Compounds for inhibiting PTPN protein and uses thereof

Abstract

The invention discloses a compound which is a compound as shown in a formula (I), or a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof. The compound provided by the invention can effectively inhibit PTPN protein activity, and can effectively prevent and treat PTPN protein related diseases.

Description

Technical Field

[0001] This application belongs to the field of biomedical technology, specifically relating to a compound for inhibiting PTPN protein and its use, and more specifically to a compound for inhibiting PTPN protein, a PTPN protein inhibitor, a pharmaceutical composition and their use. 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 disease development.

[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 cell signaling, such as in the activation, proliferation, and differentiation of immune cells. PTPN1 participates in regulating intracellular signaling by dephosphorylating various substrate proteins, particularly in T-cell development and function. Furthermore, PTPN1 expression levels are upregulated in certain cancers, potentially related to tumor cell proliferation, survival, and metastasis.

[0005] Therefore, the development of PTPN protein inhibitors holds potential for treating diseases such as cancer. Summary of the Invention

[0006] This application aims to address at least one of the technical problems existing in the prior art. To this end, this application provides a compound for inhibiting PTPN protein and its use.

[0007] In a first aspect of this application, a compound is provided, which is a compound of formula (I), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof:

[0008]

[0009] Among them, R1, R2, and R3 are each independently selected from H, -OH, halogen, and -C.1～6 Alkyl, -C 1～6 Halogenated alkyl or -C 1～6 Hydroxyalkyl;

[0010] A is selected from -C 1～6 Alkylene * Connected to B;

[0011] Ring A' is selected from one or more R's. a Substituted 7-10 membered heterocyclic alkyl groups;

[0012] "Ring A" is selected from one or more Rs. a Substituted 5-6 membered cycloalkylene groups, optionally with one or more R a Substituted 5-6 membered heterocyclic alkyl groups;

[0013] Ring A” is selected from one or more R’s. a Substituted 5-10 cyclohexene alkyl group, optionally with one or more R a Substituted 5-10 membered heterocyclic alkyl groups;

[0014] Ring L is selected from one or more R. a Substituted 4-10 membered heterocyclic alkyl groups;

[0015] R4 is selected from empty or -C 1～6 Alkylene;

[0016] R5 is selected from H or -C. 1～6 alkyl;

[0017] R6 is selected from empty, -C(O)-, -C(O)-C 1～6 Alkylene, -S(O)2-, -S(O)2-C 1～6 alkylene, or -C 1～6 Alkylene;

[0018] R7 is selected from -C 1～10 alkyl;

[0019] B is selected from empty -C, which is substituted by one or more halogens. 1～10 Alkyl, optionally with one or more R b Replacement -C 2～10 alkenyl, optionally with one or more R b Replacement -C 2～10 alkynyl group, optionally with one or more R b Substituted 3-4 membered monocyclic alkyl groups, optionally with one or more R b Substituted 5-10 cyclic alkyl groups, optionally with one or more R b Substituted 3-10 heterocyclic alkyl groups, optionally with one or more Rb Replaces the 6-20 yuan chain, arbitrarily controlled by one or more R b Replacement of 6-20 element heterocyclic rings, optionally replaced by one or more R b Replaces 5-12 elemental helical rings, optionally with one or more R b Replaces 5-12 ternary heterocyclic rings, optionally with one or more R b Replaces the 5-12 element bridge ring, optionally replaced by one or more R b Replaces the 5-12 elemental hybrid bridge ring, optionally replaced by one or more R b Replaces 5-12 element rings, optionally with one or more R b Replaced 5-12-membered heterocyclic rings; B is empty, A is selected from

[0020] Each R a Each is independently selected from -OH, halogen, oxo (=O), -C 1～6 Alkyl, -C 1～6 Halogenated alkyl, -C 1～6 Alkoxy;

[0021] Each R b Each is independently selected from -OH and -C. 0～6 Alkylene-CN, halogen, oxo (=O), -S(O)2-C 1～6 Alkyl, -C 1～6 Alkyl, -C 1～6 Halogenated alkyl, -C 1～6 Hydroxyalkyl, -C 0～6 Alkylene-C 1～6 Alkoxy, -C 2～10 alkenyl, -C 2～10 alkynyl group, -C(O)-C 1～6 Alkyl, -C(O)-C 1～6 Alkoxy, -C 0～6 Alkylene-(3-10)-membered cycloalkyl, -C 0～6 alkeneoxy-(3-10)-membered cycloalkyl, -C 0～6 Alkylene-(3-10)-membered heterocyclic alkyl, -C 0～6 Alkylene-(6-10) aryl, -C 0～6 Alkylene-(5-10)-aryl, -S(O)2-(6-10)-aryl, -S(O)2-(5-10)-aryl.

[0022] According to embodiments of this application, the compound satisfies the following conditions:

[0023] 1) When B is selected from one or more R's, b Substituted 3-4 membered monocycloalkyl, or optionally with one or more Rb When substituted with a 3-10 member heterocyclic alkyl group, A is selected from... R4 and R6 in the code are empty;

[0024] 3) When B is selected from one or more R's, b When substituted with a 5-10 member monocyclic alkyl group, A is selected from... R4 and R6 in the code are empty;

[0025] 3) When B is selected from 3-4 member monocycloalkyl or 3-10 member heteromonocycloalkyl, A is selected from When R4 is empty and R6 is not empty, the 3-4 member monocycloalkyl group or the 3-10 member heterocycloalkyl group in B is affected by one or more R b replace;

[0026] 4) A is selected from -C 1～6 When alkylene, B is selected from one or more R. b Replaces the 5-12 quinary heterocyclic spiral ring.

[0027] This application proposes a compound, which is a compound of formula (I), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof:

[0028]

[0029] Among them, R1, R2, and R3 are each independently selected from H, -OH, halogen, and -C. 1～6 Alkyl, -C 1～6 Halogenated alkyl, or -C 1～6 Hydroxyalkyl;

[0030] A is selected from * Connected to B;

[0031] Ring A' is selected from one or more R's. a Substituted 7-10 membered heterocyclic alkyl groups;

[0032] "Ring A" is selected from one or more Rs. a Substituted 5-6 membered cycloalkylene groups, optionally with one or more R a Substituted 5-6 membered heterocyclic alkyl groups;

[0033] Ring A” is selected from one or more R’s. a Substituted 5-10 cyclohexene alkyl group, optionally with one or more R a Substituted 5-10 membered heterocyclic alkyl groups;

[0034] Ring L is selected from one or more R. a Substituted 4-10 membered heterocyclic alkyl groups;

[0035] R4 is selected from empty or -C 1～6 Alkylene;

[0036] R5 is selected from H or -C. 1～6 alkyl;

[0037] R6 is selected from empty, -C(O)-, -C(O)-C 1～6 Alkylene, -S(O)2-, -S(O)2-C 1～6 alkylene, or -C 1～6 Alkylene;

[0038] R7 is selected from -C 1～10 alkyl;

[0039] B is selected from empty -C, which is substituted by one or more halogens. 1～10 Alkyl, optionally with one or more R b Replacement -C 2～10 alkenyl, optionally with one or more R b Replacement -C 2～10 alkynyl group, optionally with one or more R b Substituted 3-4 membered monocyclic alkyl groups, optionally with one or more R b Substituted 3-10 heterocyclic alkyl groups, optionally with one or more R b Substituted 5-10 cyclic alkyl groups, optionally with one or more R b Replaces the 6-20 yuan chain, arbitrarily controlled by one or more R b Replacement of 6-20 element heterocyclic rings, optionally replaced by one or more R b Replaces 5-12 elemental helical rings, optionally with one or more R b Replaces 5-12 ternary heterocyclic rings, optionally with one or more R b Replaces the 5-12 element bridge ring, optionally replaced by one or more R b Replaces the 5-12 elemental hybrid bridge ring, optionally replaced by one or more R b Replaces 5-12 element rings, optionally with one or more R b Replaced 5-12-membered heterocyclic rings; B is empty, A is selected from

[0040] Each R a Each is independently selected from -OH, halogen, oxo (=O), -C 1～6 Alkyl, -C 1～6 Halogenated alkyl, -C 1～6 Alkoxy;

[0041] Each Rb Each is independently selected from -OH, -CN, halogen, oxo (=O), -S(O)2-C 1～6 Alkyl, -C 1～6 Alkyl, -C 1～6 Halogenated alkyl, -C 1～6 Hydroxyalkyl, -C 1～6 Alkoxy, -C 2～10 alkenyl, -C 2～10 alkynyl group, -C(O)-C 1～6 Alkyl, -C 0～6 Alkylene-(3-10)-membered cycloalkyl, -C 0～6 Alkylene-(3-10)-membered heterocyclic alkyl, -C 0～6 Alkylene-(6-10) aryl, -C 0～6 Alkylene-(5-10)-aryl, -S(O)2-(6-10)-aryl, -S(O)2-(5-10)-aryl;

[0042] The condition is that when B is selected from one or more R's, b Substituted 3-4 membered monocycloalkyl, or optionally with one or more R b When substituted with a 3-10 member heterocyclic alkyl group, A is selected from... R4 and R6 in the code are empty;

[0043] When B is selected from one or more R's, b When substituted with a 5-10 member monocyclic alkyl group, A is selected from... R4 and R6 in the code are empty.

[0044] The compounds in this application can effectively inhibit PTPN protein activity, and can effectively prevent and treat PTPN protein-related diseases.

[0045] According to embodiments of this application, the above-mentioned compound may further include at least one of the following technical features:

[0046] In an optional embodiment of this application, R1, R2, and R3 are each independently selected from H, -OH, halogen, and -C. 1～3 Alkyl, -C 1～3 Halogenated alkyl, or -C 1～3 Hydroxyalkyl groups.

[0047] In one optional embodiment of this application, R1, R2, and R3 are each independently selected from H, -OH, and halogens.

[0048] In one optional embodiment of this application, R1 is a halogen and R2 is -OH.

[0049] In one optional embodiment of this application, R1 is -OH and R2 is a halogen.

[0050] In an optional embodiment of this application, R1 is F and R2 is -OH.

[0051] In one optional embodiment of this application, R1 is -OH and R2 is F.

[0052] In an optional embodiment of this application, R3 is H.

[0053] In an optional embodiment of this application, R4 is selected from empty or -C. 1～3 Alkylene.

[0054] In an optional embodiment of this application, R4 is empty.

[0055] In an optional embodiment of this application, R4 is -C 1～3 Alkylene.

[0056] In an optional embodiment of this application, R5 is selected from H or -C. 1～3 alkyl.

[0057] In an optional embodiment of this application, R6 is selected from empty, -C(O)-, -C(O)-C 1～3 Alkylene, -S(O)2-, -S(O)2-C 1～3 alkylene, or -C 1～3 Alkylene.

[0058] In an optional embodiment of this application, R6 is selected from empty, -C 1～3 Alkylene.

[0059] In an optional embodiment of this application, R7 is selected from -C 3～8 alkyl.

[0060] In one optional embodiment of this application, For optional use by one or more R a Replacement -C 1～3 Alkylene-NH-C 3～8 alkyl.

[0061] In one optional embodiment of this application, Selected from one or more R a Replaced by -N(R5)-, optionally by one or more R a Replacement -C 1～3 Alkylene-N(R5)-, optionally with one or more R a Replacement -N(R5)-C 1～3 Alkylene-, optionally with one or more R aReplacement -C 1～3 Alkylene-N(R5)-C 1～3 Alkylene-, optionally with one or more R a The -N(R5)-C(O)- substitution, optionally replaced by one or more R a Replacement -C 1～3 Alkylene-N(R5)-C(O)-, optionally with one or more R a Substituted -N(R5)-C(O)-C 1～3 Alkylene-, or optionally with one or more R a Replacement -C 1～3 Alkylene-N(R5)-C(O)-C 1～3 Alkylene-.

[0062] In one optional embodiment of this application, Selected from

[0063] In one optional embodiment of this application, Selected from

[0064] In one optional embodiment of this application, Selected from

[0065] In an optional embodiment of this application, ring A' is selected from one or more R's. a Substituted 7-8 membered heterocyclic alkylene groups.

[0066] In one optional embodiment of this application, For optional use by one or more R a The following groups are substituted:

[0067]

[0068] In one optional embodiment of this application, R6 in the code is -C 1～6 Alkylene.

[0069] In one optional embodiment of this application, For optional use by one or more R a The following groups are substituted:

[0070]

[0071] In one optional embodiment of this application, Selected from one or more Ra Substituted 5-6 membered cycloalkylene groups.

[0072] In one optional embodiment of this application, For optional use by one or more R a Replacement

[0073] In one optional embodiment of this application, Selected from one or more R a Substituted -(4-10)-membered heterocyclic alkyl-(5-10)-membered heterocyclic alkyl.

[0074] In one optional embodiment of this application, For optional use by one or more R a Replacement

[0075] In one optional embodiment of this application, Selected from one or more R a Substituted -N(R5)-(5-10) cycloalkylene group, optionally with one or more R a Substituted -N(R5)-(5-10)-membered heterocyclic alkylene, optionally with one or more R a Replacement -C 1～3 Alkylene-N(R5)-(5-10)-membered cycloalkylene, optionally with one or more R a Replacement -C 1～3 Alkylene-N(R5)-(5-10)-membered heterocyclic alkylene, optionally with one or more R a Replacement -N(R5)-C 1～3 Alkylene-(5-10)-membered cycloalkylene, optionally with one or more R a Replacement -N(R5)-C 1～3 Alkylene-(5-10)-membered heterocyclic alkylene, optionally with one or more R a Replacement -C 1～3 Alkylene-N(R5)-C 1～3 Alkylene-(5-10)-membered cycloalkylene, optionally with one or more R a Replacement -C 1～3 Alkylene-N(R5)-C 1～3 Alkylene-(5-10)-membered heterocyclic alkylene, optionally with one or more R a Substituted -N(R5)-C(O)-(5-10) cycloalkylene group, optionally with one or more R a Substituted -N(R5)-C(O)-(5-10)-membered heterocyclic alkylene, optionally with one or more R a Replacement -C1～3 Alkylene-N(R5)-C(O)-(5-10)-membered cycloalkylene, or optionally with one or more R a Replacement -C 1～3 Alkylene-N(R5)-C(O)-(5-10)-membered heterocyclic alkylene.

[0076] In one optional embodiment of this application, In For optional use by one or more R a Replacement

[0077] In one optional embodiment of this application, Selected from

[0078] In one optional embodiment of this application, Selected from

[0079] In one optional embodiment of this application, Selected from

[0080] In an optional embodiment of this application, the compound shown in formula (I) contains Selected from

[0081] In an optional embodiment of this application, the compound shown in formula (I) contains Selected from

[0082] In an optional embodiment of this application, the compound shown in formula (I) contains Selected from

[0083] In an optional embodiment of this application, the compound shown in formula (I) contains Selected from

[0084] In an optional embodiment of this application, the compound shown in formula (I) contains for

[0085] In one optional embodiment of this application, for

[0086] In an optional embodiment of this application, B is selected from one or more R. b Substituted 3-4 membered monocycloalkyl, or optionally with one or more R b Substituted 3-10 member heterocyclic alkyl groups;

[0087] A is selected from

[0088] In an optional embodiment of this application, B is selected from 3-4 member monocycloalkyl or 5-8 member heterocycloalkyl, wherein the 3-4 member monocycloalkyl or 5-8 member heterocycloalkyl is optionally -C 1～3 Halogenated alkyl, -C 1～3 One or more substitutions in hydroxyalkyl groups;

[0089] A is selected from

[0090] In an optional embodiment of this application, B is selected from 3-4 membered monocycloalkyl groups, wherein the 3-4 membered monocycloalkyl group is optionally prefixed with -(6-10) aryl or -C 1～3 Halogenated alkyl, -C 1～3 One or more substitutions in hydroxyalkyl groups;

[0091] A is selected from

[0092] In one optional embodiment of this application, B is selected from... A is selected from

[0093] In an optional embodiment of this application, B is selected from one or more R. b Substituted 3-4 membered monocycloalkyl, or optionally with one or more R b Substituted 3-10 member heterocyclic alkyl groups;

[0094] A is selected from

[0095] In one optional embodiment of this application, B is selected from... A is selected from

[0096] In an optional embodiment of this application, B is selected from one or more R. b Replacement -C 2～10 alkenyl, optionally with one or more R b Substituted 3-4 membered monocyclic alkyl groups, optionally with one or more R b Substituted 5-10 cyclic alkyl groups, optionally with one or more R b Substituted 3-10 heterocyclic alkyl groups, or optionally with one or more R groups bReplacement of 5-12 ternary spiral rings;

[0097] A is selected from

[0098] In an optional embodiment of this application, B is selected from one or more R. b Substituted 3-4 membered monocyclic alkyl groups, optionally with one or more R b Substituted 5-10 cyclic alkyl groups, or optionally with one or more R b Substituted 3-10 member heterocyclic alkyl groups;

[0099] A is selected from

[0100] In an optional embodiment of this application, B is selected from one or more R. b Substituted 3-4 membered monocyclic alkyl groups, optionally with one or more R b Substituted 5-10 cyclic alkyl groups, or optionally with one or more R b Substituted 3-10 member heterocyclic alkyl groups;

[0101] A is selected from

[0102] Each R b Each is independently selected from -C 1～6 Alkylene-CN, -C 1～6 Alkyl, -C 1～6 Halogenated alkyl, -C 1～6 Hydroxyalkyl, -C 0～6 Alkylene-C 1～6 Alkyl group.

