WO2023051648A1

WO2023051648A1 - Compound as shp2 inhibitor, and preparation method therefor and use thereof

Info

Publication number: WO2023051648A1
Application number: PCT/CN2022/122329
Authority: WO
Inventors: 白进红; 尹磊
Original assignee: 甘李药业股份有限公司
Priority date: 2021-09-28
Filing date: 2022-09-28
Publication date: 2023-04-06
Also published as: CN118019743A

Abstract

Provided are a compound as an SHP2 inhibitor, a pharmaceutical composition thereof, and the use thereof in the prevention or treatment of SHP2 activity-mediated diseases.

Description

Compounds useful as SHP2 inhibitors and their preparation and use

technical field

The present invention relates to the field of medicinal chemistry, and in particular to a compound used as a SHP2 inhibitor, its pharmaceutical composition and its use in the treatment of diseases mediated by SHP2 activity.

Background technique

SHP2 (src homology 2 domain containing phosphotyrosine phosphatase 2) is a non-receptor protein tyrosine phosphatase encoded by gene PTPN11, which contains two N-terminal SH2 (Srchomology 2) domains and a protein tyrosine phosphatase acid phosphatase (PTP) catalytic domain and a C-terminal tail rich in proline groups and tyrosine phosphorylation sites. SHP2 protein regulates multiple signaling pathways such as Ras/ERK, JAK-STAT3, NF-kB, PI3K/Akt, RHO and NFAT, participates in the signal transduction of downstream signals of various growth factors, cytokines and integrin receptors, and promotes proliferation , differentiation, cell cycle maintenance and migration and other cellular functions.

Studies have shown that activating mutations of SHP2 are closely related to the pathogenesis of Noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia (JMML), melanoma and solid tumors. Overexpression of SHP2 increases the risk of chronic myelogenous leukemia, mastocytosis, malignant glioma, lung cancer and breast cancer, suggesting that SHP2 has a wide range of roles in different types of cancer and in different stages of cancer development (Higuchi M et al.Cancer Sci,2004,95:442-447; Bentires-Al j M et al.Cancer Res,2004,64:8816-8820; Martinelli S et al.Cancer Genet Cytogenet,2006,166:124-129) . Therefore, activated SHP2 or upregulated SHP2 protein in human tumors or other diseases has become a new therapeutic target. The compounds of the present invention fulfill the need for small molecule inhibitors of SHP2.

Contents of the invention

The present invention provides a compound used as a SHP2 inhibitor, its pharmaceutical composition and its use in preventing or treating diseases mediated by SHP2 activity.

The present invention provides a compound represented by formula Q or a pharmaceutically acceptable salt thereof,

Wherein, Z is CH or N; Z ₁ is CR ₀ , N, O or S;

R ₀ is selected from H, halogen, -OH, -CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -S(=O) _0-2 -C _1-6 alkane Base, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC _1-6 alkyl, -NH ₂ , -NH(C _1-6 alkyl), -N (C _1-6 alkyl) ₂ , C _3-6 cycloalkyl, -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C(O)N(C _{1 -6} alkyl) ₂ , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, - OC _1-6 alkyl, C _2-6 alkynyl, -CN, -NH ₂ , -NH(C _1-6 alkyl), C _3-6 cycloalkyl, -N(C _1-6 alkyl) _2. Substituents of -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C(O)N(C _1-6 alkyl) ₂ ;

Ring A is selected from 5-8 membered hydrocarbon rings, 5-8 membered heterocyclic rings, 5-8 membered heteroaryl rings and 5-8 membered aromatic rings, and the hydrocarbon rings, heterocyclic rings, heteroaryl rings and aromatic rings are each Optionally replaced by one or more selected from halogen, -OH, =O, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -S(=O) _0-2 -C _1-6 alkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -OC _1-6 alkyl, -CN, -NH ₂ , -NO ₂ , -NH (C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl, C _3-6 cycloalkane and -C(O)N(C _1-6 alkyl) substituents substituted with _each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl optionally further substituted by One or more selected from halogen, -OH, =O, -OC _1-6 alkyl, -CN, -NH ₂ , -NO ₂ , -NH(C _1-6 alkyl), C _3-6 cycloalkane group, -N(C _1-6 alkyl) ₂ , -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C(O)N(C _1-6 alkyl ) is replaced by a substituent of ₂ ;

Ring B is a 5-8 membered heterocyclic ring or a 5-8 membered heteroaryl ring containing N atoms, and each of the heterocyclic ring and heteroaryl ring is optionally replaced by one or more members selected from halogen, -OH, =O, _C _1-6 alkyl, C _2-6 alkenyl, C 2-6 alkenyl, C _2-6 alkynyl, -S(=O) _0-2 -C _1-6 alkyl, 3-10 membered hetero Cyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC _1-6 alkyl, -CN, -NH ₂ , -NH(C _1-6 alkyl), C _3-6 cycloalkane group, -N(C _1-6 alkyl) ₂ , -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C(O)N(C _1-6 alkyl ) ₂ is substituted by a substituent, each of said alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl being optionally further selected from one or more of halogen, -OH, =O, - OC _1-6 alkyl, -CN, -NH ₂ , -NH(C _1-6 alkyl), C _3-6 cycloalkyl, -N(C _1-6 alkyl) ₂ , -C(O) Substituents of NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C(O)N(C _1-6 alkyl) ₂ ;

Ring C is selected from 5-8 membered aromatic rings or 5-8 membered heteroaromatic rings containing 1-3 heteroatoms independently selected from N, O, and S, and each of the aromatic rings or heteroaryl rings is optionally One or more selected from halogen, -OH, =O, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _2-6 alkenyl, -S(=O) _0-2 -C _1-6 alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC _1-6 alkyl group, -CN, -NH ₂ , - NH(C _1-6 alkyl), C _3-6 cycloalkyl, -N(C _1-6 alkyl) ₂ , -C(O)NH ₂ , -COOH, -C(O)OC _1-6 Alkyl and -C (O) N (C _1-6 alkyl) _substituent substitution, said alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl each optionally further By one or more selected from halogen, -OH, =O, -OC _1-6 alkyl, -CN, -NH ₂ , -NH(C _1-6 alkyl), C _3-6 cycloalkyl, - N(C _1-6 alkyl) ₂ , -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C(O)N(C _1-6 alkyl) ₂ substituent substitution;

Ring D is a 5-6-membered monocyclic aryl group, a 5-6-membered monocyclic heteroaryl group with 1-4 heteroatoms independently selected from N, O, and S, and 1-5 independently selected heteroatoms An 8-10 membered bicyclic heteroaryl group consisting of N, O, and S heteroatoms, or an 8-10 membered heterohydrocarbon ring and a heteroaryl ring having 1-5 heteroatoms independently selected from N, O, and S Member fused ring group;

Ring E is a C _4-8 cycloalkyl group, or a 4-8 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from N, O and S;

_Each occurrence of R is independently selected from H, halogen, -OH, -CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -S(=O) _{0 -2} -C _1-6 alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC _1-6 alkyl group, -NH ₂ , -NH(C _{1 -6} alkyl), -N(C _1-6 alkyl) ₂ , C _3-6 cycloalkyl, -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl and - C(O)N(C _1-6 alkyl) ₂ , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally selected from one or more halogen , -OH, =O, -OC _1-6 alkyl, -CN, -NH ₂ , -NH(C _1-6 alkyl), C _3-6 cycloalkyl, -N(C _1-6 alkyl ) ₂ , -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C(O)N(C _1-6 alkyl) ₂ are substituted by substituents;

Each occurrence of R _e is independently selected from H, halogen, -OH, -CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -S(=O) _{0- 2} -C _1-6 alkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -OC _1-6 alkyl, -NH ₂ , -NH(C _{1- 6} alkyl), -N(C _1-6 alkyl) ₂ , C _3-6 cycloalkyl, -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C (O)N(C _1-6 alkyl) ₂ , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, -OC _1-6 alkyl, -CN, -NH ₂ , -NH(C _1-6 alkyl), C _3-6 cycloalkyl, -N(C _1-6 alkyl) _2. Substituents of -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C(O)N(C _1-6 alkyl) ₂ ; or, two independent R _e and the atoms connected to them on the ring E form a 3-12 membered monocyclic or polycyclic hydrocarbon ring, a 3-12 membered monocyclic or polycyclic heterocyclic ring, a 3-12 membered hydrocarbon ring and a heterocyclic ring The formed polycyclic ring system, the polycyclic ring system formed by the fusion of 3-6 membered hydrocarbon ring and 5-8 membered heteroaryl ring, the condensed form of 3-6 membered hydrocarbon ring and 5-8 membered aromatic ring A polycyclic ring system, a polycyclic ring system formed by the fusion of a 3-6-membered heterocycle and a 5-8-membered heteroaromatic ring, or a condensed 3-6-membered heterocycle and a 5-8-membered aromatic ring A polycyclic ring system, and each ring is optionally replaced by one or more selected from halogen, -OH, =O, C _1-6 alkyl, C _2-6 alkenyl, -S(=O ) _0-2 -C _1-6 alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC _1-6 alkyl group, -CN, -NH ₂ , -NO ₂ , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl, C _3-6 cycloalkyl and -C (O) N (C _1-6 alkyl) _substituent substitution, the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl Each is optionally further represented by one or more selected from halogen, -OH, =O, -OC1-6 alkyl, -CN, -NH ₂ , -NO ₂ , -NH(C _1-6 alkyl), C _3-6 cycloalkyl, -N(C _1-6 alkyl) ₂ , -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C(O)N(C _1-6 alkyl) substituted by substituents of ₂ ;

L ₁ is a covalent bond, or is a C1-4 divalent saturated or unsaturated straight-chain or branched chain hydrocarbon group, or, the C1-4 divalent saturated or unsaturated straight-chain or branched chain hydrocarbon group One or two methylene groups in are independently selected from -O-, -C(O), -OC(O)-, -C(O)O-, -S-, -S(O)- and -S(O) ₂ - the group formed after the group is replaced; k is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9; m is 0, 1, 2, 3, 4 or 5; and n is 0, 1, 2, 3, 4, 5, 6 or 7.

In one embodiment according to the invention, ring E is selected from:

The present invention further provides a compound or a pharmaceutically acceptable salt thereof, which has the structural formula Q ₁ :

Wherein, R ₃ and R ₄ are each independently selected from H, halogen, -OH, -CN, C _1-6 alkyl, C _2-6 alkenyl, -S(=O) _0-2 -C _1-6 Alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC _1-6 alkyl, -NH ₂ , -NH(C _1-6 alkyl), - N(C _1-6 alkyl) ₂ , C _3-6 cycloalkyl, -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C(O)N(C _1-6 alkyl) ₂ , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, -OC _1-6 alkyl, -CN, -NH ₂ , -NH(C _1-6 alkyl), C _3-6 cycloalkyl, -N(C _1-6 alkyl) ₂ , -C(O ) NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C(O)N(C _1-6 alkyl) ₂ substituents; or the atoms to which R ₃ and R ₄ are attached Together form a 3-12 membered monocyclic or polycyclic hydrocarbon ring, a 3-12 membered monocyclic or polycyclic heterocyclic ring, a polycyclic ring system formed by a 3-12 membered hydrocarbon ring and a heterocyclic ring, a 3-6 membered A polycyclic ring system formed by the fusion of a hydrocarbon ring and a 5-8 membered heteroaromatic ring, a polycyclic ring system formed by the fusion of a 3-6-membered hydrocarbon ring and a 5-8-membered aromatic ring, a 3-6-membered heteroaromatic ring A polycyclic ring system formed by condensing a ring with a 5-8 membered heteroaromatic ring, or a polycyclic ring system formed by condensing a 3-6 membered heterocyclic ring with a 5-8 membered aromatic ring, and each ring Each is optionally replaced by one or more selected from halogen, -OH, =O, C _1-6 alkyl, C _2-6 alkenyl, -S(=O) _0-2 -C _1-6 alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC _1-6 alkyl, -CN, -NH ₂ , -NO ₂ , -NH(C _1-6 alkane radical), -N(C _1-6 alkyl) ₂ , -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl, C _3-6 cycloalkyl and -C(O )N(C _1-6 alkyl) substituted by a substituent, _each of said alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl optionally further being selected from one or more Halogen, -OH, =O, -OC1-6 alkyl, -CN, -NH ₂ , -NO ₂ , -NH(C _1-6 alkyl), C _3-6 cycloalkyl, -N(C ₁ Substituents of _-6 alkyl) ₂ , -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C(O)N(C _1-6 alkyl) ₂ ; k ₁ is 1, 2 or 3; k ₂ is 1, 2 or 3.

In one embodiment according to the invention, ring D is selected from

In another aspect, the present invention provides a general structure as shown in formula I or a pharmaceutically acceptable salt thereof:

Wherein, W ₁ , W ₂ , and W ₃ are each independently selected from CR ₁ and N;

X ₂ , X ₃ , and X ₄ are each independently selected from CR ₂ and N;

Z is CH or N;

X ₁ is CR ₈ or N;

R ₈ is independently selected from H, halogen, -OH, -CN, C _1-6 alkyl, C _2-6 alkenyl, -S(=O) _0-2 -C _1-6 alkyl, 3-10 Membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC _1-6 alkyl, -NH ₂ , -NO ₂ , -NH(C _1-6 alkyl), -N( C _1-6 alkyl) ₂ , C _3-6 cycloalkyl, -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C(O)N(C _{1- 6} alkyl) ₂ , the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, and cycloalkyl are each optionally replaced by one or more selected from halogen, -OH, =O, -OC _{1 -6} alkyl, -CN, -NH ₂ , -NO ₂ , -NH(C _1-6 alkyl), C _3-6 cycloalkyl, -N(C _1-6 alkyl) ₂ , -C( Substituents of O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C(O)N(C _1-6 alkyl) ₂ ;

Ring A is a 5-8 membered hydrocarbon ring, a 5-8 membered heterocyclic ring, a 5-8 membered heteroaryl ring or a 5-8 membered aromatic ring, and each of the hydrocarbon ring, heterocyclic ring, heteroaryl ring and aromatic ring is any Optionally replaced by one or more selected from halogen, -OH, =O, C _1-6 alkyl, C _2-6 alkenyl, -S(=O) _0-2 -C _1-6 alkyl, 3- 10-membered heterocyclic group, 6-10-membered aryl group, 5-10-membered heteroaryl group, -OC _1-6 alkyl, -CN, -NH ₂ , -NO ₂ , -NH(C _1-6 alkyl) , -N(C _1-6 alkyl) ₂ , -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl, C _3-6 cycloalkyl, and -C(O) Substituents of N(C _1-6 alkyl) ₂ , each of which is optionally further selected from the group consisting of halogen , -OH, =O, -OC _1-6 alkyl, -CN, -NH ₂ , -NO ₂ , -NH(C _1-6 alkyl), C _3-6 cycloalkyl, -N(C ₁ Substituents of _-6 alkyl) ₂ , -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C(O)N(C _1-6 alkyl) ₂ ;

Ring B is a 5-8 membered heterocyclic ring or a 5-8 membered heteroaryl ring containing N atoms, and each of the heterocyclic ring and heteroaryl ring is optionally replaced by one or more members selected from halogen, -OH, =O, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkenyl, -S(=O) _0-2 -C _1-6 alkyl, 3-10 membered heterocyclyl, 6-10 membered Aryl, 5-10 membered heteroaryl, -OC _1-6 alkyl, -CN, -NH ₂ , -NH(C _1-6 alkyl), C _3-6 cycloalkyl, -N(C ₁ Substituents of _-6 alkyl) ₂ , -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C(O)N(C _1-6 alkyl) ₂ , Each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, and cycloalkyl groups is optionally further replaced by one or more alkyl groups selected from halogen, -OH, =O, _-OC , -CN, -NH ₂ , -NH(C _1-6 alkyl), C _3-6 cycloalkyl, -N(C _1-6 alkyl) ₂ , -C(O)NH ₂ , -COOH, Substituents of -C(O)OC _1-6 alkyl and -C(O)N(C _1-6 alkyl) ₂ ;

_Each occurrence of R is independently selected from H, halogen, -OH, -CN, C _1-6 alkyl, C _2-6 alkenyl, -S(=O) _0-2 -C _1-6 Alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC _1-6 alkyl, -NH ₂ , -NH(C _1-6 alkyl), - N(C _1-6 alkyl) ₂ , C _3-6 cycloalkyl, -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C(O)N(C _1-6 alkyl) ₂ , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, -OC _1-6 alkyl, -CN, -NH ₂ , -NH(C _1-6 alkyl), C _3-6 cycloalkyl, -N(C _1-6 alkyl) ₂ , -C(O ) NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C(O)N(C _1-6 alkyl) ₂ substituents;

R ₃ and R ₄ are each independently selected from H, halogen, -OH, -CN, C _1-6 alkyl, C _2-6 alkenyl, -S(=O) _0-2 -C _1-6 alkyl , 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC _1-6 alkyl, -NH ₂ , -NH(C _1-6 alkyl), -N( C _1-6 alkyl) ₂ , C _3-6 cycloalkyl, -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C(O)N(C _{1- 6} alkyl) ₂ , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, - OC _1-6 alkyl, -CN, -NH ₂ , -NH(C _1-6 alkyl), C _3-6 cycloalkyl, -N(C _1-6 alkyl) ₂ , -C(O) Substituents of NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C(O)N(C _1-6 alkyl) ₂ ; or R ₃ and R ₄ together with the atoms to which they are attached Form 3-12 membered monocyclic or polycyclic hydrocarbon rings, 3-12 membered monocyclic or polycyclic heterocyclic rings, 3-12 membered hydrocarbon rings and polycyclic ring systems formed by heterocyclic rings, 3-6 membered hydrocarbons A polycyclic ring system formed by condensing a ring with a 5-8 membered heteroaromatic ring, a polycyclic ring system formed by condensing a 3-6-membered hydrocarbon ring with a 5-8-membered aromatic ring, and a 3-6-membered heterocyclic ring A polycyclic ring system formed by condensing a 5-8 membered heteroaromatic ring or a 3-6 membered heterocyclic ring condensed with a 5-8 membered aromatic ring, and each ring is independently Optionally replaced by one or more selected from halogen, -OH, =O, C _1-6 alkyl, C _2-6 alkenyl, -S(=O) _0-2 -C _1-6 alkyl, 3- 10-membered heterocyclic group, 6-10-membered aryl group, 5-10-membered heteroaryl group, -OC _1-6 alkyl, -CN, -NH ₂ , -NO ₂ , -NH(C _1-6 alkyl) , -N(C _1-6 alkyl) ₂ , -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl, C _3-6 cycloalkyl and -C(O)N (C _1-6 alkyl) substituted by a substituent, _each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, and cycloalkyl is optionally further selected from one or more halogen , -OH, =O, -OC _1-6 alkyl, -CN, -NH ₂ , -NO ₂ , -NH(C _1-6 alkyl), C _3-6 cycloalkyl, -N(C ₁ Substituents of _-6 alkyl) ₂ , -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C(O)N(C _1-6 alkyl) ₂ ; m is 0, 1, 2 or 3; and n is 0, 1, 2 or 3.

