CN118206550A - SHP2 inhibitor and application thereof - Google Patents

Abstract

The invention belongs to the technical field of medicines, and relates to an SHP2 inhibitor and application thereof. In particular to a compound shown in a formula (I), an isomer, a deuterated compound or a pharmaceutically acceptable salt thereof and application thereof in preparing medicaments for treating and/or preventing diseases related to abnormal SHP2 activity. Wherein each substituent in the formula (I) is as defined in the specification.

Description

SHP2 inhibitors and their applications

The present invention claims priority to a prior application filed with the State Intellectual Property Office of China on December 15, 2022, with patent application number 2022116160838 and invention name “SHP2 inhibitors and their applications”. The entire text of the above-mentioned prior application is incorporated into the present invention by reference.

Technical Field

The present invention belongs to the field of medical technology and relates to a protein tyrosine phosphatase 2 (SHP2) inhibitor represented by formula (I), its isomers, deuterated compounds or pharmaceutically acceptable salts thereof and applications thereof.

Background Art

Protein tyrosine phosphatase non-receptor type 11 (PTPN11) is a proto-oncogene that encodes protein tyrosine phosphatase 2 (SHP2), which is highly expressed in a variety of tumor tissues and is closely related to the occurrence, development and prognosis of a variety of tumors. SHP2 is a dephosphorylating enzyme that participates in multiple signaling pathways including Ras-Raf-MEK-ERK, JAK-STAT, PI3K-AKT-mTOR and PD-1/PD-L1 pathways, and can therefore regulate classical cell survival-related pathways and specific immune regulatory pathways. Dysregulation of SHP2 is associated with abnormal cell proliferation, differentiation, adhesion migration and apoptosis, making SHP2 a promising therapeutic target for cancer treatment.

The full length of SHP2 consists of two SH2 domains (N-SH2 and C-SH2), a conserved PTP domain and a C-terminal tail, with 593 amino acids and a molecular weight of 68kDa. In the inactive state, SHP2 is in a self-inhibitory state, N-SH2 binds to PTP to form a ring structure, thereby hindering the binding of PTP to the substrate, so that the enzyme catalytic activity is inhibited; when the tyrosine of the upstream receptor protein is phosphorylated, N-SH2 binds to it, releasing the PTP catalytic domain and exerting phosphatase activity.

Phosphatase inhibitors targeting SHP2 have been shown to have preliminary efficacy and safety, and are expected to become a new cancer treatment, an important supplement to traditional therapies that are resistant, intolerant, and have poor efficacy.

Summary of the invention

The purpose of the present invention is to provide a protein tyrosine phosphatase SHP2 inhibitor.

Another object of the present invention is to provide the use of the protein tyrosine phosphatase inhibitor in the preparation of a drug for preventing or treating SHP2 phosphatase-related diseases. To achieve the object of the present invention, the technical solution of the present invention is as follows:

The compound represented by formula (I) of the present invention, its isomer, deuterated compound or pharmaceutically acceptable salt thereof,

Ring A is selected from 3-8 membered heterocyclic group, 6-13 membered bicyclic fused heterocyclic group, 8-21 membered polycyclic fused heterocyclic group, wherein the 3-8 membered heterocyclic group, 6-13 membered bicyclic fused heterocyclic group, 8-21 membered polycyclic fused heterocyclic group are unsubstituted or are independently substituted by C _1-6 alkyl;

each R ₁ is independently selected from hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, 3-8 membered monocyclic group, 6-13 membered bicyclic condensed ring group, 8-21 membered polycyclic condensed ring group, 5-7 membered heteroaryl, -NR ₂ R ₃ , -S(O)R ₂ , -S(O)NR ₂ R ₃ , -NR ₂ S(O)NR ₂ R ₃ , -NR ₂ S(O)R ₃ , -S(O) ₂ R ₂ , -S(O) ₂ NR ₂ R ₃ , -NR ₂ S(O) ₂ R ₃ , -NR 2 S(O) 2 R 3 , -NR ₂ S(O) ₂ NR ₂ R ₃ , -C(O)R ₂ , -C(O)NR ₂ R ₃ , -NR ₃ C(O)R ₃ , -NR ₃ C(O)NR ₂ R ₃ , -CO ₂ R ₃ , the C _1-6 alkyl, halogenated C _1-6 alkyl, 3-8 membered monocyclic group, 6-13 membered bicyclic condensed ring group, 8-21 membered polycyclic condensed ring group, 5-7 membered heteroaryl group is unsubstituted or substituted by one to three groups independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, carboxyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halogenated C _1-6 alkoxy, 3-8 membered heterocyclic group, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 5-7 membered heteroaryl, phenyl;

q is 0, 1, 2, or 3;

Cy3 is selected from 3-8 membered heterocyclyl, 6-13 membered bicyclic condensed heterocyclyl, 5-7 membered heteroaryl, 8-13 membered bicyclic condensed heteroaryl, phenyl, 8-13 membered bicyclic condensed aryl, wherein the 3-8 membered heterocyclyl, 6-13 membered bicyclic condensed heterocyclyl, 5-7 membered heteroaryl, 8-13 membered bicyclic condensed heteroaryl, phenyl, 8-13 membered bicyclic condensed aryl is unsubstituted or substituted with 1-3 R _a3 ;

Each R _a3 is independently selected from hydrogen, hydroxy, cyano, nitro, halogen, carboxyl, amino, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, C _1-6 alkylcarbonyl, aminocarbonyl, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl, hydroxyC _1-6 alkyl;

Cy2 is selected from 3-8 membered heterocyclyl, 6-13 membered bicyclic fused heterocyclyl, 8-21 membered polycyclic fused heterocyclyl, 5-7 membered heteroaryl, phenyl, 8-13 membered bicyclic fused heteroaryl and 8-13 membered bicyclic fused aryl, wherein the 3-8 membered heterocyclyl, 6-13 membered bicyclic fused heterocyclyl, 8-21 membered polycyclic fused heterocyclyl, 5-7 membered heteroaryl, phenyl, 8-13 membered bicyclic fused heteroaryl and 8-13 membered bicyclic fused aryl are unsubstituted or substituted with 1-3 R _a2 ;

each _Ra2 is independently selected from hydrogen, hydroxy, carboxyl, halogen, nitro, cyano, _C1-6 alkyl, halogenated _C1-6 alkyl, _C2-8 alkenyl, C2-8 alkynyl, _3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, _-OR4 , _-NR4R5 , _-SR4 , -S(O) _R4 , _-S (O)NR4R5, -NR4S(O) _NR4R5 , _-NR4S (O) _R5 , -S(O _{) 2R4 , -S} ( _O ) _2NR4R5 , _-NR4S ( _O ) _2R5 , _{-NR4S (} O _{) 2NR4R5} , _-C (O _{)R4 , -C} ( _O ) _NR4R5 , -NR ₄ C(O)R ₅ , -NR ₄ C(O)NR ₄ R ₅ , -CO ₂ R ₄ , wherein the C _1-6 alkyl, C _2-8 alkenyl, C 2-8 alkynyl, _3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl is unsubstituted or substituted with one or more groups independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, carboxyl, C _1-6 alkyl, halo-substituted C _1-6 alkyl, C _1-6 alkoxy, halo-substituted C _1-6 alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkylamino, (C _1-6 alkyl) _2amino , C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkylcarbonyl, aminocarbonyl, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) _{2aminocarbonyl} ;

R ₂ , R ₃ , R ₄ and R ₅ are independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, nitro, carboxyl, amino, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halogenated C _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic fused ring cycloalkyl, 6-13 bicyclic fused ring cycloalkenyl, 6-13 membered bicyclic fused ring heterocyclyl, the amino, C _1-6 alkyl, halogenated C _{1-6 alkyl, C 1-6 alkoxy} , C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halogenated C _1-6 alkoxy, C _{2-8 alkenyl, C 2-8} alkynyl, _2-8 membered alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic fused ring cycloalkyl, 6-13 bicyclic fused ring cycloalkenyl, 6-13 membered bicyclic fused ring heterocyclyl is unsubstituted or substituted with one or more groups independently selected from hydrogen, hydroxy, carboxyl, amino, nitro, cyano, C _1-6 alkyl, C _1-6 alkylamino, (C _1-6 alkyl) _2amino , C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkylcarbonyl, aminocarbonyl, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) _{2aminocarbonyl} , 3-8 membered heterocyclyl;

m and n are independently 0 or 1;

L is selected from a bond, C _2-8 alkynyl, -C(O)NH-, -CH ₂ -, -O-, C _2-8 alkynyl-C _1-6 alkyl, C _2-8 alkynyl-C _1-6 alkyl-carbonyl, C _2-8 alkenyl;

B is selected from C _1-6 alkylamino, (C _1-6 alkyl) _2amino or Cy1;

Cy1 is selected from 3-8 membered heterocyclyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 5-7 membered heteroaryl, phenyl, 8-13 membered bicyclic fused ring heteroaryl or 8-13 membered bicyclic fused ring heterocyclyl, wherein the 3-8 membered heterocyclyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 5-7 membered heteroaryl, phenyl, 8-13 membered bicyclic fused ring heteroaryl or 8-13 membered bicyclic fused ring heterocyclyl is unsubstituted or substituted by one to three groups independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, carboxyl, C _1-6 alkyl, halo-substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halo-substituted C _1-6 alkoxy, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl.

Another embodiment of the present invention relates to a compound represented by formula (I), an isomer, a deuterated compound or a pharmaceutically acceptable salt thereof,

Ring A is selected from 3-8 membered heterocyclic group, 6-13 membered bicyclic fused heterocyclic group, 8-21 membered polycyclic fused heterocyclic group, wherein the 3-8 membered heterocyclic group, 6-13 membered bicyclic fused heterocyclic group, 8-21 membered polycyclic fused heterocyclic group are unsubstituted or are independently substituted by C _1-6 alkyl;

each R ₁ is independently selected from hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, 3-8 membered monocyclic group, 6-13 membered bicyclic condensed ring group, 8-21 membered polycyclic condensed ring group, 5-7 membered heteroaryl, -NR ₂ R ₃ , -S(O)R ₂ , -S(O)NR ₂ R ₃ , -NR ₂ S(O)NR ₂ R ₃ , -NR ₂ S(O)R ₃ , -S(O) ₂ R ₂ , -S(O) ₂ NR ₂ R ₃ , -NR ₂ S(O) ₂ R ₃ , -NR ₂ S(O) ₂ NR ₂ R ₃ , -C(O)R ₂ , -C(O)NR ₂ R ₃ , -NR ₃ C(O)R ₃ , -NR ₃ C(O)NR ₂ R ₃ , -CO ₂ R ₃ , the C _1-6 alkyl, halogenated C _1-6 alkyl, 3-8 membered monocyclic group, 6-13 membered bicyclic condensed ring group, 8-21 membered polycyclic condensed ring group, 5-7 membered heteroaryl group is unsubstituted or substituted by one to three groups independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, carboxyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halogenated C _1-6 alkoxy, 3-8 membered heterocyclic group, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 5-7 membered heteroaryl, phenyl;

q is 0, 1, 2, or 3;

Cy3 is selected from 3-8 membered heterocyclyl, 6-13 membered bicyclic condensed heterocyclyl, 5-7 membered heteroaryl, 8-13 membered bicyclic condensed heteroaryl, phenyl, 8-13 membered bicyclic condensed aryl, wherein the 3-8 membered heterocyclyl, 6-13 membered bicyclic condensed heterocyclyl, 5-7 membered heteroaryl, 8-13 membered bicyclic condensed heteroaryl, phenyl, 8-13 membered bicyclic condensed aryl is unsubstituted or substituted with 1-3 R _a3 ;

Each R _a3 is independently selected from hydrogen, hydroxy, cyano, nitro, halogen, carboxyl, amino, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, C _1-6 alkylcarbonyl, aminocarbonyl, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl, hydroxyC _1-6 alkyl;

Cy2 is selected from 3-8 membered heterocyclyl, 6-13 membered bicyclic fused heterocyclyl, 8-21 membered polycyclic fused heterocyclyl, 5-7 membered heteroaryl, phenyl, 8-13 membered bicyclic fused heteroaryl and 8-13 membered bicyclic fused aryl, wherein the 3-8 membered heterocyclyl, 6-13 membered bicyclic fused heterocyclyl, 8-21 membered polycyclic fused heterocyclyl, 5-7 membered heteroaryl, phenyl, 8-13 membered bicyclic fused heteroaryl and 8-13 membered bicyclic fused aryl are unsubstituted or substituted with 1-3 R _a2 ;

each _Ra2 is independently selected from hydrogen, hydroxy, carboxyl, halogen, nitro, cyano, _C1-6 alkyl, halogenated _C1-6 alkyl, _C2-8 alkenyl, C2-8 alkynyl, _3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, _-OR4 , _-NR4R5 , _-SR4 , -S(O) _R4 , _-S (O)NR4R5, -NR4S(O) _NR4R5 , _-NR4S (O) _R5 , -S(O _{) 2R4 , -S} ( _O ) _2NR4R5 , _-NR4S ( _O ) _2R5 , -NR4S _{( O ) 2NR4R5} , _-C (O _{)R4 , -C} ( _O ) _NR4R5 , -NR ₄ C(O)R ₅ , -NR ₄ C(O)NR ₄ R ₅ , -CO ₂ R ₄ , wherein the C _1-6 alkyl, C _2-8 alkenyl, C 2-8 alkynyl, _3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl is unsubstituted or substituted with one or more groups independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, carboxyl, C _1-6 alkyl, halo-substituted C _1-6 alkyl, C _1-6 alkoxy, halo-substituted C _1-6 alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkylamino, (C _1-6 alkyl) _2amino , C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkylcarbonyl, aminocarbonyl, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) _{2aminocarbonyl} ;

R ₂ , R ₃ , R ₄ and R ₅ are independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, nitro, carboxyl, amino, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halogenated C _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic fused ring cycloalkyl, 6-13 bicyclic fused ring cycloalkenyl, 6-13 membered bicyclic fused ring heterocyclyl, the amino, C _1-6 alkyl, halogenated C _{1-6 alkyl, C 1-6 alkoxy} , C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halogenated C _1-6 alkoxy, C _{2-8 alkenyl, C 2-8} alkynyl, _2-8 membered alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic fused ring cycloalkyl, 6-13 bicyclic fused ring cycloalkenyl, 6-13 membered bicyclic fused ring heterocyclyl is unsubstituted or substituted with one or more groups independently selected from hydrogen, hydroxy, carboxyl, amino, nitro, cyano, C _1-6 alkyl, C _1-6 alkylamino, (C _1-6 alkyl) _2amino , C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkylcarbonyl, aminocarbonyl, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) _{2aminocarbonyl} , 3-8 membered heterocyclyl;

m and n are independently 0 or 1;

L is selected from a bond, C _2-8 alkynyl, -C(O)NH-, -CH ₂ -, -O-, C _2-8 alkynyl-C _1-6 alkyl, C _2-8 alkynyl-C _1-6 alkyl-carbonyl, C _2-8 alkenyl;

B is selected from C _1-6 alkylamino, (C _1-6 alkyl) _2amino or Cy1;

