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EP-4741383-A1 - COMPOUND AND USE THEREOF AS ANTI-CANCER DRUG

EP4741383A1EP 4741383 A1EP4741383 A1EP 4741383A1EP-4741383-A1

Abstract

The present invention provides a compound having a structure of formula (I) and can be used as an SHP2 inhibitor, a pharmaceutical composition comprising the compound, a method for preparing the compound, and a use of the compound in the treatment of cancer.

Inventors

  • ZHONG, BOYU
  • WANG, QIAN
  • ZHANG, TONY YANTAO
  • DONG, Chunlan
  • PANG, Wei
  • QIN, Quan
  • WANG, ZHIQIANG
  • LU, Wanglong
  • WANG, Jifa

Assignees

  • Tyligand Bioscience (Shanghai) Limited

Dates

Publication Date
20260513
Application Date
20240705

Claims (20)

  1. A compound of formula (I), a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: represents a saturated, partially unsaturated, or aromatic ring system; represents an aromatic ring system; A 1 , A 2 , A 3 , A 4 , A 5 are each independently selected from absence, C, N, O, and S, and A6 is selected from C and N, provided that (1) at most two of A 1 ~A 5 are absent, and (2) at most four of A 1 ~A 6 are heteroatoms; R a is selected from -H, =O, =S, =N-OH, -OH, -NH 2 , halogen, -CN and -C 1-6 alkyl optionally substituted by halogen; A 7 , A 8 and A 9 are each independently selected from C, N, O, and S, provided that at least one of A 7 , A 8 and A 9 is not C; A 10 is selected from C-R b and N; A 11 is selected from C-X and N; R b is selected from H, halogen, CN and -C 1-6 alkyl substituted by halogen; X is selected from H, halogen, CN, -OH, -OC 1-6 alkyl and -C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted; Y is an optionally substituted group selected from -C 1-6 alkyl, -(CH 2 ) t -3-15 membered carbocyclyl, -(CH 2 ) t -C 6-10 aryl, -(CH 2 ) t -5-12 membered heteroaryl having one or more heteroatom(s) independently selected from N, O and S, and -(CH 2 ) t -3-15 membered heterocyclyl having one or more heteroatom(s) independently selected from N, O and S; Z is an optionally substituted divalent group selected from -C 6-10 aryl-, -3-10 membered carbocyclyl-, -5-12 membered heteroaryl having one or more heteroatom(s) independently selected from N, O and S, and -3-15 membered heterocyclyl having one or more heteroatom(s) independently selected from N, O and S; R is an optionally substituted group selected from -C 6-10 aryl, -3-15 membered carbocyclyl, -5-12 membered heteroaryl having one or more heteroatom(s) independently selected from N, O, and S, and -3-15 membered heterocyclyl having one or more heteroatom(s) independently selected from N, O, and S; and t is each optionally an integer from 0 to 3.
  2. The compound of claim 1, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: Y is an optionally substituted group selected from: - C 1-6 alkyl, - (CH 2 ) t -3-8 membered monocyclic saturated or partially unsaturated carbocycle, - (CH 2 ) t -5-10 membered bridged saturated or partially unsaturated carbocycle, - (CH 2 ) t -6-15 membered spiro or fused saturated or partially unsaturated carbocycle, - (CH 2 ) t -C 6-10 aryl, - (CH 2 ) t -5-12 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, - (CH 2 ) t -3-8 membered monocyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S, - (CH 2 ) t -5-10 membered bridged saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S, and - (CH 2 ) t -6-15 membered spiro or fused saturated or partially unsaturated heterocycle having 1-4 heteroatoms independently selected from N, O and S; Z is an optionally substituted divalent group selected from: - C 6-10 aryl-, - 3-8 membered monocyclic saturated or partially unsaturated carbocycle-, - 5-10 membered bridged saturated or partially unsaturated carbocycle-, - 5-12 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S-, - 3-8 membered monocyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S-, - 5-10 membered bridged saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S-, and - 6-15 membered spiro or fused saturated or partially unsaturated heterocycle having 1-4 heteroatoms independently selected from N, O and S-; R is an optionally substituted group selected from: - C 6-10 aryl, - 3-8 membered monocyclic saturated or partially unsaturated carbocycle, - 5-10 membered bridged saturated or partially unsaturated carbocycle, - 6-15 spiro or fused saturated or partially unsaturated carbocycle, - 5-12 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, - 3-8 membered monocyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S, - 5-10 membered bridged saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S, and - 6-15 membered spiro or fused saturated or partially unsaturated heterocycle having 1-4 heteroatoms independently selected from N, O and S.