[0103] In an optional embodiment of this application, B is selected from one or more R. b The following groups are substituted:

[0104]

[0105] A is selected from

[0106] In one optional embodiment of this application, B is selected from... A is selected from

[0107] In one optional embodiment of this application, B is selected from... A is selected from

[0108] In an optional embodiment of this application, B is selected from one or more R. b Substituted 3-4 membered monocyclic alkyl groups, optionally with one or more R b Substituted 5-10 cyclic alkyl groups, or optionally with one or more R b Substituted 3-10 member heterocyclic alkyl groups;

[0109] A is selected from R4 and R6 are empty.

[0110] In an optional embodiment of this application, B is selected from one or more R. b Substituted 3-4 membered monocyclic alkyl groups, optionally with one or more R b Substituted 5-10 cyclic alkyl groups, or optionally with one or more R b Substituted 3-10 member heterocyclic alkyl groups;

[0111] A is selected from R4 and R6 are empty.

[0112] In an optional embodiment of this application, B is selected from one or more R. b The following groups are substituted:

[0113]

[0114] A is selected from

[0115] In one optional embodiment of this application, B is selected from... A is selected from

[0116] In one optional embodiment of this application, B is selected from...

[0117] A is selected from

[0118] In an optional embodiment of this application, B is selected from one or more R b Substituted 3-4 membered monocyclic alkyl groups, with one or more R b Substituted 5-10 member monocycloalkyl, or with one or more R b Substituted 3-10 member heterocyclic alkyl groups;

[0119] A is selected from R4 is empty, R6 is empty or -C 1～6 Alkylene.

[0120] In an optional embodiment of this application, B is selected from one or more R b The following groups are substituted:

[0121]

[0122] A is selected from Where R4 is empty, R6 is empty or -C 1～6 Alkylene.

[0123] In one optional embodiment of this application, B is selected from...

[0124] A is selected from Where R4 is empty, R6 is empty or -C 1～6 Alkylene.

[0125] In an optional embodiment of this application, B is selected from one or more R. b Replaces the 6-12 element chain, arbitrarily controlled by one or more R b Replaced 6-12 member heterocyclic rings;

[0126] A is selected from

[0127] In one optional embodiment of this application, B is selected from -(4-6)-membered cycloalkyl-(3-6)-membered cycloalkyl ring, -(4-6)-membered cycloalkyl-(3-6)-membered heterocycloalkyl ring, -(4-6)-membered heterocycloalkyl-(3-6)-membered cycloalkyl ring, or -(4-6)-membered cycloalkyl-(6-10)-membered aryl ring, wherein the -(4-6)-membered cycloalkyl-(3-6)-membered cycloalkyl ring, -(4-6)-membered heterocycloalkyl-(3-6)-membered cycloalkyl ring, or -(4-6)-membered cycloalkyl-(6-10)-membered aryl ring is optionally surrounded by one or more -C 1～6 Alkyl substitution;

[0128] A is selected from

[0129] In one optional embodiment of this application, B is selected from 6-membered cycloalkyl-6-membered cycloalkyl ring, 6-membered heterocycloalkyl-3-membered cycloalkyl ring, 6-membered heterocycloalkyl-4-membered cycloalkyl ring, 6-membered heterocycloalkyl-6-membered cycloalkyl ring, 6-membered cycloalkyl-6-membered heterocycloalkyl ring, or 4-membered cycloalkyl-6-aryl ring, wherein the 6-membered cycloalkyl-6-membered cycloalkyl ring, 6-membered heterocycloalkyl-3-membered cycloalkyl ring, 6-membered heterocycloalkyl-4-membered cycloalkyl ring, 6-membered heterocycloalkyl-6-membered cycloalkyl ring, 6-membered cycloalkyl-6-membered heterocycloalkyl ring, or 4-membered cycloalkyl-6-aryl ring is optionally surrounded by one or more -C 1～6 Alkyl substitution;

[0130] A is selected from

[0131] In one optional embodiment of this application, B is selected from... A is selected from

[0132] In an alternative embodiment of this application, B is selected from -C substituted with one or more halogens. 1～10 Alkyl, optionally with one or more R b Replacement -C 2～10 alkenyl, or optionally with one or more R b Replacement -C 2～10 Alkyne group.

[0133] In one optional embodiment of this application, B is selected from...

[0134] In one optional embodiment of this application, B is selected from...

[0135] In an optional embodiment of this application, B is selected from one or more R. b Replaces 5-12 elemental helical rings, optionally with one or more R b Replaces 5-12 ternary heterocyclic rings, optionally with one or more R b Replaces the 5-12 element bridge ring, optionally replaced by one or more R b Replaces the 5-12 elemental hybrid bridge ring, optionally replaced by one or more R b Replaces the 5-12 element fused ring, or optionally is replaced by one or more R b Replaced 5-12-membered heterocyclic rings.

[0136] In an optional embodiment of this application, B is selected from one or more R. b Replaces 5-10 ductile helical rings, optionally with one or more R b Replaces 5-10 quinary heterocyclic spiral rings, optionally with one or more R b Replaces the 5-10 element bridge ring, optionally with one or more R b Replaces 5-10 element hybrid bridge rings, optionally replaced by one or more R b Replaced by 5-10 element rings, or optionally by one or more R b Replaced 5-10 quinary heterocyclic rings.

[0137] In an optional embodiment of this application, B is selected from one or more R. b Replaces 5-10 inch screw rings, or optionally with one or more R bReplaces the 5-8 cyclic ring.

[0138] In an optional embodiment of this application, B is selected from one or more R. b The following structures are replaced:

[0139]

[0140]

[0141] In an optional embodiment of this application, B is selected from one or more R. b The following structures are replaced:

[0142]

[0143] In an optional embodiment of this application, each R b Each is independently selected from -OH, -CN, oxo, halogen, and -C. 1～6 Alkyl, -C 1～6 Halogenated alkyl, -C 1～6 Hydroxyalkyl, -C(O)-C 1～6 Alkyl, -C 0～6 Alkylene-(3-10)-membered cycloalkyl, -C 0～6 Alkylene-(6-10)aryl, -S(O)2-(6-10)aryl.

[0144] In an optional embodiment of this application, each R b Each is independently selected from -OH, -CN, halogen, and -C. 1～6 Alkyl, -C 1～6 Halogenated alkyl, -C 1～6 Hydroxyalkyl, -C(O)-C 1～3 Alkyl, -(3-6)-membered cycloalkyl, -C 1～3 Alkylene-(6-8)aryl, -S(O)2-(6-8)aryl.

[0145] In an optional embodiment of this application, B is selected from the following structure:

[0146]

[0147]

[0148] In an optional embodiment of this application, B is selected from the following structure:

[0149]

[0150] In one optional embodiment of this application, A is selected from -C 1～6When alkylene, B is selected from one or more R. b The following groups are substituted:

[0151]

[0152] In one optional embodiment of this application, A is selected from -C 1～6 When alkylene, B is selected from...

[0153] In an optional embodiment of this application, the compound shown in formula (I) has the structure shown in formula (II):

[0154]

[0155] Undefined groups are as described in any of the embodiments in this application.

[0156] In an optional embodiment of this application, R1 is -OH in the structure shown in formula (II).

[0157] In an optional embodiment of this application, R2 is F in the structure shown in formula (II).

[0158] In an optional embodiment of this application, R3 is H in the structure shown in formula (II).

[0159] In an optional embodiment of this application, R4 is empty in the structure shown in formula (II).

[0160] In an optional embodiment of this application, R5 is H in the structure shown in formula (II).

[0161] In an optional embodiment of this application, R6 is empty in the structure shown in formula (II).

[0162] In an optional embodiment of this application, the compound shown in formula (I) has the structure shown in formula (IIa):

[0163]

[0164] Undefined groups are as described in any of the embodiments in this application.

[0165] In an optional embodiment of this application, in the structures shown in formula (II) and formula (IIa), B is selected from one or more R... b Replaces 5-12 elemental helical rings, optionally with one or more R b Replaces the 5-12 element bridge ring, or optionally is replaced by one or more R b Replaces the 5-12 cyclic ring.

[0166] In an optional embodiment of this application, in the structures shown in formula (II) and formula (IIa), B is selected from one or more R... b The following structures are replaced:

[0167]

[0168] In an optional embodiment of this application, in the structures shown in formula (II) and formula (IIa), B is selected from one or more R... b The following structures are replaced:

[0169]

[0170] In an optional embodiment of this application, in the structures shown in formula (II) and formula (IIa), each R b Each is independently selected from -OH, halogen, oxo, -CN, and -C. 1～3 Alkyl, -C 1～3 Haloalkyl, -C(O)-C 1～6 Alkyl, -C 1～3 Alkylene-(6-8) aryl.

[0171] In an optional embodiment of this application, in the structures shown in formula (II) and formula (IIa), each R b Each is independently selected from -OH, halogen, oxo, and -C. 1～3 Alkyl, -C 1～3 Halogenated alkyl groups.

[0172] In an optional embodiment of this application, in the structures shown in formula (II) and formula (IIa), B is selected from the following structures:

[0173]

[0174] In an optional embodiment of this application, in the structures shown in formula (II) and formula (IIa), B is selected from the following structures:

[0175]

[0176] In an optional embodiment of this application, the compound shown in formula (I) has the structure shown in formula (III):

[0177]

[0178] R8 is selected from 3-4 member monocycloalkyl or 3-10 member heteromonocycloalkyl; R9 is selected from 6-10 member aryl or 3-10 member cycloalkyl.

[0179] Undefined functional groups are as described in any of the embodiments of this application.

[0180] In an optional embodiment of this application, R1 is -OH in the structure shown in formula (III).

[0181] In an optional embodiment of this application, R2 is F in the structure shown in formula (III).

[0182] In an optional embodiment of this application, R3 is H in the structure shown in formula (III).

[0183] In an optional embodiment of this application, R4 is empty in the structure shown in equation (III).

[0184] In an optional embodiment of this application, R5 is H in the structure shown in formula (III).

[0185] In an optional embodiment of this application, R6 is empty in the structure shown in formula (III).

[0186] In an optional embodiment of this application, in the structure shown in formula (III), R8 is selected from 3-4 member monocyclic alkyl or 5-10 member heterocyclic alkyl.

[0187] In an optional embodiment of this application, in the structure shown in formula (III), R9 is selected from 6-8 aryl or 3-5 cycloalkyl.

[0188] In an optional embodiment of this application, in the structure shown in formula (III), -R8-R9 are selected from...

[0189] In an optional embodiment of this application, the compound shown in formula (I) has the structure shown in formula (IV):

[0190]

[0191] Undefined groups are as described in any of the embodiments in this application.

[0192] In an optional embodiment of this application, R1 is -OH in the structure shown in formula (IV).

[0193] In an optional embodiment of this application, R2 is F in the structure shown in formula (IV).

[0194] In an optional embodiment of this application, R3 is H in the structure shown in formula (IV).

[0195] In an optional embodiment of this application, in the structure shown in formula (IV), B is selected from one or more R.b Replacement -C 2～10 alkenyl, optionally with one or more R b Substituted 3-4 membered monocyclic alkyl groups, optionally with one or more R b Substituted 5-10 cyclic alkyl groups, optionally with one or more R b Substituted 3-10 heterocyclic alkyl groups, optionally with one or more R b Replaces 5-12 elemental helical rings, or optionally with one or more R b Replaces the 5-12 quinary heterocyclic spiral ring.

[0196] In an optional embodiment of this application, in the structure shown in formula (IV), B is selected from one or more R. b Replacement -C 2～10 alkenyl, optionally with one or more R b Substituted 3-4 membered monocyclic alkyl groups, optionally with one or more R b Substituted 5-8 membered monocycloalkyl, optionally with one or more R b Substituted 4-6 member heterocyclic alkyl group, optionally with one or more R b Replaces 5-10 inch screw rings, or optionally with one or more R b Replaces 5-10 quinary heterocyclic spiral rings.

[0197] In an optional embodiment of this application, in the structure shown in formula (IV), B is selected from one or more R. b Substituted 3-4 membered monocyclic alkyl groups, optionally with one or more R b Substituted 5-10 cyclic alkyl groups, optionally with one or more R b Replaces 5-12 elemental helical rings, or optionally with one or more R b Replaces the 5-12 quinary heterocyclic spiral ring.

[0198] In an optional embodiment of this application, in the structure shown in formula (IV), B is selected from one or more R. b Substituted 5-10 cyclic alkyl groups, or optionally with one or more R b Replaces the 5-10 inch spiral ring.

[0199] In an optional embodiment of this application, in the structure shown in formula (IV),

[0200] In an optional embodiment of this application, in the structure shown in formula (IV), B is selected from one or more R. b The following structures are replaced:

[0201]

[0202] In an optional embodiment of this application, in the structure shown in formula (IV),

[0203] In an optional embodiment of this application, in the structure shown in formula (IV), B is selected from one or more R. b The following structures are replaced:

[0204]

[0205] In an optional embodiment of this application, in the structure shown in formula (IV), B is selected from one or more R. b The following structures are replaced:

[0206]

[0207] In an optional embodiment of this application, in the structure shown in formula (IV), each R b Each is independently selected from halogens, oxometalates, and -C atoms. 1～6 Alkyl, -C 0～6 Alkylene-C 1～6 Alkoxy, -C 1～6 Halogenated alkyl groups, or 6- to 8-membered aryl groups.

[0208] In an optional embodiment of this application, in the structure shown in formula (IV),

[0209] In an optional embodiment of this application, in the structure shown in formula (IV), B is selected from the following structures:

[0210]

[0211] In an optional embodiment of this application, the compound shown in formula (I) has the structure shown in formula (IV):

[0212]

[0213] Wherein, R1 is -OH, R2 is F, and R3 is H;

[0214] B is selected from one or more R. b Substituted 3-10 membered monocyclic alkyl groups;

[0215] Undefined groups are as described in any of the embodiments in this application.

[0216] In an optional embodiment of this application, the compound shown in formula (I) has the structure shown in formula (IV):

[0217]

[0218] Wherein, R1 is -OH, R2 is F, and R3 is H;

[0219] B is selected from

[0220] Undefined groups are as described in any of the embodiments in this application.

[0221] In an optional embodiment of this application, the compound shown in formula (I) has the structure shown in formula (V):

[0222]

[0223] Undefined groups are as described in any of the embodiments in this application.

[0224] In an optional embodiment of this application, R1 is -OH in the structure shown in formula (V).

[0225] In an optional embodiment of this application, R2 is F in the structure shown in formula (V).

[0226] In an optional embodiment of this application, R3 is H in the structure shown in formula (V).

[0227] In an optional embodiment of this application, in the structure shown in formula (V), R4 is -C 1～3 Alkylene.

[0228] In an optional embodiment of this application, R5 is H in the structure shown in formula (V).

[0229] In an optional embodiment of this application, in the structure shown in formula (V), R6 is empty, -C(O)-, -S(O)2-C 1～3 alkylene, or -C 1～3 Alkylene.

[0230] In an optional embodiment of this application, in the structure shown in formula (V), R6 is empty, -C(O)-, or -C 1～3 Alkylene.

[0231] In an optional embodiment of this application, in the structure shown in formula (V), B is selected from one or more R. b Replaces 5-10 ductile helical rings, optionally with one or more R b Replaces 5-10 quinary heterocyclic spiral rings, optionally with one or more R bReplaces the 5-10 element bridge ring, optionally with one or more R b Replaces 5-10 element hybrid bridge rings, optionally replaced by one or more R b Replaced by 5-10 element rings, or optionally by one or more R b Replaced 5-10 quinary heterocyclic rings.

