Spirocyclic derivatives as wrn inhibitors and uses thereof

Abstract

The application discloses a spiro derivative as a WRN helicase inhibitor and application thereof. The spiro derivative has better WRN helicase inhibiting activity, can be used for inhibiting the growth of microsatellite instability (MSI) tumor cells by inhibiting WRN to cause high levels of DNA double-strand breaks (DSB) in the MSI cells, can be used for preventing and / or treating related cancers, especially colorectal cancer, gastric cancer, ovarian cancer and endometrial tumor, can fill the gap of specific MSI typing cancer targeting drugs, and has very good application prospect and value in the medical field.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of chemical pharmaceutical technology, in particular to a spiro derivative as a WRN helicase inhibitor and its application, especially in the treatment of cancer (especially cancer with microsatellite instability (MSI), such as colorectal cancer, gastric cancer, ovarian cancer and endometrial tumor, etc.). BACKGROUND

[0002] Microsatellite instability (MSI) is a common feature associated with a variety of cancers, most commonly in colon cancer, gastric cancer, ovarian cancer and endometrial tumor. It is characterized by small-scale expansion and contraction on short repetitive DNA elements (microsatellite) throughout the genome. MSI is the result of mutation of one or more core components of the mismatch repair mechanism (MMR), and MMR deficiency can lead to MSI (Nat Rev Clin Oncol, 7 (2010), pp. 153-162).

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

[0004] WRN is one of the five human RecQ-like helicases, and WRN plays an important role in HR-mediated replication fork restart and prevention of replication fork collapse. In 2019, multiple research groups proved that the survival of MSI cancer cells is selectively dependent 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, resulting in cell death. However, microsatellite stable (MSS) cells are not sensitive to WRN depletion. These studies have clearly identified WRN as a therapeutic target for MSI cancer.

[0005] By developing new WRN inhibitors, the growth of MSI cancer cells can be selectively inhibited, while having good safety to MSS normal paracancerous tissues. Therefore, the field of MSI cancer treatment needs to further develop WRN inhibitor drugs to accelerate the development of precision treatment for patients with MSI characteristic cancers. SUMMARY

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

[0007]

[0008] wherein,

[0009] represents a single or double bond, and two are not simultaneously a double bond;

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

[0011] J ring is a 6-18 membered spirocyclic ring;

[0012] X1, X2, X3, X4are independently selected from: C(R5), N; R5is selected from: H, D, C1-C 10 alkyl, -(C0-C6alkylene)-(C3-C 10 cycloalkyl), -(C0-C6alkylene)-(C6-C 10 aryl), -(C0-C6alkylene)-(4-10 membered heterocyclyl), halogen, cyano, nitro, azido, 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, A3are independently selected from the group consisting of: a single bond, C1-C 10 alkylene, wherein the C1-C 10 alkylene is optionally substituted with one or more R0; and wherein 0-6 methylene units in said C1-C a alkylene are independently replaced by -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 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 the group consisting of: H, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6alkylene)-(C3-C 10 cycloalkyl), -(C0-C6alkylene)-(C6-C 10 aryl), -(C0-C6alkylene)-(4-10 membered heterocyclyl); each -Cy- is independently an optionally substituted bivalent ring selected from arylene, cycloalkylene, heterocyclylene; wherein the H of the C1-C 10 alkylene is optionally substituted with one or more R0;

[0014] R1is one or more independent substituents on the A ring selected from the group consisting of: H, D, C1-C 10 alkyl, -(C0-C6alkylene)-(C3-C 10 cycloalkyl), -(C0-C6alkylene)-(C6-C 10 aryl), -(C0-C6alkylene)-(4-10 membered heterocyclyl), halogen, cyano, nitro, azido, C1-C 10haloalkyl, 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 H of the C0-C6alkylene, 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 heterocyclyl can be optionally substituted with one or more R0;

[0015] R2, R3, R4are independently selected from the group consisting of: H, D, C1-C 10 alkyl, -(C0-C6alkylene)-(C3-C 10 cycloalkyl), -(C0-C6alkylene)-(C6-C 10Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -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 group), -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 group, C 0-10 Alkyl, C3-C 10 cycloalkyl, C6-C 10 In aryl or 4-10 membered heterocyclic groups, H may optionally be substituted by one or more R0 groups; or, R3 together with Al and the atoms to which they are attached form a carbide ring or heterocycle, in which H may optionally be substituted by one or more R0 groups.

[0016] R5 is one or more independent substituents on the J ring, selected from: H, D, C1-C. 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -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 group), -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 group, C 0-10 Alkyl, C3-C 10 cycloalkyl, C6-C 10The H in the aryl and 4-10 membered heterocyclic groups may optionally be replaced by one or more R0 groups;

[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 group, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic);

[0018] 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); wherein the C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 10 cycloalkyl, C6-C 10 The hydrogen atoms in aryl and 4-10 membered heterocyclic groups 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-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10Alkyl)(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 group), -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 heteroalkylene, bicyclic heteroalkylene, tricyclic heteroalkylene, monocyclic heteroalkylene, bicyclic heteroalkylene, tricyclic heteroalkylene, tricyclic heteroalkylene.

[0020] In some embodiments of the invention, each -CY- is independently selected from the following optionally substituted divalent rings: monocyclic cycloalkyl, bicyclic cycloalkyl, monocyclic saturated heterocyclic group, and bicyclic saturated heterocyclic group.

[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 groups, -OCH2F, -OCHF2, -OCF3, C3-C 10 cycloalkyl, C6-C 10 Aryl, 4-10 membered heterocyclic groups.

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

[0023] In some embodiments of the present invention Ring for in particular

[0024] In some embodiments of the present invention Ring for Among them, X5 and X6 are independently selected from: C(H) and N, for example, in particular

[0025] Specifically, A1 is C1-C 10 Alkylene, wherein 1-3 methylene units are independently substituted with 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 invention, A1 is a C1-C6 alkylene group, wherein the H is optionally substituted by one or more groups selected from the following: H, D, halogen, -(C0-C3 alkylene)-(C3-C6 cycloalkyl), -(C0-C3 alkylene)-(phenyl), -(C0-C3 alkylene)-(4-6 saturated heterocyclic group).

[0027] In some embodiments of the present invention, A1 is... Among them, 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 invention, R3, together with R7 and the atoms bonded to them, form a 4-8 membered (e.g., 4, 5, 6, 7, 8 membered) carbon ring or heterocycle, wherein the H in the carbon ring or heterocycle may optionally be substituted by one or more R0 groups; specifically, the carbon ring or heterocycle may optionally be 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(C The compounds are: -C0-C6 alkyl, -SO2N(C0-C6 alkyl)(C0-C6 alkyl), -N(C0-C6 alkyl)SO2(C0-C6 alkyl), wherein the H in the C0-C6 alkylene, C0-C6 alkyl, C1-C6 alkyl, C3-C6 cycloalkyl, and phenyl groups may optionally be substituted with groups selected from the following: D, halogen, cyano, hydroxyl, mercapto, amino, C1-C3 alkyl, C1-C3 alkoxy; more specifically, the carbocyclic or heterocyclic ring may optionally be substituted with 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 group may optionally be substituted with 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 attached to them, form a 4-8 membered heterocycle, wherein the H in the heterocycle may optionally be replaced by one or more R0 atoms; the heterocycle may contain one or more heteroatoms selected from N, O, and S.

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

[0032] In some embodiments of the present invention, A1 is... Among them, R6': H, D, C1-C 10 Alkyl, C1-C 10 Haloalkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 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 10Alkylene, wherein 1-3 methylene units are independently substituted with 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] in,

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

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

[0044] Specifically, the Y ring is a 5-7 membered saturated heterocycle, which, in addition to the nitrogen atom shown in the above formula, may optionally contain one or more heteroatoms selected from N, O, and S, for example...

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

[0046] In some embodiments of the present invention, the J ring is a 6-12 quintile (e.g., 6, 7, 8, 9, 10, 11 quintile) saturated or partially unsaturated spirocyclic 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, 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 groups may optionally be substituted with a group selected from the following: halogen, hydroxyl, C1-C3 alkoxy; more specifically, R5 is selected from: H, halogen (such as F, Cl), hydroxyl, mercapto, amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxy-substituted alkyl, -(C0-C3 alkylene)-(C3-C5 cycloalkyl), -O(C 1-3 alkyl), -S(C 1-3 Alkyl), -N(H)(C 1-3 alkyl), -N(C) 1-3 Alkyl)(C 1-3 alkyl).

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

[0049] Specifically, Some have the following structure: in,

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

[0051] J2 rings are 3-8 quinary (e.g., 3, 4, 5, 6, 7, 8 quinary) monocyclic carbon rings or heterocyclic rings;

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

[0053] Specifically, the J1 ring is a 3-6 member saturated or partially unsaturated carbon ring or heterocycle, for example, In some embodiments of the present invention, the J1 ring is a 3-6 member partially unsaturated carbon ring; in some embodiments of the present invention, the 3-6 member saturated heterocycle has at least one ring atom of N.

[0054] Specifically, the J2 ring is a 3-6 member saturated or partially unsaturated carbon ring or heterocycle, for example, In some embodiments of the present invention, the J2 ring is a 3-6 membered saturated heterocycle, wherein at least one ring atom is N, for example...

[0055] Specifically, Some have the following structure:

[0056]

[0057]

[0058]

[0059]

[0060]

[0061] In some embodiments of the present invention Some have the following structure:

[0062] Specifically, R 51 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, and C3-C6 cycloalkyl groups may optionally be substituted with groups selected from: halogens, hydroxyl groups, and C1-C3 alkoxy groups; more specifically, R 51 Selected from: H, halogens (such as F, Cl), hydroxyl, mercapto, amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxy-substituted alkyl, -(C0-C3 alkylene)-(C3-C5 cycloalkyl), -O(C 1-3 alkyl), -S(C 1-3 Alkyl), -N(H)(C 1-3 alkyl), -N(C) 1-3 Alkyl)(C 1-3 Alkyl); in some embodiments of the invention, R 51 For H.

[0063] Specifically, R 52 Selected from: H, halogen, hydroxyl, mercapto, amino, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -O(C 1-6 alkyl), -S(C 1-6 Alkyl), -N(H)(C 1-6 alkyl), -N(C) 1-6 Alkyl)(C 1-6 Alkyl); wherein the H in the C0-C6 alkylene, C1-C6 alkyl, and C3-C6 cycloalkyl groups may optionally be substituted with groups selected from: halogens, hydroxyl groups, and C1-C3 alkoxy groups; more specifically, R 52 Selected from: H, halogens (such as F, Cl), hydroxyl, mercapto, amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxy-substituted alkyl, -(C0-C3 alkylene)-(C3-C5 cycloalkyl), -O(C 1-3 alkyl), -S(C 1-3 Alkyl), -N(H)(C 1-3 alkyl), -N(C) 1-3 Alkyl)(C 1-3 Alkyl); in some embodiments of the invention, R 52 Selected from: H, F, Cl, -OH, -NH2, methyl, ethyl.

[0064] In some embodiments of the present invention, Some have the following structure: in particular Among them, R 52a R52b With R 52 Definition.

[0065] In some embodiments of the present invention, Some have the following structure:

[0066]

[0067] In other embodiments of the present invention, Some have the following structure:

[0068]

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

[0070] A4 is selected from: 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-;

[0071] The B ring is a 4-10 membered carbon ring or a heterocyclic ring;

[0072] R 11 One or more independent substituents on the B ring, selected from: H, D, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -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, C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C 0-10 Alkyl, C3-C 10 cycloalkyl, C6-C 10 The H in the aryl or 4-10 membered heterocyclic group may optionally be replaced by one or more R0 groups.

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

[0074]

[0075] Specifically, Some have the following structure:

[0076]

[0077]

[0078] Among them, R 12 Selected from: H, D, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 alkyl), -COO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CO(C) 0-10 Alkyl); wherein, C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10alkenyl, C2-C 10 alkynyl group, C 0-10 Alkyl, C3-C 10 cycloalkyl, C6-C 10 The H in the aryl or 4-10 membered heterocyclic group may optionally be replaced by one or more R0 groups.

[0079] Specifically, R 12 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 the H in the C1-C6 alkyl group may optionally be substituted with a group selected from the following groups: halogen, -O(C 0-6 alkyl), -COO(C 0-6 Alkyl), -OCO(C 0-6 Alkyl), -CON(C) 0-6 Alkyl)(C 0-6 Alkyl), -CO(C) 0-6 Alkyl); more specifically, R 12 Selected from: H, C1-C4 alkyl, C1-C4 haloalkyl, -(C1-C4 alkylene)-C(O)OH, -(C1-C4 alkylene)-C(O)-(C 0-4 Alkyl), -(C1-C4 alkylene)-C(O)O-(C 0-4 Alkyl), -CO(C) 1-4 Alkyl). In some embodiments of the invention, R 12 For H,

[0080] Specifically, each R 11 Independently selected from: H, halogen, hydroxyl, 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 the H in the C1-C6 alkyl group may optionally be substituted with a group selected from the following groups: 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 (e.g., 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 Halogenated alkyl), -N(C) 1-4 Alkyl)(C 1-4 Halogenated alkyl), -(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 invention, R 11 H, F, methyl, ethyl,

[0081] In some embodiments of the present invention Some have the following structure:

[0082]

[0083]

[0084] in particular

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

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

[0087] The E ring is a 4-12 membered carbon ring or a heterocyclic ring;

[0088] R 21 One or more independent substituents on the E ring, selected from: H, D, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), halogen, cyano, nitro, azide, -SF5, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -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 group, C 0-10 Alkyl, C3-C 10 cycloalkyl, C6-C 10 The H in the aryl or 4-10 membered heterocyclic group may optionally be replaced by one or more R0 groups; or, two R0 groups may be replaced by one or more R0 groups. 21 Together with the ring atoms to which it is attached, it forms a carbon ring or heterocycle, wherein the H in the carbon ring or heterocycle may optionally be replaced by one or more R0 atoms.