  3. The compound of claim 1 or 2, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: is a five-membered partially unsaturated or aromatic group optionally substituted by 0-1 R a , having 3-4 cyclic heteroatoms selected from N, O, and S, preferably a five-membered aromatic group having 4 nitrogen heteroatoms, and A 6 is C; R a is selected from -H, -CN, halogen, =O and -C 1-6 alkyl substituted by halogen.
  4. The compound of any one of claims 1-3, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: one of A 7 and A 9 is a heteroatom selected from N, O and S, the other is C, and A 8 is a carbon atom; preferably A 7 is selected from C-Y and N-Y, A 9 is selected from C, O and S, and only one of A 7 and A 9 is a heteroatom, and A 8 is a carbon atom.
  5. The compound of any one of claims 1-4, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: A 10 is C-R b and A 11 is C-X; R b is selected from H, and X is selected from halogen and -OH.
  6. The compound of any one of claims 1-5, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: Y is an optionally substituted group selected from -C 1-6 alkyl, -(CH 2 ) t -3-8 membered monocyclic saturated or partially unsaturated carbocycle, -(CH 2 ) t -5-10 membered bridged saturated or partially unsaturated carbocycle, -(CH 2 ) t -C 6-10 aryl; preferably an optionally substituted group selected from -C 1-6 alkyl, -(CH 2 ) t -3-6 membered monocyclic saturated carbocycle, -(CH 2 ) t -5-8 membered bicyclic bridged saturated carbocycle, and -(CH 2 ) t -phenyl.
  7. The compound of any one of claims 1-6, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: the -C 1-6 alkyl of Y is optionally substituted by halogen or CN, and the cyclic group of Y is optionally substituted by 1-3, preferably 1 or 2, more preferably 1 group selected from -C 1-6 alkyl and -OC 1-6 alkyl.
  8. The compound of any one of claims 1-7, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: Z is selected from -C 6-10 aryl-, -3-8 membered monocyclic saturated or partially unsaturated carbocycle-, -5-10 membered bridged saturated or partially unsaturated carbocycle-, and -3-8 membered monocyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S, which is optionally substituted; preferably Z is selected from phenyl, -3-6 membered monocyclic saturated or partially unsaturated carbocycle-, -5-8 membered bridged saturated carbocycle-, and -4-7 membered monocyclic saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from N, O, and S, which is optionally substituted.
  9. The compound of any one of claims 1-8, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: Z is optionally substituted by one or more group(s) independently selected from halogen, -C 1-6 alkyl or -OC 1-6 alkyl, wherein the -C 1-6 alkyl is optionally substituted by halogen or CN; preferably Z is not substituted.
  10. The compound of any one of claims 1-9, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: R is an optionally substituted group selected from -5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, -3-8 membered monocyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S, -5-10 membered bridged saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S, and -6-15 membered spiro or fused saturated or partially unsaturated heterocycle having 1-4 heteroatoms independently selected from N, O, and S; preferably an optionally substituted group selected from -5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, -4-7 membered monocyclic saturated or unsaturated heterocycle having 1-2 heteroatoms independently selected from N, O and S, -5-8 membered bicyclic bridged saturated heterocycle having 1-2 heteroatoms independently selected from N, O and S, and 7-11 membered spiro or fused saturated heterocycle having 1-3 heteroatoms independently selected from N, O and S.
  11. The compound of any one of claims 1-10, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: R is substituted by 0 to 4, preferably 0 to 3, more preferably 0-2 groups independently selected from: halogen, CN, -OH, -NH 2 , -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -OC 1-6 alkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -(CH 2 ) t -3-8 membered monocyclic saturated or partially unsaturated carbocycle, -(CH 2 ) t -5-8 membered bridged saturated or partially unsaturated carbocycle, -(CH 2 ) t -3-8 membered monocyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S, -(CH 2 ) t -5-8 membered bridged saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S, wherein the two substituents attached to the same ring carbon atom, together with the carbon atom to which they are attached, may form a 3-8 membered saturated spirocarbocycle, and the -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or cyclic group of the substituents is each independently and optionally substituted by halogen, CN, -OH, or -OC 1-6 alkyl; preferably is substituted by groups selected from: halogen, CN, -OH, -C 1-6 alkyl, -OC 1-6 alkyl, -(CH 2 ) t -4-7 membered monocyclic saturated heterocycle having 1-2 heteroatoms independently selected from N, O, and S, wherein the two substituents attached to the same carbon atom, together with the carbon atom to which they are attached, may form a 3-6 membered saturated spirocarbocycle, and the C 1-6 alkyl of the substituents is optionally substituted by halogen, CN, -OH, or -OC 1-6 alkyl.