[0232] In an optional embodiment of this application, in the structure shown in formula (V), B is selected from one or more R. b The following structures are replaced:

[0233] In an optional embodiment of this application, in the structure shown in formula (V), B is selected from one or more R. b The following structures are replaced:

[0234] In an optional embodiment of this application, in the structure shown in equation (V), each R b Each is independently selected from halogens, -CN, oxo (=O), and -C. 1～6 Alkyl, -C 1～6 Halogenated alkyl, -C 0～6 Alkylene-(6-10) aryl, or -S(O)2-(6-10) aryl.

[0235] In an optional embodiment of this application, in the structure shown in equation (V), each R b Each is independently selected from halogens, -CN, oxo (=O), and -C. 1～3 Alkyl, -C 1～3 Halogenated alkyl, -C 0～3 Alkylene-(6-8)aryl or -S(O)2-(6-8)aryl.

[0236] In an optional embodiment of this application, in the structure shown in formula (V), B is selected from the following structures:

[0237]

[0238] In an optional embodiment of this application, in the structure shown in formula (V), B is selected from the following structures:

[0239]

[0240] In an optional embodiment of this application, in the structure shown in formula (V), B is selected from one or more R. b Substituted 3-4 membered monocyclic alkyl groups, optionally with one or more R b Substituted 3-10 heterocyclic alkyl groups, optionally with one or more Rb Replaces the 6-20 yuan chain, or optionally is one or more R b Replaces the 6-20 element hybrid ring.

[0241] In an optional embodiment of this application, in the structure shown in formula (V), B is selected from one or more R. b Substituted 3-4 membered monocycloalkyl, or optionally with one or more R b Replaces the 10-15 yuan chain.

[0242] In an optional embodiment of this application, in the structure shown in equation (V), each R b Each is independently selected from -C 1～6 Alkyl, -C 1～6 Halogenated alkyl, or -C 1～3 Hydroxyalkyl groups.

[0243] In an optional embodiment of this application, in the structure shown in formula (V), B is selected from...

[0244] In an optional embodiment of this application, the compound shown in formula (I) has the structure shown in formula (VI):

[0245]

[0246] Undefined groups are as described in any of the embodiments in this application.

[0247] In an optional embodiment of this application, R1 is -OH in the structure shown in formula (VI).

[0248] In an optional embodiment of this application, in the structure shown in formula (VI), R2 is F.

[0249] In an optional embodiment of this application, R3 is H in the structure shown in formula (VI).

[0250] In an optional embodiment of this application, in the structure shown in formula (VI), R4 is -C 1～3 Alkylene.

[0251] In an optional embodiment of this application, in the structure shown in formula (VI), R5 is H.

[0252] In an optional embodiment of this application, in the structure shown in formula (VI), R6 is selected from empty or -C. 1～3 Alkylene.

[0253] In an optional embodiment of this application, R6 is empty in the structure shown in formula (VI).

[0254] In an optional embodiment of this application, in the structure shown in formula (VI), R7 is -C 3～8 alkyl.

[0255] In an optional embodiment of this application, in the structure shown in formula (VI), -R6-R7 are selected from...

[0256] In an optional embodiment of this application, the compound shown in formula (I) has the structure shown in formula (VII):

[0257]

[0258] B is selected from one or more R. b Replacement -C 2～10 alkenyl, or optionally with one or more R b Replacement -C 2～10 alkynyl group;

[0259] Undefined groups are as described in any of the embodiments in this application.

[0260] In an optional embodiment of this application, in the structure shown in formula (VII), R4 is selected from empty.

[0261] In an optional embodiment of this application, in the structure shown in formula (VII), R6 is selected from empty.

[0262] In an optional embodiment of this application, in the structure shown in formula (VII), R5 is selected from H.

[0263] In an optional embodiment of this application, in the structure shown in formula (VII), B is selected from one or more R. b Replacement -C 2～8 alkenyl, or optionally with one or more R b Replacement -C 2～8 Alkyne group.

[0264] In an optional embodiment of this application, in the structure shown in formula (VII), B is selected from...

[0265] In an optional embodiment of this application, the compound represented by formula (I) comprises the following structure:

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275] In an optional embodiment of this application, the compound represented by formula (I) comprises the following structure:

[0276]

[0277]

[0278] In a second aspect of this application, the use of the compounds described in the first aspect in the preparation of PTPN protein inhibitors is proposed.

[0279] In a third 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.

[0280] In an optional embodiment of this application, the PTPN protein inhibitor further includes pharmaceutically acceptable excipients, carriers, and mediators.

[0281] In a fourth aspect of this application, a PROTAC drug is proposed. According to an embodiment of this application, the PROTAC drug comprises the compound described in the first aspect, a linker, and a ubiquitin ligand, wherein the compound and the ubiquitin ligand are linked by the linker.

[0282] In this paper, the PROTAC drug consists of two protein-binding moieties: one for binding to an E3 ubiquitin ligase and the other for binding to a target protein (PTPN protein in this application). PROTAC binds to the PTPN protein and carries it to the E3 ubiquitin ligase. After the formation of the tertiary complex, the E3 ubiquitin ligase transfers ubiquitin to the surface lysine residue of the target protein, resulting in a ubiquitinated target protein destined for degradation by the proteasome machinery. Following ubiquitination, PROTAC is released and continues to search for PTPN proteins for ubiquitination and degradation.

[0283] It should be noted that the linker described above is used to connect the compound and the ubiquitin ligand, and the ubiquitin ligand is used to bind to E3 ubiquitin ligand. Therefore, the linker and ubiquitin ligand in this application are not particularly limited, as long as they can achieve the above functions. The E3 ubiquitin ligand can be a peptide or small molecule capable of binding to E3 ubiquitin ligand, and its specific type is not limited.

[0284] In a fifth 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.

[0285] In an optional embodiment of this application, the pharmaceutical composition further includes pharmaceutically acceptable excipients, carriers, and mediators.

[0286] In one optional embodiment of this application, pharmaceutically acceptable excipients refer to pharmaceutical excipients conventional in the pharmaceutical field, such as: diluents, excipients, fillers (e.g., starch, sucrose, lactose, microcrystalline cellulose, etc.), binders (e.g., cellulose derivatives, alginate, gelatin, and polyvinylpyrrolidone), wetting agents (e.g., glycerin), disintegrants (e.g., sodium carboxymethyl starch, hydroxypropyl cellulose, cross-linked carboxymethyl cellulose, agar, calcium carbonate, and sodium bicarbonate), absorption enhancers (e.g., quaternary ammonium compounds); surfactants (e.g., hexadecyl alcohol, sodium dodecyl sulfate), etc., and other excipients such as flavoring agents, sweeteners, etc. may also be added.

[0287] In one alternative embodiment of this application, a pharmaceutically acceptable carrier refers to a drug carrier conventional in the pharmaceutical field, such as: adsorbent carriers (e.g., kaolin and soap clay), lubricants (e.g., talc, calcium and magnesium stearate, micronized silica gel and polyethylene glycol), etc.

[0288] In one alternative embodiment of this application, pharmaceutically acceptable mediators refer to pharmaceutical mediators conventional in the pharmaceutical field, such as creams, gels, emulsions, solutions (e.g., water) and liposomes.

[0289] In one alternative embodiment of this application, examples of suitable pharmaceutically acceptable carriers, excipients, and mediators are well known in the art. Pharmaceutical compositions comprising such carriers, excipients, and mediators can be formulated using known conventional methods.

[0290] In some alternative embodiments, the pharmaceutical composition of this application may also contain other active ingredients for treatment.

[0291] The pharmaceutical composition of this application can be administered via various routes, such as enterically, orally (e.g., pills, tablets, sublingual, sublingual, disintegrant, capsules, films, liquid solutions or suspensions, powders, solid crystals or liquids), rectally (e.g., suppositories, enemas), by injection (e.g., intravenous, subcutaneous, intramuscular, intraperitoneal, intradermal), by inhalation (e.g., intrabronchial), topically, vaginally, on the skin, or intranasally. Preferably, the pharmaceutical composition of this application is in the form of a lyophilized formulation or an aqueous solution. The clinical dosing regimen will be determined by the attending physician and clinical factors. As is known in the medical field, the dosage for any given patient depends on many factors, including the patient's physique, body surface area, age, the drug to be administered, sex, time and route of administration, general health, and other concurrently administered drugs. The pharmaceutical composition of this application can be administered topically or systemically. Preferably, it can be administered intravenously or subcutaneously. The pharmaceutical composition of this application can also be administered directly to the target site, for example, by targeted administration to internal or external target sites.

[0292] In a sixth aspect of this application, the use of the compound described in the first aspect, the PTPN protein inhibitor described in the third aspect, the PROTAC drug described in the fourth aspect, or the pharmaceutical composition described in the fifth aspect in the preparation of a medicament, said medicament being used for:

[0293] Inhibit PTPN protein, and / or

[0294] Immunotherapy, and / or

[0295] Prevention and / or treatment of PTPN protein-related diseases, and / or

[0296] Preparation of reagents to inhibit PTPN protein, and / or

[0297] Preparation of PROTAC drugs, and / or

[0298] Preparation of immunotherapy drugs, and / or

[0299] Prepare drugs for the prevention and / or treatment of PTPN protein-related diseases.

[0300] In one optional embodiment of this application, the treatment of PTPN protein-related diseases is selected from cancer and metabolic diseases.

[0301] In one alternative embodiment of this application, the cancer includes pancreatic cancer, breast cancer, multiple myeloma, melanoma, or secretory cell carcinoma.

[0302] In one optional embodiment of this application, the metabolic disease includes non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, type 2 diabetes, heart disease, atherosclerosis, arthritis, cystinemia, phenylketonuria, proliferative retinopathy, metabolic syndrome, or Kearns-Sayredisease.

[0303] In a seventh aspect of this application, a method for inhibiting PTPN protein is provided. According to embodiments of this application, the method includes contacting a cell containing PTPN protein with a compound described in the first aspect, a PTPN protein inhibitor described in the third aspect, a PROTAC drug described in the fourth aspect, or a pharmaceutical composition described in the fifth aspect.

[0304] In an eighth aspect of this application, a method of immunotherapy is proposed. 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 third aspect, the PROTAC drug described in the fourth aspect, or the pharmaceutical composition described in the fifth aspect.

[0305] In a ninth 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 a compound described in the first aspect, a PTPN protein inhibitor described in the third aspect, a PROTAC medicament described in the fourth aspect, or a pharmaceutical composition described in the fifth aspect.

[0306] In one alternative embodiment of this application, the pharmaceutically acceptable dose may be selected from the effective dose (or effective amount).

[0307] 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.

[0308] 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.

[0309] In one optional embodiment of this application, the treatment of PTPN protein-related diseases is selected from cancer and metabolic diseases.

[0310] In one alternative embodiment of this application, the cancer includes pancreatic cancer, breast cancer, multiple myeloma, melanoma, or secretory cell carcinoma.

[0311] In one optional embodiment of this application, the metabolic disease includes non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, type 2 diabetes, heart disease, atherosclerosis, arthritis, cystinemia, phenylketonuria, proliferative retinopathy, metabolic syndrome, or Kearns-Sayredisease.

[0312] 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. Attached Figure Description

[0313] Figure 1 This describes the tumor-suppressing effect of an example compound in mice according to an embodiment of the present invention. Detailed Implementation

[0314] 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.

[0315] Definitions and General Terms

[0316] 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.

[0317] 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.

[0318] 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.

[0319] 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.

[0320] 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.

[0321] 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.

[0322] 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.

[0323] 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.

[0324] 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.

[0325] 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.

[0326] 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.

[0327] 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.

[0328] 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.

[0329] 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.

[0330] 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.

[0331] 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 (e.g., Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0332] 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.

[0333] 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.

[0334] 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.

[0335] In this document, the term "pharmaceutically acceptable salt" refers to both organic and inorganic salts of the compounds of this application. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable salts formed from 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.

[0336] 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.

[0337] 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.

[0338] 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".

[0339] 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.

[0340] In this article, the term "halogen" refers to a fluorine, chlorine, bromine, or iodine atom.

[0341] 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" 1～10 In, containing C 1～9 C 1～8 C 1～7 C 1～6 C 1～5 C 1～4 C 1～3 C1～2 C 2～10 C 2～9 C 2～8 C 2～7 C 2～6 C 2～5 C 2～4 C 2～3 C 3～10 C 3～9 C 3～7 C 3～6 C 3～5 C 3～4 C 4～10 C 4～9 C 4～8 C 4～7 C 4～6 C 4～5 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 .

[0342] 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 C 1～2 C 1～3 C 1～4 C 1～5 C 1～6 Especially C 1～4 .

[0343] In this article, 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.

[0344] 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... 1～6An 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).

[0345] 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).

[0346] 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)

[0347] In this document, the term "5-6 membered cycloalkyl" or "5- to 6 membered cycloalkyl" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 5 or 6 carbon atoms. The 5- to 6 membered cycloalkyl is a monocyclic hydrocarbon ring, such as cyclopentyl or cyclohexyl.

[0348] 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.

[0349] 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.

[0350] In this document, the terms "5-10 membered heterocyclic alkyl" or "5-10 membered heterocycle" refer to 5, 6, 7, 8, 9, or 10 membered saturated or unsaturated heterocycles. The term "unsaturated" means that the group or molecule contains carbon-carbon double bonds, carbon-carbon triple bonds, carbon-oxygen double bonds, carbon-sulfur double bonds, carbon-nitrogen triple bonds, etc. 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 means that the group or molecule contains carbon-carbon double bonds, carbon-carbon triple bonds, carbon-oxygen double bonds, carbon-sulfur double bonds, carbon-nitrogen triple bonds, etc.

[0351] 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.

[0352] 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.

[0353] In this document, the term "3-4 membered monocyclic alkyl" refers to a saturated monovalent monocyclic hydrocarbon ring containing 3 or 4 carbon atoms. The 3-4 membered monocyclic alkyl is a monocyclic hydrocarbon ring, such as cyclopropyl or cyclobutyl.

[0354] In this paper, the term "3-10 membered heterocyclic alkyl" refers to a saturated monovalent monocyclic hydrocarbon heterocycle containing 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, wherein the heteroatom can be N, S, or O.

[0355] 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].

[0356] 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.

[0357] 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.

[0358] 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.

[0359] 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.

[0360] 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.

[0361] 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.

[0362] In this article, the term "cycloalkylene" refers to a group formed by removing one more hydrogen atom from a "cycloalkyl" group.

[0363] In this paper, the term "heterocyclic alkyl" refers to a group formed by removing one more hydrogen atom from a "heterocyclic alkyl".

[0364] In this article, the term "CO" or "C(=O)" refers to the carbonyl group, with the structural formula as follows:

[0365] The functional group described in this application It is used to describe the position of the substituent group.

[0366] In this article, It can be a ring or not; see the definition of B for details.

[0367] In this application, in the chemical structure of the compound, the "-" sign indicates that the configuration is not specified. If chiral isomerism exists in the chemical structure, the "-" sign can be... Or simultaneously include and Two configurations. Although all the above structural formulas are shown in some isomer forms for simplicity, this disclosure can include all isomers, such as tautomers, rotational isomers, geometric isomers, diastereomers, racemates, and enantiomers.

[0368] 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.

[0369] 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.

[0370] 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.

[0371] 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.

[0372] 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.

[0373] The present application's solution will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be construed as limiting the scope of the 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 compound's specification. Reagents or instruments whose manufacturers are not specified are all commercially available conventional compounds.

[0374] Example 1: Synthesis of compound 021A

[0375] The synthesis route is as follows:

[0376]

[0377] Step 1: Dissolve 50g of 5-bromo-1,3-difluoro-2-nitrobenzene (compound 1-1) in 500ml of anhydrous THF solution, add 23.8g of benzyl alcohol, purge with nitrogen three times, and cool to -60℃. Slowly add 220ml of potassium tert-butoxide THF solution (1mol / L) to the reaction solution at -60℃. After the addition is complete, raise the temperature to 25℃ and continue the reaction for 30min. TLC detection shows that the reaction is complete. Remove the THF by rotary evaporation, add dichloromethane and water to extract the reaction solution 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 200ml of petroleum ether to obtain compound 1-2 (112.6g).

[0378] 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).