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

[0090] in particular

[0091] In some embodiments of the present invention Some have the following structure:

[0092] in particular

[0093] Specifically, R 21 Selected from: H, halogen, cyano, -SF5, hydroxyl, mercapto, -C(O)H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -O(C 1-6 alkyl), -S(C 1-6 alkyl), -CO(C) 1-6Alkyl), wherein the H in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 alkylene, and C3-C6 cycloalkyl may optionally be substituted with a group selected from: halogen, hydroxyl, C1-C3 alkoxy; or, two R groups. 21 Together with the ring atoms to which it is attached, it forms a carbon ring or heterocycle, wherein the H in the carbon ring or heterocycle may optionally be replaced by a group selected from the following: halogen, hydroxyl, C1-C3 alkoxy.

[0094] In some embodiments of the present invention, R2 has the following structure: Among them, X7 is selected from: C(R) 23 ), N, R 22 To R 26 With R 21 The definition, or R 23 With R 24 Or R 22 Together with the atoms to which it is attached, it forms a 4-6 member saturated carbon ring, wherein the H in the carbon ring may optionally be replaced by a group selected from the following: halogen, hydroxyl, C1-C3 alkoxy.

[0095] Specifically, R 22 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 or C3-C6 cycloalkyl may optionally be substituted with a group selected from: halogen, hydroxyl, C1-C3 alkoxy; more specifically, R 22 Selected from: H, halogens (e.g., F, Cl, Br), cyano, hydroxyl, 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).

[0096] Specifically, R 23 Selected from: H, halogens (e.g., F, Cl, Br); more specifically, R 23 It can be H or F.

[0097] Specifically, R 24 Selected from: H, halogen, cyano, -SF5, hydroxyl, -C(O)H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -CO(C 1-6 Alkyl), -O(C) 1-6Alkyl), wherein the H in C1-C6 alkyl or C3-C6 cycloalkyl may optionally be substituted with a group selected from: halogen, hydroxyl, C1-C3 alkoxy; more specifically, R 24 Selected from: H, halogens (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, halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups; more specifically, R 25 Selected from: H, halogens (e.g., F, Cl, Br), C1-C4 alkyl groups (e.g., methyl, ethyl), and C1-C4 haloalkyl groups (e.g., -CF3, -CHF2, -CH2F).

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

[0100] In some embodiments of the present invention Some have the following structure:

[0101]

[0102] in particular

[0103] In some embodiments of the present invention Some have the following structure:

[0104]

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

[0106] More specifically, Some have 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: in:

[0111] The G ring is a 4-10 membered carbon ring or a heterocyclic ring;

[0112] R 41 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 heterocyclic), halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -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 group, C 0-10 Alkyl, C3-C 10 cycloalkyl, C6-C 10The H in the aryl or 4-10 membered heterocyclic group may optionally be replaced by one or more R0 groups.

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

[0114]

[0115] in particular

[0116] In some embodiments of the present invention Some have the following structure:

[0117]

[0118] Among them, R 43 To R 49 With R 41 Definition of R 42 Selected from: H, hydroxyl, protected hydroxyl.

[0119] Specifically, R 42 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 R is -OH; in some embodiments of the present invention, R 42 For H.

[0120] Specifically, R 43 To R 49 Independently selected from: H, halogen, cyano, hydroxyl, mercapto, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -O(C 1-6 Alkyl), -O (C3-C6 cycloalkyl), -S (C 1-6 Alkyl groups, -C(O)H, -CO(C)H 1-6 Alkyl), -NR 401 R 402 The H in the C0-C6 alkylene, C1-C6 alkyl, and C3-C6 cycloalkyl groups may optionally be substituted with groups selected from: halogens, hydroxyl groups, and C1-C3 alkoxy groups; R 401 and R 402 Independently selected from: H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, or R 401 and R 402 Together with the nitrogen atom it is attached to, it forms a 4-8 membered heterocycle (especially a 4-6 membered saturated heterocycle, for example...). The heterocycle is optionally substituted with a group selected from the following: halogen, hydroxyl, C1-C3 alkoxy.

[0121] More specifically, R 43 Selected from: H, halogens (e.g., F, Cl, Br), C1-C4 alkyl groups (e.g., methyl, ethyl), C1-C4 haloalkyl groups (e.g., -CF3, -CHF2, -CH2F), C1-C4 alkoxy groups (e.g., methoxy groups), C1-C4 haloalkoxy groups (e.g., -OCF3, -OCHF2, -OCH2F); In some embodiments of the invention, R 43 Selected from: H, F, Cl, methyl, -OCF3.

[0122] More specifically, R 44 Selected from: H, halogens (e.g., F, Cl, Br), C1-C4 alkyl groups (e.g., methyl, ethyl), C1-C4 haloalkyl groups (e.g., -CF3, -CHF2, -CH2F); in some embodiments of the invention, R 44 Selected from: H, F, Cl, methyl.

[0123] More specifically, R 45 Selected from: H, halogens (e.g., F, Cl, Br), C1-C4 alkyl groups (e.g., methyl, ethyl), C1-C4 haloalkyl groups (e.g., -CF3, -CHF2, -CH2F); in some embodiments of the invention, R 45 Selected from: H, Cl, methyl.

[0124] More specifically, R 46 Selected from: H, halogens (e.g., F, Cl, Br), C1-C4 alkyl groups (e.g., methyl, ethyl), C1-C4 haloalkyl groups (e.g., -CF3, -CHF2, -CH2F), -S (C1-C4 alkyl groups) (e.g., -S-CH3), -NH2, -N(H)(C 1-6 alkyl), -N(C) 1-6 Alkyl)(C 1-6 Alkyl); in some embodiments of the invention, R 46 Selected from: H, -S-CH3, methyl, -NH2.

[0125] More specifically, R 47 Selected from: H, halogens (e.g., F, Cl, Br), C1-C4 alkyl groups (e.g., methyl, ethyl), C1-C4 haloalkyl groups (e.g., -CF3, -CHF2, -CH2F), C1-C4 alkoxy groups (e.g., methoxy), C1-C4 haloalkoxy groups (e.g., -OCF3, -OCHF2, -OCH2F), C3-C4 cycloalkyl groups (e.g., cyclopropyl); In some embodiments of the invention, R 47Selected from: H, Cl, methyl, ethyl, cyclopropyl, -OCF3, -OCHF2.

[0126] Specifically, R 48 and R 49 Independently selected from: H, halogens (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).

[0127] In some embodiments of the present invention Some have the following structure:

[0128]

[0129] in particular

[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 groups may optionally be substituted with 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 structures:

[0145]

[0146]

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

[0148]

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

[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] A second aspect of the present invention provides an intermediate compound and its stereoisomers, having the following structure:

[0163]

[0164] Among them, ring A, ring J, X1, X2, X3, X4, A1, A2, R1, R2, R3, and R5 are respectively defined in the first aspect of the present invention;

[0165] R L It is a reactive group.

[0166] In some embodiments of the present invention Part of R L It is protected by H or an amino group (such as a Boc group).

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

[0168] like Among them, R L It can be an H or amino protecting group (such as a Boc group).

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

[0170] like In some embodiments of the present invention, R L For 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 also provided, having the following structure:

[0182]

[0183] Among them, ring A, ring J, X1, X2, X3, X4, A1, A2, R1, R2, R3, and R5 are respectively defined in the first aspect of the present invention;

[0184] R L R L '、R L " is an independent reactive group.

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

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

[0187] like

[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 halogen (e.g., F, Cl, Br or I), alkylsulfonyloxy, arylsulfonyloxy, etc., especially halogen.

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

[0192] In a third aspect of the invention, a method for preparing the compound described in the first aspect of the invention is provided, comprising the compound represented by formula IM-1 and... The reaction connection step, wherein A3 and R4 are respectively defined in the first aspect of the present invention, R L1 It is a leaving group.

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

[0194] In some embodiments of the present invention, the method further includes the step of preparing the compound of formula IM-1, for example by reacting the compound of formula IM-2 with R. L2 -R1 reaction, or via the compound shown in formula IM-3 with The reaction, in which R L2 R L3 It is a leaving group.

[0195] In some embodiments of the present invention, the method further includes the step of preparing the compound represented by formula IM-2, for example by... and The reaction, in which R L ”'、R L0 It is a reactive group.

[0196] In some embodiments of the present invention, the method further includes the step of preparing the compound represented by formula IM-3, for example by... and The reaction, in which R L ”'、R L0 It is a reactive group.

[0197] In other embodiments of the invention, the method further includes the step of preparing the compound shown in formula IM-1, for example, by using the compound and The reaction, in which R L ”'、R L0 R is a reactive group. In some embodiments of the present invention, R... L "' represents a leaving group, such as halogens (e.g., F, Cl, Br or I), alkylsulfonyloxy, arylsulfonyloxy, etc., for example, Br.

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

[0199] A fourth aspect of the invention provides a combination comprising the compound of the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, deuterated compound, and one or more other therapeutically active agents.

[0200] Specifically, other therapeutic agents can be anticancer drugs or chemotherapeutic agents.

[0201] Specifically, chemotherapy agents include, for example, anastrozole, bicalutamide, bleomycin sulfate, busulfan, capecitabine, N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, cyclophosphamide, cytarabine, cytosine arabinoside, cytarabine liposome injection, dacarbazine, daunorubicin (actinomycin D, Cosmegan), daunorubicin hydrochloride, daunorubicin citrate liposome injection, dexamethasone, docetaxel, doxorubicin hydrochloride, and etoposide. Glycosides, fludarabine phosphate, 5-fluorouracil, flutamide, tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea, idarubicin, ifosfamide, irinotecan, L-asparaginase, leucovorin calcium, melphalan, 6-mercaptopurine, methotrexate, mitoxantrone, mylotarg, paclitaxel, phoenix (Yttrium90 / MX-DTPA), pentostatin, polifeprosan 20 cocarmustine 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, other therapeutic agents are inhibitors of PD-1 (e.g., human PD-1). In some embodiments of the present invention, other therapeutic agents are inhibitors of PD-L1 (e.g., human PD-L1). Specifically, the inhibitor of PD-1 or PD-L1 can be an antibody molecule of PD-1 or PD-L1.

[0203] Specifically, PD-1 inhibitors include, for example, PDR001 (Novartis), nivolumab (Bristol-Myers Squibb), etc. Squibb), Pembrolizumab (Merck & Co.), Pildilizumab (CureTech), MEDI0680 (Medimmune), Cimiprizumab (REGN2810, Regeneron), Dotalizumab (TSR-042, Tesaro), PF-06801591 (Pfizer), Tislelizumab (BGB-A317, BeiGene), BGB-108 (BeiGene), INCSHR1210 (Incyte), Batesilizumab (AGEN2035, Agenus), Sintilimab (InnoVent), Toripalimab (Shanghai Junshi Biosciences Co., Ltd.) Bioscience), Camrelizumab (Jiangsu Hengrui Medicine Co.), AMP-224 (Amplimmune), Peanpulimab (Akeso Biopharma Inc.), Sepalimab (Acus Bioscience), and Prolgolimab (Biocad Ltd.), especially PDR001, and even more so tislelizumab (BGB-A317, BeiGene).

[0204] A fifth aspect of the invention provides a pharmaceutical composition comprising the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, deuterated compound, 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, antibacterial agents, suspending agents, solubilizers, thickeners, stabilizers, and preservatives.

[0206] Specifically, the pharmaceutical composition can be administered via any suitable route of administration, such as gastrointestinal administration (e.g., oral, sublingual, rectal administration) or non-gastrointestinal administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory tract administration, etc.).

[0207] In some embodiments of the present invention, the pharmaceutical composition is an oral formulation, 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, and controlled-release formulations (e.g., instantaneous-release formulations, sustained-release formulations, sustained-release microcapsules).

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

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

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

[0211] Specifically, in the pharmaceutical composition, the compound or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound may be used alone or in combination with other therapeutically active agents (as described in the fourth aspect of the invention).

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

[0213] Specifically, the pharmaceutical composition contains 0.1-99.5% (e.g., 0.1%, 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%) of an active ingredient (the compound described in the first aspect or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound, or in combination with other types of active ingredients) in a weight ratio of 0.1-99.5%.

[0214] Specifically, the pharmaceutical composition contains pharmaceutically acceptable excipients in a weight ratio of 0.5% to 99.9% (e.g., 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%).