  12. The compound of any one of claims 1-10, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: R has formula (A) wherein, f is selected from an integer from 0 to 3, preferably an integer from 0 to 2; t is selected from an integer from 0 to 3, preferably an integer from 0 to 1; G is selected from O, N-R 2 and CR 3 R 4 ; preferably O and CR 3 R 4 , and most preferably CR 3 R 4 . R 1 is selected from H and -C 1-6 alkyl optionally substituted by halogen, CN, -OH or -OC 1-6 alkyl, wherein the two R 1 attached to the same ring carbon atom, together with the carbon atom to which they are attached, may form 3-8 membered saturated spirocarbocycle; preferably R 1 is selected from H and -C 1-6 alkyl optionally substituted by -OH or -OC 1-6 alkyl; most preferably R 1 is selected from H and -C 1-6 alkyl; R 3 and R 4 are each independently selected from H, halogen, CN, -OH, -NH 2 , -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -OC 1-6 alkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -(CH 2 ) t -3-8 membered monocyclic saturated or partially unsaturated carbocycle, -(CH 2 ) t -5-8 membered bridged saturated or partially unsaturated carbocycle, -(CH 2 ) t -3-8 membered monocyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S, -(CH 2 ) t -5-8 membered bridged saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S, or R 3 and R 4 together with the ring carbon atom to which they are attached form a 3-8 membered saturated spirocarbocycle, and the -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or cyclic group in the substituents are each independently and optionally substituted by halogen, CN, -OH or - OC 1-6 alkyl; preferably R 3 and R 4 are selected from H, halogen, CN, -OH, -C 1-6 alkyl, -OC 1-6 alkyl, - (CH 2 ) t -4-7 membered monocyclic saturated heterocycle having 1-2 heteroatoms independently selected from N, O and S, or R 3 and R 4 together with the ring carbon atom to which they are attached form a 3-6 membered saturated spirocarbocycle, and the C 1-6 alkyl in the substituents is optionally substituted by halogen, CN, -OH or -OC 1-6 alkyl; more preferably R 3 and R 4 are selected from H, halogen, CN, -C 1-6 alkyl, 4-7 membered monocyclic saturated heterocycle having 1-2 heteroatoms independently selected from N, O and S, wherein the C 1-6 alkyl in the substituent is optionally further substituted by halogen, -OH or -OC 1-6 alkyl; R 2 is selected from H, -C 1-6 alkyl, -(CH 2 ) t -3-8 membered monocyclic saturated or partially unsaturated carbocycle, -(CH 2 ) t -5-8 membered bridged saturated or partially unsaturated carbocycle, -(CH 2 ) t -3-8 membered monocyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S, and -(CH 2 ) t -5-8 membered bridged saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S, wherein the C 1-6 alkyl or cyclic group in the substituent is optionally substituted by halogen, CN, - OH, or -OC 1-6 alkyl; preferably R 2 is selected fromH, -C 1-6 alkyl, -(CH 2 ) t -4-7 membered monocyclic saturated heterocycle having 1-2 heteroatoms independently selected from N, O, and S, wherein the C 1-6 alkyl in the substituent is optionally substituted by halogen, CN, -OH, or -OC 1-6 alkyl; more preferably R 2 is selected from H, -C 1-6 alkyl, 4-7 membered monocyclic saturated heterocycle having 1-2 heteroatoms independently selected from N, O and S, wherein the C 1-6 alkyl in the substituent is optionally substituted by halogen, -OH or -OC 1-6 alkyl; when f is 0, G is -CH 2 -.
  13. The compound of any one of claims 1-10, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: R has the following formula: wherein: k is an integer from 0-2, m and n are each independently an integer from 1-3, l is an integer from 1-4, preferably k is an integer from 0-2, m and n are each independently an integer from 1-2, and l is an integer from 1-3; r and p are each independent an integer from 0-3, and q is an integer from 1-4, preferably r is an integer from 0-1, p is an integer from 0-2, and q is an integer from 1-3; t is selected from an integer from 0 to 3, preferably an integer from 0 to 1; G is selected from O, N-R 2 and CR 3 R 4 , preferably O and CR 3 R 4 ; R 1 is selected from H and -C 1-6 alkyl optionally substituted by halogen, CN, -OH or -OC 1-6 alkyl, wherein two R 1 attached to the same ring carbon atom together with the carbon atom to which they are attached may form 3-8 membered saturated spirocarbocycle; preferably R 1 is selected from H and -C 1-6 alkyl optionally substituted by -OH or -OC 1-6 alkyl; more preferably R 1 is H; R 3 and R 4 are each independently selected from H, halogen, CN, -OH, -NH 2 , -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -OC 1-6 alkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -(CH 