[0379] Step 2: Dissolve 112.6 g of compound 1-2 in 1000 ml of ethanol and add 307 ml of water. Add 334 g 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 1-3 (94.2 g).

[0380] 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).

[0381] Step 3: Dissolve 394.2 g of compound 1-3 in 380 ml of DMF, add 392 g of methyl bromoacetate, and finally add 164 g of DIEA (ethylenediamine). 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 1-4 (59.6 g).

[0382] 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).

[0383] Step 4: Dissolve 32.5 g of chlorosulfonyl isocyanate in 350 ml of dichloromethane. Add 17.1 g 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 of compound 1-4 and 31 g of triethylamine in 600 ml of dichloromethane and 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 1-5 (103 g).

[0384] 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).

[0385] Step 5: Dissolve 103g of compound 1-5 from the previous step in 1000ml of dichloromethane, and add 500ml of trifluoroacetic acid (TFA) at 0℃. 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 30min. TLC monitoring shows that the reaction is complete. Quench the reaction with water at 0℃ in an ice bath. Extract three times with dichloromethane. Dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain compound 1-6 (41.3g).

[0386] 1 H 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).

[0387] Step 6: Dissolve 41.3 g of compound 1-6 from the previous step in 1.65 L of THF, and slowly add 10.7 g of sodium hydride at 0 °C. After the addition is complete, continue the reaction at 25 °C for 0.5 h, and then monitor with TLC. 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 1-7 (48.9 g).

[0388] 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).

[0389] Step 7: Take 6.0 g of compound 1-7 from the previous step and add 100 ml of 1,4-dioxane and 20 ml of water. Then add 9.07 g of potassium trifluoroborate (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (compound 7a) and 9.42 g of cesium carbonate. Finally, add the catalyst chloro[(n-butyldi(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II). 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 1-8 (4.70 g).

[0390] Step 8: Dissolve 1-81g of the compound from the previous step in 60ml of THF, add 1g of palladium on carbon, and react at 25℃ for 3h under a hydrogen balloon. LCMS showed that the reaction was complete. After filtering the reaction solution, evaporate the filtrate to dryness to obtain compound 1-9 (634mg).

[0391] Step 9: Dissolve 1-9634 mg of the compound 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 1-10 (334 mg).

[0392] 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).

[0393] Step 10: Dissolve 17.2 mg of spiro[3.4]octane-2-one in 1 ml of methanol, then add 17.2 mg of DIEA, 41.5 mg of acetic acid, and 1-1040 mg of the compound from the previous step in sequence. Stir at 25 °C for 1 h, then add sodium cyanoborohydride and continue stirring at 25 °C for 1 h. LCMS detection showed that the reaction was complete. After quenching the reaction solution with 2 M hydrochloric acid aqueous solution, the compound 021A (14 mg) was purified by reverse chromatography.

[0394] MS(M+H):398.2[M+H]+.

[0395] 1 H NMR(300MHz,DMSO-d6)δ9.57(s,1H),8.65(s,2H),6.70-6.54(m,2H),4.00(s,2H),3.71-3. 61(m,1H),3.09-2.97(m,2H),2.78(t,J=7.5Hz,2H),2.16-1.97(m,4H),1.65-1.50(m,8H).

[0396] Example 2: Following the synthetic method of compound 021A in Example 1, intermediates 1-10 were reacted with different aldehydes or ketones to obtain the following compounds, the structures and characterization information of which are as follows:

[0397]

[0398]

[0399]

[0400]

[0401]

[0402] Example 3: Synthesis of compound 030A

[0403] The synthesis route is as follows:

[0404]

[0405] 13 mg of compound 1-10 (preparation method see Example 1) was dissolved in 0.5 ml of DMF. 7 mg of spiro[3.3]heptane-2-carboxylic acid, 21 mg of DIEA, and 61.5 mg of 1-propyl phosphate cyclic anhydride (T3P, 50% ethyl acetate solution) were added. The mixture was stirred at room temperature for 2 h. LCMS showed that the reaction was complete. The reaction solution was quenched with dilute hydrochloric acid and purified by reversed-phase preparative chromatography to obtain N-(4-(1,1-dioxo-4-oxo-thiadiazol-2-yl)-3-fluoro-5-hydroxyphenyl)spiro[3.3]heptane-2-amide (i.e., compound 030A, 3 mg).

[0406] MS(M + H):412.2[M + H] + .

[0407] 1 H NMR(300MHz,DMSO-d6)δ9.49(s,1H),7.83-7.68(m,1H),6.57-6.42(m,2H),4.00(s,2H),3.2 3-3.18(m,2H),2.85-2.73(m,1H),2.63-2.54(m,2H),2.07-1.92(m,6H),1.86-1.68(m,4H).

[0408] Example 4:

[0409] Referring to the synthesis method of compound 030A in Example 3, the following compounds were obtained by reacting intermediates 1-10 with different acids, and the structures and characterization information of the compounds are as follows:

[0410]

[0411]

[0412]

[0413] Example 5: Synthesis of compound 002A

[0414] The synthesis route is as follows:

[0415]

[0416] Step 1: Take 8g of compound 1-7 (see Example 1 for specific synthesis method) and dissolve it in 160ml of dioxane and 16ml of water. Then add 7.99g of potassium vinyltrifluoroborate and 1.6g of Pd(dppf)Cl2. React at 100℃ for 1h. Monitor the reaction to ensure it is complete by LCMS. Directly evaporate the reaction solution to dryness and purify it by silica gel column chromatography to obtain compound 2-8 (5.44g).

[0417] 1 H NMR(300MHz,DMSO-d6)δ7.52(d,J=6.7Hz,2H),7.40-7.28(m,3H),7.06(s,1H),7.00(d,J=10.8Hz,1H),6 .67(dd,J=17.5,10.9Hz,1H),5.89(d,J=17.4Hz,1H),5.33(d,J=11.0Hz,1H),5.19(s,2H),3.96(s,2H).

[0418] Step 2: Dissolve 5.44 g of compound 2-8 in 80 ml of tetrahydrofuran and 16 ml of water, add 12.8 g of sodium periodate and 1.1 g of potassium osmium tetroxide dihydrate, react at 25 °C for 1 h, and monitor the reaction by LCMS until the reaction is complete. Extract with ethyl acetate three times, dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain compound 2-9 (1.1 g).

[0419] 1 H NMR (300MHz, DMSO-d6) δ9.92(s,1H),7.57-7.47(m,3H),7.42-7.30(m,4H),5.27(s,2H),4.04(s,2H).

[0420] Step 3: Dissolve 38 mg of 2-aminospiro[3.3]heptane hydrochloride in 1 ml of methanol, then add 106 mg of DIEA, 82 mg of acetic acid, and 40 mg of compound 2-9. Stir at 25 °C for 1 h, then add 52 mg of sodium cyanoborohydride. Continue the reaction at 25 °C for 1 h. LCMS detection shows that the reaction is complete. Quench the reaction solution with water, extract with ethyl acetate 3 times, dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain crude product. Purify with silica gel column to obtain compound 2-10 (50 mg).

[0421] Step 4: Dissolve compound 2-1050mg in 1ml THF, add 0.1ml BCl3 (1mol / L dichloromethane solution) at 0℃, react at 25℃ for 1h after addition, LCMS detection shows that the reaction is complete, quench with 2M hydrochloric acid aqueous solution, and purify by reversed phase chromatography to obtain compound 002A (5mg).

[0422] MS(M+H): 370.3 [M + H] + .

[0423] 1H NMR(300MHz,Methanol-d4)δ6.86-6.74(m,2H),4.27(s,2H),3.99(s,2H),3.71-3.58 (m,1H),2.53-2.37(m,2H),2.21-2.06(m,4H),2.08-1.97(m,2H),1.96-1.82(m,2H).

[0424] Example 6:

[0425] Referring to the synthetic method of compound 002A in Example 5, intermediates 2-9 were reacted with different amines, followed by debenzylation to obtain the following compounds, the structures and characterization information of which are as follows:

[0426]

[0427]

[0428]

[0429]

[0430] Example 7: Synthesis of compounds 059A, 189A and 190A

[0431] The synthesis route is as follows:

[0432]

[0433] Step 1: Dissolve 670 g of 4-bromo-2-fluorophenylacetic acid in 3350 mL of DCM, then add 42 g of DMF, followed by 547 g of oxaloyl chloride at 0 °C. Stir 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 3-2.

[0434] Step 2: 1313g of AlCl3 was added to 8L of dichloromethane solution. Then, 826g of 2-(4-bromo-2-fluorophenol)acetyl chloride (compound 3-2) was dissolved in 2L of dichloromethane solution and added dropwise to the reaction solution at -10℃. The reaction solution was stirred at -10℃ for 1h. Ethylene gas was then introduced into the reaction solution at -4℃. After 1h, the TC test showed that the reaction was complete. The reaction solution was quenched with 2L of water, extracted three times with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate, filtered, and rotary evaporated to obtain 900g of compound 3-3.

[0435] Step 3: Dissolve 900g of compound 3-3 in 8L of toluene, add 827g of ethylene glycol and 76g of p-toluenesulfonic acid, and stir at 130℃ for 2 hours. 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 450g of compound 3-4.

[0436] Step 4: Dissolve 442g of compound 3-4 in 4.5L of dioxane, add 499g of benzyl alcohol, 13.6g of N,N'-diethyloxalamide, 29.3g of cuprous iodide, and 221g of sodium tert-butoxide. Stir the reaction mixture at 110℃ for 16h. TLC showed that the reaction was complete. Quench the reaction mixture with 6L 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 900mL of isopropanol to obtain 200g of compound 3-5.

[0437] Step 5: Dissolve 121 g 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 of compound 3-5 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 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. Then extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain crude product, which is then purified by silica gel column chromatography to obtain 87 g of compound 3-6.

[0438] Step 6: Dissolve 80g of compound 3-6 in dioxane (1.6L), add 40g of glycine tert-butyl ester, 198g of cesium carbonate, 18.4g 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 10.9g of 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl. Then react at 90℃ for 12h. 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 over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the crude product, which was then purified by silica gel column chromatography to obtain 54g of compound 3-7.

[0439] MS(M+H): 444.25.

[0440] Step 7: Dissolve 25.8 g of chlorosulfonyl isocyanate in 800 mL of DCM, then add 14.1 g of allyl alcohol dropwise at -5 °C. After the addition is complete, stir at room temperature for 30 minutes. Then add 54 g of compound 3-7 and 31.4 g of DIEA at 0 °C. Stir at 25 °C for 45 minutes. LCMS indicates that the reaction is complete. Quench the reaction solution with water at 0 °C, then extract with dichloromethane. Dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain 81.5 g of compound 3-8.

[0441] MS(M+H): 607.15.

[0442] Step 8: Dissolve 81.5 g of compound 3-8 in 1.6 L of methanol, then add 2.79 g 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. Purification by silica gel column chromatography yielded 29.2 g of compound 3-9.

[0443] MS(M+H):449.10[M+H]+.

[0444] Step 9: Take 29.2g of compound 3-9 and add 150mL of formic acid. Stir at room temperature for 2 hours. TLC detection showed that the reaction was complete. Add 500mL of water to the reaction solution, precipitate, filter and dry to obtain 18.7g of compound 3-10.

[0445] MS(M+H): 405.10[M+H]+.

[0446] 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).

[0447] Step 10: Dissolve 1.2g of compound 3-10 in 50ml of THF, add 0.5g of Pd / C, stir at 25℃ for 12h under a hydrogen balloon (15Psi), and LCMS showed that the reaction was complete. After filtration, the reaction solution was evaporated to dryness to obtain 900mg of compound 3-11.

[0448] Step 11: Dissolve 88 mg of 2-aminospiro[3.3]heptane hydrochloride in 2 ml of methanol and 2 ml of tetrahydrofuran. Then add 244 mg of DIEA, 200 mg of compound 3-11, and 188 mg of acetic acid. Stir at 0°C for 1 h, then add 120 mg of sodium cyanoborohydride. Continue stirring at 0°C for 1 h after the addition is complete. LCMS analysis showed that the reaction was complete. Quench the reaction solution with 2 M dilute hydrochloric acid aqueous solution, dissolve in 2 ml of DMSO, and purify by reversed-phase chromatography to obtain 90 mg of compound 059A.

[0449] MS(M+H): 410.3[M+H]+.

[0450] 1 H NMR(600MHz,DMSO-d6)δ9.80(s,1H),9.08-8.93(m,2H),6.50(s,1H),4.18(s,2H),3.83-3.76(m,1H),3.08-3.00(m,1H),2.85-2.70(m,2H), 2.58-2.53(m,1H),2.40-2.32(m,2H),2.23-2.11(m,3H),2.05(t,J=7. 4Hz,2H),1.95(t,J=7.5Hz,2H),1.85-1.76(m,2H),1.74-1.64(m,1H).

[0451] Step 12: Take 85 mg of compound 059A and perform SFC chiral separation to obtain 24 mg of compound 189A and 25 mg of compound 190A.

[0452] The characterization data for 189A are as follows:

[0453] MS(M+H): 410.2[M+H]+.

[0454] 1 H NMR(600MHz,DMSO-d6)δ9.17(s,1H),8.68(s,2H),6.39(s,1H),3.86(s,2H),3.72(s,1H),3.01-2.92(m,1H), 2.69(s,3H),2.37-2.27(m,3H),2.12-1.96(m,5H),1.93-1.86(m,2H),1.80-1.70(m,2H),1.66-1.53(m,1H).

[0455] The characterization data for 190A are as follows:

[0456] MS(M+H):410.1[M+H]+.

[0457] 1 H NMR(600MHz,DMSO-d6)δ9.24(s,1H),8.75(s,2H),6.46(s,1H),3.93(s,2H),3.85-3.74(m,1H),3.07-2.98(m,1H),2.81-2.71(m,2H), 2.49-2.44(m,2H),2.41-2.34(m,2H),2.17-2.10(m,2H),2.09-2.02(m,3H),1.99-1.90(m,2H),1.85-1.76(m,2H),1.73-1.61(m,1H).

[0458] Example 8: Synthesis of compounds 108A, 108A-P1, and 108A-P2

[0459] The synthesis route is as follows:

[0460]

[0461] Step 1: Dissolve 36.2 mg of spiro[4.5]dec-8-amine hydrochloride in 0.5 ml of methanol and 0.5 ml of tetrahydrofuran. Then add 61 mg of DIEA, 150 mg of compound 3-1, and 47 mg of acetic acid. Stir at 0 °C for 1 h, then add 30 mg of sodium cyanoborohydride. Continue stirring at 0 °C for 1 h after the addition is complete. LCMS showed that the reaction was complete. Quench the reaction solution with 2 M dilute hydrochloric acid aqueous solution, dissolve in 0.5 ml of DMSO, and purify by reversed-phase chromatography to obtain 16 mg of compound 108A.

[0462] The characterization data for 108A are as follows:

[0463] MS(M+H):452.4[M+H]+.

[0464] 1 H NMR (600MHz, DMSO-d6) δ9.92-9.76(m,1H),8.75-8.60(m,2H),6.51(s,1H),4.19(s,2H),3.28-3.22(m,1H),3.11(dd,J=15.8,5.4Hz, 1H),2.87-2.75(m,2H),2.56(dd,J=16.0,10.2Hz,1H),2.24-2.15(m,1H),2.03-1.91(m,2H),1.77-1.66(m,1H),1.63-1.26(m,15H).

[0465] Step 2: Take 15 mg of compound 108A and perform SFC chiral separation to obtain 4 mg of compound 108A-P1 and 5 mg of compound 108A-P2.

[0466] The characterization data for 108A-P1 are as follows:

[0467] MS(M+H):452.1[M+H]+.

[0468] 1 H NMR(600MHz,DMSO-d6)δ6.44(s,1H),3.93(s,2H),3.01-2.83(m,3H),2.80-2.69(m,2H),2.4 0-2.30(m,1H),2.07-1.99(m,1H),1.88-1.79(m,2H),1.57-1.45(m,8H),1.39-1.29(m,8H).

[0469] The characterization data for 108A-P2 are as follows:

[0470] MS(M+H):452.1[M+H]+.

[0471] 1 H NMR(600MHz,DMSO-d6)δ9.24(s,1H),8.43(s,1H),6.47(s,1H),3.94(s,2H),3.58(s,1H),3.27(s,1H),3.16-3.05( m,1H),2.86-2.77(m,2H),2.53(s,1H),2.21-2.10(m,1H),2.00-1.91(m,2H),1.76-1.47(m,8H),1.45-1.31(m,8H).

