invention, R2 has the following structure: Wherein:

[0087] Ring E is a 4- to 12-membered carbocyclic or heterocyclic ring;

[0088] R 21 is one or more independent substituents on Ring E, 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- to 10-membered heterocyclic group), halogen, cyano, nitro, azide, -SF5, C1-C 10 haloalkyl, C1-C 10 haloalkoxy, -N(C 0-10 alkyl)(C 0-10 alkyl), -N(C0-10 (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, the H in 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 aryl, 4-10 membered heterocyclic group may optionally be substituted by one or more R0; or, two R 21 together with the ring atoms to which they are attached form a carbocyclic or heterocyclic ring, and the H in the carbocyclic or heterocyclic ring may optionally be substituted by one or more R0.

[0089] Specifically, ring E is a 5-10 membered aromatic or heteroaromatic ring, for example:

[0090] In particular

[0091] In some embodiments of the present invention, part has the following structure:

[0092] In particular

[0093] Specifically, R 21 is 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 the H in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 alkylene, C3-C6 cycloalkyl may optionally be substituted with a group selected from the following: halogen, hydroxyl, C1-C3 alkoxy; or, two R 21 together with the ring atom to which it is attached form a carbocyclic or heterocyclic ring, and the H in the carbocyclic or heterocyclic ring may optionally be substituted with a group selected from the following: halogen, hydroxyl, C1-C3 alkoxy.

[0094] In some embodiments of the present invention, R2 has the following structure: wherein, X7 is selected from: C(R 23 ), N, R 22 to R 26 has the definition of R 21 , or R 23 together with R 24 or R 22 together with the atom to which it is attached form a 4-6 membered saturated carbocyclic ring, and the H in the carbocyclic ring may optionally be substituted with a group selected from the following: halogen, hydroxyl, C1-C3 alkoxy.

[0095] Specifically, R 22 is selected from: H, halogen, cyano, hydroxyl, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -O(C 1-6 alkyl), wherein the H in C1-C6 alkyl, C3-C6 cycloalkyl may optionally be substituted with a group selected from the following: halogen, hydroxyl, C1-C3 alkoxy; more specifically, R 22 is selected from: H, halogen (such as F, Cl, Br), cyano, hydroxyl, C1-C4 alkyl (such as methyl, ethyl), C1-C4 haloalkyl (such as -CF3, -CHF2, -CH2F), C1-C4 alkoxy (such as methoxy), C1-C4 haloalkoxy (such as -OCF3, -OCHF2, -OCH2F).

[0096] Specifically, R 23 is selected from: H, halogen (such as F, Cl, Br); more specifically, R 23 is H or F.

[0097] Specifically, R 24 is 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 H in C1-C6 alkyl and C3-C6 cycloalkyl may optionally be substituted by a group selected from the following: halogen, hydroxy, 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.

[0098] Specifically, R 25 selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl; more specifically, R 25 selected from: H, halogen (e.g., F, Cl, Br), C1-C4 alkyl (e.g., methyl, ethyl), C1-C4 haloalkyl (e.g., -CF3, -CHF2, -CH2F).

[0099] Specifically, R 26 selected from: H, halogen, cyano, hydroxy, C1-C6 alkyl, -O(C 1-6 alkyl); more specifically, R 26 selected from: H, halogen (e.g., F, Cl, Br), cyano, hydroxy, C1-C4 alkoxy (e.g., methoxy).

[0100] In some embodiments of the present invention, the moiety has the following structure:

[0101]

[0102] In particular

[0103] In some embodiments of the present invention, the moiety has the following structure:

[0104]

[0105] Specifically, R0 is selected from: H, halogen, hydroxy, C1-C3 alkoxy.

[0106] More specifically, the moiety has the following structure:

[0107]

[0108]

[0109] In some embodiments of the present invention, A3 is selected from: -C(O)-, -S(O)-, -S(O)2-, especially -C(O)-.

[0110] In some embodiments of the present invention, R4 has the following structure: Wherein:

[0111] Ring G is a 4- to 10-membered carbocyclic or heterocyclic ring;

[0112] R 41 is one or more independent substituents on Ring G, 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- to 10-membered heterocyclic group), halogen, cyano, nitro, azide, C1-C 10 haloalkyl, 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 10The H in aryl or 4- to 10-membered heterocyclic group may optionally be substituted by one or more R0.

[0113] Specifically, the G ring is a 5- to 10-membered aromatic ring or heteroaromatic ring, for example:

[0114]

[0115] Especially

[0116] In some embodiments of the present invention, Part has the following structure:

[0117]

[0118] Wherein, R 43 to R 49 has the definition of R 41 and R 42 is selected from: H, hydroxyl group, protected hydroxyl group.

[0119] Specifically, R 42 is selected from: H, -OH, -O(C1-C6 alkyl), -O(benzyl), -O(p-methoxybenzyl), -O(C1-C6 silyl); in some embodiments of the present invention, R 42 is -OH; in some embodiments of the present invention, R 42 is H.

[0120] Specifically, R 43 to R 49 are 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 may optionally be substituted by a group selected from: halogen, hydroxyl, C1-C3 alkoxy; R 401 and R 402 are 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 they are attached form a 4- to 8-membered heterocycle (especially a 4- to 6-membered saturated heterocycle, for example ), said heterocycle is optionally substituted with a group selected from: halogen, hydroxy, C1-C3 alkoxy.

[0121] More specifically, R 43 is selected from: H, halogen (such as F, Cl, Br), C1-C4 alkyl (such as methyl, ethyl), C1-C4 haloalkyl (such as -CF3, -CHF2, -CH2F), C1-C4 alkoxy (such as methoxy), C1-C4 haloalkoxy (such as -OCF3, -OCHF2, -OCH2F); in some embodiments of the present invention, R 43 is selected from: H, F, Cl, methyl, -OCF3.

[0122] More specifically, R 44 is selected from: H, halogen (such as F, Cl, Br), C1-C4 alkyl (such as methyl, ethyl), C1-C4 haloalkyl (such as -CF3, -CHF2, -CH2F); in some embodiments of the present invention, R 44 is selected from: H, F, Cl, methyl.

[0123] More specifically, R 45 is selected from: H, halogen (such as F, Cl, Br), C1-C4 alkyl (such as methyl, ethyl), C1-C4 haloalkyl (such as -CF3, -CHF2, -CH2F); in some embodiments of the present invention, R 45 is selected from: H, Cl, methyl.

[0124] More specifically, R 46 is selected from: H, halogen (such as F, Cl, Br), C1-C4 alkyl (such as methyl, ethyl), C1-C4 haloalkyl (such as -CF3, -CHF2, -CH2F), -S(C1-C4 alkyl) (such as -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 is selected from: H, -S-CH3, methyl, -NH2.

[0125] More specifically, R 47 is selected from: H, halogen (such as F, Cl, Br), C1-C4 alkyl (such as methyl, ethyl), C1-C4 haloalkyl (such as -CF3, -CHF2, -CH2F), C1-C4 alkoxy (such as methoxy), C1-C4 haloalkoxy (such as -OCF3, -OCHF2, -OCH2F), C3-C4 cycloalkyl (such as cyclopropyl); in some embodiments of the present invention, R 47Selected from: H, Cl, methyl, ethyl, cyclopropyl, -OCF3, -OCHF2.

[0126] Specifically, R 48 and R 49 are independently selected from: H, halogen (such as F, Cl, Br), C1-C4 alkyl (such as methyl, ethyl), C1-C4 haloalkyl (such as -CF3, -CHF2, -CH2F), C1-C4 alkoxy (such as methoxy), C1-C4 haloalkoxy (such as -OCF3, -OCHF2, -OCH2F).

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

[0128]

[0129] Especially

[0130] Specifically, R3 is 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 alkyl); wherein the H in the C0-C6 alkylene, C1-C6 alkyl, and C3-C6 cycloalkyl may optionally be substituted by a group selected from the following: D, halogen, hydroxyl, C1-C3 alkoxy; more specifically, R3 is selected from: 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).

[0131] In some embodiments of the present invention, R3 is selected from: H,

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

[0133]

[0134] In some embodiments of the present invention, the compound has the following structure:

[0135]

[0136] In some embodiments of the present invention, the compound has the following structure:

[0137]

[0138] In some embodiments of the present invention, the compound has the following structure:

[0139]

[0140] In some embodiments of the present invention, the compound has the following structure:

[0141]

[0142] In some embodiments of the present invention, the compound has the following structure:

[0143]

[0144] In some embodiments of the present invention, the stereoisomers of the compound have the following structure:

[0145]

[0146]

[0147] In some embodiments of the present invention, the stereoisomers of the compound have the following structure:

[0148]

[0149] In some embodiments of the present invention, the stereoisomers of the compound have the following structure:

[0150]

[0151] In some embodiments of the present invention, the compound has the following structure:

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160] In some embodiments of the present invention, the compound has the following structure:

[0161]

[0162] The second aspect of the present invention provides an intermediate compound and its stereoisomers, which have the following structure:

[0163]

[0164] Wherein, ring A, ring J, X1, X2, X3, X4, A1, A2, R1, R2, R3, and R5 respectively have the definitions in the first aspect of the present invention;

[0165] R L is a reactive group.

[0166] In some embodiments of the present invention, part is R L is H or an amino protecting group (such as the Boc group).

[0167] In some embodiments of the present invention, the intermediate compound has the following structure:

[0168] such as Wherein, R L can be H or an amino protecting group (such as the Boc group).

[0169] In some embodiments of the present invention, the intermediate compound has the following structure:

[0170] such as In some embodiments of the present invention, R L is H.

[0171] In some embodiments of the present invention, the intermediate compound has the following structure:

[0172]

[0173] In some embodiments of the present invention, the intermediate compound has the following structure:

[0174]

[0175] In some embodiments of the present invention, the intermediate compound has the following structure:

[0176]

[0177]

[0178]

[0179]

[0180]

[0181] In some embodiments of the present invention, an intermediate compound is further provided, which has the following structure:

[0182]

[0183] Wherein, ring A, ring J, X1, X2, X3, X4, A1, A2, R1, R2, R3, R5 respectively have the definitions in the first aspect of the present invention;

[0184] R L 、R L ', R L ” are independent reaction groups.

[0185] In some embodiments of the present invention, the compound represented by formula IM-2 has the following structure:

[0186] Such as In some embodiments of the present invention, the compound represented by formula IM-3 has the following structure:

[0187] Such as

[0188] In some embodiments of the present invention, the compound represented by formula IM-3 has the following structure:

[0189]

[0190] In some embodiments of the present invention, R L ' is a leaving group, such as a halogen (e.g., F, Cl, Br or I), an alkylsulfonyloxy group, an arylsulfonyloxy group, etc., especially a halogen.

[0191] In some embodiments of the present invention, R L ” is H or an amino protecting group (such as a Boc group).

[0192] In the third aspect of the present invention, there is provided a method for preparing the compound described in the first aspect of the present invention, which comprises the step of reacting and linking the compound represented by formula IM-1 with wherein A3 and R4 have the definitions in the first aspect of the present invention, and R L1 is a leaving group.

[0193] In some embodiments of the present invention, R L1 is a halogen (such as Cl, Br) or

[0194] In some embodiments of the present invention, the method further comprises the step of preparing the compound represented by formula IM-1, for example, by reacting the compound represented by formula IM-2 with R L2 -R1, or by reacting the compound represented by formula IM-3 with wherein R L2 and R L3 are leaving groups.

[0195] In some embodiments of the present invention, the method further comprises the step of preparing the compound represented by formula IM-2, for example, by reacting with wherein R L ”' and R L0 are reactive groups.

[0196] In some embodiments of the present invention, the method further comprises the step of preparing the compound represented by formula IM-3, for example, by reacting with wherein R L ”' and R L0 are reactive groups.

[0197] In some other embodiments of the present invention, the method further comprises the step of preparing the compound represented by formula IM-1, for example, by reacting the compound with wherein R L ”' and R L0 are reactive groups. In some embodiments of the present invention, R L ”' is a leaving group, such as a halogen (for example, F, Cl, Br or I), an alkylsulfonyloxy group, an arylsulfonyloxy group, etc., for example, Br.

[0198] In some embodiments of the present invention, is for example

[0199] In a fourth aspect of the present invention, there is provided a combination comprising the compound according to the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, deuterated compound thereof, and one or more other therapeutic active agents.

[0200] Specifically, the other therapeutic active agent may be an anti-cancer agent or a chemotherapeutic agent.

[0201] 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, fludarabine phosphate, 5-fluorouracil, flutamide, tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea, idarubicin, ifosfamide, irinotecan, L-asparaginase, leucovorin calcium, melphalan, 6-mercaptopurine, methotrexate, mitoxantrone, gemtuzumab (mylotarg), paclitaxel, phoenix (Yttrium90 / MX-DTPA), pentostatin, polifeprosan 20 copolymer with carmustine implant, tamoxifen citrate, teniposide, 6-thioguanine, thiotepa, tirapazamine, topotecan hydrochloride for injection, vinblastine, vincristine and vinorelbine, especially irinotecan.

[0202] In some embodiments of the present invention, the other therapeutic active agent is an inhibitor of PD-1 (e.g., human PD-1). In some embodiments of the present invention, the other therapeutic active agent is an inhibitor of PD-L1 (e.g., human PD-L1). Specifically, the inhibitor of PD-1 or PD-L1 may be an antibody molecule against PD-1 or PD-L1.

[0203] Specifically, PD-1 inhibitors include, for example, PDR001 (Novartis AG), nivolumab (Bristol-Myers Squibb), pembrolizumab (Merck & Co), pidilizumab (CureTech), MEDI0680 (Medimmune), cemiplimab (REGN2810, Regeneron), dostarlimab (TSR-042, Tesaro), PF-06801591 (Pfizer), tislelizumab (BGB-A317, BeiGene), BGB-108 (BeiGene), INCSHR1210 (Incyte), balstilimab (AGEN2035, Agenus), sintilimab (InnoVent), toripalimab (Shanghai Junshi Bioscience), camrelizumab (Jiangsu Hengrui Medicine Co., Ltd.), and AMP-224 (Amplimmune), penpulimab (Akeso Biopharma Inc), zapalisimab (Arcus Biosciences) and Prolgolimab (Biocad Ltd), especially PDR001, more particularly tislelizumab (BGB-A317, BeiGene).

[0204] The fifth aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

[0205] Specifically, the pharmaceutically acceptable excipients may be selected from one or more of the following: fillers, binders, lubricants, disintegrants, antioxidants, buffers, bacteriostatic agents, suspending agents, solubilizers, thickeners, stabilizers, preservatives, etc.

[0206] Specifically, the pharmaceutical composition may be administered by any suitable route, such as enteral administration (e.g., oral, sublingual, rectal administration) or parenteral administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory administration, etc.) routes.

[0207] 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, oral tablets, etc.), pills, powders, granules, capsules (including soft capsules, microcapsules), lozenges, syrups, liquids, emulsions, suspensions, controlled-release preparations (e.g., immediate-release preparations, sustained-release preparations, sustained-release microcapsules).

[0208] In some embodiments of the present invention, the pharmaceutical composition is an injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection).

[0209] In other embodiments of the present invention, the pharmaceutical composition is an intravenous drip, a transdermal absorption preparation, a lotion, a suppository (e.g., a rectal suppository, a vaginal suppository), a nasal preparation, a pulmonary preparation (an inhalant), an eye drop, etc.

[0210] Specifically, the pharmaceutical composition is preferably in unit dosage form. In this form, the preparation is further divided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form can be a capsule, a tablet or any dosage form; additionally, the unit dosage form can also be a packaged preparation, such as tablets, capsules and powders packaged in vials or ampoules, etc.