[0215] A sixth aspect of the invention provides the use of the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof as a WRN helicase inhibitor, for example, in the preparation of medicaments for the prevention and / or treatment of WRN-mediated diseases.

[0216] Specifically, the disease is one in which inhibition of WRN can be beneficial for its prevention and / or treatment.

[0217] In some preferred embodiments of the present invention, the disease is a tumor, such as acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical teratoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem cell glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoma, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia. (CML), Chronic myelodysplastic disorder, Colon cancer, Colorectal cancer, Craniopharyngioma, Cutaneous T-cell lymphoma, Extrahepatic ductal carcinoma in situ (DCIS), Embryoma, CNS cancer, Endometrial cancer, Ependymoma, Esophageal cancer, Nasal glioma, Ewing sarcoma, Extracranial ectodermal cell tumor, Gonadal ectodermal cell tumor, Ocular cancer, Osteofibrous histiocytoma, Gallbladder cancer, Gastric cancer, Gastrointestinal carcinoid tumor, Gastrointestinal stromal tumor (GIST), Germ cell tumor, Gestational trophoblastoma, Pilocytic leukemia, Head and neck cancer, Heart cancer, Liver cancer, Hodgkin's 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 and occult primary squamous neck cancer, midline carcinoma, oral cancer, multiple endocrine tumor syndrome, multiple myeloma / plasma cell tumor, mycosis fungoides, myelodysplastic syndrome, spinal dysplasia / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer Papilloma, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid carcinoma, penile cancer, pharyngeal cancer, pleural pulmonary 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, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastoma, rare childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.

[0218] In particular, the tumors are cancers with microsatellite instability (MSI), such as colorectal cancer, gastric cancer, ovarian cancer, endometrial tumors, and ovarian cancer.

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

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

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

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

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

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

[0225] Specifically, the subjects are mammals, such as humans.

[0226] This invention provides a novel WRN helicase inhibitor with superior inhibitory activity. It can be used to inhibit the growth of microsatellite instability (MSI) tumor cells by inhibiting the high level of DNA double-strand breaks (DSBs) induced by WRN in microsatellite instability (MSI) cells. This inhibitor can be used for the prevention and / or treatment of related cancers, especially colorectal cancer, gastric cancer, ovarian cancer, and endometrial tumors. It can fill the gap in targeted drugs for specific MSI subtypes of cancer and has a very promising application prospect and value in the pharmaceutical field. Attached Figure Description

[0227] Fig. 1 The figure shows the IC50 curve of compound T074 inhibiting the activity of WRN helicase.

[0228] Fig. 2 The figure shows the IC50 curve of compound T074 inhibiting ATPase activity.

[0229] Fig. 3 The figure shows the EC50 curve of compound T074 inhibiting the growth of SW48 tumor cells. Detailed Implementation

[0230] Unless otherwise defined, all scientific and technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art.

[0231] In this 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 cyclic hydrocarbon group (also referred to herein as an "aliphatic ring") that is fully saturated or contains one or more unsaturated units, connected to the rest 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 "carbon ring" is composed entirely of carbon atoms and can be divided into aliphatic rings and aromatic rings.

[0233] The term "alkyl" refers to a straight-chain or branched hydrocarbon radical that does not contain unsaturated bonds and is connected to the rest of the molecule by a single bond. Typical alkyl groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc. If the alkyl group is substituted with a cycloalkyl group, it is referred to as "cycloalkylalkyl," such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc. If the alkyl group is substituted with an aryl group, it is referred to as "aralkylalkyl," such as benzyl, diphenylmethyl, or phenethyl. If the alkyl group is substituted with a heterocyclic group, it is referred to as "heterocyclicalkyl." In this invention, CO alkyl refers to H, i.e., C 0-10 Alkyl (or C0-C) 10 Alkyl groups include H and C. 1-10 Alkyl (or C1-C) 10 alkyl).

[0234] The term "alkylene" refers to a hydrocarbon group (divalent alkyl) formed by the loss of two hydrogen atoms from an alkane molecule. It can be straight-chain or branched and is connected to the rest of the molecule by a single bond. Typical alkylene groups described herein have 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 this invention, CO alkylene refers to a single bond, i.e., C... 0-10 Alkylene (or C0-C) 10 Alkylenes include single bonds and C bonds. 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, containing 3 to 18 carbon atoms, preferably 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantyl.

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

[0237] The term "aryl" refers to a monocyclic or polycyclic free radical, including polycyclic free radicals containing a monoaryl group and / or a fused aryl group, 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, and indenyl. "Arylidene" refers to a divalent group derived from aromatic hydrocarbons by removing two hydrogen atoms.

[0238] The term "heterocyclic group" includes heteroaromatic and heterocyclic groups containing 1 to 3 monocyclic and / or fused rings and 3 to 18 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18) ring atoms. Preferred heteroaromatic and heterocyclic groups contain 4 to 10 (e.g., 4, 5, 6, 7, 8, 9, 10) ring atoms. Suitable heteroaryl groups in the compounds of the present invention contain 1, 2, or 3 heteroatoms selected from N, O, or S atoms. Examples of heteroaryl groups, such as, but not limited to, coumarins, including 8-coumarins; quinolinyl groups, including 8-quinolinyl, isoquinolinyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrroloyl, thiopheneyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazoleyl, indoleyl, isoindoleyl, indazoleyl, inazinyl, phthalazinyl, pteridinyl, purineyl, oxadiazolyl, thiadiazolyl, furazolidyl, pyridazinyl, triazinyl, cenolinyl, benzimidazolyl, benzofuranyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphridinyl, and furanopyridinyl, etc. Suitable heterocyclic groups in the compounds of the present invention contain one, two, or three heteroatoms selected from N, O, or S atoms. Examples of heterocyclic groups, such as, but not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuran, tetrahydrothiophenyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, oxothiocyclohexyl, piperazine, aziridine, oxocyclobutyl, thiocyclobutyl, high-piperidinyl, oxocyclopropane, thiocyclopropane, acrylonitrile, oxoaziridine, diacylonitrile, triacylonitrile, 1,2,3,6-tetracyclyl Hydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxapentyl, pyrazolinyl, dithiaalkyl, dithiopentyl, dihydropyranyl, dihydrothiophenyl, pyrazolinyl, imidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl and quinazinyl, etc.

[0239] The above-mentioned groups can be replaced by one or more suitable groups at one or more available positions, 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'), Cl-C 12 Alkyl, C3-C 10 cycloalkyl, C2-C 12 alkenyl, C2-C 12 Alkynyl, aryl, and heterocyclic groups, wherein each R' group is independently selected from: hydrogen, OH, NO2, NH2, SH, CN, halogen, COH, COalkyl, COOH, C1-C 12 Alkyl, C3-C 10 cycloalkyl, C2-C 12 alkenyl, C2-C 12 Alkynyl, aryl, and heterocyclic groups. 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 the hydrogen atom on the alkyl group 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 or basic salt that is theoretically non-toxic, non-irritating, and non-allergenic, and that can achieve or provide clinically acceptable pharmacokinetic, absorption, distribution, and metabolic properties of a drug molecule to achieve its intended purpose. The salts described in this invention include pharmaceutically acceptable acidic or basic salts of compounds with acidic, basic, or amphoteric groups. A list of suitable salts can be found in SM Birge, et al., J. Pharm. Sci., 66, 1-19 (1977).

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

[0243] The acid addition salts include, but are not limited to, salts from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphonic acid, as well as salts from organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanic acids, hydroxyalkanic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Therefore, these salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromates, iodates, acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, maleates, amygdalinates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, and methanesulfonates, as well as salts of amino acids such as arginine salts, gluconates, and galacturonic acids. Acid addition salts can be prepared by contacting a sufficient amount of the desired acid in a conventional manner to form a salt. The free base can be regenerated by contacting the salt with a base, and the free base can be separated in a conventional manner.

[0244] The base addition salts described in this invention refer to salts formed with metals or amines, such as hydroxides of alkali metals and alkaline earth metals, or with organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Suitable amines include, but are not limited to, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucosamine, and procaine. Base addition salts can be prepared by contacting a sufficient amount of the desired base in a conventional manner to form a salt. The free acid form can be regenerated by contacting the salt form with an acid, and the free acid can be separated in a conventional manner.

[0245] The term "solvent" should be understood to refer to any form of the compounds of the present invention, wherein the compounds are linked to another molecule (usually a polar solvent) by a non-covalent bond, particularly including hydrates and alcohols, such as methanols. Hydrates are preferred solvates.

[0246] The term "prodrug" is used in its broad sense and encompasses derivatives that can be converted into the compounds of this invention in vivo. Examples of prodrugs include, but are not limited to, derivatives and metabolites of compounds, including biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable acylureas, and biohydrolyzable phosphate ester 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 "not present" indicates that the linking group is a linking bond.

[0248] Any compound referred to herein is intended to represent such a particular compound and certain variations or forms thereof. In particular, the compounds referred to herein may have an asymmetric center and therefore exist in different enantiomers or diastereomers. Thus, any given compound referred to herein represents any racemic compound, one or more enantiomers, one or more diastereomers, or mixtures thereof. Similarly, stereoisomers or geometric isomers of the double bonds may also exist, thus in some cases the molecule may exist as (E)-isomers or (Z)-isomers (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. Furthermore, the compounds referred to herein may exist as ator isomers. All stereoisomers of the compounds referred to herein, including enantiomers, diastereomers, geometric isomers, and ator isomers, and mixtures thereof, are within the scope of this invention.

[0249] The term "leaving group" is given its general meaning in the field of synthetic organic chemistry and refers to an atom or group that can be replaced by a nucleophile. See, for example, Smith, March 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 groups, arylsulfonyloxy groups, etc.

[0250] All publications, patents, and published patent specifications cited in this article are incorporated herein in their entirety through citation.

[0251] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0252] Compound Synthesis Examples

[0253] Example 1

[0254] The synthesis route is shown below:

[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 eq) was added to a 48% aqueous hydrobromic acid solution (1 mmol: 0.4 mL), followed by the dropwise addition of an aqueous solution of sodium nitrite (1.1 eq) at 0 °C. The reaction was then carried out at 100 °C for 16 hours. After the reaction was completed as monitored by LC-MS, the reaction solution was cooled to 0 °C, the pH was adjusted to 4 with 10% sodium hydroxide solution, and the mixture was extracted four times with ethyl acetate. The organic phase was dried over saturated brine and anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain intermediate A-1.

[0261] 1.2 Synthesis of intermediate B-1

[0262]

[0263] 3-Chloro-4-aminotrifluorotoluene (1.0 eq) was added to dichloromethane (1 mmol: 2 mL), and chloroacetyl chloride (1.05 eq) was added dropwise at 0 °C. The reaction was then carried out at room temperature for 16 hours. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then 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 eq) and pentafluorophenol (1.05 eq) were added to dichloromethane (1 mmol: 2 mL), and N,N'-diisopropylcarbodiimide (1.05 eq) was added dropwise at 0 °C. The reaction was then carried out at room temperature for 16 hours. After the reaction was completed as monitored by LC-MS, the reaction solution was concentrated under reduced pressure and subjected to column chromatography to obtain intermediate C-1.

[0267] 1.4 Synthesis of intermediate A-2

[0268] Ethyl propionyl acetate (1.1 eq) and intermediate A-1 (1.0 eq) were added to acetic acid (1 mmol: 0.5 mL) at room temperature, and then the mixture was heated to 80 °C and reacted for 16 hours. After the reaction was completed by LC-MS monitoring, 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] Intermediate A-2 (1.0 eq), intermediate B-1 (1.2 eq), and N,N-diisopropylethylamine (2.5 eq) were added to N,N-dimethylformamide (1 mmol: 2 mL) at room temperature, followed by reaction at 80 °C for 16 hours. After the reaction was completed by LC-MS monitoring, the reaction solution was diluted with ethyl acetate, washed twice with water and once with brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, followed by column chromatography to obtain intermediate A-3.

[0271] 1.6 Synthesis of intermediate A-4

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

[0273] 1.7 Synthesis of Intermediate A-5

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

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

[0276] A-5 (1.0 eq), N,N-diisopropylethylamine (3.0 eq), and a commercially available tert-butyloxycarbonyl-protected spirocyclic amine (S-1 or S-1') (2.5 eq) were dissolved in dimethyl sulfoxide (1 mmol: 5 mL), and the reaction was carried out at 120 °C for 16 h under nitrogen protection. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, followed by column chromatography to obtain intermediate A-6 or A-6'.

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

[0278] Intermediates A-6 and A-6' (1.0 eq) were dissolved in dichloromethane (1 mmol: 5 mL) at room temperature, followed by the addition of trifluoroacetic acid (1 mmol: 1 mL) at 0 °C, and then the reaction was brought to room temperature for 2 hours. After the reaction was completed as monitored by LC-MS, the reaction solution was concentrated to near dryness under reduced pressure, diluted with dichloromethane, and the pH of the aqueous phase was adjusted to 8-9 with saturated sodium bicarbonate. The aqueous phase was extracted twice with dichloromethane, washed with saturated brine, and the resulting 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 eq), triethylamine (3.0 eq), and intermediate C-1 (1.2 eq) were dissolved in N,N-dimethylformamide (1 mmol: 10 mL), and then reacted at 80 °C for 2 hours under nitrogen protection. After the reaction was monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then subjected to high pressure reverse reaction to prepare compound A-8 or A-8'.