Cy1 is selected from 3-8 membered heterocyclyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 5-7 membered heteroaryl, phenyl, 8-13 membered bicyclic fused ring heteroaryl or 8-13 membered bicyclic fused ring heterocyclyl, wherein the 3-8 membered heterocyclyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 5-7 membered heteroaryl, phenyl, 8-13 membered bicyclic fused ring heteroaryl or 8-13 membered bicyclic fused ring heterocyclyl is unsubstituted or substituted with one to three groups independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, carboxyl, C _1-6 alkyl, halo-substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halo-substituted C _1-6 alkoxy, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl;

Provided that, (i) when L is alkynyl, n is 1, for Cy3 Cy2 When m is 1 and B is Cy1, Cy1 is not

(ii) when L is an alkynyl group, n is 1, for Cy3 Cy2 When m is 1 and B is Cy1, Cy1 is not

Another embodiment of the present invention relates to a compound represented by formula (I), an isomer, a deuterated compound or a pharmaceutically acceptable salt thereof,

Ring A is selected from a 5-6 membered nitrogen-containing heterocyclic group, a 6-12 membered nitrogen-containing bicyclic spiro heterocyclic group, and a 10-16 membered nitrogen-containing polycyclic spiro heterocyclic group, wherein the 5-6 membered nitrogen-containing heterocyclic group, the 6-12 membered nitrogen-containing bicyclic spiro heterocyclic group, and the 10-16 membered nitrogen-containing polycyclic spiro heterocyclic group are unsubstituted or are independently substituted by C _1-6 alkyl;

each R ₁ is independently selected from hydrogen, C _1-6 alkyl, 5-6 membered nitrogen-containing heteroaryl, -S(O) ₂ R ₂ , -C(O)R ₂ , -C(O)NR ₂ R ₃ , -CO ₂ R ₃ , said C _1-6 alkyl, 5-6 membered nitrogen-containing heteroaryl is unsubstituted or substituted by one to three groups independently selected from hydrogen, halogen, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl and 3-8 membered nitrogen-containing heterocyclic group;

q is 0 or 1;

Cy3 is selected from a 5-6-membered nitrogen-containing heterocyclic group, a 5-6-membered nitrogen-containing heteroaryl group, an 8-13-membered nitrogen-containing bicyclic heteroaryl group or a phenyl group; the 5-6-membered nitrogen-containing heterocyclic group, the 5-6-membered nitrogen-containing heteroaryl group, the 8-13-membered nitrogen-containing bicyclic heteroaryl group or the phenyl group is unsubstituted or substituted with 1-3 R _a3 ;

Each R _a3 is independently selected from hydrogen, amino, C _1-6 alkyl, hydroxy C _1-6 alkyl;

Cy2 is selected from 5-6 membered nitrogen-containing heteroaryl, phenyl, 8-13 membered nitrogen-containing bicyclic heteroaryl, wherein the 5-6 membered nitrogen-containing heteroaryl, phenyl, 8-13 membered nitrogen-containing bicyclic heteroaryl is unsubstituted or substituted with 1-3 R _a2 ;

Each R _a2 is independently selected from hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, -NR ₄ R ₅ ;

R ₂ , R ₃ , R ₄ and R ₅ are independently selected at each occurrence from hydrogen, C _1-6 alkyl or halogenated C _1-6 alkyl, said C _1-6 alkyl or halogenated C _1-6 alkyl being unsubstituted or substituted with one or more groups independently selected from hydrogen, cyano, (C _1-6 alkyl) ₂ amino or 3-8 membered nitrogen-containing heterocyclic group;

m and n are independently 0 or 1;

L is selected from a bond, C _2-8 alkynyl, -C(O)NH-, C _2-8 alkynyl-C _1-6 alkyl, C _2-8 alkynyl-C _1-6 alkyl-carbonyl;

B is selected from C _1-6 alkylamino, (C _1-6 alkyl) _2amino or Cy1;

Cy1 is selected from a 5-6 membered nitrogen-containing heterocyclic group, a 5-6 membered nitrogen-containing heteroaryl group, a phenyl group, an 8-13 membered nitrogen-containing bicyclic heterocyclic group or an 8-13 membered nitrogen-containing bicyclic heteroaryl group, wherein the 5-6 membered nitrogen-containing heterocyclic group, the _{5-6 membered nitrogen-containing heteroaryl group, the phenyl group, the 8-13 membered nitrogen-containing bicyclic heterocyclic group or the 8-13 membered nitrogen-containing bicyclic heteroaryl group is unsubstituted or substituted by one to three groups independently selected from hydrogen, hydroxyl, C 1-6} alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 alkylaminocarbonyl;

Provided that, (i) when L is alkynyl, n is 1, for Cy3 Cy2 When m is 1 and B is Cy1, Cy1 is not

(ii) when L is an alkynyl group, n is 1, for Cy3 Cy2 When m is 1 and B is Cy1, Cy1 is not

Another embodiment of the present invention relates to a compound represented by formula (II), an isomer, a deuterated compound or a pharmaceutically acceptable salt thereof,

L is selected from a bond, -C(O)NH-, -CH ₂ -, -O-;

m and n are independently 0 or 1;

R ₁ is selected from hydrogen, C _1-6 alkyl, 5-6 membered heteroaryl, -S(O) ₂ R ₂ , -C(O)R ₂ , -C(O)NR ₂ R ₃ , -CO ₂ R ₃ , -S(O) ₂ NR ₂ R ₃ , wherein the C _1-6 alkyl and 5-6 membered heteroaryl are unsubstituted or substituted with one to three groups independently selected from hydrogen, halogen, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, halo-substituted C _1-6 alkyl, halo-substituted C _1-6 alkoxy, 5-6 membered heterocyclyl, 5-6 membered cycloalkyl, 5-6 membered cycloalkenyl;

_R2 and _R3 are independently selected at each occurrence from hydrogen, halogen, hydroxyl, cyano, nitro, carboxyl, amino, _C1-6 alkyl, halogenated _C1-6 alkyl, C1-6 alkoxy, _C1-6 alkylamino, ( _C1-6 alkyl) _2amino , halogenated _C1-6 alkoxy, wherein the _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylamino, ( _C1-6 alkyl) _2amino , halogenated _C1-6 alkoxy are unsubstituted or substituted _with one or more groups independently selected from hydrogen, cyano, 5-6 membered heterocyclyl, _C1-6 alkylamino, ( _C1-6 alkyl) _2amino ;

Cy3 is selected from 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, wherein the 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl is unsubstituted or substituted with 1-3 R _a3 ;

Each R _a3 is independently selected from hydrogen, amino, hydroxy, halogen, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, hydroxy C _1-6 alkyl;

Cy2 is selected from 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, phenyl, wherein the 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, phenyl is unsubstituted or substituted with 1-3 R _a2 ;

Each R _a2 is independently selected from hydrogen, hydroxy, carboxyl, halogen, nitro, cyano, amino, C _1-6 alkyl, halogenated C _1-6 alkyl;

Cy1 is selected from 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocyclyl, wherein the 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocyclyl is unsubstituted or substituted by one to three groups independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, carboxyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl.

Another embodiment of the present invention relates to a compound represented by formula (II), an isomer, a deuterated compound or a pharmaceutically acceptable salt thereof,

L is selected from a bond, -C(O)NH-;

m and n are independently 0 or 1;

R ₁ is selected from hydrogen, 5-6 membered nitrogen-containing heteroaryl, -S(O) ₂ R ₂ , -C(O)R ₂ , -C(O)NR ₂ R ₃ , -CO ₂ R ₃ , wherein the 5-6 membered nitrogen-containing heteroaryl is unsubstituted or substituted by one to three groups independently selected from hydrogen, halogen, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, 5-6 membered nitrogen-containing heterocyclic group;

R ₂ and R ₃ are independently selected from hydrogen, C _1-6 alkyl at each occurrence, wherein the C _1-6 alkyl is unsubstituted or substituted by one or more groups independently selected from hydrogen, cyano, and 5-6-membered nitrogen-containing heterocyclic group;

Cy3 is selected from a 6-membered nitrogen-containing heterocyclic group, a 6-membered nitrogen-containing heteroaryl group, or a 9-membered nitrogen-containing bicyclic heteroaryl group, wherein the 6-membered nitrogen-containing heterocyclic group, the 6-membered nitrogen-containing heteroaryl group, or the 9-membered nitrogen-containing bicyclic heteroaryl group is unsubstituted or substituted with 1-3 R _a3 groups;

Each R _a3 is independently selected from hydrogen, amino, C _1-6 alkyl;

Cy2 is selected from a 6-membered nitrogen-containing heteroaryl, a 9-membered nitrogen-containing bicyclic heteroaryl, or a phenyl group, wherein the 6-membered nitrogen-containing heteroaryl, the 9-membered nitrogen-containing bicyclic heteroaryl, or the phenyl group is unsubstituted or substituted with 1-3 R _a2 groups;

Each R _a2 is independently selected from hydrogen, halogen, amino, C _1-6 alkyl;

Cy1 is selected from a 5-6 membered nitrogen-containing heterocyclic group, a 5-6 membered nitrogen-containing heteroaryl group, and a 10 membered nitrogen-containing bicyclic heterocyclic group, wherein the 5-6 membered nitrogen-containing heterocyclic group, the 5-6 membered nitrogen-containing heteroaryl group, and the 10 membered nitrogen-containing bicyclic heterocyclic group are unsubstituted or substituted by one to three groups independently selected from hydrogen, hydroxyl, C _1-6 alkyl, and C _1-6 alkoxy.

Another embodiment of the present invention relates to a compound represented by formula (II), an isomer, a deuterated compound or a pharmaceutically acceptable salt thereof,

L is selected from a bond, -C(O)NH-;

m and n are independently 0 or 1;

_R1 is selected from hydrogen, -S(O) ₂ CH ₃ , -C(O)CH ₃ , -C(O)N(CH ₃ ) ₂ , -CO ₂ CH ₃ , -S(O) ₂ CH ₂ CH ₃ , Cy3 is selected from

Cy2 is selected from

Cy1 is selected from

Another embodiment of the present invention relates to a compound represented by formula (III), an isomer, a deuterated compound or a pharmaceutically acceptable salt thereof,

L is selected from C _2-8 alkynyl, C _2-8 alkynyl-C _1-6 alkyl, C _2-8 alkynyl-C _1-6 alkyl-carbonyl,

Ring A is selected from 4-6 membered heterocyclyl, 4-6 membered heterocyclyl-C _1-6 alkyl, 10-11 membered bicyclic spiro heterocyclyl, 14-15 membered polycyclic spiro heterocyclyl;

R ₁ is selected from hydrogen, C _1-6 alkyl, 5-6 membered heteroaryl, -S(O) ₂ R ₂ , -C(O)R ₂ , -C(O)NR ₂ R ₃ , -CO ₂ R ₃ , -S(O) ₂ NR ₂ R ₃ , wherein the C _1-6 alkyl and 5-6 membered heteroaryl are unsubstituted or substituted with one to three groups independently selected from hydrogen, halogen, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, halo-substituted C _1-6 alkyl, halo-substituted C _1-6 alkoxy, 5-6 membered heterocyclyl, 5-6 membered cycloalkyl, 5-6 membered cycloalkenyl;

_R2 and _R3 are independently selected at each occurrence from hydrogen, halogen, hydroxyl, cyano, nitro, carboxyl, amino, _C1-6 alkyl, halogenated _C1-6 alkyl, C1-6 alkoxy, _C1-6 alkylamino, ( _C1-6 alkyl) _2amino , halogenated _C1-6 alkoxy, wherein the _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylamino, ( _C1-6 alkyl) _2amino , halogenated _C1-6 alkoxy are unsubstituted or substituted _with one or more groups independently selected from hydrogen, cyano, 5-6 membered heterocyclyl, _C1-6 alkylamino, ( _C1-6 alkyl) _2amino ;

Cy3 is selected from 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, wherein the 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl is unsubstituted or substituted with 1-3 R _a3 ;

Each R _a3 is independently selected from hydrogen, hydroxy, amino, halogen, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, hydroxy C _1-6 alkyl;

Cy2 is selected from 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, phenyl, wherein the 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, phenyl is unsubstituted or substituted with 1-3 R _a2 ;

Each R _a2 is independently selected from hydrogen, hydroxy, carboxyl, halogen, nitro, cyano, amino, C _1-6 alkyl, halogenated C _1-6 alkyl;

B is selected from C _1-6 alkylamino, (C _1-6 alkyl) _2amino or Cy1;

Cy1 is selected from 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocyclyl, wherein the 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocyclyl is unsubstituted or substituted by one to three groups independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, carboxyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) _2amino , C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) _{2aminocarbonyl} ;

Provided that, (i) when L is alkynyl, n is 1, for Cy3 Cy2 When m is 1 and B is Cy1, Cy1 is not

(ii) when L is an alkynyl group, n is 1, for Cy3 Cy2 When m is 1 and B is Cy1, Cy1 is not

Another embodiment of the present invention relates to a compound represented by formula (III), an isomer, a deuterated compound or a pharmaceutically acceptable salt thereof,

L is selected from C _2-8 alkynyl, C _2-8 alkynyl-C _1-6 alkyl, C _2-8 alkynyl-C _1-6 alkyl-carbonyl,

Ring A is selected from 4-6 membered heterocyclyl, 4-6 membered heterocyclyl-C _1-6 alkyl, 10-11 membered bicyclic spiro heterocyclyl, 14-15 membered polycyclic spiro heterocyclyl;

R ₁ is selected from hydrogen, C _1-6 alkyl, 5-6 membered heteroaryl, -S(O) ₂ R ₂ , -C(O)R ₂ , -C(O)NR ₂ R ₃ , -CO ₂ R ₃ , -S(O) ₂ NR ₂ R ₃ , wherein the C _1-6 alkyl and 5-6 membered heteroaryl are unsubstituted or substituted with one to three groups independently selected from hydrogen, halogen, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, halo-substituted C _1-6 alkyl, halo-substituted C _1-6 alkoxy, 5-6 membered heterocyclyl, 5-6 membered cycloalkyl, 5-6 membered cycloalkenyl;

_R2 and _R3 are independently selected at each occurrence from hydrogen, halogen, hydroxyl, cyano, nitro, carboxyl, amino, _C1-6 alkyl, halogenated _C1-6 alkyl, C1-6 alkoxy, _C1-6 alkylamino, ( _C1-6 alkyl) _2amino , halogenated _C1-6 alkoxy, wherein the _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylamino, ( _C1-6 alkyl) _2amino , halogenated _C1-6 alkoxy are unsubstituted or substituted _with one or more groups independently selected from hydrogen, cyano, 5-6 membered heterocyclyl, _C1-6 alkylamino, ( _C1-6 alkyl) _2amino ;

Cy3 is selected from 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, wherein the 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl is unsubstituted or substituted with 1-3 R _a3 ;

Each R _a3 is independently selected from hydrogen, hydroxy, halogen, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, hydroxy C _1-6 alkyl;

Cy2 is selected from 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, phenyl, wherein the 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, phenyl is unsubstituted or substituted with 1-3 R _a2 ;

Each R _a2 is independently selected from hydrogen, hydroxy, carboxyl, halogen, nitro, cyano, amino, C _1-6 alkyl, halogenated C _1-6 alkyl;

B is selected from C _1-6 alkylamino, (C _1-6 alkyl) _2amino or Cy1;

Cy1 is selected from 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocyclyl, wherein the 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocyclyl is unsubstituted or substituted by one to three groups independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, carboxyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl.

