Protac drugs targeting ptpn proteins and uses thereof

Abstract

The application discloses a compound, which is a compound shown in formula (I), or a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, E is used for targeting E3 ubiquitin ligase complex. The PTPN-PROTAC degrading agent developed by the application has a significant selective degradation on PTPN2, and has a very low degradation rate or almost no degradation on PTPN1, and has a better safety prospect. E-L-A (I).

Description

Technical Field

[0001] This application belongs to the field of biopharmaceuticals, specifically relating to a PROTAC drug targeting PTPN protein and its application, and more specifically to a compound targeting PTPN protein, a PTPN protein degrader, a pharmaceutical composition, and their uses. Background Technology

[0002] PTPN proteins are a class of non-receptor protein tyrosine phosphatases that play an important role in cell signaling, such as regulating cell growth, development, differentiation, survival, and migration. Some members of the PTPN family, such as PTPN1, PTPN2, PTPN12, and PTPN22, have potential roles in cancer immunotherapy, and their expression in esophageal cancer, gastric cancer, and colorectal cancer is associated with the development of these diseases.

[0003] PTPN2 (also known as TCPTP or T-cell protein tyrosine phosphatase) plays a synergistic anti-inflammatory role in various inflammatory cells and regulates the development and differentiation of immune cells. Furthermore, PTPN2 expression levels are closely related to the occurrence and prognosis of certain cancers; for example, in pancreatic adenocarcinoma, high PTPN2 expression is associated with a poor prognosis and may promote cancer progression by activating the JAK-STAT signaling pathway.

[0004] PTPN1 (protein tyrosine phosphatase 1, also known as T-cell protein tyrosine phosphatase) plays a crucial role in regulating cellular signaling, such as in the activation, proliferation, and differentiation of immune cells. PTPN1 participates in regulating intracellular signaling, particularly in T-cell development and function, by dephosphorylating various substrate proteins. Studies have found that in addition to its association with tumor immunity, PTPN1 also negatively regulates the insulin signaling pathway and is closely related to obesity and type 2 diabetes. Therefore, developing a highly targeted PTPN2 protein degrader is of great importance. Summary of the Invention

[0005] This application aims to at least partially address one of the technical problems existing in the prior art. To this end, this application provides a PROTAC drug targeting the PTPN protein and its application.

[0006] This application is based on the following discoveries of the inventors:

[0007] While both PTPN1 and PTPN2 proteins are targets related to tumor immunity, studies have found that PTPN2 is solely associated with tumor immunity, while PTPN1, in addition to its role in tumor immunity, also negatively regulates the insulin signaling pathway and is closely related to obesity and type 2 diabetes. However, current small molecule inhibitors of PTPN generally lack selectivity for both PTPN1 and PTPN2. Therefore, developing a selective inhibitor targeting PTPN2 would offer significant safety advantages.

[0008] Based on this, the PTPN-PROTAC degrader developed in this application exhibits significant selective degradation of PTPN2, while showing very low or almost no degradation of PTPN1, thus demonstrating better safety prospects.

[0009] Therefore, in a first aspect of this application, a compound is proposed. According to embodiments of this application, the compound is a compound of formula (I), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof:

[0010] E——L——A (1);

[0011] E is used to target the E3 ubiquitin ligase complex;

[0012] A has the structure shown in equation (II):

[0013]

[0014] Among them, R1, R2, and R3 are each independently H, -OH, halogen, and -C. 1～6 Alkyl, -C 1～6 Halogenated alkyl, or -C 1～6 Hydroxyalkyl;

[0015] R4 is empty, and can be arbitrarily assigned to one or more R4 values. a The -N(R6)- that is replaced, optionally by one or more R a Replacement -N(R6)-C 1～6 Alkylene-, or optionally with one or more R a Substituted -N(R6)-C(O)-C 1～6 alkylene-;

[0016] R5 and R6 are independently H and -C, respectively. 1～6 Alkyl, -C 1～6 Halogenated alkyl, or -C 1～6 Hydroxyalkyl;

[0017] Ring A is empty, and can be arbitrarily controlled by one or more R. b Substituted 5-10 membered cycloalkyl, or optionally with one or more R bSubstituted 5-10 membered heterocyclic alkyl groups;

[0018] Ring B is empty, and can be arbitrarily assigned to one or more R. c Replaces 5-12 elemental helical rings, optionally with one or more R c Replaces 5-12 ternary heterocyclic rings, optionally with one or more R c Replaces the 5-12 element bridge ring, optionally replaced by one or more R c Replaces the 5-12 elemental hybrid bridge ring, optionally replaced by one or more R c Replaces 5-12 element rings, optionally with one or more R c Replaced 5-12 quinary heterocyclic rings;

[0019] Each R a R b R c Each is independently selected from -OH, halogen, oxo (=O), -C 1～6 Alkyl, -C 1～6 Halogenated alkyl, or -C 1～6 Alkoxy;

[0020] n is 0 or 1;

[0021] L has the structure shown in equation (III):

[0022]

[0023] Where L1 is -N(R7)-, arbitrarily controlled by one or more R d Substituted 4-10 membered heterocyclic alkyl groups, optionally with one or more R d Replacement -C 1～6 alkenyl-(4-10)-membered heterocyclic alkyl, or optionally with one or more R d Replacement -C 1～6 Imylacetyl-(4-10)-membered heterocyclic alkyl, wherein the 4-10-membered heterocyclic alkyl or -C 1～6 The alkenyl-(4-10)-membered heterocyclic alkyl group contains one or more nitrogen atoms;

[0024] L2 is arbitrarily assigned to one or more Rs e Replacement -C 3～15 Alkylene-, optionally with one or more R e Replacement -R8-(OC) 1～6 (alkylene)m-, optionally with one or more R e Replacement -C 1～6 Alkylene-(3-10)-membered cycloalkyl-, optionally with one or more R e Replacement -C 1～6 alkylene-(6-10) aryl-, optionally with one or more Re Replacement -C 1～6 alkylene-(3-10)-membered heterocyclic alkyl-, optionally with one or more R e Replacement -C 1～6 Alkylene-C(O)-, optionally with one or more R e Substituted -C(O)-C 1～10 Alkylene-, or optionally with one or more R e Substituted -(5-10) heteroaryl-;

[0025] L3 is empty, -C(O)-, and can be arbitrarily controlled by one or more Rs. f Replacement -C 1～6 Alkylene-, optionally with one or more R f Replaces 5-12 elemental helical rings, optionally with one or more R f Replacement -C 1～6 alkylene-(3-10)-membered cycloalkyl-C 1～6 Alkylene-, optionally with one or more R f Substituted -(5-10) heteroaryl-C 1～6 Alkylene-, optionally with one or more R f Replacement -C 1～6 alkylene-(6-10)-aryl-C 1～6 Alkylene-, optionally with one or more R f Replacement -C 1～6 alkylene-(3-10)-membered cycloalkyl-C 1～6 Alkylene-, optionally with one or more R f Substituted -C(O)-C 1～6 Alkylene-C(O)-, optionally with one or more R f The -N(R9)-(5-12) elemental spiroring is replaced, or optionally replaced by one or more R elements. f Substituted -(5-10) heteroaryl-C 1～6 Alkylene-(5-12)-membered spirocyclic-;

[0026] R7 and R9 are independently H and -C, respectively. 1～6 Alkyl, -C 1～6 Halogenated alkyl, or -C 1～6 Hydroxyalkyl;

[0027] R8 is arbitrarily assigned to one or more R... g Replace -C 1～6 Alkylene-, optionally with one or more R g Substitution -C(O)-C 1～6 Alkylene-, or optionally with one or more R g Replace -C 1～6alkylene-(6-10) aryl-;

[0028] Each R d R e R f R g Each is independently selected from -OH, halogen, oxo (=O), -C 1～6 Alkyl, or -C 1～6 Halogenated alkyl, -C 1～6 Alkoxy;

[0029] m is 1, 2, 3, 4, 5, or 6;

[0030] * indicates the connection site of E, and ** indicates the connection site of A.

[0031] The compound of this application can effectively inhibit the activity of PTPN2 protein, and can effectively prevent and treat PTPN protein-related diseases.

[0032] According to embodiments of this application, A is used to target PTPN proteins, particularly PTPN2; L is used to connect A and E.

[0033] Furthermore, the compounds of this application exhibit significant selective degradation of PTPN2, while showing very low or almost no degradation of PTPN1, suggesting better safety prospects and the potential to effectively prevent and treat PTPN protein-related diseases, such as cancer.

[0034] According to embodiments of this application, the above-mentioned compound may further include at least one of the following technical features:

[0035] In an optional embodiment of this application, A may also satisfy at least one or more of the following conditions:

[0036] According to embodiments of this application, R1, R2, and R3 are each independently H, -OH, halogen, or -C. 1～3 Alkyl, -C 1～3 Halogenated alkyl, or -C 1～3 Hydroxyalkyl groups.

[0037] According to an embodiment of this application, R1 is -OH.

[0038] According to an embodiment of this application, R2 is a halogen.

[0039] In an optional embodiment of this application, R2 is F.

[0040] According to an embodiment of this application, R3 is H.

[0041] In an optional embodiment of this application, n is 0 when ring B is empty.

[0042] According to embodiments of this application, ring A is optionally bounded by one or more R... a When substituted with 5-10 membered heterocyclic alkyl groups, ring B is empty, R4 is empty (0), and n is 0.

[0043] According to embodiments of this application, ring A is optionally bounded by one or more R... a Substituted 6-8 membered heterocyclic alkyl groups.

[0044] According to an embodiment of this application, ring A is * indicates the R4 connection site.

[0045] According to an embodiment of this application, A has the following structure:

[0046]

[0047] According to an embodiment of this application, when ring A is empty, R4 is arbitrarily selected by one or more R... a Replacement -N(R6)-C 1～6 Alkylene-, or optionally with one or more R a Substituted -N(R6)-C(O)-C 1～6 Alkylene-, with empty ring B and n=0.

[0048] According to embodiments of this application, R4 is optionally controlled by one or more R a Replacement -N(R6)-C 1～6 Alkylene-, or optionally with one or more R a Substituted -N(R6)-C(O)-C 1～6 Alkylene, where R6 is H or -C 1～6 alkyl.

[0049] According to an embodiment of this application, R4 is -N(R6)-C 1～6 Alkylene- or -N(R6)-C(O)-C 1～6 Alkylene, where R6 is H or -C 1～3 alkyl.

[0050] According to an embodiment of this application, R4 is -NH-C 1～3 Alkylene- or -NH-C(O)-C 1～3 Alkylene-.

[0051] According to an embodiment of this application, A has the following structure:

[0052]

[0053] According to an embodiment of this application, when ring B is not empty, R4 is arbitrarily selected by one or more R... aThe -N(R6)- is replaced, and n is 1.

[0054] According to embodiments of this application, R4 is optionally controlled by one or more R a The substitution is -N(R6)-, where R6 is H or -C. 1～6 alkyl.

[0055] According to an embodiment of this application, R4 is -N(R6)-, and R6 is H or -C. 1～6 alkyl.

[0056] According to an embodiment of this application, R4 is -NH-.

[0057] According to embodiments of this application, ring B is optionally controlled by one or more R... c Replaces 5-12 elemental helical rings, or optionally with one or more R c Replaces the 5-12 quinary heterocyclic spiral ring.

[0058] According to embodiments of this application, ring B is optionally controlled by one or more R... c Replaces 6-10 element screw rings, or optionally is replaced by one or more R c Replaces the 6-10 quinary heterocyclic spiral ring.

[0059] According to an embodiment of this application, ring B is a 6-10 element helical ring.

[0060] According to an embodiment of this application, ring B is

[0061] According to embodiments of this application, ring A is optionally bounded by one or more R... b Substituted 5-10 membered cycloalkyl groups.

[0062] According to embodiments of this application, ring A is optionally bounded by one or more R... b Substituted 5-8 membered cycloalkyl groups.

[0063] According to embodiments of this application, ring A is a 5-8 membered cycloalkyl group.

[0064] According to an embodiment of this application, ring A is * indicates the R4 connection site.

[0065] According to embodiments of this application, R5 is H or -C. 1～6 alkyl.

[0066] According to an embodiment of this application, R5 is H.

[0067] In an optional embodiment of this application, ring A is optionally bounded by one or more R... bThe substituted 5-10 membered cycloalkyl group, R4 is optionally replaced by one or more R a The -N(R6)- is replaced, the ring B is empty, and n is 0.

[0068] In an optional embodiment of this application, ring A is optionally bounded by one or more R... b The substituted 5-10 membered cycloalkyl group, R4 is optionally replaced by one or more R a The -N(R6)- ring is replaced by one or more R rings. c Replaces 5-12 elemental helical rings, or optionally with one or more R c Replaced 5-12 quinary heterospirorings, n is 1, R5 is H or -C 1～6 alkyl.

[0069] According to embodiments of this application, each R a R b R c Each is independently selected from halogens, -C 1～6 Alkyl, or -C 1～6 Halogenated alkyl groups.

[0070] According to an embodiment of this application, A has the following structure:

[0071]

[0072] In an optional embodiment of this application, L may also satisfy at least one or more of the following conditions:

[0073] According to an embodiment of this application, L1 is -N(R7)-, optionally controlled by one or more R d Substituted 5-8 membered heterocyclic alkyl groups, optionally with one or more R d Replacement -C 1～3 alkenyl-(5-8)-membered heterocyclic alkyl, or optionally with one or more R d Replacement -C 1～3 Imylacetyl-(4-10)-membered heterocyclic alkyl, wherein the 4-10-membered heterocyclic alkyl or -C 1～6 The alkenyl-(4-10)-membered heterocyclic alkyl group contains one or more N atoms.

[0074] According to embodiments of this application, R7 is H or -C. 1～6 alkyl.

[0075] According to an embodiment of this application, R7 is H.

[0076] According to an embodiment of this application, in L1, the -C 1～3 5-8 membered heterocyclic alkyl groups in alkenyl-(5-8)-membered heterocyclic alkyl groups, -C 1～3The 5-8 membered heterocyclic alkyl group in the ynynyl-(5-8)-membered heterocyclic alkyl group, or the 5-8 membered heterocyclic alkyl group is Among them, q1 and q2 are each independently selected from 1, 2, or 3.

[0077] According to an embodiment of this application, L1 is

[0078] According to embodiments of this application, L2 is optionally controlled by one or more R... e Replacement -C 3～15 Alkylene-, optionally with one or more R e Replacement -C 1～6 alkylene-(6-10)-aryl-, or optionally with one or more R e Replacement -C 1～6 Alkylene-(3-10)-membered heterocyclic alkyl-.

[0079] According to embodiments of this application, L2 is optionally controlled by one or more R... e Replacement -C 3～15 Alkylene-, optionally with one or more R e Replacement -C 1～3 alkylene-(6-10)-aryl-, or optionally with one or more R e Replacement -C 1～3 Alkylene-(3-10)-membered heterocyclic alkyl-.

[0080] According to an embodiment of this application, L2 is -C 3～15 alkylene-, -C 1～6 alkylene-(6-10) aryl- or -C 1～6 Alkylene-(3-10)-membered heterocyclic alkyl-.

[0081] According to embodiments of this application, L3 is empty, -C(O)-, or optionally controlled by one or more R... f Replacement -C 1～6 Alkylene-, optionally with one or more R f Replaces 5-12 elemental helical rings, optionally with one or more R f Replacement -C 1～6 alkylene-(3-10)-membered cycloalkyl-C 1～6 Alkylene-.

[0082] According to embodiments of this application, L3 is empty, -C(O)-, or optionally controlled by one or more R... f Replacement -C 1～3 Alkylene-, optionally with one or more R f Replaces 6-10 element screw rings, optionally with one or more R f Replacement -C1～3 alkylene-(5-8)-membered cycloalkyl-C 1～3 Alkylene-.

[0083] According to embodiments of this application, L3 is empty, -C(O)-, -C 1～6 Alkylene, 5-12 membered spirocyclic, or -C 1～6 alkylene-(3-10)-membered cycloalkyl-C 1～6 Alkylene-.

[0084] According to embodiments of this application, L3 is optionally controlled by one or more R... f The following screw rings can be replaced:

[0085]

[0086] According to embodiments of this application, R7 and R9 are each independently H or -C. 1～6 alkyl.

[0087] In an optional embodiment of this application, L1 is -N(R7)-, and L2 is optionally defined by one or more R... e Replacement -C 7～15 Alkylene-, L3 is empty.

[0088] In an optional embodiment of this application, L1 is -N(R7)-, and L2 is optionally defined by one or more R... e Replacement -C 8～12 Alkylene-, L3 is empty.

[0089] In an optional embodiment of this application, L1 is -N(R7)-, and L2 is optionally defined by one or more R... e Replacement -C 5～10 Alkylene-, L3 is empty.

[0090] In an optional embodiment of this application, L1 is -N(R7)-, and L2 is optionally defined by one or more R... e Replacement -C 5～6 Alkylene-, L3 is empty.