[0472] Example 9: Synthesis of compounds 159A, 159A-P1, and 159A-P2

[0473] The synthesis route is as follows:

[0474]

[0475] Step 1: Dissolve 2.64 g of allylamine hydrochloride in 150 mL of tetrahydrofuran, then add 8.74 g of DIEA and stir the mixture at 20 °C for 10 minutes. Next, add 6.09 g of acetic acid and 118.86 g of compound 3-1 to the mixture. Continue stirring the mixture at 20 °C for 50 minutes, then add 5.31 g of sodium cyanoborohydride. Continue stirring the mixture at 20 °C for 1 hour. LCMS analysis showed the reaction was complete. The reaction solution was quenched with 2 M dilute hydrochloric acid aqueous solution, dissolved in 10 mL of DMSO, and purified by reversed-phase chromatography to obtain 6.1 g of compound 159A.

[0476] The characterization data for 159A are as follows:

[0477] MS(M+H):356.3[M+H]+.

[0478] 1 H NMR (600MHz, DMSO-d6) δ10.09(s,1H),9.13(s,2H),6.53(s,1H),6.04-5.89(m,1H),5.55(d,J=17.2Hz,1H),5.43(d,J=10.3Hz,1H),4.28(s,2H), 3.74-3.70(m,2H),3.13(dd,J=16.1,5.5Hz,1H),2.87-2.80(m,1H),2.8 0-2.71(m,1H),2.66-2.58(m,1H),2.26-2.18(m,1H),1.80-1.69(m,1H).

[0479] Step 2: Take 6g of compound 159A and perform SFC chiral separation to obtain 2.1g of compound 159A-P1 and 1.89g of compound 159A-P2.

[0480] The characterization data for 159A-P1 are as follows:

[0481] MS(M+H):356.1[M+H]+.

[0482] 1H NMR (600MHz, DMSO-d6) δ9.33(s,1H),8.77(s,1H),6.53(s,1H),6.06-5.90(m,1H),5.67-5.55(m,1H),5.49(d,J=10.4Hz,1H),4.00(s,2 H),3.79(d,J=6.5Hz,2H),3.47(s,1H),3.22-3.08(m,1H),2.92-2.72(m,2H),2.65-2.59(m,1H),2.28-2.19(m,1H),1.82-1.67(m,1H).

[0483] The characterization data for 159A-P2 are as follows:

[0484] MS(M+H):356.1[M+H]+.

[0485] 1 H NMR (600MHz, DMSO-d6) δ9.30(s,1H),8.63(s,1H),6.47(s,1H),6.00-5.85(m,1H),5.60-5.48(m,1H),5.42(d,J=10.3Hz,1H),3. 94(s,2H),3.73(d,J=6.6Hz,2H),3.48-3.39(m,1H),3.16-3.06(m,1H),2.87-2.67(m,2H),2.22-2.12(m,1H),1.78-1.60(m,1H).

[0486] Example 10:

[0487] Following the synthetic methods of compounds 108A, 108A-P1, 108A-P2 and 159A, 159A-P1, 159A-P2 in Examples 8 and 9, the following compounds were obtained by reacting intermediate 3-11 with different amines and chiral resolution. The structures and characterization information of the compounds are as follows:

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505] Example 10: Synthesis of Compound 100A

[0506] The synthesis route is as follows:

[0507]

[0508] Step 1: Dissolve 800 mg of compound 3-10 (see Example 7 for specific preparation method) in 10 ml MeOH and 10 ml THF. Add 3.05 g ammonium acetate, 1.73 g Boc₂O, and 2.09 g NaBH₃CN at 0 °C, and continue stirring 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 4-11.

[0509] 1H 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).

[0510] Step 2: Dissolve 730 mg of compound 4-11 in 10 ml of 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 4-12 is obtained.

[0511] Step 3: Dissolve 460 mg of compound 4-12 in 5 ml of THF, add 2.5 ml of 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 slurried with methyl tert-butyl ether to obtain 290 mg of compound 4-13.

[0512] Step 4: Take 100 mg of compound 4-13 and add 60.2 mg of DIEA, 42.0 mg of acetic acid, and 28.9 mg of spiro[3.4]octane-2-one. Stir at 25°C for 1 h. LCMS monitoring showed that the reaction was complete. Quench the reaction solution with 2 M dilute hydrochloric acid aqueous solution. After purification by reversed-phase preparative chromatography, 25 mg of compound 100A was obtained.

[0513] MS(M+H):424.3[M+H]+.

[0514] 1 H NMR(600MHz,DMSO-d6)δ9.67(s,1H),9.15-9.01(m,2H),6.49(s,1H),4.09(s,2H),3.94-3.85(m,1H),3. 06(dd,J=16.0,5.4Hz,1H),2.84-2.71(m,2H),2.59-2.53(m,1H),2.22-2.11(m,5H),1.75-1.44(m,10H).

[0515] Example 11: Synthesis of Compound 101A

[0516] The synthesis route is as follows:

[0517]

[0518] 30 mg of compound 4-13 (see Example 10 for specific preparation method) was dissolved in 0.5 ml DMF, 22.6 mg of DIEA and 18.5 mg of 6,6-difluorospiro[3.3]heptane-2-carboxylic acid were added, and 66.7 mg of 1-n-propylphosphonic anhydride (50% ethyl acetate solution) was added at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction was monitored by LCMS until it was complete. The reaction solution was quenched with 2 M dilute hydrochloric acid aqueous solution. After purification by reverse-phase preparative chromatography, 5 mg of compound 101A was obtained.

[0519] MS(M+H): 474.3[M+H]+.

[0520] 1 H NMR(600MHz,DMSO-d6)δ9.94(s,0H),7.83(d,J=7.3Hz,1H),6.48(s,1H),4.29(s,2H),2.96-2.92(m,1H),2.75-2.71(m, 1H),2.65-2.60(m,5H),2.56-2.52(m,4H),2.36-2.30(m,1H),2.20-2.13(m,2H),1.88-1.81(m,1H),1.62-1.54(m,1H).

[0521] Example 12: Synthesis of Compound 141A

[0522] The synthesis route is as follows:

[0523]

[0524] 15 mg of compound 100A was dissolved in a mixture of 0.3 ml MeOH, 0.3 ml THF and 0.3 ml 37% formaldehyde aqueous solution. 13.7 mg of DIEA and 10.6 mg of acetic acid were added. 11.1 mg of sodium cyanoborohydride was added at 0 °C and the mixture was stirred at 25 °C for 1 h. The reaction was monitored by LCMS until it was complete. The reaction solution was quenched with 2 M dilute hydrochloric acid aqueous solution. After purification by reversed-phase preparative chromatography, 3 mg of compound 141A was obtained.

[0525] MS(M+H): 438.4[M+H]+.

[0526] 1H NMR(600MHz,DMSO-d6)δ10.20-9.85(m,1H),9.75-9.56(m,1H),6.50(s,1H),4.11(s,2H),4.01-3.88( m,1H),3.07-2.92(m,1H),2.91-2.69(m,3H),2.65-2.61(m,3H),2.28-2.09(m,5H),1.88-1.46(m,9H).

[0527] Example 13:

[0528] Compound 133A was prepared using the same synthetic method as compound 141A in Example 12. The structural formula and characterization data of the compound are as follows:

[0529]

[0530]

[0531] Example 14: Synthesis of Compound 175A

[0532] The synthesis route is as follows:

[0533]

[0534] Step 1: Dissolve 50g of 5-bromo-1,3-difluoro-2-nitrobenzene (compound 5-1) in 500ml of anhydrous THF solution, add 23.8g of benzyl alcohol, purge with nitrogen three times, and cool to -60℃. Slowly add 220ml of potassium tert-butoxide THF solution (1mol / L) to the reaction solution at -60℃. After the addition is complete, raise the temperature to 25℃ and continue the reaction for 30min. TLC detection shows that the reaction is complete. Remove the THF by rotary evaporation, add dichloromethane and water to extract the reaction solution 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 200ml of petroleum ether to obtain 112.6g of compound 5-2.

[0535] 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).

[0536] Step 2: Dissolve 24g of 1-(benzyloxy)-5-bromo-3-fluoro-2-nitrobenzene (compound 5-2) in 240ml of anhydrous tetrahydrofuran, cool to -70℃, and add dropwise LDA solution (73.6ml, 2M THF solution). After the addition is complete, continue stirring at -70℃ for 30min. Add 1,2,3-oxathiazolidin-3-carboxylic acid tert-butyl ester 2,2-dioxide (19.7g dissolved in 300ml THF), and stir at -70℃ for 1h. 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 14.3g of compound 5-3.

[0537] Step 3: Dissolve 8.34 g of compound 5-3 in 85 ml of 1,4-dioxane solution and 17 ml of water. Add 17.6 g of (E)-1-ethoxyvinyl-2-boronate pinacol ester and 17.3 g of cesium carbonate. Finally, add 1.95 g of catalyst Pd(dppf)Cl2. After nitrogen purging 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.

[0538] 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).

[0539] Step 4: Dissolve 4.26 g 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 hour. TLC monitoring showed 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.

[0540] Step 5: Dissolve 3.02 g of compound 5-5 in 120 ml of ethanol and add 40 ml of water. Heat to 80 °C and add 10.1 g of sodium dithionite. Continue stirring at 80 °C for 30 min. TLC monitoring showed that the reaction was complete. After rotary evaporating the 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.

[0541] MS(M+H): 385.3[M+H]+.

[0542] 1 H 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).

[0543] Step 6: Dissolve 2.16 g of compound 5-6 in 20 ml of DMF, add 2.31 g of methyl bromoacetate and 2.90 g of DIEA. Stir the reaction at 60 °C for 1.5 h, and TLC monitoring shows that the reaction is 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.

[0544] MS(M+H):457.4[M+H]+.

[0545] Step 7: Dissolve 861 mg of chlorosulfonyl isocyanate in 10 mL of dichloromethane. Add 658 mg of benzyl alcohol dropwise at 0 °C, maintaining a temperature of 10 °C. After the addition is complete, stir at 25 °C for 0.5 h. Dissolve 1.49 g of compound 5-7 from the previous step in 15 mL of dichloromethane, and add 924 mg of triethylamine to prepare a mixed solution. Add this 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.

[0546] Step 8: Dissolve 2.84g of compound 5-8 in 60ml of THF, add 1g of palladium on carbon, and stir for 1h in a hydrogen balloon (15PSI) at 25℃. 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 1.10g of compound 5-9.

[0547] Step 9: Dissolve 1.10 g of compound 5-9 in 30 ml of THF. Add 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.

[0548] 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).

[0549] Step 10: Dissolve 330 mg 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 5-11.

[0550] MS(M+H):316.3[M+H]+.

[0551] 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).

[0552] Step 11: Dissolve 50 mg of compound 5-11 in 0.5 ml DMSO, add 45.3 mg DIEA, 19.3 mg spiro[3.3]heptan-2-one, and 35.0 mg acetic acid. Stir at 25 °C for 1 h, then add 22.0 mg sodium cyanoborohydride. Continue stirring at 25 °C for 1 h. LCMS monitoring showed that the reaction was complete. The reaction solution was quenched with 2 M dilute hydrochloric acid aqueous solution. After purification by reversed-phase preparative chromatography, 11 mg of compound 175A was obtained.

[0553] MS(M+H): 410.3[M+H]+.

[0554] 1H NMR(600MHz,DMSO-d6)δ10.24(s,1H),9.63(s,1H),6.61(s,1H),4.01(s,2H),3.60-3.49(m,3H) ,3.23-3.12(m,2H),2.97-2.73(m,4H),2.38-2.21(m,4H),2.05-1.93(m,4H),1.87-1.76(m,2H).

[0555] Example 15: Synthesis of compounds 279A-P1 and 279A-P2

[0556] The synthesis route is as follows:

[0557]

[0558] Step 1: Dissolve 50 mg of compound 5-11 in 0.5 ml DMSO and 0.5 ml MeOH, add 45.1 mg DIEA, stir at 25 °C for 30 min, then add 41.9 mg 3,3-difluorocyclobutane-1-one and 35.0 mg acetic acid, stir under nitrogen protection for 0.5 h, then add 22.0 mg sodium cyanoborohydride at 25 °C, and continue stirring at 25 °C for another 0.5 h. LCMS monitoring showed the reaction was complete. The reaction solution was quenched with 2 M dilute hydrochloric acid aqueous solution, and lyophilized to obtain 50 mg of crude 279A.

[0559] Step 2: After purifying 50 mg of crude 279A by reversed-phase preparative chromatography, 31 mg of compound 279A-P1 and 6 mg of compound 279A-P2 were obtained.

[0560] The reversed-phase preparative chromatographic separation conditions were as follows: (Column: Phenomenex Luna C18 (250*70mm, 15um); Mobile phase: 0.01% trifluoroacetic acid aqueous solution and acetonitrile solution; Gradient: acetonitrile phase increased from 0% to 25% over 18.0 min).

[0561] The characterization data for 279A-P1 are as follows:

[0562] Retention time Rt = 2.225 min, detected by chiral SFC chromatography. Conditions: Column: Chiralpak IK-3, 100 × 4.6 mm ID, 3 μm; Mobile phase A: CO2; Mobile phase B: methanol solution containing 0.2% ammonia; Mobile phase gradient: 0-0.2 min, mobile phase B maintained at 10%; 0.2-2.4 min, mobile phase B gradually increased from 10% to 50%; 2.4-3.4 min, mobile phase B maintained at 50%; 3.5-4.0 min, mobile phase B gradually decreased from 50% to 10%.

[0563] Flow rate: 3.4 mL / min; column temperature: 35℃

[0564] The characterization data for 279A-P1 are as follows:

[0565] MS(M+H): 420.2[M+H]+.

[0566] 1 H NMR(600MHz,DMSO-d6)δ10.10(s,1H),9.72(s,1H),6.63(s,1H),6.24-5.95(m,1H),4.15-4.01(m,2H),3.69-3.62(m,1 H),3.60-3.50(m,3H),3.23-3.10(m,2H),3.00-2.92(m,1H),2.92-2.81(m,3H),2.39-2.32(m,2H),2.31-2.22(m,2H).

[0567] 19 F NMR: (400MHz, DMSO-d6)δ-122.0(s,1F),-122.8(s,2F).

[0568] X-ray single-crystal diffraction analysis confirmed that the absolute configuration of 279A-P1 is S,S configuration. The characterization data for 279A-P2 are as follows:

[0569] Retention time Rt = 2.298 min, detected by chiral SFC chromatography. Conditions: Column: Chiralpak IK-3, 100 × 4.6 mm ID, 3 μm; Mobile phase A: CO2; B: methanol solution containing 0.2% ammonia; Mobile phase gradient: 0-0.2 min, mobile phase B maintained at 10%; 0.2-2.4 min, mobile phase B gradually increased from 10% to 50%; 2.4-3.4 min, mobile phase B maintained at 50%; 3.5-4.0 min, mobile phase B gradually decreased from 50% to 10%; Flow rate: 3.4 mL / min; Column temperature: 35 °C.

[0570] MS(M+H): 420.3[M+H]+.

[0571] 1H NMR(600MHz,DMSO-d6)δ10.26(s,1H),9.73(s,1H),8.78(s,1H),6.63(s,1H),6.35-6.17(m,1H),4.10-4.04(m,2H),3.81-3.74(m,1H) ,3.60-3.53(m,2H),3.22-3.15(m,2H),3.00-2.94(m,1H),2.88-2.82(m,2H),2.72-2.66(m,1H),2.63-2.57(m,2H),2.34-2.28(m,2H).

[0572] 19 F NMR: (400MHz, DMSO-d6)δ-121.9(s,1F),-123.3(s,2F).

[0573] Example 15:

[0574] Referring to the synthetic method of compound 175A in Example 14, a similar method was used to react intermediate 5-11 with different ketones or aldehydes to obtain the following compounds, the structures of which and their characterization data are as follows:

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581] Example 16: Synthesis of Compound 237A

[0582] The synthesis route is as follows:

[0583]

[0584] Step 1: Dissolve 5g of compound 1-7 in 50ml of 1,4-dioxane and 5ml of water, add 4.77g of (E)-1-ethoxyvinyl-2-boronic acid pinacol ester and 4.99g of potassium carbonate, purge with nitrogen three times, then add 880mg of Pd(dppf)Cl2, purge with nitrogen three times, heat to 95℃, and stir for 1 hour. TLC monitoring showed the reaction was complete. Filter the reaction solution, evaporate the filtrate to dryness to obtain the crude product, and purify by silica gel column chromatography to obtain 3.2g of compound 6-2.