[0211] 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 therapeutic active ingredients (as described in the fourth aspect of the present invention).

[0212] Specifically, the various dosage forms of the pharmaceutical composition can be prepared according to the conventional production methods in the pharmaceutical field. For example, the active ingredient is mixed with one or more carriers and then made into the required dosage form.

[0213] Specifically, the pharmaceutical composition contains 0.1-99.5% by weight (such as 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%) of the active ingredient (the compound described in the first aspect or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound, or its combination with other types of active ingredients).

[0214] Specifically, the pharmaceutical composition contains pharmaceutically acceptable excipients in a weight ratio of 0.5% - 99.9% (such as 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%).

[0215] In a sixth aspect of the present invention, there is provided the use of the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, deuterated compound thereof as a WRN helicase inhibitor, for example, in the preparation of a medicament for preventing and / or treating WRN-mediated diseases.

[0216] Specifically, the disease is a disease that can benefit from its prevention and / or treatment by inhibiting WRN.

[0217] In some preferred embodiments of the present invention, the disease is a tumor, for example, acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical teratoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoid tumor, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS) of extrahepatic ducts, embryonal tumor, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, nasal glioma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, cardiac 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 tumor, mycosis fungoides, myelodysplastic syndrome, myelodysplasia / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal 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 / gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of renal pelvis and ureter, trophoblastic tumor, rare childhood cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer or virus-induced cancer.

[0218] In particular, the tumor is a cancer with microsatellite instability (MSI), such as colorectal cancer, gastric cancer, ovarian cancer, endometrial tumor, ovarian cancer, etc.

[0219] In some embodiments of the present invention, the disease is a non-cancerous hyperproliferative disorder, for example, a benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostatic hypertrophy (e.g., benign prostatic hyperplasia (BPH)).

[0220] In a seventh aspect of the present invention, there is provided a method for inhibiting WRN helicase, which comprises the step of using the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, deuterated compound thereof.

[0221] In some embodiments of the present invention, the method is carried out in vivo.

[0222] In some embodiments of the present invention, the method is carried out in vitro.

[0223] In an eighth aspect of the present invention, there is provided a method for preventing and / or treating a WRN-mediated disease, which comprises the step of administering to a subject in need thereof an effective amount of the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, deuterated compound thereof, or the combination described in the fourth aspect, or the pharmaceutical composition described in the fifth aspect.

[0224] Specifically, the disease is as described in the sixth aspect of the present invention.

[0225] Specifically, the subject is a mammal, such as a human.

[0226] The present invention provides a novel WRN helicase inhibitor, which has good inhibitory activity and can be used to inhibit the growth of tumor cells with microsatellite instability (MSI) by inhibiting WRN to cause a high level of DNA double-strand breaks (DSBs) in MSI cells, for preventing and / or treating related cancers, especially colorectal cancer, gastric cancer, ovarian cancer, endometrial tumors, etc., and can fill the gap of specific MSI-typed cancer-targeted drugs, having very good application prospects and value in the pharmaceutical field. BRIEF DESCRIPTION OF THE DRAWINGS

[0227] Figure 1 Shown is the IC50 curve of compound T074 for inhibiting WRN helicase activity.

[0228] Figure 2 Shown is the IC50 curve of compound T074 for inhibiting ATPase activity.

[0229] Figure 3 Shown is the EC50 curve of compound T074 for inhibiting the growth of SW48 tumor cells. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0230] Unless otherwise defined, all scientific and technical terms used in the present invention have the same meanings as those commonly understood by those skilled in the technical field to which the present invention pertains.

[0231] In the present invention, the term "aliphatic group" refers to a straight-chain or branched hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a cycloalkyl group (also referred to herein as "alicyclic ring") that is fully saturated or contains one or more unsaturated units, which is connected to other parts of the molecule by a single bond. Suitable aliphatic groups include, but are not limited to, straight-chain 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.

[0232] The term "carbocyclic ring" is composed entirely of carbon atoms and can be divided into alicyclic rings and aromatic rings.

[0233] The term "alkyl" refers to a straight-chain or branched hydrocarbon chain radical that does not contain unsaturated bonds and is connected to other parts 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 is substituted by a cycloalkyl group, it is correspondingly "cycloalkylalkyl", such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc. If the alkyl is substituted by an aryl group, then it is correspondingly "arylalkyl", such as benzyl, diphenylmethyl, or phenethyl. If the alkyl is substituted by a heterocyclic group, then it is correspondingly "heterocyclic alkyl". In the present invention, C0 alkyl refers to H, that is, C 0-10 alkyl (or C0-C 10 alkyl) includes H and C 1-10 alkyl (or C1-C 10 alkyl).

[0234] The term "alkylene" refers to a hydrocarbon group (divalent alkyl) formed by removing two hydrogen atoms from an alkane molecule, which can be straight-chain or branched and is connected to other parts of the molecule by a single bond. In this context, typical alkylene 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 methylene (-CH2-), ethylene, propylene, butylene, etc. In the present invention, C0 alkylene refers to a single bond, that is, C 0-10 alkylene (or C0-C 10 alkylene) includes a single bond and C 1-10 alkylene (or C1-C 10(alkylene).

[0235] The term "cycloalkyl" refers to alicyclic hydrocarbons, such as those containing 1 to 4 monocyclic and / or fused rings, having 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.

[0236] The term "alkoxy" refers to a substituent formed by replacing the hydrogen in a hydroxyl group with an alkyl group, such as an alkoxy group containing 1 - 10 carbon atoms, for example, methoxy, ethoxy, propoxy, butoxy, etc.

[0237] The term "aryl" refers to a monocyclic or polycyclic radical, including polycyclic radicals containing monoaryl groups and / or fused aryl groups, such as those 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 group derived from an aromatic hydrocarbon by removing two hydrogen atoms.

[0238] The term "heterocyclic group" includes heteroaromatic groups and heterocycloaliphatic groups having 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 groups and heterocycloaliphatic groups have 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 kinds of heteroatoms selected from N, O or S atoms. Examples of heteroaryl groups include, for example, but not limited to, coumarin, including 8-coumarin, quinolinyl, including 8-quinolinyl, isoquinolinyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furanopyridyl, etc. Suitable heterocycloaliphatic groups in the compounds of the present invention contain 1, 2 or 3 kinds of heteroatoms selected from N, O or S atoms. Examples of heterocycloaliphatic groups include, for example, but not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuran, tetrahydrothienyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, oxathianyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxiranyl, thiiranyl, azepinyl, oxazepinyl, diazepinyl, triazepinyl, 1,2,3,6-tetrahydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl and quinuclidinyl, etc.

[0239] 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, =N-R', 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 group, where 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 heterocyclic group. Among them, these groups are themselves substituted, and the substituents can be selected from the aforementioned list.

[0240] "Halogen" refers to bromine, chlorine, iodine or fluorine. Haloalkyl refers to a group in which a hydrogen atom on the alkyl is replaced by a halogen atom (F, Cl, Br, I), such as -CH2Rh, -CHRh2, -CRh3, where Rh is F, Cl, Br or I; such as -CF3.

[0241] The term "pharmaceutically acceptable salt" refers to an acidic salt or a basic salt that is theoretically non-toxic, non-irritating and non-allergenic, and can achieve or provide clinically acceptable pharmacokinetic properties, absorption, distribution and metabolism properties of the drug molecule, and can achieve the expected purpose. The salts described in the present invention include pharmaceutically acceptable acidic salts or basic salts of acidic groups, basic groups or amphoteric groups of the compound. A list of suitable salts can be found in S.M. Birge, et al., J. Pharm. Sci., 66, 1-19 (1977).

[0242] The pharmaceutically acceptable salts described in the present invention include acid addition salts and base addition salts.

[0243] The acid addition salts described above include, but are not limited to, salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphonic acid, and salts derived from organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Accordingly, these salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, iodide, acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, and mesylate, and also include salts of amino acids such as arginine salts, gluconate salts, galacturonate salts, etc. The acid addition salts can be prepared by contacting the free base form in a conventional manner with a sufficient amount of the desired acid to form the salt. The free base form can be regenerated by contacting the salt form with a base and the free base can be isolated in a conventional manner.

[0244] The base addition salts described in the present invention refer to salts formed with metals or amines, such as hydroxides of alkali metals and alkaline earth metals, or formed 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-methylglucosamine, and procaine. The base addition salts can be prepared by contacting the free acid form in a conventional manner with a sufficient amount of the desired base to form the salt. The free acid form can be regenerated by contacting the salt form with an acid and the free acid can be isolated in a conventional manner.

[0245] The term "solvate" should be understood to refer to any form of the compounds of the present invention, in which the compound is connected to another molecule (usually a polar solvent) by non-covalent bonds, particularly including hydrates and alcoholates, such as methanolates. The preferred solvate is the hydrate.

[0246] The term "prodrug" is used in its broadest sense and encompasses derivatives that can be converted in vivo into the compounds of the present invention. Examples of prodrugs include, but are not limited to, derivatives and metabolites of the compounds, including biolyzable moieties such as biolyzable amides, biolyzable esters, biolyzable carbamates, biolyzable carbonates, biolyzable ureas, and biolyzable phosphate analogs. Preferably, prodrugs having a carboxyl functional group are lower alkyl esters of carboxylic acids. The carboxylic acid esters are 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's "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).

[0247] The term "absent" means that the linking group is a bond.

[0248] Any compound referred to herein is intended to represent such a specific compound and certain of its variations or certain forms thereof. In particular, the compounds referred to herein may have asymmetric centers and thus exist in different enantiomeric or diastereomeric forms. Accordingly, any given compound referred to herein represents any one of the racemate, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof. Similarly, there may be stereoisomers or geometric isomers of double bonds, and thus in some cases the molecule may exist as the (E)-isomer or the (Z)-isomer (trans and cis isomers). If the molecule contains multiple double bonds, then each double bond will have its own stereoisomerism, which may be the same as or different from the stereoisomerism of the other double bonds of the molecule. In addition, atropisomers may exist for the compounds referred to herein. All stereoisomers of the compounds referred to herein, including enantiomers, diastereoisomers, geometric isomers, and atropisomers, and mixtures thereof, are within the scope of the present invention.

[0249] The term "leaving group" is given its ordinary meaning in the field of synthetic organic chemistry and refers to an atom or group that can be displaced by a nucleophile. See, for example, Smith, March's Advanced Organic Chemistry, 6th Edition, (501-502). Examples of suitable leaving groups include, but are not limited to, halogens (e.g., F, Cl, Br, or I), alkylsulfonyloxy, arylsulfonyloxy, etc.

[0250] All publications, patents, and published patent specifications cited herein are hereby incorporated by reference in their entirety.

[0251] The technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0252] Compound Synthesis Example

[0253] Example 1

[0254] The synthesis route is as follows:

[0255]

[0256]

[0257] The specific steps are as follows:

[0258] 1.1 Synthesis of Intermediate A-1

[0259]

[0260] Under nitrogen protection, 3,5-diamino-1,2,4-triazole (1.0 e.q.) was added to 48% aqueous hydrobromic acid solution (1 mmol: 0.4 mL), and an aqueous solution of sodium nitrite (1.1 e.q.) was added dropwise at 0 °C. Subsequently, the reaction was carried out at 100 °C for 16 hours. After the reaction was monitored by LC-MS and ended, the reaction solution was cooled to 0 °C, the pH was adjusted to 4 with 10% sodium hydroxide solution, and extracted with ethyl acetate 4 times. The organic phase was dried over saturated brine and anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Intermediate A-1.

[0261] 1.2 Synthesis of Intermediate B-1

[0262]

[0263] 3-chloro-4-aminobenzotrifluoride (1.0 e.q.) was added to dichloromethane (1 mmol: 2 mL), and chloroacetyl chloride (1.05 e.q.) was added dropwise at 0 °C. Subsequently, the reaction was carried out at room temperature for 16 hours. After the reaction was monitored by TLC and ended, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was slurried with petroleum ether to obtain Intermediate B-1.

[0264] 1.3 Synthesis of Intermediate C-1

[0265]

[0266] Under nitrogen protection, 3-hydroxy-2-pyridinecarboxylic acid (1.0 e.q.) and pentafluorophenol (1.05 e.q.) were added to dichloromethane (1 mmol: 2 mL), and N,N'-diisopropylcarbodiimide (1.05 e.q.) was added dropwise at 0 °C, followed by reaction at room temperature for 16 hours. After monitoring the reaction by LC-MS and completion, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain intermediate C-1.

[0267] 1.4 Synthesis of intermediate A-2

[0268] At room temperature, ethyl 3-oxobutanoate (1.1 e.q.) and intermediate A-1 (1.0 e.q.) were added to acetic acid (1 mmol: 0.5 mL), and then the temperature was raised to 80 °C and reacted for 16 hours. After monitoring the reaction by LC-MS and completion, the reaction solution was cooled to 0 °C and stirred for one hour. The solid obtained by filtration was washed with a small amount of ethanol and then dried to obtain intermediate A-2.

[0269] 1.5 Synthesis of intermediate A-3

[0270] At room temperature, intermediate A-2 (1.0 e.q.), intermediate B-1 (1.2 e.q.) and N,N-diisopropylethylamine (2.5 e.q.) were added to N,N-dimethylformamide (1 mmol: 2 mL), and then the temperature was raised to 80 °C and reacted for 16 hours. After monitoring the reaction by LC-MS and completion, the reaction solution was diluted with ethyl acetate, washed twice with water and once with brine. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain intermediate A-3.

[0271] 1.6 Synthesis of intermediate A-4

[0272] Intermediate A-3 (1.0 e.q.), 3,6-dihydro-2H-pyran-4-ylboronic acid pinacol ester (1.2 e.q.), XPhosPd G3 (0.05 e.q.) and potassium phosphate (2.5 e.q.) were added to a mixture of N,N-dimethylformamide and water (7:1, 1 mmol: 5 mL), and the mixture was purged with nitrogen three times, and then the temperature was raised to 80 °C and reacted for 16 hours. After monitoring the reaction by LC-MS and completion, the reaction solution was diluted with ethyl acetate, washed twice with water and once with brine. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain intermediate A-4.

[0273] 1.7 Synthesis of intermediate A-5

[0274] At room temperature, intermediate A-4 (1.0 e.q.) was dissolved in N,N-dimethylformamide (1 mmol: 10 mL), and then N-bromosuccinimide (1.5 e.q.) was added in batches, and the reaction was carried out for 4 hours. After the reaction was monitored by LC-MS and completed, the reaction solution was diluted with ethyl acetate, washed once with saturated sodium bicarbonate, washed twice with water, and washed once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain intermediate A-5.

[0275] 1.8 Synthesis of intermediate A-6 or A-6'

[0276] A-5 (1.0 e.q.), N,N-diisopropylethylamine (3.0 e.q.) and commercially available tert-butoxycarbonyl-protected spiroamine (S-1 or S-1') (2.5 e.q.) were dissolved in dimethyl sulfoxide (1 mmol: 5 mL). Then, under nitrogen protection, the reaction was carried out at 120 °C for 16 hours. After the reaction was monitored by LC-MS and completed, the reaction solution was diluted with ethyl acetate, washed twice with water, and washed once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain intermediate A-6 or A-6'.

[0277] 1.9 Synthesis of intermediate A-7 or A-7'

[0278] At room temperature, intermediate A-6 and A-6' (1.0 e.q.) were dissolved in dichloromethane (1 mmol: 5 mL). Then, trifluoroacetic acid (1 mmol: 1 mL) was added at 0 °C, and then the reaction was carried out at room temperature for 2 hours. After the reaction was monitored by LC-MS and completed, 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 aqueous phase was extracted twice with dichloromethane, and the organic phase was washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain intermediate A-7 or A-7'.