[0091] In an optional embodiment of this application, L1 is optionally controlled by one or more R... d Substituted 5-8 membered heterocyclic alkyl groups, optionally with one or more R d Replacement -C 1～3 alkenyl-(5-8)-membered heterocyclic alkyl, or optionally with one or more R d Replacement -C 1～3 Imyynyl-(4-10)-membered heterocyclic alkyl, wherein the -C 1～3 5-8 membered heterocyclic alkyl groups in alkenyl-(5-8)-membered heterocyclic alkyl groups, -C1～3 The 5-8 membered heterocyclic alkyl group in the ynynyl-(5-8)-membered heterocyclic alkyl group, or the 5-8 membered heterocyclic alkyl group is Where q1 and q2 are each independently selected from 1, 2, or 3; L2 is arbitrarily selected by one or more R... e Replacement -C 1～6 alkylene-(3-10)-membered cycloalkyl-, or optionally with one or more R e Replacement -C 1～6 alkylene-(6-10) aryl-; L3 is optionally coated with one or more R f Replacement -C 1～6 Alkylene-.

[0092] In an optional embodiment of this application, L1 is optionally controlled by one or more R... d Substituted 5-8 membered heterocyclic alkyl groups, or optionally with one or more R d Replacement -C 1～3 Imyynyl-(4-10)-membered heterocyclic alkyl, wherein the -C 1～3 The 5-8 membered heterocyclic alkyl group in the ynynyl-(5-8)-membered heterocyclic alkyl group, or the 5-8 membered heterocyclic alkyl group is Where q1 and q2 are each independently selected from 1, 2, or 3; L2 is arbitrarily selected by one or more R... e Replacement -C 1～6 alkylene-(6-10) aryl-; L3 is optionally coated with one or more R f Replacement -C 1～6 Alkylene-.

[0093] In an optional embodiment of this application, L1 is optionally controlled by one or more R... d Substituted 5-8 membered heterocyclic alkyl groups, wherein the 5-8 membered heterocyclic alkyl group is Where q1 and q2 are each independently selected from 1, 2, or 3; L2 is arbitrarily selected by one or more R... e Replacement -C 3～15 Alkylene-; L3 is empty.

[0094] In an optional embodiment of this application, L1 is optionally controlled by one or more R... d Substituted 5-8 membered heterocyclic alkyl groups, wherein the 5-8 membered heterocyclic alkyl group is Where q1 and q2 are each independently selected from 1, 2, or 3; L2 is arbitrarily selected by one or more R... e Replacement -C 1～6 alkylene-(3-10)-membered heterocyclic alkyl-; L3 is optionally surrounded by one or more R f Replaces 5-12 elemental helical rings, optionally with one or more R f Replacement -C1～6 alkylene-(3-10)-membered cycloalkyl-C 1～6 Alkylene-.

[0095] According to embodiments of this application, each R d R e R f Each is independently selected from halogens, -C 1～6 Alkyl, -C 1～6 Halogenated alkyl, or -C 1～6 Alkyl group.

[0096] According to an embodiment of this application, L has the following structure:

[0097]

[0098]

[0099] In an optional embodiment of this application, -LA may also satisfy at least one or more of the following conditions:

[0100] According to an embodiment of this application, L1 is -N(R7)-, and L2 is optionally controlled by one or more R... e Replacement -C 5～15 Alkylene-, L3 is empty.

[0101] According to embodiments of this application, ring A is optionally bounded by one or more R... b When the substituted 5-10 membered cycloalkyl group is empty of ring B, L1 is -N(R7)-, and L2 is optionally substituted with one or more R groups. e Replacement -C 7～15 Alkylene-, L3 is empty.

[0102] According to embodiments of this application, ring A is optionally bounded by one or more R... b The substituted 5-10 membered cycloalkyl group, wherein ring B is optionally replaced by one or more R c Replaces 5-12 elemental helical rings, or optionally with one or more R c The 5-12 ternary heterocyclic spiroring is replaced, and L2 is optionally replaced by one or more R e Replacement -C 5～10 Alkylene-, L3 is empty.

[0103] According to embodiments of this application, L1 is optionally controlled by one or more R... d Substituted 5-8 membered heterocyclic alkyl groups, L2 is optionally replaced by one or more R e Replacement -C 3～15 Alkylene-, L3 is empty.

[0104] According to embodiments of this application, ring A is optionally bounded by one or more R...b When the substituted 5-10 membered cycloalkyl group is empty and ring B is empty, L1 is optionally replaced by one or more R groups. d Substituted 5-8 membered heterocyclic alkyl groups, L2 is optionally replaced by one or more R e Replacement -C 8～15 Alkylene-, L3 is empty.

[0105] According to embodiments of this application, ring A is optionally bounded by one or more R... b The substituted 5-10 membered cycloalkyl group, wherein ring B is optionally replaced by one or more R c Replaces 5-12 elemental helical rings, or optionally with one or more R c The 5-12 ternary heterocyclic spiroring is replaced, and L1 is optionally replaced by one or more R d Substituted 5-8 membered heterocyclic alkyl groups, L2 is optionally replaced by one or more R e Replacement -C 3～6 Alkylene-, L3 is empty.

[0106] According to the embodiments of this application, L1 is a 5-8 membered heterocyclic alkyl group.

[0107] According to an embodiment of this application, L1 is Among them, q1 and q2 are each independently selected from 1, 2, or 3.

[0108] According to an embodiment of this application, L1 is

[0109] According to embodiments of this application, L1 is optionally controlled by one or more R... d Substituted 5-8 membered heterocyclic alkyl groups, optionally with one or more R d Replacement -C 1～3 alkenyl-(5-8)-membered heterocyclic alkyl, or optionally with one or more R d Replacement -C 1～3 Ethyne-(4-10)-membered heterocyclic alkyl, L2 is optionally surrounded by one or more R e Replacement -C 1～6 alkylene-(6-10) aryl-, L3 is optionally surrounded by one or more R f Replacement -C 1～6 Alkylene-.

[0110] According to embodiments of this application, ring A is optionally bounded by one or more R... b When the substituted 5-10 membered cycloalkyl group is empty of ring B; or

[0111] Ring A is arbitrarily controlled by one or more R b The substituted 5-10 membered cycloalkyl group, wherein ring B is optionally replaced by one or more R cReplaces 5-12 elemental helical rings, or optionally with one or more R c Replaces the 5-12 quinary heterocyclic spiral ring.

[0112] According to embodiments of this application, L1 is optionally controlled by one or more R... d Substituted 5-8 membered heterocyclic alkyl groups, L2 is optionally replaced by one or more R e Replacement -C 1～6 alkylene-(3-10)-membered heterocyclic alkyl-, L3 is optionally surrounded by one or more R f Replaces 5-12 elemental helical rings, or optionally with one or more R f Replacement -C 1～6 alkylene-(3-10)-membered cycloalkyl-C 1～6 Alkylene-.

[0113] According to embodiments of this application, ring A is optionally bounded by one or more R... b When the substituted 5-10 membered cycloalkyl group is empty of ring B; or

[0114] Ring A is arbitrarily controlled by one or more R b The substituted 5-10 membered cycloalkyl group, wherein ring B is optionally replaced by one or more R c Replaces 5-12 elemental helical rings, or optionally with one or more R c Replaces the 5-12 quinary heterocyclic spiral ring.

[0115] According to an embodiment of this application, LA has the following structure:

[0116]

[0117]

[0118]

[0119] According to an embodiment of this application, E has the structure shown in formula (IV):

[0120]

[0121] Among them, R9, R 10 Each is independently selected from H, oxo (=O), -C 1～6 Alkyl, -C 1～6 Halogenated alkyl, or -C 1～6 Hydroxyalkyl; Y1 and Y2 are each independently -CH-, C= or N.

[0122] According to the embodiments of this application, Connect to Y2, where Y2 is -CH- or C=, preferably C=.

[0123] According to the embodiments of this application, Connected to N, both Y1 and Y2 are -CH-.

[0124] According to the embodiments of this application, Connected to Y2, Y1 is -CH- or N, preferably N.

[0125] According to the embodiments of this application, R9, R 10 They are not both H.

[0126] According to embodiments of this application, E has the structure shown in formula (IVa) or (IVb):

[0127]

[0128] According to an embodiment of this application, E has the following structure:

[0129]

[0130] According to embodiments of this application, the compound represented by formula (I) has the following structure:

[0131]

[0132]

[0133]

[0134]

[0135]

[0136] In a second aspect of this application, a PTPN protein inhibitor is proposed. According to embodiments of this application, the PTPN protein inhibitor comprises the compound described in the first aspect.

[0137] In a third aspect of this application, a pharmaceutical composition is provided. According to embodiments of this application, the pharmaceutical composition comprises the compounds described in the first aspect.

[0138] According to embodiments of this application, the pharmaceutical composition may further include pharmaceutically acceptable excipients, carriers, and mediators.

[0139] In a fourth aspect of this application, the application provides for the use of a compound described in the first aspect, a PTPN protein inhibitor described in the second aspect, or a pharmaceutical composition described in the third aspect, the use comprising:

[0140] Inhibit PTPN protein, and / or

[0141] Immunotherapy, and / or

[0142] Prevention and / or treatment of PTPN protein-related diseases, and / or

[0143] Preparation of immunotherapy drugs, and / or

[0144] To prepare drugs for the prevention and / or treatment of PTPN protein-related diseases;

[0145] In one alternative embodiment of this application, the treatment of PTPN protein-related diseases is selected from cancer.

[0146] In one alternative embodiment of this application, the cancer includes pancreatic cancer, breast cancer, multiple myeloma, melanoma, or secretory cell carcinoma.

[0147] In a fifth aspect of this application, a method of immunotherapy is provided. According to embodiments of this application, the method includes administering to a subject a pharmaceutically acceptable dose of the compound described in the first aspect, the PTPN protein inhibitor described in the second aspect, or the pharmaceutical composition described in the third aspect.

[0148] In a sixth aspect of this application, a method for preventing and / or treating PTPN protein-related diseases is provided. According to embodiments of this application, the method comprises administering to a subject a pharmaceutically acceptable dose of the compound described in the first aspect, the PTPN protein inhibitor described in the second aspect, or the pharmaceutical composition described in the third aspect.

[0149] In one alternative embodiment of this application, the pharmaceutically acceptable dose may be selected from the effective dose (or effective amount).

[0150] The effective amount of the compound described in this application may vary depending on the administration method and the severity of the disease to be treated. A preferred effective amount can be determined by those skilled in the art based on various factors (e.g., through clinical trials). These factors include, but are not limited to: pharmacokinetic parameters of the active ingredient, such as bioavailability, metabolism, and half-life; the severity of the disease to be treated, the patient's weight, the patient's immune status, and the route of administration. For example, due to the urgency of the treatment condition, several separate doses may be administered daily, or the dose may be reduced proportionally.

[0151] The compounds or pharmaceutical compositions of this application may be incorporated into suitable pharmaceuticals, which may be prepared in various forms, such as liquid, semi-solid, and solid dosage forms, including but not limited to solid dosage forms, semi-solid dosage forms, liquid dosage forms, and gaseous dosage forms. Various routes of administration of the compounds, pharmaceutical compositions, or pharmaceuticals of this application are contemplated, including peritoneal, intravenous, intramuscular, subcutaneous, dermal, oral, topical, nasal, pulmonary, rectal, and topical administration; however, this application is not limited to these exemplified routes of administration.

[0152] In one alternative embodiment of this application, the treatment of PTPN protein-related diseases is selected from cancer.

[0153] In one alternative embodiment of this application, the cancer includes pancreatic cancer, breast cancer, multiple myeloma, melanoma, or secretory cell carcinoma.

[0154] Additional aspects and advantages of this application will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of this application. Detailed Implementation

[0155] The embodiments of this application are described in detail below. The embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application.

[0156] This application details

[0157] Definitions and General Terms

[0158] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Furthermore, in the description of this application, unless otherwise stated, "multiple" means two or more.

[0159] It should be noted that the structural and chemical formula descriptions in the embodiments or implementations of this application are intended to cover all alternatives, modifications, and equivalent technical solutions, all of which are within the scope of this application as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice this application. This application is by no means limited to the methods and materials described herein. In the event that one or more of the cited documents, patents, and similar materials differ from or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0160] It should be further appreciated that some features of this application, for clarity, have been described in multiple independent embodiments or implementations, but may also be provided in combination in a single embodiment or implementation. Conversely, various features of this application, for the sake of brevity, have been described in a single embodiment or implementation, but may also be provided individually or in any suitable sub-combination.

[0161] Unless otherwise stated, the technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains, and unless otherwise stated, all patent publications cited in the entirety of this application are incorporated herein by reference.

[0162] Unless otherwise stated, the following definitions will apply in this application. For the purposes of this application, chemical elements are defined according to the periodic table, CAS version, and the Chemical Handbook, 75th Ed, 1994. Furthermore, general principles of organic chemistry are found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007; therefore, all contents of this application incorporate the references.

[0163] In this document, the terms “comprising” or “including” are open-ended expressions, meaning that they include the contents specified in this application but do not exclude other contents.

[0164] In this document, the compounds of this application also include isotopically labeled compounds of this application that are identical to those compounds described herein except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those of naturally common atomic masses or mass numbers. Exemplary isotopes that may also be introduced into the compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 13 C 14 C 15 N、 16 O、 17 O、 31 P, 32 P, 36 S, 18 F and 37 Cl.

[0165] Compounds of this application containing other isotopes of the aforementioned isotopes and / or other atoms, as well as pharmaceutically acceptable salts of said compounds, are included within the scope of this application. Isotope-labeled compounds of this application, such as radioactive isotopes, are also included. 3 H and 14 The incorporation of tritium into the compounds of this application can be used for drug and / or substrate tissue distribution analysis. Due to its ease of preparation and detection, tritium-substituted compounds... 3 H, and carbon-14, i.e. 14 C isotopes are particularly preferred. In addition, heavier isotopes, such as deuterium, are used. 2 H substitution can offer therapeutic advantages stemming from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements. Therefore, it may be preferred in some cases.

[0166] The stereochemical definitions and conventions used in this application are generally in accordance with S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994. The compounds of this application may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of this application, including but not limited to diastereomers, enantiomers, and atropisomers, and mixtures thereof such as racemic mixtures, are also included within the scope of this application. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes d and l, or (+) and (-), are symbols used to specify the plane-polarized rotation caused by a compound, where (-) or l indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be called enantiomers, and mixtures of such isomers are generally called mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method.

[0167] Depending on the choice of raw materials and methods, the compounds of this application may exist as one or a mixture of possible isomers, for example, as pure optical isomers, or as mixtures of isomers, such as as racemic and non-corresponding isomer mixtures, depending on the number of asymmetric carbon atoms. Optically active (R)- or (S)- isomers can be prepared using chiral synthons or chiral formulations, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may be cis or trans (cis- or trans-) configuration.

[0168] The compounds of this application may contain asymmetric or chiral centers, and thus exist in different stereoisomer forms. It is contemplated that all stereoisomer forms of the compounds of this application, including but not limited to diastereomers, enantiomers, atropisomers, and geometric (or conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of this application.

[0169] Unless otherwise stated, the structures described in this application also represent all isomers including this structure (e.g., enantiomers, diastereotropic atropisomers, and geometric (or conformational) forms; for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers). Therefore, individual stereochemical isomers of the compounds of this application, as well as mixtures of enantiomers, diastereomeric mixtures, and mixtures of geometric isomers (or conformational isomers), are all within the scope of this application.

[0170] Any asymmetric atom (e.g., carbon) in the compounds of this application may exist in a racemic or enantiomerically enriched form, such as (R)-, (S)-, or (R,S)- configuration. In some embodiments, each asymmetric atom has at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% enantiomeric excess in the (R)- or (S)- configuration. If possible, substituents on atoms having unsaturated double bonds may be present in cis-(Z)- or trans-(E)- form.

[0171] Therefore, as described in this application, the compounds of this application may exist in the form of one of the possible isomers, rotational isomers, tautomers, tautomers or mixtures thereof, for example, in the form of essentially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0172] Any mixture of isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, and racemates based on the physicochemical differences of the components, for example by chromatography and / or stepwise crystallization.

[0173] Racemic derivatives of any resulting final compound or intermediate can be separated into optical enantiomers using known methods familiar to those skilled in the art, such as by separating salts of their diastereomers. Racemic compounds can also be separated by chiral chromatography, such as high-performance liquid chromatography (HPLC) using chiral adsorbents. In particular, enantiomers can be prepared by asymmetric synthesis.

[0174] In this document, the terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerization is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also known as prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. Unless otherwise stated, all tautomer forms of the compounds in this application are within the scope of this application.

[0175] In this document, the term "solvent" refers to an association formed by one or more solvent molecules with a compound of this application. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed by solvent molecules that are water.

[0176] In this document, the term "pharmaceutically acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with other components of the formulation and / or the mammals to which it is treated.

[0177] In this document, the term "pharmaceutically acceptable salt" refers to the organic and inorganic salts of the compounds of this application. Pharmaceutically acceptable salts are well known in the art. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts (such as hydrochlorides, hydrobromic acids, phosphates, sulfates, and perchlorates) formed by reaction with amino groups, and organic acid salts (such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates), or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, glucono-heptahydrate, glycerophosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pyruvate, pectinate, persulfate, 3-phenylpropionate, picrate, pentanoate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained by means of appropriate bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1～4 Salts of alkyl groups (4). This application also contemplates quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed compounds can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1～8 Sulfonates and aromatic sulfonates.