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

[0282] When Y is absent, n=2, m=1, A-8 obtained according to the above synthesis steps is compound T004.

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

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

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

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

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

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

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

[0290] When Y is CH2, n=2, m=2, A-8' is obtained according to the above synthesis steps. In particular, when the configuration of the spiro atom is S-type, it is compound T12.

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

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

[0293] When Y is CH2, n=2, m=2, A-8' is obtained according to the above synthesis steps. In particular, when the configuration of the spiro atom is R-type, it is compound T015.

[0294] The structure and general analytical data of the target compound 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] 3-Hydroxy-4-methylpyridine (1.0 eq) and sodium carbonate (2.3 eq) were dissolved in water (1 mmol: 5 mL), followed by the addition of iodine (1.0 eq), and the reaction was carried out at room temperature for 4 hours. After the reaction was completed by LC-MS monitoring, the pH of the reaction solution was adjusted to 4-5 with 2 mol / L hydrochloric acid at 0 °C. The solution was extracted three times with ethyl acetate, washed with saturated brine, and the resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was then subjected to column chromatography to obtain intermediate C-2-1.

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

[0302] Intermediate C-2-1 (1.0 eq) and cuprous cyanide (4.0 eq) were added to N,N-dimethylformamide (1 mmol: 2 mL) at room temperature, purged three times with nitrogen, and then heated to 100 °C for 2 hours. After the reaction was completed by LC-MS monitoring, the mixture was cooled to room temperature, diluted with ethyl acetate and water, filtered to separate the organic phase, washed once with water and once with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then subjected to column chromatography to obtain intermediate C-2-2.

[0303] 2.1.3 Synthesis of intermediate C-2

[0304] Potassium hydroxide (6.0 eq) was dissolved in water (1 mmol: 2 mL), followed by the addition of intermediate C-2-2 (1.0 eq). The mixture was heated to 90 °C and reacted for 16 hours. After the reaction was completed, the mixture was cooled to 0 °C, and the pH of the reaction solution was adjusted to approximately 3 using 2 mol / L hydrochloric acid. The filtered solid was washed twice with a small amount of water, and the solid was collected and dried to obtain intermediate C-2.

[0305] 2.2 Synthesis of compound T002

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

[0307] Intermediates A-7 (1.0 eq), C-2 (2.0 eq), and N,N-diisopropylethylamine (5 e.g.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL) at room temperature. Then, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (2.0 eq) was added at 0 °C, followed by reaction at room temperature for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound T002 was then prepared by reverse high-pressure reaction. Its 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] Intermediate C2-1-1 (1.0 eq) and potassium carbonate (1.5 eq) were added to N,N-dimethylformamide (1 mmol: 3 mL) at room temperature, followed by the addition of benzyl bromide (1.05 eq). The reaction mixture was then heated to 40 °C and reacted for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with a large amount of water, extracted twice with ethyl acetate, and the resulting organic phase was washed once with brine, dried over anhydrous sodium sulfate, 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] Intermediate C-3-1 (1.0 eq), benzyl mercaptan (2.0 eq), XanPhos (0.15 eq), Pd2(dba)3 (0.075 eq), and N,N-diisopropylethylamine (3.0 eq) were added to 1,4-dioxane (1 mmol: 4 mL) at room temperature. The mixture was purged with nitrogen three times, and then heated to 100 °C for 2 hours. After the reaction was 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] Intermediate C-3-2 (1.0 eq) was dissolved in acetonitrile (1 mmol: 4 mL) and water (1 mmol: 0.5 mL), cooled to 0 °C, and acetic acid (6.0 eq) and 1,3-dichloro-5,5-dimethylhydantoin (1.0 eq) were added. The mixture was then allowed to rise to room temperature for 2 hours. After the reaction was completed by LC-MS monitoring, the pH of the reaction solution was adjusted to 7 with saturated sodium bicarbonate, extracted three times with ethyl acetate, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain intermediate C-3.

[0317] 3.2 Synthesis of compound T003

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

[0319] Intermediate A-7 (1.0 eq) and triethylamine (5 e.q.) were dissolved in dichloromethane (1 mmol: 10 mL). The reaction solution was then cooled to 0 °C, and intermediate C-3 (2.5 eq) was added. The reaction was then brought to room temperature and reacted for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with water, extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound T003 was then prepared by reverse high pressure reaction. Its structure and general analytical data are shown in Table 1.

[0320] Example 4

[0321] The synthesis route is shown below:

[0322]

[0323] The specific steps are as follows:

[0324] 4.1 Synthesis of intermediate A-9

[0325] Ethyl acetoacetate (1.0 eq) and ammonium acetate (0.3 eq) were added to anhydrous diethyl ether (1 mmol: 5 mL), followed by the addition of NBS (1.08 eq) in portions. The solution was stirred at room temperature for 4 hours. The reaction was monitored by TLC until completion. The ether was evaporated to dryness, diluted with ethyl acetate, washed three times with brine, and the organic phase was collected and dried over anhydrous sodium sulfate to obtain crude product A-9. No purification is required; it can be used directly in the next step.

[0326] 4.2 Synthesis of intermediate A-10

[0327] Intermediate A-9 (1.0 eq), (R)-1-BOC-1,7-diazaspiro[4.4]nonane (0.8 eq), and potassium carbonate (3.0 eq) were weighed and dissolved in acetonitrile (1 mmol: 2 mL). The mixture was then stirred at room temperature for 2–3 h. After the reaction was completed as monitored by LC-MS, the acetonitrile was removed by rotary evaporation, the mixture was diluted with ethyl acetate, washed three times with brine, dried over anhydrous sodium sulfate, and the organic phase was retained and evaporated to dryness to obtain the crude product. Finally, A-10 was obtained by column chromatography.

[0328] 4.3 Synthesis of intermediate A-11

[0329] Under nitrogen protection, WRI-INT-1 (1.5 eq) and 85% aqueous phosphoric acid (1.0 eq) were added to an ethanol solution (1 mmol: 0.5 mL) of intermediate A-10 (1.0 eq), followed by stirring at 90 °C for 16 hours. After the reaction was completed as monitored by LC-MS, the solution was cooled to room temperature, the ethanol was evaporated to dryness, diluted with ethyl acetate, washed with ammonium chloride aqueous solution, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain the crude product. Finally, product A-11 was obtained by column chromatography.

[0330] 4.4 Synthesis of intermediate A-12

[0331] Intermediate A-11 (1.0 eq), pinacol 3,6-dihydro-2H-pyran-4-boronic acid (1.2 eq), XPhosPd G3 (0.05 eq), and potassium phosphate (2.5 eq) were added to 1,4-dioxane and water (5:1, 1 mmol:5 mL), purged three times with nitrogen, and then heated to 80 °C for 4 hours. After the reaction was completed by LC-MS monitoring, the reaction solution was diluted with ethyl acetate, washed with brine, and the organic phase was collected, dried over anhydrous sodium sulfate, and evaporated to dryness. The resulting solution was then subjected to column chromatography to obtain intermediate A-12.

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

[0333] Intermediate A-12 (1.0 eq), intermediate B-1 (1.2 eq), and N,N-diisopropylethylamine (2.5 eq) were added to N,N-dimethylformamide (1 mmol: 2 mL) at room temperature, and then the mixture was heated to 80 °C and reacted for 16 hours. After the reaction was completed by LC-MS monitoring, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then subjected to column chromatography to obtain intermediate A-13-1.

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

[0335] Intermediate A-13-1 (1.0 eq) was dissolved in dichloromethane (1 mmol: 5 mL) at room temperature, followed by the addition of trifluoroacetic acid (1 mmol: 3 mL) at 0 °C, and then the reaction was carried out at 40 °C for 16 hours. After the reaction was completed as monitored by LC-MS, the reaction solution was concentrated to near dryness under reduced pressure, diluted with dichloromethane, and the pH of the aqueous phase was adjusted to 8-9 with saturated sodium bicarbonate. The aqueous phase was extracted twice with dichloromethane, washed with saturated brine, and the resulting 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 the target product T016

[0338]

[0339] Intermediates A-14-1 (1.0 eq), C-4 (2.0 eq), and N,N-diisopropylethylamine (5 e.g.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL) at room temperature. Then, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (2.0 eq) was added at 0 °C, followed by reaction at 40 °C for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound T016 was then prepared by reverse high-pressure reaction. Its structure and general analytical data are shown in Table 1.

[0340] 4.7.2 Synthesis of the target product T017

[0341]

[0342] Intermediates A-14-1 (1.0 eq), C-5 (2.0 eq), and N,N-diisopropylethylamine (5 e.g.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL) at room temperature. Then, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (2.0 eq) was added at 0 °C, followed by reaction at 40 °C for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound T017 was then prepared by reverse high-pressure reaction. Its structure and general analytical data are shown in Table 1.

[0343] 4.7.3 Synthesis of the target product T018

[0344]

[0345] Intermediates A-14-1 (1.0 eq), C-6 (2.0 eq), and N,N-diisopropylethylamine (5 e. q.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL) at room temperature. Then, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.5 eq) was added at 0 °C, followed by reaction at 40 °C for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound T018 was then prepared by reverse high-pressure reaction. Its structure and general analytical data are shown in Table 1.

[0346] 4.7.4 Synthesis of the target product T019

[0347]

[0348] Intermediates A-14-1 (1.0 eq), C-7 (2.0 eq), and N,N-diisopropylethylamine (5 e.g.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL) at room temperature. Then, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (2.0 eq) was added at 0 °C, followed by reaction at 40 °C for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound T019 was then prepared by reverse high-pressure reaction. Its structure and general analytical data are shown in Table 1.

[0349] 4.7.5 Synthesis of the target product T020

[0350]

[0351] Intermediates A-14-1 (1.0 eq), C-8 (2.0 eq), and N,N-diisopropylethylamine (5 e.g.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL) at room temperature. Then, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (2.0 eq) was added at 0 °C, followed by reaction at 40 °C for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound T020 was then prepared by reverse high-pressure reaction. Its structure and general analytical data are shown in Table 1.

[0352] 4.7.6 Synthesis of the target product T021

[0353]

[0354] Intermediates A-14-1 (1.0 eq), C-2 (2.0 eq), and N,N-diisopropylethylamine (5 e.g.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL) at room temperature. Then, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (2.0 eq) was added at 0 °C, followed by reaction at 40 °C for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound T021 was then prepared by reverse high-pressure reaction. 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] Intermediate A-14-1 (1.0 eq), C-9 (2.0 eq), and N,N-diisopropylethylamine (5 e.g.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL) at room temperature. Then, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (2.0 eq) was added at 0 °C, followed by reaction at 40 °C for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, followed by column chromatography purification to obtain intermediate A-15-1.

[0359] 4.7.7.2 Synthesis of the target product T006

[0360] Intermediate A-15-1 (1.0 eq) was dissolved in trifluoroacetic acid solution (1 mmol: 1 mL) at room temperature, and the reaction solution was heated to 40 °C and reacted for 12 hours. After the reaction was monitored by LC-MS, the trifluoroacetic acid was evaporated to dryness, the concentrate was diluted with ethyl acetate, washed once with saturated sodium bicarbonate solution and once with saturated brine, the organic phase was evaporated to dryness, and then compound T006 was prepared by reverse high pressure reaction. 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] Intermediate A-14-1 (1.0 eq), C-10 (2.0 eq), and N,N-diisopropylethylamine (5 e.g.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL) at room temperature. Then, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (2.0 eq) was added at 0 °C, followed by reaction at 40 °C for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, followed by column chromatography purification to obtain intermediate A-15-1.

[0365] 4.7.8.2 Synthesis of the target product T013

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

[0367] 4.7.9 Synthesis of the target product T014

[0368]

[0369] Intermediates A-14-1 (1.0 eq), C-11 (2.0 eq), and N,N-diisopropylethylamine (5 e.g.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL) at room temperature. Then, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (2.0 eq) was added at 0 °C, followed by reaction at 40 °C for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound T014 was then prepared by reverse high-pressure reaction. Its structure and general analytical data are shown in Table 1.

[0370] Example 5

[0371] The synthesis route is shown below:

[0372]

[0373] The specific steps are as follows:

[0374] 5.1 The synthetic route for intermediate B-2 is as follows:

[0375]

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

[0377] 1.0 eq of 4-amino-2-chlorotrifluorotoluene was dissolved in CH3OH:DCM = 3:2 mL (1.0 mmol:5 mL) at room temperature. Iodine monochloride (1.5 eq) was added at 0 °C, and the reaction mixture was then allowed to rise to room temperature for 2 hours. After the reaction was completed as monitored by LC-MS, the reaction solution was concentrated to dryness under reduced pressure, diluted with ethyl acetate, and slowly added to a saturated sodium thiosulfate solution while stirring for 5–10 minutes. Finally, the mixture was washed twice with water and then washed with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude intermediate B-2-1. The crude product was purified by column chromatography to obtain pure intermediate B-2-1.