[0279] 1.10 Synthesis of compound A-8 or A-8'

[0280] Intermediate A-7 or A-7' (1.0 e.q.), triethylamine (3.0 e.q.) and intermediate C-1 (1.2 e.q.) were dissolved in N,N-dimethylformamide (1 mmol: 10 mL). Then, under nitrogen protection, the reaction was carried out at 80 °C for 2 hours. After the reaction was monitored by LC-MS and completed, the reaction solution was diluted with ethyl acetate, washed twice with water, and washed once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by high-pressure reverse preparation to obtain compound A-8 or A-8'.

[0281] When Y is CH2, n = 1, and m = 1, A-8 obtained according to the above synthesis steps is compound T001.

[0282] When Y does not exist, n = 2, and m = 1, A-8 obtained according to the above synthesis implementation steps is the compound T004.

[0283] When Y is CH2, n = 1, and m = 1, A-8' obtained according to the above synthesis implementation steps is the compound T005.

[0284] When Y is CH2, n = 1, and m = 0, A-8' obtained according to the above synthesis implementation steps is the compound T006.

[0285] When Y is CH2, n = 1, and m = 3, A-8 obtained according to the above synthesis implementation steps is the compound T007.

[0286] When Y is CH2, n = 1, and m = 2, A-8 obtained according to the above synthesis implementation steps is the compound T008.

[0287] When Y is CH2, n = 1, and m = 2, A-8' obtained according to the above synthesis implementation steps is the compound T009.

[0288] When Y is CH2, n = 2, and m = 1, A-8 obtained according to the above synthesis implementation steps is the compound T010.

[0289] When Y is CH2, n = 2, and m = 2, A-8 obtained according to the above synthesis implementation steps is the compound T011.

[0290] When Y is CH2, n = 2, and m = 2, A-8', particularly when the configuration of the spiro atom is S-type, is the compound T12.

[0291] When Y is CH2, n = 0, and m = 2, A-8' obtained according to the above synthesis implementation steps is the compound T013.

[0292] When Y is CH2, n = 1, and m = 3, A-8' obtained according to the above synthesis implementation steps is the compound T014.

[0293] When Y is CH2, n = 2, and m = 2, A-8', particularly when the configuration of the spiro atom is R-type, is the compound T015.

[0294] The structures and general analysis data of the target compounds are shown in Table 1.

[0295] Example 2

[0296] The specific steps are as follows:

[0297] 2.1 Synthesis of Intermediate C-2

[0298]

[0299] 2.1.1 Synthesis of Intermediate C-2

[0300] Dissolve 3-hydroxy-4-methylpyridine (1.0 e.q.) and sodium carbonate (2.3 e.q.) in water (1 mmol: 5 mL), then add iodine (1.0 e.q.), and react at room temperature for 4 hours. After monitoring the reaction by LC-MS until completion, adjust the pH of the reaction solution to 4 - 5 with 2 M hydrochloric acid at 0 °C, extract three times with ethyl acetate, wash the organic phase with saturated brine, dry the obtained organic phase over anhydrous sodium sulfate and concentrate under reduced pressure, and then obtain Intermediate C-2-1 through column chromatography.

[0301] 2.1.2 Synthesis of Intermediate C-2-2

[0302] Add Intermediate C-2-1 (1.0 e.q.) and cuprous cyanide (4.0 e.q.) to N,N-dimethylformamide (1 mmol: 2 mL) at room temperature, displace with nitrogen three times, and then heat to 100 °C and react for 2 hours. After monitoring the reaction by LC-MS until completion, cool to room temperature, dilute the reaction solution with ethyl acetate and water, filter to separate the organic phase, wash the organic phase once with water and once with brine, dry the obtained organic phase over anhydrous sodium sulfate and concentrate under reduced pressure, and then obtain Intermediate C-2-2 through column chromatography.

[0303] 2.1.3 Synthesis of Intermediate C-2

[0304] Dissolve potassium hydroxide (6.0 e.q.) in water (1 mmol: 2 mL), then add Intermediate C-2-2 (1.0 e.q.) and heat to 90 °C and react for 16 hours. After monitoring the reaction by LC-MS until completion, cool to 0 °C, adjust the pH of the reaction solution to approximately 3 with 2 M hydrochloric acid, filter the obtained solid, wash it twice with a small amount of water, and collect the solid and dry it to obtain Intermediate C-2.

[0305] 2.2 Synthesis of Compound T002

[0306] Compound T002 is synthesized by condensing Intermediate A-7 (Y is CH2, n = 1, m = 1) obtained from the synthesis implementation steps of Example 1 with C-2.

[0307] At room temperature, intermediate A-7 (1.0 e.q.), C-2 (2.0 e.q.) and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL). Subsequently, 1H-benzotriazol-1-yloxytris-pyrrolidinophosphonium hexafluorophosphate (2.0 e.q.) was added at 0 °C, and then the reaction mixture was warmed to room temperature and stirred for 2 hours. After the reaction was monitored by LC-MS and completed, the reaction solution was diluted with ethyl acetate, washed twice with water and once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then purified by high-pressure reverse preparation to obtain compound T002. The structure and general analytical data are shown in Table 1.

[0308] Example 3

[0309] 3.1 Synthesis of intermediate C-3

[0310]

[0311] 3.1.1 Synthesis of intermediate C-3-1

[0312] At room temperature, intermediate C2-1-1 (1.0 e.q.) and potassium carbonate (1.5 e.q.) were added to N,N-dimethylformamide (1 mmol: 3 mL). Subsequently, benzyl bromide (1.05 e.q.) was added, and then the reaction mixture was warmed to 40 °C and stirred for 2 hours. After the reaction was monitored by LC-MS and completed, the reaction solution was diluted with a large amount of water and extracted twice with ethyl acetate. The obtained organic phase was washed once with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then purified by column chromatography to obtain intermediate C-3-1.

[0313] 3.1.2 Synthesis of intermediate C-3-2

[0314] At room temperature, intermediate C-3-1 (1.0 e.q.), benzyl mercaptan (2.0 e.q.), XanPhos (0.15 e.q.), Pd2(dba)3 (0.075 e.q.) and N,N-diisopropylethylamine (3.0 e.q.) were added to 1,4-dioxane (1 mmol: 4 mL). The reaction mixture was purged with nitrogen three times, and then heated to 100 °C and stirred for 2 hours. After the reaction was monitored by LC-MS and completed, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain intermediate C-3-2.

[0315] 3.1.3 Synthesis of intermediate C-3

[0316] Dissolve intermediate C-3-2 (1.0 e.q.) in acetonitrile (1 mmol: 4 mL) and water (1 mmol: 0.5 mL), cool to 0 °C, add acetic acid (6.0 e.q.) and 1,3-dichloro-5,5-dimethylhydantoin (1.0 e.q.), and then raise the temperature to room temperature and react for 2 hours. After monitoring the reaction by LC-MS until completion, adjust the pH of the reaction solution to 7 with saturated sodium bicarbonate, extract three times with ethyl acetate, combine the organic phases, wash with brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then obtain intermediate C-3 through column chromatography.

[0317] 3.2 Synthesis of Compound T003

[0318] Compound T003 is synthesized by condensing intermediate A-7 (Y is CH2, n = 1, m = 1) obtained from the synthesis implementation steps of Example 1 with C-3.

[0319] Dissolve intermediate A-7 (1.0 e.q.) and triethylamine (5 e.q.) in dichloromethane (1 mmol: 10 mL), then cool the reaction solution to 0 °C, add intermediate C-3 (2.5 e.q.), and then raise the temperature to room temperature and react for 2 hours. After monitoring the reaction by LC-MS until completion, dilute the reaction solution with water, extract twice with dichloromethane, combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then obtain compound T003 through high-pressure reverse preparation. Its structure and general analytical data are shown in Table 1.

[0320] Example 4

[0321] The synthesis route is as follows:

[0322]

[0323] The specific steps are as follows:

[0324] 4.1 Synthesis of Intermediate A-9

[0325] Add ethyl acetoacetate (1.0 e.q.) and ammonium acetate (0.3 e.q.) to anhydrous ether (1 mmol: 5 mL), then add NBS (1.08 e.q.) in batches, and then stir the solution at room temperature for 4 hours. Monitor the reaction by TLC until completion, rotary evaporate the ether, dilute with ethyl acetate, wash three times with brine, collect the organic phase, dry over anhydrous sodium sulfate to obtain the crude product A-9. It can be directly used in the next step without purification.

[0326] 4.2 Synthesis of Intermediate A-10

[0327] Weigh intermediate A-9 (1.0 e.q.), (R)-1-BOC-1,7-diazaspiro[4.4]nonane (0.8 e.q.) and potassium carbonate (3.0 e.q.), and dissolve them in acetonitrile (1 mmol: 2 mL). Then stir the reaction at room temperature for 2 - 3 h. After monitoring the end of the reaction by LC-MS, rotary evaporate the acetonitrile, dilute with ethyl acetate, wash three times with brine, dry over anhydrous sodium sulfate, retain the organic phase, rotary evaporate to dryness to obtain the crude product. Finally, obtain A-10 through column chromatography.

[0328] 4.3 Synthesis of intermediate A-11

[0329] Under nitrogen protection, add WRI-INT-1 (1.5 e.q.) and 85% aqueous phosphoric acid solution (1.0 e.q.) to the ethanol solution of intermediate A-10 (1.0 e.q.) (1 mmol: 0.5 mL), then stir at 90 °C for 16 h. After monitoring the end of the reaction by LC-MS, cool the solution to room temperature, rotary evaporate the ethanol, dilute with ethyl acetate, wash with aqueous ammonium chloride solution, collect the organic phase, dry over anhydrous sodium sulfate, rotary evaporate to dryness to obtain the crude product. Finally, obtain product A-11 through column chromatography.

[0330] 4.4 Synthesis of intermediate A-12

[0331] Add intermediate A-11 (1.0 e.q.), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.2 e.q.), XPhosPd G3 (0.05 e.q.) and potassium phosphate (2.5 e.q.) to 1,4-dioxane and water (5:1, 1 mmol: 5 mL), displace with nitrogen three times, then heat up to 80 °C and react for 4 h. After monitoring the end of the reaction by LC-MS, dilute the reaction solution with ethyl acetate, wash with brine, collect the organic phase, dry over anhydrous sodium sulfate, rotary evaporate to dryness. Then obtain intermediate A-12 through column chromatography.

[0332] 4.5 Synthesis of intermediate A-13-1

[0333] At room temperature, add intermediate A-12 (1.0 e.q.), intermediate B-1 (1.2 e.q.) and N,N-diisopropylethylamine (2.5 e.q.) to N,N-dimethylformamide (1 mmol: 2 mL), then heat up to 80 °C and react for 16 h. After monitoring the end of the reaction by LC-MS, dilute the reaction solution with ethyl acetate, wash twice with water and once with brine, dry the obtained organic phase over anhydrous sodium sulfate and concentrate under reduced pressure, then obtain intermediate A-13-1 through column chromatography.

[0334] 4.6 Synthesis of intermediate A-14-1

[0335] At room temperature, intermediate A-13-1 (1.0 e.q.) was dissolved in dichloromethane (1 mmol: 5 mL), then trifluoroacetic acid (1 mmol: 3 mL) was added at 0 °C, and then the temperature was raised to 40 °C and the reaction was carried out for 16 hours. After the reaction was monitored by LC-MS and ended, the reaction solution was concentrated under reduced pressure until nearly dry, diluted with dichloromethane, and the pH of the aqueous phase was adjusted to 8 - 9 with saturated sodium bicarbonate. The aqueous phase was extracted twice with dichloromethane, and the organic phase was washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain intermediate A-14-1.

[0336] 4.7 Synthesis of the target product

[0337] 4.7.1 Synthesis of target product T016

[0338]

[0339] At room temperature, intermediate A-14-1 (1.0 e.q.), C-4 (2.0 e.q.) and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL), then 1H-benzotriazol-1-yloxytris-pyrrolidinophosphonium hexafluorophosphate (2.0 e.q.) was added at 0 °C, and then the temperature was raised to 40 °C and the reaction was carried out for 2 hours. After the reaction was monitored by LC-MS and ended, the reaction solution was diluted with ethyl acetate, washed twice with water and once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then compound T016 was obtained by high-pressure reverse preparation. Its structure and general analytical data are shown in Table 1.

[0340] 4.7.2 Synthesis of target product T017

[0341]

[0342] At room temperature, intermediate A-14-1 (1.0 e.q.), C-5 (2.0 e.q.) and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL), then 1H-benzotriazol-1-yloxytris-pyrrolidinophosphonium hexafluorophosphate (2.0 e.q.) was added at 0 °C, and then the temperature was raised to 40 °C and the reaction was carried out for 2 hours. After the reaction was monitored by LC-MS and ended, the reaction solution was diluted with ethyl acetate, washed twice with water and once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then compound T017 was obtained by high-pressure reverse preparation. Its structure and general analytical data are shown in Table 1.

[0343] 4.7.3 Synthesis of target product T018

[0344]

[0345] At room temperature, intermediate A-14-1 (1.0 e.q.), C-6 (2.0 e.q.) and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL). Subsequently, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.5 e.q.) was added at 0 °C, and then the temperature was raised to 40 °C and the reaction was carried out for 2 hours. After the reaction was monitored by LC-MS and completed, the reaction solution was diluted with ethyl acetate, washed twice with water and once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then prepared by high-pressure reverse phase to obtain compound T018. Its structure and general analytical data are shown in Table 1.

[0346] 4.7.4 Synthesis of target product T019

[0347]

[0348] At room temperature, intermediate A-14-1 (1.0 e.q.), C-7 (2.0 e.q.) and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL). Subsequently, 1H-benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (2.0 e.q.) was added at 0 °C, and then the temperature was raised to 40 °C and the reaction was carried out for 2 hours. After the reaction was monitored by LC-MS and completed, the reaction solution was diluted with ethyl acetate, washed twice with water and once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then prepared by high-pressure reverse phase to obtain compound T019. Its structure and general analytical data are shown in Table 1.

[0349] 4.7.5 Synthesis of target product T020

[0350]

[0351] At room temperature, intermediate A-14-1 (1.0 e.q.), C-8 (2.0 e.q.) and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL). Subsequently, 1H-benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (2.0 e.q.) was added at 0 °C, and then the temperature was raised to 40 °C and the reaction was carried out for 2 hours. After the reaction was monitored by LC-MS and completed, the reaction solution was diluted with ethyl acetate, washed twice with water and once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then prepared by high-pressure reverse phase to obtain compound T020. Its structure and general analytical data are shown in Table 1.

[0352] 4.7.6 Synthesis of target product T021

[0353]

[0354] At room temperature, intermediate A-14-1 (1.0 e.q.), C-2 (2.0 e.q.) and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL). Subsequently, 1H-benzotriazol-1-yloxytris-pyrrolidinophosphonium hexafluorophosphate (2.0 e.q.) was added at 0 °C, and then the temperature was raised to 40 °C and the reaction was carried out for 2 hours. After the reaction was monitored by LC-MS to completion, the reaction solution was diluted with ethyl acetate, washed twice with water and once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by high-pressure reverse preparation to obtain compound T021. Its structure and general analytical data are shown in Table 1.