In some embodiments, R ₈ is independently selected from H, halogen, -OH, -CN, C _1-6 alkyl, -OC _1-6 alkyl, -NH ₂ , -NO ₂ , -NH(C _{1 -6} alkyl), -N(C _1-6 alkyl) ₂ , C _3-6 cycloalkyl, -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl and - C(O)N(C _1-6 alkyl) ₂ , the alkyl and cycloalkyl are optionally replaced by one or more selected from halogen, -OH, =O, -OC _1-6 alkyl, -CN , -NH ₂ , -NO ₂ , -NH(C _1-6 alkyl), C _3-6 cycloalkyl, -N(C _1-6 alkyl) ₂ , -C(O)NH ₂ , -COOH , -C(O)OC _1-6 alkyl and -C(O)N(C _1-6 alkyl) _substituent substitution; and/or

The ring A is selected from a 5-8 membered hydrocarbon ring, a 5-8 membered heterocyclic ring, a 5-8 membered heteroaryl ring or a 5-8 membered aromatic ring, and the hydrocarbon ring, heterocyclic ring, heteroaryl ring and aromatic Each ring is optionally replaced by one or more groups selected from halogen, -OH, =O, C _1-6 alkyl, -OC _1-6 alkyl, -CN, -NH ₂ , -NH(C _1-6 alkane radical), -N(C _1-6 alkyl) ₂ , -C(O)NH ₂ , -COOH, -C(O)OC C _1-6 alkyl and -C(O)N(C _1-6 alkane substituted by a substituent _of C 1-6 alkyl, said C _1-6 alkyl being optionally further selected from halogen, -OH, =O, -OC _1-6 alkyl, -CN, -NH ₂ and -NH(C _1-6 alkyl) substituent substitution; and/or

The ring B is selected from a 5-8-membered heterocyclic ring or a 5-8-membered heteroaryl ring containing N atoms, and each of the heterocyclic ring and the heteroaryl ring is optionally replaced by one or more members selected from halogen, -OH, Substituents of =O, C _1-6 alkyl, -OC _1-6 alkyl, -CN, -NH ₂ and -NH(C _1-6 alkyl); and/or

Each occurrence of R ₁ is independently selected from H, halogen, -OH, -CN, C _1-6 alkyl, -OC _1-6 alkyl, -NH ₂ , -NH(C _1-6 alkyl ), -N(C _1-6 alkyl) ₂ and C _3-6 cycloalkyl, wherein each of the C _1-6 alkyl and C _3-6 cycloalkyl is optionally selected from one or more Substituents from halogen, -OH, =O, -OC _1-6 alkyl, -CN, -NH _, and -NH(C _1-6 alkyl); and/or, _R at each occurrence each independently selected from H, halogen, -OH, -CN, C _1-6 alkyl, -OC _1-6 alkyl, -NH ₂ , -NH(C _1-6 alkyl), -N(C _{1 -6} alkyl) ₂ , -C(O)NH ₂ , -COOH and -C(O)OC _1-6 alkyl, wherein the C _1-6 alkyl is optionally selected from one or more halogen , -OH, =O, -OC _1-6 alkyl, -CN, -NH ₂ and -NH (C _1-6 alkyl) substituent substitution; and/or

R ₃ and R ₄ are each independently selected from H, halogen, -OH, -CN, C _1-6 alkyl, -OC _1-6 alkyl, -NH ₂ , -NH(C _1-6 alkyl) and -N(C _1-6 alkyl) ₂ , wherein each of the C _1-6 alkyl groups is optionally replaced by one or more selected from halogen, -OH, =O, -OC _1-6 alkyl, -CN , -NH ₂ and -NH (C _1-6 alkyl) substituent substitution; or R ₃ and R ₄ form a 3-6 membered monocyclic or polycyclic hydrocarbon ring together with the atoms they are connected to, 3-6 membered Monocyclic or polycyclic heterocyclic rings, polycyclic ring systems formed by 3-6 membered hydrocarbon rings and heterocyclic rings, bicyclic or more Ring system, a bicyclic or more ring system formed by condensing a 3-6-membered hydrocarbon ring with a 5-6-membered aromatic ring, a bicyclic ring formed by condensing a 3-6-membered heterocycle and a 5-6-membered heteroaromatic ring or more ring systems, or bicyclic or more ring systems formed by the fusion of 3-6 membered heterocycles and 5-6 membered aromatic rings.

In some embodiments, Ring A is a 5-8 membered hydrocarbon ring, a 5-8 membered heterocyclic ring, or a 5-8 membered heteroaromatic ring. Preferably, Ring A has 1, 2, 3 or 4 independently A 5-6 membered heterocyclic or heteroaryl ring with heteroatoms selected from N, O and S, preferably, ring A is a 5-6 membered heterocyclic ring with 1 or 2 heteroatoms independently selected from N and O or a heteroaromatic ring, preferably ring A is a 5-8 membered hydrocarbon ring or a 5-8 membered heterocyclic ring, preferably, ring A is a heterocyclic ring with 1, 2, 3 or 4 independently selected from N, O and S 5-6 membered heterocyclic rings with atoms, further preferably, ring A is selected from partially unsaturated morpholine rings, partially unsaturated pyrazolidine rings, partially unsaturated piperidine rings, partially unsaturated piperazine rings, partially unsaturated piperazine rings, partially Unsaturated hexahydropyrimidine ring, partially unsaturated pyrrolidine ring, pyrazole ring, pyrrole ring, imidazole ring and partially unsaturated imidazolidine ring;

In some embodiments, ring A is optionally replaced by one or more selected from halogen, -OH, =O, C _1-6 alkyl, -OC _1-6 alkyl, -CN, -NH ₂ , -C Substituents of (O)NH ₂ , -COOH, -C(O)N(C _1-6 alkyl) ₂ , -C _1-6 alkylene-OH and halogenated C _1-6 alkyl, in In a preferred embodiment, ring A is optionally replaced by one or more selected from F, Cl, Br, -OH, =O, C _1-3 alkyl, -OC _1-3 alkyl, -CN, -NH _2. Substitution of -C(O)NH ₂ , -COOH, -C(O)N(C _1-3 alkyl) ₂ , -C _1-3 alkylene-OH and halogenated C _1-3 alkyl In a more preferred embodiment, ring A is optionally substituted by one or more selected from F, =O, -CH ₃ , -C(O)NH ₂ , -COOH, -C(O)N( Substituents of CH ₃ ) ₂ and -CH ₂ -OH.

In some embodiments, ring B is selected from 5, 6, 7 or 8 membered heterocycles containing N atoms, preferably, ring B is a partially unsaturated piperidine ring, a partially unsaturated piperazine ring, a partially unsaturated A diazepane ring, a partially unsaturated imidazoline ring, a partially unsaturated morpholine ring or a partially unsaturated pyrazolidine ring, and the ring B is optionally selected from one or more halogen , -OH, =O, C _1-3 alkyl, -OC _1-3 alkyl, -CN, -NH ₂ , and -NH(C _1-3 alkyl) substituents.

In some embodiments,

Part is the following chemical structure:

Wherein, W ₄ is selected from C(R ₅ ) ₂ , O, and NR ₅ ; p is 0, 1 or 2; q is 0 or 1; R ₅ is each independently selected from H, halogen, - OH, =O, C _1-6 alkyl, -OC _1-6 alkyl, -CN, -NH ₂ , -C(O)NH ₂ , -COOH, -C(O)N(C _1-6 alkane group) ₂ , -C _1-6 alkylene-OH, and halogenated C _1-6 alkyl; in a preferred embodiment, each occurrence of R ₅ is independently selected from H, F, Cl, Br, -OH, =O, C _1-3 alkyl, -OC _1-3 alkyl, -CN, -NH ₂ , -C(O)NH ₂ , -COOH, -C(O)N(C _{1 -3} alkyl) ₂ , -C _1-3 alkylene-OH, and haloC _1-3 alkyl; in a more preferred embodiment, each occurrence of _R is independently selected from H, -F, =O, -CH ₃ , -C(O)NH ₂ , -COOH, -C(O)N(CH ₃ ) ₂ , -CH ₂ -OH; and f is 0, 1, 2, 3, 4 or 5.

In some embodiments,

Partially selected from the following chemical structures:

Wherein, _R and f are as defined above.

In some embodiments, each occurrence of R ₁ is independently selected from H, halogen, -OH, -CN, C _1-3 alkyl, -OC _1-3 alkyl, -NH ₂ , haloC _1-3 alkyl and C _3-4 cycloalkyl; in a preferred embodiment, each occurrence _{of R} is independently selected from H, -CN, _-CH and cyclopropyl.

In some embodiments, each occurrence _of R is independently selected from H, halogen, -OH, -CN, C _1-3 alkyl, -OC _1-3 alkyl, -NH ₂ , -C( O)NH ₂ , -COOH, -C(O)OC _1-3 alkyl, -C _1-3 alkylene-OH and halogenated C _1-3 alkyl; in a preferred embodiment, R ₂ is at Each occurrence is independently selected from H, halogen, -OH, -CN, C _1-3 alkyl, -C(O)NH ₂ and -C _1-3 alkylene-OH; in a more preferred embodiment In the scheme, each occurrence of R ₂ is independently selected from H, F, -OH, -CN, -CH ₃ , -C(O)NH ₂ and -CH ₂ -OH.

In some embodiments, R _and R are _each independently selected from H, halogen, -OH, -CN, C _1-3 alkyl, -OC _1-3 alkyl, -C _1-3 alkylene- NH ₂ , -NH ₂ , -NH(C _1-3 alkyl) and -N(C _1-3 alkyl) ₂ ; in a preferred embodiment, R ₃ and R ₄ are each independently selected from H, halogen , -OH, -CN, C _1-3 alkyl, -C _1-3 alkylene -NH ₂ and -NH ₂ ; in a preferred embodiment, R ₃ and R ₄ are each independently selected from H, - F, -OH, _-CH2 - _NH2 and _-NH2 ; or

R ₃ and R ₄ form a 3, 4, 5 or 6-membered monocyclic hydrocarbon ring, or a 3, 4, 5 or 6-membered monocyclic heterocyclic ring together with the atoms they are connected to. In a preferred embodiment, R ₃ and _R together with the atoms to which they are attached form a 5-6 membered monocyclic heterocycle having 1, 2, 3 or 4 heteroatoms selected from N, O or S, wherein each of the hydrocarbon ring and heterocycle is optionally One or more selected from halogen, -OH, -CN, C _1-6 alkyl, -OC _1-6 alkyl, -NH ₂ , -C(O)N(C _1-6 alkyl) ₂ , -C _1-6 alkylene-OH and halogenated C _1-6 alkyl substituents, preferably substituted by one or more substituents selected from F, Cl, Br, -OH, -CN, C _1-3 Alkyl, -OC _1-3 alkyl, -NH ₂ , -C _1-3 alkylene-OH, -C(O)N(C _1-3 alkyl) ₂ and halogenated C _1-3 alkyl substituted by one or more substituents selected from F, Cl, Br, -OH, -CN, -CH ₃ , -OCH ₃ , -NH ₂ , -CH ₂ -OH, -C(O)N Substituents of (CH ₃ ) ₂ and -CF ₃ are substituted;

In a more preferred embodiment,

Part is the following chemical structure:

Wherein, Y1 is selected from O, S, C(R ₆ ) ₂ , or NR ₆ , and each occurrence of R ₆ is independently selected from H, halogen, -OH, -CN, C _1-3 alkyl, - OC _1-3 alkyl, -NH ₂ and halogenated C _1-3 alkyl, in a preferred embodiment, each occurrence of _R is independently selected from H, halogen, -OH, -CN, - CH ₃ , -OCH ₃ , -NH ₂ , -CH ₂ -OH, -C(O)N(CH ₃ ) ₂ and -CF ₃ , g is 0, 1, 2, 3, 4, 5 or 6; or R ₃ and R ₄ together with the atoms they connect form a bicyclic ring system formed by condensing a 5-6 membered hydrocarbon ring with a 5-6 membered heteroaromatic ring, a 5-6 membered hydrocarbon ring and a 5-6 membered aromatic ring A bicyclic ring system formed by fusion, a bicyclic system formed by the fusion of a 5-6 membered heterocyclic ring and a 5-6 membered heteroaryl ring, or a fused 5-6 membered heterocyclic ring and a 5-6 membered aromatic ring Bicyclic ring system, wherein said hydrocarbon ring, heterocycle, heteroaromatic ring and aromatic ring are each optionally replaced by one or more selected from halogen, -OH, =O, C _1-6 alkyl, -OC _1-6 alkane radical, -CN, -NH ₂ , -C(O)NH ₂ , -COOH, -C(O)N(C _1-6 alkyl) ₂ , -C _1-6 alkylene-OH, halogenated C _1-6 alkyl substituents are substituted, preferably by one or more selected from halogen, -OH, C _1-3 alkyl, -OC _1-3 alkyl, -CN, -NH ₂ , -C(O ) NH ₂ , -C _1-3 alkylene-OH, -C(O)N(C _1-3 alkyl) ₂ , and substituents of halogenated C _1-3 alkyl, preferably substituted by one or Multiple selected from F, Cl, Br, -OH, -CN, -CH ₃ , -OCH ₃ , -NH ₂ , -CH ₂ -OH, -C(O)N(CH ₃ ) ₂ and -CF ₃ Substituents are substituted; also preferably,

Part is the following chemical structure:

Wherein, Y ₂ is selected from O, S, CH ₂ , and NH, preferably selected from O, and CH ₂ ; Y ₃ , Y ₄ , Y ₅ , and Y ₆ are each independently selected from CR ₇ and N, in preferred In an embodiment, Y ₃ , Y ₄ , Y ₅ , and Y ₆ are each independently selected from CH and N; each occurrence of R ₇ is independently selected from H, halogen, -OH, C _1-3 alkyl , -OC _1-3 alkyl, -CN, -NH ₂ , -C(O)NH ₂ , -C _1-3 alkylene-OH, -C(O)N(C _1-3 alkyl) ₂ , and halogenated C _1-3 alkyl, in a preferred embodiment, each occurrence of R ₇ is independently selected from H, F, Cl, Br, -OH, -CN, -CH ₃ , -OCH ₃ , -NH ₂ , -CH ₂ -OH, -C(O)N(CH ₃ ) ₂ and -CF ₃ ; and h is 0, 1, 2, 3 or 4.

In some embodiments, the compound of Formula I has the structure of Formula II:

wherein, W ₁ , W ₂ , W ₃ , X ₁ , X ₂ , X ₃ , X ₄ , Z, m and n are as defined above, R ₁ and R ₂ are as defined above, W ₄ , R ₅ , p , q and f are as defined above, Y ₂ , Y ₃ , Y ₄ , Y ₅ and Y ₆ are as defined above; preferably, both X ₁ and X ₂ are N, and/or p is 1 or 2, q is 0 or 1.

In a preferred embodiment, the present invention provides a compound or a pharmaceutically acceptable salt thereof, the compound is selected from:

Further, the present invention provides a preferred compound or a pharmaceutically acceptable salt thereof, the compound is selected from:

The present invention also provides an intermediate for preparing the above compound, or a salt thereof, wherein the intermediate is selected from:

Wherein, R ₉ and R ₁₀ are each independently selected from H, halogen, -OH, -CN, C _1-6 alkyl, C _2-6 alkenyl, -S(=O) _0-2 -C _1-6 Alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC _1-6 alkyl, -NH ₂ , -NH(C _1-6 alkyl), - N(C _1-6 alkyl) ₂ , C _3-6 cycloalkyl, -C(O)NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C(O)N(C _1-6 alkyl) ₂ , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, -OC _1-6 alkyl, -CN, -NH ₂ , -NH(C _1-6 alkyl), C _3-6 cycloalkyl, -N(C _1-6 alkyl) ₂ , -C(O )NH ₂ , -COOH, -C(O)OC _1-6 alkyl and -C(O)N(C _1-6 alkyl) ₂ are substituted.

In a preferred embodiment, the above-mentioned intermediates are selected from:

The present invention also provides a preparation method of the compound shown in formula II or a pharmaceutically acceptable salt thereof:

wherein, W ₁ , W ₂ , W ₃ , Z, m and n are as defined above, R ₁ and R ₂ are as defined in claim 5, 6, 11, or 15, W ₄ , R ₅ , p, q and f are as defined above, Y ₂ , Y ₃ , Y ₄ , Y ₅ and Y ₆ are as defined above, X ₁ , X ₂ , X ₃ , X ₄ are all N, and n is 0, including: using the corresponding The first key intermediate of the structure of part A, the second key intermediate corresponding to the structure of part B, and the third key intermediate corresponding to the structure of part C are subjected to substitution reactions to prepare the compound shown in formula II.

In a preferred embodiment, the structural formula of the third key intermediate corresponding to the C part is shown in formula III:

Wherein, R ₉ and R ₁₀ are as defined above.