Another embodiment of the present invention relates to a compound represented by formula (III), an isomer, a deuterated compound or a pharmaceutically acceptable salt thereof,

L is selected from C _2-8 alkynyl, C _2-8 alkynyl-C _1-6 alkyl, C _2-8 alkynyl-C _1-6 alkyl-carbonyl,

Ring A is selected from a 5-6 membered nitrogen-containing heterocyclic group, a 5-6 membered nitrogen-containing heterocyclic group-C _1-6 alkyl group, a 10-11 membered nitrogen-containing bicyclic spiro heterocyclic group, and a 14-15 membered nitrogen-containing polycyclic spiro heterocyclic group;

R ₁ is selected from hydrogen, C _1-6 alkyl, 6-membered nitrogen-containing heteroaryl, -C(O)R ₂ ;

R ₂ is selected from hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, the C _1-6 alkyl is unsubstituted or substituted by one or more groups independently selected from hydrogen, cyano, (C _1-6 alkyl) ₂ amino;

Cy3 is selected from a 6-membered nitrogen-containing heteroaryl, a 6-membered nitrogen-containing heterocyclic group, or a 9-membered nitrogen-containing bicyclic heteroaryl, wherein the 6-membered nitrogen-containing heteroaryl, the 6-membered nitrogen-containing heterocyclic group, or the 9-membered nitrogen-containing bicyclic heteroaryl is unsubstituted or substituted with 1-3 R _a3 ;

Each R _a3 is independently selected from hydrogen, C _1-6 alkyl, hydroxy C _1-6 alkyl;

Cy2 is selected from a 6-membered nitrogen-containing heteroaryl group or a phenyl group, wherein the 6-membered nitrogen-containing heteroaryl group or the phenyl group is unsubstituted or substituted with 1 to 3 R _a2 groups;

Each R _a2 is independently selected from hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl;

B is selected from C _1-6 alkylamino, (C _1-6 alkyl) _2amino or Cy1;

Cy1 is selected from a 5-6 membered nitrogen-containing heterocyclic group, a 5-6 membered nitrogen-containing heteroaryl group, a 9-membered nitrogen-containing bicyclic heteroaryl group, and a 9-membered nitrogen-containing bicyclic heterocyclic group, wherein the 5-6 membered nitrogen-containing heterocyclic group, the 5-6 membered nitrogen-containing heteroaryl group, the 9-membered nitrogen-containing bicyclic heteroaryl group, and the 9-membered nitrogen-containing bicyclic heterocyclic group are unsubstituted or substituted by one to three groups independently selected from hydrogen, C _1-6 alkyl, C _1-6 alkylamino, and C _1-6 alkylaminocarbonyl.

Another embodiment of the present invention relates to a compound represented by formula (III), an isomer, a deuterated compound or a pharmaceutically acceptable salt thereof,

L is C _2-8 alkynyl, C _2-8 alkynyl-C _1-6 alkyl, C _2-8 alkynyl-C _1-6 alkyl-carbonyl;

Selected from

R ₁ is selected from hydrogen, methyl, -C(O)CH ₃ , -C(O)CH ₂ CN, -C(O)CH ₂ N(CH ₃ ) ₂ , -C(O)CF ₃ ;

Cy3 is selected from

Cy2 is selected from

Cy1 is selected from

Another embodiment of the present invention relates to a compound represented by formula (III), an isomer, a deuterated compound or a pharmaceutically acceptable salt thereof,

Selected from

L is C _2-8 alkynyl;

R ₁ is selected from hydrogen, C _1-6 alkyl, 6-membered nitrogen-containing heteroaryl, -C(O)R ₂ ;

Cy3 is selected from a 6-membered nitrogen-containing heteroaryl group;

Cy2 is selected from a 6-membered nitrogen-containing heteroaryl group or a phenyl group, wherein the 6-membered nitrogen-containing heteroaryl group or the phenyl group is unsubstituted or substituted with 1-3 R _a2 groups;

Each R _a2 is independently selected from hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl;

R ₂ is selected from hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, the C _1-6 alkyl is unsubstituted or substituted by one or more groups independently selected from hydrogen, cyano, (C _1-6 alkyl) ₂ amino;

Cy1 is a 5-membered nitrogen-containing heteroaryl group, which is unsubstituted or substituted by a C _1-6 alkyl group.

Another embodiment of the present invention relates to a compound represented by formula (IV), an isomer, a deuterated compound or a pharmaceutically acceptable salt thereof,

L is selected from C _2-8 alkynyl, C _2-8 alkynyl-C _1-6 alkyl, C _2-8 alkynyl-C _1-6 alkyl-carbonyl,

Cy3 is selected from 6-membered nitrogen-containing heteroaryl, 9-membered nitrogen-containing bicyclic heteroaryl, wherein the 6-membered nitrogen-containing heteroaryl, 9-membered nitrogen-containing bicyclic heteroaryl is unsubstituted or substituted with 1-3 R _a3 ;

Each R _a3 is independently selected from hydrogen, C _1-6 alkyl, hydroxy C _1-6 alkyl;

Cy2 is selected from a 6-membered nitrogen-containing heteroaryl group or a phenyl group, wherein the 6-membered nitrogen-containing heteroaryl group or the phenyl group is unsubstituted or substituted with 1-3 R _a2 groups;

Each R _a2 is independently selected from hydrogen, halogen, C _1-6 alkyl;

B is selected from C _1-6 alkylamino, (C _1-6 alkyl) _2amino or Cy1;

Cy1 is selected from a 5-6 membered nitrogen-containing heterocyclic group, a 5-6 membered nitrogen-containing heteroaryl group, a 9-membered nitrogen-containing bicyclic heteroaryl group, and a 9-membered nitrogen-containing bicyclic heterocyclic group, wherein the 5-6 membered nitrogen-containing heterocyclic group, the 5-6 membered nitrogen-containing heteroaryl group, the 9-membered nitrogen-containing bicyclic heteroaryl group, and the 9-membered nitrogen-containing bicyclic heterocyclic group are unsubstituted or substituted by one to three groups independently selected from hydrogen, C _1-6 alkyl, C _1-6 alkylamino, and C _1-6 alkylaminocarbonyl.

Another embodiment of the present invention relates to a compound represented by formula (V), an isomer, a deuterated compound or a pharmaceutically acceptable salt thereof,

Selected from

R ₁ is selected from C _1-6 alkyl, 6-membered nitrogen-containing heteroaryl, -C(O)R ₂ ;

R ₂ is selected from hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, the C _1-6 alkyl is unsubstituted or substituted by one or more groups independently selected from hydrogen, cyano, (C _1-6 alkyl) ₂ amino;

Cy2 is selected from a 6-membered nitrogen-containing heteroaryl group or a phenyl group, wherein the 6-membered nitrogen-containing heteroaryl group or the phenyl group is unsubstituted or substituted with 1-3 R _a2 groups;

Each R _a2 is independently selected from hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl;

Cy1 is selected from a 5-6 membered nitrogen-containing heterocyclic group, a 5-6 membered nitrogen-containing heteroaryl group, a 9-membered nitrogen-containing bicyclic heteroaryl group, and a 9-membered nitrogen-containing bicyclic heterocyclic group, wherein the 5-6 membered nitrogen-containing heterocyclic group, the 5-6 membered nitrogen-containing heteroaryl group, the 9-membered nitrogen-containing bicyclic heteroaryl group, and the 9-membered nitrogen-containing bicyclic heterocyclic group are unsubstituted or substituted by one to three groups independently selected from hydrogen, C _1-6 alkyl, C _1-6 alkylamino, and C _1-6 alkylaminocarbonyl.

Another embodiment of the present invention relates to a compound represented by formula (III), an isomer, a deuterated compound or a pharmaceutically acceptable salt thereof,

L is a C ₂ alkynyl group;

B is Cy1;

Cy3 is selected from

Cy2 is selected from

Cy1 is selected from

Another embodiment of the present invention relates to a compound represented by formula (III), an isomer, a deuterated compound or a pharmaceutically acceptable salt thereof,

L is a C ₂ alkynyl group;

for

B is Cy1;

Cy3 is selected from

Cy2 is selected from

Cy1 is selected from

Another embodiment of the present invention relates to a compound represented by formula (III), an isomer, a deuterated compound or a pharmaceutically acceptable salt thereof,

L is a C ₂ alkynyl group;

for

B is Cy1;

Cy3 is selected from

Cy2 is selected from

Cy1 is selected from

Another embodiment of the present invention relates to a compound represented by formula (VI), an isomer, a deuterated compound or a pharmaceutically acceptable salt thereof,

Cy3 is selected from a 6-membered nitrogen-containing heteroaryl group;

Cy2 is selected from a 6-membered nitrogen-containing heteroaryl group substituted by halogen;

Cy1 is selected from Phenyl, Said Phenyl, Unsubstituted or substituted by C _1-6 alkyl.

Another embodiment of the present invention relates to a compound represented by formula (VII), an isomer, a deuterated compound or a pharmaceutically acceptable salt thereof,

Cy3 is selected from a 6-membered nitrogen-containing heterocyclic group, wherein the 6-membered nitrogen-containing heterocyclic group is unsubstituted or substituted by 1-3 R _a3 ;

Each R _a3 is independently selected from hydrogen, amino, C _1-6 alkyl, hydroxy C _1-6 alkyl;

R _a2 is selected from hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl;

Cy1 is selected from a 5-membered nitrogen-containing heteroaryl group substituted by a C _1-6 alkyl group.

Another embodiment of the present invention relates to a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,

Ring A is selected from 5-6 membered nitrogen-containing heterocyclic group, 5-6 membered nitrogen-containing heterocyclic group-C _1-6 alkyl group, 10-11 membered nitrogen-containing bicyclic spiro heterocyclic group, 14-15 membered nitrogen-containing polycyclic spiro heterocyclic group; preferably, it is 10-11 membered nitrogen-containing bicyclic spiro heterocyclic group.

Another embodiment of the present invention relates to a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,

Selected from

Preferably

Another embodiment of the present invention relates to a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,

Selected from

Another embodiment of the present invention relates to a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,

Cy3 is selected from a 6-membered nitrogen-containing heteroaryl, a 6-membered nitrogen-containing heterocyclic group, a 9-membered nitrogen-containing bicyclic heteroaryl, a phenyl group, and a 9-membered nitrogen-containing bicyclic heterocyclic group; preferably a 6-membered nitrogen-containing heteroaryl and a 9-membered nitrogen-containing bicyclic heteroaryl, wherein the 6-membered nitrogen-containing heteroaryl, the 6-membered nitrogen-containing heterocyclic group, the 9-membered nitrogen-containing bicyclic heteroaryl, the phenyl group, and the 9-membered nitrogen-containing bicyclic heterocyclic group are unsubstituted or substituted with 1-3 R _a3 .

Another embodiment of the present invention relates to a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,

Cy3 is selected from Phenyl,

Preferably

More preferably Said Phenyl, Unsubstituted or substituted with 1-3 _Ra3 .

Another embodiment of the present invention relates to a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,

Cy2 is selected from a 9-membered nitrogen-containing bicyclic heteroaryl, a 6-membered nitrogen-containing heteroaryl, and a phenyl group; preferably a 6-membered nitrogen-containing heteroaryl group, wherein the 9-membered nitrogen-containing bicyclic heteroaryl, the 6-membered nitrogen-containing heteroaryl, and the phenyl group are unsubstituted or substituted with 1-3 R _a2 groups.

Another embodiment of the present invention relates to a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,

Cy2 is selected from Phenyl, preferably Said The phenyl group is unsubstituted or substituted with 1 to 3 R _a2 groups.

Another embodiment of the present invention relates to a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,

Cy1 is selected from a 5-6 membered nitrogen-containing heterocyclic group, a 5-6 membered nitrogen-containing heteroaryl group, a 9-10 membered nitrogen-containing heteroaryl group, and a 9-10 membered nitrogen-containing heterocyclic group, preferably a 5-6 membered nitrogen-containing heteroaryl group, wherein the 5-6 membered nitrogen-containing heterocyclic group, the 5-6 membered nitrogen-containing heteroaryl group, the 9-10 membered nitrogen-containing heteroaryl group, and the 9-10 membered nitrogen-containing heterocyclic group are unsubstituted or substituted with a substituent.

Another embodiment of the present invention relates to a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,

Cy1 is selected from Phenyl, Preferably Said Phenyl, Unsubstituted or substituted with a substituent.

Another embodiment of the present invention relates to a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,

Each R ₁ is independently selected from hydrogen and methyl.

Another embodiment of the present invention relates to a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,

Cy1 is selected from

Another embodiment of the present invention relates to a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,

Each _Ra2 is independently selected from hydrogen, F, Cl, Br, methyl, trifluoromethyl.

Another embodiment of the present invention relates to a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,

Each _Ra3 is independently selected from hydrogen, methyl, hydroxymethyl, and amino, preferably hydrogen, methyl, and hydroxymethyl.

In some embodiments of the present invention, the compound of the aforementioned formula (I), its isomer, deuterated compound or pharmaceutically acceptable salt thereof is shown in Table 1-2:

Table 1

Table 2

Another embodiment of the present invention protects a pharmaceutical composition comprising the compound of the present invention, its isomer, deuterated compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and excipients.

Another embodiment of the present invention protects the use of the compound of the present invention, its isomer, deuterated compound or its pharmaceutically acceptable salt or the pharmaceutical composition of the present invention in the preparation of a medicament for treating and/or preventing diseases associated with abnormal SHP2 activity, including but not limited to cancers, such as leukemia, neuroblastoma, melanoma, lung cancer, breast cancer, esophageal cancer, colon cancer, head and neck cancer, gastric cancer, etc.

Another embodiment of the invention protects a method for treating and/or preventing SHP2-related diseases, which comprises a therapeutically effective amount of the compound of the present invention, its isomer, deuterated compound or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 Inhibitory effect of compound I-20 on the growth of H358 cell transplanted tumors in nude mice

DETAILED DESCRIPTION OF THE INVENTION

The "halogen" described in the present invention refers to fluorine, chlorine, bromine, iodine, etc., preferably fluorine and chlorine.

The term "halogenated" as used herein means that any hydrogen atom in a substituent group may be replaced by one or more halogen atoms which are the same or different. "Halogen" is as defined above.

The "C _1-6 alkyl" of the present invention refers to a straight or branched alkyl derived from a hydrocarbon portion containing 1 to 6 carbon atoms by removing a hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl and 1-methyl-2-methylpropyl, etc. The "C _1-6 alkyl" is preferably a C _1-4 alkyl or a C _1-3 alkyl.

The " _C2-8 alkenyl" mentioned in the present invention refers to a straight chain, branched or cyclic olefin group derived from an olefin portion of 2 to 8 carbon atoms containing a carbon-carbon double bond by removing a hydrogen atom, such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl and 1,4-hexadienyl.

The "C _2-8 alkynyl" of the present invention refers to a straight-chain or branched alkynyl derived from an alkyne moiety of 2 to 8 carbon atoms containing a carbon-carbon triple bond by removing a hydrogen atom, such as ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl, etc. The "C _2-8 alkynyl" is preferably C _2-4 alkynyl or C _2-3 alkynyl.