[0355] 4.7.7 Synthesis of the target product T006

[0356]

[0357] 4.7.7.1 Synthesis of intermediate A-15-1

[0358] At room temperature, intermediate A-14-1 (1.0 e.q.), C-9 (2.0 e.q.) and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL). Subsequently, 1H-benzotriazol-1-yloxytris-pyrrolidinophosphonium hexafluorophosphate (2.0 e.q.) was added at 0 °C, and then the temperature was raised to 40 °C and the reaction was carried out for 2 hours. After the reaction was monitored by LC-MS to completion, the reaction solution was diluted with ethyl acetate, washed twice with water and once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain intermediate A-15-1.

[0359] 4.7.7.2 Synthesis of the target product T006

[0360] At room temperature, intermediate A-15-1 (1.0 e.q.) was dissolved in trifluoroacetic acid solution (1 mmol: 1 mL), and the reaction solution was heated to 40 °C and reacted for 12 hours. After the reaction was monitored by LC-MS to completion, the trifluoroacetic acid was evaporated, the concentrated solution was diluted with ethyl acetate, washed once with saturated sodium bicarbonate solution and once with saturated brine, the organic phase was evaporated, and then purified by high-pressure reverse preparation to obtain compound T006. Its structure and general analytical data are shown in Table 1.

[0361] 4.7.8 Synthesis of the target product T013

[0362]

[0363] 4.7.8.1 Synthesis of intermediate A-15-2

[0364] At room temperature, intermediate A-14-1 (1.0 e.q.), C-10 (2.0 e.q.) and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL). Subsequently, 1H-benzotriazol-1-yloxytris-pyrrolidinophosphonium hexafluorophosphate (2.0 e.q.) was added at 0 °C, and then the temperature was raised to 40 °C for reaction for 2 hours. After the reaction was monitored by LC-MS to completion, the reaction solution was diluted with ethyl acetate, washed twice with water and once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain intermediate A-15-1.

[0365] 4.7.8.2 Synthesis of target product T013

[0366] At room temperature, intermediate A-15-2 (1.0 e.q.) was dissolved in trifluoroacetic acid solution (1 mmol: 1 mL). The reaction solution was heated to 40 °C for reaction for 12 hours. After the reaction was monitored by LC-MS to completion, the trifluoroacetic acid was evaporated, the concentrated solution was diluted with ethyl acetate, washed once with saturated sodium bicarbonate solution and once with saturated brine, the organic phase was evaporated, and then compound T013 was obtained by high-pressure reverse preparation. Its structure and general analytical data are shown in Table 1.

[0367] 4.7.9 Synthesis of target product T014

[0368]

[0369] At room temperature, intermediate A-14-1 (1.0 e.q.), C-11 (2.0 e.q.) and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL). Subsequently, 1H-benzotriazol-1-yloxytris-pyrrolidinophosphonium hexafluorophosphate (2.0 e.q.) was added at 0 °C, and then the temperature was raised to 40 °C for reaction for 2 hours. After the reaction was monitored by LC-MS to completion, the reaction solution was diluted with ethyl acetate, washed twice with water and once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then compound T014 was obtained by high-pressure reverse preparation. Its structure and general analytical data are shown in Table 1.

[0370] Example 5

[0371] The synthesis route is as follows:

[0372]

[0373] The specific steps are as follows:

[0374] 5.1 The synthesis route of intermediate B-2 is as follows:

[0375]

[0376] 5.1.1 Synthesis of Intermediate B-2-1

[0377] Dissolve 4-amino-2-chlorobenzotrifluoride (1.0 e.q.) in CH3OH:DCM = 3:2 mL (1.0 mmol:5 mL) at room temperature. Add iodine monochloride (1.5 e.q.) at 0 °C, and then raise the temperature to room temperature and react for 2 hours. After monitoring the reaction by LC-MS until completion, concentrate the reaction solution under reduced pressure to dryness, dilute with ethyl acetate, and slowly add it to a saturated sodium thiosulfate solution. Stir for 5 - 10 minutes. Finally, wash twice with water and wash the organic phase with saturated brine. The obtained organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude intermediate B-2-1. The crude product is purified by column chromatography to obtain the pure intermediate B-2-1.

[0378] 5.1.2 Synthesis of Intermediate B-2-2

[0379] Add intermediate B-2-1 (1.0 e.q.), trimethylcyclotriboroxane (2.5 e.q.), DPPF palladium dichloride methane complex (0.05 e.q.), and potassium carbonate (2.5 e.q.) to 1,4-dioxane (1 mmol:2 mL). Replace the gas with nitrogen three times, and then raise the temperature to 100 °C and react for 16 hours. After monitoring the reaction by LC-MS until completion, dilute the reaction solution with ethyl acetate, wash with brine, collect the organic phase, dry over anhydrous sodium sulfate, and evaporate to dryness. Then obtain intermediate B-2-2 through column chromatography.

[0380] 5.1.3 Synthesis of Intermediate B-2

[0381] Add intermediate B-2-2 (1.0 e.q.) to dichloromethane (1 mmol:2 mL). Dropwise add chloroacetyl chloride (1.05 e.q.) at 0 °C, and then react at room temperature for 16 hours. After monitoring the reaction by TLC until completion, concentrate the reaction solution under reduced pressure to obtain the crude product, and slurry with petroleum ether to obtain intermediate B-2.

[0382] 5.2 Synthesis of Intermediate A-3b

[0383] Add intermediate A-2 (1.0 e.q.), intermediate B-2 (1.2 e.q.), and N,N-diisopropylethylamine (2.5 e.q.) to N,N-dimethylformamide (1 mmol:2 mL) at room temperature. Then raise the temperature to 80 °C and react for 16 hours. After monitoring the reaction by LC-MS until completion, dilute the reaction solution with ethyl acetate, wash twice with water and once with brine. The obtained organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then obtain intermediate A-3b through column chromatography.

[0384] 5.3 Synthesis of Intermediate A-4b

[0385] Intermediate A-3b (1.0 e.q.), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.2 e.q.), XPhosPd G3 (0.05 e.q.) and potassium phosphate (2.5 e.q.) were added to N,N-dimethylformamide and water (7:1, 1 mmol:5 mL). After three nitrogen displacements, the temperature was then raised to 80 °C and the reaction was carried out for 16 hours. After monitoring the reaction by LC-MS until completion, the reaction solution was diluted with ethyl acetate, washed twice with water and once with brine. The obtained organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then intermediate A-4b was obtained by column chromatography.

[0386] 5.4 Synthesis of Intermediate A-5b

[0387] Intermediate A-4b (1.0 e.q.) was dissolved in N,N-dimethylformamide (1 mmol:10 mL) at room temperature. Subsequently, N-bromosuccinimide (1.5 e.q.) was added in portions, and the reaction was carried out for 4 hours. After monitoring the reaction by LC-MS until completion, the reaction solution was diluted with ethyl acetate, washed once with saturated sodium bicarbonate, twice with water and once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then intermediate A-5b was obtained by column chromatography.

[0388] 5.5 Synthesis of Intermediate A-6b

[0389] Intermediate A-5b (1.0 e.q.), N,N-diisopropylethylamine (3.0 e.q.) and commercially available (R)-1-BOC-1,7-diazaspiro[4.4]nonane (2.5 e.q.) were dissolved in dimethyl sulfoxide (1 mmol:5 mL). Subsequently, under nitrogen protection, the reaction was carried out at 120 °C for 16 hours. After monitoring the reaction by LC-MS until completion, the reaction solution was diluted with ethyl acetate, washed twice with water and once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then intermediate A-6b was obtained by column chromatography.

[0390] 5.6 Synthesis of Intermediate A-7b

[0391] Intermediate A-6b (1.0 e.q.) was dissolved in dichloromethane (1 mmol:5 mL) at room temperature. Subsequently, trifluoroacetic acid (1 mmol:1 mL) was added at 0 °C, and then the temperature was raised to room temperature and the reaction was carried out for 2 hours. After monitoring the reaction by LC-MS until completion, 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 aqueous phase was extracted twice with dichloromethane, and the organic phase was washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain intermediate A-7b.

[0392] 5.7 Synthesis of the target product

[0393] 5.7.1 The synthesis steps of the target product T022 are based on the synthesis of A-8, and its structure and general analysis data are shown in Table 1.

[0394] 5.7.2 The synthesis steps of the target product T023 are based on the synthesis of T016, and its structure and general analysis data are shown in Table 1.

[0395] 5.7.3 The synthesis steps of the target product T024 are based on the synthesis of T017, and its structure and general analysis data are shown in Table 1.

[0396] 5.7.4 The synthesis steps of the target product T025 are based on the synthesis of T018, and its structure and general analysis data are shown in Table 1.

[0397] 5.7.5 The synthesis steps of the target product T026 are based on the synthesis of T019, and its structure and general analysis data are shown in Table 1.

[0398] 5.7.6 The synthesis steps of the target product T027 are based on the synthesis of T020, and its structure and general analysis data are shown in Table 1.

[0399] 5.7.7 The synthesis steps of the target product T028 are based on the synthesis of T021, and its structure and general analysis data are shown in Table 1.

[0400] 5.7.8 The synthesis steps of the target product T029 are based on the synthesis of T006, and its structure and general analysis data are shown in Table 1.

[0401] 5.7.9 The synthesis steps of the target product T030 are based on the synthesis of T013, and its structure and general analysis data are shown in Table 1.

[0402] 5.7.10 The synthesis steps of the target product T031 are based on the synthesis of T014, and its structure and general analysis data are shown in Table 1.

[0403] Example 6

[0404] The synthesis route is as follows:

[0405]

[0406] 6.1 Synthesis of intermediate B-3

[0407]

[0408] 6.1.1 Synthesis of intermediate B-3-1

[0409] At room temperature, 3-fluoro-2-methylaniline was dissolved in acetic acid (1 mmol: 1 mL), and then N-iodosuccinimide (1.0 e.q.) was added. After that, the reaction solution was heated to 95 °C and reacted for 2.5 hours. After the reaction was monitored by LC-MS and ended, the reaction solution was concentrated nearly to dryness, diluted with ethyl acetate, and poured into a saturated sodium thiosulfate solution and stirred for 5 - 10 minutes. Then, it was washed twice with water and once with saturated brine. The obtained organic phase was concentrated under reduced pressure over anhydrous sodium sulfate and then purified by column chromatography to obtain intermediate B-3-1.

[0410] 6.1.2 Synthesis of Intermediate B-3-2

[0411] At room temperature, intermediate B-3-1 (1.0 e.q.) and triethylamine (2.0 e.q.) were dissolved in DCM (1 mmol: 3 mL). Then, the reaction solution was cooled to 0 °C and acetyl chloride (1.5 e.q.) was added. After that, the reaction solution was slowly warmed to room temperature and reacted for 4 hours. After the reaction was monitored by TLC and ended, the reaction solution was diluted with dichloromethane, washed twice with water and once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then purified by column chromatography to obtain intermediate B-3-2.

[0412] 6.1.3 Synthesis of Intermediate B-3-3

[0413] Intermediate B-3-2 (1.0 e.q.), hexamethylphosphoric triamide (5.0 e.q.), methyl fluorosulfonyldifluoroacetate (5.0 e.q.) and cuprous iodide (2.0 e.q.) were dissolved in DMF (1 mmol: 2 mL). After purging with nitrogen three times, the reaction solution was heated to 80 °C and reacted for 16 hours. After the reaction was monitored by LCMS and ended, the reaction solution was diluted with ethyl acetate, washed 3 times with water and 1 time with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then purified by column chromatography to obtain intermediate B-3-3.

[0414] 6.1.4 Synthesis of Intermediate B-3-4

[0415] At room temperature, intermediate B-3-3 (1.0 e.q.) was dissolved in ethanol (1 mmol: 2 mL), and 2N HCl in dioxane (5.0 e.q.) was added. Then, the reaction solution was heated to reflux and reacted for 2 hours. After the reaction was monitored by LCMS and ended, the reaction solution was concentrated nearly to dryness, and the concentrate was triturated with ethyl acetate and petroleum ether (1:2) to obtain pure intermediate B-3-4.

[0416] 6.1.5 Synthesis of Intermediate B-3

[0417] Intermediate B-3-4 (1.0 e.q.) and sodium bicarbonate (3.0 e.q.) were added to dichloromethane (1 mmol: 2 mL), and chloroacetyl chloride (1.05 e.q.) was added dropwise at 0 °C, followed by reaction at room temperature for 16 h. After the reaction was monitored by TLC and completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was slurried with petroleum ether to obtain Intermediate B-3.

[0418] 6.2 Synthesis of Intermediate A-3c was carried out according to the synthesis steps of Reaction Example A-3b.

[0419] 6.3 Synthesis of Intermediate A-4c was carried out according to the synthesis steps of Reaction Example A-4b.

[0420] 6.4 Synthesis of Intermediate A-5c was carried out according to the synthesis steps of Reaction Example A-5b.

[0421] 6.5 Synthesis of Intermediate A-6c was carried out according to the synthesis steps of Reaction Example A-6b.

[0422] 6.6 Synthesis of Intermediate A-7c was carried out according to the synthesis steps of Reaction Example A-7b.

[0423] 6.7 Synthesis of the target product

[0424] 6.7.1 The synthesis steps of target product T032 were based on the synthesis of A-8, and its structure and general analysis data are shown in Table 1.

[0425] 6.7.2 The synthesis steps of target product T033 were based on the synthesis of T016, and its structure and general analysis data are shown in Table 1.

[0426] 6.7.3 The synthesis steps of target product T034 were based on the synthesis of T017, and its structure and general analysis data are shown in Table 1.

[0427] 6.7.4 The synthesis steps of target product T035 were based on the synthesis of T018, and its structure and general analysis data are shown in Table 1.

[0428] 6.7.5 The synthesis steps of target product T036 were based on the synthesis of T019, and its structure and general analysis data are shown in Table 1.

[0429] 6.7.6 The synthesis steps of target product T037 were based on the synthesis of T020, and its structure and general analysis data are shown in Table 1.

[0430] 6.7.7 The synthesis steps of target product T038 were based on the synthesis of T021, and its structure and general analysis data are shown in Table 1.

[0431] 6.7.8 The synthesis steps of target product T039 were based on the synthesis of T006, and its structure and general analysis data are shown in Table 1.

[0432] 6.7.9 The synthesis steps of the target product T040 are based on the synthesis of T013, and its structure and general analysis data are shown in Table 1.

[0433] 6.7.10 The synthesis steps of the target product T041 are based on the synthesis of T014, and its structure and general analysis data are shown in Table 1.

[0434] Example 7

[0435] The synthesis route is as follows:

[0436]

[0437] 7.1 Synthesis of Intermediate B-4

[0438]

[0439] 7.1.1 Synthesis of Intermediate B-4-1

[0440] At room temperature, dissolve intermediate 4-amino-2-fluorobenzotrifluoride (1.0 e.q.) and boron trifluoride diethyl etherate (1.0 e.q.) in dichloromethane (1 mmol: 3 mL). Then cool the reaction solution to 0 °C and dropwise add NIS (1.0 e.q.). Heat the reaction solution to room temperature and react for 2 hours. After monitoring the reaction by LCMS until completion, rotary evaporate and concentrate the reaction solution, dilute it with ethyl acetate, pour it into saturated sodium thiosulfate solution, stir at room temperature for 5 - 10 minutes, then retain the organic phase, wash it twice with water and once with saturated brine. Rotary evaporate the organic phase and then purify it by column chromatography to obtain intermediate B-4-1.