Further, wherein the third key intermediate is selected from:

Preferably, the first key intermediate corresponding to part A is selected from:

Preferably, wherein the second key intermediate corresponding to part B is selected from:

In some preferred embodiments, (A) when the compound or a pharmaceutically acceptable salt thereof has the structural formula

, prepared by a method comprising the following steps:

(a1) compound

Dissolve in DCM, add trifluoroacetic acid, stir for 2 hours, neutralize the reaction solution with saturated sodium bicarbonate, extract with dichloromethane, combine the organic phases, concentrate under reduced pressure, and purify the compound

(a2) will

Dissolve in DMF, add triethylamine and compound

Stir at 50°C, dilute the reaction mixture with saturated brine, extract, dry the organic layer with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the compound

(a3) compound

and compound

Dissolve in toluene, add Pd ₂ (dba) ₃ , RuPhos and Cs ₂ CO ₃ under nitrogen protection, stir at 100°C for 16 hours, cool to RT and concentrate under reduced pressure, purify the residue by preparative TLC (DCM:MeOH=10:1) compound

compound

Dissolved in HCl/Dioxane and methanol, stirred for 1 hour, concentrated under reduced pressure, and purified to obtain

And/or, (B) when the compound or a pharmaceutically acceptable salt thereof has the formula

, prepared by a method comprising the following steps:

(b1) compound

Dissolve in dioxane, add compound under nitrogen protection

Pd ₂ (dba) ₃ , Xantphos and Cs ₂ CO ₃ , stirred overnight at 100°C, diluted with EA, filtered, concentrated the filtrate, and purified the compound

(b2) compound

Dissolve in THF/H ₂ O/MeOH, add palladium/carbon and ammonium formate, stir overnight at 50°C, dilute the reaction solution with EA, filter, concentrate the filtrate, and purify the compound

(b3) compound

Dissolve in DCM, add p-toluenesulfonyl chloride and DIEA, stir at RT for 1.5 hours, concentrate, and purify the compound

(b4) compound

Dissolve in DMF, add TEA and compound

Stir overnight at 50°C, dilute the reaction solution with EA, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify the compound

(b5) compound

Dissolved in HCl/dioxane, stirred at RT for 1 hour, concentrated under reduced pressure, and purified to obtain

And/or, (C) when the compound or a pharmaceutically acceptable salt thereof has the structural formula

, prepared by a method comprising the following steps:

(c1) compound

and compound

Dissolve in toluene, under nitrogen protection, add Pd ₂ (dba) ₃ , Ruphos and Cs ₂ CO ₃ , stir at 110°C, concentrate the reaction solution under reduced pressure, and purify the compound

(c2) compound

Dissolved in NH ₃ /MeOH, stirred at 70°C for 4 hours, concentrated to give the compound

(c3) compound

And/or, (D) when the compound or a pharmaceutically acceptable salt thereof has the formula

, prepared by a method comprising the following steps:

(d1) the intermediate

Dissolve in MeOH/DMSO, add silver nitrate and trifluoroacetic acid, stir at 70°C for 1 hour, add (NH ₄ ) ₂ S ₂ O ₈ and H ₂ O, stir at 70°C for 2 hours, dilute the reaction solution with EA, wash with NaOH aqueous solution , the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified to obtain the compound

(d2) compound

Dissolve in DMF, add triethylamine and compound

Stir at 50°C, dilute the reaction solution with EA, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify the compound

(d3) compound

and compound

Dissolve in toluene, add Pd ₂ (dba) ₃ , RuPhos and Cs ₂ CO ₃ under nitrogen protection, stir at 100°C for 16 hours, cool to RT and concentrate under reduced pressure to obtain the compound

(d4) compound

Dissolved in HCl/Dioxane and methanol, stirred at RT for 1 hour, concentrated under reduced pressure, and purified to obtain

And/or, (E) when the compound or a pharmaceutically acceptable salt thereof has the formula

, prepared by a method comprising the following steps:

(e1) Dissolve 6-chloro-1H-pyrazolo[3,4-b]pyridine in DMF, add NIS, stir at 80°C for 4 hours, dilute the reaction solution with water, extract with EA, and wash the organic phase with saturated brine , dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the compound

(e2) compound

Dissolved in DCM, added DHP and p-toluenesulfonic acid, stirred at RT for 3 hours, concentrated under reduced pressure, and purified to obtain the compound

(e3) compound

Dissolve in DMF, add compound

and triethylamine, stirred at 50°C for 12 hours, diluted with water, extracted with EA, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified to obtain the compound

(e4) compound

and compound

(e5) compound

Pharmaceutical compositions, formulations and kits

The present invention also provides a pharmaceutical composition, which comprises a compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of this invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injections. Pharmaceutically acceptable carriers include pharmaceutical excipients. Suitable pharmaceutical excipients include, but are not limited to, starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene glycol , water, ethanol, etc. The composition may also contain small amounts of wetting agents, emulsifiers, lubricants, stabilizers or pH buffering agents, etc., as required. Oral formulations can contain standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).

Another aspect of the present invention also relates to a pharmaceutical preparation comprising the compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient, or the pharmaceutical composition of the present invention. In some embodiments, the formulation is in the form of a solid formulation, a semi-solid formulation, a liquid formulation, or a gaseous formulation.

The pharmaceutical compositions of the present invention can be administered by a variety of routes, depending on whether local or systemic treatment is desired and the area to be treated. Topical (e.g., transdermal, dermal, ocular, and mucous membranes, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powder or aerosol, including by nebulizer; intratracheal, intranasal), Oral or parenteral administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, eg, intrathecal or intracerebroventricular, administration.

A further object of the present invention is to provide a product, for example in the form of a kit. As used herein, articles of manufacture are intended to include, but are not limited to, kits and packages. The kit may also include instructions for use.

Treatments and uses

Another object of the present invention is to provide a use of a compound of formula I or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating diseases mediated by SHP2 activity.

In another aspect, the present invention provides a method for preventing or treating a disease mediated by SHP2 activity, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof or the present invention to an individual in need thereof. Invented pharmaceutical composition.

In yet another aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention for preventing or treating diseases mediated by SHP2 activity.

According to one embodiment of the invention, the diseases mediated by SHP2 activity which can be prevented or treated using the compounds of the invention are diseases which are sensitive or responsive to inhibition of the SHP2 enzyme. In a further embodiment, the disease mediated by SHP2 activity is non-small cell lung cancer.

Beneficial effect

The present invention provides a new type of highly active SHP2 inhibitor, which can achieve at least one of the following technical effects:

(1) High inhibitory activity against SHP2 enzyme.

(2) Excellent tumor cell inhibitory activity.

(3) Excellent pharmacokinetic properties (such as good bioavailability, suitable half-life and duration of action).

General Terms and Definitions

Unless defined otherwise hereinafter, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

Certain compounds of the present invention may exist in free form or, where appropriate, as pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, prodrugs, stereoisomers (including but not limited to diastereoisomers and enantiomers), Tautomers, solvates, polymorphs and isotopic compounds are capable of providing, directly or indirectly, a compound of formula I or its metabolites after their administration to a patient in need thereof. Therefore, when a "compound of the present invention" is referred to herein, it is also intended to cover the above-mentioned various derivative forms of the compound.

The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free acids and bases of the specified compound without adverse biological effects. Examples of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, salts formed with inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid, etc.; Maleic acid, maleic acid, benzoic acid, phenylacetic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, glycolic acid, cinnamic acid, pyruvic acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid , acrylic acid, mandelic acid, etc.; or (2) alkali addition salts, salts formed with alkali metals such as lithium, sodium, potassium, etc.; salts formed with alkaline earth metals such as calcium, magnesium, etc.; and organic bases such as ammonium , choline, diethanolamine, lysine, ethylenediamine, tert-butylamine, tert-octylamine, tris(hydroxymethyl)aminomethane, N-methylglucamine, triethanolamine, dehydroabietamine, etc. Other pharmaceutically acceptable salts are known to those skilled in the art.

The prodrugs of the compounds of the present invention are included in the protection scope of the present invention. In general, the prodrugs refer to functional derivatives that are readily converted in vivo to the desired compound. Therefore, the term "administering" in the treatment method provided by the present invention includes administering the compound disclosed in the present invention, or although not explicitly disclosed but can be converted into the compound disclosed in the present invention after administration to the subject to treat the described compound. various diseases. Routine methods for selecting and preparing suitable prodrug derivatives are described, for example, in such books as Design of Prodrugs, H. Bundgaard, Elsevier, 1985.

The compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereoisomers and optical isomers. The present invention includes all possible diastereoisomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.

The above formula I does not exactly define the stereostructure of a certain position of the compound. The present invention includes all stereoisomers of the compound represented by formula I and pharmaceutically acceptable salts thereof. Furthermore, mixtures of stereoisomers and isolated specific stereoisomers are also included in the present invention. During the synthesis of such compounds, or during the use of racemization or epimerization procedures well known to those of ordinary skill in the art, the products obtained may be mixtures of stereoisomers.

When the compound represented by formula I has tautomers, unless otherwise stated, the present invention includes any possible tautomers and their pharmaceutically acceptable salts, and their mixtures.

When the compound represented by formula I and its pharmaceutically acceptable salts exist in the form of solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent forming a solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone, and the like can be used.

The invention also includes all pharmaceutically acceptable isotopic compounds which are identical to the compounds of the invention except that one or more atoms have the same atomic number but an atomic mass or mass number different from the atomic mass or mass prevailing in nature Atomic substitution of numbers. Examples of isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( ^2H ), tritium ( ^3H )); isotopes of carbon (e.g., ^13C and ^14C ); Isotopes (such as ³⁷ Cl); isotopes of iodine (such as ¹²⁵ I); isotopes of nitrogen (such as ¹³ N and ¹⁵ N); isotopes of oxygen (such as ¹⁷ O and ¹⁸ O); isotopes of phosphorus (such as ³² P); Isotopes of sulfur (eg ³⁴ S).

For example, the expression "C ₁ -C ₆ " should be understood to cover any subrange therein as well as every point value, such as C ₂ -C ₅ , C ₃ -C ₄ , C ₁ -C ₂ , C ₁ -C ₃ , C ₁ -C ₄ , C ₁ -C _{5 ,} etc., and C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , etc. As another example, the expression "5-10 yuan" should also be understood in a similar manner, for example, can cover any sub-range and point value contained therein, such as 5-6 yuan, 5-7 yuan, 5-8 yuan, 5- 9 yuan, 5-10 yuan, 6-7 yuan, 6-8 yuan, 6-9 yuan, 6-10 yuan, 7-8 yuan, etc. and 5, 6, 7, 8, 9, 10 yuan, etc.

The term "alkyl", as used herein alone or in combination with other groups, refers to a saturated straight or branched chain hydrocarbon group. As used herein, the term "C _1-6 alkyl" refers to a saturated linear or branched hydrocarbon group having 1-6 carbon atoms (eg, 1, 2, 3, 4, 5 or 6 carbon atoms). For example, "C _1-6 alkyl" can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo Pentyl or n-hexyl etc.

The term "alkylene" refers to a saturated linear or branched divalent hydrocarbon group. For example, as used herein, the term "C _1-6 alkylene" refers to a saturated linear or branched divalent hydrocarbon group having 1-6 carbon atoms. For example, methylene, ethylene, propylene or butylene and the like.

The term "cycloalkyl", as used herein alone or in combination with other groups, refers to a saturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g. monocyclic, such as cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl; or bicyclic, including spiro, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1] Heptyl, bicyclo [3.2.1] octyl or bicyclo [5.2.0] nonyl, decahydronaphthyl, etc.). Cycloalkyl includes C _3-10 cycloalkyl, preferably C _3-6 cycloalkyl, more C _5-6 cycloalkyl is preferred.

For example, the term "C _3-10 cycloalkyl" refers to a cycloalkyl group having 3-10 ring carbon atoms (eg, 3, 4, 5, 6, 7, 8, 9 or 10).

The term "hydrocarbon ring", when used alone or in combination with other groups herein, refers to the Saturated or partially unsaturated (ie having one or more double and/or triple bonds within the ring, but not forming an aromatic ring system) monocyclic or polycyclic hydrocarbon rings with preferably 5-6) ring carbon atoms, wherein Monocyclic rings include but are not limited to cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclohexyl rings, cycloheptyl rings, cyclooctyl rings, cyclononyl rings, cyclohexenyl rings, etc., and polycyclic hydrocarbon rings include Linked ring, spiro ring, parallel ring or bridged ring, which has 6-16 carbon atoms.

The term "halo" or "halogen" group, when used herein alone or in combination with other groups, means F, Cl, Br or I.

The term "haloalkyl", as used herein alone or in combination with other groups, refers to an alkyl group as described above, wherein one or more hydrogen atoms are replaced by a halogen. For example, the term "haloC _1-6 alkyl" refers to a C _1-6 alkyl optionally substituted with one or more (eg, 1-3) halogen. Those skilled in the art should understand that when there is more than one halogen substituent, the halogens may be the same or different, and may be located on the same or different C atoms. _Examples of haloalkyl groups are for example _-CH2F , _-CHF2 _{, -CF3, -CCl3, -C2F5} _, _-C2Cl5 _, _-CH2CF3 _, _-CH2Cl _or _-CH2CH ₂ CF ₃ etc.

The term "heterocycle", when used herein alone or in combination with other groups, refers to a - 6, more preferably 5-6) ring atoms of monocyclic or polycyclic non-aromatic ring systems (eg 3-10, 4-10, 5-10, 6-10, 3-8 , 3-6 membered or 5-6 membered heterocyclic ring), wherein at least one ring atom (eg 1, 2 or 3) is a heteroatom selected from N, O and S, and the remaining ring atoms are C. The ring system may be saturated (also understood as the corresponding "saturated heterocycloalkane") or unsaturated (ie have one or more double and/or triple bonds within the ring). The term also covers cases where a C atom may be substituted by (=0) and/or a ring S atom may be substituted by 1 or 2 (=0). A heterocyclyl group is a group derived from a heterocyclic ring by removal of a hydrogen atom, examples of which include, but are not limited to: oxiranyl, cyclothioethyl, cycloazaethyl, azetidinyl, oxa Cyclobutyl, thietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxolyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl base, piperidinyl, morpholinyl, 1,4-thiaxanyl, 1,4-dioxanyl, dithianyl, tetrahydropyridyl, thiomorpholinyl, piperazinyl or trithianyl Alkyl etc.

The term "aromatic ring", as used herein alone or in combination with other groups, refers to an all-carbon monocyclic or fused-ring polycyclic (eg, bicyclic) aromatic ring having a conjugated π-electron system. An aryl group is a group derived from an aromatic ring by removal of one hydrogen atom. As used herein, the term "C _6-10 aryl" refers to an aromatic group derived from an aromatic ring containing 6-10 carbon atoms. Examples of aryl include, but are not limited to, phenyl, naphthyl, and the like.

The term "heteroaromatic ring", as used herein alone or in combination with other groups, refers to an aromatic ring in which one or more (such as 1, 2 or 3) ring atoms are selected from N, O and S heteroatom, and the remaining ring atoms are C. A heteroaryl group is a group derived from a heteroaryl ring by removal of one hydrogen atom. A heteroaryl or heteroaryl ring can be characterized by the number of ring atoms. For example, a 5-10 membered heteroaryl group may contain 5-10 (eg 5, 6, 7, 8, 9 or 10) ring atoms, especially 5, 6, 9, 10 ring atoms, 5 A 6-membered heteroaryl group may contain, for example, 5 or 6 ring atoms. And in each case, the heteroaryl or heteroaryl ring may optionally be further benzo-fused. For example, examples of heteroaryl groups are thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazinyl, isoxazolyl, isothiazolyl, oxadiazolyl, tri Azolyl, thiadiazolyl, etc., and their benzo derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolyl, benzofuryl, Benzothienyl, indolyl, isoindolyl, etc., and their benzo derivatives.

The terms "substituted" and "substituted" mean that one or more (e.g., one, two, three or four) hydrogens on the indicated atom are replaced by a selection from the indicated group, provided that no more than the indicated Atoms are indicated at their normal valences at the present situation and such substitutions result in stable compounds. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

If a substituent is described as "optionally substituted," the substituent can be (1) unsubstituted, or (2) substituted. If an atom or group is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the atom or group may be independently selected, optional substituents substitute. If substituents are described as being "independently selected from" or "each independently being", each substituent is selected independently of the other. Accordingly, each substituent may be the same as or different from another (other) substituent. For example, a certain substituent or substituent position or different substituents or substituent positions may have the R groups indicated by the same or different symbols (such as but not limited to R ² , R ³ , ^Rh , R ⁱ , R ^x and/or or R ^y ), each R is independently selected, and may be the same or different. The same goes for the choice of values such as d, g, m, n.

As used herein, unless otherwise indicated, the point of attachment of a substituent may be from any suitable position of the substituent.

When a bond for a substituent is shown as being through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring-forming atom in such a substitutable ring.

The terms "comprising", "comprising", "having", "containing" or "involving" and other variations thereof herein are inclusive or open-ended and do not exclude other unrecited elements or method steps . Those skilled in the art should understand that the above terms such as "comprising" cover the meaning of "consisting of".

"Pharmaceutically acceptable carrier" in the present invention refers to a diluent, adjuvant, excipient or vehicle administered together with the active ingredient, and it is suitable for contacting human beings and/or Tissues from other animals without undue toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit/risk ratio. The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that is effective in treating one or more symptoms of the targeted disorder or condition.

As used herein, the term "effective amount" (eg, "therapeutically effective amount" or "prophylactically effective amount") refers to the amount of the active ingredient which, when administered, will achieve to some extent the desired effect, such as alleviation of a part of the condition being treated. one or more symptoms or prevent the occurrence of a disorder or its symptoms.

Unless otherwise stated, the term "treating" as used herein means reversing, alleviating, inhibiting the progression of the disorder or condition to which the term applies or one or more symptoms of said disorder or condition, or preventing said disorder or condition. A disorder or condition or one or more symptoms of said disorder or condition.

Detailed ways

The experimental methods in the following examples are conventional methods unless otherwise specified. The chemical raw materials and reagents used in the following examples are all commercially available products unless otherwise specified.