The "C _1-6 alkoxy" of the present invention refers to a group in which the "C _1-6 alkyl" defined above is connected to the parent molecule through an oxygen atom, i.e., a "C _1-6 alkyl-O-" group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy, neopentoxy and n-hexoxy. The "C _1-6 alkoxy" is preferably a C _1-4 alkoxy, a C _1-3 alkoxy,

The "C _1-6 alkylamino", "(C _1-6 alkyl) ₂ amino", "C _1-6 alkylcarbonylamino", "C _1-6 alkylsulfonylamino", "C _1-6 alkylaminocarbonyl", "(C _1-6 alkyl) ₂ amino-carbonyl", "C _1-6 alkoxy-carbonyl", "C _1-6 alkylsulfonyl", "C _1-6 alkylthio", "C _1-6 alkylcarbonyl", "aminocarbonyl" and "hydroxyC _1-6 alkyl" mentioned in the present invention refer to C _1-6 alkyl-NH-, (C _{1-6 alkyl)(C 1-6 alkyl} )N-, C _1-6 alkyl-C(O)-NH-, C _1-6 alkyl-S(O) ₂ -NH ₂ -, C _1-6 alkyl-NH-C(O)-, (C _1-6 alkyl)(C _1-6 alkyl)NC(O)-, C _1-6 alkyl-OC(O)-, C _1-6 alkyl-S(O) ₂ -, C _1-6 alkyl-S-, C _1-6 alkyl-C(O)-, NH _2- C(O)-, OH-C _1-6 alkyl-; the "C _1-6 alkyl" is as defined above, preferably "C _1-4 alkyl, C _1-3 alkyl".

The "condensed ring" described in the present invention refers to a multi-ring structure formed by two or more cyclic structures in the form of parallel, spiro, or bridge connection. Each cyclic structure refers to any monocyclic alkyl, monoheterocyclic, monocyclic alkenyl, phenyl, or monoheteroaryl. The parallel ring refers to a condensed ring structure formed by two or more cyclic structures sharing two adjacent ring atoms (i.e., sharing a bond). The bridged ring refers to a condensed ring structure formed by two or more cyclic structures sharing two non-adjacent ring atoms. The spiro ring refers to a condensed ring structure formed by two or more cyclic structures sharing one ring atom. Multiple cyclic structures are optionally connected in parallel, spiro, or bridge mode.

Two ring structures connected by parallel, spiro or bridge connection are bicyclic fused ring groups, such as 6-13 membered bicyclic fused ring groups. 6-13 membered bicyclic fused ring groups include 6-13 membered bicyclic fused cycloalkyl, 6-13 membered bicyclic fused cycloalkenyl, 6-13 membered bicyclic fused heterocyclic group, 8-13 membered bicyclic fused heteroaryl, 8-13 membered bicyclic fused aryl.

A polycyclic fused ring group is a group in which two or more cyclic structures are connected in parallel, spiro or bridge mode, such as a monocyclic ring structure connected to a 6-13-membered bicyclic fused ring group in parallel, spiro or bridge mode, such as an 8-21-membered polycyclic fused ring group. The 8-21-membered polycyclic fused ring group further includes an 8-21-membered polycyclic fused cycloalkyl, an 8-21-membered polycyclic fused cycloalkenyl, an 8-21-membered polycyclic fused heterocyclic group, an 8-21-membered polycyclic fused heteroaryl, and an 8-21-membered polycyclic fused aryl.

The 8-21-membered polycyclic fused heterocyclic group includes an 8-21-membered polycyclic bridged heterocyclic group, an 8-21-membered polycyclic fused heterocyclic group and an 8-21-membered polycyclic spiro heterocyclic group.

Examples of 8-21 membered polycyclic heterocyclic groups include, but are not limited to

8-21-membered polycyclic spiro heterocyclic groups include 14-15-membered polycyclic spiro heterocyclic groups and 10-16-membered polycyclic spiro heterocyclic groups, and examples thereof include but are not limited to

The 3-8 membered monocyclic group of the present invention includes monocyclic alkyl, monocyclic heterocyclic, monocyclic alkenyl, monocyclic heteroaryl and phenyl.

Monocycloalkyl is a cycloalkyl group containing 3-8 carbon atoms, including 3-8-membered cycloalkyl, 4-7-membered cycloalkyl, 4-6-membered cycloalkyl, 5-6-membered cycloalkyl. Examples of 3-8-membered cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The ring C atoms may be optionally oxidized to C(O).

A monoheterocyclic group refers to a non-aromatic cyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, and N, preferably 1 to 3 heteroatoms. The ring C atoms may be optionally oxidized to C(O). A monoheterocyclic group may be saturated or partially saturated, including 3-8 membered heterocyclic groups, 3-6 membered heterocyclic groups, 4-6 membered heterocyclic groups, 4-7 membered heterocyclic groups, 5-7 membered heterocyclic groups, 5-6 membered heterocyclic groups, 4-6 membered nitrogen-containing heterocyclic groups, 5-6 membered oxygen-containing heterocyclic groups, 3-8 membered nitrogen-containing heterocyclic groups, 5-6 membered nitrogen-containing heterocyclic groups, 5-6 membered saturated heterocyclic groups, and the like. “3-8” membered saturated heterocyclic group”, examples of which include but are not limited to aziridine, oxirane, thiirane, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2-thiazolidinyl, 1,3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxanyl, 1,4-oxathiinyl; “3-8 membered partially saturated heterocyclic group”, examples of which include but are not limited to 4,5-dihydro- 4,5-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl, 4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-3H-pyrazolyl, 4,5-dihydrothiazolyl, 2,5-dihydrothiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-thiopyranyl, 4H-thiopyranyl, 2,3,4,5-tetrahydropyridinyl, 1,2-isoxazinyl, 1,4-isoxazinyl or 6H-1,3-oxazinyl.

The monocycloalkenyl group refers to a partially saturated carbon ring group, including 3-8 membered cycloalkenyl, 4-7 membered cycloalkenyl, and 5-6 membered cycloalkenyl.

The heteroaryl group of the present invention refers to an aromatic cyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, and N. The monoheteroaryl group may be a 5-7-membered heteroaryl group or a 5-6-membered heteroaryl group, and examples thereof include but are not limited to furanyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thienyl, triazolyl, and triazinyl.

6-13 bicyclic condensed cycloalkyl includes cycloalkyl, bridged cycloalkyl, spirocycloalkyl. Cycloalkyl can be 6-11-membered cycloalkyl, 7-10-membered cycloalkyl, and its representative examples include but are not limited to bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane and bicyclo[4.2.1]nonane. The spirocyclyl can be 7-12-membered spirocyclyl, 7-11-membered spirocyclyl, 10-11-membered spirocyclyl, and its examples include but are not limited to: The bridged ring group may be a 6-11-membered bridged ring group or a 7-10-membered bridged ring group, examples of which include but are not limited to:

The 6-13 bicyclic fused cycloalkenyl group includes a bicyclic cycloalkenyl group, a bridged cycloalkenyl group, and a spirocyclic cycloalkenyl group.

6-13 membered bicyclic fused heterocyclyls include bis-heterocyclyls, spiro-heterocyclyls, bridged heterocyclyls, and may be saturated, partially saturated, or unsaturated, but not aromatic. Fused heterocyclyls are 5-6 membered monocyclic heterocyclyl rings fused to a benzene ring, a 5-6 membered monocyclic cycloalkyl, a 5-6 membered monocyclic cycloalkenyl, a 5-6 membered monocyclic heterocyclyl, or a 5-6 membered monocyclic heteroaryl. The heterocyclic group can be a 6-12-membered heterocyclic group, a 7-10-membered heterocyclic group, a 6-10-membered heterocyclic group, an 8-10-membered bicyclic heterocyclic group, or a 6-12-membered saturated heterocyclic group. Representative examples include, but are not limited to, 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.2.0]heptyl, 3,8-diazabicyclo[4.2.0]octyl, 3,7-diazabicyclo[4.2.0]octyl, octahydropyrrolo[ 3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,4-b][1,4]oxazinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, dihydroindole-1-yl, dihydroindole-2-yl, dihydroindole-3-yl, 2,3-dihydrobenzothiophene-2-yl, octahydro-1H-indolyl, octahydrobenzofuranyl. The spiro heterocyclic group may be a 6-12-membered spiro heterocyclic group, a 7-11-membered spiro heterocyclic group, a 6-12-membered saturated spirocyclic group, or a 10-11-membered bicyclic spiro heterocyclic group, examples of which include but are not limited to:

The bridged heterocyclic group may be a 6-12-membered bridged heterocyclic group, a 7-11-membered bridged heterocyclic group, or a 6-12-membered saturated bridged ring group, examples of which include but are not limited to:

8-13 membered bicyclic fused heteroaryl refers to a group formed by a monocyclic heteroaryl ring fused to a phenyl group or a monoheteroaryl group. The fused heteroaryl group may be an 8-13 membered fused heteroaryl group, a 9-10 membered fused heteroaryl group, or an 8-10 membered bicyclic fused heteroaryl group, and examples thereof include but are not limited to

The 8-13 membered bicyclic fused aryl group refers to a group formed by condensing a single aromatic ring to a single aromatic group, including naphthalene, phenanthrene and the like.

Any ring C atom of the present invention may be optionally oxidized to C(O).

The "isomers" mentioned in the present invention refer to stereoisomers and tautomers.

Stereoisomers refer to enantiomers produced when asymmetric atoms exist in a compound; cis-trans isomers are produced when a double bond or a ring structure exists in a compound; all enantiomers, diastereomers, racemates, cis-trans isomers, geometric isomers, epimers and mixtures thereof of compounds of formula (I) are included in the scope of the present invention.

"Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions. Tautomers are a special type of functional group isomers. For example, the tautomerism of carbonyl compounds containing α-H is as follows: Such as other proton migration tautomerism, specifically phenol-keto tautomerism, nitroso-oxime tautomerism, imine-enamine tautomerism.

T, T1, and T2 are each independently any group that complies with the bonding rules of the compound.

The deuterated compound of the present invention refers to a compound in which any one or more hydrogen atoms are replaced by deuterium atoms.

DETAILED DESCRIPTION

The present invention is described below with reference to specific examples. It will be appreciated by those skilled in the art that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention in any way.

The experimental methods in the following examples are conventional methods unless otherwise specified. The medicinal materials, reagents, etc. used in the following examples are commercially available products unless otherwise specified.

The preparation method of the compound of formula (I) of the present invention is as follows:

Route 1

Route 2

For the range of substituents of R ₁ , Cy1, Cy2 and ring A, please refer to the various embodiments in the Summary of the Invention section.

Example 1: Synthesis of 9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3-(pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-1-amine (Compound I-1)

Step 1: Synthesis of ethyl 2-(1-benzylpiperidin-4-ylidene)-2-cyanoacetate

At room temperature, 1-benzylpiperidin-4-one (50 g, 0.264 mol) and N,N-diisopropylethylamine (68 g, 0.528 mol) were dissolved in dichloromethane (500 mL), and ethyl cyanoacetate (29.8 g, 0.264 mol) was slowly added. The reaction solution was stirred at room temperature overnight, washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and purified by column chromatography (ethyl acetate/petroleum ether = 1:9) to obtain 21.8 g of white solid, yield: 29%, MS (ESI) m/z: 285.5 [M+H] ⁺ .

Step 2: Synthesis of ethyl 2-(1-benzyl-4-(1,2-dimethoxy-2-oxoethyl)piperidin-4-yl)-2-cyanoacetate

At room temperature, lithium bis(trimethylsilyl)amide (71.8 mL, 71.8 mmol) was added to tetrahydrofuran (100 mL), cooled to -78 degrees, ethyl methoxyacetate (6.4 g, 58 mmol) was slowly added, and the reaction solution was stirred at -78 degrees for 40 minutes. A solution of ethyl 2-(1-benzylpiperidin-4-ylidene)-2-cyanoacetate (15 g, 52.8 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise to the above reaction solution, reacted at -78 degrees for 1 hour, naturally warmed to room temperature, stirred at room temperature for 2 hours, quenched with water (100 mL), extracted with ethyl acetate (2X50 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. Purification by column chromatography (ethyl acetate: petroleum ether = 1:4) gave 14 grams of light yellow oil, with a yield of 70%, MS (ESI) m/z: 389.6 [M+H] ⁺ .

Step 3: Synthesis of methyl 2-(1-benzyl-4-(cyanomethyl)piperidin-4-yl)-2-methoxyacetate

At room temperature, ethyl 2-(1-benzyl-4-(1,2-dimethoxy-2-oxoethyl)piperidin-4-yl)-2-cyanoacetate (3.3 g, 8.5 mmol) and lithium chloride (882 mg, 20.8 mmol) were dissolved in a mixture of dimethyl sulfoxide (40 mL) and water (20 mL). The reaction temperature was raised to 110 degrees, the reaction was allowed to react overnight, and the mixture was cooled to room temperature. Water (100 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The organic phase was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. The mixture was purified by column chromatography (ethyl acetate/petroleum ether=1:4) to obtain 2 g of a light yellow oil with a yield of 71%. MS (ESI) m/z: 317.4 [M+H] ⁺ .

Step 4: Synthesis of 9-benzyl-1-methoxy-3,9-diazaspiro[5.5]undecanedione

In an ice-water bath, an aqueous solution (100 mL) of cobaltous chloride hexahydrate (8.09 g, 34 mmol) was added to a solution of methyl 2-(1-benzyl-4-(cyanomethyl)piperidin-4-yl)-2-methoxyacetate (10.75 g, 34 mmol) in tetrahydrofuran (200 mL), and then solid sodium borohydride (6.46 g, 170 mmol) was slowly added. The temperature was controlled below 20 degrees during the addition. The reaction solution was stirred at room temperature overnight. After the reaction was completed, water (200 mL) was slowly added, filtered, and the filtrate was extracted with ethyl acetate (2X100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and purified by column chromatography (methanol/dichloromethane=1:10) to obtain 6.53 g of colorless oil, with a yield of 84%. MS (ESI) m/z: 289.5 [M+H] ⁺ .

Step 5: Synthesis of 9-benzyl-1-hydroxy-3,9-diazaspiro[5.5]undecanedione

In an ice-water bath, boron tribromide (11.37 g, 45.48 mmol) was slowly added dropwise to a dichloromethane (50 mL) solution of 9-benzyl-1-methoxy-3,9-diazaspiro[5.5]undecanedione (4.37 g, 15.16 mmol), and the reaction solution was stirred at room temperature for 2 days. Anhydrous methanol (10 mL) was slowly added dropwise to quench the reaction. The reaction solution was spin-dried, the concentrate was dissolved in dichloromethane (100 mL), washed with saturated aqueous sodium bicarbonate solution (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and purified by column chromatography (methanol/dichloromethane=1:10) to obtain 2.4 g of colorless oil, yield: 57.8%, MS (ESI) m/z: 275.5[M+H] ⁺ .

Step 6: Synthesis of 9-benzyl-3,9-diazaspiro[5.5]undecane-1-ol

9-Benzyl-1-hydroxy-3,9-diazaspiro[5.5]undecanedione (2.3 g, 8.39 mmol) was dissolved in tetrahydrofuran (20 mL), and N2 was protected. A tetrahydrofuran solution of lithium aluminum hydride (1 Mol/L, 42 mL, 42 mmol) was slowly added dropwise in an ice-water bath. The mixture was heated to reflux for 3 hours, cooled to room temperature, and water (1.6 mL), 15% aqueous sodium hydroxide solution (1.6 mL), and water (4.8 mL) were slowly added dropwise in an ice-water bath. The mixture was stirred at room temperature for 15 minutes, filtered, and the solid was washed with tetrahydrofuran (40 mL). The filtrate was selected and dried to obtain 2 g of colorless oil, which was directly used in the next step. MS (ESI) m/z: 261.6 [M+H] ⁺ .