[0441] 7.1.2 Synthesis of Intermediate B-4-2

[0442] Dissolve intermediate B-4-1 (1.0 e.q.), trimethylcyclotriboroxane (3.2 e.q.), Pd(PPh3)4 (0.05 e.q.) and potassium carbonate (4.6 e.q.) in 1,4-dioxane (1 mmol: 3 mL). Heat the reaction solution to 80 °C and react for 16 hours. After monitoring the reaction by LCMS until completion, cool it to room temperature, dilute the reaction solution with ethyl acetate, wash it twice with water and once with saturated brine. Rotary evaporate the organic phase and then purify it by column chromatography to obtain intermediate B-4-2.

[0443] 7.1.3 Synthesis of Intermediate B-4

[0444] Intermediate B-4-2 (1.0 e.q.) and sodium bicarbonate (3.0 e.q.) were added to dichloromethane (1 mmol: 2 mL), and chloroacetyl chloride (1.05 e.q.) was added dropwise at 0 °C. Subsequently, the reaction was carried out at room temperature for 16 hours. After monitoring the reaction by TLC until completion, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was triturated with petroleum ether to obtain Intermediate B-4.

[0445] 7.2 The synthesis of Intermediate A-3d was carried out according to the synthesis procedure of Reaction Example A-3b.

[0446] 7.3 The synthesis of Intermediate A-4d was carried out according to the synthesis procedure of Reaction Example A-4b.

[0447] 7.4 The synthesis of Intermediate A-5d was carried out according to the synthesis procedure of Reaction Example A-5b.

[0448] 7.5 The synthesis of Intermediate A-6d was carried out according to the synthesis procedure of Reaction Example A-6b.

[0449] 7.6 The synthesis of Intermediate A-7d was carried out according to the synthesis procedure of Reaction Example A-7b.

[0450] 7.7 Synthesis of the target product

[0451] 7.7.1 The synthesis procedure of the target product T042 was based on the synthesis of A-8, and its structure and general analysis data are shown in Table 1.

[0452] 7.7.2 The synthesis procedure of the target product T043 was based on the synthesis of T016, and its structure and general analysis data are shown in Table 1.

[0453] 7.7.3 The synthesis procedure of the target product T044 was based on the synthesis of T017, and its structure and general analysis data are shown in Table 1.

[0454] 7.7.4 The synthesis procedure of the target product T045 was based on the synthesis of T018, and its structure and general analysis data are shown in Table 1.

[0455] 7.7.5 The synthesis procedure of the target product T046 was based on the synthesis of T019, and its structure and general analysis data are shown in Table 1.

[0456] 7.7.6 The synthesis procedure of the target product T047 was based on the synthesis of T020, and its structure and general analysis data are shown in Table 1.

[0457] 7.7.7 The synthesis procedure of the target product T048 was based on the synthesis of T021, and its structure and general analysis data are shown in Table 1.

[0458] 7.7.8 The synthesis procedure of the target product T049 was based on the synthesis of T006, and its structure and general analysis data are shown in Table 1.

[0459] 7.7.9 The synthesis procedure of the target product T050 is based on the synthesis of T013, and its structure and general analysis data are shown in Table 1.

[0460] 7.7.10 The synthesis procedure of the target product T051 is based on the synthesis of T014, and its structure and general analysis data are shown in Table 1.

[0461] Example 8

[0462] The synthesis route is as follows:

[0463]

[0464] 8.1 Synthesis of intermediate B-5

[0465]

[0466] p-Trifluoromethylaniline (1.0 e.q.) was added to dichloromethane (1 mmol: 2 mL), and chloroacetyl chloride (1.05 e.q.) was added dropwise at 0 °C. Subsequently, the reaction was carried out at room temperature for 16 hours. After monitoring the reaction by TLC until completion, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was slurried with petroleum ether to obtain intermediate B-5.

[0467] 8.2 The synthesis of intermediate A-3e was carried out according to the synthesis procedure of reaction example A-3b.

[0468] 8.3 The synthesis of intermediate A-4e was carried out according to the synthesis procedure of reaction example A-4b.

[0469] 8.4 The synthesis of intermediate A-5e was carried out according to the synthesis procedure of reaction example A-5b.

[0470] 8.5 The synthesis of intermediate A-6e was carried out according to the synthesis procedure of reaction example A-6b.

[0471] 8.6 The synthesis of intermediate A-7e was carried out according to the synthesis procedure of reaction example A-7b.

[0472] 8.7 Synthesis of the target product

[0473] 8.7.1 The synthesis procedure of the target product T052 is based on the synthesis of A-8, and its structure and general analysis data are shown in Table 1.

[0474] 8.7.2 The synthesis procedure of the target product T053 is based on the synthesis of T016, and its structure and general analysis data are shown in Table 1.

[0475] 8.7.3 The synthesis procedure of the target product T054 is based on the synthesis of T017, and its structure and general analysis data are shown in Table 1.

[0476] 8.7.4 The synthesis steps of the target product T055 are based on the synthesis of T018, and its structure and general analysis data are shown in Table 1.

[0477] 8.7.5 The synthesis steps of the target product T056 are based on the synthesis of T019, and its structure and general analysis data are shown in Table 1.

[0478] 8.7.6 The synthesis steps of the target product T057 are based on the synthesis of T020, and its structure and general analysis data are shown in Table 1.

[0479] 8.7.7 The synthesis steps of the target product T058 are based on the synthesis of T021, and its structure and general analysis data are shown in Table 1.

[0480] 8.7.8 The synthesis steps of the target product T059 are based on the synthesis of T006, and its structure and general analysis data are shown in Table 1.

[0481] 8.7.9 The synthesis steps of the target product T060 are based on the synthesis of T013, and its structure and general analysis data are shown in Table 1.

[0482] 8.7.10 The synthesis steps of the target product T061 are based on the synthesis of T014, and its structure and general analysis data are shown in Table 1.

[0483] Example 9

[0484] The synthesis route is as follows:

[0485]

[0486] 9.1 Synthesis of Intermediate B-6

[0487]

[0488] Add 2-methyl-4-(trifluoromethyl)aniline (1.0 e.q.) to dichloromethane (1 mmol: 2 mL), and dropwise add chloroacetyl chloride (1.05 e.q.) at 0 °C. Then react at room temperature for 16 hours. After monitoring the reaction by TLC and completion, concentrate the reaction solution under reduced pressure to obtain the crude product, and slurry with petroleum ether to obtain Intermediate B-6.

[0489] 9.2 The synthesis of Intermediate A-3f is based on the synthesis steps of Reaction Example A-3b.

[0490] 9.3 The synthesis of Intermediate A-4f is based on the synthesis steps of Reaction Example A-4b.

[0491] 9.4 The synthesis of Intermediate A-5f is based on the synthesis steps of Reaction Example A-5b.

[0492] 9.5 The synthesis of intermediate A-6f was carried out according to the synthesis steps of reaction example A-6b.

[0493] 9.6 The synthesis of intermediate A-7f was carried out according to the synthesis steps of reaction example A-7b.

[0494] 9.7 Synthesis of the target product

[0495] 9.7.1 The synthesis steps of target product T062 were based on the synthesis of A-8, and its structure and general analysis data are shown in Table 1.

[0496] 9.7.2 The synthesis steps of target product T063 were based on the synthesis of T016, and its structure and general analysis data are shown in Table 1.

[0497] 9.7.3 The synthesis steps of target product T064 were based on the synthesis of T017, and its structure and general analysis data are shown in Table 1.

[0498] 9.7.4 The synthesis steps of target product T065 were based on the synthesis of T018, and its structure and general analysis data are shown in Table 1.

[0499] 9.7.5 The synthesis steps of target product T066 were based on the synthesis of T019, and its structure and general analysis data are shown in Table 1.

[0500] 9.7.6 The synthesis steps of target product T067 were based on the synthesis of T020, and its structure and general analysis data are shown in Table 1.

[0501] 9.7.7 The synthesis steps of target product T068 were based on the synthesis of T021, and its structure and general analysis data are shown in Table 1.

[0502] 9.7.8 The synthesis steps of target product T069 were based on the synthesis of T006, and its structure and general analysis data are shown in Table 1.

[0503] 9.7.9 The synthesis steps of target product T070 were based on the synthesis of T013, and its structure and general analysis data are shown in Table 1.

[0504] 9.7.10 The synthesis steps of target product T071 were based on the synthesis of T014, and its structure and general analysis data are shown in Table 1.

[0505] Example 10

[0506] The synthesis route is as follows:

[0507]

[0508] 10.1 Synthesis of intermediate B-7

[0509]

[0510] 2-Fluoro-4-(trifluoromethyl)aniline (1.0 e.q.) was added to dichloromethane (1 mmol: 2 mL), and chloroacetyl chloride (1.05 e.q.) was added dropwise at 0 °C, followed by reaction at room temperature for 16 h. After the reaction was monitored by TLC and completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was slurried with petroleum ether to obtain intermediate B-7.

[0511] 10.2 The synthesis of intermediate A-3g was based on the synthesis procedure of A-3b.

[0512] 10.3 The synthesis of intermediate A-4g was based on the synthesis procedure of A-4b.

[0513] 10.4 The synthesis of intermediate A-5g was based on the synthesis procedure of A-5b.

[0514] 10.5 The synthesis of intermediate A-6g was based on the synthesis procedure of A-6b.

[0515] 10.6 The synthesis of intermediate A-7g was based on the synthesis procedure of A-7b.

[0516] 10.7 Synthesis of the target product

[0517] 10.7.1 The synthesis procedure of the target product T072 was based on the synthesis of A-8, and its structure and general analytical data are shown in Table 1.

[0518] 10.7.2 The synthesis procedure of the target product T073 was based on the synthesis of T016, and its structure and general analytical data are shown in Table 1.

[0519] 10.7.3 The synthesis procedure of the target product T074 was based on the synthesis of T017, and its structure and general analytical data are shown in Table 1.

[0520] 10.7.4 The synthesis procedure of the target product T075 was based on the synthesis of T018, and its structure and general analytical data are shown in Table 1.

[0521] 10.7.5 The synthesis procedure of the target product T076 was based on the synthesis of T019, and its structure and general analytical data are shown in Table 1.

[0522] 10.7.6 The synthesis procedure of the target product T077 was based on the synthesis of T020, and its structure and general analytical data are shown in Table 1.

[0523] 10.7.7 The synthesis procedure of the target product T078 was based on the synthesis of T021, and its structure and general analytical data are shown in Table 1.

[0524] 10.7.8 The synthesis steps of the target product T079 are based on the synthesis of T006, and its structure and general analysis data are shown in Table 1.

[0525] 10.7.9 The synthesis steps of the target product T080 are based on the synthesis of T013, and its structure and general analysis data are shown in Table 1.

[0526] 10.7.10 The synthesis steps of the target product T081 are based on the synthesis of T014, and its structure and general analysis data are shown in Table 1.

[0527] 10.7.11 Synthesis of the target product T094

[0528]

[0529] Dissolve intermediate A-7g (1.0 e.q.), PyBOP (2.5 e.q.) and DIEA (3 e.q.) in DMF (1 mmol: 10 mL), and finally add 3-hydroxy-2-pyrazinecarboxylic acid (2.5 e.q.). Then raise the temperature to 50 °C and react for 2 hours. After monitoring the reaction by LC-MS until completion, dilute the reaction solution with water, extract twice with dichloromethane, wash the combined organic phase once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then obtain compound T094 through high-pressure reverse preparation. Its structure and general analysis data are shown in Table 1.

[0530] 10.7.12 Synthesis of the target product T095

[0531]

[0532] Dissolve intermediate A-7g (1.0 e.q.), PyBOP (2.5 e.q.) and DIEA (3 e.q.) in DMF (1 mmol: 10 mL), then add 6-methylpyrimidine-4-carboxylic acid (2.5 e.q.). Then raise the temperature to 50 °C and react for 2 hours. After monitoring the reaction by LC-MS until completion, dilute the reaction solution with water, extract twice with dichloromethane, wash the combined organic phase once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then obtain compound T095 through high-pressure reverse preparation. Its structure and general analysis data are shown in Table 1.

[0533] 10.7.13 Synthesis of the target product T096

[0534]

[0535] Intermediate A-7g (1.0 e.q.), PyBOP (2.5 e.q.), and DIEA (3 e.q.) were dissolved in DMF (1 mmol: 10 mL). Finally, 2-aminopyrimidine-4-carboxylic acid (2.5 e.q.) was added, and the mixture was then heated to 50 °C and reacted for 2 hours. After the reaction was monitored by LC-MS and completed, the reaction solution was diluted with water, 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 prepared by high-pressure reverse-phase chromatography to obtain compound T096. Its structure and general analytical data are shown in Table 1.

[0536] 10.7.14 Synthesis of target product T099

[0537]

[0538] Intermediate A-7g (1.0 e.q.), PyBOP (2.5 e.q.), and DIEA (3 e.q.) were dissolved in DMF (1 mmol: 10 mL). 3-Carboxypyridazine (2.5 e.q.) was added, and the mixture was then heated to 50 °C and reacted for 2 hours. After the reaction was monitored by LC-MS and completed, the reaction solution was diluted with water, 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 prepared by high-pressure reverse-phase chromatography to obtain compound T099. Its structure and general analytical data are shown in Table 1.

[0539] 10.7.15 Synthesis of target product T100

[0540]

[0541] Intermediate A-7g (1.0 e.q.), PyBOP (2.5 e.q.), and DIEA (3 e.q.) were dissolved in DMF (1 mmol: 10 mL). Subsequently, 4-pyrimidinecarboxylic acid (2.5 e.q.) was added, and the mixture was then heated to 50 °C and reacted for two hours. After the reaction was monitored by LC-MS and completed, the reaction solution was diluted with water, 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 prepared by high-pressure reverse-phase chromatography to obtain compound T100. Its structure and general analytical data are shown in Table 1.

[0542] 10.7.16 Synthesis of target product T101

[0543]

[0544] Dissolve intermediate A-7g (1.0 e.q.), PyBOP (2.5 e.q.) and DIEA (3 e.q.) in DMF (1 mmol: 10 mL), add 2,6-dimethylpyrimidine-4-carboxylic acid (2.5 e.q.), and then raise the temperature to 50 °C and react for 2 hours. After monitoring the reaction by LC-MS until completion, dilute the reaction solution with water, extract twice with dichloromethane, combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then obtain compound T101 through high-pressure reverse preparation. Its structure and general analytical data are shown in Table 1.

[0545] 10.7.17 Synthesis of target product T102

[0546]

[0547] Dissolve intermediate A-7g (1.0 e.q.), PyBOP (2.5 e.q.) and DIEA (3 e.q.) in DMF (1 mmol: 10 mL), finally add 5-fluoro-2-pyridinecarboxylic acid (2.5 e.q.), and then raise the temperature to 50 °C and react for 2 hours. After monitoring the reaction by LC-MS until completion, dilute the reaction solution with water, extract twice with dichloromethane, combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then obtain compound T102 through high-pressure reverse preparation. Its structure and general analytical data are shown in Table 1.

[0548] 10.7.18 Synthesis of target product T103

[0549]

[0550] Dissolve intermediate A-7g (1.0 e.q.), PyBOP (2.5 e.q.) and DIEA (3 e.q.) in DMF (1 mmol: 10 mL), finally add 3-fluoropyridine-2-carboxylic acid (2.5 e.q.), and then raise the temperature to 50 °C and react for 2 hours. After monitoring the reaction by LC-MS until completion, dilute the reaction solution with water, extract twice with dichloromethane, combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then obtain compound T103 through high-pressure reverse preparation. Its structure and general analytical data are shown in Table 1.