Abbreviations and their meanings appearing in this document are as follows:

缩写abbreviation	含义meaning	缩写abbreviation	含义meaning
DMFDMF	N，N-二甲基甲酰胺N,N-Dimethylformamide	NBSNBS	N-溴代丁二酰亚胺N-Bromosuccinimide
THFTHF	四氢呋喃Tetrahydrofuran	NISNIS	N-碘代丁二酰亚胺N-iodosuccinimide

MeCNMeCN	乙腈Acetonitrile	TFATFA	三氟乙酸Trifluoroacetate
DioxaneDioxane	二氧六环Dioxane	NaOEtNaOEt	乙醇钠sodium ethylate
TEATEA	三乙胺Triethylamine	Na ₂S ₂O ₃ Na ₂ S ₂ O ₃	硫代硫酸钠Sodium thiosulfate
PEPE	石油醚petroleum ether	NaHNaH	氢化钠sodium hydride
EAEA	乙酸乙酯ethyl acetate	PPh ₃ PPh ₃	三苯基膦Triphenylphosphine
DCMDCM	二氯甲烷Dichloromethane	XantPhosXantPhos	4，5-双(二苯基膦)-9，9-二甲基氧杂蒽4,5-bis(diphenylphosphine)-9,9-dimethylxanthene
DMSODMSO	二甲基亚砜Dimethyl sulfoxide	RuPhosRuPhos	2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯2-Dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl
MeOHMeOH	甲醇Methanol	Pd(PPh ₃) ₄ Pd(PPh ₃ ) ₄	四(三苯基膦)钯Tetrakis(triphenylphosphine)palladium
EtOHEtOH	乙醇ethanol	Pd ₂(dba) ₃ Pd ₂ (dba) ₃	三(二亚苄基丙酮)二钯Tris(dibenzylideneacetone)dipalladium
Ti(OEt) ₄ Ti(OEt) ₄	钛酸乙酯Ethyl titanate	Pd(OAc) ₂ Pd(OAc) ₂	醋酸钯palladium acetate
NMPNMP	1-甲基-2-吡咯烷酮1-methyl-2-pyrrolidone	LDALDA	二异丙基氨基锂lithium diisopropylamide
RTRT	室温room temperature	DIBAL-HDIBAL-H	二异丁基氢化铝Diisobutylaluminum hydride
TLCTLC	薄层色谱法TLC	PPAPPAs	多聚磷酸polyphosphoric acid
(NH ₄) ₂S ₂O ₈ (NH ₄ ) ₂ S ₂ O ₈	过硫酸铵Ammonium persulfate	HEPESHEPES	4-羟乙基呱嗪乙磺酸4-Hydroxyethylpiperazineethanesulfonic acid
DTTDTT	二硫苏糖醇Dithiothreitol	BSABSA	牛血清白蛋白bovine serum albumin
DiFMUPDiFMUP	6,8-二氟-4-甲基伞形酮磷酸盐6,8-Difluoro-4-methylumbelliferone phosphate	Triton X-100Triton X-100	聚乙二醇对异辛基苯基醚Polyethylene glycol p-isooctyl phenyl ether
PBSPBS	磷酸盐缓冲液Phosphate buffer	FBSFBS	胎牛血清fetal bovine serum

Intermediate A1

Dissolve 2-amino-3-nitrophenol (5.0g, 32.5mmol) in 50mL tetrahydrofuran, add triethylamine (9.85g, 97.5mmol), cool to 0°C and add 2-bromo-2-methylpropyl Bromine (7.4g, 32.5mmol), stirred at room temperature for 16 hours. The reaction solution was quenched with 100 mL of saturated ammonium chloride and extracted three times with 100 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound A1-1 (3.6 g white solid, Yield 36%). MS(ESI):303.0[M+H] ⁺ .

Compound A1-1 (3.6 g, 11.9 mmol) was dissolved in 40 mL of DMF, cesium carbonate (11.6 g, 35.7 mmol) was added, and stirred at 75° C. for 1.5 hours. The reaction mixture was diluted with 100 mL of saturated aqueous ammonium chloride, and extracted three times with 100 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound A1-2 (2.5 g yellow solid, obtained rate of 96%). MS(ESI):223.0[M+H] ⁺ .

To a solution of compound A1-2 (2.5 g, 11.3 mmol) in methanol (20 mL) was added 200 mg Pd/C under H ₂ atmosphere, and stirred at room temperature for 3 hours. Filter and concentrate under reduced pressure to obtain compound A1-3 (2.0 g yellow solid, yield 93%). MS(ESI):193.1[M+H] ⁺ .

Compound A1-3 (2.0 g, 10.4 mmol) was dissolved in 20 mL of DMF, and 1,2-dibromoethane (2.95 g, 15.6 mmol) and cesium carbonate (10 g, 31.2 mmol) were added. Stir at 80°C for 5 hours, dilute with 100 mL of saturated ammonium chloride, and extract with ethyl acetate three times, 100 mL each time. The organic phases were combined, washed with 100 mL saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain intermediate A1 (700 mg yellow solid , yield 31%). MS(ESI):219.1[M+H] ⁺ .

Using the above synthetic methods or modified methods, the following intermediates were synthesized from the corresponding starting materials.

Intermediate A2

Ethyl 2-hydroxyacetate (3.6g, 34.68mmol) was dissolved in THF (100mL), cooled to 0°C, NaH (11.39g, 0.624mmo, dispersed in mineral oil, content 60%) was added in batches, at room temperature Reaction 2h. Then 2-chloro-3-nitropyridin-4-amine (5 g, 28.9 mmol) was added. The resulting mixture was stirred at 80 °C for 6 h, cooled to room temperature, quenched by pouring into ice water, and then extracted with EA (100 mL x 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Purification by reverse phase column chromatography (H2O/ACN) gave compound A2-1 (2.9 g yellow solid, yield 42%). MS(ESI):242.1[M+H] ⁺ .

Compound A2-1 (2.7 g, 11.2 mmol) was dissolved in MeOH (50 mL), Pd/C (270 mg) was added, replaced with hydrogen 3 times, and reacted at room temperature under hydrogen atmosphere for 7 hours. The mixture was filtered, and the filtrate was concentrated to obtain compound A2-2 (2.2 g of yellow solid, yield 99%). MS(ESI):212.1[M+H] ⁺ .

Compound A2-2 (2.7 g, 12.8 mmol) was dissolved in AcOH (30 mL), stirred for 10 min, concentrated to obtain a solid, and slurried with petroleum ether/ethyl acetate (20:1). Filtration afforded compound A2-3 (1.6 g off-white solid, 76%). MS(ESI):166.1[M+H] ⁺ .

Compound A2-3 (500mg, 3mmol) was dissolved in DMF (15mL), 1,2-dibromoethane (1.7g, 9mmol) and cesium carbonate (1.96g, 6mmol) were added, and the mixture was reacted at 80°C for 18 hours . Dilute with tetrahydrofuran (20 mL), and wash with saturated brine three times, 10 mL each time. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by reverse-phase column chromatography (water/acetonitrile) and preparative TLC (DCM:MeOH=15:1) to obtain intermediate A2 (53 mg white solid, yield 9%). MS(ESI):192.2[M+H] ⁺ .

Intermediate A3

Dissolve 2-amino-3-nitrophenol (20g, 130mmol) in DMF (200mL), add potassium fluoride (22g, 390mmol) and diethyl 2-bromo-2-methylmalonate (40g, 156 mmol). The resulting reaction was stirred at room temperature for 30 minutes and at 60°C overnight. The reaction solution was diluted with EA and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (EA:PE=1:4) to obtain compound A3-1 (19 g yellow solid, yield 52%). MS(ESI):281.1[M+H] ⁺ .

Compound A3-1 (3 g, 10.67 mmol) was dissolved in methanol (80 ml), Pd/C (300 mg) was added, and hydrogen replacement was performed 3 times. Stir at 40°C for 2 hours under a hydrogen atmosphere. After filtering, washing with methanol, the filtrate was concentrated to obtain compound A3-2 (2.2 g yellow solid, yield 84%). MS(ESI):251.1[M+H] ⁺ .

Compound A3-2 (2.5g, 9.9mmol) was dissolved in DMF (20mL), potassium carbonate (4.1g, 29.7mmol) and 1,2-dibromoethane (2.4g, 12.87mmol) were added, stirred at 80°C overnight. The reaction solution was diluted with EA and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by reverse-phase column chromatography (acetonitrile/water) to obtain compound A3-3 (1.1 g brown solid, yield 40%). MS(ESI):277.1[M+H] ⁺ .

Compound A3-3 (600mg, 2.16mmol) was dissolved in tetrahydrofuran (10mL), cooled to 0°C, and lithium triethylborohydride (1N solution in THF, 5.4mL) was added. Warm to room temperature and stir the reaction for 2 hours. Quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by silica gel column chromatography (EA:PE=1:2) to obtain intermediate A3 (200mg white solid, yield 39%). MS(ESI):235.1[M+H] ⁺ .

Intermediate A4

4-Chloro-1H-pyrrolo[2,3-b]pyridine (5g, 32.9mmol) was dissolved in acetonitrile (100ml), N-iodosuccinimide (11.1g, 49.4mmol) was added, and the reaction The solution was heated to 50°C and stirred for 2 hours. The solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (PE:EA=1:1) to obtain compound A4-1 (8.7 g light brown solid, yield 95%). MS(ESI):279.0[M+H] ⁺ .

Dissolve compound A4-1 (8.3g, 29.8mmol) in tetrahydrofuran (50mL), add sodium hydride (2.4g, 59.7mmol, 60% mineral oil mixture), stir at room temperature for 1 hour, add 2-(trimethylsilane yl) ethoxymethyl chloride (7.5 g, 44.7 mmol). Stir at room temperature for 1 hour, and quench with saturated aqueous ammonium chloride solution (1 ml). The solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (PE:EA=7:1) to obtain compound A4-2 (5.4 g of yellow oil, yield 44%). MS(ESI):409.2[M+H] ⁺ .

Compound A4-2 (5.4g, 13.2mmol) was dissolved in dioxane (50mL), methyl acrylate (1.7g, 19.8mmol), triphenylphosphine (346mg, 1.32mmol), palladium acetate (148mg , 0.66mmol) and triethylamine (2.7g, 26.4mmol). Under nitrogen protection, the mixture was stirred at 100°C for 18 hours. After filtration and concentration, the residue was purified by silica gel column chromatography (PE:EA=9:1) to obtain compound A4-3 (3.16 g of yellow oil, yield 65%). MS(ESI):367.1[M+H] ⁺ .

Compound A4-3 (3.16 g, 8.6 mmol) was dissolved in ethyl acetate (80 mL), and Raney nickel (3 g) was added. The system was replaced with hydrogen 3 times, and stirred for 3 hours under a hydrogen atmosphere (hydrogen balloon). The filtrate was filtered and concentrated, and the crude product was purified by silica gel column chromatography (PE:EA=10:1) to obtain compound A4-4 (2.7 g yellow oil, yield 85%). MS(ESI):368.2[M+H] ⁺ .

Compound A4-4 (2.0 g, 5.4 mmol) was dissolved in methanolic ammonia solution (7N, 40 ml), and stirred at 130° C. for 18 hours. The solvent was removed, and the crude product was purified by silica gel column chromatography (100% EA) to obtain compound A4-5 (1.7 g light yellow solid, yield 89%). MS(ESI):354.2[M+H] ⁺ .

Compound A4-5 (580 mg, 1.6 mmol) was dissolved in acetonitrile (6 ml) and water (6 mL), and iodobenzene acetate (1.6 g, 4.9 mmol) was added. The reaction was stirred at room temperature for 2 hours. The crude product solution was filtered and purified by reverse phase flash chromatography to obtain compound A4-6 (440 mg light yellow solid, yield 82%). MS(ESI):326.1[M+H] ⁺ .

Compound A4-6 (100mg, 0.3mmol) was dissolved in dimethylsulfoxide (3ml), cesium carbonate (196mg, 0.6mmol), cuprous iodide (57mg, 0.3mmol) and L-proline ( 52 mg, 0.45 mmol). Under nitrogen protection, the resulting mixture was stirred at 80°C for 1 hour. After filtration, the resulting crude solution was purified by reverse-phase flash chromatography to obtain intermediate A4 (60 mg yellow oil, yield 69%). MS(ESI):290.2[M+H] ⁺ .

Intermediate A5

Dissolve 3-fluoro-2-nitroaniline (20g, 128.2mmol) in N,N-dimethylformamide (40mL), add cesium carbonate (84g, 256.4mmol) and diethyl malonate (41g , 256.4mmol), reflux at 100°C for 6 hours. Cool to room temperature, dilute with ethyl acetate (100 mL), and wash with saturated brine (100 ml x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by reverse-phase flash chromatography to obtain compound A5-1 (19 g of red solid, yield 50%). MS(ESI):297.0[M+H] ⁺ .

Compound A5-1 (4 g, 13.5 mmol) was dissolved in tetrahydrofuran (30 mL), and 4-dimethylaminopyridine (4.1 g, 33.75 mmol) and di-tert-butyl dicarbonate (7.4 g, 33.75 mmol) were added. After stirring at 40°C overnight, the solvent was removed under reduced pressure, and the obtained crude product was purified by column chromatography (EA:PE=1:2) to obtain compound A5-2 (1.8 g brown solid, yield 27%). MS(ESI):497.2[M+H] ⁺ .

Dissolve compound A5-2 (1.8g, 3.6mmol) in N,N-dimethylformamide (10mL), add iodomethane (2g, 14.4mmol) and cesium carbonate (2.3g, 7.2mmol), stir at room temperature After 3 hours, it was diluted with ethyl acetate (100 mL), and washed with saturated brine. The organic phase was dried and concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (PE:EA=3:1) to obtain compound A5-3 (1.8 g yellow oil, yield 99%). MS(ESI):511.2[M+H] ⁺ .

Compound A5-3 (7.5g, 14.67mmol) was dissolved in ethanol/water (100mL/10mL), iron powder (8.2g, 146.7mmol) and ammonium chloride (3.8g, 73.35mmol) were added. The reaction solution was stirred at 100°C for 4 hours. The solid was filtered off, concentrated, diluted with ethyl acetate, and washed with saturated brine. The organic phase was concentrated to obtain compound A5-4 (4.5 g brown solid, yield 95%). MS(ESI):335.2[M+H] ⁺ .

Compound A5-4 (4.9 g, 14.6 mmol) was dissolved in hydrochloric acid in dioxane (4N, 10 mL), and stirred at room temperature for 2 hours. Concentration gave compound A5-5 (3.9 g of yellow solid). MS(ESI):235.1[M+H] ⁺ .

Compound A5-5 (2g, 7.38mmol) was dissolved in N,N-dimethylformamide (20ml), and 1,2-dibromoethane (2.4g, 12.75mmol) and potassium carbonate (5.8g, 42.5 mmol). The reaction solution was stirred overnight at 85°C. Diluted with ethyl acetate, washed with saturated brine. The organic phase was concentrated, and the obtained crude product was purified by silica gel column chromatography (EA:PE=1:1) to obtain compound A5-6 (600mg yellow solid, yield 27%). MS(ESI):261.1[M+H] ⁺ .

Compound A5-6 (200mg, 0.76mmol) was dissolved in tetrahydrofuran (3ml), cooled to 0°C, and borane-dimethylsulfide solution (10N, 3ml) was added. The reaction solution was stirred at 70°C for 3 hours, quenched with methanol, concentrated, and the obtained crude product was purified by preparative TLC (DCM:MeOH=10:1) to obtain compound A5 (120 mg, 76%). MS(ESI):205.1[M+H] ⁺ .

Intermediate A6

2-Chloro-3-nitropyridin-4-amine (5.0g, 28.8mmol) was dissolved in dichloromethane (100ml), di-tert-butyl dicarbonate (7.5g, 34.5mmol) and triethylamine ( 8.6 g, 86.1 mmol) and 4-dimethylaminopyridine (400 mg, 2.9 mmol). The reaction solution was stirred at room temperature for 5 hours. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA=10:1) to obtain compound A6-1 (7.8 g of yellow solid, yield 99%). MS(ESI):274.1[M+H] ⁺ .

Compound A6-1 (7.8g, 28.6mmol) and benzylamine (3.7g, 34.3mmol) were dissolved in ethanol (100ml), and potassium acetate (7.2g, 85.8mmol) was added. The reaction solution was stirred at 80°C for 5 hours. After concentration, the obtained crude product was purified by silica gel column chromatography (PE:EA=1:1) to obtain compound A6-2 (6.3 g yellow solid, yield 64%). MS(ESI):345.2[M+H] ⁺ .

Compound A6-2 (4.0 g, 11.6 mmol) was dissolved in ethyl acetate (200 ml) and glacial acetic acid (20 ml), and palladium on carbon (800 mg) was added. Under a hydrogen atmosphere (hydrogen balloon), the reaction solution was stirred at room temperature for 20 hours. After filtration and concentration, the obtained crude product was purified by silica gel column chromatography (DCM:MeOH=10:1) to obtain compound A6-3 (600mg yellow solid, yield 23%). MS(ESI):225.0[M+H] ⁺ .

Compound A6-3 (600mg, 2.7mmol) was dissolved in diethyl oxalate (3ml), and stirred at 80°C for 8 hours. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA=1:1) to obtain compound A6-4 (400 mg yellow solid, yield 54%). MS(ESI):279.1[M+H] ⁺ .

Compound A6-4 (400 mg, 1.4 mmol) and 1,2-dibromoethane (404 mg, 2.2 mmol) were dissolved in DMF (5 ml), and cesium carbonate (1.3 g, 4.2 mmol) was added. The reaction solution was stirred at 80°C for 8 hours. Diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA=1:1) to obtain compound A6-5 (80mg yellow solid, Yield 18%). MS(ESI):305.3[M+H] ⁺ .

Compound A6-5 (80mg, 0.26mmol) was dissolved in methanol (2ml), and a solution of dioxane hydrochloride (4N, 1.0ml) was added, and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to obtain intermediate A6 (50mg yellow solid, yield 80%). MS(ESI):205.2[M+H] ⁺ .

Intermediate B1

Dissolve (bromomethyl)benzene (5.0 g, 47.6 mmol) in DMF (50 mL), add diethanolamine (8.0 g, 47.6 mmol) and triethylamine (9.6 g, 95.2 mmol), and stir at room temperature for 2 hours. The reaction liquid was diluted with water (500ml), and extracted three times with 100mL of DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound B1-1 (13 g of brown oil). MS(ESI):196.2[M+H] ⁺ .

Compound B1-1 (13g, 66.7mmol) was dissolved in toluene (50mL), phosphorus tribromide (27.1g, 100mmol) was added, and the reaction was stirred overnight at 100°C. Cool to 0°C, quench with aqueous sodium hydroxide solution, concentrate under reduced pressure, extract 3 times with dichloromethane, 100 mL each time, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound B1 -2 (10.7 g brown oil). MS(ESI):320.0[M+H] ⁺ .

Compound B1-2 (4.0g, 31mmol) was dissolved in DMF (100mL), cooled to -20°C, sodium hydride (3.1g, 77.5mmol) was added in batches, stirring was continued for 30 minutes, and N,N-bis( 2-Bromoethyl)-3-(bromomethyl)aniline (10.6g, 31mmol), raised to 0°C and stirred overnight. The reaction was quenched with water, and the reaction solution was extracted three times with ethyl acetate, 100 mL each time. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the crude product was purified by silica gel chromatography (EA:PE=1:1) to obtain compound B1-3 (4.9 g khaki solid, yield 49 %). MS(ESI):322.2[M+H] ⁺ .

Dissolve compound B1-3 (4.9g, 15.2mmol) in dichloroethane (50mL), add 1-chloroethylcarbonyl chlorate (4.36g, 30.5mmol), stir at 80°C for 6 hours, and concentrate the reaction solution , diluted with methanol (40 mL), stirred at 80° C. for 1 hour, cooled to room temperature, and concentrated to obtain compound B1-4 (5.1 g yellow solid). MS(ESI):232.2[M+H] ⁺ .