Step 7: Synthesis of tert-butyl 9-benzyl-1-hydroxy-3,9-diazaspiro[5.5]undecane-3-carboxylate

At room temperature, 9-benzyl-3,9-diazaspiro[5.5]undecane-1-ol (2 g, 7.69 mmol) was dissolved in dichloromethane (50 mL), triethylamine (932 mg, 9.2 mmol) and di-tert-butyl dicarbonate (1.85 g, 8.46 mmol) were added, the reaction solution was stirred at room temperature for 3 hours, water (50 mL) was added, the layers were separated, the aqueous phase was extracted with dichloromethane (2×30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and column chromatography (MeOH/DCM=1:20) was performed to obtain 2.42 g of colorless oil, yield: 87.4%. MS (ESI) m/z: 361.6 [M+H] ⁺ .

Step 8: Synthesis of tert-butyl 9-benzyl-1-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate

Dissolve tert-butyl 9-benzyl-1-hydroxy-3,9-diazaspiro[5.5]undecane-3-carboxylate (2.42 g, 6.72 mmol) in dichloromethane (50 mL), add Dess-Martin periodinane (4.27 g, 10.1 mmol) in an ice-water bath, and stir at room temperature for 3 hours. Wash the reaction solution with saturated aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, filter, spin-dry the filtrate, and perform column chromatography (MeOH:DCM=1:20) to obtain 1.25 g of a yellow semisolid compound. Yield: MS (ESI) m/z: 359.6 [M+H] ⁺ .

Step 9: Synthesis of tert-butyl-9-benzyl-1-(hydroxyimino)-3,9-diazaspiro[5.5]undecane-3-carboxylate

Dissolve tert-butyl 9-benzyl-1-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.25 g, 3.49 mmol) in ethanol (30 mL), add hydroxylamine hydrochloride (364 mg, 5.23 mmol) and potassium acetate (513 mg, 5.23 mmol), raise the temperature to 80 degrees, react for 3 hours, spin dry, add dichloromethane (40 mL), filter, concentrate the filtrate and spin dry, column chromatography (MeOH/DCM=1:20) to obtain 1 gram of white semisolid, yield: 77%, MS (ESI) m/z: 374.7 [M+H] ⁺ .

Step 10: Synthesis of tert-butyl 1-amino-9-benzyl-3,9-diazaspiro[5.5]undecane-3-carboxylate

Dissolve tert-butyl-9-benzyl-1-(hydroxyimino)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1 g, 2.68 mmol) in methanol (40 mL), add Raney Ni (200 mg) and aqueous ammonia (10 mL), stir at room temperature for 5 hours under a hydrogen balloon, filter, spin dry, wash with methanol, spin dry to obtain 860 mg of crude product, which is directly used in the next step, MS (ESI) m/z: 360.5 [M+H] ⁺ .

Step 11: Synthesis of tert-butyl 9-benzyl-1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate

At room temperature, tert-butyl 1-amino-9-benzyl-3,9-diazaspiro[5.5]undecane-3-carboxylate (860 mg, 2.4 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (290 mg, 2.87 mmol) and di-tert-butyl dicarbonate (574 mg, 2.64 mmol) were added in sequence. The mixture was stirred at room temperature for 3 hours, concentrated, and purified by column chromatography (methanol/dichloromethane = 1/20) to give 700 mg of a white solid, yield; 63.7%, MS (ESI) m/z: 460.7 [M+H] ⁺ .

Step 12: Synthesis of tert-butyl 1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate

At room temperature, tert-butyl 9-benzyl-1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate (550 mg, 1.2 mmol) was dissolved in methanol (40 mL), Pd/C (100 mg) was added, and the mixture was reacted at room temperature for 2 hours under hydrogen balloon pressure. The mixture was filtered and the filtrate was concentrated to give 440 mg of a colorless oil, yield: 100%. It was used directly in the next step without purification. MS (ESI) m/z: 370.6 [M+H] ⁺ .

Step 13: Synthesis of 5-bromo-4-chloro-2-methyl-2H-indazole

At room temperature, 5-bromo-4-chloro-2H-indazole (500 mg, 2.17 mmol) was dissolved in ethyl acetate (40 mL), trimethyloxonium tetrafluoroborate (354 mg, 2.39 mmol) was added and stirred at room temperature for four hours, water (50 mL) was added, and the mixture was extracted with ethyl acetate (2×30 mL). The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 440 mg of an orange-red solid, yield: 83%, which was directly used for the next step. MS (ESI) m/z: 245.3 [M+H] ⁺ .

Step 14: Synthesis of methyl 3-((4-chloro-2-methyl-2H-indazol-5-yl)thio)propanoate

At room temperature, 5-bromo-4-chloro-2-methyl-2H-indazole (640 mg, 2.62 mmol), methyl 3-mercaptopropionate (378 mg, 3.15 mmol), tris(dibenzylideneacetone)dipalladium(0) (240 mg, 0.262 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (303 mg, 0.524 mmol) and N,N-diisopropylethylamine (676 mg, 5.24 mmol) were dissolved in dioxane (50 mL), the reaction temperature was raised to 110 degrees, the reaction was allowed to react for 3 hours, the mixture was concentrated and dried, and the mixture was purified by column chromatography (EA/PE=1:4) to obtain 450 mg of a yellow solid, yield: 60%, MS (ESI) m/z: 285.4 [M+H] ⁺ .

Step 15: Synthesis of 4-chloro-2-methyl-2H-indazole-5-sodium hydrogen sulfate

At room temperature, methyl 3-((4-chloro-2-methyl-2H-indazol-5-yl)thio)propanoate (30 mg, 0.106 mmol) was dissolved in methanol (3 mL), and a methanol solution of sodium methoxide (6.9 mg, 0.127 mmol) was added, stirred at room temperature for 3 days, and directly spin-dried for the next step without purification. Yield: 100%, MS (ESI) m/z: 199.4 [M+H] ⁺ .

Step 16: Synthesis of 4-chloro-5-((5-chloropyrazin-2-yl)thio)-2-methyl-2H-indazole

At room temperature, 4-chloro-2-methyl-2H-indazole-5-sodium hydrogen sulfate (200 mg, 0.91 mmol), 2-bromo-5-chloropyrazine (176 mg, 0.91 mmol), tris(dibenzylideneacetone)dipalladium(0) (83 mg, 0.091 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (105 mg, 0.182 mmol) and N,N-diisopropylethylamine (235 mg, 1.82 mmol) were dissolved in dioxane (20 mL), the reaction temperature was raised to 90 degrees, the reaction was allowed to react for 12 hours, the reaction mixture was concentrated and dried, and the mixture was purified by column chromatography (EA/PE=1:4) to obtain 253 mg of a yellow solid, yield: 90%, MS (ESI) m/z: 311.4 [M+H] ⁺ .

Step 17: Synthesis of tert-butyl 1-((tert-butyloxycarbonyl)amino)-9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

At room temperature, 4-chloro-5-((5-chloropyrazin-2-yl)thio)-2-methyl-2H-indazole (60 mg, 0.193 mmol), tert-butyl 1-((tert-butyloxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate (71 mg, 0.193 mmol) and N,N-diisopropylethylamine (49.8 mg, 0.386 mmol) were dissolved in dimethyl sulfoxide (10 mL). Under nitrogen protection, the temperature was raised to 100 degrees for 15 hours, cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (3X10 mL). The organic phase was washed twice with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. Column chromatography (ethyl acetate/petroleum ether) was purified to give 40 mg of a yellow solid with a yield of 32.2%. MS (ESI) m/z: 645 [M+H] ⁺ .

Step 18: Synthesis of 9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-amine hydrochloride

At room temperature, tert-butyl 1-((tert-butoxycarbonyl)amino)-9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (40 mg, 0.062 mmol) was dissolved in methanol (2 mL), and methanolic hydrogen chloride solution (2 mL) was added. The mixture was stirred at room temperature for 10 hours and concentrated to give 30 mg of a light yellow solid. Yield: 100%, which was used directly in the next step. MS (ESI) m/z: 223.1 [M+H] ⁺ .

Step 19: Synthesis of 9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3-(pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-1-amine

At room temperature, 9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-amine hydrochloride (30 mg, 0.058 mmol) was dissolved in ethanol (2 mL), and N,N-diisopropylethylamine (15 mg, 0.116 mmol) and 2-chloropyrimidine (13.3 mg, 0.116 mmol) were added. The reaction temperature was raised to 50 degrees, reacted for 24 hours, concentrated, and purified by column chromatography (methanol/dichloromethane = 1:20) to obtain 4 mg of a yellow solid with a yield of 13.3%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.48 (s, 1H), 8.35 (d, J = 4.7Hz, 2H), 8.30 (s, 1H), 8.13 (s, 1H), 7.54 (d, J＝9.0Hz,1H),7.07(d,J＝9.0Hz,1H),6.59(t,J＝4.7Hz,1H),4.19(s,3H),4.05-4.02(m,2H),3.96- 3.93(m,1H),3.69-3.6(m,1H),3.57-3.55(m,1H),3.40 -3.22(m,3H),2.64-2.62(m,1H),2.03–1.95(m,2H),1.65-1.63(m,2H),1.37-1.30(m,2H).MS(ESI)m/ z:522.6[M+H] ⁺ .

Example 2: Synthesis of 9-(8-((2-amino-3-chloropyridin-4-yl)thio)-(1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-1-amine (Compound I-2)

Synthesis of tert-butyl 1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate Reference Example 1.

Step 1: Synthesis of 2-chloro-4-hydrazino-5-iodopyrimidine

At room temperature, 2,4-dichloro-5-iodopyrimidine (15.57 g, 56.85 mmol) was dissolved in ethanol (100 mL), cooled to 0 degrees, and aqueous ammonia (10.7 g, 170.5 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 3 hours, filtered, and the solid was washed with ethanol and dried in vacuo to obtain 10 g of a white solid with a yield of 65%.

Step 2: Synthesis of 5-chloro-8-iodo-[1,2,4]triazolo[4,3-c]pyrimidine

At room temperature, 2-chloro-4-hydrazino-5-iodopyrimidine (7.53 g, 27.89 mmol) and trimethyl orthoformate (29.6 g, 278.9 mmol) were heated to 80 degrees under _N2 protection, reacted overnight, concentrated to dryness, and purified by column chromatography (ethyl acetate/petroleum ether = 1:4-1:1) to obtain 200 mg of white solid, yield: 3.8%.

Step 3: Synthesis of tert-butyl 1-((tert-butyloxycarbonyl)amino)-9-(8-iodo-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

At room temperature, 5-chloro-8-iodo-[1,2,4]triazolo[4,3-c]pyrimidine (159 mg, 0.568 mmol), tert-butyl 1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate (252 mg, 0.682 mmol) and N,N-diisopropylethylamine (146 mg, 1.136 mmol) were dissolved in dimethyl sulfoxide (10 mL), and the temperature was raised to 85 degrees under nitrogen protection for 2 hours. The mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (2×10 mL). The organic phase was washed twice with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. The mixture was purified by column chromatography (ethyl acetate/petroleum ether=1:1) to obtain 264 mg of a yellow solid with a yield of 75.8%.

Step 4: Synthesis of methyl 3-(2-amino-3-chloropyridin-4-yl)thio)propanoate

3-Chloro-4-iodopyridin-2-amine (2.5 g, 9.8 mmol), methyl 3-mercaptopropionate (1.3 g, 10.8 mmol), palladium acetate (110 mg, 0.49 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (340 mg, 0.59 mmol) and N,N-diisopropylethylamine (2.53 g, 19.6 mmol) were dissolved in dioxane (50 mL), the reaction temperature was raised to 100 degrees, the reaction was allowed to react for 3 hours, the mixture was concentrated and dried, and the mixture was purified by column chromatography (EA/PE=1:1) to obtain 2.28 g of a yellow solid with a yield of 94%.

Step 5: Synthesis of 2-amino-3-chloropyridine-4-sodium hydrogen sulfate

At room temperature, methyl 3-(2-amino-3-chloropyridin-4-yl)thio)propanoate (2.2 g, 8.9 mmol) was dissolved in tetrahydrofuran (28 mL), added to sodium ethoxide ethanol solution (3.2 g, 9.39 mmol), reacted for one hour under nitrogen protection, added dichloromethane (60 mL), stirred at room temperature for 10 minutes, filtered, the solid was vacuum dried and used directly in the next step.

Step 6: Synthesis of tert-butyl 9-(8-((2-amino-3-chloropyridin-4-yl)thio)-(1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate

At room temperature, 2-amino-3-chloropyridine-4-sodium hydrogen sulfate (94 mg, 0.518 mmol), tert-butyl 1-((tert-butyloxycarbonyl)amino)-9-(8-iodo-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (212 mg, 0.346 mmol), tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.034 6mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (40mg, 0.0692mmol) and N,N-diisopropylethylamine (111mg, 0.865mmol) were dissolved in dioxane (10mL), the reaction temperature was raised to 100 degrees, the reaction was carried out for 3 hours, the reaction mixture was concentrated and dried, and the mixture was purified by column chromatography (methanol/dichloromethane = 1:20-10) to obtain 138mg of a brown-yellow solid, with a yield of 61.8%.

Step 7: Synthesis of 9-(8-((2-amino-3-chloropyridin-4-yl)thio)-(1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undec-1-amine hydrochloride

At room temperature, tert-butyl 9-(8-((2-amino-3-chloropyridin-4-yl)thio)-(1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate (130 mg, 0.2 mmol) was dissolved in methanol (8 mL), and a methanol solution of hydrochloric acid (4 M, 4 mL) was added. The mixture was stirred at room temperature overnight, concentrated and dried, and used directly in the next step.

Step 8: Synthesis of 9-(8-((2-amino-3-chloropyridin-4-yl)thio)-(1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-1-amine

At room temperature, 9-(8-((2-amino-3-chloropyridin-4-yl)thio)-(1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undec-1-amine hydrochloride (0.2mmol), dichloropyrimidine (64mg, 0.565mmol) and N,N-diisopropylethylamine (104mg, 0.806mmol) were dissolved in dimethyl sulfoxide (2mL), heated to 50 degrees, reacted under nitrogen for 24 hours, cooled to room temperature, added with water (20mL), extracted with ethyl acetate (2X10mL), combined organic phases, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (methanol/dichloromethane=1:20) to obtain ^10mg of white solid, yield: 9.5%. NMR (400MHz, DMSO) δ9.40(s,1H),8.37(d,J＝4.8Hz,2H),7.97(s,1H),7.58(d,J＝5.4Hz,1H),6.63(t,J＝4.8Hz,1H),6.34(s,2H),5.95(d,J＝5.4Hz,1H),4.01( m,2H),3.86(m,1H),3.62(m,3H),3.31–3.24(m,2H),2.83(m,1H),2.03(m,2H),1.72(m,2H),1.54(m,2H).MS(ESI)m/z:524.44[M+H] ⁺ .

Example 3: Synthesis of 9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-(1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-1-amine (Compound I-3)

Synthesis of tert-butyl 1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate Reference Example 1.