[0178] In this document, the terms “optionally,” “optionally,” or “optionally” generally refer to an event or condition that may, but may not, occur, and the description includes both cases in which the event or condition occurs and cases in which the event or condition does not occur.

[0179] In this document, the terms "optionally substituted," "optionally substituted," and "substituted or unsubstituted" are used interchangeably. Generally, the term "optionally," whether preceding or following the term "substituted," indicates that one or more hydrogen atoms in the given structure are substituted by a specific substituent. Unless otherwise indicated, an optional substituent may be substituted at each substituted position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions. The substituents mentioned may be, but are not limited to, F, Cl, Br, CN, OH, NH2, NO2, etc.

[0180] In this document, the term "one or more" (e.g., in the definition of substituents in compounds of the general formula of this application) means "one, two, three, four or five, especially one, two, three or four, more especially one, two or three, and even more especially one or two".

[0181] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently is”, “…each…independently is”, and “…independently is” used in this application are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0182] In this article, the term "halogen" refers to a fluorine, chlorine, bromine, or iodine atom.

[0183] In this paper, the minimum and maximum carbon atom content in hydrocarbon groups are indicated by prefixes, for example, prefix C. a～b This refers to a carbon atom, which is "a" to "b". For example, "C 1～n "C" refers to a saturated / unsaturated carbon chain, either straight or branched, containing 1, 2, 3, 4, 5, ..., or n carbon atoms; further understanding, "C" 1～n "Should be interpreted as any subranges included, such as C" 3～15 In, containing C 3～14 C 3～13 C 3～12 C 3～11 C 3～10 C 3～9 C 3～8 C 3～7 C 3～6 C 3～5 C 3～4 C 4～15 C 4～14 C 4～13 C 4～12C 4～11 C 4～10 C 4～9 C 4～8 C 4～7 C 4～6 C 4～5 C 5～15 C 5～14 C 5～13 C 5～12 C 5～11 C 5～10 C 5～9 C 5～8 C 5～7 C 5～6 C 7～15 C 7～14 C 7～13 C 7～12 C 7～11 C 7～10 C 7～9 C 7～8 C 8～15 C 8～14 C 8～13 C 8～12 C 8～11 C 8～10 C 8～9 C 1～6 In, containing C 1～5 C 1～4 C 1～3 C 1～2 C 2～6 C 2～5 C 2～4 C 2～3 C 3～6 C 3～5 C 3～4 C 4～6 C 4～5 .

[0184] It should be noted that the term "C" is used in this article. 1～6 For example, in "C" 1～6 Alkyl or C 1～6 In the context of the definition of "alkoxy", it refers to an alkyl group having a finite number of carbon atoms, i.e., 1, 2, 3, 4, 5, or 6 carbon atoms. Further understanding, the term "C"... 1～6 "Should be interpreted as any subranges included, such as C" 1～6 C 2～5 C 3～4 C 1～2 C 1～3 C 1～4 C 1～5 Especially C1～2 C 1～3 C 1～4 C 1～5 C 1～6 Especially C 1～4 .

[0185] In this document, the term "alkyl" refers to a straight-chain or branched saturated monovalent hydrocarbon group having one or more carbon atoms. For example, the term "C 1～6 "Alkyl" refers to a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, such as C64. 1～5 Alkyl, C 1～4 Alkyl, C 1～3 Alkyl, C 2～5 Alkyl, C 2～4 Alkyl, C 2～3 Alkyl groups. These include, but are not limited to, methyl, ethyl, n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), and n-pentyl (-CH2CH2CH2C). H2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl ( -CH2CH2CH2CH2CH2CH3), 2-hexyl(-CH(CH3)CH2CH2CH2CH3), 3-hexyl(-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl(-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl(-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl(-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl(-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl(-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl(-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl(-CH(CH3)C(CH3)3), wherein the alkyl groups may be independently unsubstituted or substituted by one or more substituents described in this application.

[0186] In this article, the term "C" 1～6 "Oxyalkyl" or "C" 1～6 "Alkoxy" refers to a C- group containing "-O-". 1～6 Alkyl, wherein the term "alkyl" is as defined above. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentoxy, isopentoxy, and n-hexyloxy, or isomers of the above groups. In particular, the "C" group... 1～6 An alkoxy group can contain 1, 2, 3, 4, or 5 carbon atoms ("C"). 1～5 Alkoxy group), preferably, may contain 1, 2, 3 or 4 carbon atoms ("C"). 1～4 (alkoxy group).

[0187] In this article, the term "C" 1～6 "Halogenated alkyl" refers to a C-shaped compound containing one or more "halogens". 1～6 Alkyl, wherein the term "alkyl" is as defined above. Examples include: -CH2F, -CHF2, -CF3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CHF-CH3, -CF2-CH3, -CHF-CH2F, or isomers of the above groups. In particular, the "C" group... 1～6 The halogenated group can contain 1, 2, 3, 4, or 5 carbon atoms ("C"). 1～5 Haloalkyl), preferably, may contain 1, 2, 3 or 4 carbon atoms (“C”). 1～4 (Halogenated alkyl group).

[0188] In this article, the term "C" 1～6 "Hydroxyalkyl" refers to a C-type compound containing one or more "-OH" groups. 1～6 Alkyl, wherein the term "alkyl" is as defined above. Examples include: -CH2(OH), -CH(OH)2, -CH2-CH2(OH), -CH2-CH(OH)2, -CH(OH)-CH3, -CH(OH)-CH2(OH), or isomers of the above groups. In particular, the "C" group... 1～6 The halogenated group can contain 1, 2, 3, 4, or 5 carbon atoms ("C"). 1～5 Hydroxyalkyl group), preferably, may contain 1, 2, 3 or 4 carbon atoms (“C”). 1～4 (hydroxyalkyl)

[0189] In this document, the terms "3-10 membered cycloalkyl" or "3 to 10 membered cycloalkyl" refer to a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 3 or 10 carbon atoms. Examples include 3-8 membered cycloalkyl, 3-6 membered cycloalkyl, and 5-6 membered cycloalkyl. The 5-6 membered cycloalkyl is a monocyclic hydrocarbon ring, such as cyclopentyl or cyclohexyl.

[0190] In this document, the terms "heterocyclic alkyl," "heterocyclic," and "heterocyclic alkane" all refer to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom; where heteroatoms refer to nitrogen, oxygen, sulfur, etc. Typically, it represents a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system with multiple ring atoms, containing one, two, or three cyclic heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon.

[0191] Unless otherwise stated, heteroatoms may be linked by carbon or nitrogen, wherein the -CH2- group is optionally replaced by -C(O)-; and wherein, unless otherwise stated to the contrary, the cyclic nitrogen atom or cyclic sulfur atom may optionally be oxidized to form an N-oxide or S-oxide, or the cyclic nitrogen atom may optionally be quaternized; wherein the -NH in the ring may optionally be replaced by an acetyl, formyl, methyl, or methanesulfonyl group; and the ring may optionally be replaced by one or more halogens. It should be understood that when the total number of S and O atoms in the heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other. If the heterocyclic group is monocyclic, it is necessarily not aromatic. Examples of heterocyclic groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methanesulfonylpiperazinyl, homopiperazinyl, piperazinyl, azacyclic butyl, oxacyclic butyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydroindolyl, tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, tetrahydrothiaranyl, tetrahydrothiaran-1-oxide, tetrahydrothiaran-1,1-dioxide, 1H-pyridin-2-one, and 2,5-dioxoimidazolyl.

[0192] In this document, the terms "4-10 membered heterocyclic alkyl" or "4-10 membered heterocycle" refer to 4, 5, 6, 7, 8, 9, or 10 membered saturated or unsaturated heterocycles. The term "unsaturated" refers to the presence of carbon-carbon double bonds, carbon-carbon triple bonds, carbon-oxygen double bonds, carbon-sulfur double bonds, carbon-nitrogen triple bonds, etc., in the group or molecule. Similarly, "7-10 membered heterocyclic alkyl" or "7-10 membered heterocycle" refer to 7, 8, 9, or 10 membered saturated or unsaturated heterocycles. The term "unsaturated" also refers to the presence of carbon-carbon double bonds, carbon-carbon triple bonds, carbon-oxygen double bonds, carbon-sulfur double bonds, carbon-nitrogen triple bonds, etc., in the group or molecule.

[0193] In this document, the term "6-10 aryl" should be understood as a monovalent monocyclic, bicyclic, or tricyclic aromatic ring group having 6, 7, 8, 9, or 10 ring atoms. Examples include 6-8 aryl and 6-7 aryl.

[0194] In this document, the term "5-10-membered heteroaryl" should be understood as a monovalent monocyclic, bicyclic, or tricyclic aromatic ring group having 5, 6, ... 10 ring atoms and containing one or more heteroatoms independently selected from N, O, and S. Preferably, it is a monovalent monocyclic, bicyclic, or tricyclic aromatic ring group with 1 to 3 heteroatoms independently selected from N, O, and S, and in each case, it may be benzofused. In particular, the heteroaryl group is selected from thiophene, furanyl, pyrrole, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.; or borazinyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphridinyl, pteridinyl, carbazolyl, acridineyl, phenazinyl, phenothiazinyl, phenothiazinyl, etc. For example, 5-8 nucleotide heteroaryl and 5-6 nucleotide heteroaryl.

[0195] In this paper, the term "5-12 membered spirocycle" refers to two or more rings connected by a common carbon atom, but these rings do not share any other atoms, and the two or more rings contain a total of 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. For example, spiro[3.3], spiro[3.4], spiro[3.5], spiro[3.6], spiro[3.7], spiro[4.3], spiro[4.4], spiro[4.5], spiro[4.6], spiro[4.7], spiro[5.3], spiro[5.4], spiro[5.5], spiro[5.6], spiro[5.7], spiro[6.3], spiro[6.4], spiro[6.5], spiro[6.6], spiro[6.7], spiro[7.3], spiro[7.4], spiro[7.5], spiro[7.6].

[0196] In this paper, the term "5-12 membered heterospirocyclic ring" refers to a 5-12 membered spirocyclic ring containing at least one ring containing a heteroatom, as defined above.

[0197] In this paper, the term "5-12-membered bridging ring" refers to one or more carbon atoms (or other atoms) connecting two or more rings, but these carbon atoms are not located in the plane of the rings, and the two or more rings contain a total of 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Bridging rings can be single-bridged or multi-bridged, depending on the number of atoms connecting the rings.

[0198] In this paper, the term "5-12 membered heterobridged ring" refers to a 5-12 membered bridged ring containing at least one ring containing a heteroatom, as defined above.

[0199] In this paper, the term "5-12 fused rings" refers to two or more rings sharing two atoms that are integral to the ring, and the two or more rings contain a total of 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Fused rings can be coplanar or non-coplanar, depending on the stereochemistry of the molecule.

[0200] In this paper, the term "5-12 fused ring" refers to a 5-12 fused ring containing at least one ring containing a heteroatom, as defined above.

[0201] In this article, the term "alkylene" refers to a group formed by removing one hydrogen atom from an "alkyl" group, wherein "C" 1～6 "alkylene" includes methylene, ethylene, propylene, and isopropylene (e.g., ...). ), butylide (such as) ), pentylene (e.g.) ), hexyl (such as) )wait.

[0202] In this article, the term "CO" or "C(=O)" refers to the carbonyl group, with the structural formula as follows:

[0203] The functional group described in this application It is used to describe the position of the substituent group.

[0204] In this application, the bond “” in the chemical structure of the compound indicates an unspecified configuration. If chiral isomerism exists in the chemical structure, the bond “” can be… Or simultaneously include Two configurations. Although all the above structural formulas are shown in certain isomer forms for simplicity, this disclosure can include all isomers, such as tautomers, rotational isomers, geometric isomers, diastereomers, racemates, and enantiomers.

[0205] In the chemical structure of the ligands or compounds described in this disclosure, the bonds... This indicates that the configuration is not specified. If cis-trans isomerism exists in the chemical structure, the bond... The configuration can be E-type, Z-type, or both E-type and Z-type.

[0206] In this document, the term "pharmaceuticalally acceptable excipient" includes any solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (e.g., antibacterial, antifungal), isotonic agent, salt, pharmaceutical stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, colorant, or combination thereof, all of which are known to those skilled in the art (as described in Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except where any conventional excipient is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is covered.

[0207] In this document, the term "administration" refers to the introduction of a predetermined amount of a substance into a patient in a suitable manner. The recombinant cell or pharmaceutical composition of this application can be administered via any common route, as long as it can reach the intended tissue. Various routes of administration are foreseeable, including peritoneal, intravenous, intramuscular, subcutaneous, etc., but this application is not limited to these exemplified routes of administration. Preferably, the composition of this application is administered via intravenous or subcutaneous injection.

[0208] In this document, the term "treatment" refers to the administration of a drug or compound to an individual to achieve a desired pharmacological and / or physiological effect. This effect may be preventative in terms of complete or partial prevention of a disease or its symptoms, and / or therapeutic in terms of partial or complete cure of a disease and / or adverse effects caused by the disease. As used herein, "treatment" encompasses diseases in mammals, particularly humans, including: (a) prevention of disease or the onset of a condition in an individual who is susceptible but has not yet been diagnosed with the disease; (b) inhibition of disease, such as blocking disease progression; or (c) relief of disease, such as reducing symptoms associated with the disease. As used herein, "treatment" encompasses any administration of a drug or compound to an individual to treat, cure, relieve, improve, reduce, or inhibit the individual's disease, including but not limited to administration of a drug containing a compound described herein to an individual in need.

[0209] In this document, the terms "cancer" or "tumor" can refer to any unregulated cell growth. Examples include, but are not limited to, non-small cell lung cancer, papillary thyroid carcinoma, glioblastoma multiforme, colon cancer, rectal cancer, lung cancer, head and neck cancer, kidney cancer, bladder cancer, breast cancer, ovarian cancer, liver cancer, bile duct cancer or sarcoma, acute myeloid leukemia, large cell neuroendocrine carcinoma, neuroblastoma, prostate cancer, neuroblastoma, pancreatic cancer, melanoma, head and neck squamous cell carcinoma, cervical cancer, skin cancer, glioma, esophageal cancer, oral squamous cell carcinoma, or gastric cancer, etc.

[0210] The following will explain the solution of this application with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of this application. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0211] Example 1: Synthesis of intermediate IntA

[0212] The synthesis route is as follows:

[0213]

[0214] Step 1: Compound I-1 (4-bromo-2-fluorophenylacetic acid, 670 g, 2.87 mol) was dissolved in 3.3 L of DCM, followed by the addition of DMF (42 g, 0.57 mol), and then oxalyl chloride (547 g, 4.31 mol) at 0 °C. The mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. TLC monitoring showed that the reaction was complete. The reaction solution was evaporated to dryness to obtain 826 g of compound 1-2.

[0215] Step 2: 1313 g (9.85 mmol) of AlCl3 was added to 8 L of dichloromethane solution. Then, 2-(4-bromo-2-fluorophenol)acetyl chloride (compound 1-2, 826 g, 3.42 mol) was dissolved in 2 L of dichloromethane solution and added dropwise to the reaction solution at -10 °C. The reaction solution was stirred at -10 °C for 1 h. Ethylene gas was introduced into the reaction solution at -4 °C. After 1 h, the TC test showed that the reaction was complete. The reaction solution was quenched with 2 L of water, extracted three times with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate, filtered, and rotary evaporated to obtain 900 g of compound 1-3.

[0216] Step 3: Dissolve 900 g (3.70 mol) of compound 1-3 in 8 L of toluene, add 827 g (13.3 mol) of ethylene glycol and 76 g (0.44 mol) of p-toluenesulfonic acid, and stir at 130 °C for 2 h. TC detection indicates the reaction is complete. Cool the reaction solution to room temperature. Extract the reaction solution three times with ethyl acetate. Dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. Purify the crude product using silica gel column chromatography to obtain 450 g of compound 1-4.

[0217] Step 4: Dissolve 442 g (1.54 mol) of compounds 1-4 in 4.5 L of dioxane, add 499 g (4.61 mol) of benzyl alcohol, 13.6 g (45.9 mmol) of N,N'-diphenylethyl oxalamide, 29.3 g (154 mmol) of cuprous iodide, and 221 g (2.30 mol) of sodium tert-butoxide. Stir the reaction mixture at 110 °C for 16 h. TLC showed that the reaction was complete. Quench the reaction mixture with 6 L of water and extract with ethyl acetate. Dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. Purify the crude product by slurrying with 900 mL of isopropanol to obtain 200 g of compounds 1-5.