Compound B1-4 (5.2 g, 22.5 mmol) was dissolved in DCM (40 mL), (Boc) ₂ O (7.36 g, 33.7 mmol) and triethylamine (6.8 g, 67.5 mmol) were added, and stirred at room temperature for 2 hours. The reaction solution was concentrated, and the crude product was purified by silica gel chromatography (EA:PE=1:3) to obtain compound B1-5 (5.0 g yellow solid, 67%). MS(ESI):276.2[M+H-56] ⁺ .

Dissolve compound B1-5 (5.0 g, 15.1 mmol) in ethyl titanate (100 mL), add (R)-2-methylpropane-2-sulfinamide (2.2 g, 18.1 mmol), and stir overnight at room temperature . The reaction solution was poured into a mixture of EA and brine, and stirred at room temperature for 15 minutes. The solid was filtered off and separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (EA:PE=1:3) to obtain compound B1-6 (3.5g Yellow solid, yield 53%). MS(ESI):435.2[M+H] ⁺ .

Compound B1-6 (2.4g, 5.5mmol) was dissolved in THF (15mL), sodium borohydride (419mg, 11mmol) was added in batches at -70°C, stirred for 70h, raised to room temperature, the reaction solution was diluted with EA, saturated with salt Wash with water, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by silica gel chromatography (EA:PE=1:1) to obtain compound B1-7 (1.0 g white solid, yield 43%). MS(ESI):337.2[M+H-100] ⁺ _.

The HCl/Dioxane (4N, 10.0mL) solution of compound B1-7 (1.0g, 2.3mmol) was stirred at RT for 2 hours, ethyl acetate (5mL) was added, suction filtered, the filter cake was washed with ethyl acetate, and dried in vacuo Intermediate B1 (600 mg white solid) was obtained. MS(ESI):233.2[M+H] ⁺ .

Intermediate B2

3-Bromo-2-picoline (10g, 58mmol) was dissolved in carbon tetrachloride (50mL), and benzoyl peroxide (844mg, 3.48mmol) and N-bromosuccinimide ( 11.35g, 63.8mmol), stirred overnight at 90°C. The reaction solution was diluted with water and extracted three times with 50 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (EA:PE=1:15) to obtain compound B2-1 (10 g yellow liquid, yield 71%). MS(ESI):249.8[M+H] ⁺ .

Compound B2-1 (8.4g, 39.8mmol) was dissolved in THF (300mL), under nitrogen protection, LDA (2N THF solution, 39.8mL, 79.6mmol) was added dropwise at -50°C, stirred for 2 hours, and cooled to -78 °C, 3-bromo-2-(bromomethyl)pyridine (10 g, 39.8 mmol) was added dropwise to the reaction solution and stirred overnight. Saturated ammonium chloride aqueous solution was quenched, and the reaction solution was extracted three times with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (EA:PE=1:8) to obtain compound B2-2 (3.8 g yellow liquid, yield 25%). MS(ESI):324.0[M+H-56] ⁺ .

In a mixed solvent of dimethylacetamide and water (10:1, 50mL), add compound B2-2 (3.8g, 10mmol), dichlorodi-tert-butyl-(4-dimethylaminophenyl) phosphorus Palladium(II) (710mg, 1mmol) and triethylamine (4g, 40.1mmol) were stirred overnight at 130°C. The reaction solution was diluted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained crude product was purified by silica gel chromatography (EA:PE=1:1) to obtain compound B2-3 (2.5 g brown solid, Yield 83%). MS(ESI):303.2[M+H] ⁺ .

Compound B2-3 (2.5 g, 8.27 mmol) and (R)-2-methylpropane-2-sulfinamide (1.3 g, 10.76 mmol) were added to ethyl titanate (50 mL), and stirred overnight at 110°C. Cool to room temperature, pour the reaction solution into ethyl acetate/saturated brine, stir at room temperature for 15 minutes, filter out the solid, separate the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the resulting crude product was purified by silica gel column chromatography (EA:PE=1:2) to obtain compound B2-4 (3.2 g yellow solid, yield 95%). MS(ESI):406.2[M+H] ⁺ .

Compound B2-4 (3.7g, 9.13mmol) was dissolved in THF (15mL), cooled to -70°C, sodium borohydride (694mg, 18.27mmol) was added in batches, stirred for 8 hours, then warmed to room temperature. The reaction solution was diluted with EA and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (EA:PE=1:2) to obtain compound B2-5 (600mg yellow solid, yield 16%). MS(ESI):408.2[M+H] ⁺ .

The HCl/Dioxane (4N, 6.0mL) solution of compound B2-5 (500mg, 1.2mmol) was stirred at RT for 2 hours, ethyl acetate (3mL) was added, filtered with suction, the filter cake was washed with ethyl acetate, and dried in vacuo to obtain Intermediate B2 (350 mg white solid). MS(ESI):204.2[M+H] ⁺ .

Intermediate B3

2-Fluorobenzaldehyde (5.0 g, 40 mmol) was dissolved in DCM (30 mL), propane-1,3-dithiol (4.35 g, 40 mmol) and _I2 (307 mg, 1.2 mmol) were added slowly. The resulting solution was stirred overnight at room temperature. The reaction solution was poured into Na ₂ S ₂ O ₃ (aq) and NaOH (aq), extracted with DCM. The organic phases were combined, washed with saturated brine, dried, filtered, and concentrated to obtain compound B3-1 (7.0 g white solid, yield 81%). MS(ESI):215.0[M+H] ⁺ .

Compound B3-1 (6.2g, 28.8mmol) was dissolved in THF (50mL), cooled to -78°C, LDA (2N, 28.8mL, 57.6mmol) was added dropwise, and stirred at -20°C for 30 minutes after dropping, A solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.7 g, 28.8 mmol) in THF (50 mL) was then added at -78 °C. The reaction was stirred at -78°C for 2 hours. The reaction mixture was quenched with saturated aqueous NH ₄ Cl and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by silica gel column chromatography (EA:PE=1:4) to obtain compound B3-2 (6.2 g white solid, yield 52%). MS(ESI):414.1[M+H] ⁺ .

Compound B3-2 (6.2g, 14.97mmol) was dissolved in DCM (100mL)/H ₂ O (25mL), and pyridine (2.36g, 29.94mmol), pyridinium tribromide (5.75g, 17.96mmol) and four Butylammonium bromide (482mg, 1.49mmol), the reaction solution was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous ammonium chloride and extracted with EA. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by silica gel column chromatography (EA:PE=1:4) to obtain compound B3-3 (2.6 g yellow oil, 54%). MS(ESI):324.2[M+H] ⁺ .

Compound B3-3 (2.6 g, 8 mmol) was dissolved in THF (20 mL), and potassium tert-butoxide (1.35 g, 12 mmol) was added. The resulting solution was stirred at 70°C for 2 hours. The reaction solution was diluted with EA and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by silica gel column chromatography (EA:PE=1:4) to obtain compound B3-4 (1.2 g white solid, yield 50%). MS(ESI):304.1[M+H] ⁺ .

Compound B3-4 (1.2g, 3.9mmol) was dissolved in Ti(OEt) ₄ (30mL) and THF (5mL), and (R)-2-methylpropane-2-sulfinamide (1.6g, 13.65 mmol). The reaction solution was stirred overnight at 90°C. Pour the mixture into cold water. The solid was filtered off and washed with EA. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (PE:EA=5:1) to obtain compound B3-5 (1.5 g yellow oil, yield 93%). MS(ESI):407.2[M+H] ⁺ .

Compound B3-5 (1.5 g, 3.68 mmol) was dissolved in THF (20 mL), cooled to -20°C, and sodium borohydride (420 mg, 11.04 mmol) was added. The reaction was warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with EA. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by silica gel column chromatography (PE:EA=4:1) to obtain compound B3-6 (550mg white solid, yield 33% ). MS(ESI):409.2[M+H] ⁺ .

Compound B3-6 (200 mg, 0.488 mmol) was dissolved in HCl/Dioxane (4N, 5 mL), stirred at RT for 1 hour. The reaction mixture was concentrated, and the resulting solid was washed with EA to give intermediate B3 (100 mg white solid). MS(ESI):205.2[M+H] ⁺ .

Intermediate C1

Benzyl alcohol (17.0 g, 157.96 mmol) was dissolved in THF (300 mL), cooled to 0 °C, NaH (6.89 g, 172.32 mmol) was added in portions, and the resulting mixture was stirred at 0 °C for 1 hour. This mixture was then added to a solution of 3,5-dichloropyrazine-2-carbonitrile (25.0 g, 143.6 mmol) in THF (200 mL) at -78 °C. The resulting solution was stirred at -78°C for 2 hours, and the reaction was quenched by adding saturated ammonium chloride. The reaction mixture was diluted with EA and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (EA:PE=1:15) to obtain compound C1-1 (25.0 g white solid, yield 71%). MS(ESI):246.1[M+H] ⁺ .

Compound C1-1 (25.0 g, 101.6 mmol) was dissolved in THF (500 mL), cooled to -78°C, and DIBAL-H (1N hexane solution, 305 mL, 304.8 mmol) was added dropwise under nitrogen protection.

The reaction was stirred at -78°C for 2 hours. Quenched with HOAc (10% aq) and extracted with EA. The organic layer was washed successively with aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound C1-2 (26.0 g, 99%) without further purification. MS(ESI):249.0[M+H] ⁺ .

Triethylamine (52 g, 57 mmol) and hydrazine monohydrate (15.6 g, 342 mmol) were added to a solution of compound C1-2 (26.0 g, 104 mmol) in ethanol (400 mL). The resulting solution was stirred overnight at 80°C. The solvent was removed in vacuo and the residue was diluted with EA and washed with saturated ammonium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give compound C1-3 (22.0 g brown oil, 95%) without further purification. MS(ESI):227.1[M+H] ⁺ .

Compound C1-3 (16.0 g, 70.48 mmol) was dissolved in DMF (200 mL), and N-iodosuccinimide (20.6 g, 91.6 mmol) was added. The resulting solution was stirred at 85°C for 3 hours. EA was diluted, washed successively with saturated sodium sulfite solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound C1-4 (22.0 g, 91%) without further purification. MS(ESI):353.0[M+H] ⁺ .

Compound C1-4 (22 g, 62.3 mmol) was dissolved in DCM (200 mL), 3,4-dihydropyran (15.7 g, 186.9 mmol) and p-toluenesulfonic acid (3.5 mg, 18.69 mmol) were added. The resulting solution was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (EA:PE=1:1) to obtain intermediate C1 (14.0 g white solid, 52%). MS(ESI):437.1[M+H] ⁺ .

Intermediate C2

Dissolve 3,5-dichloropyrazine-2-carboxylic acid (25.0g, 130mmol) in DMF (200mL), cool to 0°C, add sodium bicarbonate (13.1g, 156mmol) and iodomethane (133g, 937mmol ), and the resulting mixture was stirred at RT for 6 h. Diluted with water, extracted with EA, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (EA:PE=1:10) to obtain compound C2-1 ( 26.0 g white solid, 96% yield). MS(ESI):207.1[M+H] ⁺ .

Compound C2-1 (26g, 126mmol) was dissolved in tetrahydrofuran (250mL) and methanol (28mL), cooled to -20°C, and a solution of lithium borohydride (2N in THF, 76mL, 151.4mmol) was added dropwise. The resulting mixture was stirred at -20°C for 2 hours, and the reaction was quenched with HCl (1 N, aq.). The mixture was diluted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (EA:PE=1:1) to obtain compound C2-2 (15 g white solid, Yield 68%). MS(ESI):179.1[M+H] ⁺ .

Compound C2-2 (22.6 g, 128 mmol) was dissolved in DCM (400 mL), and active manganese dioxide (161 g, 1.92 mol) was added, and stirred at RT for 24 hours. Filter and wash the filter cake with DCM. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (EA:PE=1:5) to obtain compound C2-3 (16.5 g yellow oil, yield 72%). MS(ESI):177.0[M+H] ⁺ .

Compound C2-3 (8 g, 45.4 mmol) was dissolved in NMP (20 mL), cooled to 0° C., added with hydrazine monohydrate (6.8 g, 136.3 mmol), and stirred overnight at RT. Add HCl (1N, aq.) to quench the reaction, dilute with EA, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The obtained crude product is subjected to silica gel column chromatography (DCM: MeOH=20 : 1) Compound C2-4 (3.4 g yellow solid, yield 48%) was purified. MS(ESI):155.1[M+H] ⁺ .

N-bromosuccinimide (13.8 g, 77.9 mmol) was added in portions to a solution of compound C2-4 (8 g, 51.9 mmol) in acetonitrile (150 mL), and stirred at RT for 3 hours. The solvent was distilled off under reduced pressure to obtain compound C2-5 (12 g of brown solid), without further purification. MS(ESI):233.0[M+H]+.

Compound C2-5 (12g, 51.9mmol) was dissolved in DCM (300mL), added 3,4-dihydropyran (13g, 155.7mmol) and p-toluenesulfonic acid (2.96g, 15.5mmol), stirred at RT for 2 Hour. After concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography (EA:PE=1:1) to obtain intermediate C2 (9.5 g white solid, yield 59%). MS(ESI):317.1[M+H] ⁺ .

Example 1

Compound 1-1 (12 g, 29.5 mmol) was dissolved in DCM (90 mL), added trifluoroacetic acid (30 mL), and stirred at RT for 2 hours. The reaction liquid was neutralized (pH adjusted to 8) with saturated sodium bicarbonate (200 mL), and extracted three times with dichloromethane, 100 mL each time. The organic phases were combined and concentrated under reduced pressure, and the residue was purified by C18 column chromatography (water/acetonitrile) to obtain compound 1-2 (9 g white solid, yield 99%). MS(ESI):307.2[M+H] ⁺ .

Intermediate C2 (3.0 g, 9.4 mmol) was dissolved in DMF (20 mL), triethylamine (2.8 g, 28.2 mmol) and compound 1-2 (2.9 g, 9.4 mmol) were added, and stirred overnight at 50°C. The reaction mixture was diluted with saturated brine, extracted with EA, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-3 (4.0 g yellow solid, yield 73%). MS(ESI):587.2[M+H] ⁺ .

Compound A1 (37 mg, 0.17 mmol) and compound 1-3 (100 mg, 0.17 mmol) were dissolved in toluene (2 mL), and Pd ₂ (dba) ₃ (16 mg, 0.017 mmol), RuPhos (16 mg, 0.034 mmol) and Cs ₂ CO ₃ (111 mg, 0.34 mmol), stirred at 100°C for 16 hours. After cooling to RT and concentrating under reduced pressure, the residue was purified by preparative TLC (DCM:MeOH=10:1) to obtain compound 1-4 (100 mg yellow solid, yield 81%). MS(ESI):725.3[M+H] ⁺ .

Compound 1-4 (100mg, 0.14mmol) was dissolved in HCl/Dioxane (4N, 3mL) and methanol (1mL), stirred at RT for 1 hour, concentrated under reduced pressure, and the obtained crude product was purified by Pre-HPLC to obtain Example 1 (20mg Yellow solid, yield 26%). MS(ESI):mass calcd.for C ₃₀ H3 ₂ N ₈ O ₂ 536.3,m/z found 537.2[M+H]+.1H-NMR(400MHz,DMSO-d6):δppm 12.63(brs,1H), 8.35(s,1H),7.31-7.15(m,4H),6.94-6.91(m,1H),6.81-6.76(m,1H),6.51-6.48(m,1H),4.33-4.28(m,2H ),4.06-4.03(m,2H),3.95-3.93(m,2H),3.88(s,1H),3.34-3.27(m,2H),3.11(d,J＝15.6Hz,1H),2.68( d,J＝15.6Hz,1H),1.89-1.52(m,3H),1.46(s,6H),1.13-1.05(m,1H).

Using the above method or a modified method, the following examples were synthesized from the corresponding starting materials.

Example 12

Compound A1 (300mg, 0.77mmol) was dissolved in dioxane (2mL), and compound C1 (111mg, 0.51mmol), Pd ₂ (dba) ₃ (47mg, 0.051mmol), Xantphos (59mg, 0.102 mmol) and Cs ₂ CO ₃ (499 mg, 1.53 mmol). Stir overnight at 100°C, dilute with EA, filter, and concentrate the filtrate. The residue was purified by silica gel column chromatography (EA:PE=1:10) to obtain compound 12-1 (400 mg of brown oil, yield 50%). MS(ESI):527.2[M+H] ⁺ .

Compound 12-1 (390 mg, 0.74 mmol) was dissolved in THF/H ₂ O/MeOH (2:1:0.5, 7 mL in total), palladium/carbon (100 mg) and ammonium formate (933 mg, 14.8 mmol) were added, 50 Stirred at ℃ overnight, the reaction solution was diluted with EA, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH=10:1) to obtain compound 12-2 (300mg brown solid, yield 93%). MS(ESI):437.2[M+H]+.

Compound 12-2 (300 mg, 0.68 mmol) was dissolved in DCM (10 mL), p-toluenesulfonyl chloride (143.8 mg, 0.75 mmol) and DIEA (105 mg, 0.816 mmol) were added, and stirred at RT for 1.5 hours. After concentration, the residue was purified by silica gel column chromatography (EA:PE=1:5) to obtain compound 12-3 (230 mg brown solid, 56%). MS(ESI):591.2[M+H] ⁺ .

Compound 12-3 (200 mg, 0.338 mmol) was dissolved in DMF (5 mL), TEA (171 mg, 1.695 mmol) and compound B1 (103 mg, 0.338 mmol) were added, and stirred overnight at 50°C.

The reaction solution was diluted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by C18 reverse phase column chromatography (acetonitrile/water) to obtain compound 12-4 (110mg yellow solid, yield 50% ). MS(ESI):651.2[M+H] ⁺ .

Compound 12-4 (100mg, 0.154mmol) was dissolved in HCl/dioxane (4N, 2mL), stirred at RT for 1 hour, concentrated under reduced pressure, and the residue was purified by prep-HPLC to obtain Example 12 (21mg yellow solid, yield 24 %). MS(ESI):mass calcd.for C ₃₁ H ₃₄ N ₈ O ₃ 566.3,m/z found 567.2[M+H] ⁺ .1H-NMR(400MHz,DMSO-d6):δppm 12.61(s,1H), 8.35(s,1H),7.22-7.20(m,1H),6.94-6.91(m,1H),6.80-6.76(m,3H),6.51-6.48(m,1H),4.32-4.29(m,2H ),4.05-3.86(m,5H),3.72(s,3H),3.45-3.38(m,2H),3.05-3.11(m,1H),2.62-2.71(m,1H),1.82-1.60(m ,2H),1.55-1.46(m,1H),1.45(s,6H),1.30-1.25(m,1H).