Step 1: Synthesis of 2,2,2-trichloroethyl 1-((tert-butyloxycarbonyl)amino)-9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-(1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

At room temperature, 4-chloro-2-methyl-2H-indazole-5-sodium hydrogen sulfate (60 mg, 0.274 mmol), 2-(trimethylsilyl)ethyl 1-(tert-butoxycarbonyl)amino)-9-(8-iodo-[1,2,4]triazolyl[4,3-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (150 mg, 0.228 mmol), tris(dibenzylideneacetone)dipalladium(0) (21 mg, 0.0228mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (26.5mg, 0.0456mmol) and N,N-diisopropylethylamine (58.8mg, 0.456mmol) were dissolved in dioxane (20mL), the reaction temperature was raised to 100 degrees, the reaction was carried out for 3 hours, the reaction was concentrated and dried, and the reaction was purified by column chromatography (methanol/dichloromethane = 1:20-10) to obtain 132mg of brown yellow solid, yield: 79.5%.

Step 2: Synthesis of tert-butyl (9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-(1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate

At room temperature, 2,2,2-trichloroethyl 1-((tert-butoxycarbonyl)amino)-9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-(1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (130 mg, 0.179 mmol) was dissolved in tetrahydrofuran (2 mL), tetrabutylammonium fluoride monohydrate (113 mg, 0.357 mmol) was added, and the mixture was reacted at 30 degrees for 5 hours, dried by rotation, water (20 mL) was added, and the mixture was extracted with ethyl acetate (2×20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotation. The mixture was purified by column chromatography (methanol/dichloromethane=1:20-1:5) to give 60 mg of a light yellow solid with a yield of 57%.

Step 3: Synthesis of tert-butyl (9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-(1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(pyrimidin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate

At room temperature, tert-butyl (9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-(1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate (60 mg, 0.103 mmol) was dissolved in dimethyl sulfoxide (2 mL), N,N-diisopropylethylamine (32 mg, 0.247 mmol) and 2-chloropyrimidine (14 mg, 0.123 mmol) were added, the reaction temperature was raised to 40 degrees, the reaction was reacted for 3 hours, cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (2×10 mL). The organic phase was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and purified by column chromatography (ethyl acetate/petroleum ether=1:1) to give 53 mg of a yellow solid, yield: 78%.

Step 4: Synthesis of 9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-(1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-1-amine

At room temperature, tert-butyl (9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-(1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(pyrimidin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate (50 mg, 0.076 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 3 hours under nitrogen protection, and then dried by rotation. Aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (2×10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotation. The mixture was purified by column chromatography (methanol/dichloromethane=1:20) to obtain 8 mg of a white solid, with a yield of 19%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.36(s,1H),8.48(s,1H),8.39(d,J＝4.7Hz,2H),7.82(s,1H),7.46(d,J＝9.0Hz,1H),7.03(d,J＝9.0Hz,1H),6.66(t,J＝4.7Hz,1H),4.18(s,3H),3.90 -3.8(m,4H),3.69-3.6(m,1H),3.54-3.5(m,2H),3.39 -3.3(m,2H),3.03-3(m,1H),2.07–1.97(m,2H),1.82-1.79(m,2H),1.65-1.5(m,2H).MS(ESI)m/z :562.5[M+H] ⁺ .

Example 4: Synthesis of 9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-1-amine (I-4)

Synthesis of tert-butyl (9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate Reference Example 1.

Step 1: Synthesis of tert-butyl (9-(5-(4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate

At room temperature, tert-butyl (9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate (53 mg, 0.098 mmol) was dissolved in dimethyl sulfoxide (2 mL), N,N-diisopropylethylamine (30 mg, 0.235 mmol) and 2-chloro-5-trifluoromethylpyrimidine (21.3 mg, 0.117 mmol) were added, the reaction temperature was raised to 40 degrees, the reaction was reacted for 3 hours, cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (2×10 mL). The organic phase was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and purified by column chromatography (ethyl acetate/petroleum ether=1:1) to give 30 mg of a yellow solid, yield: 44.4%.

Step 2: Synthesis of 9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-1-amine

At room temperature, tert-butyl (9-(5-(4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate (30 mg, 0.0435 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 3 hours under nitrogen protection, dried by rotation, and aqueous sodium bicarbonate solution was added, extracted with ethyl acetate (2×10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was dried by rotation, and purified by column chromatography (methanol/dichloromethane=1:20) to give 24 mg of a white solid, yield: 93.7%. ¹ H NMR (400MHz, DMSO) δ8.70(s,2H),8.48(s,1H),8.32(d,J＝1.5Hz,1H),8.13(d,J＝1.3Hz,0H),7.55(d,J＝8.8Hz,1H),7.08(d,J＝8.8Hz,1H),4.19(s,3H),4 .02(m,1H),3.87(m,2H),3.78(m,1H),3.46(m,2H),3.25(m,2H),2.84(m,1H),2.06–1.93(m,2H),1.63(m,2H),1.47(m,2H). MS(ESI)m/z:590.5[M+H] ⁺ .

Example 5: Synthesis of 9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3-(5-chloropyrimidin-2-yl)-3,9-diazaspiro[5.5]undecan-1-amine (I-5)

Synthesis of tert-butyl (9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate Reference Example 1.

Step 1: Synthesis of tert-butyl (9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3-(5-chloropyrimidin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate

At room temperature, tert-butyl (9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate (40 mg, 0.074 mmol) was dissolved in dimethyl sulfoxide (2 mL), N,N-diisopropylethylamine (22.8 mg, 0.177 mmol) and 2,5-dichloropyrimidine (13 mg, 0.088 mmol) were added, the reaction was heated to 40 degrees, reacted for 5 hours, cooled to room temperature, water (20 mL) was added, extracted with ethyl acetate (2X10 mL), the organic phase was washed twice with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and purified by column chromatography (ethyl acetate/petroleum ether=1:1-1:0) to give 43 mg of light yellow solid, yield: 88.8%.

Step 2: Synthesis of 9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3-(5-chloropyrimidin-2-yl)-3,9-diazaspiro[5.5]undecan-1-amine

At room temperature, tert-butyl (9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3-(5-chloropyrimidin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate (42 mg, 0.064 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 3 hours under nitrogen protection, dried by rotation, and aqueous sodium bicarbonate solution was added, extracted with ethyl acetate (2×10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was dried by rotation, and purified by column chromatography (methanol/dichloromethane=1:20-1:10) to give 26 mg of a white solid, yield: 57.14%. ¹ H NMR (400MHz, DMSO) δ8.48(s,1H),8.40(s,2H),8.30(d,J＝1.5Hz,1H),8.13(d,J＝1.4Hz,1H),7.54(d,J＝9.0Hz,1H),7.07(d,J＝8.9Hz,1H),4.19(s,3H),4 .02–3.87(m,4H),3.60(m,1H),3.46(m,1H),3.25(m,2H),2.67(m,1H),1.97(m,2H),1.62(m,2H),1.34(m,2H).MS(ESI)m/z:556.4[M+H] ⁺ .

Example 6: Synthesis of 9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-(pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-1-amine (I-6)

Synthesis of tert-butyl 9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate Reference Example 1.

Step 1: Synthesis of 9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-amine hydrochloride

At room temperature, tert-butyl 9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate (90 mg, 0.149 mmol) was dissolved in methanol (5 mL), and a methanol solution of hydrogen chloride (3 mL) was added. The mixture was stirred at room temperature for 10 hours and concentrated to give 30 mg of a light yellow solid (yield: 100%), which was used directly in the next step.

Step 2: Synthesis of 9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-(pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-1-amine

At room temperature, 9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-amine hydrochloride (0.149 mmol) was dissolved in DMSO (2 mL), N,N-diisopropylethylamine (96 mg, 0.745 mmol) and 2-chloropyrimidine (26 mg, 0.224 mmol) were added, the reaction temperature was raised to 50 degrees, the reaction was allowed to react for 24 hours, concentrated, and purified by column chromatography (methanol/dichloromethane = 1:20) to obtain 15 mg of a yellow solid with a yield of 20.8%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.47(s,1H),8.37(d,J＝4.7Hz,2H),8.30(s,1H),7.66(d,J＝5.4Hz,1H),6.63(t,J＝4.7Hz,1H),6.34(s,2H),5.82(d,J＝5.4Hz,1H),4.15–4.05(m,2H) ,3.99-3.89( m,1H),3.86–3.79(m,1H),3.7-3.66(m,1H),3.37-3.39(m,2H),2.85-2.8(m,1H),2.00-1.92(m,2H),1.66-1.5(m,2H),1.48-1.34(m,2H).MS(ESI)m/ z:484.46[M+H] ⁺ .

Example 7: Synthesis of 9-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-(pyrimidin-2-yl)-3,9-diazaspiro[5.5]undec-1-amine (I-7)

Synthesis of tert-butyl (9-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate Reference Example 1.

Step 1: Synthesis of tert-butyl (9-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-(pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate

At room temperature, tert-butyl (9-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate (80 mg, 0.147 mmol) was dissolved in dimethyl sulfoxide (2 mL), N,N-diisopropylethylamine (46 mg, 0.353 mmol) and 2-chloropyrimidine (20 mg, 0.176 mmol) were added, the reaction temperature was raised to 60 degrees, the reaction was reacted for 5 hours, cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (2×10 mL). The organic phase was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and purified by column chromatography (methanol/dichloromethane=1:20) to give 40 mg of a yellow solid, yield: 44%.

Step 2: Synthesis of 9-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-(pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecan-1-amine

At room temperature, tert-butyl (9-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-(pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (40 mg, 0.064 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours under nitrogen protection, dried by rotation, and aqueous sodium bicarbonate solution was added, extracted with ethyl acetate (2×10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was dried by rotation, and purified by column chromatography (methanol/dichloromethane=1:20) to give 25 mg of a white solid, yield: 75.6%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.39 (d, J = 4.7Hz, 1H), 8.03 (s, 1H), 7.59 (s, 1H), 7.55 (d, J = 5.4Hz, 1H), 6.66 (t, J = 4.6Hz, 1H), 6.33 (s, 2H), 5.80 (d ,J＝5.3Hz,1H),3.94–3.71(m,6H),3.46(m,2H),3.05-2.95(m,1H),2.16–2.02(m,2H),1.85-1.7(m,2H),1.64–1.44(m,2H).MS(ESI)m/z:523.45[M+H] ⁺ .

Example 8: Synthesis of 9-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-(methylsulfonyl)-3,9-diazaspiro[5.5]undecane-1-amine (I-8)

Synthesis of tert-butyl (9-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate Reference Example 1.

Step 1: Synthesis of tert-butyl (9-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-(methylsulfonyl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate

At room temperature, tert-butyl (9-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (50 mg, 0.092 mmol) was dissolved in dichloromethane (10 mL), N,N-diisopropylethylamine (24 mg, 0.184 mmol) and methyl chloride (12.6 mg, 0.11 mmol) were added, and the mixture was reacted for half an hour at 0 degrees. Water (20 mL) was added, and the organic phase was separated. The organic phase was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and purified by column chromatography (methanol/dichloromethane=1:20) to obtain 40 mg of a yellow solid with a yield of 70%.

Step 2: Synthesis of 9-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-(methylsulfonyl)-3,9-diazaspiro[5.5]undecane-1-amine

At room temperature, tert-butyl (3-acetyl-9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (40 mg, 0.064 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 3 hours under nitrogen protection, and then dried by rotation. Aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (2×10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotation. The filtrate was purified by column chromatography (methanol/dichloromethane=1:20) to obtain 12 mg of a white solid, with a yield of 35.7%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.01(s,1H),7.84(s,1H),7.58–7.52(m,2H),6.32(s,2H),5.79(d,J＝5.4Hz,1H),3.86–3.77(m,2H),3.38-3.3(m,2H),3.2-3.24(m,2H),3.19-3. 11(m,1H),3.11-3.09(m,1H),2.89(s,3H),2.66(m,1H),2.17–2.06(m,2H),1.85-1.8(m,1H),1.67-1.61(m,1H),1.45-1.38(m,2H).MS(ESI)m/z:52 3.48[M+H] ⁺ .

Example 9: Synthesis of 9-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-(pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-1-amine (I-9)

Synthesis of tert-butyl 9-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate Reference Example 1.

Step 1: Synthesis of 9-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-amine hydrochloride

At room temperature, tert-butyl 9-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazine-2-yl)-1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate (100 mg, 0.16 mmol) was dissolved in dioxane (2 mL), and dioxane hydrochloride (2 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction solution was directly concentrated to dryness to obtain 130 mg of the crude target product as a white solid. MS (ESI) m/z: 421.5 [M+H] ⁺ .

Step 2: Synthesis of 9-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-(pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-1-amine

At room temperature, 9-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-amine hydrochloride (100 mg, 0.237 mmol) was dissolved in DMSO (5 mL), 2-chloropyrimidine (41 mg, 0.36 mmol) and DIEA (0.12 g, 0.95 mmol) were added, the temperature was raised to 80°C, stirred for 1 hour, the reaction was completed, cooled to room temperature, water (100 mL) and ethyl acetate (100 mL) were added for separation, the aqueous phase was extracted with ethyl acetate (50 mL*2), the organic phases were combined, and the organic phases were washed with saturated brine (100 mL*2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and freeze-dried to obtain 0.014 g of the target product as an off-white solid with a yield of 12%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.33(d,J＝4.7Hz,2H),7.68–7.57(m,2H),6.57(t,J＝4.7Hz,1H),6.25(s,2H),6.11(s,2H),5.75(d,J＝5.4Hz,1H),4.11–3.86(m,4H),3.46(t,J＝10. 8Hz,1H),3.22(dt,J＝16.0,7.6Hz,3H),2.07(d,J＝13.4Hz,1H),2.01–1.94(m,1H),1.64(d,J＝5.6Hz,2H),1.27(d,J＝13.4Hz,2H).MS(ESI)m/z:499.5[M+H] ⁺ .

Example 10: Synthesis of 2-(7-amino-9-(pyrimidin-2-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-3,6-dimethylpyrimidin-4(3H)-one (I-10)

Synthesis of tert-butyl 1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate Reference Example 1.

Step 1: Synthesis of 5-bromo-2-chloro-6-methylpyrimidin-4(3H)-one

At room temperature, 5-bromo-2,4-dichloro-6-methylpyrimidine (3 g, 12.5 mmol) was dissolved in tetrahydrofuran (14 mL), and 2 M aqueous sodium hydroxide solution (10 mL) was added. The mixture was stirred over the weekend, and water (30 mL) was added to the reaction solution. The pH was adjusted to 1 with 1 M dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (2×30 mL). The organic phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate/petroleum ether=1:1) to obtain 1.3 g of a yellow solid. The yield was 47%, and MS (ESI) m/z: 223.3 [M+H] ⁺ .

Step 2: Synthesis of 5-bromo-2-chloro-3,6-dimethylpyrimidin-4(3H)-one

At room temperature, 5-bromo-2-chloro-6-methylpyrimidin-4(3H)-one (1.29 g, 5.8 mmol) was dissolved in tetrahydrofuran (20 mL), and N,N-diisopropylethylamine (1.12 g, 8.7 mmol) and iodomethane (1.24 g, 8.7 mmol) were added. The mixture was protected by nitrogen and heated to 60 degrees. The reaction was allowed to react overnight. The reaction solution was directly dried by spin drying and purified by column chromatography (ethyl acetate/petroleum ether = 1:4) to obtain 620 mg of light yellow solid. The yield was 45%. MS (ESI) m/z: 237.2 [M+H] ⁺ .