[0218] Step 5: Dissolve 121 g (0.86 mol) of 2,2,6,6-tetramethylpiperidine in 3.6 L of THF, and add n-BuLi (227 mL, 2.5 M petroleum ether solution) at -10 °C. Stir the reaction solution at -10 °C for 40 minutes, then dilute the reaction solution with 3.6 L of THF and cool to -80 °C. Then dissolve 180 g (0.57 mol) of compounds 1-5 in 144 mL of THF solution and add it dropwise to the cooled reaction solution at -70 °C. Continue stirring at -70 °C for 2 hours. Then dissolve 297 g (1.14 mol) of 1,2-dibromotetrafluoroethane in 360 mL of THF and slowly add it dropwise to the reaction solution at -70 °C. Heat the reaction solution to -5 °C and continue stirring for 15 minutes. TLC showed that the reaction was complete. Quench the reaction solution with saturated ammonium chloride aqueous solution at -10 °C. The product was then extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate, filtered, and rotary evaporated to obtain a crude product. The crude product was then purified by silica gel column chromatography to obtain 87g of compounds 1-6.

[0219] Step 6: Dissolve 80 g (0.20 mol) of compounds 1-6 in dioxane (1.6 L), add 40 g (0.30 mol) of glycine tert-butyl ester, 198 g (0.61 mol) of cesium carbonate, 18.4 g (0.67 mmol) of methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), and 10.9 g (0.02 mol) of 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl. Then react at 90 °C for 12 h. TLC confirmed the reaction was complete. The reaction solution was quenched with saturated ammonium chloride aqueous solution and then extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, filtered, and rotary evaporated to obtain a crude product, which was then purified by silica gel column chromatography to obtain 54g of compounds 1-7.

[0220] MS(M+H): 444.25.

[0221] Step 7: Dissolve 25.8 g (182 mmol) of chlorosulfonyl isocyanate in 800 mL of DCM, then add 14.1 g (243 mmol) of allyl alcohol dropwise at -5 °C. After the addition is complete, stir at room temperature for 30 minutes. Then add 54 g (122 mmol) of compounds 1-7 and 31.4 g (247 mmol) of DIEA at 0 °C and stir at 25 °C for 45 minutes. LCMS analysis showed that the reaction was complete. The reaction solution was quenched with water at 0 °C and then extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain 81.5 g of compounds 1-8.

[0222] MS(M+H): 607.15.

[0223] Step 8: Dissolve 81.5 g (134 mmol) of compounds 1-8 in 1.6 L of methanol, then add 2.79 g (2.41 mmol) of tetraphenylphosphine palladium and 130.6 g of sodium methoxide (30% methanol solution). Stir the reaction mixture at 60 °C for 1 h. LCMS confirmed the reaction was complete. After cooling to room temperature, the reaction mixture was quenched with 1 mol / L HCl. The organic solvent was removed by rotary evaporation, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the crude product. After purification by silica gel column chromatography, 29.2 g of compounds 1-9 were obtained.

[0224] MS(M+H):449.10[M+H]+.

[0225] Step 9: Take 29.2 g (65.2 mmol) of compounds 1-9 and add 150 mL of formic acid. Stir at room temperature for 2 h. TLC detection showed that the reaction was complete. Add 500 mL of water to the reaction solution, precipitate, filter and dry to obtain 18.7 g of compounds 1-10.

[0226] MS(M+H): 405.10[M+H]+.

[0227] 1 H NMR (400MHz, DMSO-d6) δ7.55–7.45(m,2H),7.43–7.30(m,3H),7.07(d,J=1.4Hz,1H),5 .20(s,2H),4.44(s,2H),3.48(s,2H),3.07(dd,J=7.6,5.9Hz,2H),2.52-2.49(m,2H).

[0228] Step 10: Dissolve 11.4 g (28.2 mmol) of compound 1-10 in 50 ml of THF, add 6 g of Pd / C and 6 g of Pd(OH)2, stir at 25 °C for 3 h under a hydrogen balloon (15 Psi), and LCMS showed that the reaction was complete. After filtration, the reaction solution was evaporated to dryness to obtain compound 8.86 IntA.

[0229] 1 H NMR (400MHz, DMSO-d6) δ10.22(s,1H),6.73(s,1H),4.38(s,2H),3.04(t,J=6.7Hz,2H),2.55–2.48(m,2H).

[0230] Example 2: Synthesis of intermediate IntB

[0231] The synthesis route is as follows:

[0232]

[0233] Step 1: Dissolve 800 mg (1.98 mmol) of compound 1-10 (see Example 1 for specific preparation method) in 10 ml MeOH and 10 ml THF. Add 3.05 g (39.6 mmol) ammonium acetate, 1.73 g (7.93 mmol) Boc₂O, and 2.09 g (33.2 mmol) NaBH₃CN at 0 °C. Stir at 25 °C for 1 h, then at 50 °C for another 1 h. TLC monitoring showed the reaction was complete. Quench the reaction with water in an ice bath at 0 °C. Extract three times with ethyl acetate. Dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. Purify by silica gel column chromatography to obtain 730 mg of compound 2-11.

[0234] 1 H NMR(600MHz,DMSO-d6)δ7.52–7.45(m,2H),7.38–7.33(m,2H),7.31–7.27( m,1H),7.02–6.97(m,1H),6.69(s,1H),5.10(s,2H),4.13–4.08(m,2H),3.9 8–3.89(m,2H),3.60(s,2H),3.19–3.16(m,4H),2.86–2.70(m,3H),2.42–2. 33(m,1H),1.94–1.88(m,1H),1.60–1.50(m,1H),1.41(s,9H),1.24(s,2H).

[0235] Step 2: Dissolve 730 mg (1.45 mmol) of compound 2-11 in 10 ml THF, add 200 mg of Pd / C, stir at 25 °C for 8 h under a hydrogen balloon (15 PSI), and monitor the reaction by TLC until the reaction is complete. After filtration and rotary evaporation of the reaction solution, 460 mg of compound 2-12 is obtained.

[0236] Step 3: Dissolve 460 mg (0.91 mmol) of compound 2-12 in 5 ml THF, add 2.5 ml TFA, stir at 25 °C for 1 h, and monitor the reaction by LCMS until the reaction is complete. After the reaction solution is concentrated by rotary evaporation, it is purified by slurrying with methyl tert-butyl ether to obtain 290 mg of compound Int B.

[0237] Example 3: Synthesis of intermediate Int C

[0238] The synthesis route is as follows:

[0239]

[0240] Step 1: Dissolve 50 g (0.21 mol) of 5-bromo-1,3-difluoro-2-nitrobenzene (compound 3-1) in 500 ml of anhydrous THF solution, add 23.8 g (0.22 mol) of benzyl alcohol, purge with nitrogen three times, and cool to -60°C. Slowly add 220 ml of potassium tert-butoxide THF solution (1 mol / L) to the reaction solution at -60°C. After the addition is complete, raise the reaction temperature to 25°C and continue the reaction for 30 min. TLC detection shows that the reaction is complete. Quench the reaction with 100 ml of saturated ammonium chloride aqueous solution, remove THF by rotary evaporation, and extract the reaction solution three times with dichloromethane and water. Dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. Purify the crude product by slurrying with 200 ml of petroleum ether to obtain compound 3-2 (112.6 g).

[0241] 1 H NMR (300MHz, DMSO-d6) δ7.63 (t, J = 1.7Hz, 1H), 7.61–7.56 (m, 1H), 7.44–7.34 (m, 5H), 5.36 (s, 2H).

[0242] Step 2: Dissolve 112.6 g (0.34 mol) of compound 3-2 in 1000 ml of ethanol, and add 307 ml of water. Add 334 g (1.92 mol) of sodium dithionite in an oil bath at 80 °C. After the addition is complete, continue stirring in an oil bath at 80 °C for 30 min. TLC monitoring shows that the reaction is complete. Discard the ethanol from the reaction solution by rotary evaporation. Extract with ethyl acetate and water. Dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain compound 3-3 (94.2 g).

[0243] 1 H NMR (300MHz, DMSO-d6) δ7.57–7.45(m,2H),7.44–7.25(m,3H),6.96(t,J=4.2Hz,2H),5.15(s,2H),4.84(s,2H),2.49(s,2H).

[0244] Step 3: Dissolve 94.2 g (0.32 mol) of compound 3-3 in 380 ml of DMF, add 392 g (2.56 mol) of methyl bromoacetate, and finally add 164 g (1.27 mol) of DIEA. Heat the mixture at 70 °C for 2 h. TLC monitoring showed that the reaction was complete. Quench the reaction with 300 ml of water in an ice bath at 0 °C. Extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. Purify the crude product by slurrying with 90 ml of methyl tert-butyl ether to obtain compound 3-4 (59.6 g).

[0245] 1 H NMR (300MHz, DMSO-d6) δ7.53–7.29(m,5H),7.05–6.94(m,2H),5.22(s,1H),5.16(s,2H),4.10–3.97(m,2H),3.59(s,3H).

[0246] Step 4: Dissolve 32.5 g (0.23 mol) of chlorosulfonyl isocyanate in 350 mL of dichloromethane. Add 17.1 g (0.23 mol) of tert-butanol dropwise at 0 °C. After the addition is complete, allow the mixture to return to room temperature and continue reacting for 15 min before adding more. Cool the mixture back to 0 °C. Dissolve 59.6 g (0.16 mol) of compound 3-4 from the previous step and 31 g (0.31 mol) of triethylamine in 600 mL of dichloromethane, and then add this solution dropwise to the reaction mixture. After 1 h, monitor the reaction for completeness using TLC. Quench the reaction with water at 0 °C and extract three times with dichloromethane. Dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain compound 3-5 (103 g).

[0247] 1 H NMR (300MHz, DMSO-d6) δ11.35(s,1H),7.50–7.21(m,7H),5.34–5.22(m,2H),4.67–4.31(m,2H),3.56(s,4H),1.31(s,9H).

[0248] Step 5: Dissolve 103 g (0.19 mol) of compound 3-5 from the previous step in 1000 ml of dichloromethane, and add 500 ml of trifluoroacetic acid (TFA) at 0 °C. After the TFA is added, remove the mixture from the ice bath, allow the reaction solution to return to room temperature, and continue stirring for 30 min. TLC monitoring shows that the reaction is complete. Quench the reaction with water at 0 °C in an ice bath. Extract three times with dichloromethane. Dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain compound 3-6 (41.3 g).

[0249] 1H NMR (300MHz, DMSO-d6) δ7.51(d,J=6.8Hz,2H),7.45–7.30(m,3H),7.20(d,J=8.8Hz,2H),7.04(s,2H),5.20(s,2H),4.45–4.15(m,2H),3.57(s,3H).

[0250] Step 6: Dissolve 41.3 g (92.3 mmol) of compound 3-6 from the previous step in 1.65 L of THF, and slowly add 10.7 g (60% purity) of sodium hydride at 0 °C. After the addition is complete, continue the reaction at 25 °C for 0.5 h, and TLC monitoring shows that the reaction is complete. Quench the reaction with saturated ammonium chloride aqueous solution at 0 °C, extract three times with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain compound 3-7 (48.9 g).

[0251] 1 H NMR (300MHz, DMSO-d6) δ7.56–7.46(m,2H),7.42–7.29(m,3H),7.27(s,1H),7.24–7.15(m,2H),7.10(s,1H),5.19(s,2H),3.97(s,2H).

[0252] Step 7: Dissolve 3g (7.22mmol) of compound 3-7 and 2.78g (38.0mol) of tert-butyl acrylate in 20ml of DMF, then add 3.66g (36.2mmol) of TEA and 439mg (1.44mmol) of tris(o-tolyl)phosphine, purge with nitrogen three times, and then add 162mg (0.72mmol) of Pd(OAc). 2， The reaction was heated to 140℃ and carried out for 2 hours. The reaction was confirmed to be complete by LCMS. The reaction solution was added to water (100 ml). The aqueous phase was extracted three times with 30 ml of ethyl acetate each time. The combined organic phases were dried with anhydrous sodium sulfate, filtered, and rotary evaporated to obtain crude product. The crude product was then purified by silica gel column chromatography to obtain 4.4 g of compound 3-8 as a red oil.

[0253] MS: 461.2 [MH] -

[0254] Step 8: Dissolve 2.5 g (5.40 mmol) of compound 3-8 in 60 ml of THF, add 250 mg of 20% Pd(OH)₂ and 250 mg of 10% Pd / C, purge three times with hydrogen, and react at 25 °C for 5 h. LCMS analysis indicates the reaction is complete. Filter the reaction solution, concentrate to obtain the crude product, and then purify by silica gel column chromatography to obtain 1.9 g of compound 3-9. Ms: 373.2 [MH] -

[0255] Step 9: Dissolve 2.9g (7.74mmol) of compound 3-9 in 30ml DCM, add 15ml TFA solution, react at 25℃ for 2h, and detect complete reaction by TLC. Concentrate the reaction solution to obtain crude product, then pulp and filter through DCM (10ml) to obtain 2.5g of compound Int C.

[0256] MS: 317.0 [MH] -

[0257] Example 4: Synthesis of intermediate Int D

[0258] The synthesis route is as follows:

[0259]

[0260] Step 1: Take 6.0 g (14.4 mmol) of compound 3-7 from the previous step (see Example 3 for specific preparation method) and add 100 ml of 1,4-dioxane and 20 ml of water. Then add 9.07 g (21.8 mmol) of potassium trifluoroborate (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate and 9.42 g (28.9 mmol) of cesium carbonate. Finally, add the catalyst chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (cataCXium A-Pd-G2, 0.96 g, 1.44 mmol). After purging with nitrogen three times, heat to 100 °C and react for 12 h. LCMS showed that the reaction was complete. The reaction solution was directly evaporated to dryness and purified by silica gel column chromatography to obtain compound 4-2 (4.70 g).

[0261] Step 2: Dissolve 1 g (2.09 mmol) of compound 4-2 from the previous step in 60 ml of THF, add 1 g of palladium on carbon, and react at 25 °C for 3 h under a hydrogen balloon. LCMS showed that the reaction was complete. After filtering the reaction solution, evaporate the filtrate to dryness to obtain compound 4-3 (634 mg).

[0262] Step 3: Dissolve 634 mg (1.63 mmol) of compound 4-3 from the previous step in 10 ml of dichloromethane, add 1.3 ml of trifluoroacetic acid at 0 °C, and react at 25 °C for 30 min after the addition is complete. LCMS monitoring showed that the reaction was complete. After the reaction solution was evaporated to dryness, it was slurried with methyl tert-butyl ether to obtain compound Int D (334 mg).

[0263] 1 H NMR (300MHz, DMSO-d6) δ9.39(s,1H),7.70(s,3H),6.66–6.52(m,2H),3.92(s,2H),3.07–2.95(m,2H),2.73(t,J=7.6Hz,2H).

[0264] Example 5: Synthesis of intermediate Int E

[0265] The synthesis route is as follows:

[0266]

[0267] Step 1: Dissolve 50 g of 5-bromo-1,3-difluoro-2-nitrobenzene (compound 5-1, 0.24 mol) in 500 ml of anhydrous THF solution, add 23.8 g (0.22 mol) of benzyl alcohol, purge with nitrogen three times, and cool to -60°C. Slowly add 220 ml of potassium tert-butoxide THF solution (1 mol / L) to the reaction mixture at -60°C. After the addition is complete, raise the temperature to 25°C and continue the reaction for 30 min. TLC analysis shows the reaction is complete. Remove the THF by rotary evaporation, add dichloromethane and water, and extract the reaction mixture three times. Dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. Purify the crude product by slurrying with 200 ml of petroleum ether to obtain 112.6 g of compound 5-2.

[0268] 1 H NMR (300MHz, DMSO-d6) δ7.63 (t, J = 1.7Hz, 1H), 7.61–7.56 (m, 1H), 7.44–7.34 (m, 5H), 5.36 (s, 2H).

[0269] Step 2: Dissolve 24 g of 1-(benzyloxy)-5-bromo-3-fluoro-2-nitrobenzene (compound 5-2, 73.6 mmol) in 240 mL of anhydrous tetrahydrofuran. Cool to -70 °C and add LDA solution (73.6 mL, 2 M THF solution). After the addition is complete, continue stirring at -70 °C for 30 min. Add 1,2,3-oxathiazolidin-3-carboxylic acid tert-butyl ester 2,2-dioxide (19.7 g, 88.2 mmol dissolved in 300 mL THF). Stir at -70 °C for 1 h. After TLC monitoring shows that the reaction is complete, quench the reaction with saturated ammonium chloride aqueous solution. After rotary evaporation to remove THF, extract the aqueous phase three times with ethyl acetate. Dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. Purify by silica gel column chromatography to obtain 14.3 g of compound 5-3.

[0270] Step 3: Dissolve 8.34 g (17.7 mmol) of compound 5-3 in 85 ml of 1,4-dioxane solution and 17 ml of water. Add 17.6 g (88.9 mmol) of (E)-1-ethoxyvinyl-2-boronate pinacol ester and 17.3 g (53.1 mmol) of cesium carbonate. Finally, add 1.95 g (2.67 mmol) of Pd(dppf)Cl2 catalyst. After purging with nitrogen three times, stir at 100 °C for 1.5 h. TLC monitoring showed that the reaction was complete. Quench the reaction with saturated ammonium chloride aqueous solution. After rotary evaporation to remove THF, extract the aqueous phase three times with ethyl acetate. Dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. Purify by silica gel column chromatography to obtain 4.26 g of compound 5-4.