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

[0379] Intermediate B-2-1 (1.0 eq), trimethylcycloboroxane (2.5 eq), DPPF palladium dichloride methane complex (0.05 eq), and potassium carbonate (2.5 eq) were added to 1,4-dioxane (1 mmol: 2 mL), purged three times with nitrogen, and then heated to 100 °C for 16 hours. After the reaction was completed by LC-MS monitoring, the reaction solution was diluted with ethyl acetate, washed with brine, and the organic phase was collected, dried over anhydrous sodium sulfate, and evaporated to dryness. The resulting solution was then subjected to column chromatography to obtain intermediate B-2-2.

[0380] 5.1.3 Synthesis of intermediate B-2

[0381] Intermediate B-2-2 (1.0 eq) was added to dichloromethane (1 mmol: 2 mL), and chloroacetyl chloride (1.05 eq) was added dropwise at 0 °C. The reaction was then carried out at room temperature for 16 hours. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was then slurried with petroleum ether to obtain intermediate B-2.

[0382] 5.2 Synthesis of intermediate A-3b

[0383] Intermediate A-2 (1.0 eq), intermediate B-2 (1.2 eq), and N,N-diisopropylethylamine (2.5 eq) were added to N,N-dimethylformamide (1 mmol: 2 mL) at room temperature, followed by reaction at 80 °C for 16 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water and once with brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, followed by column chromatography to obtain intermediate A-3b.

[0384] 5.3 Synthesis of intermediate A-4b

[0385] Intermediate A-3b (1.0 eq), pinacol 3,6-dihydro-2H-pyran-4-boronate (1.2 eq), XPhosPd G3 (0.05 eq), and potassium phosphate (2.5 eq) were added to N,N-dimethylformamide and water (7:1, 1 mmol:5 mL). The mixture was purged with nitrogen three times, and then the temperature was raised to 80 °C for 16 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, followed by column chromatography to obtain intermediate A-4b.

[0386] 5.4 Synthesis of intermediate A-5b

[0387] Intermediate A-4b (1.0 eq) was dissolved in N,N-dimethylformamide (1 mmol: 10 mL) at room temperature, followed by the addition of N-bromosuccinimide (1.5 eq) in portions, and the reaction was carried out for 4 hours. After the reaction was completed as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed once with saturated sodium bicarbonate, twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, followed by column chromatography to obtain intermediate A-5b.

[0388] 5.5 Synthesis of intermediate A-6b

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

[0390] 5.6 Synthesis of intermediate A-7b

[0391] Intermediate A-6b (1.0 eq) was dissolved in dichloromethane (1 mmol: 5 mL) at room temperature, followed by the addition of trifluoroacetic acid (1 mmol: 1 mL) at 0 °C, and then the reaction was brought to room temperature for 2 hours. After the reaction was completed as monitored by LC-MS, the reaction solution was concentrated to near dryness under reduced pressure, diluted with dichloromethane, and the pH of the aqueous phase was adjusted to 8-9 with saturated sodium bicarbonate. The solution was extracted twice with dichloromethane, and the organic phase was washed with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to 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 analytical 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 analytical 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 analytical 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 analytical 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 analytical data are shown in Table 1.

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

[0403] Example 6

[0404] The synthesis route is shown below:

[0405]

[0406] 6.1 Synthesis of intermediate B-3

[0407]

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

[0409] 3-Fluoro-2-methylaniline was dissolved in acetic acid (1 mmol: 1 mL) at room temperature, followed by the addition of N-iodosuccinimide (1.0 eq). The reaction mixture was then heated to 95 °C and reacted for 2.5 h. After the reaction was completed as monitored by LC-MS, the reaction mixture was concentrated to near dryness and diluted with ethyl acetate. The solution was then poured into a saturated sodium thiosulfate solution and stirred for 5–10 min. The mixture was then washed twice with water and once with saturated brine. The resulting organic phase was concentrated under reduced pressure using anhydrous sodium sulfate and then subjected to column chromatography to obtain intermediate B-3-1.

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

[0411] Intermediate B-3-1 (1.0 eq) and triethylamine (2.0 eq) were dissolved in DCM (1 mmol: 3 mL) at room temperature. The reaction solution was then cooled to 0 °C, and acetyl chloride (1.5 eq) was added. The reaction solution was then slowly heated to room temperature and reacted for 4 hours. After the reaction was completed by TLC monitoring, the reaction solution was diluted with dichloromethane, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, followed 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 eq), hexamethylphosphoric triamine (5.0 eq), methyl fluorosulfonyl difluoroacetate (5.0 eq), and cuprous iodide (2.0 eq) were dissolved in DMF (1 mmol: 2 mL). The mixture was purged with nitrogen three times, and the reaction solution was heated to 80 °C and reacted for 16 hours. After the reaction was monitored by LCMS, the reaction solution was diluted with ethyl acetate, washed three times with water, and washed once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, followed by column chromatography to obtain intermediate B-3-3.

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

[0415] Intermediate B-3-3 (1.0 eq) was dissolved in ethanol (1 mmol: 2 mL) at room temperature, and 2N HCl indioxane (5.0 eq) was added. The reaction mixture was then heated under reflux for 2 hours. After the reaction was completed by LCMS monitoring, the reaction mixture was concentrated to near dryness, and the concentrate was slurried using 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 eq) and sodium bicarbonate (3.0 eq) were added to dichloromethane (1 mmol: 2 mL), and chloroacetyl chloride (1.05 eq) was added dropwise at 0 °C. The mixture was then reacted at room temperature for 16 hours. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then slurried with petroleum ether to obtain intermediate B-3.

[0418] 6.2 The synthesis of intermediate A-3c is based on the synthesis steps of reaction example A-3b.

[0419] 6.3 The synthesis of intermediate A-4c is based on the synthesis steps of reaction example A-4b.

[0420] 6.4 The synthesis of intermediate A-5c is based on the synthesis steps of reaction example A-5b.

[0421] 6.5 The synthesis of intermediate A-6c is based on the synthesis steps of reaction example A-6b.

[0422] 6.6 The synthesis of intermediate A-7c is based on the synthesis steps of reaction example A-7b.

[0423] 6.7 Synthesis of the target product

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

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

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

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

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

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

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

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

[0434] Example 7

[0435] The synthesis route is shown below:

[0436]

[0437] 7.1 Synthesis of intermediate B-4

[0438]

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

[0440] Intermediate 4-amino-2-fluorotrifluorotoluene (1.0 eq) and boron trifluoride diethyl ether (1.0 eq) were dissolved in dichloromethane (1 mmol: 3 mL) at room temperature. The reaction solution was then cooled to 0 °C, and NIS (1.0 eq) was added dropwise. The reaction solution was heated to room temperature and reacted for 2 hours. After the reaction was completed by LCMS monitoring, the reaction solution was concentrated to dryness, diluted with ethyl acetate, and poured into a saturated sodium thiosulfate solution. The solution was stirred at room temperature for 5–10 minutes, and the organic phase was retained. The solution was washed twice with water and once with saturated brine. The organic phase was then concentrated to dryness and purified by column chromatography to obtain intermediate B-4-1.

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

[0442] Intermediate B-4-1 (1.0 eq), trimethylcycloboroxane (3.2 eq), Pd(PPh3)4 (0.05 eq), and potassium carbonate (4.6 eq) were dissolved in 1,4-dioxane (1 mmol: 3 mL). The reaction mixture was heated to 80 °C and reacted for 16 hours. After the reaction was completed by LCMS monitoring, the mixture was cooled to room temperature, diluted with ethyl acetate, washed twice with water, and once with saturated brine. The organic phase was evaporated to dryness, and then purified 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 eq) and sodium bicarbonate (3.0 eq) were added to dichloromethane (1 mmol: 2 mL), and chloroacetyl chloride (1.05 eq) was added dropwise at 0 °C. The reaction was then carried out at room temperature for 16 hours. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then slurried with petroleum ether to obtain intermediate B-4.

[0445] 7.2 The synthesis of intermediate A-3d is based on the synthesis steps of reaction example A-3b.

[0446] 7.3 The synthesis of intermediate A-4d is based on the synthesis steps of reaction example A-4b.

[0447] 7.4 The synthesis of intermediate A-5d is based on the synthesis steps of reaction example A-5b.

[0448] 7.5 The synthesis of intermediate A-6d is based on the synthesis steps of reaction example A-6b.

[0449] 7.6 The synthesis of intermediate A-7d is based on the synthesis steps of reaction example A-7b.

[0450] 7.7 Synthesis of the target product

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

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

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

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

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

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

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

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

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

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

[0461] Example 8

[0462] The synthesis route is shown below:

[0463]

[0464] 8.1 Synthesis of intermediate B-5

[0465]

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

[0467] 8.2 The synthesis of intermediate A-3e is based on the synthesis steps of reaction example A-3b.

[0468] 8.3 The synthesis of intermediate A-4e is based on the synthesis steps of reaction example A-4b.

[0469] 8.4 The synthesis of intermediate A-5e is based on the synthesis steps of reaction example A-5b.

[0470] 8.5 The synthesis of intermediate A-6e is based on the synthesis steps of reaction example A-6b.

[0471] 8.6 The synthesis of intermediate A-7e is based on the synthesis steps of reaction example A-7b.

[0472] 8.7 Synthesis of the target product

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

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

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

[0483] Example 9

[0484] The synthesis route is shown below:

[0485]

[0486] 9.1 Synthesis of intermediate B-6

[0487]

[0488] 1.0 eq of 2-methyl-4-trifluoromethylaniline was added to dichloromethane (1 mmol: 2 mL), and 1.05 eq of chloroacetyl chloride was added dropwise at 0 °C. The mixture was then reacted at room temperature for 16 hours. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was then slurried 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 is based on the synthesis steps of reaction example A-6b.

[0493] 9.6 The synthesis of intermediate A-7f is based on the synthesis steps of reaction example A-7b.

[0494] 9.7 Synthesis of the target product

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

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

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

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

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

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

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

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

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

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

[0505] Example 10

[0506] The synthesis route is shown below:

[0507]

[0508] 10.1 Synthesis of Intermediate B-7

[0509]

[0510] 1.0 eq of 2-fluoro-4-(trifluoromethyl)aniline was added to dichloromethane (1 mmol: 2 mL), and 1.05 eq of chloroacetyl chloride was added dropwise at 0 °C. The mixture was then reacted at room temperature for 16 hours. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then slurried with petroleum ether to obtain intermediate B-7.

[0511] 10.2 The synthesis of intermediate A-3g follows the synthesis steps of A-3b.

[0512] 10.3 The synthesis of intermediate A-4g follows the same steps as the synthesis of A-4b.

[0513] 10.4 The synthesis of intermediate A-5g follows the same steps as the synthesis of A-5b.

[0514] 10.5 The synthesis of intermediate A-6g follows the same steps as the synthesis of A-6b.

[0515] 10.6 The synthesis of intermediate A-7g follows the same steps as the synthesis of A-7b.

[0516] 10.7 Synthesis of the target product

[0517] 10.7.1 The synthesis steps of the target product T072 are 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 steps of the target product T073 are based on the synthesis of T016, and its structure and general analytical data are shown in Table 1.

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

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

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

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

[0523] 10.7.7 The synthesis steps of the target product T078 are 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 analytical 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 analytical 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 analytical data are shown in Table 1.

[0527] 10.7.11 Synthesis of target product T094

[0528]

[0529] Intermediate A-7g (1.0 eq), PyBOP (2.5 eq), and DIEA (3e.q.) were dissolved in DMF (1 mmol: 10 mL), and 3-hydroxy-2-pyrazinic acid (2.5 eq) was added. The mixture was then heated to 50 °C and reacted for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with water, extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound T094 was then prepared by reverse high pressure reaction. Its structure and general analytical data are shown in Table 1.

[0530] 10.7.12 Synthesis of target product T095

[0531]

[0532] Intermediate A-7 g (1.0 eq), PyBOP (2.5 eq), and DIEA (3 e.g.) were dissolved in DMF (1 mmol: 10 mL), followed by the addition of 6-methylpyrimidine-4-carboxylic acid (2.5 eq), and the reaction was carried out at 50 °C for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with water, extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound T095 was then prepared by reverse high pressure reaction. Its structure and general analytical data are shown in Table 1.

[0533] 10.7.13 Synthesis of target product T096

[0534]

[0535] Intermediate A-7g (1.0 eq), PyBOP (2.5 eq), and DIEA (3 e.g.) were dissolved in DMF (1 mmol: 10 mL), and 2-aminopyrimidine-4-carboxylic acid (2.5 eq) was added. The mixture was then heated to 50 °C and reacted for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with water, extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound T096 was then prepared by reverse high pressure reaction. 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 eq), PyBOP (2.5 eq), and DIEA (3e.q.) were dissolved in DMF (1 mmol: 10 mL), and 3-carboxypyridazine (2.5 eq) was added. The mixture was then heated to 50 °C and reacted for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with water, extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound T099 was then prepared by reverse high pressure reaction. Its structure and general analytical data are shown in Table 1.