Step 3: Synthesis of tert-butyl 9-(5-bromo-1,4-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate

A suspension of 5-bromo-2-chloro-3,6-dimethylpyrimidin-4(3H)-one (63.7 mg, 0.27 mmol), tert-butyl 1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate (100 mg, 0.27 mmol) and potassium carbonate (130 mg, 0.945 mmol) in acetonitrile (10 mL) was heated to 80 degrees, reacted overnight under nitrogen protection, concentrated to dryness, and purified by column chromatography (ethyl acetate/petroleum ether=1:1) to obtain 142 mg of colorless oil, yield: 92.2%, MS (ESI) m/z: 570.3 [M+H] ⁺ .

Step 4: Synthesis of tert-butyl 1-((tert-butoxycarbonyl)amino)-9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-1,4-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

A suspension of tert-butyl 9-(5-bromo-1,4-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-1-((tert-butyloxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate (62 mg, 0.109 mmol), 4-chloro-2-methyl-2H-indazole-5-sodium hydrogen sulfate (36 mg, 0.163 mmol), cuprous iodide (3.1 mg, 0.0163 mmol), potassium phosphate (35 mg, 0.163 mmol) and 1,10-phenanthroline (3 mg, 0.0163 mmol) in dioxane (2 mL) was heated to 110 degrees, reacted under nitrogen protection for 50 hours, concentrated and dried, and purified by column chromatography (ethyl acetate) to obtain 30 mg of colorless oil with a yield of 40.5%. MS (ESI) m/z: 688.9 [M+H] ⁺ .

Step 5: Synthesis of 2-(7-amino-3,9-diazaspiro[5.5]undecen-3-yl)-5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-3,6-dimethylpyrimidine-4(3H)-hydrochloride

At room temperature, tert-butyl 1-((tert-butyloxycarbonyl)amino)-9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-1,4-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (30 mg, 0.0436 mmol) was dissolved in methanol (2 mL), and a hydrochloric acid dioxane solution (4 M, 1 mL) was added. The mixture was stirred at room temperature overnight, concentrated and dried, and used directly in the next step. MS (ESI) m/z: 488.1 [M+H] ⁺ .

Step 6: Synthesis of 2-(7-amino-9-(pyrimidin-2-yl)-3,9-diazaspiro[5.5]undec-3-yl)-5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-3,6-dimethylpyrimidin-4(3H)-one

2-(7-amino-3,9-diazaspiro[5.5]undecen-3-yl)-5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-3,6-dimethylpyrimidine-4(3H)-hydrochloride (30 mg, 0.062 mmol), dichloropyrimidine (8.4 mg, 0.074 mmol) and N,N-diisopropylethylamine (32 mg, 0.248 mmol) were dissolved in dimethyl sulfoxide (1 mL), heated to 50 degrees, reacted for 48 hours under nitrogen, cooled to room temperature, added with water (20 mL), extracted with ethyl acetate (2×10 mL), combined organic phases, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (methanol/dichloromethane=1:20) to obtain 10 mg of white solid, yield: 28.7%, MS (ESI) m/z: 566.5 [M+H] ⁺ .

Example 11: Synthesis of 9-(6-amino-5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3-(pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecan-1-amine (I-11)

Synthesis of tert-butyl 9-(6-amino-5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate Reference Example 1.

Step 1: Synthesis of 9-(6-amino-5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-1-amine hydrochloride

At room temperature, tert-butyl 9-(6-amino-5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate (40 mg, 0.061 mmol) was dissolved in methanol (2 mL), and dioxane hydrochloride solution (4 M, 1 mL) was added. The mixture was stirred at room temperature overnight, concentrated and dried, and used directly in the next step. MS (ESI) m/z: 230.4 [M+H] ⁺ .

Step 2: Synthesis of 9-(6-amino-5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3-(pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecan-1-amine

9-(6-amino-5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-1-amine hydrochloride (40 mg, 0.087 mmol), dichloropyrimidine (10 mg, 0.087 mmol) and N,N-diisopropylethylamine (45 mg, 0.348 mmol) were dissolved in dimethyl sulfoxide (2 mL), heated to 50 degrees, reacted under nitrogen for 48 hours, cooled to room temperature, added with water (20 mL), extracted with ethyl acetate (2X10 mL), combined organic phases, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (methanol/dichloromethane = 1:20) to obtain 8 mg of white solid, with a yield of 17.4%. MS (ESI) m/z: 537.1 [M+H] ⁺ .

Example 12: Synthesis of 1-(1-amino-9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)ethan-1-one (I-12)

Synthesis of 2-(trimethylsilyl)ethyl 1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate Reference Example 1.

Step 1: Synthesis of 2,2,2-trichloroethyl 1-((tert-butyloxycarbonyl)amino)-9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

At room temperature, 5-chloro-8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)imidazole[1,2-c]pyrimidine (90 mg, 0.258 mmol), 1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid 2-(trimethylsilyl)ethyl ester (130 mg, 0.292 mmol) and N,N-diisopropylethylamine (73 mg, 0.567 mmol) were dissolved in dimethyl sulfoxide (2 mL). The temperature was raised to 110 degrees under microwave conditions for 2 hours. The mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (2×10 mL). The organic phase was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The mixture was purified by column chromatography (methanol/dichloromethane=1:20) to give 150 mg of a yellow solid with a yield of 80%.

Step 2: Synthesis of tert-butyl (9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate

At room temperature, (150 mg, 0.206 mmol) was dissolved in tetrahydrofuran (20 mL), tetrabutylammonium fluoride monohydrate (130 mg, 0.412 mmol) was added, and the mixture was reacted at 30 degrees for 5 hours, dried by rotation, water (20 mL) was added, and the mixture was extracted with ethyl acetate (2×20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotation. The mixture was purified by column chromatography (methanol/dichloromethane=1:20-1:5) to give 70 mg of a dark green solid, with a yield of 58.1%.

Step 3: Synthesis of tert-butyl (3-acetyl-9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate

At room temperature, (70 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL), and N, N-diisopropylethylamine (37 mg, 0.288 mmol) and acetyl chloride (11.3 mg, 0.144 mmol) were added. The reaction was carried out at 0 degrees for half an hour, and water (20 mL) was added. The organic phase was separated, and the organic phase was washed twice with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin drying. Purification by column chromatography (methanol/dichloromethane = 1:20) gave 45 mg of a yellow solid, with a yield of 60.8%.

Step 4: Synthesis of 1-(1-amino-9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)ethan-1-one

At room temperature, tert-butyl (3-acetyl-9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (45 mg, 0.072 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 3 hours under nitrogen protection, and dried by rotation. Aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (2×10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotation. The mixture was purified by column chromatography (methanol/dichloromethane=1:20) to give 25 mg of a white solid, with a yield of 66%. ¹ H NMR (400MHz, DMSO-d ₆ )8.48(s,1H),7.79(s,1H),7.72(s,1H),7.58(s,1H),7.45(d,J＝8.9Hz,1H),7.00(d,J＝9.0Hz,1H),4.18(s,3H),3.71–3.45(m,6H ),3.3–3.2(m,2H),2.83-2.76(m,1H),2.02(s,3H),1.93–1.78(m,2H),1.62–1.54(m,2H),1.5-1.38(m,2H).MS(ESI)m/z:525.4[M+H] ⁺ Example 13: Synthesis of N-(3-((5-(7-amino-9-(pyrimidin-2-yl)-3,9-diazaspiro[5.5]undec-3-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxy-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide (I-13)

Synthesis of tert-butyl 1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate Reference Example 1.

Step 1: Synthesis of 2-chloro-3-((5-chloropyrazin-2-yl)thio)aniline

At room temperature, 2,5-dichloropyrazine (329 mg, 2.21 mmol), sodium 3-amino-2-chlorobenzene sulfate (400 mg, 2.21 mmol) and potassium carbonate (607 mg, 4.4 mmol) were dissolved in DMF/ACN (10 mL/10 mL), reacted at 85 degrees for 3 hours under N2 protection, cooled to room temperature, filtered, the filtrate was dried, and purified by column chromatography (EA/PE=1:4) to obtain 170 mg of yellow solid with a yield of 28%.

Step 2: Synthesis of tert-butyl 9-(5-(3-amino-2-chlorophenyl)thio)pyrazin-2-yl)-1-(tert-butyloxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate

At room temperature, 2-chloro-3-((5-chloropyrazin-2-yl)thio)aniline (95 mg, 0.35 mmol), 1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (129 mg, 0.35 mmol) and N,N-diisopropylethylamine (90 mg, 0.7 mmol) were dissolved in dimethyl sulfoxide (2 mL), heated to 100 degrees under microwave conditions for 2 hours, cooled to room temperature, added with water (20 mL), extracted with ethyl acetate (2×10 mL), the organic phase was washed twice with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and purified by column chromatography (ethyl acetate/petroleum ether=1:1) to obtain 138 mg of a yellow solid, yield: 65.4%. Step 3: Synthesis of tert-butyl 1-((tert-butyloxycarbonyl)amino)-9-(5-((2-chloro-3-(2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyridin[1,2-a]pyrimidine-3-carboxamido)phenyl)thio)pyrazin-2-yl)-3,9-diazaspiro[5,5]undecane-3-carboxylate

At room temperature, tert-butyl 9-(5-(3-amino-2-chlorophenyl)thio)pyrazine-2-yl)-1-(tert-butyloxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate (130 mg, 0.215 mmol) and methyl 2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyridine[1,2-a]pyrimidine-3-carboxylate (58 mg, 0.258 mmol) were dissolved in bromobenzene (2 mL), and the mixture was reacted at 160 degrees in a microwave for 2 hours. The solvent was dried and purified by column chromatography (ethyl acetate/petroleum ether=1:1) to give 152 mg of a yellow solid with a yield of 88.8%.

Step 4: Synthesis of N-(3-((5-(7-amino-3,9-diazaspiro[5.5]undec-3-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyridinyl[1,2-a]pyrimidine-3-carboxamide hydrochloride

At room temperature, tert-butyl 1-((tert-butoxycarbonyl)amino)-9-(5-((2-chloro-3-(2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyridin[1,2-a]pyrimidine-3-carboxamido)phenyl)thio)pyrazin-2-yl)-3,9-diazaspiro[5,5]undecane-3-carboxylate (150 mg, 0.188 mmol) was dissolved in methanol (8 mL), and a methanol solution of hydrochloric acid (4 M, 4 mL) was added. The mixture was stirred at room temperature overnight, concentrated and dried, and used directly in the next step.

Step 5: Synthesis of N-(3-((5-(7-amino-9-(pyrimidin-2-yl)-3,9-diazaspiro[5.5]undec-3-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxy-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide

N-(3-((5-(7-amino-3,9-diazaspiro[5.5]undec-3-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyridyl[1,2-a]pyrimidine-3-carboxamide hydrochloride (0.188 mmol), dichloropyrimidine (32 mg, 0.282 mmol) and N,N-diisopropylethylamine (97 mg, 0.753 mmol) were dissolved in dimethyl sulfoxide (5 mL), heated to 50 degrees, reacted under nitrogen for 15 hours, cooled to room temperature, added with water (20 mL), extracted with ethyl acetate (2×10 mL), combined the organic phases, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (methanol/dichloromethane=1:20) to obtain 10 mg of a white solid, yield: 8%. ¹ H NMR (400MHz, DMSO) δ14.18(s,1H),13.08(s,1H),8.39(s,1H),8.33(d,J＝4.8Hz,2H),8.25(s,1H),7.71(m,1H),7.24(m,1H),6.63(m,1H),6.57(m,1H ),4.07(m,4H),4.0(m,2H),3.83–3.76(m,2H),3.29–3.25(m,2H),2.70(m,1H),2.34(m,2H),2.00(m,2H),1.86(m,2H),1.77(m,2H),1.66(m,2H), 1.46(m,2H). MS (ESI) m/z: 675.5 [M + H] ⁺ .

Example 14: Synthesis of 9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-1-amine (I-14)

Synthesis of tert-butyl 1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate Reference Example 1.

Step 1: Synthesis of 2-chloro-N-(2,2-dimethoxyethyl)-5-iodopyrimidin-4-amine

At room temperature, 2,4-dichloro-5-iodopyrimidine (15 g, 0.0547 mol) and aminoacetaldehyde dimethyl acetal (11.5 g, 0.109 mol) were dissolved in ethanol (200 mL), cooled to 0 degrees, triethylamine (11 g, 0.109 mol) was added dropwise, and the temperature was naturally raised to a large amount of white solid. The suspension was stirred overnight and concentrated under reduced pressure. Water (100 mL) was added to the concentrate, and it was extracted with dichloromethane (3X100 mL). The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 18 grams of crude product, which was directly used in the next step with a yield of 96%. MS (ESI) m/z: 334.3 [M + H] ⁺ .

Step 2: Synthesis of 8-iodoimidazole[1,2-c]pyrimidin-5-ol

At room temperature, 2-chloro-N-(2,2-dimethoxyethyl)-5-iodopyrimidine-4-amine (17.8 g, 51.9 mmol) was slowly added to concentrated sulfuric acid (100 mL), the reaction temperature was raised to 65 degrees, the reaction was allowed to react for 2 hours, and the reaction solution was slowly added to a large amount of ice cubes. The pH value of the solution was adjusted to 6 with 4 M sodium hydroxide aqueous solution. A large amount of light yellow solid precipitated, which was filtered, washed with water, and vacuum dried to obtain 10 grams of light yellow solid with a yield of 59%.

Step 3: Synthesis of 5-chloro-8-iodoimidazole[1,2-c]pyrimidine

At room temperature, 8-iodoimidazole [1,2-c] pyrimidine-5-ol (8.5 g, 32.6 mmol) was slowly added to phosphorus oxychloride (80 mL), and diisopropylethylamine (2 mL) was slowly added dropwise. The reaction solution was heated to 120 degrees and reacted overnight. The next day, the solution was spin-dried and a saturated aqueous solution of sodium bicarbonate was slowly added dropwise to adjust the pH to > 7. The solution was extracted with ethyl acetate (2X20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (ethyl acetate, petroleum ether = 1:9-1:4) to obtain 440 mg of a light yellow solid with a yield of 4.5%. MS (ESI) m/z: 280.2 [M+H] ⁺ .

Step 4: Synthesis of 5-chloro-8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)imidazo[1,2-c]pyrimidine

5-Chloro-8-iodoimidazole[1,2-c]pyrimidine (190 mg, 0.68 mmol), 4-chloro-2-methyl-2H-indazole-5-hydrogensulfate (224 mg, 1 mmol), tris(dibenzyl-baseacetone)dipalladium(0) (62 mg, 0.068 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (79 mg, 0.136 mmol) and N,N-diisopropylethylamine (263 mg, 2.04 mmol) were dissolved in dioxane (10 mL), heated to 90 degrees, reacted under nitrogen protection for 18 hours, concentrated and dried, added with dichloromethane, filtered, the filtrate was dried, and purified by column chromatography (ethyl acetate/petroleum ether=1:4) to obtain 190 mg of a yellow solid with a yield of 90%. MS (ESI) m/z: 350.3 [M+H] ⁺ .