[0271] 1 H NMR(600MHz,DMSO-d6)δ7.47–7.40(m,5H),7.39–7.33(m,1H),7.26(s,1H),7.03–6.96(m,1H),6.08(d,J =12.6Hz,1H),5.32(s,2H),4.07–3.99(m,2H),3.06–2.97(m,2H),2.76–2.69(m,2H),1.38–1.27(m,12H).

[0272] Step 4: Dissolve 4.26 g (9.25 mmol) of compound 5-4 in 45 ml of 1,4-dioxane, place in an ice bath, and purge with nitrogen three times. Add 10 ml of dioxane hydrochloride at 10 °C, restore the reaction solution to 25 °C, and continue stirring for 1 h. TLC monitoring showed that the reaction was complete. Quench the reaction solution with 100 ml of saturated sodium carbonate aqueous solution, extract three times with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. Purify by silica gel column chromatography to obtain 3.80 g of compound 5-5.

[0273] Step 5: Dissolve 3.02 g (7.29 mmol) of compound 5-5 in 120 ml of ethanol and add 40 ml of water. Heat to 80 °C and add 10.1 g (58.0 mmol) of sodium dithionite. Continue stirring at 80 °C for 30 min. TLC monitoring showed that the reaction was complete. After rotary evaporation of ethanol from the reaction solution, extract three times with ethyl acetate. Dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. Purify by silica gel column chromatography to obtain 2.46 g of compound 5-6.

[0274] MS(M+H): 385.3[M+H]+.

[0275] 1H NMR(600MHz,DMSO-d6)δ7.53–7.48(m,2H),7.43–7.37(m,2H),7.36–7.29(m,1H),6.68(s, 2H),5.46(s,1H),5.11(s,2H),4.69(s,2H),3.79–3.71(m,2H),2.90(s,2H),1.47(s,9H).

[0276] Step 6: Dissolve 2.16 g (5.62 mmol) of compound 5-6 in 20 mL of DMF, add 2.31 g (15.1 mmol) of methyl bromoacetate and 2.90 g (22.4 mmol) of DIEA. Stir the reaction at 60 °C for 1.5 h; TLC monitoring showed the reaction was complete. Quench the reaction with saturated ammonium chloride solution in an ice bath. Extract three times with ethyl acetate. Dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. Purify by silica gel column chromatography to obtain 1.49 g of compound 5-7.

[0277] MS(M+H):457.4[M+H]+.

[0278] Step 7: Dissolve 861 mg (6.08 mmol) of chlorosulfonyl isocyanate in 10 mL of dichloromethane. Add 658 mg (6.08 mmol) of benzyl alcohol dropwise at 0°C, controlling the temperature between 0-10°C. After the addition is complete, stir at 25°C for 0.5 h. Dissolve 1.49 g (3.26 mmol) of compound 5-7 from the previous step in 15 mL of dichloromethane, and add 924 mg (9.13 mmol) of triethylamine to prepare a mixed solution. Add the above mixed solution dropwise to the reaction mixture at 10°C. After the addition is complete, continue stirring at 10°C for 0.5 h. TLC monitoring shows the reaction is complete. Quench the reaction with saturated ammonium chloride aqueous solution in an ice bath. Extract three times with ethyl acetate. Dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. Purify by silica gel column chromatography to obtain 2.84 g of compound 5-8.

[0279] Step 8: Dissolve 2.84 g (3.26 mmol) of compound 5-8 (9.01 mmol) in 60 ml of THF, add 1 g of palladium on carbon, and stir for 1 h in a hydrogen balloon (15 PSI) at 25 °C. TLC monitoring showed that the reaction was complete. Filter the reaction solution, concentrate the filtrate by rotary evaporation to obtain the crude product, and purify it by reversed-phase preparative chromatography to obtain 1.10 g of compound 5-9.

[0280] Step 9: Dissolve 1.10 g (2.46 mmol) of compound 5-9 in 30 mL of THF. Add 0.39 g of sodium hydride at 10 °C, and continue stirring at 25 °C for 1 h after the addition is complete. TLC monitoring showed that the reaction was complete. Quench the reaction by adding saturated ammonium chloride aqueous solution at 0 °C. Extract the organic phase three times with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. Purify by silica gel column chromatography to obtain 330 mg of compound 5-10.

[0281] 1 H NMR (600MHz, DMSO-d6) δ9.14(s,1H),6.52(s,1H),3.92(s,2H),3.44(d,J=6.3Hz,4H),2.77(s,4H),1.41(s,9H),1.24(s,5H).

[0282] Step 10: Dissolve 330 mg (0.79 mmol) of compound 5-10 in 5 ml of dichloromethane, and add 1.3 ml of trifluoroacetic acid at 0 °C. After the addition is complete, stir at 25 °C for 30 min. LCMS monitoring shows that the reaction is complete. After the reaction solution is concentrated by rotary evaporation, it is slurried with methanol:methyl tert-butyl ether = 3:1 to obtain 262 mg of compound Int E.

[0283] MS(M+H):316.3[M+H]+.

[0284] 1 H NMR (600MHz, DMSO-d6) δ9.36(s,1H),8.75(s,2H),6.59(s,1H),3.92(s,2H),3.18(s,5H),2.98(s,4H).

[0285] Example 6: Synthesis of Compound 010A

[0286] The synthesis route is as follows:

[0287]

[0288] Step 1: Dissolve 300 mg (1.09 mmol) of compound 6-1 and 295 mg (1.09 mmol) of compound (10-aminododecyl) tert-butyl carbamate in 5 ml of DMSO, then add 421 mg (3.26 mmol) of DIEA, heat to 120 °C and react for 3 h. The reaction was confirmed to be complete by LCMS. The reaction solution was added to 50 ml of water and extracted three times with 30 ml of ethyl acetate each time. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the crude product. The crude product was then purified by silica gel column chromatography to obtain 300 mg of compound 6-2.

[0289] Step 2: Dissolve 300 mg (0.57 mmol) of compound 6-2 in 3 ml of DCM, then add 1.5 ml of TFA. Stir the reaction solution at 30 °C for 0.5 h. TLC monitoring showed that the reaction was complete. After concentration, 300 mg of compound 6-3 was obtained.

[0290] Step 3: 120 mg (0.23 mmol) of compound 6-3 and 70 mg (0.22 mmol) of compound IntA (see Example 1 for specific synthesis method) were dissolved in 5 ml of methanol. 86 mg (0.66 mmol) of DIEA was added at 0 °C, and the mixture was stirred for 5 min. Then, 66 mg of AcOH (1.1 mmol) was added to the reaction solution, and the reaction was carried out at 0 °C for 1.5 h. Finally, 41 mg (0.65 mmol) of NaBH3CN was added to the reaction solution, and the mixture was heated to 25 °C and reacted for 1 h. After the reaction was confirmed to be complete by LCMS, HCl (1 M, 0.3 ml) was added to quench the reaction. The solution was concentrated and purified by reversed-phase chromatography to obtain 10.6 mg of compound 010A.

[0291] Ms: 727.7 [M+H] +

[0292] 1 H NMR(600MHz,DMSO-d6)δ11.10(s,1H),9.57(s,1H),8.67–8.47(m,2H),7.59(dd,J=8.6,7.1Hz,1H),7 .10(d,J=8.6Hz,1H),7.03(d,J=7.0Hz,1H),6.55–6.51(m,1H),6.49(s,1H),5.05(dd,J=12.9,5.4Hz, 1H),4.07(s,2H),3.10(dd,J=15.9,5.4Hz,1H),3.05–2.98(m,2H),2.92–2.71(m,3H),2.64–2.53(m, 2H),2.22–2.13(m,1H),2.07–1.95(m,1H),1.74–1.66(m,1H),1.64–1.54(m,4H),1.39–1.21(m,14H).

[0293] Example 7: Synthesis of compound 019A

[0294] The synthesis route is as follows:

[0295]

[0296] Step 1: Dissolve 100 mg (0.36 mmol) of compound 7-1 and 102 mg (0.39 mmol) of compound N-Boc-1,9-nonanediamine in 5 ml of DMSO, then add 140 mg (1.08 mmol) of DIEA, heat to 120 °C and react for 2 h. The reaction was confirmed to be complete by TLC. The reaction solution was added to 40 ml of water and extracted three times with 20 ml of ethyl acetate each time. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the crude product. The crude product was then purified by silica gel column chromatography to obtain 80 mg of compound 7-2.

[0297] Step 2: Dissolve 80 mg (0.16 mmol) of compound 7-2 in 3 ml of DCM, then add 1.5 ml of TFA. Stir the reaction solution at 28 °C for 0.5 h. TLC monitoring showed that the reaction was complete. After concentration, 100 mg of compound 7-3 was obtained.

[0298] Step 3: 100 mg (0.20 mmol) of compound 7-3 was dissolved in 1 ml of methanol and 1 ml of tetrahydrofuran. 61 mg (0.47 mmol) of DIEA was added, and the mixture was stirred at 25 °C for 3 min. Then, 50 mg (0.16 mmol) of compound IntA (see Example 1 for specific synthesis method) and 47 mg (0.78 mmol) of AcOH were added to the reaction solution. The mixture was purged with nitrogen three times and reacted at 0 °C for 1.5 h. Finally, 29.99 mg (0.48 mmol) of NaBH3CN was added to the reaction solution, and the temperature was raised to 25 °C for 2 h. LCMS analysis confirmed the reaction was complete. The reaction was quenched by adding 0.3 ml of 1 M HCl aqueous solution. After concentration, the mixture was purified by reversed-phase chromatography to obtain 35.3 mg of compound 019A.

[0299] Ms: 713.6 [M+H] +

[0300] 1H NMR(600MHz,DMSO-d6)δ11.06(s,1H),10.28(s,0H),9.32–9.03(m,3H),8.15(s,1H),7.56(d,J=8.3Hz,1H),6.95(s,1H), 6.85(dd,J=8.2,2.1Hz,1H),6.56(s,1H),5.03(dd,J=12.8,5.4Hz,1H),4.35(s,2H),3.42–3.35(m,1H),3.19–3.10(m,3H ),2.97(t,J=7.6Hz,2H),2.92–2.79(m,2H),2.78–2.69(m,1H),2.65(dd,J=16.0,10.3Hz,1H),2.62–2.55(m,1H),2.23(d ,J=11.8Hz,1H),2.03–1.96(m,1H),1.80–1.72(m,1H),1.67(t,J=7.9Hz,2H),1.58(d,J=7.3Hz,2H),1.42–1.25(m,11H).

[0301] Example 8: Synthesis of compound 028A

[0302]

[0303] Step 1: Dissolve 858 mg (3.11 mmol) of compound 8-1 and 1 g (3.42 mmol) of compound N-Boc-1,11-diamino-3,6,9-trioxaundecan in 10 ml of DMSO, then add 1.07 g (8.28 mmol) of DIEA, heat to 120 °C and react for 2 h. The reaction was confirmed to be complete by TLC. The reaction solution was added to water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the crude product. The crude product was then purified by silica gel column chromatography to obtain 360 mg of compound 8-2.

[0304] Step 2: Dissolve 230 mg (0.42 mmol) of compound 8-2 in 2 ml of DCM, then add 0.5 ml of TFA. Stir the reaction solution at 30 °C for 1.5 h. LCMS monitoring showed that the reaction was complete. After concentration, 89.5 mg of compound 8-3 was obtained.

[0305] Step 3: Dissolve 89.5 mg (0.16 mmol) of compound 8-3 in 1 ml of methanol and 1 ml of tetrahydrofuran. Add 61.7 mg (0.48 mmol) of DIEA. Stir at 25 °C for 5 min. Then add 50 mg of compound IntA (0.16 mmol) and 47.8 mg (0.80 mmol) of AcOH to the reaction solution. Purge with nitrogen three times. React at 0 °C for 1.5 h. Then add 30.0 mg (0.48 mmol) of NaBH3CN to the reaction solution. Heat to 25 °C and react for 2 h. After the reaction is complete as detected by LCMS, quench the reaction with HCl (1 M, 0.1 ml). Concentrate and purify by reversed-phase chromatography to obtain 67.7 mg of compound 028A.

[0306] Ms: 747.6 [M+H] +

[0307] 1 H NMR (600MHz, DMSO-d6) δ11.07(s,1H),10.12(s,1H),9.09–8.95(m,2H),7.57(d,J=8.4Hz,1H),7.01(d,J= 2.1Hz,1H),6.90(dd,J=8.4,2.1Hz,1H),6.53(s,1H),5.03(dd,J=12.9,5.4Hz,1H),4.29(s,2H),3.73(t,J =5.3Hz,2H),3.36(t,J=5.5Hz,2H),3.26–3.21(m,2H),3.20–3.10(m,2H),2.92–2.81(m,2H),2.78–2.69( m,1H),2.63–2.56(m,2H),2.55(d,J=4.6Hz,8H),2.27–2.17(m,1H),2.05–1.97(m,1H),1.78–1.67(m,1H).

[0308] Example 9:

[0309] Following the synthetic methods of the compounds in Examples 6, 7, and 8, the following compounds were obtained, and their structures and characterization information are as follows:

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316] Example 10: Synthesis of compound 031A

[0317]

[0318] Step 1: Dissolve 5 g (18.1 mmol) of compound 10-1 and 3.37 g (18.1 mmol) of compound N-Boc-piperazine in 80 mL of DMSO, then add 7.02 g (54.3 mmol) of DIEA, heat to 120 °C and react for 3 h. The reaction was confirmed to be complete by TLC. The reaction solution was added to water (300 mL), and extracted with 50 mL of ethyl acetate each time. The organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the crude product. The crude product was then purified by silica gel column chromatography to obtain 7.9 g of compound 10-2.

[0319] Step 2: Dissolve 7.9 g (17.9 mmol) of compound 10-2 in hydrochloric acid / dioxane solution (concentration 4 M, volume 100 mL). Stir the reaction solution at 15 °C for 5 h. TLC monitoring showed that the reaction was complete. After concentration, 11 g of compound 10-3 was obtained.

[0320] Step 3: 200 mg (0.58 mmol) of compound 10⁻³, 102 mg (0.42 mmol) of compound 8-(Boc-amino)octanal, and 135 mg (1.05 mmol) of DIEA were dissolved in 5 mL of methanol solution. After stirring at 30 °C for 10 min, 105 mg (1.75 mmol) of AcOH was added to the reaction solution. The mixture was purged with nitrogen three times and reacted at 30 °C for 16 h. Then, 66.1 mg (1.05 mmol) of NaBH₃CN was added to the reaction solution, and the reaction was continued at 30 °C for another 0.5 h. After the reaction was confirmed to be complete by LCMS, the reaction solution was added to water (50 mL), and extracted with 30 mL of ethyl acetate each time. The organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the crude product. The crude product was then purified by silica gel column chromatography to obtain 120 mg of compound 10⁻⁴.

[0321] Ms: 570.5 [Ms+H] +

[0322] Step 4: Dissolve 120 mg (0.21 mmol) of compound 10-4 in 6 ml DCM and 3 ml TFA solution. React the solution at 30 °C for 0.5 h. TLC detection showed that the reaction was complete. Concentrate the reaction solution directly to obtain 130 mg of compound 10-5.

[0323] Step 5: Dissolve 129 mg (0.27 mmol) of compound 10⁻⁵ in 2 ml of methanol and 2 ml of tetrahydrofuran. Add 102 mg (0.79 mmol) of DIEA. Stir at 30 °C for 5 min, then cool to 0 °C. Add 50 mg (0.16 mmol) of compound Int A (synthesis method see Example 1) and 76 mg (1.3 mmol) of acetic acid to the above reaction solution. Continue stirring at 0-10 °C for 1 h. Add 29 mg of NaBH₃CN to the reaction solution, raise the temperature to 30 °C, and continue the reaction for 1 h. After the reaction is complete as detected by LCMS, add HCl (1 M) to the reaction solution until the pH is adjusted to 1-2. After concentration, obtain the crude product. The crude product is then separated by high pressure to obtain 30 mg of O₃₁A.

[0324] Ms = 768.7 [M+H] +

[0325] 1 H NMR (600MHz, DMSO-d6) δ10.62(s,1H),9.35(s,1H),8.87(s,2H),7.77(d,J=8.4Hz,1H),7.49(d,J=2.3Hz,1H),7.3 6(dd,J=8.6,2.3Hz,1H),6.48(s,1H),5.10(dd,J=12.9,5.4Hz,1H),4.21(d,J=13.8Hz,2H),3.98(s,2H),3.56(s,2 H),3.11(t,J=8.3Hz,4H),3.01(t,J=6.6Hz,2H),2.93–2.85(m,1H),2.85–2.78(m,1H),2.78–2.70(m,1H),2.64–2. 52(m,3H),2.21(d,J=12.1Hz,1H),2.08–2.01(m,1H),1.77–1.69(m,3H),1.65(d,J=8.5Hz,2H),1.40–1.21(m,9H).