Example 29

Intermediate A3-3 (60mg, 0.216mmol) and compound 1-3 (127mg, 0.216mmol) were dissolved in toluene (3mL), under nitrogen protection, Pd ₂ (dba) ₃ (20mg, 0.0216mmol), Ruphos ( 20mg, 0.0432mmol) and Cs ₂ CO ₃ (212mg, 0.648mmol), stirred overnight at 110°C. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA=4:1) to obtain compound 29-1 (90 mg brown solid, yield 53%). MS(ESI):783.2[M+H] ⁺ .

Compound 29-1 (70mg, 0.089mmol) was dissolved in NH ₃ /MeOH (7N, 3mL), stirred at 70°C for 4 hours, and concentrated to obtain Compound 29-2 (67mg brown solid). MS(ESI):754.2[M+H] ⁺ .

Compound 29-2 (67mg, 0.089mmol) was dissolved in HCl/dioxane (4N, 2mL), stirred at RT for 1 hour, concentrated under reduced pressure, and the residue was purified by Prep-HPLC (water/acetonitrile) to obtain Example 29 (10mg yellow solid). MS(ESI):mass calcd.for C ₃₀ H ₃₁ N ₉ O ₃ 565.3,m/z found 566.2[M+H]+.1H-NMR(400MHz,DMSO-d6):δppm 12.64(s,1H), 8.35(s,1H),7.67(s,1H),7.45(s,1H),7.29(d,J=6.0Hz,1H),7.18-7.16(m,3H),6.93(d,J=8.4Hz ,1H),6.82-6.77(m,1H),6.63(d,J＝7.6Hz,1H),4.35-4.23(m,3H),4.15-4.11(m,1H),3.86-3.83(m,2H ),3.67-3.63(m,1H),3.34-3.23(m,2H),3.12-3.08(m,1H),2.66-2.62(m,1H),1.81-1.69(m,1H),1.65-1.55 (m,4H),1.52-1.43(m,1H),1.13-1.09(m,1H).

Example 33

Dissolve intermediate C2 (810mg, 2.5mmol) in MeOH/DMSO (1mL/10mL), add silver nitrate (174 mg, 1.0mmol) and trifluoroacetic acid (0.19mL), stir at 70°C for 1 hour, add (NH ₄ ) ₂ S ₂ O ₈ (1.45g, 6.4mmol) and H ₂ O (3mL), stirred at 70°C for 2 hours, the reaction solution was diluted with EA, washed with NaOH aqueous solution, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue The compound was purified by silica gel column chromatography (EA:PE=1:5) to obtain compound 33-1 (340mg white solid, yield 39%). MS(ESI):347.0[M+H] ⁺ .

Compound 33-1 (300 mg, 0.8 mmol) was dissolved in DMF (5 mL), triethylamine (0.6 mL, 4.3 mmol) and compound 1-2 (265 mg, 0.8 mmol) were added, and stirred overnight at 50°C. The reaction solution was diluted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by silica gel column chromatography (EA:PE=2:1) to obtain compound 33-2 (260mg yellow solid, yield 48%). MS(ESI):617.2[M+H] ⁺ .

Using Compound 33-2 instead of Compound 1-3 in Example 1, Example 33 can be synthesized in a manner similar to Example 1. MS(ESI):mass calcd.for C ₃₁ H ₃₄ N ₈ O ₃ 566.3,m/z found567.2[M+H] ⁺ .1H-NMR(400MHz,DMSO-d6):δ12.95(brs,1H ), 7.32(d, J=6.4Hz, 1H), 7.17(d, J=6.8Hz, 3H), 6.91(d, J=8.4Hz, 1H), 6.81-6.79(m, 1H), 6.52-6.50 (m,1H),5.29(m,1H),4.58(d,J=5.6Hz,2H),4.10-4.08(m,2H),3.97-3.94(m,2H),3.87(s,1H), 3.76-3.72(m,2H),3.08-3.04(m,1H),2.64(s,1H),1.85-1.82(m,2H),1.56(d,J=8Hz,1H),1.46(s,6H ),1.18-1.14(m,1H).

Example 37

6-Chloro-1H-pyrazolo[3,4-b]pyridine (100mg, 0.65mmol) was dissolved in DMF (2ml), NIS (189mg, 0.84mmol) was added, and stirred at 80°C for 4 hours. The reaction solution was diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 37-1 (160 mg yellow solid, 88%). MS(ESI):280.0[M+H] ⁺ .

Compound 37-1 was dissolved in DCM (4mL), DHP (144mg, 1.71mmol) and p-toluenesulfonic acid (11.4mg, 0.057mmol) were added, stirred at RT for 3 hours, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (PE:EA=10:1) was purified to obtain compound 37-2 (130mg white solid, yield 63%). MS(ESI):364.0[M+H] ⁺ .

Compound 37-2 (130 mg, 0.36 mmol) was dissolved in DMF (2 mL), compound 1-2 (109 mg, 0.36 mmol) and triethylamine (181 mg, 1.80 mmol) were added, and stirred at 50°C for 12 hours. Diluted with water, extracted with EA, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (PE:EA=1:1) to obtain compound 37-3 (70mg white solid, yield 31%). MS (ESI): 634.2 [M+H] ⁺ .

Compound 37-3 was used to replace compound 1-3 in Example 1, and Example 37 was synthesized in a manner similar to Example 1. MS(ESI):mass calcd.for C ₃₁ H ₃₃ N ₇ O ₂ 535.3,m/z found 536.2[M+H] ⁺ . ¹ H-NMR(400MHz,DMSO-d6):δppm 12.47(s,1H) ,7.54(d,J=9.2Hz,1H),7.30(d,J=6.4Hz,1H),7.19-7.16(m,3H),6.80-6.73(m,2H),6.53-6.46(m,2H ),4.26-4.25(m,2H),3.94-3.92(m,2H),3.85-3.81(m,3H),3.11-2.97(m,3H),2.65-2.61(m,1H),1.85-1.50 (m, 3H), 1.46 (s, 6H), 1.19-1.10 (m, 1H). Using the above method or a modified method, the following examples were synthesized from the corresponding starting materials.

Test example 1 : SHP2 (protein tyrosine phosphatase) in vitro enzymatic activity inhibition test

1.1 Test materials and instruments

试验材料和仪器Test Materials and Instruments	厂家factory	货号Item No.
SHP099SHP099	SelleckSelleck	S8278S8278
DMSODMSO	SigmaSigma	D2650D2650
SHP2蛋白(PTPN11)SHP2 protein (PTPN11)	ORIGENEORIGENE	TP320029TP320029
SHP2 Activating PeptideSHP2 Activating Peptide	BioscienceBioscience	79319-279319-2
DiFMUPDiFMUP	ThermoThermo	21132942113294
NaClNaCl	SigmaSigma	S9888S9888
BSABSA	SigmaSigma	V900933V900933
HEPESHEPES	gibcogibco	15630-08015630-080
DTTDTT	SigmaSigma	4381643816
EDTAEDTA	SCRSCR	1000971710009717
Triton X-100Triton X-100	SigmaSigma	T9284T9284
多功能酶联免疫仪Spark M1000proMultifunctional ELISA Spark M1000pro	TECANTECAN	----
96孔U底黑板96-hole U-bottom blackboard	ThermoThermo	237108237108

1.2 Test system

SHP2 protein solution concentration: 0.5nM; enzyme buffer solution: 55mM HEPES, 100mM NaCl, 0.2% BSA, 1mM EDTA, 1mM DTT, 0.1% Triton X-100; SHP2Activating Peptide solution concentration: 0.5μM; DiFMUP solution concentration: 120μM; Positive Concentration of DMSO solution of drug SHP099: 10000nM, 2500nM, 625nM, 156.25nM, 39.06nM, 9.77nM, 2.44nM, 0.61nM, 0.15nM, 0nM, wherein the compound concentration of 0nM is the blank group; the DMSO solution concentration of the test compound : 10000nM, 2500nM, 625nM, 156.25nM, 39.06nM, 9.77nM, 2.44nM, 0.61nM, 0.15nM, 0nM, wherein the compound concentration of 0nM is the blank group.

1.3 Test steps

Take a 96-well U-bottom black plate, add 30 μL of enzyme buffer, 5 μL of SHP2 protein solution and 5 μL of SHP2 Activating Peptide to each well, and incubate on a shaker at room temperature 25°C for 30 minutes; add 5 μL of positive drug or test compound solution to each well, at room temperature of 25°C Shaking plate machine was incubated for 30 min; 5 μL DiFMUP was added to each well as the reaction substrate to start the reaction (the total volume of the system was 50 μL), and after 30 min incubation with shaking plate machine at room temperature of 25 °C, the fluorescence intensity of the reaction solution was detected using a multifunctional enzyme-linked immunosorbent assay ( Excitation light 340nm, emission light 450nm).

1.4 Data processing

The inhibition rate of each compound at each concentration point was calculated according to the following formula, and the IC50 value was obtained by curve fitting with the software Graphpad Prism 8.0.

1.5 Test results

The inhibitory activity of the compounds on SHP2 activity was determined according to the above method, and the results are shown in the following table.

化合物compound	IC50(nM)IC50(nM)
SHP099SHP099	107.81107.81
实施例1Example 1	5.465.46
实施例4Example 4	2.192.19
实施例5Example 5	35.5035.50
实施例6Example 6	22.2122.21
实施例7Example 7	32.8032.80
实施例8Example 8	4.154.15
实施例9Example 9	17.7317.73
实施例12Example 12	7.287.28
实施例19Example 19	8.278.27
实施例20Example 20	26.1826.18
实施例21Example 21	3.563.56
实施例22Example 22	12.2912.29
实施例23Example 23	4.994.99
实施例29Example 29	8.448.44
实施例30Example 30	3.333.33
实施例31Example 31	2.682.68
实施例32Example 32	7.367.36
实施例33Example 33	6.856.85
实施例52Example 52	7.177.17
实施例59Example 59	65.5965.59
实施例60Example 60	13.2813.28
实施例61Example 61	9.819.81
实施例63Example 63	4.74.7
实施例64Example 64	5.725.72
实施例65Example 65	11.2611.26
实施例66Example 66	3.843.84
实施例67Example 67	8.798.79
实施例68Example 68	9.849.84
实施例69Example 69	6.546.54
实施例70Example 70	4.364.36
实施例71Example 71	18.4218.42
实施例72Example 72	6.726.72
实施例73Example 73	4.174.17
实施例74Example 74	4.654.65
实施例75Example 75	2.512.51
实施例76Example 76	5.785.78
实施例77Example 77	5.735.73
实施例78Example 78	7.897.89
实施例79Example 79	13.913.9
实施例80Example 80	3.243.24

实施例81Example 81	3.093.09
实施例83Example 83	8.458.45
实施例84Example 84	1.71.7
实施例85Example 85	11.6111.61
实施例86Example 86	6.876.87
实施例87Example 87	46.546.5
实施例88Example 88	7.197.19
实施例89Example 89	13.0213.02
实施例90Example 90	22.9522.95
实施例91Example 91	11.511.5
实施例92Example 92	6.146.14
实施例93Example 93	15.1315.13
实施例94Example 94	9.249.24
实施例95Example 95	10.5610.56
实施例96Example 96	70.1670.16
实施例97Example 97	7.827.82
实施例98Example 98	7.067.06
实施例99Example 99	8.868.86
实施例100Example 100	336.83336.83
实施例101Example 101	277.66277.66
实施例102Example 102	520.61520.61
实施例103Example 103	205.46205.46

Conclusion: In the SHP2 enzyme activity inhibition test, compared with the positive drug SHP099, the compound of the present invention shows better inhibitory activity.

Test Example 2 Compounds of the present invention inhibit the proliferation of non-small cell lung cancer H358 cells

2.1 Test materials and instruments

2.2 Test system

Medium: 1640 high glucose medium + 10% FBS + 1% (penicillin/streptomycin); DMSO solution concentration of positive drug SHP099: 80000nM, 20000nM, 5000nM, 1250nM, 312.5nM, 78.13nM, 19.53nM, 4.88nM , 1.22nM and 0nM, wherein the compound concentration of 0nM is the blank group; the DMSO solution concentration of the test compound: 80000nM, 20000nM, 5000nM, 1250nM, 312.5nM, 78.13nM, 19.53nM, 4.88nM, 1.22nM and 0nM, where The compound concentration of 0nM group was the blank group.

2.3 Test steps

H358 cells were cultured in the culture medium and placed at 37°C, 5% CO ₂ culture conditions for culture. Take the H358 cells in the logarithmic growth phase, digest and resuspend the cells, count them, adjust the cell density and inoculate them into a transparent black plate at the bottom of 96 wells, inoculate 2,500 cells per well, and place them in an incubator at 37°C and 5% CO ₂ Cultivate for 72h. After 72 hours, 20 μL of positive drug or test compound solution was added to each well, and incubated at a constant temperature of 37° C., 5% CO ₂ and 90% relative humidity for 120 hours. After 120 hours, add 60 μL of detection reagent to each well

The 3D Cell Viability solution was placed on a shaker and incubated at room temperature for 30 minutes, and then the value of each well was read using a multifunctional enzyme-linked immunosorbent analyzer.

2.4 Data processing

2.5 Test results

The inhibitory activity of the compounds on H358 cell proliferation was determined according to the above method, and the results are shown in the following table.

化合物compound	IC50(nM)IC50(nM)
SHP099SHP099	631.22631.22
实施例1Example 1	6.706.70
实施例2Example 2	22.1022.10
实施例3Example 3	25.7525.75
实施例4Example 4	5.145.14
实施例6Example 6	14.9214.92
实施例8Example 8	7.177.17
实施例9Example 9	38.3638.36
实施例12Example 12	25.9625.96
实施例19Example 19	39.6339.63
实施例21Example 21	54.1154.11
实施例23Example 23	45.6645.66
实施例25Example 25	76.5276.52
实施例29Example 29	5.355.35
实施例30Example 30	3.903.90
实施例32Example 32	14.8214.82
实施例33Example 33	4.74.7
实施例34Example 34	50.2250.22
实施例35Example 35	16.4616.46
实施例52Example 52	39.2439.24
实施例59Example 59	470.24470.24

实施例60Example 60	224.3224.3
实施例61Example 61	72.8972.89
实施例63Example 63	216.9216.9
实施例64Example 64	22.8122.81
实施例65Example 65	29.129.1
实施例66Example 66	54.0954.09
实施例67Example 67	159.5159.5
实施例68Example 68	28.4328.43
实施例69Example 69	13.1813.18
实施例70Example 70	16.216.2
实施例71Example 71	8.518.51
实施例72Example 72	5.215.21
实施例73Example 73	1.981.98
实施例74Example 74	6.96.9
实施例75Example 75	11.3211.32
实施例76Example 76	55.655.6
实施例77Example 77	42.7142.71
实施例78Example 78	45.5245.52
实施例79Example 79	40.5140.51
实施例80Example 80	10.1810.18
实施例81Example 81	8.318.31
实施例83Example 83	3.153.15
实施例84Example 84	13.3313.33
实施例85Example 85	27.2627.26
实施例86Example 86	8.238.23
实施例87Example 87	732.7732.7
实施例88Example 88	30.3830.38
实施例89Example 89	48.4248.42
实施例90Example 90	32.8532.85
实施例91Example 91	32.2132.21
实施例92Example 92	30.2630.26
实施例93Example 93	159.36159.36
实施例94Example 94	54.0454.04
实施例95Example 95	63.9363.93
实施例96Example 96	578.5578.5
实施例97Example 97	30.3130.31
实施例98Example 98	27.2527.25
实施例99Example 99	39.7639.76
实施例100Example 100	16981698
实施例101Example 101	752.2752.2
实施例102Example 102	12651265
实施例103Example 103	28512851

Conclusion: In the non-small cell lung cancer H358 cell proliferation inhibition test, compared with the positive drug SHP099, the compound of the present invention exhibits better inhibitory activity.

Test Example 3 Compounds of the present invention inhibit test of hERG potassium ion channel

3.1 Test materials and instruments

试验材料和仪器Test Materials and Instruments	厂家或机构Manufacturer or organization	货号Item No.
CHO细胞CHO cells	B’SYS GmbHB’SYS GmbH	----

For other test materials and instruments, refer to the above test examples. Reagents without specific sources indicated are conventional reagents purchased in the market.

3.2 Test system

F-12 (HAM) medium: 10% FBS buffer, 100U/mL penicillin/streptomycin, 100μg/mL Hygronycin and 100μg/mL G418; NMDG 60 standard external solution: (use HCl to adjust the pH to 7.4, infiltrate Pressure is 289mOsm/kg) 80mM sodium chloride, 60mM NMDG, 4mM potassium chloride, 2mM calcium chloride, 1mM magnesium chloride, 5mM polydextrose, 10mM HEPES; NMDG 60 cell sealing solution: (use HCl to adjust the pH to 7.4 , osmotic pressure is 313mOsm/kg) 80mM sodium chloride, 60mM NMDG, 4mM potassium chloride, 10mM calcium chloride, 1mM magnesium chloride, 5mM polydextrose, 10mM HEPES; chip filling solution: (use NaOH to adjust the pH to 7.4, The osmotic pressure is 289mOsm/kg) 140mM sodium chloride, 4mM potassium chloride, 5mM polydextrose, 10mM HEPES; Standard standard external solution: (use NaOH to adjust the pH to 7.4, the osmotic pressure is 298mOsm/kg) 140mM sodium chloride , 4mM potassium chloride, 2mM calcium chloride, 1mM magnesium chloride, 5mM polydextrose, 10mM HEPES; KF110 intracellular fluid: (use KOH to adjust pH to 7.2, osmotic pressure greater than 280mOsm/kg) 10mM EGTA, 10mM HEPES, 10mM chlorine Potassium chloride, 10mM sodium chloride, 110mM potassium fluoride.

3.3 Test steps

Before the test, the compound was first diluted with DMSO to 3.33, 1.11 and 0.37 mM stock solutions in a serial dilution manner, and then diluted with extracellular fluid to the final dilution of the compound into the following concentrations (30, 10, 3.33, 1.11 and 0.37 μM ) for testing. The final concentration of DMSO in each concentration test solution was 0.1%. All stock and test solutions were sonicated and shaken for 5-10 minutes to ensure complete dissolution of the compound.