[0585] Step 2: Dissolve 100 mg of compound 6-2 in 1 ml of dichloromethane, add 1 ml of trifluoroacetic acid at 25 °C, and stir at 25 °C for 0.5 hours. LC-MS monitoring showed the reaction was complete. After rotary evaporation of the solvent from the reaction solution, 100 mg of compound 6-3 was obtained. MS (MH): 377.0 [MH]+.

[0586] Step 3: Dissolve 52.2 mg of compound 2,2-difluoro-7-azaspiro[3.5]nonane hydrochloride in 1 ml of anhydrous methanol, add 85 mg of DIEA, stir at 25 °C for 15 minutes, then add compound 6-3 and 66 mg of acetic acid. Cool the reaction solution to 0 °C, stir for 10 minutes, and then add 41.7 mg of sodium cyanoborohydride under nitrogen protection at 0 °C. Continue stirring at 0 °C for 30 minutes. LCMS monitoring showed that the reaction was complete. Quench the reaction solution with 2 M dilute hydrochloric acid aqueous solution, and purify by reversed-phase preparative chromatography to obtain 24 mg of compound 6-4. MS(MH): 524.0 [M+H]+.

[0587] Step 4: Dissolve 24 mg of compound 6-4 in 2 ml of EtOH and sonicate to aid dissolution. Under nitrogen protection, add 200 mg of ammonium formate and 100 mg of wet palladium on carbon at 25 °C, and stir at 90 °C for 2 hours. LCMS monitoring showed that the reaction was complete. Filter and concentrate the reaction solution to obtain the crude product, which was then purified by reversed-phase preparative chromatography to obtain 1.9 mg of compound 237A.

[0588] MS(M+H):434.2[M+H]+.

[0589] 1 H NMR(600MHz,DMSO-d6)δ9.49(s,1H),9.32(s,1H),6.64(dd,J=10.8,1.9Hz,1H),6.61(s,1H),3.94(s ,2H),3.50-3.44(m,2H),3.31-3.26(m,2H),2.98-2.88(m,4H),2.50-2.44(m,4H),1.92-1.81(m,4H).

[0590] Example 17: Following the synthetic method of compound 237A in Example 16, intermediate 6-4 was reacted with different amines to obtain the following compounds, the structures of which and their characterization data are as follows:

[0591]

[0592] Test Example 1:

[0593] 1. PTPN1 enzyme activity assay

[0594] This experiment will use the PTPN1 activity inhibition assay to evaluate the selectivity and efficacy of the inhibitor.

[0595] The compound of this application was serially diluted using DMSO in a compound dilution plate (384PP Plate). 0.1 μL of the diluted compound was transferred to a 384-well reaction plate (Proxiplate 384F Plus) using ECHO, followed by the addition of 5 μL of PTPN1 enzyme solution. The mixture was centrifuged at 1000 rpm for 1 min, incubated at 25°C for 10 min, and then 5 μL of DIFMUP solution was added. The mixture was centrifuged at 1000 rpm for 1 min and incubated at 25°C for 30 min, ensuring the final DMSO concentration was 1%. The final concentrations of the reaction system were: 50 mM Tris-HCl (pH 7.2), 50 mM NaCl, 0.01% Triton X-100, 1 mM DTT, 0.2 nM PTPN1, and 10 μM DIFMUP. Fluorescence values ​​(EX / EM: 360 nm / 460 nm) were read using a BMG (CLARIO Star Plusacu). Wells containing both enzyme solution and DMSO were designated as High Controls, while wells containing the same DMSO concentration but with added buffer were designated as Low Controls. The inhibition rate (% inhibition) of the compound pores was calculated as 100 * (High control - Sample) / (High control - Low control). Then, a four-parameter IC was fitted using XLfit 5.5.0. 50 The curve was analyzed.

[0596] 2. PTPN2 enzyme activity assay

[0597] This experiment will use the PTPN2 activity inhibition assay to evaluate the selectivity and efficacy of the inhibitor.

[0598] The compound of this application was serially diluted using DMSO in a compound dilution plate (384PP Plate). 0.1 μL of the diluted compound was transferred to a 384-well reaction plate (Proxiplate 384F Plus) using ECHO, followed by 5 μL of PTPN2 enzyme solution. The mixture was centrifuged at 1000 rpm for 1 min, incubated at 25°C for 10 min, and then 5 μL of DIFMUP solution was added. The mixture was centrifuged at 1000 rpm for 1 min and incubated at 25°C for 30 min, ensuring the final DMSO concentration was 1%. The final concentrations of the reaction system were: 50 mM Tris-HCl (pH 7.2), 50 mM NaCl, 0.01% Triton X-100, 1 mM DTT, 0.5 nM PTPN2, and 10 μM DIFMUP. Fluorescence values ​​(EX / EM: 360 nm / 460 nm) were read using BMG (CLARIO Star Plusacu). Wells containing both enzyme solution and DMSO were designated as High Controls, while wells containing the same DMSO concentration but with added buffer were designated as Low Controls. The inhibition rate (% inhibition) of the compound pores was calculated as 100 * (High control - Sample) / (High control - Low control). Then, a four-parameter IC was fitted using XLfit 5.5.0. 50 The curve was analyzed.

[0599] In Table 1, "A" represents IC. 50 Less than 1.8 nM; "B" indicates IC 50 Between 1.8 nM and 10 nM; "C" indicates IC 50 It is greater than 10nM to 50nM; "D" indicates IC 50 Greater than 50 nM and less than 100 nM; "E" indicates IC 50 Greater than 100 nM.

[0600] Table 1: IC50 of each compound 50 result

[0601]

[0602]

[0603]

[0604]

[0605] Test Example 2: B16F10 Cell Growth Inhibition Assay

[0606] B16F10 cells were seeded at a density of 200 cells per well in 96-well clear-bottom plates (Corning, catalog number 3603), and 100 μL of DMEM (Gibco, 11995065) complete medium containing 10% FBS (Avantor, catalog number 76294-180) was added. Cells were incubated overnight at 37°C and 5% CO2. The next day, 50 μL of medium was aspirated from each well, and the compound of this application was serially diluted three-fold in DMSO, ranging from 7.5 mM to 0.0001 mM, including a DMSO-only control group, for a total of 10 concentration gradients. The compound / DMSO dilution was further diluted in the complete medium at a ratio of 1:500 using an ECHO ultrasonic pipetting workstation (Bechman, model ECHO 655) to form a 2-fold concentration compound solution. Then, 50 μL of diluent was added to the cell culture plate to achieve a 4-fold serial dilution, bringing the final compound concentration to 7.5 μM to 0.0001 μM, with a final DMSO concentration of 0.1%. Subsequently, 1 μL of mouse IFN-γ (RDsystems, 485-M1 / CF) was added to the cell culture plate to achieve a final assay concentration of 30 ng / mL. The cell culture plates were incubated at 37°C with 5% CO2 for 4 days. After incubation, the cell culture plates were removed and allowed to equilibrate at room temperature for 10 minutes. Then, 60 μL of CellCounting-Lite 2.0 Luminescent Cell Viability Assay (Vazyme, DD1101-03) was added to each well and incubated at room temperature in the dark for 30 minutes. Finally, the luminescence signal was read using a multi-mode microplate reader (BMG, model PHERAstar FSX). Dose-response curves were calculated using GraphPadPrism 8.0 software, and the IC50 of the compounds was determined accordingly. 50 The results showed that the compound of this application can effectively inhibit the growth of B16F10 cells. This embodiment exemplifies some of the results, as detailed in Table 2. In Table 2, "A" represents IC50. 50 Less than 100 nM.

[0607] Table 2: IC50 of each compound 50 result

[0608] compound <![CDATA[B16F10IC 50 (nM)]]> 059A A 060A A 061A A 100A A 103A A 107A A 108A A 109A / 110A A 119A A 159A A 189A / 190A A 195A A 197A A 198A A 201A A 205A A 206A A 213A A 218A A 100A-P1 / 100A-P2 A 108A-P1 / 108A-P2 A 110A-P1 / 110A-P2 A 159A-P1 / 159A-P2 A 205A-P1 / 205A-P2 A 261A A 277A A 279A-P1 A 313A A 335A A

[0609] Test Example 3: Determination of protein binding rate and free state ratio of various compounds in SD rat, CD-1 mouse and human plasma

[0610] The experimental steps are as follows:

[0611] The plasma protein binding rate of the compounds was determined using a 96-well balanced dialysis plate (HTDialysis device, molecular weight cutoff 12–14 kDa). Before the experiment, the dialysis membrane was pretreated according to the instruction manual, and then the dialysis device was assembled as required. Plasma samples from the three species were taken, and a certain volume of the compound working solution was added to prepare plasma samples of a specific concentration. First, a certain volume of the compound-containing plasma sample was transferred to the sample receiving plate as the initial spiked sample (T0 sample). Second, the compound-containing plasma sample was added to one side of the dialysis membrane (plasma end), and a certain volume of dialysis buffer was added to the other side of the dialysis membrane (buffer end). Then, the dialysis plate was placed in a humidified incubator containing 5% carbon dioxide and incubated at 37°C for 4 hours. After incubation, a certain volume of the dialysis buffer sample (F sample), the dialysis plasma sample (T sample), and the T0 sample were transferred to the sample receiving plate. All samples were analyzed by LC-MS / MS after matrix balancing and protein precipitation. The results showed that the compound of this application exhibited a high proportion of free form in SD rats, CD-1 mice, and human plasma, demonstrating significant efficacy advantages. Some results are illustrated in Table 3 of this embodiment.

[0612] Table 3: Protein binding rates of the compounds of the present invention in SD rats, CD-1 mice and human plasma, respectively.

[0613]

[0614] Test Example 4: Plasma Stability Study of Various Compounds in Different Species

[0615] The experimental steps are as follows:

[0616] The compound powder of this application was dissolved in DMSO to prepare a 2.00 mM stock solution, and then the stock solution was further diluted with 50% acetonitrile / water to prepare a 50.0 μM working solution for later use. Then, 98.0 μL of blank plasma from CD-1 mice, SD rats, and humans were added to the corresponding incubation plates, which included T0 (0 min), T5 (5 min), T15 (15 min), T30 (30 min), T60 (60 min), and T120 (120 min), with two parallel wells for each sample. The incubation plates were then pre-incubated in a 37°C water bath for 10 minutes. After 10 minutes, 2.00 μL of the compound working solution was added to the incubation plate containing the blank plasma, and the mixture was quickly mixed. The corresponding incubation plate was then incubated in a 37°C water bath. The final incubation concentration of the compound was 1.00 μM. Finally, at the end of each incubation time point, the corresponding incubation plate was removed, stop solution was added, the protein was precipitated, mixed, and centrifuged for 20 minutes. The supernatant was collected, diluted with diluent, and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The concentration of the analyte in the sample was semi-quantitatively determined using LC-MS / MS.

[0617] The results showed that the compounds of this application exhibit excellent stability in CD-1 mice, SD rats, and human plasma. Some of the results are illustrated in Table 4 of this embodiment.

[0618] Table 4: Stability results in CD1 mice, SD rats and human plasma

[0619]

[0620] Test Example 5: Detection of the Inhibition of CYP Enzymes by Various Compounds

[0621] The experimental steps are as follows:

[0622] The inhibition rates of the compounds against CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A were determined using specific probe substrates of human liver microsomal cytochrome P450 isoenzymes. First, 100 μL of human liver microsomal working solution containing the substrate was added to the reaction plate. Next, 2.00 μL of the compound working solution was added to the corresponding well, and the reaction plate was preheated in a 37°C water bath for 10 minutes. Then, 98.0 μL of the preheated cofactor was added to the reaction plate to start the reaction. For CYP1A2, CYP2B6, CYP2C9, and CYP3A (using testosterone as a substrate), the reaction was terminated by adding a stop solution after 10 minutes. For CYP2C8, the reaction was terminated by adding a stop solution after 5 minutes. For CYP2C19 and CYP2D6, the reaction was terminated by adding a stop solution after 20 minutes. For CYP3A (using midazolam as a substrate), the reaction was terminated by adding a stop solution after 3 minutes. Finally, the reaction plate was centrifuged at 3,220 × g for 20 minutes, and 100 μL of the supernatant was collected and diluted with 100 μL of ultrapure water. After mixing, the solution was analyzed by LC-MS / MS. The results showed that the compound of this application had no significant inhibitory effect on CYP enzymes at 10 μM and had good safety. Some results are shown in Table 5 of this embodiment.

[0623] Table 5

[0624]

[0625] Test Example 6: Detection of the inhibitory effect of various compounds on hERG

[0626] The experimental steps are as follows:

[0627] Compound preparation:

[0628] The weighed analyte was prepared into a 10 mM stock solution using DMSO. The stock solution was then sequentially diluted with DMSO to prepare 3.33 mM, 1 mM, 0.33 mM, and 0.1 mM diluents. The stock solution and diluents were then sequentially diluted with extracellular fluid to prepare 30 μM, 10 μM, 3 μM, 1 μM, and 0.3 μM working solutions, ensuring a DMSO concentration of 0.3%. All concentrations were sonicated for 20 min. The solubility of the sample was visually inspected; all concentrations dissolved completely without any visible precipitation.

[0629] Cell culture

[0630] The HEK-293 cell line, stably expressing hERG potassium channels, was used. These hERG potassium channel cells were purchased from Creacell (catalog number: A-0320). The cell culture method is as follows:

[0631] HEK-293 cell lines stably expressing hERG potassium channels were cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg / mL G418 at 37°C and 5% carbon dioxide.

[0632] Cell passage: Remove the old culture medium and wash once with PBS, then add 1 mL TrypLE TM Incubate with Express solution at 37°C for approximately 0.5 min. Once cells detach from the bottom of the dish, add approximately 5 mL of preheated (37°C) complete culture medium. Gently pipette the cell suspension to separate any aggregated cells. Transfer the cell suspension to sterile centrifuge tubes and centrifuge at 1000 rpm for 5 min to collect the cells. For expansion or maintenance culture, seed cells into 6 cm cell culture dishes at a density of 2.5 × 10⁶ cells per dish. 5 Cells (final volume: 5 mL). To maintain the electrophysiological activity of the cells, the cell density must not exceed 80%.

[0633] Before patch-clamp detection, cells were treated with TrypLE. TM Express separation, 4×10 3 Cells were seeded onto coverslips and cultured in 24-well plates (final volume: 500 μL). After 18 hours, the cells were tested.

[0634] Electrophysiological recording

[0635] Record the liquid used

[0636] Extracellular fluid: K-007-1

[0637] 140mM NaCl, 3.5mM KCl, 1mM MgCl2·6H2O, 2mM CaCl2·2H2O, 10mM D-Glucose, 10mM HEPES, 1.25mM NaH2PO4·2H2O, with NaOH adjusted to pH 7.4.

[0638] Intracellular fluid: K-002-2

[0639] 20mM KCl, 115mM K-Aspartic, 1mM MgCl2·6H2O, 5mM EGTA, 10mM HEPES, 2mM Na2-ATP, KOH adjust pH=7.2.

[0640] Extracellular fluid was stored for 2 weeks. Intracellular fluid, after preparation, was aliquoted into 1 mL tubes and stored at -20°C. Freshly thawed intracellular fluid was used daily for experiments. All intracellular fluid was used within three months. After three months, the old intracellular fluid was discarded and freshly prepared.

[0641] Patch clamp testing

[0642] The voltage stimulation protocol for whole-cell patch-clamp recording of hERG currents is as follows: After whole-cell sealing, the cell membrane voltage is clamped at -80 mV. The clamping voltage is depolarized from -80 mV to -50 mV and maintained for 0.5 s (as a leakage current detection), then stepped to 30 mV and maintained for 2.5 s, and then rapidly restored to -50 mV and maintained for 4 s to excite the tail current of the hERG channel. Data is collected every 10 s to observe the effect of the drug on the hERG tail current. Experimental data are acquired by an IPA amplifier (Sutter Instrument) and stored in SutterPatch (with Igor Pro) software. The patch-clamp procedure first involves using a microelectrode puller to pull a capillary glass tube into a recording electrode, then inserting the electrode filled with intracellular fluid into the microelectrode holder. Under an inverted microscope, the microelectrode manipulator is used to immerse the electrode in the extracellular fluid and record the electrode resistance (Rpip). Then, the electrode is slowly brought into contact with the cell surface, and negative pressure is applied to aspirate and form a GΩ seal. Fast capacitance compensation is then performed, and negative pressure is applied to rupture the cell membrane, establishing a whole-cell recording mode. Finally, slow capacitance compensation is performed, and experimental parameters such as series resistance (Rs) are recorded. No leakage compensation is applied. Once the hERG current recorded in the whole cells stabilizes, drug administration begins. Each drug concentration is administered for approximately 5 minutes (or until the current stabilizes), and the next concentration is measured. Multiple concentrations are measured for each test compound. A coverslip containing cells is placed in a recording bath under an inverted microscope. Blank control solution and working solution of the test compound are perfused sequentially from low to high concentration through the recording bath using gravity, acting on the cells. A peristaltic pump is used for fluid exchange during recording. The current detected in the solution without the compound serves as the control group for each cell. Each concentration is measured twice independently using at least two cells. All electrophysiological experiments are performed at room temperature.