[0326] Example 11: Synthesis of compound 034A

[0327]

[0328] Step 1: 200 mg (0.58 mmol) of compound 10-3 (synthesis shown in Example 10) and 104 mg (0.42 mmol) of compound (4-formylphenylethyl) tert-butyl carbamate were dissolved in 5 mL of methanol solution. 135 mg (1.04 mmol) of DIEA was added, and the mixture was stirred at 30°C for 30 min. Then, 168 mg of AcOH was added to the reaction solution, and the mixture was purged with nitrogen three times. After reacting at 30°C for 16 h, 66 mg (1.05 mmol) of NaBH3CN was added to the reaction solution, and the reaction was continued at 30°C for 1 h. After the reaction was confirmed to be complete by TLC, the methanol was removed by concentration, and 30 mL of water was added. The mixture was extracted with 30 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the crude product. The crude product was then purified by silica gel column chromatography to obtain 130 mg of compound 11-4.

[0329] Step 2: Dissolve 130 mg (0.23 mmol) of compound 11-4 in 6 ml of DCM and 3 ml of TFA solution. The reaction solution was reacted at 30 °C for 0.5 h. TLC showed that the reaction was complete. The reaction solution was then concentrated to obtain 140 mg of compound 11-5.

[0330] Step 3: Dissolve 130 mg (0.27 mmol) of compound 11-5 in 1 ml of methanol and 1 ml of tetrahydrofuran, add 102 mg (0.79 mmol) of DIEA, stir at 30 °C for 5 min, then cool to 0 °C. Add 50 mg (0.16 mmol) of compound intA (synthesis method see Example 1) and 76.4 mg (1.26 mmol) of acetic acid to the above reaction solution, continue stirring at 0-10 °C for 1 h, then add 30 mg (0.48 mmol) of NaBH3CN to the reaction solution, raise the temperature to 30 °C, and continue the reaction for 1 h. After the reaction is complete as detected by LCMS, add 5 ml of 1 M dilute HCl aqueous solution to the reaction solution until the pH is adjusted to 1-2, concentrate to obtain crude product, and use high pressure separation to obtain 46.8 mg of compound 034A.

[0331] Ms = 774.5[M+H] +

[0332] 1H NMR (600MHz, DMSO-d6) δ11.10(s,1H),9.78(s,1H),9.16(s,2H),7.76(d,J=8.5Hz,1H),7.59(d,J=7.8H z,2H),7.49–7.41(m,3H),7.33(dd,J=8.6,2.3Hz,1H),6.52(s,1H),5.09(dd,J=12.9,5.5Hz,1H),4.36( s,2H),4.14(s,4H),3.15(dd,J=15.5,5.3Hz,2H),3.11–3.01(m,2H),2.93–2.79(m,2H),2.79–2.69(m,1 H),2.69–2.56(m,2H),2.24(d,J=12.2Hz,1H),2.08–1.95(m,2H),1.84–1.71(m,1H),1.31–1.16(m,4H).

[0333] Example 12: Synthesis of compound 037A

[0334]

[0335] Step 1: Dissolve 5 g (14.9 mmol) of compound 12-1 and 3.1 g (14.8 mmol) of compound 1-Boc-4-ethynylpiperidine in 80 ml of DMF, then add 282 mg (1.48 mmol) of CuI and 15 g (0.15 mmol) of TEA, purge with nitrogen three times, add 120 mg of Pd(dppf)Cl2 (0.16 mmol), heat to 85 °C and react for 12 h. The reaction was confirmed to be complete by TLC. The reaction solution was added to water and extracted with DCM. The organic phase was dried with anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the crude product. The crude product was then purified by silica gel column chromatography to obtain 5.39 g of compound 12-2.

[0336] Step 2: Dissolve 5g (10.7mmol) of compound 12-2 in 15ml DCM and 10ml TFA solution. Stir the reaction solution at 30℃ for 0.5h. TLC monitoring showed that the reaction was complete. After concentration, 5.4g of compound 12-3 was obtained.

[0337] Ms: 366.28 [M+H] +

[0338] Step 3: 200 mg (0.55 mmol) of compound 12-3 and 104 mg (0.42 mmol) of compound 4-formylphenylethylcarbamate tert-butyl ester were dissolved in 3 mL of methanol solution. 161 mg (1.25 mmol) of DIEA was added, and the mixture was stirred at 25 °C for 30 min. Then, 200 mg (3.33 mmol) of AcOH was added to the reaction solution, and the mixture was purged with nitrogen three times. After reacting at 30 °C for 16 h, 78.6 mg (1.25 mmol) of NaBH3CN was added to the reaction solution, and the reaction was continued at 30 °C for 1 h. After the reaction was confirmed to be complete by LCMS, water (30 mL) was added, and the mixture was extracted with 30 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the crude product. The crude product was then purified by silica gel column chromatography to obtain 80 mg of compound 12-4.

[0339] Ms: 599.52 [M+H] +

[0340] Step 4: Dissolve 80 mg (0.13 mmol) of compound 12-4 in 6 ml DCM and 3 ml TFA solution. React the solution at 30 °C for 0.5 h. TLC detection showed that the reaction was complete. Concentrate the reaction solution directly to obtain 120 mg of compound 12-5.

[0341] Step 5: Dissolve 115 mg (0.23 mmol) of compound 12-5 in 1 ml of methanol and 1 ml of tetrahydrofuran. Add 102 mg (0.79 mmol) of DIEA, stir at 30 °C for 5 min, then cool to 0 °C. Add 50 mg (0.16 mmol) of compound intA (synthesis method see Example 1) and 76.4 mg (1.27 mmol) of acetic acid to the above reaction solution. Continue stirring at 0-10 °C for 1 h. Then add 30.0 mg (0.48 mmol) of NaBH3CN to the reaction solution, heat to 30 °C, and continue the reaction for 2 h. After the reaction is complete as detected by LCMS, add 3 ml of dilute HCl aqueous solution (1 M) to adjust the pH to 1-2. Concentrate to obtain the crude product, which is purified by reversed-phase chromatography to obtain 20.5 mg of compound 037A.

[0342] Ms = 797.6 [M+H] +

[0343] 1H NMR (600MHz, DMSO-d6) δ10.81–10.53(m,1H),9.78(s,1H),9.24(s,2H),8.07–7.84(m,3H),7.62(dd,J=29.8,7 .7Hz,2H),7.42(d,J=7.8Hz,2H),6.52(s,1H),5.23–5.10(m,1H),4.37(d,J=4.6Hz,1H),4.27(s,1H),4.15(s, 2H),3.25–3.13(m,2H),3.10–3.02(m,2H),2.98–2.80(m,4H),2.80–2.70(m,1H),2.69–2.58(m,2H),2.57–2.5 2(m,1H),2.25(d,J=12.0Hz,1H),2.22–2.13(m,2H),2.10–1.95(m,3H),1.83–1.73(m,1H),1.33–1.20(m,1H).

[0344] Example 13: Synthesis of Compound 040A

[0345]

[0346] Step 1: Dissolve 2 g (7.24 mmol) of compound 13-1 in 20 ml of DMSO solution, add 1.57 g (7.24 mmol) of compound N-Boc-1,6-hexanediamine and 2.80 g (21.7 mmol) of DIEA, purge with nitrogen three times, and heat to 120 °C. After stirring for 3 h, the reaction was monitored by TLC until complete. Extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. Purify by silica gel column chromatography to obtain 1.07 g of compound 13-2.

[0347] MS(M+H): 473.3[M+H]+

[0348] Step 2: Dissolve 1 g (2.12 mmol) of compound 13-2 in 10 ml of dichloromethane, add 3 ml of trifluoroacetic acid at room temperature, and stir at room temperature for 2 h. Monitor the reaction by TLC until complete. After concentration under reduced pressure, the crude product is purified by slurry mixing with 10 ml of a 5:1 mixture of methyl tert-butyl ether and ethyl acetate. After filtration, 1.01 g of compound 13-3 is obtained.

[0349] MS(M+H): 373.2[M+H]+.

[0350] Step 3: Dissolve 300 mg (0.81 mmol) of compound 13-3 in 6 ml of methanol, add 0.5 ml of DIEA, stir at 30 °C for 10 min, add compound B and 1 ml of HOAc, measure the pH to be 6, continue stirring at 30 °C for 6 h, LCMS monitoring shows that 20% of the raw material remains, add saturated ammonium chloride aqueous solution to quench the reaction, extract the aqueous phase three times with ethyl acetate, and purify by silica gel column chromatography to obtain 150 mg of compound 13-4.

[0351] MS(M+H):582.4[M+H]+.

[0352] Step 4: Dissolve 100 mg (0.17 mmol) of compound 13-4 in 2 ml of dichloromethane, add 0.5 ml of trifluoroacetic acid at room temperature, and stir at room temperature for 2 h. Monitor the reaction by LCMS until complete, and concentrate under reduced pressure to obtain 100 mg of compound 13-5.

[0353] MS(M+H):482.2[M+H]+.

[0354] Step 5: Dissolve 87 mg (0.18 mmol) of compound 13-5 in 2 ml of methanol, and add 70 mg (0.54 mmol) of DIEA. After stirring at room temperature for 10 min, cool to 0 °C, and add 50 mg (0.16 mmol) of intA (synthesis method see Example 1) and 100 mg (1.67 mmol) of HOAc. Continue stirring at 0 °C for 30 min, and add 46 mg (0.73 mmol) of sodium cyanoborohydride. After stirring at room temperature for 30 min, monitor the reaction for completeness using LCMS. Quench the reaction with 0.5 ml of 1 M HCl aqueous solution, filter, and purify by reversed-phase chromatography to obtain 10 mg of compound 040A.

[0355] MS(M+H):780.6[M+H]+.

[0356] 1H NMR (600MHz, DMSO-d6) δ11.06(s,1H),9.18(s,2H),8.83(s,2H),7.64–7.52(m,1H),6.95(d,J=2 .1Hz,1H),6.86(dd,J=8.5,2.1Hz,1H),6.50(s,1H),5.03(dd,J=12.9,5.4Hz,1H),4.17(s,2H),3 .88–3.80(m,1H),3.17(t,J=6.9Hz,3H),3.08–3.01(m,1H),2.91–2.71(m,6H),2.62–2.54(m,2H) ,2.48–2.40(m,3H),2.34–2.19(m,8H),2.17–1.97(m,2H),1.75–1.66(m,1H),1.62–1.52(m,6H).

[0357] Example 14: Synthesis of compound 044A

[0358]

[0359] Step 1: Dissolve 300 mg (0.88 mmol) of compound 10-3 (see Example 10 for synthesis) and 183 mg (0.69 mmol) of compound 2-[2-(tert-Butoxycarbonylamino)ethoxy]ethoxyacetic acid in 3 ml of DCM solution. Add 254 mg (1.97 mmol) of DIEA and 1 g of n-butylphosphine (T4P, 50% ethyl acetate solution). Stir at room temperature for 1 h. The reaction was monitored by LCMS until it was complete. Quench the reaction solution with 5 ml of water. Extract with DCM. Dry the organic phase with anhydrous sodium sulfate. After concentration, the crude product was purified by silica gel column chromatography to obtain 247 mg of compound 14-2.

[0360] MS(M+H): 610.3[M+H]+

[0361] Step 2: Dissolve 247 mg (0.42 mmol) of compound 14-2 in 5 ml of dichloromethane, add 2 ml of trifluoroacetic acid at room temperature, and stir for 1 h at room temperature. Monitor the reaction by LCMS until complete, and concentrate under reduced pressure to obtain 180 mg of compound 14-3.

[0362] MS(M+H):488.4[M+H]+.

[0363] Step 3: Dissolve 95 mg (0.20 mmol) of compound 14-3 in 3 ml of methanol, add 125 mg (0.97 mmol) of DIEA, stir at 30 °C for 10 min, add 50 mg (0.16 mmol) of compound intA (synthesis method see Example 1) and 95 mg (1.58 mmol) of HOAc, stir at 0 °C for 30 min, add 30.2 mg (0.48 mmol) of sodium cyanoborohydride at 0 °C, stir at room temperature for 30 min, and monitor the reaction at room temperature until complete. Quench the reaction with 0.5 ml of dilute HCl aqueous solution (1 M), filter, and purify by reversed-phase chromatography to obtain 11 mg of compound 044A.

[0364] MS(M+H):786.2[M+H]+.

[0365] 1 H NMR(600MHz,DMSO-d6)δ11.09(s,1H),9.58(s,1H),8.84–8.64(m,3H),7.72(d,J=8.5Hz,1H ),7.37(d,J=2.3Hz,1H),7.26(dd,J=8.7,2.4Hz,1H),6.49(s,1H),5.08(dd,J=12.9,5.5Hz ,1H),4.25(s,2H),4.09(s,2H),3.75(s,2H),3.65(d,J=6.0Hz,4H),3.61–3.49(m,9H),3.1 6–3.11(m,1H),2.94–2.70(m,4H),2.65–2.56(m,2H),2.19(s,1H),2.02(d,J=13.2Hz,1H).

[0366] Example 15: Synthesis of Compound 048A

[0367]

[0368] Step 1: Dissolve 5 g (18.1 mmol) of compound 15-1 and 6.16 g (21.7 mmol) of compound 4-(piperazin-1-ylmethyl)piperidine-1-carboxylic acid tert-butyl ester in 50 ml of DMSO, then add 7.02 g (54.3 mmol) of DIEA, heat to 130 °C and react for 4 h. The reaction was confirmed to be complete by TLC. The reaction solution was added to water (150 ml) and extracted with 100 ml of ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, filtered, and rotary evaporated to obtain crude product. Then, it was purified by slurrying with methyl tert-butyl ether (50 ml) and filtered to obtain 8 g of compound 15-2.

[0369] Step 2: Dissolve 8g of compound 15-2 (14.8mmol) in 100ml of solution (DCM:TFA = 3:1). Stir the reaction solution at 30℃ for 1.5h. Monitor the reaction by TLC until it is complete. After the reaction solution is concentrated, add 100ml of water and freeze-dry to obtain 10g of compound 15-3.

[0370] Step 3: 300 mg (0.68 mmol) of compound 15-3 and 125 mg (0.55 mmol) of compound (6-oxospiro[3.3]hept-2-yl) tert-butyl carbamate were dissolved in 5 ml of methanol solution. 360 mg (2.79 mmol) of DIEA was added, and the mixture was stirred at 25 °C for 30 min. Then, 268 mg (4.47 mmol) of AcOH was added to the reaction solution. The mixture was purged with nitrogen three times and reacted at 25 °C for 16 h. Finally, 105 mg (1.67 mmol) of NaBH3CN was added to the reaction solution, and the reaction was continued at 25 °C for 1 h. After the reaction was confirmed to be complete by LCMS, the methanol was removed by concentration, and the mixture was extracted with 30 ml of DCM:MeOH = 10:1. The organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the crude product. The crude product was then purified by silica gel column chromatography to obtain 250 mg of compound 15-4.

[0371] Ms: 649.6 [M+H] +

[0372] Step 4: Dissolve 250 mg (0.39 mmol) of compound 15-4 in 6 ml of DCM and 3 ml of TFA solution. React the solution at 30 °C for 0.5 h. TLC detection showed that the reaction was complete. Concentrate the reaction solution directly to obtain 400 mg of compound 15-5.

[0373] Step 5: Dissolve 159 mg (0.29 mmol) of compound 15-5 in 2 ml of methanol and 2 ml of tetrahydrofuran. Add 61.7 mg (0.48 mmol) of DIEA, stir at 30 °C for 5 min, then cool to 0 °C. Add 50 mg (0.16 mmol) of compound Int A (synthesis method see Example 1) and 47.7 mg (0.8 mmol) of acetic acid to the above reaction solution. Continue stirring at 0-10 °C for 1 h. Then add 30.0 mg of NaBH3CN (0.48 mmol) to the reaction solution, heat to 30 °C, and continue the reaction for 2 h. After the reaction is complete as detected by LCMS, quench the reaction with dilute hydrochloric acid aqueous solution (1 M), adjust the pH to 1-2, concentrate to obtain crude product, and purify the crude product by reversed-phase chromatography to obtain 39.7 mg of compound 048A.

[0374] Ms = 847.7[Ms+H] +

[0375] 1H NMR(600MHz,DMSO-d6)δ11.10(s,1H),10.88–10.75(m,1H),9.86(s,1H),9.36(s,2H),7.77(d,J=8 .4Hz,1H),7.50(s,1H),7.36(dd,J=8.7,2.2Hz,1H),6.52(s,1H),5.10(dd,J=12.9,5.5Hz,1H),4.2 0(d,J=14.1Hz,4H),3.94–3.83(m,1H),3.34(d,J=11.2Hz,4H),3.17–3.03(m,5H),2.94–2.85(m,1 H),2.84–2.64(m,4H),2.63–2.56(m,2H),2.48–2.23(m,9H),2.19–2.00(m,5H),1.86–1.52(m,3H).

[0376] Example 16: Synthesis of compounds 058A and 059A

[0377]

[0378] Step 1: Dissolve 1 g (2.27 mmol) of compound 15-3 (see Example 15 for detailed synthesis) in 10 mL of DMSO solution, add 389 mg (2.72 mmol) of compound 5-chloropyrazine-2-carboxaldehyde and 1.05 g (8.12 mmol) of DIEA, purge with nitrogen three times, and heat to 120 °C. After stirring for 2 h, the reaction was monitored by LCMS until complete. Add 30 mL of water, wash and extract with 50 mL of ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain crude product. Purify by slurrying with 10 mL of a mixed solution of methyl tert-butyl ether and ethyl acetate (10:1) to obtain 820 mg of compound 16-2.