2 ) t -3-8 membered monocyclic saturated or partially unsaturated carbocycle, -(CH 2 ) t -5-8 membered bridged saturated or partially unsaturated carbocycle, -(CH 2 ) t -3-8 membered monocyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S, -(CH 2 ) t -5-8 membered bridged saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S, or R 3 and R 4 together with the ring carbon atom to which they are attached form a 3-8 membered saturated spirocarbocycle, wherein the -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or cyclic group in the substituents is each independently and optionally substituted by halogen, CN, -OH or - OC 1-6 alkyl; preferably R 3 and R 4 are selected from H, halogen, CN, -OH, -C 1-6 alkyl, -OC 1-6 alkyl, - (CH 2 ) t -4-7 membered monocyclic saturated heterocycle having 1-2 heteroatoms independently selected from N, O and S, or R 3 and R 4 together with the ring carbon atom to which they are attached form a 3-6 membered saturated spirocarbocycle, and the C 1-6 alkyl in the substituents is optionally substituted by halogen, CN, -OH or -OC 1-6 alkyl; more preferably R 3 and R 4 are selected from H, - OH, -C 1-6 alkyl, wherein the C 1-6 alkyl in the substituents is optionally further substituted by halogen, -OH or -OC 1-6 alkyl; R 2 is selected from H, -C 1-6 alkyl, -(CH 2 ) t -3-8 membered monocyclic saturated or partially unsaturated carbocycle, -(CH 2 ) t -5-8 membered bridged saturated or partially unsaturated carbocycle, -(CH 2 ) t -3-8 membered monocyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S, and -(CH 2 ) t -5-8 membered bridged saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S, wherein the C 1-6 alkyl or cyclic group in the substituent is optionally substituted by halogen, CN, - OH, or -OC 1-6 alkyl; preferably R 2 is selected from H, -C 1-6 alkyl, -(CH 2 ) t -4-7 membered monocyclic saturated heterocycle having 1-2 heteroatoms independently selected from N, O, and S, wherein the C 1-6 alkyl or cyclic group in the substituent is optionally substituted by halogen, CN, -OH, or -OC 1-6 alkyl; more preferably R 2 is selected from H, -C 1-6 alkyl, wherein the C 1-6 alkyl is optionally further substituted by halogen, -OH or -OC 1-6 alkyl.
  14. The compound of claim 1, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, having the following formula: wherein A 1 ~A 11 , R a , R b , Y, G, R 1 , t, f, m, k, n, l, r, p and q are each as defined in the preceding claims for the compound of formula (I), the structural fragment of formula (A), formula (B) and formula (C); wherein is preferably a five-membered partially unsaturated or aromatic group having 3-4 ring heteroatoms selected from N, O and S, optionally substituted by 0-1 R a ; more preferably a five-membered aromatic group having 3-4 nitrogen heteroatoms, optionally substituted by 0-1 R a ; most preferably a five-membered aromatic group having 4 nitrogen heteroatoms; A 11 is preferably C-X, A 10 is selected from N and C-R b , A 8 is C, R b is preferably H, A 7 is selected from C-Y or N-Y, A 9 is selected from C, O and S, and only one of A 7 and A 9 is a heteroatom; preferably, having the following formula:
  15. A compound, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, which are the compounds of Examples 1-134.
  16. A pharmaceutical composition, comprising a compound according to any one of claims 1-15, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, and a pharmaceutically acceptable excipient.
  17. The compound of any one of claims 1-15, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, or the pharmaceutical composition of claim 16, for use as a medicament for treating and/or preventing a disease mediated by SHP2.
  18. Use of a compound of any one of claims 1-15, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, or the pharmaceutical composition of claim 16 in the preparation of a medicament for preventing or treating a disease mediated by SHP2.
  19. A method for treating and/or preventing a disease mediated by SHP2, comprising administering to a subject in need a therapeutically effective amount of a compound of any one of claims 1-15, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, or a pharmaceutical composition of claim 16.
  20. The compound of claim 17, the use of claim 18, and the method of claim 19, wherein the disease mediated by SHP2 is cancer or tumor, cardiovascular disease, immune dysregulation, fibrosis, ocular dysregulation, systemic lupus erythematosus, diabetes, neutropenia, or a combination thereof, preferably selected from Noonan syndrome (NS), leopard syndrome (LS), juvenile myelomonocytic leukemia (JMML), myelodysplastic syndrome (MDS), neuroblastoma, melanoma, squamous cell carcinoma of the head and neck, acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL), breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric cancer, lymphoma, glioblastoma, stomach cancer, pancreatic cancer, or a combination thereof.