[0551] 10.7.19 Synthesis of target product T104

[0552]

[0553] Dissolve intermediate A-7g (1.0 e.q.), PyBOP (2.5 e.q.), and DIEA (3 e.q.) in DMF (1 mmol: 10 mL). Finally, add 3,5-difluoro-2-pyridinecarboxylic acid (2.5 e.q.). Then, raise the temperature to 50 °C and react for 2 hours. After monitoring the reaction by LC-MS until completion, dilute the reaction solution with water, extract twice with dichloromethane, combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then obtain compound T104 through high-pressure reverse preparation. Its structure and general analytical data are shown in Table 1.

[0554] 10.7.20 Synthesis of target product T105

[0555]

[0556] Dissolve intermediate A-7g (1.0 e.q.), PyBOP (2.5 e.q.), and DIEA (3 e.q.) in DMF (1 mmol: 10 mL). Finally, add 5-fluoro-6-methylpyridine-2-carboxylic acid (2.5 e.q.). Then, raise the temperature to 50 °C and react for 2 hours. After monitoring the reaction by LC-MS until completion, dilute the reaction solution with water, extract twice with dichloromethane, combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then obtain compound T105 through high-pressure reverse preparation. Its structure and general analytical data are shown in Table 1.

[0557] 10.7.21 Synthesis of target product T106

[0558]

[0559] Dissolve intermediate A-7g (1.0 e.q.), PyBOP (2.5 e.q.), and DIEA (3 e.q.) in DMF (1 mmol: 10 mL). Finally, add 5-fluoro-3-methylpicolinic acid (2.5 e.q.). Then, raise the temperature to 50 °C and react for 2 hours. After monitoring the reaction by LC-MS until completion, dilute the reaction solution with water, extract twice with dichloromethane, combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then obtain compound T106 through high-pressure reverse preparation. Its structure and general analytical data are shown in Table 1.

[0560] Example 11

[0561] The synthesis route is as follows:

[0562]

[0563] 11.1 Synthesis of intermediate B-8

[0564]

[0565] Synthesis of Intermediate B-8-1 in 11.1.1

[0566] At room temperature, dissolve Intermediate 4-amino-2-fluorobenzotrifluoride (1.0 e.q.) in acetonitrile (1 mmol: 2 mL), add N-chlorosuccinimide (1.05 e.q.) in batches, and then heat the reaction solution to 50 °C and react for 6 hours. After monitoring the reaction by LCMS and finishing, rotary evaporate the acetonitrile, dilute the concentrated solution with ethyl acetate, wash the organic phase twice with water and once with saturated brine. Rotary evaporate the organic phase and then purify it by column chromatography to obtain the pure Intermediate B-8-1.

[0567] Synthesis of Intermediate B-8 in 11.1.2

[0568] Add Intermediate B-8-1 (1.0 e.q.) to dichloromethane (1 mmol: 2 mL), dropwise add chloroacetyl chloride (1.05 e.q.) at 0 °C, and then react at room temperature for 16 hours. After monitoring the reaction by TLC and finishing, concentrate the reaction solution under reduced pressure to obtain the crude product, and slurry it with petroleum ether to obtain Intermediate B-8.

[0569] The synthesis of Intermediate A-3h is based on the synthesis steps of A-3b.

[0570] The synthesis of Intermediate A-4h is based on the synthesis steps of A-4b.

[0571] The synthesis of Intermediate A-5h is based on the synthesis steps of A-5b.

[0572] The synthesis of Intermediate A-6h is based on the synthesis steps of A-6b.

[0573] The synthesis of Intermediate A-7h is based on the synthesis steps of A-7b.

[0574] Synthesis of the Target Product in 11.7

[0575] 11.7.1 The synthesis steps of the target product T082 are based on the synthesis of A-8, and its structure and general analysis data are shown in Table 1.

[0576] 11.7.2 The synthesis steps of the target product T083 are based on the synthesis of T016, and its structure and general analysis data are shown in Table 1.

[0577] 11.7.3 The synthesis steps of the target product T084 are based on the synthesis of T017, and its structure and general analysis data are shown in Table 1.

[0578] 11.7.4 The synthesis steps of the target product T085 are based on the synthesis of T018, and its structure and general analysis data are shown in Table 1.

[0579] 11.7.5 The synthesis steps of the target product T086 are based on the synthesis of T019, and its structure and general analysis data are shown in Table 1.

[0580] 11.7.6 The synthesis steps of the target product T087 are based on the synthesis of T020, and its structure and general analysis data are shown in Table 1.

[0581] 11.7.7 The synthesis steps of the target product T088 are based on the synthesis of T021, and its structure and general analysis data are shown in Table 1.

[0582] 11.7.8 The synthesis steps of the target product T089 are based on the synthesis of T006, and its structure and general analysis data are shown in Table 1.

[0583] 11.7.9 The synthesis steps of the target product T090 are based on the synthesis of T013, and its structure and general analysis data are shown in Table 1.

[0584] 11.7.10 The synthesis steps of the target product T091 are based on the synthesis of T014, and its structure and general analysis data are shown in Table 1.

[0585] Example 12

[0586] The synthesis route is as follows:

[0587]

[0588] 12.1 The synthesis of intermediate A-3i is based on the synthesis steps of A-3b.

[0589] 12.2 The synthesis of intermediate A-4i is based on the synthesis steps of A-4b.

[0590] 12.3 The synthesis of intermediate A-5i is based on the synthesis steps of A-5b.

[0591] 12.4 The synthesis of intermediate A-6i is based on the synthesis steps of A-6b.

[0592] 12.5 The synthesis of intermediate A-7i is based on the synthesis steps of A-7b.

[0593] 12.6 The synthesis of intermediate 8i is based on the synthesis steps of A-8h.

[0594] 12.7 Synthesis of the target product

[0595] 12.7.1 Synthesis of the target products T097 and T098, where B-X = B-7.

[0596]

[0597] At room temperature, intermediate A-7i (1.0 e.q.), C-5 (2.0 e.q.) and N,N-diisopropylethylamine (3 e.q.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL). Subsequently, 1H-benzotriazol-1-yloxytris-pyrrolidinophosphonium hexafluorophosphate (2.0 e.q.) was added at 0 °C, and then the temperature was raised to 40 °C for reaction for 2 hours. After monitoring the reaction by LC-MS and completion, the reaction solution was diluted with ethyl acetate, washed twice with water and once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After purification by column chromatography and then by SFC chiral resolution, the target products T097 and T098 were obtained in the order of elution peaks. Their structures and general analytical data are shown in Table 1.

[0598] The chiral resolution conditions are as follows:

[0599] Prep-HPLC conditions:

[0600] Column: CHIRALPAK IG, 2 cm × 25 cm, 5 μm;

[0601] Mobile phase: A: hexane (0.1% FA); B: MeOH:DCM;

[0602] Flow rate: 20 mL / min;

[0603] Wavelength: UV 220 nm;

[0604] Column temperature: 25 °C;

[0605] Prep-HPLC instrument: Prep-HPLC-Gilson.

[0606] 12.7.2 Synthesis of target products T113 and T114 Based on the synthesis of T111, the target products T113 and T114 were obtained by SFC chiral resolution in the order of elution peaks. Their structures and general analytical data are shown in Table 1. The chiral resolution conditions are the same as those for T097 and T098.

[0607] 12.7.3 Synthesis of target products T115 and T116, where B-X = B-5.

[0608]

[0609] At room temperature, the intermediate P-10 (1.0 e.q.) was dissolved in trifluoroacetic acid (1 mmol: 5 mL), and then the temperature was raised to 60 °C and reacted for 12 hours. After the reaction was monitored by LC-MS and completed, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then the target products T115 and T116 were obtained in sequence according to the elution order through SFC chiral resolution. The chiral resolution conditions were the same as those of T097 and T098. Its structure and general analytical data are shown in Table 1.

[0610] Example 13

[0611] The synthetic route is as follows:

[0612]

[0613] 13.1 Synthesis of intermediate A-2-1 was based on the synthesis steps of A-2.

[0614] 13.2 Synthesis of intermediate A-4j was based on the synthesis steps of A-3.

[0615] 13.3 Synthesis of intermediate A-5j was based on the synthesis steps of A-5b.

[0616] 13.4 Synthesis of intermediate A-6j was based on the synthesis steps of A-6b.

[0617] 13.5 Synthesis of intermediate A-7j was based on the synthesis steps of A-7b.

[0618] 13.6 Synthesis of intermediate A-8j was based on the synthesis steps of A-8i.

[0619] 13.7 Synthesis of the target product

[0620] 13.7.1 Synthesis of the target product T093, where B-X = B-5.

[0621]

[0622] At room temperature, the intermediate A-7l (1.0 e.q.), C-5 (2.0 e.q.) and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL), and then 1H-benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (2.0 e.q.) was added at 0 °C, and then the temperature was raised to 40 °C and reacted for 2 hours. After the reaction was monitored by LC-MS and completed, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then the compound T093 was obtained through high-pressure reverse preparation. Its structure and general analytical data are shown in Table 1.

[0623] 13.7.2 Synthesis of the target product T111, where B-X = B-7.

[0624] Its synthesis is based on the synthesis of T093, and the structure and general analysis data are shown in Table 1.

[0625] 13.7.3 The synthesis of the target product T112 is based on the synthesis of T019, where B-X = B-5, and its structure and general analysis data are shown in Table 1.

[0626]

[0627] Add 2-fluoro-4-(pentafluorothio)aniline (1.0 e.q.) to dichloromethane (1 mmol: 2 mL), and dropwise add chloroacetyl chloride (1.05 e.q.) at 0 °C, then react at room temperature for 16 hours. After monitoring the reaction by TLC until completion, concentrate the reaction solution under reduced pressure to obtain the crude product, and slurry it with petroleum ether to obtain the intermediate B-9.

[0628] 13.7.4 The synthesis of the target product T121 is based on the synthesis of T019, where B-X = B-9, and its structure and general analysis data are shown in Table 1.

[0629] Example 14

[0630] The synthesis route is as follows:

[0631]

[0632] 14.1 Synthesis of intermediate C-12-1

[0633] Dissolve 3-hydroxy-2-iodopyridine (1.0 e.q.), benzyl bromide (1.05 e.q.) and potassium carbonate (1.5 e.q.) in DMF (1 mmol: 5 mL) at room temperature. Heat the reaction solution to 50 °C and stir for two hours. After monitoring the reaction by LC-MS until completion, dilute the reaction solution with ethyl acetate, wash it twice with water and once with saturated brine. The obtained organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain the product C-12-1.

[0634] 14.2 Synthesis of intermediate C-12-2

[0635] At room temperature, C-12-1 (1.0 e.q.), benzyl mercaptan (1.2 e.q.), PD2DBA3 (0.02 e.q.) and Xantphos (0.06 e.q.) were dissolved in 1,4-dioxane (1 mmol: 10 mL), and the atmosphere was replaced with nitrogen. The reaction solution was heated to 100 °C and stirred for two hours. After the reaction was monitored by LC-MS and completed, the reaction solution was diluted with ethyl acetate, washed twice with water and once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain the product C-12-2.

[0636] 14.3 Synthesis of Intermediate C-12

[0637] Intermediate C-12-2 (1.0 e.q.) was dissolved in acetonitrile (1 mmol: 4 mL) and water (1 mmol: 0.5 mL), cooled to 0 °C, acetic acid (6.0 e.q.) and 1,3-dichloro-5,5-dimethylhydantoin (1.0 e.q.) were added, and then the temperature was raised to room temperature and the reaction was carried out for 5 hours. After the reaction was monitored by LC-MS and completed, the pH of the reaction solution was adjusted to 7 with saturated sodium bicarbonate, 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 purified by column chromatography to obtain Intermediate C-12.

[0638] 14.4 Synthesis of Intermediate P-12

[0639] Compound P-12 was synthesized by condensing Intermediate A-7g (Y is CH2, n = 1, m = 1) obtained from the synthesis implementation steps of Example 10 with C-12.

[0640] Intermediate A-7 (1.0 e.q.) and triethylamine (5 e.q.) were dissolved in dichloromethane (1 mmol: 10 mL), and then the reaction solution was cooled to 0 °C, Intermediate C-3 (2.5 e.q.) was added, and then the temperature was raised to room temperature and the reaction was carried out for 2 hours. After the reaction was monitored by LC-MS and completed, the reaction solution was diluted with water, 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 purified by column chromatography to obtain the pure product Intermediate P-12.

[0641] 14.5 Synthesis of Target Product T092

[0642] Intermediate P-12 was dissolved in trifluoroacetic acid (1 mmol: 5 mL) solution, and the reaction solution was heated to 80 °C and reacted overnight. After the reaction was monitored by LC-MS and completed, the reaction solution was diluted with ethyl acetate, washed twice with water and once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then prepared by high-pressure reverse phase to obtain Compound T092, and its structure and general analysis data are shown in Table 1.

[0643] Example 15

[0644]

[0645] 15.1 Synthesis of Intermediate A-3k

[0646]

[0647] Intermediate A-3k was prepared from Intermediate A-2 obtained by the implementation steps of Example 1.

[0648] Weigh A-2 (1.0 e.q.) at room temperature and dissolve it in DMF:THF = 1:1 (1 mmol: 15 mL). After cooling the reaction solution to 0 °C, add NaH (1.5 e.q.) in batches. After reacting in an ice bath for two hours, replace the air in the reaction flask with a nitrogen atmosphere. Then, at 0 °C, add SEMCl (2.0 e.q.) dropwise. The reaction solution was slowly warmed to room temperature and stirred overnight. After monitoring the reaction by LC-MS until completion, 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 then purified by column chromatography to obtain the pure product Intermediate A-3k.

[0649] 15.2 Synthesis of Intermediate A-4k

[0650]

[0651] Weigh A-3k (1.0 e.q.) at room temperature and dissolve it in anhydrous THF. After replacing the air in the reaction flask with a nitrogen atmosphere, cool it to -78 °C, then add NaHMDS (1.5 e.q.) dropwise. After stirring at -78 °C for two hours, add allyl iodide (1.5 e.q.) dropwise. The reaction solution was slowly warmed to room temperature and stirred overnight. After monitoring the reaction by LC-MS until completion, the reaction was quenched with an aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were washed once with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain the pure product A-4k.

[0652] 15.3 Synthesis of Intermediate A-5k

[0653]

[0654] Weigh A-4k (1.0 e.q.) and m-CPBA (2.5 e.q.) at room temperature and dissolve them in DCM (1 mmol: 10 mL). React at room temperature overnight. After monitoring the reaction by LC-MS until completion, dilute with water, extract twice with dichloromethane. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain the pure product Intermediate A-5k.

[0655] 15.4 Synthesis of Intermediate A-6k

[0656]

[0657] Weigh A-5k (1.0 e.q.) and DIEA (3.0 e.q.) at room temperature and dissolve them in DMSO (1 mmol: 10 mL). Under nitrogen protection, heat the reaction solution to 120 °C and stir overnight. After monitoring the reaction by LC-MS until completion, dilute the reaction solution with water, extract twice with ethyl acetate, combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then purify by column chromatography to obtain intermediate A-6k.

[0658] 15.5 Synthesis of Intermediate A-7k

[0659]

[0660] First, prepare fresh Jones reagent. Dissolve chromium trioxide (5 g, 0.25 mol) in water (15 mL) in a 100 mL beaker. Under an ice bath, slowly add concentrated sulfuric acid (25 mL) while stirring. Keep the temperature of the solution at 0 - 5 °C. The prepared reagent concentration is 2.5 M. Weigh A-6k (1.0 e.q.) and dissolve it in acetone (1 mmol, 10 mL). Cool the reaction solution to 0 °C, add the freshly prepared Jones reagent (2.5 e.q., 2.5 M) dropwise, stir at room temperature for two hours. After monitoring the reaction by LC-MS until completion, dilute the reaction solution with water, extract twice with ethyl acetate, combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then purify by column chromatography to obtain intermediate A-7k.