[0539] 10.7.15 Synthesis of the target product T100

[0540]

[0541] Intermediate A-7 g (1.0 eq), PyBOP (2.5 eq), and DIEA (3 e.g.) were dissolved in DMF (1 mmol: 10 mL), followed by the addition of 4-pyrimidinecarboxylic acid (2.5 eq), and the reaction mixture was heated to 50 °C for two hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with water, extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound T100 was then prepared by reverse high-pressure reaction. Its structure and general analytical data are shown in Table 1.

[0542] 10.7.16 Synthesis of target product T101

[0543]

[0544] Intermediate A-7g (1.0 eq), PyBOP (2.5 eq), and DIEA (3e.q.) were dissolved in DMF (1 mmol: 10 mL), and 2,6-dimethylpyrimidine-4-carboxylic acid (2.5 eq) was added. The mixture was then heated to 50 °C and reacted for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with water, extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound T101 was then prepared by reverse high pressure reaction. Its structure and general analytical data are shown in Table 1.

[0545] 10.7.17 Synthesis of the target product T102

[0546]

[0547] Intermediate A-7 g (1.0 eq), PyBOP (2.5 eq), and DIEA (3 e.g.) were dissolved in DMF (1 mmol: 10 mL), and finally 5-fluoro-2-pyridinecarboxylic acid (2.5 eq) was added. The reaction mixture was then heated to 50 °C and reacted for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with water, extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound T102 was then prepared by reverse high pressure reaction. Its structure and general analytical data are shown in Table 1.

[0548] 10.7.18 Synthesis of the target product T103

[0549]

[0550] Intermediate A-7g (1.0 eq), PyBOP (2.5 eq), and DIEA (3e.q.) were dissolved in DMF (1 mmol: 10 mL), and 3-fluoropyridine-2-carboxylic acid (2.5 eq) was added. The reaction mixture was then heated to 50 °C and reacted for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with water, extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound T103 was then prepared by reverse high pressure reaction. Its structure and general analytical data are shown in Table 1.

[0551] 10.7.19 Synthesis of the target product T104

[0552]

[0553] Intermediate A-7 g (1.0 eq), PyBOP (2.5 eq), and DIEA (3 e.g.) were dissolved in DMF (1 mmol: 10 mL), and finally 3,5-difluoro-2-pyridinecarboxylic acid (2.5 eq) was added. The reaction mixture was then heated to 50 °C and reacted for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with water, extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound T104 was then prepared by reverse high pressure reaction. Its structure and general analytical data are shown in Table 1.

[0554] 10.7.20 Synthesis of the target product T105

[0555]

[0556] Intermediate A-7g (1.0 eq), PyBOP (2.5 eq), and DIEA (3 e.g.) were dissolved in DMF (1 mmol: 10 mL), and finally 5-fluoro-6-methylpyridine-2-carboxylic acid (2.5 eq) was added. The reaction mixture was then heated to 50 °C and reacted for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with water, extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound T105 was then prepared by reverse high pressure reaction. Its structure and general analytical data are shown in Table 1.

[0557] 10.7.21 Synthesis of the target product T106

[0558]

[0559] Intermediate A-7 g (1.0 eq), PyBOP (2.5 eq), and DIEA (3 e.g.) were dissolved in DMF (1 mmol: 10 mL), and 5-fluoro-3-methylpicolinic acid (2.5 eq) was added. The mixture was then heated to 50 °C and reacted for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with water, extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound T106 was then prepared by reverse high pressure reaction. Its structure and general analytical data are shown in Table 1.

[0560] Example 11

[0561] The synthesis route is shown below:

[0562]

[0563] 11.1 Synthesis of Intermediate B-8

[0564]

[0565] 11.1.1 Synthesis of intermediate B-8-1

[0566] Intermediate 4-amino-2-fluorotrifluorotoluene (1.0 eq) was dissolved in acetonitrile (1 mmol: 2 mL) at room temperature. N-chlorosuccinimide (1.05 eq) was added in portions, and the reaction mixture was then heated to 50 °C and reacted for 6 hours. After the reaction was monitored by LCMS, the acetonitrile was evaporated to dryness, the concentrate was diluted with ethyl acetate, and the organic phase was washed twice with water and once with saturated brine. The organic phase was evaporated to dryness, and then purified by column chromatography to obtain pure intermediate B-8-1.

[0567] 11.1.2 Synthesis of intermediate B-8

[0568] Intermediate B-8-1 (1.0 eq) was added to dichloromethane (1 mmol: 2 mL), and chloroacetyl chloride (1.05 eq) was added dropwise at 0 °C. The reaction was then carried out at room temperature for 16 hours. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was then slurried with petroleum ether to obtain intermediate B-8.

[0569] 11.2 The synthesis of intermediate A-3h follows the synthesis steps of A-3b.

[0570] 11.3 The synthesis of intermediate A-4h follows the same steps as the synthesis of A-4b.

[0571] 11.4 The synthesis of intermediate A-5h follows the synthesis steps of A-5b.

[0572] 11.5 The synthesis of intermediate A-6h follows the same steps as the synthesis of A-6b.

[0573] 11.6 The synthesis of intermediate A-7h follows the same steps as the synthesis of A-7b.

[0574] 11.7 Synthesis of the target product

[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 analytical 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 analytical 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 analytical 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 analytical 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 analytical 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 analytical 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 analytical 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 analytical 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 analytical 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 analytical data are shown in Table 1.

[0585] Example 12

[0586] The synthesis route is shown below:

[0587]

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

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

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

[0591] 12.4 The synthesis of intermediate A-6i follows the same steps as the synthesis of A-6b.

[0592] 12.5 The synthesis of intermediate A-7i follows the same steps as the synthesis of A-7b.

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

[0594] 12.7 Synthesis of the target product

[0595] 12.7.1 Synthesis of target products T097 and T098, wherein BX = B-7.

[0596]

[0597] Intermediates A-7i (1.0 eq), C-5 (2.0 eq), and N,N-diisopropylethylamine (3 e.g.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL) at room temperature. Then, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (2.0 eq) was added at 0 °C, followed by reaction at 40 °C for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After obtaining the pure product by column chromatography, the target products T097 and T098 were obtained by chiral resolution by SFC according to the elution order. Their structures and general analytical data are shown in Table 1.

[0598] The conditions for chiral splitting are as follows:

[0599] Prep-HPLC conditions:

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

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

[0602] Flow rate: 20 mL / min;

[0603] Wavelength: UV 220nm;

[0604] Column temperature: 25℃;

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

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

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

[0608]

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

[0610] Example 13

[0611] The synthesis route is shown below:

[0612]

[0613] 13.1 The synthesis of intermediate A-2-1 follows the synthesis steps of A-2.

[0614] 13.2 The synthesis of intermediate A-4j follows the synthesis steps of A-3.

[0615] 13.3 The synthesis of intermediate A-5j follows the synthesis steps of A-5b.

[0616] 13.4 The synthesis of intermediate A-6j follows the synthesis steps of A-6b.

[0617] 13.5 The synthesis of intermediate A-7j follows the same steps as the synthesis of A-7b.

[0618] 13.6 The synthesis of intermediate A-8j follows the synthesis steps of A-8i.

[0619] 13.7 Synthesis of the target product

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

[0621]

[0622] Intermediates A-7l (1.0 eq), C-5 (2.0 eq), and N,N-diisopropylethylamine (5 e.g.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL) at room temperature. Then, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (2.0 eq) was added at 0 °C, followed by reaction at 40 °C for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound T093 was then prepared by reverse high-pressure reaction. Its structure and general analytical data are shown in Table 1.

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

[0624] Its synthesis follows the synthesis of T093, and its structure and general analytical 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 BX = B-5, and its structure and general analytical data are shown in Table 1.

[0626]

[0627] 2-Fluoro-4-(pentafluorothio)aniline (1.0 eq) was added to dichloromethane (1 mmol: 2 mL), and chloroacetyl chloride (1.05 eq) was added dropwise at 0 °C. The reaction was then carried out at room temperature for 16 hours. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was then slurried with petroleum ether to obtain intermediate B-9.

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

[0629] Example 14

[0630] The synthesis route is shown below:

[0631]

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

[0633] 3-Hydroxy-2-iodopyridine (1.0 eq), benzyl bromide (1.05 eq), and potassium carbonate (1.5 eq) were dissolved in DMF (1 mmol: 5 mL) at room temperature. The reaction solution was heated to 50 °C and stirred for two hours. After the reaction was completed by LC-MS monitoring, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, followed by column chromatography purification to obtain product C-12-1.

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

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

[0636] 14.3 Synthesis of intermediate C-12

[0637] Intermediate C-12-2 (1.0 eq) was dissolved in acetonitrile (1 mmol: 4 mL) and water (1 mmol: 0.5 mL), cooled to 0 °C, and acetic acid (6.0 eq) and 1,3-dichloro-5,5-dimethylhydantoin (1.0 eq) were added. The mixture was then allowed to rise to room temperature for 5 hours. After the reaction was completed by LC-MS monitoring, the pH of the reaction solution was adjusted to 7 with saturated sodium bicarbonate, extracted three times with ethyl acetate, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain intermediate C-12.

[0638] 14.4 Synthesis of intermediate P-12

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

[0640] Intermediate A-7 (1.0 eq) and triethylamine (5 e.q.) were dissolved in dichloromethane (1 mmol: 10 mL). The reaction solution was then cooled to 0 °C, and intermediate C-3 (2.5 eq) was added. The mixture was then heated to room temperature and reacted for 2 hours. After the reaction was completed as monitored by LC-MS, the reaction solution was diluted with water, extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Finally, it was purified by column chromatography to obtain pure intermediate P-12.

[0641] 14.5 Synthesis of the target product T092

[0642] Intermediate P-12 was dissolved in trifluoroacetic acid (1 mmol: 5 mL), and the reaction solution was heated to 80 °C and reacted overnight. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed twice with water, and washed once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Then, compound T092 was prepared by reverse high pressure reaction. Its structure and general analytical 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 steps of Example 1.

[0648] Weigh out 1.0 eq of A-2 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 eq) in batches. React in an ice bath for two hours. Then, replace the air in the reaction flask with a nitrogen atmosphere and add SEMCl (2.0 eq) dropwise at 0°C. Slowly heat the reaction solution to room temperature and stir overnight. After the reaction is completed as monitored by LC-MS, dilute the reaction solution with water, extract three times with ethyl acetate, combine the organic phases, wash once with saturated brine, dry under reduced pressure with anhydrous sodium sulfate, and then purify by column chromatography to obtain pure intermediate A-3k.

[0649] 15.2 Synthesis of intermediate A-4k

[0650]

[0651] Weigh 1.0 eq of A-3k at room temperature and dissolve it in anhydrous THF. After replacing the air in the reaction flask with a nitrogen atmosphere, cool to -78°C and add 1.5 eq of NaHMDS. Stir at -78°C for two hours, then add 1.5 eq of allyl iodine. Slowly raise the reaction solution to room temperature and stir overnight. After the reaction is completed by LC-MS monitoring, quench the reaction with ammonium chloride aqueous solution and extract three times with ethyl acetate. Combine the organic phases and wash once with saturated ammonium chloride aqueous solution. Dry the mixture with anhydrous sodium sulfate, concentrate under reduced pressure, and then purify by column chromatography to obtain pure A-4k.

[0652] 15.3 Synthesis of intermediate A-5k

[0653]

[0654] A-4k (1.0 eq) and m-CPBA (2.5 eq) were weighed and dissolved in DCM (1 mmol: 10 mL) at room temperature and reacted overnight at room temperature. After the reaction was completed as monitored by LC-MS, the mixture was diluted with water, extracted twice with dichloromethane, and the combined organic phases were washed once with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then purified by column chromatography to obtain pure intermediate A-5k.

[0655] 15.4 Synthesis of intermediate A-6k

[0656]

[0657] Weigh out A-5k (1.0 eq) and DIEA (3.0 eq) 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 the reaction is completed as monitored by LC-MS, dilute the reaction solution with water, extract twice with ethyl acetate, combine the organic phases, wash once with saturated brine, dry under reduced pressure with anhydrous sodium sulfate, and then purify by column chromatography to obtain intermediate A-6k.

[0658] Synthesis of intermediate A-7k (15.5)

[0659]

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

[0661] Synthesis of intermediate A-8k (15.5)

[0662]

[0663] Intermediate A-7k (1.0 eq), 2-fluoro-4-(trifluoromethyl)aniline (1.2 eq), 50% T3P in EA (4.5 eq), and triethylamine (15 e.q.) were weighed and dissolved in ethyl acetate (1 mmol, 10 mL). The reaction mixture was then heated to 50 °C and stirred for one hour. After the reaction was completed by LC-MS monitoring, the reaction mixture was diluted with water, extracted twice with ethyl acetate, and the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain intermediate A-8k.

[0664] 15.6 Synthesis of intermediate A-9k

[0665]

[0666] Intermediate A-8k (1.0 eq), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.2 eq), Pd(dppf)Cl2 (0.05 eq), and potassium phosphate (2.5 eq) were added to 1,4-dioxane and water (2.5:1, 1 mmol:5 mL). The mixture was purged with nitrogen three times, and then heated to 80 °C for 4 hours. After the reaction was completed by LC-MS monitoring, the reaction solution was diluted with ethyl acetate, washed with brine, and the organic phase was collected, dried over anhydrous sodium sulfate, and evaporated to dryness. The resulting solution was then subjected to column chromatography to obtain intermediate A-9k.