Description

Cross-reference This application claims priority to Chinese invention patent application 2023108367770, filed on July 7, 2023. Technical Field The present invention relates to the field of pharmaceutical chemistry. More specifically, the present invention relates to a class of compounds with novel structures that can be used as SHP2 inhibitors, pharmaceutical compositions comprising such compounds, methods of using such compounds to treat or prevent diseases mediated by SHP2, especially cancer or tumors, and the use of these compounds in the treatment or prevention of diseases mediated by SHP2, especially cancer or tumors. Background Technology Dysregulation in the level of molecular phosphorylation in the body often leads to the development and progression of various diseases, such as cancer. Specifically, the phosphorylation state of tyrosine in signaling proteins plays a decisive role in the initiation, development, and termination of many cellular signaling cascades. Tyrosine phosphorylation is regulated by protein tyrosine kinase (PTK, phosphorylation) and protein tyrosine phosphatase (PTP, dephosphorylation). Abnormal regulation of these two enzymes leads to dysregulation of tyrosine phosphorylation, resulting in the development of diseases, including diabetes, cancer, and autoimmune diseases. As a member of the PTP family, protein tyrosine phosphatase 2 (SHP2), containing Src homology-2, is a dephosphorylase with a full length of 593 amino acids encoded by the PTPN1 1 gene. SHP2 consists of two N-terminal SH2 domains, N-SH2 and C-SH2, a conserved PTP domain, and a flexible C-terminal tail. The N-SH2 and C-SH2 domains are primarily used for substrate recognition, enzyme activity regulation, and downstream signaling protein binding, while the PTP domain binds to phosphorylated tyrosine peptide fragments and catalyzes the hydrolysis of their phosphate ester groups. In the basal state of SHP2, N-SH2 and C-SH2 bind to PTP, masking its catalytic active center and forming a self-inhibiting, inactive "off" conformation. This inhibits the activity of the SHP2 protein and restricts substrate access to the catalytic site. Under the stimulation of appropriate signaling factors such as growth factors or cytokines, or in some pathogenic mutations, N-SH2 and C-SH2 leave PTP, opening the PTP active center and exposing the catalytic site. This enables the catalysis of dephosphorylation for phosphorylated substrates, such as receptors, kinases, and phospholipids, thereby regulating downstream signaling. SHP2 is located at the intersection of multiple signaling pathways and is a crucial hub connecting various intracellular oncogenic signaling pathways. For example, it is a convergence node in multiple signaling pathways such as Ras-Raf-MEK-ERK, JAK-STAT, PI3K-AKT-mTOR, and PD-1/PD-L1, participating in the regulation of various signaling pathways in the body. Overactivated SHP2 can stimulate the activation of multiple signaling pathways, thereby driving the occurrence and development of various cancers. In other words, the occurrence of many cancers is often closely related to the overactivation of signaling pathways regulated by SHP2. Therefore, inhibiting SHP2 activity can suppress the survival and proliferation of tumor cells. However, the development of SHP2 inhibitors has seen limited progress for a considerable period, even leading to a consensus within the industry that they are "untreatable". This is because early development of small-molecule SHP2 inhibitors focused on the catalytic active center. These active center inhibitors have low biological activity; the enzyme activity of the strongest inhibitor to date (the salicylic acid-based active center inhibitor 11a-1) only achieves an IC50 of about 0.2 µM, with cellular activity not exceeding an IC50 of 1 µM. Furthermore, their druggability is poor, with an oral bioavailability of only 0.07% (J. Med. Chem. 2014, 57, 6594-6609). Moreover, the catalytic domain of SHP2 is highly conserved, and inhibitors at catalytic sites generally lack selectivity, potentially leading to severe toxic reactions due to off-target effects. SHP2 inhibitors designed to inhibit the transition of SHP2 to its "open" active conformation by stabilizing its basal state (inactive "off" conformation) are called "allosteric inhibitors". Allosteric inhibitors bind to the interaction regions of the three protein modules, rather than the catalytic active center. Currently, nine structurally very similar allosteric inhibitors, guided by the pioneer TNO155, have entered clinical trials. However, these allosteric inhibitors have exhibited numerous problems in clinical trials, including severe cardiotoxicity, low specificity, easy off-target toxicity, rapid development of resistance in solid tumors with mutations occurring on the N-SH2 and C-SH2 modules that affect the binding of the PTP module in the "off" conformation, and ineffectiveness in diseases where SHP2 only exists in the "open" conformatio