[0661] 15.5 Synthesis of Intermediate A-8k

[0662]

[0663] Weigh intermediate A-7k (1.0 e.q.), 2-fluoro-4-(trifluoromethyl)aniline (1.2 e.q.), 50% T3P in EA (4.5 e.q.) and triethylamine (15 e.q.) and dissolve them in ethyl acetate (1 mmol, 10 mL). Then heat the reaction solution to 50 °C and stir for one hour. After monitoring the reaction by LC-MS until completion, dilute the reaction solution with water, extract twice with ethyl acetate, combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then purify by column chromatography to obtain intermediate A-8k.

[0664] 15.6 Synthesis of Intermediate A-9k

[0665]

[0666] Intermediate A-8k (1.0 e.q.), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.2 e.q.), Pd(dppf)Cl2 (0.05 e.q.) and potassium phosphate (2.5 e.q.) were added to 1,4-dioxane and water (2.5:1, 1 mmol:5 mL). After purging with nitrogen three times, the temperature was raised to 80 °C and the reaction was carried out for 4 hours. After monitoring the reaction by LC-MS until completion, the reaction solution was diluted with ethyl acetate, washed with brine, the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. Then, Intermediate A-9k was obtained by column chromatography.

[0667] 15.7 Synthesis of Intermediate A-10k

[0668]

[0669] Intermediate A-9k (1.0 e.q.) was dissolved in N,N-dimethylformamide (1 mmol:10 mL) at room temperature. Subsequently, N-bromosuccinimide (1.5 e.q.) was added in portions, and the reaction was carried out for 4 hours. After monitoring the reaction by LC-MS until completion, the reaction solution was diluted with ethyl acetate, washed once with saturated sodium bicarbonate, twice with water, and once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Then, Intermediate A-10k was obtained by column chromatography.

[0670] 15.8 Synthesis of Intermediate A-11k

[0671]

[0672] Intermediate A-9 (1.0 e.q.), (R)-1-BOC-1,7-diazaspiro[4.4]nonane (0.8 e.q.) and DIEA (3.0 e.q.) were weighed and dissolved in DMSO (1 mmol:2 mL). Subsequently, the temperature was raised to 120 °C and stirred overnight. After monitoring the reaction by LC-MS until completion, the reaction solution was diluted with ethyl acetate, washed once with saturated sodium bicarbonate, twice with water, and once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Then, Intermediate A-11k was obtained by column chromatography.

[0673] 15.9 Synthesis of Intermediate A-12k

[0674]

[0675] Intermediate A-11k (1.0 e.q.) was dissolved in CF3COOH:DCM = (1:1; 1 mmol:10 Ml) at room temperature. The reaction solution was heated to 40 °C and reacted for 12 hours. After monitoring the reaction by LC-MS until completion, the solution was concentrated by rotary evaporation. The concentrated solution was diluted with ethyl acetate, washed once with saturated sodium bicarbonate solution and once with saturated brine, and the organic phase was concentrated by rotary evaporation to obtain Product A-12k.

[0676] Synthesis of Intermediate P-13 at 15.10

[0677]

[0678] At room temperature, Intermediate A-12k (1.0 e.q.), 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (2.0 e.q.) and N,N-diisopropylethylamine (5 e.q.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL). Subsequently, 1H-benzotriazole-1-yloxytris-pyrrolidinophosphonium hexafluorophosphate (2.0 e.q.) was added at 0 °C, and then the temperature was raised to 40 °C for reaction for 2 hours. After the reaction was monitored by LC-MS and completed, the reaction solution was diluted with ethyl acetate, washed twice with water and once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain pure product P-13.

[0679] 15.11 Target Products T107, T108, T109 and T110

[0680]

[0681] At room temperature, Intermediate A-11k (1.0 e.q.) was dissolved in trifluoroacetic acid solution, and the reaction solution was heated to 60 °C for reaction for 12 hours. After the reaction was monitored by LC-MS and completed, the reaction solution was diluted with ethyl acetate, washed twice with water and once with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and after obtaining pure product by column chromatography, it was further subjected to SFC chiral resolution. According to the elution order, target products T107, T108, T109 and T110 were obtained successively, and their structures and general analytical data are shown in Table 1.

[0682] The chiral resolution conditions used are as follows:

[0683] First Prep-HPLC Conditions:

[0684] Chromatographic column: CHIRALPAK IBN, 2 cm × 25 cm, 5 μm;

[0685] Mobile phase: A: MTBE (0.1% FA); B: MeOH:DCM;

[0686] Flow rate: 20 mL / min;

[0687] Wavelength: UV 220 nm;

[0688] Column temperature: 25 °C;

[0689] Chromatograph: Prep-HPLC-Gilson.

[0690] Second Prep-HPLC conditions:

[0691] Column: CHIRALPAK IC, 2 cm × 25 cm, 5 μm;

[0692] Mobile phase: A: MTBE (0.1% FA); B: MEOH;

[0693] Flow rate: 20 mL / min;

[0694] Wavelength: UV 220 nm;

[0695] Column temperature: 25 °C;

[0696] Chromatograph: Prep-HPLC-Gilson.

[0697] Example 16

[0698] The synthesis route is as follows:

[0699]

[0700] 16.1 Synthesis of Intermediate D-1

[0701]

[0702] 16.1.1 Synthesis of Intermediate D-1-1

[0703] Dissolve intermediate thiophene-2,3-dicarboxylic acid (1.0 e.q.) in tetrahydrofuran (1 mmol: 2 mL) at 0 °C, slowly add dropwise a tetrahydrofuran solution of 1 mol / L lithium aluminum hydride (4.0 e.q.), and then heat the reaction solution to 70 °C and react for 16 hours. After monitoring the reaction by LCMS and completion, cool the reaction solution to 0 °C, add dropwise water and 10% sodium hydroxide solution to quench, dry over anhydrous sodium sulfate overnight, filter and concentrate to obtain the pure intermediate D-1-1.

[0704] 16.1.2 Synthesis of Intermediate D-1-2

[0705] Add intermediate D-1-1 (1.0 e.q.) to tetrahydrofuran (1 mmol: 2 mL), add N-bromosuccinimide (1.05 e.q.) portionwise at 0 °C, and then react at room temperature for 4 hours. After monitoring the reaction by TLC and completion, dilute the reaction solution with ethyl acetate, wash the organic phase with saturated sodium bicarbonate solution and saturated brine, and concentrate the organic phase under reduced pressure at low temperature to obtain intermediate D-1-2.

[0706] 16.1.3 Synthesis of Intermediate D-1-3

[0707] Add intermediate D-1-2 (1.0 e.q.) to dimethyl carbonate (1 mmol: 1 mL), and add sodium methoxide (1.5 e.q.) in batches. Subsequently, react at 120 °C for 4 hours. After monitoring the reaction by LCMS until completion, cool the reaction solution to room temperature. Then dilute the reaction solution with ethyl acetate and water, filter and separate the layers. The obtained organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain intermediate D-1-3.

[0708] 16.1.4 Synthesis of Intermediate D-1

[0709] Add intermediate D-1-3 (1.0 e.q.) to tetrahydrofuran (1 mmol: 2 mL), and dropwise add a n-hexane solution of n-butyllithium (1.5 e.q.) at -78 °C. After reacting at -78 °C for half an hour, dropwise add isopropyl alcohol pinacol borate (1.2 e.q.) and react at -78 °C for two hours. After monitoring the reaction by LCMS until completion, cool the reaction solution and quench it with saturated ammonium chloride. Extract twice with ethyl acetate. The obtained organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain intermediate D-1.

[0710] 16.2 The synthesis of intermediate A-3l follows the synthesis procedure of A-3b.

[0711] 16.3 The synthesis of intermediate A-4l follows the synthesis procedure of A-4b.

[0712] 16.4 The synthesis of intermediate A-5l follows the synthesis procedure of A-5b.

[0713] 16.5 The synthesis of intermediate A-6l follows the synthesis procedure of A-6b.

[0714] 16.6 The synthesis of intermediate A-7l follows the synthesis procedure of A-7b.

[0715] 16.6 Synthesis of the Target Product

[0716] 16.6.1 When B-X = B-5, the synthesis procedure of the target product T117 follows that of T019, and its structure and general analytical data are shown in Table 1.

[0717] 16.6.2 When B-X = B-7, the synthesis of the target product T-118 follows that of T019, and its structure and general analytical data are shown in Table 1.

[0718] 16.6.3 When B-X = B-1, the synthesis of the target product T-119 follows that of T019, and its structure and general analytical data are shown in Table 1.

[0719] Replace the intermediate D-1 in Synthesis Example 16 with 4-dimethylaminopiperidine (Cas No.: 50533-97-6). Through the same steps as in Synthesis Examples 16.2 to 16.6, when B-X = B-7, according to the synthesis of T019, the target product T120 is obtained, and its structure and general analysis data are shown in Table 1.

[0720] Replace the intermediate D-1 in Synthesis Example 16 with pyrrolidine (Cas No.: 123-75-1). Through the same steps as in Synthesis Examples 16.2 to 16.6, when B-X = B-7, according to the synthesis of T019, the target product T122 is obtained, and its structure and general analysis data are shown in Table 1.

[0721] Replace the intermediate D-1 in Synthesis Example 16 with N-BOC-piperazine (Cas No.: 57260-71-6). Through the same steps as in Synthesis Examples 16.2 to 16.5, when B-X = B-7, the corresponding intermediate A-6m is obtained.

[0722]

[0723] Dissolve the intermediate A-6m (1.0 e.q.) in dichloromethane (1 mmol: 5 mL) at room temperature, then add trifluoroacetic acid (1 mmol: 1 mL) at 0 °C, and then raise the temperature to room temperature and react for 2 hours. After monitoring the reaction by LC-MS until it is completed, the reaction solution is concentrated under reduced pressure until nearly dry, diluted with dichloromethane, and the pH of the aqueous phase is adjusted to 8-9 with saturated sodium bicarbonate. Extract with dichloromethane twice, wash the organic phase with saturated brine, and the obtained organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the intermediate A-7m.

[0724] Dissolve the intermediate A-7m (1.0 e.q.) in tetrahydrofuran (1 mmol: 5 mL) at 0 °C, add di-tert-butyl dicarbonate (1.0 e.q.) and sodium bicarbonate (1.0 e.q.), and let the reaction slowly warm up to room temperature. After stirring for 1.5 hours, concentrate the reaction solution. The obtained organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography to obtain the compound A-8m.

[0725] Dissolve the intermediate A-8m (1.0 e.q.), C-7 (2.0 e.q.) and N,N-diisopropylethylamine (5 e.q.) in N,N-dimethylformamide (1 mmol: 5 mL) at room temperature, then add 1H-benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (2.0 e.q.) at 0 °C, and then raise the temperature to 40 °C and react for 2 hours. After monitoring the reaction by LC-MS until it is completed, the reaction solution is diluted with ethyl acetate, washed twice with water, and washed once with saturated brine. The obtained organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography to obtain the compound A-9m.

[0726] At room temperature, intermediate A-9m (1.0 e.q.) was dissolved in dichloromethane (1 mmol: 5 mL), then trifluoroacetic acid (1 mmol: 1 mL) was added at 0 °C, and then the mixture was warmed to room temperature and reacted for 2 hours. After the reaction was monitored by LC-MS and completed, the reaction solution was concentrated under reduced pressure until nearly dry, diluted with dichloromethane, and the pH of the aqueous phase was adjusted to 8 - 9 with saturated sodium bicarbonate. The aqueous phase was extracted twice with dichloromethane, and the organic phase was washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then prepared by high-pressure reverse phase to obtain the target product T123. Its structure and general analytical data are shown in Table 1.

[0727] Table 1 Compounds of Examples and General Analytical Data

[0728]

[0729]

[0730]

[0731]

[0732]

[0733]

[0734]

[0735]

[0736]

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761] Activity test example:

[0762] Example 1: Determination of the inhibitory effect of the test substance on tumor cell growth

[0763] Taking SW48 cells as an example, the inhibitory activity of the compound of the present invention on tumor growth was tested.

[0764] 1.1 Cell seeding

[0765] Human colon cancer SW48 cells (ZQ0793) were cultured in DMEM (C3113 - 0500) medium containing 10% fetal bovine serum (FBS) and 1% penicillin - streptomycin mixture (C3421 - 0100) at 37°C and 5% CO2. The medium in the T25 flask was aspirated, 1 mL of PBS solution was added for rinsing twice, then 1 mL of trypsin (C3530 - 0500) digestion solution was added, and the cells were incubated in a 37°C incubator for 2 min to digest the cells. When the cell edges became round, 1 mL of medium containing 10% FBS was added to terminate the cell digestion and the cells were pipetted into a cell suspension, counted, and then the cell density was diluted to 5×10 4cells / mL. Add 100 μL of cell suspension to each well of a 96-well plate with a white transparent bottom (Coring, CLS3903) (add PBS solution to the edges of the plate), and place the cell plate in an incubator at 37 °C with 5% CO2 overnight.

[0766] 1.2 Compound Preparation

[0767] Dilute the compound stock solution (100 mM DMSO stock) to 1 or 10 mM secondary stock solutions using DMSO. Take 1 μL of the secondary stock solution and add it to 1 mL of complete DMEM medium. Place it on an oscillator to dissolve, and prepare a maximum dosing concentration of 1 or 10 μM. Prepare 8 - 10 dosing concentrations according to a 3-fold dilution ratio, and mix well. Add 0.1% DMSO vehicle to the control group.

[0768] 1.3 Drug Treatment

[0769] After the cells adhere, carefully aspirate the medium, and add 100 μL of complete DMEM medium containing drug molecules at different concentrations to the corresponding wells of the 96-well plate. Set 3 replicates for each concentration. Place the cell plate after dosing in an incubator at 37 °C with 5% CO2 for 4 days.

[0770] 1.4 Biological Analysis Method

[0771] After incubating for 4 days, add 50 μL of reagent detection reagent (Promega, G7572) to each well, mix by oscillation and incubate, react at room temperature for 10 min, use a microplate reader to detect the chemiluminescence value RLU (Relative Luminescence Unit), calculate the cell viability at different drug concentrations according to the following formula, and use Prism to fit the IC50.

[0772] Cell viability (%) = ((As - Ab)) / ((Ac - Ab) * 100)

[0773] As: RLU of the experimental group (containing cells, medium, and drug molecules)

[0774] Ac: RLU of the control group (containing cells, medium, and DMSO vehicle)

[0775] Ab: RLU of the blank well (containing only medium)

[0776] 2 Experimental Results

[0777] The experimental results are shown in Table 2.

[0778] Example 2: Enzyme Activity Experiment

[0779] 2.1 Determination of the Inhibition of WRN Helicase Activity by the Test Substance

[0780] The helicase activity assay method established in the literature was referred to evaluate the effect of the compound on the DNA-dependent WRN helicase activity (PMC6326523 DOI: 10.1371 / journal.pone.0210525).

[0781] The protein used was WRN(500-1229) (Sino biological, 17475-HNCB), the expression host was baculovirus-insect cells, and the test was carried out in a 384-well black microplate (Loctite, M38-3111). The double-stranded sequences of the fluorescent DNA fork substrate 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 and then cooling gradiently (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.