[0379] MS(M+H): 546.4[M+H]+

[0380] Step 2: Dissolve 74 mg (0.26 mmol) of compound int D (synthesis details in Example 4) in 1 ml DMF, add 70 mg (7.78 mmol) DIEA, and stir at room temperature for 10 min. Cool to 0 °C, add 140 mg (0.26 mmol) of compound 16-2 and 100 mg HOAc (1.67 mmol), and stir at 0 °C for 30 min. Add 34 mg (0.54 mmol) of sodium cyanoborohydride, and stir at room temperature for 30 min. Monitor the reaction for completeness using LCMS, quench the reaction with 0.5 ml of 1 M HCl aqueous solution, and purify by reversed-phase chromatography to obtain 50 mg of compound 058A.

[0381] MS(M+H):819.2[M+H]+.

[0382] 1 H NMR (600MHz, DMSO-d6) δ10.35(s,1H),10.08(s,1H),9.13(s,2H),8.41(s,1H),8.21(s,1H),7.78(d,J=8.4Hz,1H),7.5 0(d,J=2.2Hz,1H),7.37(dd,J=8.6,2.3Hz,1H),6.69–6.61(m,2H),5.10(dd,J=12.8,5.4Hz,1H),4.41(d,J=13.2Hz,2H ),4.23–4.14(m,5H),3.62(d,J=11.9Hz,2H),3.16(dt,J=21.2,10.1Hz,4H),3.08(d,J=6.5Hz,2H),2.98(t,J=12.5Hz, 2H),2.93–2.86(m,3H),2.63–2.55(m,2H),2.21(s,1H),2.07–2.01(m,1H),1.94(d,J=11.6Hz,2H),1.27–1.16(m,3H).

[0383] Step 3: Dissolve 50 mg (0.16 mmol) of compound int E (see Example 5 for detailed synthesis) in 1 ml DMSO, add 45 mg (0.35 mmol) of DIEA, stir at room temperature for 10 min, add 86 mg (0.16 mmol) of compound 16-2 and 35 mg (0.58 mmol) of HOAc, continue stirring at room temperature for 30 min, add 22 mg (0.35 mmol) of sodium cyanoborohydride, stir at room temperature for 30 min, and LCMS monitoring shows that the reaction is complete. Add 0.3 ml of HCl aqueous solution (1 M) to quench the reaction, and purify by reversed-phase chromatography to obtain 50 mg of compound 059A.

[0384] MS(M+H): 845.6[M+H]+.

[0385] 1H NMR(600MHz,DMSO-d6)δ11.10(s,1H),10.23(s,1H),9.78(s,1H),9.43(s,1H),8.42(s,1H),8.21(s,1H),7 .78(d,J=8.4Hz,1H),7.50(s,1H),7.37(d,J=8.7Hz,1H),6.58(s,1H),5.10(dd,J=12.8,5.4Hz,1H),4.43(d ,J=13.1Hz,2H),4.36(s,2H),4.21(s,2H),3.94(s,2H),3.64(s,4H),3.17(s,4H),2.98(t,J=12.2Hz,5H), 2.89(s,2H),2.59(t,J=13.2Hz,2H),2.18(s,1H),2.07–2.00(m,1H),1.94–1.85(m,2H),1.28–1.17(m,3H).

[0386] Example 17: Synthesis of Compound 029A

[0387]

[0388] Step 1: 300 mg (0.68 mmol) of compound 15-3 (see Example 15 for detailed synthesis) and 185 mg (0.76 mmol) of compound 4-[(BOC-amino)methyl]cyclohexaneformaldehyde were dissolved in 5 mL of methanol solution. 248 mg (1.92 mmol) of DIEA was added, and the mixture was stirred at 30 °C for 30 min. Then, 184 mg (3.1 mmol) of AcOH was added to the reaction solution. The mixture was purged with nitrogen three times and reacted at 30 °C for 16 h. Finally, 72.3 mg (1.15 mmol) of NaBH3CN was added to the reaction solution, and the reaction was continued at 30 °C for 1 h. After the reaction was confirmed to be complete by LCMS, the methanol was removed by concentration. Water (50 mL) was added, and the mixture was extracted with 30 mL of DCM:MeOH = 10:1. The organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the crude product. This crude product was then purified by silica gel column chromatography to obtain 210 mg of compound 17-2.

[0389] Ms: 665.6 [M+H] +

[0390] Step 2: Dissolve 210 mg (0.32 mmol) of compound 17-2 in 6 ml of DCM and 3 ml of TFA solution. The reaction solution was reacted at 30 °C for 0.5 h. TLC showed that the reaction was complete. The reaction solution was then concentrated to obtain 350 mg of compound 17-3.

[0391] Step 3: Dissolve 50 mg (0.089 mmol) of compound 17-3 in 1 ml of DMF solution, add 71.6 mg (0.19 mmol) of HATU, 160 mg (0.50 mmol) of compound int C (see Example 3 for detailed synthesis) and 162 mg (1.25 mmol) of DIEA, stir at 25 °C for 2 h, and after the reaction is complete as detected by LCMS, the reaction solution is purified by reversed-phase preparative chromatography to obtain 28.3 mg of compound 029A.

[0392] Ms = 865.6 [M+H] +

[0393] 1 H NMR (600MHz, DMSO-d6) δ11.11(s,1H),9.54(s,1H),8.67(s,1H),7.80(dd,J=19.9,7.2Hz,2H),7.51(d,J =2.5Hz,1H),7.38(dd,J=8.7,2.3Hz,1H),6.57–6.49(m,2H),5.10(dd,J=12.9,5.5Hz,1H),4.03(s,2H),3 .53(s,2H),3.09(d,J=6.2Hz,2H),2.94–2.84(m,6H),2.78–2.72(m,2H),2.64–2.54(m,2H),2.37(t,J=6. 9Hz,2H),2.15–1.93(m,4H),1.80–1.63(m,3H),1.60–1.43(m,4H),1.33–1.21(m,4H),0.94–0.80(m,4H).

[0394] Example 18: Synthesis of compounds 054A, 055A, and 065A

[0395]

[0396]

[0397] Step 1: Dissolve 1 g (2.40 mmol) of compound 18-1 in a mixture of 10 ml THF solution and 1 ml H2O. Add 807 mg (2.40 mmol) of compound 6-bromo-3-iodo-1-methyl-1H-indazole (CAS: 1260741-78-3) and 2.34 g (7.18 mmol) of cesium carbonate. Purge the mixture with nitrogen three times. Add 196 mg (0.24 mmol) of the [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloromethane complex. Purge the mixture with nitrogen three times again. Heat the mixture to 75 °C and stir for 12 h. The reaction is complete as monitored by LCMS. Add 30 ml of water to the reaction mixture and extract with ethyl acetate. Dry the resulting organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. Purify the crude product by silica gel column chromatography to obtain 0.7 g of compound 18-2 as a white solid.

[0398] MS(M+H):500.2 / 502.1[M+H]+

[0399] Step 2: 610 mg (1.22 mmol) of compound 18-2 was dissolved in 6 mL of 1,4-dioxane to obtain a reaction solution. 524 mg (2.43 mmol) of 2-(4-hydroxypiperidin-4-yl) tert-butyl acetate (CAS: 180532-52-9), 940 mg (2.89 mmol) of cesium carbonate, 112 mg (0.24 mmol) of RuPhos, and 200 mg (0.24 mmol) of RuPhosPdG3 were added to the reaction solution. The mixture was purged with nitrogen three times, heated to 100 °C, and stirred for 2 h. The reaction was monitored by LCMS until complete. 5 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 0.81 g of compound 18-3.

[0400] MS(M+H): 635.2[M+H]+

[0401] Step 3: Dissolve 810 mg (1.28 mmol) of compound 18-3 in 30 mL of anhydrous tetrahydrofuran. Under nitrogen protection, add 700 mg each of Pd / C and Pd(OH)2. After purging with hydrogen three times, stir at room temperature for 8 hours. LCMS monitoring showed that the reaction was complete. Filter the reaction solution with diatomaceous earth, wash the filter cake with methanol, concentrate the mother liquor to obtain the crude product, and purify it by silica gel column chromatography to obtain 500 mg of compound 18-4.

[0402] MS(M+H): 457.3[M+H]+.

[0403] Step 4: Dissolve 500 mg (1.10 mmol) of compound 18-4 in 2 ml of dichloromethane, add 1 ml of trifluoroacetic acid at room temperature, and stir at room temperature for 2 h. Monitor the reaction by TLC until complete, and concentrate under reduced pressure to obtain 500 mg of compound 18-5.

[0404] MS(M+H):401.4.[M+H]+.

[0405] Step 5: Dissolve 60 mg (0.15 mmol) of compound 18-5 in 0.7 ml of DMF, add 58 mg (0.45 mmol) of DIEA, 43 mg (0.15 mmol) of int D (see Example 4 for detailed synthesis) and 162 mg of T4P (50% ethyl acetate solution), stir at room temperature for 1 h, and monitor the reaction as complete by LCMS. Concentrate the reaction solution under reduced pressure, filter, and purify by reversed-phase chromatography to obtain 10 mg of compound 054A.

[0406] MS(M+H): 672.4[M+H]+.

[0407] 1 H NMR(600MHz,DMSO-d6)δ10.90(s,1H),10.19(s,0H),8.16(s,1H),7.67(s,1H),7.46–7.13(m,1H),6.67–6.58(m,2H),4.28(s,3H) ,3.97(s,3H),3.34–3.30(m,5H),2.71–2.59(m,4H),2.41–2.29(m,3H),2.24–2.14(m,1H),2.06–1.85(m,1H),1.75–1.63(m,2H).

[0408] Step 6: Dissolve 60 mg (0.15 mmol) of compound 18-5 in 0.7 mL of DMF, add 58 mg (0.45 mmol) of DIEA, 64 mg (0.20 mmol) of int E (see Example 5 for detailed synthesis), and 162 mg of T4P (50% ethyl acetate solution). Stir at room temperature for 16 h, and the reaction is monitored by LCMS until complete. The reaction solution is concentrated under reduced pressure, filtered, and purified by reversed-phase chromatography to obtain 10 mg of compound 055A.

[0409] MS(M+H):698.4[M+H]+.

[0410] 1H NMR (600MHz, DMSO-d6) δ10.91(s,1H),10.16(s,0H),7.78–7.48(m,1H),7.29(s,1H),6.63(d,J=10.6Hz,1H),4.40–4.27(m,3H),3.99(s, 3H),2.95–2.86(m,2H),2.86–2.75(m,2H),2.73–2.57(m,4H),2.43–2.32(m,1H),2.21–2.13(m,1H),2.08(s,1H),1.84(d,J=13.4Hz,2H).

[0411] Step 7: Dissolve 14 mg (0.035 mmol) of compound 18-5 in 0.7 ml of DMF, add 30 mg (0.23 mmol) of DIEA, 15 mg (0.048 mmol) of int B (see Example 2 for detailed synthesis), 15 mg (0.11 mmol) of HOBT, and 25 mg (0.13 mmol) of EDCI, stir at room temperature for 1 h, and monitor the reaction until complete by LCMS. The reaction solution was purified by reversed-phase chromatography to obtain 2.4 mg of compound 065A.

[0412] MS(M+H):698.4[M+H]+.

[0413] 1 H NMR (600MHz, DMSO-d6) δ10.90(s,1H),10.08(s,1H),8.18(s,1H),6.52(s,1H),4.34(s,3H),3.99(s,4H),2.89(dd,J=16.0,5.4Hz,1H),2. 81–2.65(m,3H),2.65–2.58(m,1H),2.55(s,3H),2.44–2.31(m,5H),2 .20–2.14(m,1H),1.94–1.86(m,1H),1.76(s,2H),1.71–1.62(m,1H).

[0414] Example 19:

[0415] Synthesis of compounds 062A and 063A:

[0416]

[0417] Step 1: Dissolve 350 mg (1.02 mmol) of compound 10-3 (synthesis details in Example 10) in 4 mL of DMF solution. Add 176 mg (0.76 mmol) of compound 8-(tert-butoxy)-8-oxooctanoic acid, 197 mg (1.52 mmol) of DIEA, and 1.65 g of T4P (50% ethyl acetate solution). Stir at room temperature for 1 h. The reaction was monitored by LCMS until complete. Add 10 mL of H2O to the reaction solution, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. Purify by silica gel column chromatography to obtain 214 mg of compound 19-2.

[0418] MS(M+H): 499.4[M+H]+

[0419] Step 2: Dissolve 214 mg (0.39 mmol) of compound 19-2 in 5 ml of DCM, add 1.5 ml of trifluoroacetic acid at room temperature, and stir at room temperature for 2 h. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure and purified by slurrying with methyl tert-butyl ether to obtain 187 mg of compound 19-3.

[0420] MS(M+H): 499.4[M+H]+

[0421] Step 3: Dissolve 62 mg (0.12 mmol) of compound 19-3 in 1 ml of DMF, add 112 mg (0.87 mmol) of DIEA, 50 mg (0.17 mmol) of int D (see Example 4 for synthesis), and 162 mg of T4P (50% ethyl acetate solution). Stir at room temperature for 2 h, and the reaction is monitored by LCMS until complete. The reaction solution is concentrated under reduced pressure, filtered, and purified by reversed-phase chromatography to obtain 10 mg of compound 062A.

[0422] MS(M+H): 770.5[M+H]+.

[0423] 1H NMR (600MHz, DMSO-d6) δ10.14(s,1H),8.84(s,1H),7.89(t,J=5.6Hz,1H),7.71(d,J=8.5Hz, 1H),7.35(d,J=2.3Hz,1H),7.25(dd,J=8.6,2.3Hz,1H),6.62–6.51(m,2H),5.08(dd,J=12.8, 5.5Hz,1H),4.28(s,2H),3.64–3.61(m,4H),3.25–3.21(m,3H),2.93–2.84(m,1H),2.62(t,J =7.2Hz,3H),2.34(t,J=7.5Hz,2H),2.06–1.99(m,3H),1.55–1.44(m,6H),1.32–1.24(m,6H).

[0424] Step 4: Dissolve 60 mg of compound 19-3 (0.12 mmol) in 0.7 ml of DMF, add 116 mg (0.90 mmol) of DIEA, 50 mg (0.16 mmol) of int E (see Example 5 for synthesis), and 162 mg of T4P (50% ethyl acetate solution). Stir at room temperature for 2 h, and monitor the reaction until complete by LCMS. Concentrate the reaction solution under reduced pressure, filter, and purify by reversed-phase chromatography to obtain 10 mg of compound 063A.

[0425] MS(M+H):796.6[M+H]+.

[0426] 1 H NMR(600MHz,DMSO-d6)δ11.09(s,1H),10.07(s,1H),8.86(s,1H),7.71(d,J=8.5Hz,1H),7 .35(d,J=2.3Hz,1H),7.25(dd,J=8.6,2.2Hz,1H),6.58(d,J=7.2Hz,1H),5.08(dd,J=12.9 ,5.5Hz,1H),4.31(s,2H),3.65–3.59(m,6H),2.94–2.80(m,4H),2.80–2.69(m,2H),2.66– 2.55(m,2H),2.42–2.31(m,4H),2.08–1.99(m,1H),1.57–1.45(m,6H),1.39–1.28(m,4H).

[0427] Example 20:

[0428] Following the synthetic methods of the compounds in Examples 10-19, the following compounds were obtained, and their structures and characterization information are as follows:

[0429]

[0430]

[0431]

[0432]

[0433]

[0434] Test Example 1: Degradation Activity Detection of PTPN1 and PTPN2

[0435] The testing steps are as follows:

[0436] Mouse melanoma cells B16-F10 were cultured in complete cell culture medium (DMEM + 10% FBS) at 37°C in a 5% CO2 incubator. Cells in the exponential growth phase were collected, and the cell suspension was adjusted to the appropriate concentration with complete culture medium for plating. Cells were seeded into 12-well plates at 10 × 10⁶ cells / well. 5 Cells / well were cultured overnight in an incubator, and then different concentrations of the test compounds (the compounds prepared in Examples 6-20) were added. The cells were then incubated at 37°C with 5% CO2 for 24 hours. After incubation, the cells were washed with pre-chilled PBS, and then lysed on ice for 15 minutes with cell lysis buffer (CST, Cat. 9803, cocktail: cell lysis buffer 1:100). Cells were scraped into new pre-chilled EP tubes and centrifuged at 13500 rpm at 4°C for 20 minutes. The supernatant protein sample was collected, and protein quantification was performed using a BCA kit (Thermofisher, Cat. 23225). The protein was then diluted to 2 mg / mL. The prepared sample was loaded into a 4-12% precast gel at a volume of 5 μL (10 μg). The TCPTP (TC45)(D7T7D) Rabbit mAb (CST, Cat. 58935S), PTPN1 antibody (Bio-Techne Cat. AF3954), and internal control Vinculin (E1E9V) were detected using conventional Western blot methods. Rabbit mAb (CST, Cat. 13901S) expression was assessed using HRP-labeled Anti-rabbit IgG Antibody (CST, Cat. 7074V) and Anti-Goat (Solarbio Cat. A10705D-HRP) as secondary antibodies. The expression level of AR relative to the internal control was calculated using the protein expression quantification software "Image J," and DC was calculated using GraphPad Prism 8.0 software according to Equation (1). 50 Value. Where R compound R represents the relative expression levels of PTPN1 and PTPN2 in different drug concentration groups. DMSO The relative expression level of AR in the DMSO control group.