[0667] 15.7 Synthesis of intermediate A-10k

[0668]

[0669] Intermediate A-9k (1.0 eq) was dissolved in N,N-dimethylformamide (1 mmol: 10 mL) at room temperature, followed by the addition of N-bromosuccinimide (1.5 eq) in portions, and the reaction was carried out for 4 hours. After the reaction was completed as monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed once with saturated sodium bicarbonate, twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then subjected to column chromatography to obtain intermediate A-10k.

[0670] 15.8 Synthesis of intermediate A-11k

[0671]

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

[0673] 15.9 Synthesis of intermediate A-12k

[0674]

[0675] Intermediate A-11k (1.0 eq) 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 the reaction was completed, the solution was evaporated to dryness by LC-MS. The concentrate was diluted with ethyl acetate, washed once with water in a saturated sodium bicarbonate solution, and once with saturated brine. The organic phase was then evaporated to dryness to obtain product A-12k.

[0676] Synthesis of intermediate P-13 (15.10)

[0677]

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

[0679] 15.11 Target products T107, T108, T109 and T110.

[0680]

[0681] Intermediate A-11k (1.0 eq) was dissolved in trifluoroacetic acid at room temperature, and the reaction solution was heated to 60 °C and reacted for 12 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed twice with water, and washed once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After obtaining the pure product by column chromatography, it was further chirally resolved by SFC. The target products T107, T108, T109, and T110 were obtained in the order of peak elution. Their structures and general analytical data are shown in Table 1.

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

[0683] First Prep-HPLC conditions:

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

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

[0686] Flow rate: 20 mL / min;

[0687] Wavelength: UV 220nm;

[0688] Column temperature: 25℃;

[0689] Chromatograph: Prep-HPLC-Gilson.

[0690] Second Prep-HPLC conditions:

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

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

[0693] Flow rate: 20 mL / min;

[0694] Wavelength: UV 220nm;

[0695] Column temperature: 25℃;

[0696] Chromatograph: Prep-HPLC-Gilson.

[0697] Example 16

[0698] The synthesis route is shown below:

[0699]

[0700] 16.1 Synthesis of Intermediate D-1

[0701]

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

[0703] The intermediate thiophene-2,3-dicarboxylic acid (1.0 eq) was dissolved in tetrahydrofuran (1 mmol: 2 mL) at 0 °C, and a 1 mol / L solution of lithium aluminum hydride in tetrahydrofuran (4.0 eq) was slowly added dropwise. The reaction mixture was then heated to 70 °C and reacted for 16 hours. After the reaction was completed by LCMS monitoring, the reaction mixture was cooled to 0 °C, quenched with water and 10% sodium hydroxide solution, dried overnight with anhydrous sodium sulfate, and the concentrated pure intermediate D-1-1 was obtained by filtration.

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

[0705] Intermediate D-1-1 (1.0 eq) was added to tetrahydrofuran (1 mmol: 2 mL), and N-bromosuccinimide (1.05 eq) was added in portions at 0 °C, followed by reaction at room temperature for 4 hours. After the reaction was completed by TLC monitoring, the reaction solution was diluted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate solution and saturated brine. The organic phase was concentrated under reduced pressure at low temperature to obtain intermediate D-1-2.

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

[0707] Intermediate D-1-2 (1.0 eq) was added to dimethyl carbonate (1 mmol: 1 mL), followed by the addition of sodium methoxide (1.5 eq) in portions. The reaction mixture was then reacted at 120 °C for 4 hours. After the reaction was completed as monitored by LCMS, the reaction solution was cooled to room temperature, diluted with ethyl acetate and water, filtered, and the resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was then subjected to column chromatography to obtain intermediate D-1-3.

[0708] 16.1.4 Synthesis of Intermediate D-1

[0709] Intermediate D-1-3 (1.0 eq) was added to tetrahydrofuran (1 mmol: 2 mL), and a solution of n-butyllithium in n-hexane (1.5 eq) was added dropwise at -78 °C. After reacting at -78 °C for half an hour, isopropanol pinacol borate (1.2 eq) was added dropwise, and the reaction was carried out at -78 °C for two hours. After the reaction was monitored by LCMS, the reaction solution was cooled and quenched with saturated ammonium chloride. The solution was extracted twice with ethyl acetate, and the resulting organic phase was washed with saturated brine, dried under reduced pressure with anhydrous sodium sulfate, and concentrated. Then, it was subjected to column chromatography to obtain intermediate D-1.

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

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

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

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

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

[0715] 16.6 Synthesis of the target product

[0716] 16.6.1 When BX = B-5, the synthesis steps of the target product T117 are based on the synthesis of T019, and its structure and general analytical data are shown in Table 1.

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

[0718] 16.6.3 When BX = B-1, the synthesis of the target product T-119 is based on the synthesis of T019. Its structure and general analytical data are shown in Table 1.

[0719] By replacing intermediate D-1 in synthesis example 16 with 4-dimethylaminopiperidine (CAS No.: 50533-97-6), and following the same steps as in synthesis examples 16.2 to 16.6, when BX = B-7, the target product T120 was obtained according to the synthesis of T019, and its structure and general analytical data are shown in Table 1.

[0720] By replacing intermediate D-1 in synthesis example 16 with tetrahydropyrrole (CAS No.: 123-75-1), and following the same steps as in synthesis examples 16.2 to 16.6, when BX = B-7, the target product T122 was obtained according to the synthesis of T019, and its structure and general analytical data are shown in Table 1.

[0721] By replacing intermediate D-1 in Synthesis Example 16 with N-BOC-piperazine (CAS No.: 57260-71-6), and following the same steps as in Synthesis Examples 16.2 to 16.5, when BX = B-7, the corresponding intermediate A-6m was obtained.

[0722]

[0723] Intermediate A-6m (1.0 eq) was dissolved in dichloromethane (1 mmol: 5 mL) at room temperature, followed by the addition of trifluoroacetic acid (1 mmol: 1 mL) at 0 °C, and then the reaction was allowed to proceed to room temperature for 2 hours. After the reaction was completed as monitored by LC-MS, the reaction solution was concentrated to near dryness under reduced pressure, diluted with dichloromethane, and the pH of the aqueous phase was adjusted to 8-9 with saturated sodium bicarbonate. The solution was extracted twice with dichloromethane, and the organic phase was washed with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain intermediate A-7m.

[0724] Intermediate A-7m (1.0 eq) was dissolved in tetrahydrofuran (1 mmol: 5 mL) at 0 °C. Di-tert-butyl dicarbonate (1.0 eq) and sodium bicarbonate (1.0 eq) were added. The reaction was allowed to slowly heat to room temperature and stirred for 1.5 hours. The reaction solution was then concentrated. The resulting organic phase was dried under reduced pressure with anhydrous sodium sulfate and then separated by column chromatography to obtain compound A-8m.

[0725] Intermediates A-8m (1.0 eq), C-7 (2.0 eq), and N,N-diisopropylethylamine (5 e.g.) were dissolved in N,N-dimethylformamide (1 mmol: 5 mL) at room temperature. Then, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (2.0 eq) was added at 0 °C, followed by reaction at 40 °C for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was diluted with ethyl acetate, washed twice with water, and once with saturated brine. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, followed by column chromatography to obtain compound A-9m.

[0726] Intermediate A-9m (1.0 eq) was dissolved in dichloromethane (1 mmol: 5 mL) at room temperature, followed by the addition of trifluoroacetic acid (1 mmol: 1 mL) at 0 °C, and then the reaction was brought to room temperature for 2 hours. After the reaction was completed as monitored by LC-MS, the reaction solution was concentrated to near dryness under reduced pressure, diluted with dichloromethane, and the pH of the aqueous phase was adjusted to 8-9 with saturated sodium bicarbonate. The aqueous phase was extracted twice with dichloromethane, washed with saturated brine, and the resulting organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and then prepared by reverse high pressure to obtain the target product T123. Its structure and general analytical data are shown in Table 1.

[0727] Table 1. Compounds and general analytical data of the examples.

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

[0764] 1.1 Cell Seeding

[0765] Human colon cancer SW48 cells (ZQ0793) were cultured in DMEM (C3113-0500) medium containing a mixture of 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin (C3421-0100) at 37°C and 5% CO2. The medium in the T25 flask was aspirated, and the cells were rinsed twice with 1 mL of PBS solution. Then, 1 mL of trypsin (C3530-0500) digestion solution was added, and the cells were incubated at 37°C for 2 min to digest the cells. Once the cell edges became rounded, 1 mL of medium containing 10% FBS was added to stop cell digestion, and the cells were pipetted to form a cell suspension. Cell counts were performed, and the cell density was then diluted to 5 × 10⁶ cells using complete culture medium. 4cells / mL. Add 100 μL of cell suspension to each well of a white transparent 96-well plate (Coring, CLS3903) (add PBS solution to the edge of the well), and incubate the cell plate overnight in an incubator at 37°C and 5% CO2.

[0766] 1.2 Compound Preparation

[0767] Dilute the compound stock solution (100mM DMSO stock solution) with DMSO to a secondary stock solution of 1 or 10mM. Take 1μL of the secondary stock solution into 1mL of DMEM complete culture medium, place it on a shaker to dissolve, and prepare the maximum dosing concentration of 1 or 10μM. Prepare 8 to 10 dosing concentrations according to a 3-fold dilution ratio, mix thoroughly, and add 0.1% DMSO solvent to the control group.

[0768] 1.3 Drug treatment

[0769] After the cells adhered, the culture medium was carefully aspirated, and 100 μL of DMEM complete culture medium containing different concentrations of drug molecules was added to each well of a 96-well plate, with three replicates for each concentration. The cell plates were then incubated at 37°C in a 5% CO2 incubator for 4 days.

[0770] 1.4 Bioanalytical Methods

[0771] After incubation for 4 days, add 50 μL to each well. The reagent (Promega, G7572) was used for testing. After shaking and incubation at room temperature for 10 min, the chemiluminescence value (RLU) was detected using an ELISA reader. Cell viability at different drug concentrations was calculated using the following formula, and the IC50 was fitted using Prism.

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

[0773] As: Experimental RLU (containing cells, culture medium, and drug molecules)

[0774] Ac: Control group RLU (containing cells, culture medium, and DMSO solvent)

[0775] Ab: Zeroing well RLU (containing culture medium only)

[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 inhibitory effect of the test substance on WRN helicase activity

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

[0781] The protein used was WRN(500-1229) (Sino Biological, 17475-HNCB), and the expression host was baculovirus-insect cells. The assay was performed in 384-well black ELISA plates (Loctite, M38-3111). The fluorescent DNA fork substrate double-stranded sequences were fork-F (TAMRA-5'-GCACTGGCCGTCGTTTTACGGTCGTGACT-3') and fork-R (5'-TTTTTTCCAAGTAAAACGACGGCCAGTGC-3'-BHQ2). The fluorescent DNA substrate fork was obtained by heating to 96°C followed by gradient cooling (annealing buffer: 25mM Tris, 2mM MgCl2, 5mM NaCl, pH 8.0). The reaction system consisted of 50 μL of buffer solution containing 25 mM Tris, 2 mM MgCl2, 5 mM NaCl, 1 mM DTT, 2.5 μg / mL calf thymus DNA, and pH 8.0.

[0782] The IC50 of the test compound inhibiting the helicase activity of WRN protein was tested. The reaction system was prepared in two parts, with two replicates for each group. In the first part, WRN protein and the test compound were mixed and incubated. Three-fold serially diluted DMSO compound solutions were prepared. 44 μL of WRN protein with a final concentration of 50 nM and 1 μL of different concentrations of the compound (final concentration 1 μM, three-fold dilution) were added to a 384 plate, vortexed, and incubated for 1 h. In the second part, 5 μL of ATP and fluorescent DNA substrate were added, with a final concentration of 2 mM for ATP and 200 nM for the fluorescent DNA substrate. After the small molecule and protein incubation was completed, the mixture was added to the reaction system and reacted for 1 h. The RFU value was detected using a microplate reader with an excitation wavelength of 544 nm and an emission wavelength of 590 nm. In addition, an experimental group containing only protein and the corresponding DMSO solvent was set as a high control, and a group containing only buffer without protein was set as a blank control (low control). The inhibition rate of the compound on helicase activity was calculated using the formula Inhibition = (high control - sample) / (high control - low control), and the IC50 value was obtained by fitting the four parameters of GraphPad Prism.

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

[0784] The protein used was WRN(500-1229) (Sino Biological, 17475-HNCB), and the assay was performed in 384-well white microplates (LABSELECT, 31432). The DNA fork substrate double-stranded sequences were fork-F (5'-GCACTGGCCGTCGTTTTACGGTCGTGACT-3') and fork-R (5'-TTTTTTCCAAGTAAAACGACGGCCAGTGC-3'). The assay buffer consisted of 25 mM Tris, 2 mM MgCl2, 5 mM NaCl, 1 mM DTT, 2.5 μg / mL calf thymus DNA, pH 8.0.