CHO cells were grown in the culture dish containing the above cell culture medium, and cultured at 37°C in an incubator containing 5% CO2. 24 to 48 hours before electrophysiological experiments, CHO cells were transferred to round glass slides placed in petri dishes, and grown in the same culture medium and culture conditions as above. The density of CHO cells on each circular slide needs to be such that most of the cells are independent and single.

In this experiment, a manual patch clamp system was used to record whole-cell currents. A circular glass slide with CHO cells grown on the surface was placed in the electrophysiological recording tank under an inverted microscope. The recording tank was continuously perfused with extracellular fluid (about 1 ml per minute). The experimental process used conventional whole-cell patch-clamp current recording technique. Unless otherwise specified, experiments were performed at normal room temperature (~25°C). Cells were clamped at a voltage of -90 mV. Cell voltage clamps were depolarized to +30mV to activate hERG potassium channels, and then clamped to -50mV after 5 seconds to eliminate inactivation and generate tail currents. The peak tail current was used as a measure of hERG current magnitude. After the hERG potassium current recorded in the above steps reaches a steady state under the continuous perfusion of extracellular fluid in the recording tank, the drug to be tested can be superimposed and perfused until the inhibitory effect of the drug on the hERG current reaches a steady state. Generally, the coincidence of the latest three consecutive current recording lines is used as the criterion for judging whether it is in a stable state. After reaching a steady state, extracellular fluid was used to perfuse and wash until the hERG current returned to the size before adding drugs. One or more drugs, or multiple concentrations of the same drug, can be tested on a cell, but extracellular fluid washing is required between different drugs.

3.4 Data processing

Refer to the formula of Test Example 2 to calculate the result.

3.5 Test results

The hERG potassium ion channel inhibitory activity of the compounds was determined according to the above method, and the results are shown in the following table.

compound

IC50(nM)

实施例5Example 5	9.29.2
实施例29Example 29	>30>30
实施例64Example 64	>30>30
实施例66Example 66	>30>30
实施例68Example 68	6.836.83
实施例69Example 69	19.1219.12
实施例70Example 70	4.234.23
实施例71Example 71	4.554.55
实施例75Example 75	4.284.28
实施例76Example 76	7.027.02
实施例77Example 77	16.4916.49
实施例78Example 78	6.136.13
实施例79Example 79	7.647.64
实施例94Example 94	4.654.65

Pharmacokinetic test of test example 4 compounds of the present invention in BALB/C mice

Take 45 BALB/C male mice (purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) for pharmacokinetic test, the drug configuration (solvent) is 5% DMSO+40% PEG400+55% NS, the drug is effective The components are the compounds in Examples 80 and 81 respectively, and the administration frequency and administration volume are single, oral administration (p.o.) 10mg/kg; intravenous injection (i.v.) 2mg/kg, grouping and administration are as follows.

Samples were collected after administration, sample collection time points: 15min, 30min, 1h, 2h, 4h, 8h, 12h, 24h; the distribution of sample collection points is shown in the table below.

组/时间group/time	15min15min	30min30min	1h1h	2h2 hours	4h4h	8h8 hours	12h12h	24h24 hours
11	√√			√√		√√
22		√√			√√		√√

33	the	the	√√	the	the	√√	the	√√
44	√√	the	the	√√	the	√√	the	the
55	the	√√	the	the	√√	the	√√	the
66	the	the	√√	the	the	√√	the	√√
77	√√	the	the	√√	the	√√	the	the
88	the	√√	the	the	√√	the	√√	the
99	the	the	√√	the	the	√√	the	√√
1010	√√	the	the	√√	the	√√	the	the
1111	the	√√	the	the	√√	the	√√	the
1212	the	the	√√	the	the	√√	the	√√

Whole blood was collected from the orbits of each dosing group, 3 mice/time point, the blood collection volume was 0.2ml/time point, EDTA anticoagulated whole blood, and centrifuged after the whole blood collection was completed to obtain the supernatant, the centrifugation speed was 4000rpm, and the centrifugation time was 10min. The results of the mouse pharmacokinetic parameters of the examples detected by the LCMS/MS method are as follows.

Compound 80

Compound 81

Experimental example 5 in vivo pharmacodynamics test of the compound of the present invention in NCI-H1975 subcutaneous xenograft model

NCI-H1975 human non-small cell lung adenocarcinoma cells were cultured in a single layer in vitro, and the culture conditions were 1640 medium plus 10% fetal bovine serum, cultured at 37°C and 5% CO ₂ . Routine digestion with trypsin-EDTA was performed twice a week for passaging. When the cells are in the exponential growth phase, the cells are collected, counted, and inoculated.

54 BALB/c female nude mice weighing about 15-18 g (purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) were selected for 6 weeks. Each mouse was subcutaneously inoculated with (2 x 10 ⁶ ) NCI-H1975 cells at the posterior scapula, and the cell suspension was composed of serum-free medium mixed with 50% medium gel. The drug treatment was started after the average tumor volume reached the appropriate size.

The experiments were started after the animals were fed for 3-7 days. Cages, feed and drinking water were changed twice a week. Temperature: 20-26°C, humidity: 40-70%, photoperiod: 12 hours with light, 12 hours with no light. The feed meets the food identification standards for experimental animals. The maximum content of pollutants is within the controllable range and the manufacturer is responsible for the routine inspection. Drinking water was autoclaved drinking water.

Animals were weighed before administration, and tumor volume was measured. Randomized grouping according to tumor volume (see table below).

Data analysis was performed with GraphPad Prism 8. p<0.05 considered significant difference. The tumor growth inhibition rate is calculated with the following formula: TGI (%)=[1-(Ti-T0)/(Vi-V0)]×100, wherein Ti is the average tumor volume of a certain administration group on a certain day, and T0 is given for this purpose. The average tumor volume of the drug group at the beginning of administration; Vi is the average tumor volume of the vehicle control group on a certain day (the same day as Ti), and V0 is the average tumor volume of the vehicle control group at the beginning of drug administration. If TGI (%)<40%, the drug is considered ineffective; if ≥40% and P<0.05, the drug is considered effective. After the end of the experiment, the tumor weight will be detected, and the T/C percentage will be calculated. T and C represent the tumor weight of the administration group and the vehicle control group, respectively. The results are shown in the following table, the compounds of Examples 80 and 81 of the present invention all had a significant inhibitory effect on tumor growth:

化合物compound	TGITGI	PP
实施例81Example 81	90％90%	<0.0001<0.0001
实施例80Example 80	91％91%	<0.0001<0.0001

The present invention has been described through the above-mentioned embodiments, but it should be understood that the above-mentioned embodiments are only for the purpose of illustration and description, and are not intended to limit the present invention to the scope of the described embodiments. In addition, those skilled in the art can understand that the present invention is not limited to the above-mentioned embodiments, and more variations and modifications can be made according to the teachings of the present invention, and these variations and modifications all fall within the claimed scope of the present invention. within the range. The protection scope of the present invention is defined by the appended claims and their equivalent scope.

Claims

A compound represented by formula Q or a pharmaceutically acceptable salt thereof,

Wherein, Z is CH or N;

Z 1 is CR 0 , N, O or S;

R 0 is selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -S(=O) 0-2 -C 1-6 alkane Base, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), -N (C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1 -6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, - OC 1-6 alkyl, C 2-6 alkynyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2. Substituents of -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ;

Ring A is selected from 5-8 membered hydrocarbon rings, 5-8 membered heterocyclic rings, 5-8 membered heteroaryl rings and 5-8 membered aromatic rings, and the hydrocarbon rings, heterocyclic rings, heteroaryl rings and aromatic rings are each Optionally replaced by one or more selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -S(=O) 0-2 -C 1-6 alkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -OC 1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH (C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl, C 3-6 cycloalkane and -C(O)N(C 1-6 alkyl) substituents substituted with each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl optionally further substituted by One or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkane group, -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl ) is replaced by a substituent of 2 ;

Ring B is a 5-8 membered heterocyclic ring or a 5-8 membered heteroaryl ring containing N atoms, and each of the heterocyclic ring and heteroaryl ring is optionally replaced by one or more members selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkenyl, C 2-6 alkynyl, -S(=O) 0-2 -C 1-6 alkyl, 3-10 membered hetero Cyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkane group, -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl ) 2 is substituted by a substituent, each of said alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl being optionally further selected from one or more of halogen, -OH, =O, - OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O) Substituents of NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ;

Ring C is selected from 5-8 membered aromatic rings or 5-8 membered heteroaromatic rings containing 1-3 heteroatoms independently selected from N, O, and S, and each of the aromatic rings or heteroaryl rings is optionally One or more selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl group, -CN, -NH 2 , - NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 Alkyl and -C (O) N (C 1-6 alkyl) substituent substitution, said alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl each optionally further By one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, - N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 substituent substitution;

Ring D is a 5-6-membered monocyclic aryl group, a 5-6-membered monocyclic heteroaryl group with 1-4 heteroatoms independently selected from N, O, and S, and 1-5 independently selected heteroatoms An 8-10 membered bicyclic heteroaryl group consisting of N, O, and S heteroatoms, or an 8-10 membered heterohydrocarbon ring and a heteroaryl ring having 1-5 heteroatoms independently selected from N, O, and S Member fused ring group;

Ring E is a C 4-8 cycloalkyl group, or a 4-8 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from N, O and S;

Each occurrence of R is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -S(=O) 0 -2 -C 1-6 alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl group, -NH 2 , -NH(C 1 -6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and - C(O)N(C 1-6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally selected from one or more halogen , -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl ) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 are substituted by substituents;

Each occurrence of R is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -S(=O) 0 -2 -C 1-6 alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl group, -NH 2 , -NH(C 1 -6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and - C(O)N(C 1-6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally selected from one or more halogen , -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl ) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 are substituted by substituents;

Each occurrence of R e is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -S(=O) 0- 2 -C 1-6 alkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -OC 1-6 alkyl, -NH 2 , -NH(C 1- 6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C (O)N(C 1-6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2. Substituents of -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ; or, two independent R e and the atoms connected to them on the ring E form a 3-12 membered monocyclic or polycyclic hydrocarbon ring, a 3-12 membered monocyclic or polycyclic heterocyclic ring, a 3-12 membered hydrocarbon ring and a heterocyclic ring The formed polycyclic ring system, the polycyclic ring system formed by the fusion of 3-6 membered hydrocarbon ring and 5-8 membered heteroaryl ring, the condensed form of 3-6 membered hydrocarbon ring and 5-8 membered aromatic ring A polycyclic ring system, a polycyclic ring system formed by the fusion of a 3-6-membered heterocycle and a 5-8-membered heteroaromatic ring, or a condensed 3-6-membered heterocycle and a 5-8-membered aromatic ring A polycyclic ring system, and each ring is optionally replaced by one or more selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, -S(=O ) 0-2 -C 1-6 alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl group, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl, C 3-6 cycloalkyl and -C (O) N (C 1-6 alkyl) substituent substitution, the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl Each is optionally further represented by one or more selected from halogen, -OH, =O, -OC1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) substituted by substituents of 2 ;

L 1 is a covalent bond, or is a C1-4 divalent saturated or unsaturated straight-chain or branched chain hydrocarbon group, or, the C1-4 divalent saturated or unsaturated straight-chain or branched chain hydrocarbon group One or two methylene groups in are independently selected from -O-, -C(O), -OC(O)-, -C(O)O-, -S-, -S(O)- and -S(O) 2 - the group formed after the group is replaced;

k is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;

m is 0, 1, 2, 3, 4 or 5; and

n is 0, 1, 2, 3, 4, 5, 6 or 7.
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring E is selected from:
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which has the structural formula Q 1 :

Wherein, R 3 and R 4 are each independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 Alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), - N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O ) NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 substituents; or the atoms to which R 3 and R 4 are attached Together form a 3-12 membered monocyclic or polycyclic hydrocarbon ring, a 3-12 membered monocyclic or polycyclic heterocyclic ring, a polycyclic ring system formed by a 3-12 membered hydrocarbon ring and a heterocyclic ring, a 3-6 membered A polycyclic ring system formed by the fusion of a hydrocarbon ring and a 5-8 membered heteroaromatic ring, a polycyclic ring system formed by the fusion of a 3-6-membered hydrocarbon ring and a 5-8-membered aromatic ring, a 3-6-membered heteroaromatic ring A polycyclic ring system formed by condensing a ring with a 5-8 membered heteroaromatic ring, or a polycyclic ring system formed by condensing a 3-6 membered heterocyclic ring with a 5-8 membered aromatic ring, and each ring Each is optionally replaced by one or more selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkane radical), -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl, C 3-6 cycloalkyl and -C(O )N(C 1-6 alkyl) substituted by a substituent, each of said alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl optionally further being selected from one or more Halogen, -OH, =O, -OC1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1 Substituents of -6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ;

k 1 is 1, 2 or 3;

k 2 is 1, 2 or 3.
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring D is selected from
The compound shown in formula I or its pharmaceutically acceptable salt:

Wherein, W 1 , W 2 , and W 3 are each independently selected from CR 1 and N;

X 2 , X 3 , and X 4 are each independently selected from CR 2 and N;

Z is CH or N;

X 1 is CR 8 or N;

R 8 is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 alkyl, 3-10 Membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), -N( C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1- 6 alkyl) 2 , the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl are each optionally replaced by one or more selected from halogen, -OH, =O, -OC 1- 6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O ) NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 substituents;

Ring A is a 5-8 membered hydrocarbon ring, a 5-8 membered heterocyclic ring, a 5-8 membered heteroaryl ring or a 5-8 membered aromatic ring, and each of the hydrocarbon ring, heterocyclic ring, heteroaryl ring and aromatic ring is any Optionally replaced by one or more selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 alkyl, 3- 10-membered heterocyclic group, 6-10-membered aryl group, 5-10-membered heteroaryl group, -OC 1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl) , -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl, C 3-6 cycloalkyl and -C(O)N (C 1-6 alkyl) substituted by a substituent, each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally further selected from one or more halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1- 6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 are substituted by substituents;

Ring B is a 5-8 membered heterocyclic ring or a 5-8 membered heteroaryl ring containing N atoms, and each of the heterocyclic ring and heteroaryl ring is optionally replaced by one or more members selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 alkyl, 3-10 membered heterocyclyl, 6-10 membered Aryl, 5-10 membered heteroaryl, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1 Substituents of -6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 , Each of said alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally further replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, - Substituents of C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ;

Each occurrence of R is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 Alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), - N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O ) NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 substituents;

Each occurrence of R is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 Alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), - N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O ) NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 substituents;

R 3 and R 4 are each independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 alkyl , 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), -N( C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1- 6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O)NH 2. Substituents of -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 ; or R 3 and R 4 form together with the atoms they are attached to 3-12 membered monocyclic or polycyclic hydrocarbon ring, 3-12 membered monocyclic or polycyclic heterocyclic ring, polycyclic ring system formed by 3-12 membered hydrocarbon ring and heterocyclic ring, 3-6 membered hydrocarbon ring A polycyclic ring system formed by condensing a 5-8-membered heteroaromatic ring, a polycyclic ring system formed by condensing a 3-6-membered hydrocarbon ring with a 5-8-membered aromatic ring, a 3-6-membered heterocyclic ring and A polycyclic ring system formed by condensing a 5-8 membered heteroaromatic ring, or a polycyclic ring system formed by condensing a 3-6 membered heterocyclic ring and a 5-8 membered aromatic ring, and each ring is independently Optionally replaced by one or more selected from halogen, -OH, =O, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 alkyl, 3- 10-membered heterocyclic group, 6-10-membered aryl group, 5-10-membered heteroaryl group, -OC 1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl) , -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl, C 3-6 cycloalkyl and -C(O)N (C 1-6 alkyl) substituted by a substituent, each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally further selected from one or more halogen, -OH, =O, -OC1-6 alkyl, -CN, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 Alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 are substituted by substituents;

m is 0, 1, 2 or 3; and

n is 0, 1, 2 or 3.
The formula I compound or its pharmaceutically acceptable salt according to claim 5, wherein

R 8 is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NO 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N( C 1-6 alkyl) 2 , the alkyl and cycloalkyl are optionally replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , - NO 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O) OC 1-6 alkyl and -C (O) N (C 1-6 alkyl) substituent substitution; and/or

The ring A is a 5-8 membered hydrocarbon ring, a 5-8 membered heterocyclic ring, a 5-8 membered heteroaryl ring or a 5-8 membered aromatic ring, and the hydrocarbon ring, heterocyclic ring, heteroaryl ring and aromatic ring Each is optionally replaced by one or more selected from halogen, -OH, =O, C 1-6 alkyl, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl ), -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl ) 2 is substituted by a substituent, the C 1-6 alkyl is optionally further selected from one or more halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 and - Substituent substitution of NH(C 1-6 alkyl); and/or

The ring B is a 5-8 membered heterocyclic ring or a 5-8 membered heteroaryl ring containing N atoms, and each of the heterocyclic ring and the heteroaryl ring is optionally replaced by one or more members selected from halogen, -OH, = Substituent substitution of O, C 1-6 alkyl, -OC 1-6 alkyl, -CN, -NH 2 and -NH(C 1-6 alkyl); and/or

Each occurrence of R 1 is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl ), -N(C 1-6 alkyl) 2 and C 3-6 cycloalkyl, wherein each of the C 1-6 alkyl and C 3-6 cycloalkyl is optionally selected from one or more Substituents from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 and -NH(C 1-6 alkyl); and/or

Each occurrence of R 2 is independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl ), -N(C 1-6 alkyl) 2 , -C(O)NH 2 , -COOH and -C(O)OC 1-6 alkyl, wherein the C 1-6 alkyl is optionally One or more substituents selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 and -NH(C 1-6 alkyl); and/or