[0782] To test the IC50 of the test compound for inhibiting the helicase activity of the WRN protein, the preparation of the reaction system was divided into two parts, with two replicates set for each group. The first part was the incubation of the WRN protein and the test compound. A DMSO compound solution with a three-fold serial dilution was prepared. 44 μL of the WRN protein with a final concentration of 50 nM was added to 1 μL of the compound with different concentrations (final concentration of 1 μM, three-fold dilution) in a 384-well plate, shaken well and incubated for 1 h. The second part was the addition of ATP and the fluorescent DNA substrate, with a volume of 5 μL, where the final concentration of ATP was 2 mM and the concentration of the fluorescent DNA substrate was 200 nM. After the incubation of the small molecule and the protein was completed, the reaction system was added and reacted for 1 h. The RFU value was detected using a microplate reader, and the excitation wavelength of the instrument was set at 544 nm and the emission wavelength was set at 590 nm. In addition, an experimental group containing only the protein and the corresponding DMSO solvent was set as the high control, and the group containing only the buffer without the protein was set as the blank control (low control). The inhibition rate calculation formula for the compound to inhibit the helicase activity was Inhibition = (high control - sample) / (high control - low control), and the IC50 value was obtained by four-parameter fitting using GraphPad prism.

[0783] 2.2 Determination of the inhibition of test substance on WRN ATPase activity

[0784] The protein used was WRN(500 - 1229)(Sino biological, 17475 - HNCB), and the test was carried out in a 384 - well white - bottomed white microplate (LABSELECT, 31432). The double - strand sequence of the DNA fork substrate was fork - F(5'-GCACTGGCCGTCGTTTTACGGTCGTGACT - 3') and fork - R(5'-TTTTTTCCAAGTAAAACGACGGCCAGTGC - 3'). The buffer solution (Assay buffer) was 25 mM Tris, 2 mM MgCl2, 5 mM NaCl, 1 mM DTT, 2.5 μg / mL calf thymus DNA, pH 8.0.

[0785] Compound preparation: The compound stock solution (10 mM DMSO stock solution) was diluted with DMSO to a 500 μM secondary stock solution, and then serially diluted three - fold (6 + 12 μL) with DMSO to prepare 10 gradients of drug molecules. Then, they were 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 serially diluted three - fold with 10 gradients (diluted and prepared using a 96 - well skirtless PCR plate).

[0786] Enzyme activity system reaction (3.75 μL pro+3.75 μL cpds+7.5 μL DNA / ATP mix): According to the protein concentration determined by WRN protease activity detection (final: 25 nM), an adequate amount of protein solution was prepared and added to a 96 - well skirtless PCR plate for enzyme activity reaction. 3.75 μL of protein solution was dispensed into each well, then 3.75 μL of the pre - prepared compound solution was added, centrifuged, and incubated for 30 min. After the incubation, 7.5 μL of a mixture of DNA (final: 200 nM) and ATP (final: 300 μM) was added to the plate and incubated for 30 min. After the enzyme activity reaction, the solution was dispensed into a 384 - well plate, 5 μL per well, with two replicates. In addition, an experimental group containing only the corresponding DMSO solvent was set as high control, and a blank control group containing only ATP buffer solution without protein was set as low control.

[0787] ADP-GloTM Assay (5 + 5 + 10 μL): Immediately after the enzyme activity assay system was completed and aliquoted, 5 μL of ATP consumption reagent was added, and the reaction was carried out for 60 min. After the Regeant reaction was complete, 10 μL of kinase detection reagent was added, and the reaction was carried out for 60 min. The chemiluminescence value RLU (Relative Luminescence Unit) was detected using a microplate reader. The data analysis and the fitting method of IC50 were the same as those in the above-mentioned helicase activity experiment.

[0788] 3 Experimental Results

[0789] The experimental results are shown in Table 2.

[0790] Table 2. Biochemical and Cellular Activities of Compounds

[0791]

[0792]

[0793]

[0794]

[0795] Note: ++++: IC50 < 100 nM; +++: 100 nM ≤ IC50 < 1 μM; ++: 1 μM ≤ IC50 < 10 μM; +: 10 μM ≤ IC50.

[0796] The IC50 curve for compound T074 inhibiting WRN helicase activity, the IC50 curve for inhibiting ATPase activity, and the EC50 curve for inhibiting the growth of tumor cells (SW48) are respectively as Figures 1 - 3 shown.

[0797] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

[0798] The foregoing embodiments and methods described in the present invention may vary based on the capabilities, experience, and preferences of those skilled in the art.

[0799] The mere listing of the steps of the method in a certain order in the present invention 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, deuterated compound thereof, the compound having the following structure: Wherein, represents a single bond or a double bond, and the two are not both double bonds at the same time; Ring A is a 4- to 6-membered heterocycle; Ring J is a 6- to 18-membered spiro ring; X1, X2, X3, and 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, azide, C1-C 10 haloalkyl, 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: a single bond, C1-C 10 alkylene, wherein 0-6 methylene units in the C1-C 10 alkylene are independently substituted by the following groups: -Cy-, -O-, -S-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -OC(O)O-, -O-S(O)2-, -OC(O)N(R a ), -C(O)N(R a ), -N(R a )(O)-, -N(R a )(O)O-, -N(R a )(O)N(R b ), -N(R a ), -S(O)2-, -S(O)2N(R a ), -N(R a )(O)2-, -S(O)-, -S(O)N(R a ), -N(R a )(O)-, -Si-, wherein, R a and R b are 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 heterocyclic group); each -Cy- is independently an optionally substituted divalent ring selected from: arylene, cycloalkylene, heterocyclene; wherein the H in the C1-C 10 alkylene is optionally substituted by one or more R0; R1 is one or more independent substituents on the A 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, azide, C1-C 10 haloalkyl, 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 aryl or 4- to 10-membered heterocyclic group may optionally be substituted by one or more R0; R2, R3, and 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, azide, C1-C 10 haloalkyl, 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 aryl or 4- to 10-membered heterocyclic group may optionally be substituted by one or more R0; or, R3 and A1 together with the atoms to which they are attached form a carbocyclic ring or a heterocyclic ring, and the H in the carbocyclic ring or heterocyclic ring may optionally be 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, azide, C1-C 10 haloalkyl, 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 aryl or 4- to 10-membered heterocyclic group may optionally be substituted by one or more R0; R0 is selected from: D, =O, halogen, cyano, nitro, azide, -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 haloalkyl, C1-C 10 haloalkoxy, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group); Each R' and R” is independently 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); wherein the H in the C0-C6 alkylene, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 4-10 membered heterocyclic group may optionally be substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, 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 haloalkyl, 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, ring J is a 6- to 12-membered saturated or partially unsaturated spiro heterocycle having at least one ring atom as N.

2. The compound according to claim 1, characterized in that, has the following structure: wherein, Ring J1 is a 3- to 8-membered monocyclic carbocyclic or heterocyclic ring; Ring J2 is a 3- to 8-membered monocyclic carbocyclic or heterocyclic ring; R 51 and R 52 are each independently one or more substituents on the J1 and J2 rings and 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, azide, C1-C 10 haloalkyl, 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 The H in cycloalkyl, C6-C 10 in aryl, or 4- to 10-membered heterocyclic group may optionally be substituted by one or more R0; Preferably, selected in part from the following structures: Preferably, R 51 is selected from: H, halogen, 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); Preferably, R 52 is 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, The ring is wherein, X5 and X6 are independently selected from: C(H), N; Preferably, The ring is In particular 4. The compound according to any one of claims 1 to 3, characterized in that, 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 together with the atoms to which they are attached form a 4- to 8-membered carbocyclic or heterocyclic ring (such as a 5- to 7-membered saturated heterocyclic ring), and the H in the carbocyclic or heterocyclic ring may optionally be substituted by one or more R0; more preferably, the carbocyclic or heterocyclic ring is optionally substituted by one or more groups selected from the following: H, D, halogen, cyano, hydroxyl, mercapto, 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, phenyl may optionally be substituted by a group selected from the following: D, halogen, cyano, hydroxyl, mercapto, amino, C1-C3 alkyl, C1-C3 alkoxy.

5. The compound according to any one of claims 1-4, characterized in that, 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); Preferably, R8 is H.

6. The compound according to any one of claims 1-5, characterized in that, R1 has the following structure: Where: A4 is selected from: a single bond, C1-C6 alkylene, wherein 0-3 methylene units in the C1-C6 alkylene are independently substituted by the following groups: -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- to 10-membered carbocyclic or heterocyclic ring; R 11 is one or more independent substituents on ring B and is 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, azide, C1-C 10 haloalkyl, 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, H in 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 aryl, 4-10 membered heterocyclic group may optionally be substituted by one or more R0; Preferably, A4 is a single bond; Preferably, is selected from the following structures: Wherein, R 12 is 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 haloalkyl, C1-C 10 haloalkoxy, -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, H in 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 aryl, 4-10 membered heterocyclic group may optionally be 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 is H, 8. The compound according to claim 6, wherein, Each R 11 is 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 is H, F, methyl, ethyl, 9. The compound according to claim 6, wherein Partially selected from the following structure: In particular 10. The compound according to any one of claims 1-9, characterized in that, R2 has the following structure: where: Ring E is a 4- to 12-membered carbocyclic or heterocyclic ring; R 21 is one or more independent substituents on the E ring and is 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, azide, -SF5, C1-C 10 haloalkyl, 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, H in 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 aryl, 4-10 membered heterocyclic group may optionally be substituted by one or more R0; or, two Rs 21 together with the ring atoms to which they are attached form a carbocyclic or heterocyclic ring, and H in the carbocyclic or heterocyclic ring may optionally be substituted by one or more R0; Preferably, has the following structure: In particular More preferably, R2 has the following structure: wherein, X7 is selected from: C(R 23 )、N; R 22 to R 26 are independently selected from: H, halogen, cyano, -SF5, hydroxy, 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 the H in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 alkylene, C3-C6 cycloalkyl may optionally be substituted with a group selected from: halogen, hydroxy, C1-C3 alkoxy; or, two R 21 together with the ring atoms to which they are attached form a carbocyclic or heterocyclic ring, and the H in the carbocyclic or heterocyclic ring may optionally be substituted with a group selected from: halogen, hydroxy, C1-C3 alkoxy.

11. The compound according to claim 10, wherein, 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 optionally be substituted with a group selected from: halogen, hydroxy, C1-C3 alkoxy; Preferably, R 23 is selected from: H, halogen; Preferably, R 24 is selected from: H, halogen, cyano, -SF5, hydroxy, -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 H in C1-C6 alkyl and C3-C6 cycloalkyl may optionally be substituted with a group selected from: halogen, hydroxy, C1-C3 alkoxy; Preferably, R 25 is selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl; Preferably, R 26 is selected from: H, halogen, cyano, hydroxy, 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 1-12, characterized in that, A3 is selected from: -C(O)-, -S(O)-, -S(O)2-, in particular -C(O)-.

14. The compound according to any one of claims 1-13, characterized in that, R4 has the following structure: Where: Ring G is a 4- to 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, azide, C1-C 10 haloalkyl, 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, H in 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 aryl, 4-10 membered heterocyclic group may optionally be substituted by one or more R0; Preferably, is selected from the following structures: Wherein, R 43 to R 47 are independently selected from: H, halogen, cyano, hydroxy, 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, and C3-C6 cycloalkyl may optionally be substituted with a group selected from: halogen, hydroxy, C1-C3 alkoxy; R 401 and R 402 are 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 they are attached form a 4- to 8-membered heterocycle, and the heterocycle is optionally substituted with a group selected from: 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 is 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 is 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 is 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 is 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 is 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 (such as cyclopropyl); Preferably, R 48 and R 49 are independently selected from: H, halogen (such as F, Cl, Br), C1-C4 alkyl (such as methyl, ethyl), C1-C4 haloalkyl (such as -CF3, -CHF2, -CH2F), C1-C4 alkoxy (such as methoxy), C1-C4 haloalkoxy (such as -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 1-16, characterized in that, R3 is 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 alkyl); wherein the H in the C0-C6 alkylene, C1-C6 alkyl, and C3-C6 cycloalkyl may optionally be substituted by a group selected from: D, halogen, hydroxyl, C1-C3 alkoxy; Preferably, R3 is selected from: H, 18. The compound according to any one of claims 1-17, characterized in that, The compound has the following structure: Preferably, Among them, R9 is one or more independent substituents on the Y ring, and is selected from: H, D, halogen, cyano, hydroxyl, mercapto, 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, phenyl may optionally be substituted by a group selected from: D, halogen, cyano, hydroxyl, mercapto, amino, C1-C3 alkyl, C1-C3 alkoxy; Preferably, each R9 is independently selected from: H, D, halogen, cyano, hydroxyl, mercapto, amino, C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted by one or more groups selected from: D, halogen, cyano, hydroxyl, amino, C1-C3 alkoxy.

19. The compound according to any one of claims 1-18, 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, wherein, The compound is selected from the following structures:

21. An intermediate of the compound according to any one of claims 1-20, which has the following structure: Among them, R L is a reactive group; Preferably, the intermediate is selected from the following structures: wherein, 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 1-20, which has the following structure: Among them, R L 、R L ', R L ” are independent reactive groups; Preferably, the intermediate has the following structure: Wherein, 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 the compound according to any one of claims 1-20, which comprises the step of reacting and linking the compound represented by formula IM-1 with wherein, R L1 is a leaving group, Among them, R L is a reactive group.

24. A combination, which comprises the compound according to any one of claims 1-20 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, deuterated compound thereof, and one or more other therapeutic active agents; Preferably, the other therapeutic active agent is an anti-cancer agent or a chemotherapeutic agent; More preferably, the chemotherapeutic agent is selected from: 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, docetaxel, doxorubicin hydrochloride, etoposide, fludarabine phosphate, 5-fluorouracil, flutamide, tezacitibine, gemcitabine, hydroxyurea, idarubicin, ifosfamide, irinotecan, L-asparaginase, leucovorin calcium, melphalan, 6-mercaptopurine, methotrexate, mitoxantrone, gemtuzumab, paclitaxel, phoenix, pentostatin, polifeprosan 20 with carmustine implant, tamoxifen citrate, teniposide, 6-thioguanine, thiotepa, tirapazamine, topotecan hydrochloride for injection, vinblastine, vincristine and vinorelbine, especially irinotecan; More preferably, the other therapeutic active agent is a PD-1 inhibitor; More preferably, the PD-1 inhibitor is selected from: PDR001, nivolumab, pembrolizumab, pidilizumab, MEDI0680, cemiplimab, dostarlimab, PF-06801591, tislelizumab, BGB-108, INCSHR1210, balstilimab, sintilimab, toripalimab, camrelizumab, AMP-224, pamiparib, sepaclitamab and Prolgolimab, especially PDR001, more especially tislelizumab.

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

26. Use of the compound according to any one of claims 1-20 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, deuterated compound thereof in the preparation of a drug for preventing and / or treating WRN-mediated diseases; Preferably, the disease is a tumor, especially a cancer with microsatellite instability (MSI); More preferably, the tumor is selected from: acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancer, anal cancer, appendiceal cancer, astrocytoma, atypical teratoid rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoid rhabdoid tumor, embryonal tumor, embryonal cell carcinoma, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS) of the extrahepatic ducts, embryonal tumor, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, nasal glioma, Ewing sarcoma, extracranial embryonal cell tumor, extragonadal embryonal cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), embryonal cell carcinoma, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, cardiac 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 cervical cancer with occult primary, midline carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell tumor, mycosis fungoides, myelodysplastic syndrome, myelodysplasia / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cancer, parathyroid carcinoma, 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, gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, rare childhood cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer or virus-induced cancer, especially colorectal cancer, gastric cancer, ovarian cancer, endometrial tumor, ovarian cancer; Preferably, the disease is a non-cancerous hyperplastic disorder, for example, benign hyperplasia of the skin, restenosis or prostatic hypertrophy.

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