[0643] Data Analysis

[0644] First, the peak tail current after each drug concentration was applied was recorded. compound Peak tail current (and blank control) control Normalize, and then calculate the inhibition rate corresponding to each drug concentration. For each concentration inhibition rate, the mean (Mean), standard deviation (SD), and standard error (SE) were calculated, and the data are expressed as Mean ± SE.

[0645] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)).

[0646] Calculate the IC for each compound using the above equations. 50 The values ​​were calculated, and the dose-response curve was nonlinearly fitted, where IC 50 This is the half-inhibitory concentration (IC50). 50 The calculations and curve fitting were performed using GraphPad Prism software. The results show that the compounds in this application exhibit IC50 inhibition of hERG. 50 >30µM, exhibiting good security. The results of this embodiment are illustrated in Table 6.

[0647] Table 6

[0648] compound hERG inhibition (IC50, μM) 189A / 190A >30uM 279A-P1 >30uM

[0649] Test Example 7: Stability Study of Different Compounds in Liver Microsomes of Different Species

[0650] The experimental steps are as follows:

[0651] First, the compound powder of this application was dissolved in DMSO to prepare a 2.00 mM stock solution, which was then further diluted with DMSO to a 100 μM working solution. Second, the microsomes were diluted with blank phosphate buffer to a 1.00 mg / mL working solution. Then, 100 μL of blank liver microsome working solution from CD-1 mice, SD rats, and humans was added to the corresponding incubation plates, with incubation times including T0 (0 min), T5 (5 min), T15 (15 min), T30 (30 min), and T45 (45 min). For T60 (60 min) and NCF60 (60 min), prepare two parallel wells for each sample. Finally, pre-incubate the plates in a 37°C water bath for 10 minutes. After 10 minutes, add 2.00 μL of the compound working solution and 98.0 μL of coenzyme factor working solution (for NCF60 samples, add 2.00 μL of the compound working solution and 98.0 μL of blank phosphate buffer) to the corresponding incubation plate containing blank liver microsome working solution. Mix quickly and incubate the plates in a 37°C water bath until the final compound concentration is 1.00 μM. At the end of each incubation time point, remove the corresponding incubation plate, add stop solution, precipitate the protein, mix, centrifuge for 20 minutes, collect the supernatant, dilute with diluent, and analyze using liquid chromatography-tandem mass spectrometry (LC-MS / MS). The concentration of the analyte in the samples was semi-quantitatively determined using LC-MS / MS.

[0652] The results showed that the compounds of this application exhibit excellent stability in CD-1 mice, SD rats, and human liver microsomes. Some of the results are illustrated in Table 7 of this embodiment.

[0653] Table 7: Stability results in CD-1 mice, SD rats and human liver microsomes

[0654]

[0655] Test Example 8: Study on the metabolic stability of various compounds in hepatocytes of different species

[0656] The experimental steps are as follows:

[0657] First, the compound powder of this application was dissolved in DMSO to prepare a 10 mM stock solution. 10.0 μL of the 10.0 mM stock solution was diluted with 90.0 μL of DMSO to prepare a 1.00 mM intermediate solution. 10.0 μL of the 1.00 mM intermediate solution was then diluted with 190 μL of 20% ACN / H2O to obtain a 50.0 μM working solution. Human hepatocyte suspensions, SD rat hepatocyte suspensions, and beagle dog hepatocyte suspensions were diluted to 0.52 x 10⁶ cells / mL using preheated Williams' Medium E (WEM) medium. Then, 576.0 μL of cell suspension was added to the corresponding wells. The cell suspensions were pre-incubated in a 37°C CO₂ incubator for 10 min. 24 μL of working solution was added to the corresponding wells to initiate the reaction. At each time point (0, 5, 15, 30, 60, and 120 minutes), 50 μL of the reaction mixture was transferred from the sample plate to 500 μL of stop solution. The stop solution was an acetonitrile solution containing 50.0 ng / mL tolbutamide, ethoxybenzamide, and 10.0 ng / mL labetalol and buspirone, all containing 0.1% formic acid. The mixture was then centrifuged at 3200 × g for 20 minutes. 100 μL of the supernatant was added to 100 μL of ultrapure water, mixed well, and analyzed by LC-MS / MS.

[0658] The results showed that the compounds of this application exhibit excellent metabolic stability in human hepatocytes, SD rat hepatocytes, and beagle dog hepatocytes. Some of the results are illustrated in Table 8 of this embodiment.

[0659] Table 8: Stability results in human hepatocytes, SD rat hepatocytes, and beagle dog hepatocytes

[0660]

[0661] Test Example 9: Pharmacokinetic Studies of Various Compounds

[0662] 1. Laboratory animals:

[0663] Male CD-1 mice and male SD rats, 6–9 weeks old, were purchased from Vital River.

[0664] Male Beagle, 10-14 months old, purchased from Mars.

[0665] 2. Solvent and dosage for animal administration

[0666] For mice and rats: Intravenous administration was given at a dose of 1 mg / kg via 5% DMSO + 95% (5% glucose aqueous solution); oral administration was given at a dose of 10 mg / kg via 5% DMSO + 5% Tween 80 + 90% physiological saline.

[0667] For Beagles: Intravenous administration with 5% DMSO + 95% (5% glucose aqueous solution) as the solvent, at a dose of 1 mg / kg; or oral administration with 5% DMSO + 5% Tween 80 + 90% physiological saline as the solvent, at a dose of 5 mg / kg.

[0668] 3. Experimental Procedure

[0669] The pharmacokinetic characteristics of the compound after intravenous injection and gavage were tested using a standard protocol. First, animals were randomly selected and administered the compound by a single dose or a single administration. For intravenous injection, a clear solution of the compound at 0.200 mg / mL (1.00 mg / kg) was administered to animals; for gavage, a clear solution of the compound at 1.00 mg / mL (10.0 mg / kg) was administered. Second, plasma samples were obtained by collecting blood from the facial vein at time points of 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration and centrifuged. Then, a certain volume of plasma sample was transferred, and a stop solution was added to terminate the sample collection. The supernatant was collected by centrifugation and diluted with diluent before the concentration of the compound was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Finally, pharmacokinetic (PK) parameters were calculated using Phoenix WinNonlin software and the non-compartmental model statistical moment method. The results are shown in Table 8. All samples were stored at -60 to -90°C before analysis. The results showed that the compounds of this application exhibited good pharmacokinetics in mouse plasma. Some of the results are illustrated in Tables 9-11 of this embodiment.

[0670] Table 9: Oral pharmacokinetic parameters of mice in each group

[0671]

[0672]

[0673] Table 10: Oral pharmacokinetic parameters of rats in each group

[0674]

[0675] Table 11: Oral pharmacokinetic parameters of each group of beagle dogs

[0676]

[0677] Test Example 10: In vivo efficacy evaluation in mice

[0678] Evaluation of the antitumor efficacy of drugs in mouse subcutaneous xenograft models of EMT6 breast cancer, MC38 colon cancer, CT26 colon cancer, 4T1 breast cancer, B16 melanoma, and KPC pancreatic cancer.

[0679] 2. Cell Culture

[0680] Cancer cells were cultured in 1640 or DMEM medium containing 10% fetal bovine serum and 1% P / S; the cells were cultured in an incubator at 37°C and 5% carbon dioxide.

[0681] Cell passage: When the cell density reaches 1×10⁻⁶ 6 When cells / mL, use 2×10 5 Cells / mL passage. Transfer the cell suspension to a sterile 50mL centrifuge tube and collect the cells by centrifugation at 1000rpm (TDZ5-WS Xiangyi Centrifuge Instrument Co., Ltd.) for 5 minutes at 4℃.

[0682] To maintain cell viability, the cell density is maintained at around 80%.

[0683] 3. Cell transplantation

[0684] Tumor cells were collected after digestion, counted, and resuspended in a mixture of equal proportions of culture medium and matrix gel. These cells were then inoculated and transplanted subcutaneously into the right anterior shoulder and back of mice. 4. Grouping Method

[0685] The average size of mouse tumors reached 50-80 mm. 3 The tumors were randomly grouped, and the SEM value of the tumor volume in each group was reduced to below 10 as much as possible.

[0686] The day on which medication is started is marked as Day 0.

[0687] 5. Observe, weigh, and measure the tumor.

[0688] After cell inoculation, closely monitor the mice's condition, mobility, food intake, and water consumption daily. If any death, abnormal behavior, or disease symptoms are found, report and record the situation immediately to determine whether further action is necessary.

[0689] The mice's weight was measured once a day.

[0690] The tumor volume was measured twice a week using calipers. The formula for calculating the tumor volume is TV = 0.5 * length * width * width.

[0691] Calculate the tumor suppression rate (TGI). The formula for calculating the tumor inhibition rate (TGI%) is: TGI% = (1 - Ti / Ci) × 100%.

[0692] Ti and Ci represent the average tumor volumes of the treatment group and the control group at a given time point, respectively.

[0693] The results showed that the compounds of this application significantly inhibited tumors in mice. Specifically, 279A-P1, at a dose of 50 mg / kg, achieved a tumor inhibition rate of 64.1% against EMT6 breast cancer after oral administration for 21 days. Figure 1 As shown. All 279A-P1 mice were in good condition, with an average weight gain of 9.8% after 21 days of administration. The compounds of this invention have good in vivo efficacy and safety.

[0694] 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.

[0695] 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, which is a compound of formula (I), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof: in, R1, R2, and R3 are each independently selected from H, -OH, halogens, and -C. 1～6 Alkyl, -C 1～6 Halogenated alkyl or -C 1～6 Hydroxyalkyl; A is selected from -C 1～6 Alkylene * Connected to B; Ring A' is selected from one or more R's. a Substituted 7-10 membered heterocyclic alkyl groups; "Ring A" is selected from one or more Rs. a Substituted 5-6 membered cycloalkylene groups, optionally with one or more R a Substituted 5-6 membered heterocyclic alkyl groups; Ring A” is selected from one or more R’s. a Substituted 5-10 cyclohexene alkyl group, optionally with one or more R a Substituted 5-10 membered heterocyclic alkyl groups; Ring L is selected from one or more R. a Substituted 4-10 membered heterocyclic alkyl groups; R4 is selected from empty or -C 1～6 Alkylene; R5 is selected from H or -C. 1～6 alkyl; R6 is selected from empty, -C(O)-, -C(O)-C 1～6 Alkylene, -S(O)2-, -S(O)2-C 1～6 alkylene, or -C 1～6 Alkylene; R7 is selected from -C 1～10 alkyl; B is selected from empty -C, which is substituted by one or more halogens. 1～10 Alkyl, optionally with one or more R b Replacement -C 2～10 alkenyl, optionally with one or more R b Replacement -C 2～10 alkynyl group, optionally with one or more R b Substituted 3-4 membered monocyclic alkyl groups, optionally with one or more R b Substituted 5-10 cyclic alkyl groups, optionally with one or more R b Substituted 3-10 heterocyclic alkyl groups, optionally with one or more R b Replaces the 6-20 yuan chain, arbitrarily controlled by one or more R b Replacement of 6-20 element heterocyclic rings, optionally replaced by one or more R b Replaces 5-12 elemental helical rings, optionally with one or more R b Replaces 5-12 ternary heterocyclic rings, optionally with one or more R b Replaces the 5-12 element bridge ring, optionally replaced by one or more R b Replaces the 5-12 elemental hybrid bridge ring, optionally replaced by one or more R b Replaces 5-12 element rings, optionally by one or more R b Replaced 5-12-membered heterocyclic rings; B is empty, A is selected from Each R a Each is independently selected from -OH, halogen, oxo (=O), -C 1～6 Alkyl, -C 1～6 Haloalkyl, -C 1～6 Alkoxy; Each R b Each is independently selected from -OH and -C. 0～6 Alkylene-CN, halogen, oxo (=O), -S(O)2-C 1～6 Alkyl, -C 1～6 Alkyl, -C 1～6 Haloalkyl, -C 1～6 Hydroxyalkyl, -C 0～6 Alkylene-C 1～6 Alkoxy, -C 2～10 alkenyl, -C 2～10 alkynyl group, -C(O)-C 1～6 Alkyl, -C(O)-C 1～6 Alkoxy, -C 0～6 Alkylene-(3-10)-membered cycloalkyl, -C 0～6 alkeneoxy-(3-10)-membered cycloalkyl, -C 0～6 Alkylene-(3-10)-membered heterocyclic alkyl, -C 0～6 Alkylene-(6-10) aryl, -C 0～6 Alkylene-(5-10)-aryl, -S(O)2-(6-10)-aryl, -S(O)2-(5-10)-aryl.

2. The compound according to claim 1, characterized in that, The compound satisfies the following conditions: 1) When B is selected from one or more R's, b Substituted 3-4 membered monocycloalkyl, or optionally with one or more R b When substituted with a 3-10 member heterocyclic alkyl group, A is selected from... or R4 and R6 in the code are empty; 3) When B is selected from one or more R's, b When substituted with a 5-10 member monocyclic alkyl group, A is selected from... R4 and R6 in the code are empty; 3) When B is selected from 3-4 member monocyclic alkyl or 3-10 member heterocyclic alkyl, A is selected from... When R4 is empty and R6 is not empty, the 3-4 member monocycloalkyl group or the 3-10 member heterocycloalkyl group in B is affected by one or more R b replace; 4) A is selected from -C 1～6 When alkylene, B is selected from one or more R. b Replaces the 5-12 quinary heterocyclic spiral ring.