R 3 and R 4 are each independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl) and -N(C 1-6 alkyl) 2 , wherein each of the C 1-6 alkyl groups is optionally replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN , -NH 2 and -NH (C 1-6 alkyl) substituent substitution; or R 3 and R 4 form a 3-6 membered monocyclic or polycyclic hydrocarbon ring together with the atoms they are connected to, 3-6 membered Monocyclic or polycyclic heterocyclic rings, polycyclic ring systems formed by 3-6 membered hydrocarbon rings and heterocyclic rings, bicyclic or more Ring system, a bicyclic or more ring system formed by condensing a 3-6-membered hydrocarbon ring with a 5-6-membered aromatic ring, a bicyclic ring formed by condensing a 3-6-membered heterocycle and a 5-6-membered heteroaromatic ring or more ring systems, or bicyclic or more ring systems formed by the fusion of 3-6 membered heterocycles and 5-6 membered aromatic rings.
The compound of formula I according to claim 5 or 6 or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-8 membered hydrocarbon ring, a 5-8 membered heterocyclic ring, or a 5-8 membered heteroaromatic ring, preferably Preferably, ring A is a 5-6 membered heterocyclic or heteroaromatic ring having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, preferably, ring A is having 1 or 2 independently A 5-6-membered heterocyclic or heteroaryl ring of heteroatoms selected from N and O, preferably ring A is a 5-8-membered hydrocarbon ring or a 5-8-membered heterocyclic ring, preferably, ring A has 1, 2 , 3 or 4 5-6 membered heterocyclic rings independently selected from N, O and S heteroatoms, further preferably, ring A is selected from partially unsaturated morpholine rings, imidazole rings, pyrazole rings, pyrrole rings, partially unsaturated pyrazolidine ring, partially unsaturated piperidine ring, partially unsaturated piperazine ring, partially unsaturated hexahydropyrimidine ring, partially unsaturated pyrrolidine ring and partially unsaturated imidazolidine ring; and / or

Ring A is optionally replaced by one or more members selected from halogen, -OH, =O, C 1-6 alkyl, -OC 1-6 alkyl, -CN, -NH 2 , -C(O)NH 2 , Substituents of -COOH, -C(O)N(C 1-6 alkyl) 2 , -C 1-6 alkylene-OH and halogenated C 1-6 alkyl, preferably, ring A is optionally is one or more selected from F, Cl, Br, -OH, =O, C 1-3 alkyl, -OC 1-3 alkyl, -CN, -NH 2 , -C(O)NH 2 , Substituents of -COOH, -C(O)N(C 1-3 alkyl) 2 , -C 1-3 alkylene-OH and halogenated C 1-3 alkyl, more preferably ring A is optionally is substituted with one or more substituents selected from F, =O, -CH 3 , -C(O)NH 2 , -COOH, -C(O)N(CH 3 ) 2 and -CH 2 -OH.
The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 5-7, wherein ring B is selected from 5, 6, 7 or 8-membered heterocycles containing N atoms, preferably, ring B is A partially unsaturated piperidine ring, a partially unsaturated piperazine ring, a partially unsaturated diazepane ring, a partially unsaturated imidazoline ring, a partially unsaturated morpholine ring, or a partially unsaturated pyrazole ring alkane ring, and the ring B is optionally replaced by one or more selected from halogen, -OH, =O, C 1-3 alkyl, -OC 1-3 alkyl, -CN, -NH 2 , and - NH (C 1-3 alkyl) substituent substitution.
A compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 5-8,

in
Part is the following chemical structure:

Wherein, W 4 is selected from C(R 5 ) 2 , O, and NR 5 ;

p is 0, 1 or 2;

q is 0 or 1;

Each occurrence of R is independently selected from H, halogen, -OH, =O, C 1-6 alkyl, -OC 1-6 alkyl, -CN, -NH 2 , -C(O)NH 2 , -COOH, -C(O)N(C 1-6 alkyl) 2 , -C 1-6 alkylene-OH, and halogenated C 1-6 alkyl; preferably, R 5 in each When present, each is independently selected from H, F, Cl, Br, -OH, =O, C 1-3 alkyl, -OC 1-3 alkyl, -CN, -NH 2 , -C(O)NH 2 , -COOH, -C(O)N(C 1-3 alkyl) 2 , -C 1-3 alkylene-OH, and halogenated C 1-3 alkyl; more preferably, R 5 in each each occurrence is independently selected from H, -F, =O, -CH3 , -C(O) NH2 , -COOH, -C(O)N( CH3 ) 2 , and -CH2 - OH; and

f is 0, 1, 2, 3, 4 or 5.
The compound of formula I according to claim 9 or a pharmaceutically acceptable salt thereof,

in,
Partially selected from the following chemical structures:

wherein R and f are as defined in claim 9.
A compound of formula I according to any one of claims 5-10, or a pharmaceutically acceptable salt thereof, wherein R is each independently selected from H, halogen, -OH, -CN, C at each occurrence -3 alkyl, -OC 1-3 alkyl, -NH 2 , halogenated C 1-3 alkyl and C 3-4 cycloalkyl; preferably, each occurrence of R is independently selected from H , -CN, -CH 3 and cyclopropyl.
The compound of formula I according to any one of claims 5-11, or a pharmaceutically acceptable salt thereof, wherein R 2 are each independently selected from H, halogen, -OH, -CN, C 1- 3 alkyl, -OC 1-3 alkyl, -NH 2 , -C(O)NH 2 , -COOH, -C(O)OC 1-3 alkyl, -C 1-3 alkylene-OH and Halogenated C 1-3 alkyl; preferably, each occurrence of R is independently selected from H, halogen, -OH, -CN, C 1-3 alkyl, -C(O)NH 2 and - C 1-3 alkylene-OH; also preferably, each occurrence of R 2 is independently selected from H, F, -OH, -CN, -CH 3 , -C(O)NH 2 and -CH 2 -OH.
The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 5-12, wherein:

R 3 and R 4 are each independently selected from H, halogen, -OH, -CN, C 1-3 alkyl, -OC 1-3 alkyl, -C 1-3 alkylene -NH 2 , -NH 2 , -NH(C 1-3 alkyl) and -N(C 1-3 alkyl) 2 ; preferably, R 3 and R 4 are each independently selected from H, halogen, -OH, -CN, C 1- 3 alkyl, -C 1-3 alkylene -NH 2 and -NH 2 ; also preferably, R 3 and R 4 are each independently selected from H, -F, -OH, -CH 2 -NH 2 and - NH2 ; or

R 3 and R 4 form a 3, 4, 5 or 6-membered monocyclic hydrocarbon ring, or a 3, 4, 5 or 6-membered monocyclic heterocyclic ring together with the atoms they are connected to, preferably, R 3 and R 4 are combined with The atoms they connect together form a 5-6 membered monocyclic heterocyclic ring having 1, 2, 3 or 4 heteroatoms selected from N, O or S, wherein the hydrocarbon ring and heterocyclic ring are each optionally replaced by one or Multiple selected from halogen, -OH, -CN, C 1-6 alkyl, -OC 1-6 alkyl, -NH 2 , -C(O)N(C 1-6 alkyl) 2 , -C 1 -6 alkylene-OH and halogenated C 1-6 alkyl substituents are preferably substituted by one or more selected from F, Cl, Br, -OH, -CN, C 1-3 alkyl, - Substituents of OC 1-3 alkyl, -NH 2 , -C 1-3 alkylene-OH, -C(O)N(C 1-3 alkyl) 2 and halogenated C 1-3 alkyl , preferably one or more selected from F, Cl, Br, -OH, -CN, -CH 3 , -OCH 3 , -NH 2 , -CH 2 -OH, -C(O)N(CH 3 ) 2 and the substituents of -CF 3 are substituted; more preferably,
Part is the following chemical structure:
Wherein, Y 1 is selected from O, S, C(R 6 ) 2 , or NR 6 , and each occurrence of R 6 is independently selected from H, halogen, -OH, -CN, C 1-3 alkyl, -OC 1-3 alkyl, -NH 2 and halogenated C 1-3 alkyl, preferably, each occurrence of R is independently selected from H, halogen, -OH, -CN, -CH 3 , - OCH 3 , -NH 2 , -CH 2 -OH, -C(O)N(CH 3 ) 2 and -CF 3 , g is 0, 1, 2, 3, 4, 5 or 6; or

R 3 and R 4 together with the atoms they connect form a bicyclic ring system formed by condensing a 5-6 membered hydrocarbon ring with a 5-6 membered heteroaromatic ring, a 5-6 membered hydrocarbon ring and a 5-6 membered aromatic ring A bicyclic ring system formed by fusion, a bicyclic system formed by the fusion of a 5-6 membered heterocyclic ring and a 5-6 membered heteroaryl ring, or a fused 5-6 membered heterocyclic ring and a 5-6 membered aromatic ring Bicyclic ring system, wherein said hydrocarbon ring, heterocycle, heteroaromatic ring and aromatic ring are each optionally replaced by one or more selected from halogen, -OH, =O, C 1-6 alkyl, -OC 1-6 alkane radical, -CN, -NH 2 , -C(O)NH 2 , -COOH, -C(O)N(C 1-6 alkyl) 2 , -C 1-6 alkylene-OH, and halo Substituents of C 1-6 alkyl are preferably substituted by one or more selected from halogen, -OH, C 1-3 alkyl, -OC 1-3 alkyl, -CN, -NH 2 , -C( Substituents of O)NH 2 , -C 1-3 alkylene-OH, -C(O)N(C 1-3 alkyl) 2 , and halogenated C 1-3 alkyl are preferably substituted by one or more selected from F, Cl, Br, -OH, -CN, -CH 3 , -OCH 3 , -NH 2 , -CH 2 -OH, -C(O)N(CH 3 ) 2 and -CF 3 Substituents are substituted; also preferably,
part is as follows

Chemical structure:
Wherein, Y 2 is selected from O, S, CH 2 , and NH, preferably, selected from O, and CH 2 ; Y 3 , Y 4 , Y 5 , and Y 6 are each independently selected from CR 7 and N, preferably Y 3 , Y 4 , Y 5 , and Y 6 are each independently selected from CH and N; each occurrence of R 7 is independently selected from H, halogen, -OH, C 1-3 alkyl, -OC 1 -3 alkyl, -CN, -NH 2 , -C(O)NH 2 , -C 1-3 alkylene-OH, -C(O)N(C 1-3 alkyl) 2 , and halo C 1-3 alkyl, preferably each occurrence of R 7 is independently selected from H, F, Cl, Br, -OH, -CN, -CH 3 , -OCH 3 , -NH 2 , -CH 2 - OH, -C(O)N( CH3 ) 2 and -CF3 ; and h is 0, 1, 2, 3 or 4.
The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 5-13, wherein the compound of formula I has the structure of formula II:

Wherein, W 1 , W 2 , W 3 , X 1 , X 2 , X 3 , X 4 , Z, m and n are as defined in claim 5, R 1 and R 2 are as defined in claim 5, 6, 11, or 12, W 4 , R 5 , p, q and f are as defined in claim 9, Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are as defined in claim 13;

Preferably, both X1 and X2 are N, and/or p is 1 or 2, and q is 0 or 1.
A compound or a pharmaceutically acceptable salt thereof, the compound being selected from:
The compound or a pharmaceutically acceptable salt thereof as claimed in claim 15, which is selected from the group consisting of:
An intermediate for the preparation of the compound according to any one of claims 1-16, or a salt thereof, selected from:

Wherein, R 9 and R 10 are each independently selected from H, halogen, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, -S(=O) 0-2 -C 1-6 Alkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OC 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), - N(C 1-6 alkyl) 2 , C 3-6 cycloalkyl, -C(O)NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 , wherein each of the alkyl, alkenyl, heterocyclyl, aryl, heteroaryl and cycloalkyl is optionally replaced by one or more selected from halogen, -OH, =O, -OC 1-6 alkyl, -CN, -NH 2 , -NH(C 1-6 alkyl), C 3-6 cycloalkyl, -N(C 1-6 alkyl) 2 , -C(O )NH 2 , -COOH, -C(O)OC 1-6 alkyl and -C(O)N(C 1-6 alkyl) 2 are substituted.
The intermediate as claimed in claim 17, or a salt thereof, selected from:
The preparation method of the compound whose structural formula is shown as formula II or its pharmaceutically acceptable salt:

Wherein, W 1 , W 2 , W 3 , Z, m and n are as defined in claim 1, R 1 and R 2 are as defined in claim 5, 6, 11, or 15, W 4 , R 5 , p, q and f are as defined in claim 5, Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are as defined in claim 13, X 1 , X 2 , X 3 , and X 4 are all N, n is 0,

It is characterized in that, comprising, using the first key intermediate corresponding to the structure of part A, the second key intermediate corresponding to the structure of part B, and the third key intermediate corresponding to the structure of part C to perform substitution reactions to prepare the formula II the indicated compounds.
The preparation method according to claim 19, wherein the structural formula of the third key intermediate is shown in formula III:

wherein R 9 and R 10 are as defined in claim 17.
The preparation method according to claim 20, wherein the third key intermediate is selected from:
The preparation method according to any one of claims 19-21, wherein the first key intermediate is selected from:
The preparation method according to claims 19-21, wherein the second key intermediate is selected from:
The preparation method according to claims 19-23, characterized in that it comprises:

(A) When the compound or its pharmaceutically acceptable salt has the structural formula
, prepared by a method comprising the following steps:

(a1) compound
Dissolve in DCM, add trifluoroacetic acid, stir for 2 hours, neutralize the reaction solution with saturated sodium bicarbonate, extract with dichloromethane, combine the organic phases, concentrate under reduced pressure, and purify the compound

(a2) will
Dissolve in DMF, add triethylamine and compound
Stir at 50°C, dilute the reaction mixture with saturated brine, extract, dry the organic layer with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the compound

(a3) compound
and compounds
Dissolve in toluene, add Pd 2 (dba) 3 , RuPhos and Cs 2 CO 3 under nitrogen protection, stir at 100°C for 16 hours, cool to room temperature and concentrate under reduced pressure, and purify the residue by preparative TLC (DCM:MeOH=10:1) compound
compound
Dissolved in HCl/Dioxane and methanol, stirred for 1 hour, concentrated under reduced pressure, and purified to obtain

And/or, (B) when the compound or a pharmaceutically acceptable salt thereof has the formula
, prepared by a method comprising the following steps:

(b1) compound
Dissolve in dioxane, add compound under nitrogen protection
Pd 2 (dba) 3 , Xantphos and Cs 2 CO 3 , stirred overnight at 100°C, diluted with EA, filtered, concentrated the filtrate, and purified the compound

(b2) compound
Dissolve in THF/H 2 O/MeOH, add palladium/carbon and ammonium formate, stir overnight at 50°C, dilute the reaction solution with EA, filter, concentrate the filtrate, and purify the compound

(b3) compound
Dissolve in dichloromethane (DCM), add p-toluenesulfonyl chloride and N,N-diisopropylethylamine (DIEA), stir at room temperature for 1.5 hours, concentrate, and purify the compound

(b4) compound
Dissolve in DMF, add triethylamine (TEA) and compound
Stir overnight at 50°C, dilute the reaction solution with EA, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify the compound

(b5) compound
Dissolved in HCl/dioxane, stirred at room temperature for 1 hour, concentrated under reduced pressure, and purified to obtain

And/or, (C) when the compound or a pharmaceutically acceptable salt thereof has the structural formula
, prepared by a method comprising the following steps:

(c1) compound
and compounds
Dissolve in toluene, under nitrogen protection, add Pd 2 (dba) 3 , Ruphos and Cs 2 CO 3 , stir at 110°C, concentrate the reaction solution under reduced pressure, and purify the compound

(c2) compound
Dissolved in NH 3 /MeOH, stirred at 70°C for 4 hours, concentrated to give the compound

(c3) compound
Dissolved in HCl/dioxane, stirred at room temperature for 1 hour, concentrated under reduced pressure, and purified to obtain

And/or, (D) when the compound or a pharmaceutically acceptable salt thereof has the formula
, prepared by a method comprising the following steps:

(d1) the intermediate
Dissolve in MeOH/DMSO, add silver nitrate and trifluoroacetic acid, stir at 70°C for 1 hour, add (NH 4 ) 2 S 2 O 8 and H 2 O, stir at 70°C for 2 hours, dilute the reaction solution with EA, wash with NaOH aqueous solution , the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified to obtain the compound

(d2) compound
Dissolve in DMF, add triethylamine and compound
Stir at 50°C, dilute the reaction solution with EA, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify the compound

(d3) compound
and compounds
Dissolve in toluene, add Pd 2 (dba) 3 , RuPhos and Cs 2 CO 3 under nitrogen protection, stir at 100°C for 16 hours, cool to room temperature and concentrate under reduced pressure to obtain compound

(d4) compound
Dissolved in HCl/Dioxane and methanol, stirred at room temperature for 1 hour, concentrated under reduced pressure, and purified to obtain

And/or, (E) when the compound or a pharmaceutically acceptable salt thereof has the formula
, prepared by a method comprising the following steps:

(e1) Dissolve 6-chloro-1H-pyrazolo[3,4-b]pyridine in dimethylformamide (DMF), add (N-iodosuccinimide)NIS, stir at 80°C For 4 hours, the reaction solution was diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the compound

(e2) compound
Dissolve in DCM, add dihexyl phthalate (DHP) and p-toluenesulfonic acid, stir at room temperature for 3 hours, concentrate under reduced pressure, and purify the compound

(e3) compound
Dissolve in DMF, add compound
and triethylamine, stirred at 50°C for 12 hours, diluted with water, extracted with EA, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified to obtain the compound

(e4) compound
and compounds
Dissolve in toluene, add Pd 2 (dba) 3 , RuPhos and Cs 2 CO 3 under nitrogen protection, stir at 100°C for 16 hours, cool to room temperature and concentrate under reduced pressure to obtain compound

(e5) compound
Dissolved in HCl/Dioxane (Dioxane) and methanol, stirred at room temperature for 1 hour, concentrated under reduced pressure, and purified to obtain
A pharmaceutical composition comprising the compound according to any one of claims 1-16 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.
Use of the compound according to any one of claims 1-16 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 25 in the preparation of a medicament for preventing or treating a disease mediated by SHP2 activity;

Preferably, the disease mediated by SHP2 activity is a disease that is sensitive or responsive to SHP2 inhibition;

Also preferably, the disease mediated by SHP2 activity is non-small cell lung cancer.
A method for preventing or treating a disease mediated by SHP2 activity, comprising administering to a subject in need an effective amount of the compound of any one of claims 1-16 or a pharmaceutically acceptable salt thereof, or the subject the pharmaceutical composition described in claim 25;

Preferably, the disease mediated by SHP2 activity is a disease that is sensitive or responsive to SHP2 inhibition;

Also preferably, the disease mediated by SHP2 activity is non-small cell lung cancer.
The compound according to any one of claims 1-16 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 25, which is used for preventing or treating diseases mediated by SHP2 activity;

Preferably, the disease mediated by SHP2 activity is a disease that is sensitive or responsive to SHP2 inhibition;

Also preferably, the disease mediated by SHP2 activity is non-small cell lung cancer.