[0785] Compound preparation: The compound stock solution (10 mM DMSO stock solution) was diluted to a secondary stock solution of 500 μM using DMSO, and then tertiary diluted with DMSO (6 + 12 μL) to prepare 10 gradient drug molecules. Then, the solutions were uniformly diluted with Assay Buffer (1 μL secondary stock solution + 11.5 μL Assay Buffer) to prepare compound solutions with a maximum concentration of 40 μM and tertiary dilutions containing 10 gradients (dilution and preparation were performed using a 96-well skirtless PCR plate).

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

[0787] ADP-Glo™ reaction system (5+5+10μL): Immediately after the enzyme activity system reaction is completed and dispensed, add 5μL of ATP-consuming reagent and react for 60 min. After the Regeant reaction is complete, add 10μL of kinase detection reagent and react for 60 min. Detect the chemiluminescence value (RLU - Relative Luminescence Unit) using a microplate reader. Data analysis and IC50 fitting methods are the same as those described for the helicase activity experiment.

[0788] 3 Experimental Results

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

[0790] Table 2. Biochemistry and cell activity 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 curves for compound T074 inhibiting WRN helicase activity, inhibiting ATPase activity, and inhibiting tumor cell (SW48) growth are shown below. Figs. 1-3 As shown.

[0797] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

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

[0799] Listing the steps of the method in a certain order in this invention does not constitute any restriction on the order of the method steps.

Claims

1. A compound or a pharmaceutically acceptable salt or stereoisomer thereof, said compound having the following structure: （Ⅶ） in, A2 is -C(O)N(R8)- or -S(O)2N(R8)-, where R8 is selected from: H, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C6 cycloalkyl); A3 is selected from: -C(O)-, -S(O)-, -S(O)2-, ; A4 is selected from: 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-; 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 groups is optionally substituted with a group selected from the following groups: halogen, hydroxyl, C1-C3 alkoxy; R6 and R7 are independently selected from: H, 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); or, R3 and R7, along with the atoms bonded to them, form a 4-8 membered heterocycle, which is optionally substituted by one or more groups selected from the following: H, halogen, cyano, hydroxyl, mercapto, amino, -(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) The unsubstituted or C1-C6 alkyl group, wherein the H in the unsubstituted or C1-C6 alkyl group is optionally substituted with a group selected from: halogen, cyano, hydroxy, mercapto, amino, C1-C3 alkyl, C1-C3 alkoxy, wherein the H in the C0-C6 alkylene, C0-C6 alkyl, C3-C6 cycloalkyl, or phenyl group is optionally substituted with a group selected from: halogen, cyano, hydroxy, mercapto, amino, C1-C3 alkyl, C1-C3 alkoxy; The B ring is a 4-10 membered carbon ring or a heterocyclic ring; R 11 One or more independent substituents on the B ring, selected from: H, unsubstituted, or C1-C rings where H is optionally substituted by one or more R0 groups. 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 heterocyclic), halogen, cyano, nitro, azide, C1-C 10 Halogenated alkoxy groups, -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, C2-C 10 alkenyl, C2-C 10 alkynyl group, C 0-10 Alkyl, C3-C 10 cycloalkyl, C6-C 10 The H in the aryl and 4-10 membered heterocyclic groups is optionally replaced by one or more R0 groups; R 21 It is one or more independent substituents on the benzene ring, 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, and C3-C6 cycloalkyl is optionally substituted by a group selected from the following groups: halogen, hydroxyl, and C1-C3 alkoxy. The G ring is pyridinyl, pyrimidinyl, or pyridazinyl; R 41 One or more independent substituents on the G ring, selected from: H, unsubstituted, or C1-C rings where H is optionally substituted by one or more R0 groups. 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 heterocyclic), halogen, cyano, nitro, azide, C1-C 10 Halogenated alkoxy groups, -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, C2-C 10 alkenyl, C2-C 10 alkynyl group, C 0-10 Alkyl, C3-C 10 cycloalkyl, C6-C 10 The H in the aryl and 4-10 membered heterocyclic groups is optionally replaced by one or more R0 groups; R 51 Selected from: H, halogen, hydroxyl, mercapto, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 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); R 52 Selected from: H, halogen, hydroxyl, mercapto, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 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); R0 is selected from: =O, halogen, cyano, -OR', -C(O)R', -C(O)OR', -C(O)NR'R'', -NR'R''; Each R' and R'' is independently selected from: H, C1-C 10 alkyl.

2. The compound according to claim 1, characterized in that, Some are selected from the following structure: 。 3. The compound according to claim 1, characterized in that, R6 and R7 are independently selected from: H, C1-C3 alkyl groups.

4. The compound according to claim 1, characterized in that, R8 is H.

5. The compound according to claim 1, characterized in that, A4 is a single bond.

6. The compound according to claim 1, characterized in that, Some are selected from the following structure: Among them, R 12 Selected from: H, unsubstituted, or C1-C where H is optionally substituted by one or more R0s. 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), C1-C 10 Halogenated alkoxy groups, -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 alkyl), -COO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CO(C) 0-10 Alkyl); wherein, C0-C6 alkylene, C2-C 10 alkenyl, C2-C 10 alkynyl group, C 0-10 Alkyl, C3-C 10 cycloalkyl, C6-C 10 The H in the aryl or 4-10 membered heterocyclic group is optionally replaced 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)-(C 0-4 Alkyl), -(C1-C4 alkylene)-C(O)O-(C 0-4 Alkyl), -CO(C) 1-4 alkyl).

8. The compound according to claim 6, characterized in that, R 12 For H, .

9. The compound according to claim 6, characterized in that, Each R 11 Independently selected from: H, halogen, 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 Halogenated alkyl), -N(C) 1-4 Alkyl)(C 1-4 (halogenated alkyl), -(C1-C4 alkylene)-C(O)-(C 0-4 Alkyl), -(C1-C4 alkylene)-C(O)O-(C 0-4 Alkyl), -CO(C) 1-4 alkyl).

10. The compound according to claim 6, characterized in that, R 11 H, F, methyl, ethyl, .

11. The compound according to claim 6, characterized in that, Some are selected from the following structure: 。 12. The compound according to claim 1, characterized in that, Part of .

13. The compound according to claim 1, characterized in that, Some have the following structure: ,in, X7 is C(R) 23 ); R 22 To R 26 Independently selected from: H, halogen, cyano, -SF5, hydroxyl, mercapto, -C(O)H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -O(C 1-6 alkyl), -S(C 1-6 Alkyl), -CO(C) 1-6 Alkyl), wherein the H in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C0-C6 alkylene, and C3-C6 cycloalkyl is optionally substituted by a group selected from the following groups: halogen, hydroxyl, and C1-C3 alkoxy.

14. The compound according to claim 13, characterized in that, R 22 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 or C3-C6 cycloalkyl is optionally substituted by a group selected from the following groups: halogen, hydroxyl, C1-C3 alkoxy.

15. The compound according to claim 13, characterized in that, R 23 Selected from: H, halogens.

16. The compound according to claim 13, characterized in that, R 24 Selected from: H, halogen, cyano, -SF5, hydroxyl, -C(O)H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -CO(C 1-6 Alkyl), -O(C) 1-6 Alkyl), wherein the H in C1-C6 alkyl or C3-C6 cycloalkyl is optionally substituted by a group selected from the following groups: halogen, hydroxyl, C1-C3 alkoxy.

17. The compound of claim 13, characterized in that, R 25 Selected from: H, halogens, C1-C6 alkyl groups, and C1-C6 haloalkyl groups.

18. The compound of claim 13, characterized in that, R 26 Selected from: H, halogen, cyano, hydroxyl, C1-C6 alkyl, -O(C 1-6 alkyl).

19. The compound according to claim 1, characterized in that, Some are selected from the following structure: 。 20. The compound according to claim 1, characterized in that, Some are selected from the following structure: .

21. The compound according to claim 1, characterized in that, A3 is -C(O)-.

22. The compound according to claim 1, characterized in that, Some are selected from the following structure: Among them, R 43 To R 49 With R 41 Definition; R 42 Selected from: H, -OH.

23. The compound according to claim 22, characterized in that, R 42 For H.

24. The compound according to claim 22, characterized in that, R 42 It is -OH.

25. The compound according to claim 22, characterized in that, R 43 Selected from: H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy.

26. The compound of claim 22, characterized in that, R 43 Selected from: H, F, Cl, Br, methyl, ethyl, -CF3, -CHF2, -CH2F, methoxy, -OCF3, -OCHF2, -OCH2F.

27. The compound of claim 22, characterized in that, R 44 Selected from: H, halogens, C1-C4 alkyl groups, and C1-C4 haloalkyl groups.

28. The compound of claim 22, characterized in that, R 44 Selected from: H, F, Cl, Br, methyl, ethyl, -CF3, -CHF2, -CH2F.

29. The compound according to claim 22, characterized in that, R 45 Selected from: H, halogens, C1-C4 alkyl groups, and C1-C4 haloalkyl groups.

30. The compound according to claim 22, characterized in that, R 45 Selected from: H, F, Cl, Br, methyl, ethyl, -CF3, -CHF2, -CH2F.

31. The compound according to claim 22, characterized in that, R 46 Selected from: H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, -S(C1-C4 alkyl), -NH2, -N(H)(C 1-6 alkyl), -N(C) 1-6 Alkyl)(C 1-6 alkyl).

32. The compound according to claim 22, characterized in that, R 46 Selected from: H, F, Cl, Br, methyl, ethyl, -CF3, -CHF2, -CH2F, -S-CH3.

33. The compound according to claim 22, characterized in that, R 47 Selected from: H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C4 cycloalkyl.

34. The compound according to claim 22, characterized in that, R 47 Selected from: H, F, Cl, Br, methyl, ethyl, -CF3, -CHF2, -CH2F, methoxy, -OCF3, -OCHF2, -OCH2F, cyclopropyl.

35. The compound of claim 22, characterized in that, R 48 and R 49 Independently selected from: H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy.

36. The compound of claim 22, characterized in that, R 48 and R 49 Independently selected from: H, F, Cl, Br, methyl, ethyl, -CF3, -CHF2, -CH2F, methoxy, -OCF3, -OCHF2, -OCH2F.

37. The compound according to claim 1, characterized in that, Some are selected from the following structure: 。 38. The compound according to claim 1, characterized in that, Some are selected from the following structure: .

39. The compound according to claim 1, characterized in that, R3 is selected from: H, halogen, hydroxyl, mercapto, amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl-substituted C1-C4 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).

40. The compound according to claim 1, characterized in that, R3 is selected from: H, .

41. The compound according to any one of claims 1-38, characterized in that, The compound has the following structure: （Ⅷ） Wherein, R9 is one or more independent substituents on the ring, each R9 being independently selected from: H, halogen, cyano, hydroxyl, mercapto, amino, C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted by one or more groups selected from: halogen, cyano, hydroxyl, amino, C1-C3 alkoxy.

42. The compound according to claim 1, characterized in that, The stereoisomers of the compound have the following structures: 。 43. The compound according to claim 41, characterized in that, The stereoisomers of the compound have the following structures: 。 44. A compound or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that, The compound is selected from the following structures: 。 45. An intermediate of the compound according to any one of claims 1-43, having the following structure: in, R L It is protected by H or an amino group.

46. ​​An intermediate, characterized in that, The intermediate is selected from the following structures: 。 47. An intermediate of the compound according to any one of claims 1-43, having the following structure: ， in, R L R is an H or amino protecting group. L ' is the leaving group, R L '' represents an H or amino protecting group.

48. A method for preparing the compound of claim 1, comprising the compound of formula IM-1 and... The reaction connection step, wherein, R L1 As a leaving group, R4 has the following structure: The compound represented by formula IM-1 is as described in claim 45 or 46.

49. A pharmaceutical composition comprising the compound of any one of claims 1-44 or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

50. Use of the compound of any one of claims 1-44 or a pharmaceutically acceptable salt or stereoisomer thereof in the preparation of a medicament for the prevention and / or prevention of WRN-mediated diseases; The disease is either a tumor or a non-cancerous hyperplasia disorder.

51. The application as described in claim 50, characterized in that, The tumors mentioned are selected from: acute myeloid leukemia, childhood adrenocortical carcinoma, AIDS-related cancers, bile duct cancer, bladder cancer, bone cancer, breast cancer, bronchial tumors, carcinoid tumors, chordomas, cardiac tumors, chronic lymphocytic leukemia, chronic myeloid leukemia, colorectal cancer, CNS cancers, endometrial cancer, esophageal cancer, nasal glioma, eye cancer, gallbladder cancer, gastric cancer, hairy cell leukemia, head and neck cancer, pancreatic neuroendocrine tumors, kidney cancer, liver cancer, metastatic and occult primary squamous neck cancer, multiple endocrine tumor syndrome, plasma cell tumors, mycosis fungoides, lip and oral cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, prostate cancer, testicular cancer, pharyngeal cancer, thymoma, thyroid cancer, trophoblastoma, urethral cancer, vaginal cancer, and vulvar cancer.

52. The application as described in claim 50, characterized in that, The tumors are selected from: colorectal cancer, gastric cancer, ovarian cancer, brain tumor, lung cancer, and endometrial tumors.

53. The application as described in claim 50, characterized in that, The condition is benign skin hyperplasia, restenosis, or benign prostatic hyperplasia.

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