3. The compound according to claim 1, characterized in that, R1, R2, and R3 are each independently selected from H, -OH, halogens, and -C. 1～3 Alkyl, -C 1～3 Halogenated alkyl, or -C 1～3 Hydroxyalkyl; And / or, R1 is a halogen and R2 is -OH; And / or, R1 is -OH, and R2 is a halogen; And / or, R1 is F, R2 is -OH; And / or, R1 is -OH, R2 is F; And / or, R3 is H; And / or, R4 is selected from empty, or -C 1～3 Alkylene; And / or, R4 is empty; And / or, R4 is -C 1～3 Alkylene; And / or, R5 is selected from H, or -C 1～3 alkyl; And / or, R6 is selected from empty, -C(O)-, -C(O)-C 1～3 Alkylene, -S(O)2-, -S(O)2-C 1～3 alkylene, or -C 1～3 Alkylene; And / or, R6 is selected from empty, -C 1～3 Alkylene; And / or, R7 is selected from -C 3～8 alkyl; And / or, For optional use by one or more R a Replacement -C 1～3 Alkylene-NH-C 3～8 alkyl; And / or, Selected from one or more R a Replaced by -N(R5)-, optionally by one or more R a Replacement -C 1～3 Alkylene-N(R5)-, optionally with one or more R a Replacement -N(R5)-C 1～3 Alkylene-, optionally with one or more R a Replacement -C 1～3 Alkylene-N(R5)-C 1～3 Alkylene-, optionally with one or more R a The -N(R5)-C(O)- substitution, optionally replaced by one or more R a Replacement -C 1～3 Alkylene-N(R5)-C(O)-, optionally with one or more R a Substituted -N(R5)-C(O)-C 1～3 Alkylene-, or optionally with one or more R a Replacement -C 1～3 Alkylene-N(R5)-C(O)-C 1～3 alkylene-; And / or, Selected from And / or, ring A' is selected from one or more R's. a Substituted 7-8 membered heterocyclic alkyl groups; And / or, For optional use by one or more R a The following groups are substituted: And / or, R6 in the code is -C 1～6 Alkylene; And / or, For optional use by one or more R a The following groups are substituted: And / or, Selected from one or more R a Substituted 5-6 membered cycloalkylene groups; And / or, For optional use by one or more R a Replacement And / or, Selected from one or more R a Substituted -(4-10)-membered heterocyclic alkylene-(5-10)-membered cycloalkylene; And / or, For optional use by one or more R a Replacement And / or, Selected from one or more R a Substituted -N(R5)-(5-10) cycloalkylene group, optionally with one or more R a Substituted -N(R5)-(5-10)-membered heterocyclic alkylene, optionally with one or more R a Replacement -C 1～3 Alkylene-N(R5)-(5-10)-membered cycloalkylene, optionally with one or more R a Replacement -C 1～3 Alkylene-N(R5)-(5-10)-membered heterocyclic alkylene, optionally with one or more R a Replacement -N(R5)-C 1～3 Alkylene-(5-10)-membered cycloalkylene, optionally with one or more R a Replacement -N(R5)-C 1～3 Alkylene-(5-10)-membered heterocyclic alkylene, optionally with one or more R a Replacement -C 1～3 Alkylene-N(R5)-C 1～3 Alkylene-(5-10)-membered cycloalkylene, optionally with one or more R a Replacement -C 1～3 Alkylene-N(R5)-C 1～3 Alkylene-(5-10)-membered heterocyclic alkylene, optionally with one or more R a Substituted -N(R5)-C(O)-(5-10) cycloalkylene group, optionally with one or more R a Substituted -N(R5)-C(O)-(5-10)-membered heterocyclic alkylene, optionally with one or more R a Replacement -C 1～3 Alkylene-N(R5)-C(O)-(5-10)-membered cycloalkylene, or optionally with one or more R a Replacement -C 1～3 Alkylene-N(R5)-C(O)-(5-10)-membered heterocyclic alkylene; And / or, In For optional use by one or more R a Replacement And / or, Selected from And / or, in the compound shown in formula (I) Selected from And / or, in the compound shown in formula (I) for And / or, for 4. The compound according to claim 1, characterized in that, B is selected from one or more R. b Substituted 3-4 membered monocycloalkyl, or optionally with one or more R b Substituted 3-10 member heterocyclic alkyl groups; A is selected from And / or, B is selected from 3-4 membered monocycloalkyl or 5-8 membered heterocycloalkyl, wherein the 3-4 membered monocycloalkyl or 5-8 membered heterocycloalkyl is optionally pre-C 1～3 Haloalkyl, -C 1～3 One or more substitutions in hydroxyalkyl groups; A is selected from And / or, B is selected from 3-4 membered monocycloalkyl groups, wherein the 3-4 membered monocycloalkyl group is optionally prefixed with a -(6-10) membered aryl group or a -C membered aryl group. 1～3 Haloalkyl, -C 1～3 One or more substitutions in hydroxyalkyl groups; A is selected from And / or, B is selected from A is selected from And / or, B is selected from one or more Rs. b Substituted 3-4 membered monocycloalkyl, or optionally with one or more R b Substituted 3-10 member heterocyclic alkyl groups; A is selected from And / or, B is selected from A is selected from And / or, B is selected from one or more Rs. b Replacement -C 2～10 alkenyl, optionally with one or more R b Substituted 3-4 membered monocyclic alkyl groups, optionally with one or more R b Substituted 5-10 cyclic alkyl groups, optionally with one or more R b Substituted 3-10 member heterocyclic alkyl group, or optionally with one or more R b Replacement of 5-12 ternary spiral rings; A is selected from And / or, B is selected from one or more Rs. b The following groups are substituted: A is selected from And / or, B is selected from A is selected from And / or, B is selected from one or more Rs. b Substituted 3-4 membered monocyclic alkyl groups, optionally with one or more R b Substituted 5-10 cyclic alkyl groups, or optionally with one or more R b Substituted 3-10 member heterocyclic alkyl groups; A is selected from R4 and R6 are empty; And / or, B is selected from one or more Rs. b The following groups are substituted: A is selected from And / or, B is selected from Selected from And / or, B is selected from one or more R b Substituted 3-4 membered monocyclic alkyl groups, with one or more R b Substituted 5-10 member monocycloalkyl, or with one or more R b Substituted 3-10 member heterocyclic alkyl groups; A is selected from R4 is empty, R6 is empty or -C 1～6 Alkylene; And / or, B is selected from one or more R b The following groups are substituted: A is selected from Where R4 is empty, R6 is empty or -C 1～6 Alkylene; And / or, B is selected from A is selected from Where R4 is empty, R6 is empty or -C 1～6 Alkylene; And / or, B is selected from one or more Rs. b Replaces the 6-12 element chain, arbitrarily controlled by one or more R b Replaced 6-12 member heterocyclic rings; A is selected from And / or, B is selected from -(4-6)-membered cycloalkyl-(3-6)-membered cycloalkyl ring, -(4-6)-membered cycloalkyl-(3-6)-membered heterocycloalkyl ring, -(4-6)-membered heterocycloalkyl-(3-6)-membered cycloalkyl ring, or -(4-6)-membered cycloalkyl-(6-10)-membered aryl ring, wherein the -(4-6)-membered cycloalkyl-(3-6)-membered cycloalkyl ring, -(4-6)-membered heterocycloalkyl-(3-6)-membered cycloalkyl ring, or -(4-6)-membered cycloalkyl-(6-10)-membered aryl ring is optionally surrounded by one or more -C 1～6 Alkyl substitution; A is selected from And / or, B is selected from 6-membered cycloalkyl-6-membered cycloalkyl ring, 6-membered heterocycloalkyl-3-membered cycloalkyl ring, 6-membered heterocycloalkyl-4-membered cycloalkyl ring, 6-membered heterocycloalkyl-6-membered cycloalkyl ring, 6-membered cycloalkyl-6-membered heterocycloalkyl ring, or 4-membered cycloalkyl-6-aryl ring, wherein the 6-membered cycloalkyl-6-membered cycloalkyl ring, 6-membered heterocycloalkyl-3-membered cycloalkyl ring, 6-membered heterocycloalkyl-4-membered cycloalkyl ring, 6-membered heterocycloalkyl-6-membered cycloalkyl ring, 6-membered cycloalkyl-6-membered heterocycloalkyl ring, or 4-membered cycloalkyl-6-aryl ring is optionally surrounded by one or more -C 1～6 Alkyl substitution; A is selected from And / or, B is selected from A is selected from And / or, B is selected from -C substituted with one or more halogens. 1～10 Alkyl, optionally with one or more R b Replacement -C 2～10 alkenyl, or optionally with one or more R b Replacement -C 2～10 alkynyl group; And / or, B is selected from And / or, B is selected from one or more Rs. b Replaces 5-12 elemental helical rings, optionally with one or more R b Replaces 5-12 ternary heterocyclic rings, optionally with one or more R b Replaces the 5-12 element bridge ring, optionally replaced by one or more R b Replaces the 5-12 elemental hybrid bridge ring, optionally replaced by one or more R b Replaces the 5-12 element fused ring, or optionally is replaced by one or more R b Replaced 5-12 quinary heterocyclic rings; And / or, B is selected from one or more Rs. b Replaces 5-10 ductile helical rings, optionally with one or more R b Replaces 5-10 ternary heterocyclic spiral rings, optionally with one or more R b Replaces the 5-10 element bridge ring, optionally with one or more R b Replaces 5-10 element hybrid bridge rings, optionally replaced by one or more R b Replaced by 5-10 fused rings, or optionally by one or more R b Replaced 5-10 quintic heterocyclic rings; And / or, B is selected from one or more Rs. b The following structures are replaced: And / or, each R b Each is independently selected from -OH, -CN, oxo, halogen, and -C. 1～6 Alkyl, -C 1～6 Haloalkyl, -C 1～6 Hydroxyalkyl, -C(O)-C 1～6 Alkyl, -C 0～6 Alkylene-(3-10)-membered cycloalkyl, -C 0～6 Alkylene-(6-10)-aryl, -S(O)2-(6-10)-aryl; And / or, each R b Each is independently selected from -OH, -CN, halogen, and -C. 1～6 Alkyl, -C 1～6 Haloalkyl, -C 1～6 Hydroxyalkyl, -C(O)-C 1～3 Alkyl, -(3-6)-membered cycloalkyl, -C 1～3 Alkylene-(6-8)-aryl, -S(O)2-(6-8)-aryl; And / or, B is selected from the following structures: And / or, A is selected from -C 1～6 When alkylene, B is selected from one or more R. b The following groups are substituted: And / or, A is selected from -C 1～6 When alkylene, B is selected from...

5. The compound according to any one of claims 1 to 4, characterized in that, The compound shown in formula (I) has the structure shown in formula (II): Optionally, R1 is -OH; And / or, R2 is F; And / or, R3 is H; And / or, R4 is empty; And / or, R5 is H; And / or, R6 is empty; And / or, B is selected from one or more Rs. b Replacement -C 2～10 alkenyl, optionally with one or more R b Replacement -C 2～10 alkynyl group, optionally with one or more R b Replaces 5-12 elemental helical rings, optionally with one or more R b Replaces the 5-12 element bridge ring, or optionally is replaced by one or more R b Replaced by 5-12 cyclic rings; And / or, B is selected from one or more Rs. b The following structures are replaced: And / or, B is selected from one or more Rs. b The following structures are replaced: And / or, each R b Each is independently selected from -OH, halogen, oxo, -CN, and -C. 1～3 Alkyl, -C 1～3 Haloalkyl, -C(O)-C 1～6 Alkyl, -C 1～3 alkylene-(6-8) aryl; And / or, each R b Each is independently selected from -OH, halogen, oxo, and -C. 1～3 Alkyl, -C 1～3 Halogenated alkyl groups; And / or, B is selected from the following structures: And / or, B is selected from the following structures:

6. The compound according to any one of claims 1 to 4, characterized in that, The compound shown in formula (I) has the structure shown in formula (III): R8 is selected from 3-4 member monocyclic alkyl groups or 3-10 member heterocyclic alkyl groups; R9 is selected from 6-10 membered aryl groups or 3-10 membered cycloalkyl groups; Optionally, R1 is -OH; And / or, R2 is F; And / or, R3 is H; And / or, R4 is empty; And / or, R5 is H; And / or, R6 is empty; And / or, R8 is selected from 3-4 member monocycloalkyl or 5-10 member heterocycloalkyl; And / or, R9 is selected from 6-8 aryl groups or 3-5 cycloalkyl groups; And / or, -R8-R9 selected from 7. The compound according to any one of claims 1 to 4, characterized in that, The compound shown in formula (I) has the structure shown in formula (IV): Optionally, R1 is -OH; And / or, R2 is F; And / or, R3 is H; And / or, B is selected from one or more Rs. b Replacement -C 2～10 alkenyl, optionally with one or more R b Substituted 3-4 membered monocyclic alkyl groups, optionally with one or more R b Substituted 5-10 cyclic alkyl groups, optionally with one or more R b Substituted 3-10 heterocyclic alkyl groups, optionally with one or more R b Replaces 5-12 elemental helical rings, or optionally with one or more R b Replacement of 5-12 quinary heterocyclic spiral rings; And / or, B is selected from one or more Rs. b Replacement -C 2～10 alkenyl, optionally with one or more R b Substituted 3-4 membered monocyclic alkyl groups, optionally with one or more R b Substituted 5-8 membered monocycloalkyl, optionally with one or more R b Substituted 4-6 member heterocyclic alkyl group, optionally with one or more R b Replaces 5-10 inch screw rings, or optionally with one or more R b Replacement of 5-10 quinary heterocyclic spiral rings; And / or, B is selected from one or more Rs. b Substituted 5-10 cyclic alkyl groups, or optionally with one or more R b Replacement of 5-10 inch helical rings; And / or, B is selected from one or more Rs. b The following structures are replaced: And / or, B is selected from one or more Rs. b The following structures are replaced: And / or, B is selected from one or more Rs. b The following structures are replaced: And / or, each R b Each is independently selected from halogens, oxometalates, and -C atoms. 1～6 Alkyl, -C 0～6 Alkylene-C 1～6 Alkoxy, -C 1～6 Haloalkyl, or 6-8 aryl; And / or, B is selected from the following structures:

8. The compound according to any one of claims 1 to 4, characterized in that, The compound shown in formula (I) has the structure shown in formula (V): Optionally, R1 is -OH; And / or, R2 is F; And / or, R3 is H; And / or, R4 is -C 1～3 Alkylene; And / or, R5 is H; And / or, R6 is empty, -C(O)-, -S(O)2-C 1～3 alkylene, or -C 1～3 Alkylene; And / or, R6 is empty, -C(O)-, or -C 1～3 Alkylene.

9. The compound according to claim 8, characterized in that, B is selected from one or more R. b Replaces 5-10 ductile helical rings, optionally with one or more R b Replaces 5-10 ternary heterocyclic spiral rings, optionally with one or more R b Replaces the 5-10 element bridge ring, optionally with one or more R b Replaces 5-10 element hybrid bridge rings, optionally replaced by one or more R b Replaced by 5-10 fused rings, or optionally by one or more R b Replaced 5-10 quintic heterocyclic rings; And / or, B is selected from one or more Rs. b The following structures are replaced: And / or, B is selected from one or more Rs. b The following structures are replaced: And / or, each R b Each is independently selected from halogens, -CN, oxo (=O), and -C. 1～6 Alkyl, -C 1～6 Haloalkyl, -C 0～6 Alkylene-(6-10)-aryl, or -S(O)2-(6-10)-aryl; And / or, each R b Each is independently selected from halogens, -CN, oxo (=O), and -C. 1～3 Alkyl, -C 1～3 Haloalkyl, -C 0～3 Alkylene-(6-8)-aryl, or -S(O)2-(6-8)-aryl; And / or, B is selected from the following structures: And / or, B is selected from the following structures: And / or, B is selected from one or more Rs. b Substituted 3-4 membered monocyclic alkyl groups, optionally with one or more R b Substituted 3-10 heterocyclic alkyl groups, optionally with one or more R b Replaces the 6-20 yuan chain, or optionally is one or more R b Replaced by 6-20 quinary heterocyclic rings; And / or, B is selected from one or more Rs. b Substituted 3-4 membered monocycloalkyl, or optionally with one or more R b Replaced by 10-15 yuan chain; And / or, each R b Each is independently selected from -C 1～6 Alkyl, -C 1～6 Halogenated alkyl, or -C 1～3 Hydroxyalkyl; And / or, B is selected from 10. The compound according to any one of claims 1 to 4, characterized in that, The compound shown in formula (I) has the structure shown in formula (VI): Optionally, R1 is -OH; And / or, R2 is F; And / or, R3 is H; And / or, R4 is -C 1～3 Alkylene; And / or, R5 is H; And / or, R6 is selected from empty, or -C 1～3 Alkylene; And / or, R6 is empty; And / or, R7 is -C 3～8 alkyl; And / or, -R6-R7 are selected from 11. The compound according to any one of claims 1 to 4, characterized in that, The compound shown in formula (I) has the structure shown in formula (VII): B is selected from one or more R. b Replacement -C 2～10 alkenyl, or optionally with one or more R b Replacement -C 2～10 alkynyl group; Optionally, R4 is selected from empty; And / or, R6 is selected from empty; And / or, R5 is selected from H; And / or, B is selected from one or more Rs. b Replacement -C 2～8 alkenyl, or optionally with one or more R b Replacement -C 2～8 alkynyl group; And / or, B is selected from 12. The compound according to claim 1, characterized in that, The compound shown in formula (I) has the following structure:

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

14. Use of the compound according to any one of claims 1 to 13 in the preparation of PTPN protein inhibitors.

15. A PTPN protein inhibitor, characterized in that, It includes the compounds described in any one of claims 1 to 13, as well as optionally pharmaceutically acceptable excipients, carriers, and mediators.

16. A PROTAC drug, characterized in that, It includes the compound, linker, and ubiquitin ligand as described in any one of claims 1 to 13, wherein the compound and ubiquitin ligand are linked by the linker.

17. A pharmaceutical composition, characterized in that, It includes the compounds according to any one of claims 1 to 13, and optionally pharmaceutically acceptable excipients, carriers, and mediators.

18. Use of the compound according to any one of claims 1 to 13, the PTPN protein inhibitor according to claim 15, the PROTAC drug according to claim 16, or the pharmaceutical composition according to claim 17, 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 reagents to inhibit PTPN protein, and / or Preparation of PROTAC drugs, 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 for PTPN protein-related diseases is selected from cancer and metabolic diseases.

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