[0437] %Degradation=(AVE_R DMSO -R compound ) / AVE_R DMSO ×100% formula (1).

[0438] The results showed that the compounds of this application exhibited significant selective degradation of PTPN2, while showing very low or almost no degradation of PTPN1. This application exemplarily demonstrates the IC50 values ​​of some compounds. 50 For the results, please refer to Table 1.

[0439] Table 1: IC50 of each compound 50 result

[0440]

[0441]

[0442]

[0443] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of this application. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0444] Although embodiments of this application have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting this application. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of this application.

Claims

1. A compound, characterized in that, The compound is a compound of formula (I), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof: ELA (I); E is used to target the E3 ubiquitin ligase complex; A has the structure shown in equation (II): Among them, R1, R2, and R3 are each independently H, -OH, halogen, and -C. 1～6 Alkyl, -C 1～6 Halogenated alkyl, or -C 1～6 Hydroxyalkyl; R4 is empty, and can be arbitrarily assigned to one or more R4 values. a The -N(R6)- that is replaced, optionally by one or more R a Replacement -N(R6)-C 1～6 Alkylene-, or optionally with one or more R a Substituted -N(R6)-C(O)-C 1～6 alkylene-; R5 and R6 are independently H and -C, respectively. 1～6 Alkyl, -C 1～6 Halogenated alkyl, or -C 1～6 Hydroxyalkyl; Ring A is empty, and can be arbitrarily controlled by one or more R. b Substituted 5-10 membered cycloalkyl, or optionally with one or more R b Substituted 5-10 membered heterocyclic alkyl groups; Ring B is empty, and can be arbitrarily assigned to one or more R. c Replaces 5-12 elemental helical rings, optionally with one or more R c Replaces 5-12 ternary heterocyclic rings, optionally with one or more R c Replaces the 5-12 element bridge ring, optionally replaced by one or more R c Replaces the 5-12 elemental hybrid bridge ring, optionally replaced by one or more R c Replaces 5-12 element rings, optionally with one or more R c Replaced 5-12 quinary heterocyclic rings; Each R a R b R c Each is independently selected from -OH, halogen, oxo (=O), -C 1～6 Alkyl, -C 1～6 Halogenated alkyl, or -C 1～6 Alkoxy; n is 0 or 1; L has the structure shown in equation (III): Where L1 is -N(R7)-, arbitrarily controlled by one or more R d Substituted 4-10 membered heterocyclic alkyl groups, optionally with one or more R d Replacement -C 1～6 alkenyl-(4-10)-membered heterocyclic alkyl, or optionally with one or more R d Replacement -C 1～6 Imylacetyl-(4-10)-membered heterocyclic alkyl, wherein the 4-10-membered heterocyclic alkyl or -C 1～6 The alkenyl-(4-10)-membered heterocyclic alkyl group contains one or more nitrogen atoms; L2 is arbitrarily assigned to one or more Rs e Replacement -C 3～15 Alkylene-, optionally with one or more R e Replacement -R8-(OC) 1～6 (alkylene)m-, optionally with one or more R e Replacement -C 1～6 Alkylene-(3-10)-membered cycloalkyl-, optionally with one or more R e Replacement -C 1～6 alkylene-(6-10) aryl-, optionally with one or more R e Replacement -C 1～6 alkylene-(3-10)-membered heterocyclic alkyl-, optionally with one or more R e Replacement -C 1～6 Alkylene-C(O)-, optionally with one or more R e Substituted -C(O)-C 1～10 Alkylene-, or optionally with one or more R e Substituted -(5-10) heteroaryl-; L3 is empty, -C(O)-, and can be arbitrarily controlled by one or more Rs. f Replacement -C 1～6 Alkylene-, optionally with one or more R f Replaces 5-12 elemental helical rings, optionally with one or more R f Replacement -C 1～6 alkylene-(3-10)-membered cycloalkyl-C 1～6 Alkylene-, optionally with one or more R f Substituted -(5-10) heteroaryl-C 1～6 Alkylene-, optionally with one or more R f Replacement -C 1～6 alkylene-(6-10)-aryl-C 1～6 Alkylene-, optionally with one or more R f Replacement -C 1～6 alkylene-(3-10)-membered cycloalkyl-C 1～6 Alkylene-, optionally with one or more R f Substituted -C(O)-C 1～6 Alkylene-C(O)-, optionally with one or more R f The -N(R9)-(5-12) elemental spiroring is replaced, or optionally replaced by one or more R elements. f Substituted -(5-10) heteroaryl-C 1～6 Alkylene-(5-12)-membered spirocyclic-; R7 and R9 are independently H and -C, respectively. 1～6 Alkyl, -C 1～6 Halogenated alkyl, or -C 1～6 Hydroxyalkyl; R8 is arbitrarily assigned to one or more R... g Replace -C 1～6 Alkylene-, optionally with one or more R g Substitution -C(O)-C 1～6 Alkylene-, or optionally with one or more R g Replace -C 1～6 alkylene-(6-10) aryl-; Each R d R e R f R g Each is independently selected from -OH, halogen, oxo (=O), -C 1～6 Alkyl, or -C 1～6 Halogenated alkyl, -C 1～6 Alkoxy; m is 1, 2, 3, 4, 5, or 6; * indicates the connection site of E, and ** indicates the connection site of A.

2. The compound according to claim 1, characterized in that, The compound satisfies one or more of the following conditions: 1) R1, R2, and R3 are each independently H, -OH, halogen, or -C. 1～3 Alkyl, -C 1～3 Halogenated alkyl, or -C 1～3 Hydroxyalkyl; Optionally, R1 is -OH; Optionally, R2 is a halogen, preferably F; Optionally, R3 is H; 2) Ring A is arbitrarily controlled by one or more R a When substituted with 5-10 membered heterocyclic alkyl groups, ring B is empty, R4 is empty (0), and n is 0; Optionally, ring A is arbitrarily controlled by one or more R... a Substituted 6-8 membered heterocyclic alkyl groups; Choose any location, ring A is * indicates an R4 connection site; 3) When ring A is empty, R4 is arbitrarily selected by one or more R... a Replacement -N(R6)-C 1～6 Alkylene-, or optionally with one or more R a Substituted -N(R6)-C(O)-C 1～6 Alkylene-, and ring B is empty and n is 0; Optionally, R4 is optionally controlled by one or more R... a Replacement -N(R6)-C 1～6 Alkylene-, or optionally with one or more R a Substituted -N(R6)-C(O)-C 1～6 Alkylene, where R6 is H or -C 1～6 alkyl; Optionally, R4 is -N(R6)-C 1～6 Alkylene- or -N(R6)-C(O)-C 1～6 Alkylene, where R6 is H or -C 1～3 alkyl; Optionally, R4 is -NH-C 1～3 Alkylene- or -NH-C(O)-C 1～3 alkylene-; 4) When ring B is not empty, R4 is arbitrarily selected by one or more R... a The -N(R6)- is replaced, and n is 1; Optionally, R4 is optionally controlled by one or more R... a The substitution is -N(R6)-, where R6 is H or -C. 1～6 alkyl; Optionally, R4 is -N(R6)-, and R6 is H or -C. 1～6 alkyl; Optionally, R4 is -NH-; Optionally, ring B is arbitrarily controlled by one or more R... c Replaces 5-12 elemental helical rings, or optionally with one or more R c Replacement of 5-12 quinary heterocyclic spiral rings; Optionally, ring B is arbitrarily controlled by one or more R... c Replaces 6-10 element screw rings, or optionally is replaced by one or more R c Replacement of 6-10 quinary heterocyclic spiral rings; Optionally, ring B is a 6-10 element spiral ring; Choose any location, ring B is Optionally, ring A is arbitrarily controlled by one or more R... b Substituted 5-10 membered cycloalkyl groups; Optionally, ring A is arbitrarily controlled by one or more R... b Substituted 5-8 membered cycloalkyl groups; Optionally, ring A is a 5-8 membered cycloalkyl group; Choose any location, ring A is * indicates an R4 connection site; 6) R5 is H or -C 1～6 alkyl; Optionally, R5 is H; 7) Each R a R b R c Each is independently selected from halogens and -C 1～6 Alkyl, or -C 1～6 Halogenated alkyl groups; 8) A has the following structure:

3. The compound according to claim 1, characterized in that, The compound satisfies one or more of the following conditions: 1) L1 is -N(R7)-, arbitrarily controlled by one or more R d Substituted 5-8 membered heterocyclic alkyl groups, optionally with one or more R d Replacement -C 1～3 alkenyl-(5-8)-membered heterocyclic alkyl, or optionally with one or more R d Replacement -C 1～3 Imylacetyl-(4-10)-membered heterocyclic alkyl, wherein the 4-10-membered heterocyclic alkyl or -C 1～6 The alkenyl-(4-10)-membered heterocyclic alkyl group contains one or more nitrogen atoms; Optionally, R7 can be H or -C 1～6 alkyl; Optionally, R7 is H; Optionally, in L1, the -C 1～3 The 5-8 membered heterocyclic alkyl group in the alkenyl-(5-8)-membered heterocyclic alkyl group, or the 5-8 membered heterocyclic alkyl group is Among them, q1 and q2 are each independently selected from 1, 2, or 3; Optional, L1 is 2) L2 is arbitrarily assigned to one or more Rs e Replacement -C 3～15 Alkylene-, optionally with one or more R e Replacement -C 1～6 alkylene-(6-10)-aryl-, or optionally with one or more R e Replacement -C 1～6 alkylene-(3-10)-membered heterocyclic alkyl-; Optionally, L2 is arbitrarily controlled by one or more R... e Replacement -C 3～15 Alkylene-, optionally with one or more R e Replacement -C 1～3 alkylene-(6-10)-aryl-, or optionally with one or more R e Replacement -C 1～3 alkylene-(3-10)-membered heterocyclic alkyl-; Optionally, L2 is -C 3～15 alkylene-, -C 1～6 alkylene-(6-10) aryl- or -C 1～6 alkylene-(3-10)-membered heterocyclic alkyl-; 3) L3 is empty, -C(O)-, and can be arbitrarily controlled by one or more Rs. f Replacement -C 1～6 Alkylene-, optionally with one or more R f Replaces 5-12 elemental helical rings, optionally with one or more R f Replacement -C 1～6 alkylene-(3-10)-membered cycloalkyl-C 1～6 alkylene-; Optionally, L3 is empty, -C(O)-, or optionally controlled by one or more R... f Replacement -C 1～3 Alkylene-, optionally with one or more R f Replaces 6-10 element screw rings, optionally with one or more R f Replacement -C 1～3 alkylene-(5-8)-membered cycloalkyl-C 1～3 alkylene-; Optionally, L3 can be empty, -C(O)-, or -C. 1～6 Alkylene, 5-12 membered spirocyclic, or -C 1～6 alkylene-(3-10)-membered cycloalkyl-C 1～6 alkylene-; Optionally, L3 is optionally controlled by one or more R... f The following screw rings can be replaced: 4) R7 and R9 are each independently H or -C 1～6 alkyl; 5) Each R d R e R f Each is independently selected from halogens and -C 1～6 Alkyl, -C 1～6 Halogenated alkyl, or -C 1～6 Alkoxy; 6) L has the following structure:

4. The compound according to claim 1, characterized in that, The compound satisfies one or more of the following conditions: 1) L1 is -N(R7)-, L2 is arbitrarily assigned to one or more R e Replacement -C 5～15 Alkylene-, L3 is empty; Optionally, ring A is arbitrarily controlled by one or more R... b When the substituted 5-10 membered cycloalkyl group is empty of ring B, L1 is -N(R7)-, and L2 is optionally substituted with one or more R groups. e Replacement -C 7～15 Alkylene-, L3 is empty; Optionally, ring A is arbitrarily controlled by one or more R... b The substituted 5-10 membered cycloalkyl group, wherein ring B is optionally replaced by one or more R c Replaces 5-12 elemental helical rings, or optionally with one or more R c The 5-12 ternary heterocyclic spiroring is replaced, and L2 is optionally replaced by one or more R e Replacement -C 5～10 Alkylene-, L3 is empty; 2) L1 is arbitrarily selected by one or more R d Substituted 5-8 membered heterocyclic alkyl groups, L2 is optionally replaced by one or more R e Replacement -C 3～15 Alkylene-, L3 is empty; Optionally, ring A is arbitrarily controlled by one or more R... b When the substituted 5-10 membered cycloalkyl group is empty and ring B is empty, L1 is optionally replaced by one or more R groups. d Substituted 5-8 membered heterocyclic alkyl groups, L2 is optionally replaced by one or more R e Replacement -C 8～15 Alkylene-, L3 is empty; Optionally, ring A is arbitrarily controlled by one or more R... b The substituted 5-10 membered cycloalkyl group, wherein ring B is optionally replaced by one or more R c Replaces 5-12 elemental helical rings, or optionally with one or more R c The 5-12 ternary heterocyclic spiroring is replaced, and L1 is optionally replaced by one or more R d Substituted 5-8 membered heterocyclic alkyl groups, L2 is optionally replaced by one or more R e Replacement -C 3～6 Alkylene-, L3 is empty; Optionally, L1 is a 5-8 membered heterocyclic alkyl group; Optional, L1 is in, q1 and q2 are each independently selected from 1, 2, or 3; Optional, L1 is 3) L1 is arbitrarily selected by one or more R d Substituted 5-8 membered heterocyclic alkyl groups, optionally with one or more R d Replacement -C 1～3 alkenyl-(5-8)-membered heterocyclic alkyl, or optionally with one or more R d Replacement -C 1～3 Ethyne-(4-10)-membered heterocyclic alkyl, L2 is optionally surrounded by one or more R e Replacement -C 1～6 alkylene-(6-10) aryl-, L3 is optionally surrounded by one or more R f Replacement -C 1～6 alkylene-; Optionally, ring A is arbitrarily controlled by one or more R... b When the substituted 5-10 membered cycloalkyl group is empty of ring B; or Ring A is arbitrarily controlled by one or more R b The substituted 5-10 membered cycloalkyl group, wherein ring B is optionally replaced by one or more R c Replaces 5-12 elemental helical rings, or optionally with one or more R c Replacement of 5-12 quinary heterocyclic spiral rings; 4) L1 is arbitrarily selected by one or more R d Substituted 5-8 membered heterocyclic alkyl groups, L2 is optionally replaced by one or more R e Replacement -C 1～6 alkylene-(3-10)-membered heterocyclic alkyl-, L3 is optionally surrounded by one or more R f Replaces 5-12 elemental helical rings, or optionally with one or more R f Replacement -C 1～6 alkylene-(3-10)-membered cycloalkyl-C 1～6 alkylene-; Optionally, ring A is arbitrarily controlled by one or more R... b When the substituted 5-10 membered cycloalkyl group is empty of ring B; or Ring A is arbitrarily controlled by one or more R b The substituted 5-10 membered cycloalkyl group, wherein ring B is optionally replaced by one or more R c Replaces 5-12 elemental helical rings, or optionally with one or more R c Replacement of 5-12 quinary heterocyclic spiral rings; 5) LA has the following structure:

5. The compound according to claim 1, characterized in that, E has the structure shown in equation (IV): Among them, R9, R 10 Each is independently selected from H, oxo (=O), -C 1～6 Alkyl, -C 1～6 Halogenated alkyl, or -C 1～6 Hydroxyalkyl; Y1 and Y2 are each independently -CH-, C=, or N.

6. The compound according to claim 5, characterized in that, The compound satisfies one or more of the following conditions: 1) Connect to Y2, where Y2 is -CH- or C=, preferably C=; 2) Connected to N, both Y1 and Y2 are -CH-; 3) Connected to Y2, Y1 is -CH- or N, preferably N; 4) R9, R 10 Not both H; 5) E has the structure shown in formula (IVa) or (IVb): 6) E has the following structure:

7. The compound according to claim 1, characterized in that, The compound represented by formula (I) has the following structure:

8. A PTPN protein inhibitor, characterized in that, Includes the compounds described in any one of claims 1 to 7.

9. A pharmaceutical composition, characterized in that, It includes the compounds according to any one of claims 1 to 7, or the PTPN protein inhibitor according to claim 8, and optionally pharmaceutically acceptable excipients, carriers, or mediators.

10. Use of the compound according to any one of claims 1 to 7, the PTPN protein inhibitor according to claim 8, or the pharmaceutical composition according to claim 9, wherein the use comprises: Inhibit PTPN protein, and / or Immunotherapy, and / or Prevention and / or treatment of PTPN protein-related diseases, and / or Preparation of immunotherapy drugs, and / or To prepare drugs for the prevention and / or treatment of PTPN protein-related diseases; Optionally, the treatment of PTPN protein-related diseases is selected from cancer.

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