Step 5: Synthesis of tert-butyl 1-((tert-butoxycarbonyl)amino)-9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

At room temperature, 5-chloro-8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)imidazole (120 mg, 0.344 mmol), tert-butyl 1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate (152 mg, 0.41 mmol) and N,N-diisopropylethylamine (88.7 mg, 0.688 mmol) were dissolved in dimethyl sulfoxide (10 mL). In the reaction mixture, the temperature was raised to 80 degrees under nitrogen protection for 15 hours, cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (2X10 mL). The organic phase was washed twice with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The filtrate was purified by column chromatography (ethyl acetate/petroleum ether = 1:1-1:0) to obtain 100 mg of a yellow solid, with a yield of 42.6%, and MS (ESI) m/z: 683.5 [M+H] ⁺

Step 6: Synthesis of 9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-1-amine hydrochloride

At room temperature, tert-butyl 1-((tert-butoxycarbonyl)amino)-9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (100 mg, 0.147 mmol) was dissolved in methanol (5 mL), and dioxane hydrochloride solution (4 M, 2 mL) was added. The mixture was stirred at room temperature overnight, concentrated and dried, and used directly in the next step. MS (ESI) m/z: 242.4 [M+H] ⁺ .

Step 7: Synthesis of 9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-(pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-1-amine

9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-1-amine hydrochloride (0.147 mmol), dichloropyrimidine (25 mg, 0.22 mmol) and N,N-diisopropylethylamine (76 mg, 0.587 mmol) were dissolved in dimethyl sulfoxide (2 mL), heated to 70 degrees, reacted under nitrogen for 48 hours, cooled to room temperature, added with water (20 mL), extracted with ethyl acetate (2X10 mL), combined the organic phases, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (methanol/dichloromethane=1:20) to obtain 10 mg of a white solid with a yield of 12%. ¹ HNMR (400MHz, DMSO) δ8.48(s,1H),8.35(d,J＝4.7Hz,2H),7.81(d,J＝1.5Hz,1H),7.73(s,1H),7.58(d,J＝1.5Hz,1H),7.47(d,J＝9Hz,1H),7.00(d,J＝9Hz,1H ),6.60(t,J＝4.8Hz,1H),4.19(s,3H),4.06–3.57(m,6H),3.31-3.27(m,2H),2.69-2.66(m,1H).1.92–1.41(m,6H).MS(ESI)m/z:561.46[M+H] ⁺ .

Example 15: Synthesis of 9-(5-(2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-(5-methylpyrimidin-2-yl)-3,9-diazaspiro[5.5]undecan-1-amine (I-15)

Synthesis of 2-(trimethylsilyl)ethyl 1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate Reference Example 1.

Step 1: Synthesis of 2-(trimethylsilyl)ethyl 9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate

3-Chloro-4-((5-chloropyrazin-2-yl)thio)pyridin-2-amine (300 mg, 1.1 mmol), 2-(trimethylsilyl)ethyl 1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate (560 mg, 1.3 mmol), DIEA (780 mg, 6.0 mmol), and NMP (5 ml) were added to the reaction flask in sequence, and the temperature was raised to 100 degrees Celsius and stirred overnight under nitrogen protection. LCMS detected that the raw material reaction was complete. Water (100 ml) and ethyl acetate (100 ml x 2) were added to the reaction solution, and the organic phase was dried and spin-dried. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 15: 1) to obtain 570 mg of yellow solid. Yield: 80%. MS (ESI) m/z: 650.1 [M+H] ⁺ . Step 2: Synthesis of tert-butyl (9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate

Dissolve 2-(Trimethylsilyl)ethyl 9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate (570 mg, 0.87 mmol) in tetrahydrofuran (10 ml), add TBAF (550 mg, 1.74 mmol) to the reaction bottle, and stir at room temperature overnight. LCMS detected that the raw material reacted completely. The reaction solution was directly purified by reverse flash to obtain 300 mg of yellow solid. Yield: 70%. MS (ESI) m/z: 506.2 [M + H] ⁺

Step 3: Synthesis of tert-butyl (9-(5-(2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-(5-methylpyrimidin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate

Tert-butyl (9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate (30 mg, 0.06 mmol), 2-chloro-5-methylpyrimidine (20 mg, 0.15

mmol), DIEA (130mg, 1.0mmol) and NMP (2ml) were added to the reaction flask in sequence, and the temperature was raised to 60 degrees Celsius and stirred overnight under nitrogen protection. LCMS detected that the raw material reaction was complete. Ethyl acetate (50ml*3) and water (100ml) were added to the reaction solution, and the organic phase was dried and concentrated. The crude product was separated and purified by silica gel preparation plate (dichloromethane: methanol = 15:1) to obtain 20 mg of light yellow oil. Yield: 60%. MS (ESI) m/z: 638.2 [M + H] ⁺

Step 4: Synthesis of 9-(5-(2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-(5-methylpyrimidin-2-yl)-3,9-diazaspiro[5.5]undecan-1-amine

Tert-butyl (9-(5-(2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-(5-methylpyrimidin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate (20 mg, 0.03 mmol) was dissolved in a mixed solvent of EA (5 ml) and HCl/EA (5 ml) and stirred for 10 min. LCMS detected that the raw material was completely reacted. The reaction solution was directly spin-dried. The crude oil was dissolved in dichloromethane (100 ml), washed with saturated sodium bicarbonate solution, and the organic phase was dried and spin-dried. The crude product was purified by silica gel preparation plate (dichloromethane: methanol = 10: 1) to obtain 10 mg of the final product. The yield was 60%. MS (ESI) m/z: 538.5 [M + H] ⁺ .

Example 16: Synthesis of 1-(1-amino-9-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-3-yl)ethan-1-one (I-16)

Synthesis of tert-butyl (9-(8-iodoimidazole [1,2-c] pyrimidin-5-yl) -3,9-diazolido [5.5] undecane-1-yl) carbamate Reference Example 1.

Step 1: Synthesis of tert-butyl (3-acetyl-9-(8-iodoimidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate

At room temperature, tert-butyl (9-(8-iodoimidazole [1,2-c] pyrimidin-5-yl) -3,9-diazolyl [5.5] undecane-1-yl) carbamate (0.50 g, 0.10 mmol), potassium carbonate (0.03 g, 0.20 mmol), acetonitrile (2 mL) were added to the reaction flask in sequence. Under ice bath, acetic anhydride (0.01 g, 0.12 mmol) was added, nitrogen atmosphere was placed, and the reaction was carried out under ice bath for 1 h. LCMS detected that the raw material reaction was complete. The reaction solution was filtered and the filtrate was dried by spin drying. The crude product was subjected to column chromatography (MeOH/DCM system) to obtain 0.05 g of white solid, with a yield of 93%. MS (ESI) m/z: 555.2 [M+H] ⁺ .

Step 2: Synthesis of tert-butyl (3-acetyl-9-(8-((-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazo[5.5]undecane-1-yl)carbamate

At room temperature, tert-butyl (3-acetyl-9-(8-iodoimidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (0.05 g, 0.09 mmol), sodium 2-amino-3-chloropyridine-4-thioate (0.02 g, 0.11 mmol), Pd ₂ (dba) ₃ (0.01 g, 0.01 mmol), Xantphos (0.01 g, 0.005 mmol), DIEA (0.04 g, 0.27 mmol) and dioxane (5 mL) were added to the bottle in sequence. The reaction was carried out at 95°C for 5 h. LCMS detected that the raw material reacted completely. The reaction solution was filtered, the filtrate was spin-dried, sanded, and column chromatography (MeOH/DCM system) was performed to obtain 0.03 g of brown solid, with a yield of 57%. MS (ESI) m/z: 587.2 [M+H] ⁺ .

Step 3: Synthesis of 1-(1-amino-9-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-3-yl)ethan-1-one

At room temperature, tert-butyl (3-acetyl-9-(8-((-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazo[5.5]undecane-1-yl)carbamate (0.03 g, 0.05 mmol) and 4N hydrochloric acid methanol solution (1 mL) were added to the bottle in sequence. The reaction was carried out at room temperature for 1 h. LCMS detected that the raw material reacted completely. Under ice bath, saturated sodium carbonate solution was added to the reaction system until the pH of the system was greater than 12, filtered, and the filtrate was spin-dried and separated on a preparative plate (MeOH/DCM system) to obtain 0.02 g of white solid, with a yield of 83%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.01(s,1H),7.84(d,J＝1.5Hz,1H),7.59–7.51(m,2H),6.32(s,2H),5.79(d,J＝5.4Hz,1H),3.84–3.74(m,2H),3.70–3.46(m, 3H),3.32–3.17(m,3H),2.72–2.62(m,1H),2.14–1.93(m,5H),1.89–1.29(m,6H).MS(ESI)m/z:487.2[M+H] ⁺ .

Example 17: Synthesis of 1-(1-amino-9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-3-yl)ethan-1-one (I-17)

Synthesis of 2-(trimethylsilyl)ethyl 1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate Reference Example 1.

Step 1: Synthesis of 2-(trimethylsilyl)ethyl 9-(5-bromopyrazin-2-yl)-1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate

At room temperature, 2-(trimethylsilyl)ethyl 1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate (0.05g, 0.12mmol), 2,5-dibromopyrazine (0.03g, 0.13mmol), DIEA (0.03g, 0.24mmol), and DMSO (1mL) were added to the reaction bottle in sequence, and reacted at 80°C for 2h under nitrogen atmosphere. LCMS detected that the raw material reaction was complete. Water (5ml) and ethyl acetate (10ml*2) were added to the reaction solution, and the organic phase was washed with water, dried, and spin-dried. The crude product was subjected to column chromatography (MeOH/DCM system) to obtain 0.05g of yellow solid, with a yield of 72%. MS (ESI) m/z: 570.2[M+H] ⁺ .

Step 2: Synthesis of tert-butyl (9-(5-bromopyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate

At room temperature, 2-(trimethylsilyl)ethyl 9-(5-bromopyrazin-2-yl)-1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate (0.05 g, 0.09 mmol), TBAF (0.05 g, 0.18 mmol), and tetrahydrofuran (2 mL) were added to the bottle in sequence. The reaction was carried out at 40°C for 12 h. LCMS detected that the reaction of the raw material was complete. The reaction solution was dried by rotation, and the crude product was directly used for the next step.

Step 3: Synthesis of tert-butyl (3-acetyl-9-(5-bromopyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate

At room temperature, tert-butyl (9-(5-bromopyrazine-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (0.10 g, crude product), potassium carbonate (0.02 g, 0.18 mmol), and acetonitrile (5 mL) were added to the bottle in sequence. At 0°C, acetic anhydride (0.01 g, 0.11 mmol) was added to the reaction system and reacted at room temperature for 1 h. LCMS detected that the raw material reacted completely. The reaction solution was filtered, the filtrate was spin-dried and sanded, and column chromatography (EA/PE system) was performed to obtain 0.03 g of yellow solid, with a two-step yield of 73%. MS (ESI) m/z: 468.2 [M+H] ⁺ .

Step 4: Synthesis of tert-butyl (3-acetyl-9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate

At room temperature, tert-butyl (3-acetyl-9-(5-bromopyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (0.03 g, 0.06 mmol), sodium 4-chloro-2-methyl-2H-indazole-5-thiolate (0.17 g, 0.08 mmol), Pd ₂ (dba) ₃ (0.01 g, 0.01 mmol), XantPhos (0.01 g, 0.01 mmol), DIEA (0.02 g, 0.18 mmol), and dioxane (5 mL) were added to the bottle in sequence. The reaction was carried out at 90°C for 2 h. LCMS detected that the raw material reacted completely. The reaction solution was filtered, the filtrate was spin-dried and sanded, and column chromatography (MeOH/DCM system) was performed to obtain 0.02 g of yellow solid, with a yield of 54%. MS (ESI) m/z: 586.2 [M+H] ⁺ .

Step 5: Synthesis of 1-(1-amino-9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-3-yl)ethan-1-one

At room temperature, tert-butyl (3-acetyl-9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazine-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (0.02 g, 0.03 mmol) was dissolved in methanol (1 mL), and 4N hydrochloric acid methanol solution (1 mL) was added. The reaction was carried out at room temperature for 2 h. LCMS detected that the raw material reacted completely. Sodium carbonate solution was added to the reaction solution until the pH was greater than 9. The reaction solution was filtered, the filtrate was spin-dried, and the preparative plate was separated (MeOH/DCM=10:1) to obtain 0.01 g of white solid with a yield of 63%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.49(s,1H),8.31(s,1H),8.11(s,1H),7.54(d,J＝8.9Hz,1H),7.07(d,J＝8.9Hz,1H),4.18(s,3H),3.96–3.85(m,3H),3.68–3 .49(m,2H),3.25–2.99(m,5H),2.03(s,1H),1.82–1.42(m,8H).MS(ESI)m/z:486.2[M+H] ⁺ .

Step 6: Preparation of (R)-1-(1-amino-9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-3-yl)ethan-1-one or (S)-1-(1-amino-9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-3-yl)ethan-1-one (I-26 and I-27)

1-(1-Amino-9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-3-yl)ethan-1-one (0.22 g, 0.45 mmol) was prepared by chiral column separation to obtain the product absolute configuration A peak (retention time 3.116 min, I-26), 0.05 g of white solid, and a yield of 23%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.46(s,1H),8.27(s,1H),8.11(s,1H),7.53(d,J＝8.9Hz,1H),7.06(d,J＝8.9Hz,1H),4.17(s,3H),4.00–3.89(m,2H),3.74–3 .62(m,1H),3.52–3.46(m,2H),3.26–3.15(m,4H),3.12–3.02(m,1H),1.99(s,3H),1.94–

1.75(m,2H),1.63–1.19(m,5H).MS(ESI)m/z:486.5[M+H] ⁺ .

The product absolute configuration B peak (retention time 3.764 min, I-27) was obtained as a white solid (0.05 g), with a yield of 23%. ¹ HNMR(400MHz, DMSO-d ₆ )δ8.46(s,1H),8.28(s,1H),8.11(s,1H),7.53(d,J＝8.9Hz,1H),7.06(d,J＝8.9Hz,1H),4.18(s,3H),4.03–3.85(m,2H),3.73–3.4 7(m,1H),3.44–3.40(m,2H),3.26–3.14(m,4H),3.10–3.00(m,1H),1.99(s,3H),1.92–1.75(m,2H),1.61–1.21(m,5H).MS(ESI)m/z:486.5[M+H] ⁺

Separation and preparation method:

Instrument: Gilson GX-281

Chromatographic column: CHIRALPAK IG-3, 3cm×25cm, 5μm

Mobile phase: A is (Hex:DCM); B is EtOH

Wavelength: 220nm

Flow rate: 20mL/min

Solvent: EtOH:DCM＝1:1

Gradient conditions: None

Cycle time: None

Column temperature: 25°C

Separation detection method:

Instrument: SHIMADZU LC-20

Chromatographic column: CHIRALPAK IG-3, 4.6×50mm, 3μm

Mobile phase: (Hex:DCM=1:1) (0.1% DEA):EtOH=75:25

Wavelength: 254nm

Column temperature: 25°C

Flow rate: 1mL/min

Injection volume: 3μL

Injection concentration: 0.01 mg/mL

Solvent: ETOH

Gradient conditions: B 25%

Running time: 5min

Retention time: 3.111min, 3.732min

Example 18: Synthesis of 9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3-(thiazol-2-yl)-3,9-diazaspiro[5.5]undecane-1-amine (I-18)

Synthesis of 2-(trimethylsilyl)ethyl 1-((tert-butoxycarbonyl)amino)-3,9-diazaspiro[5.5]undecane-3-carboxylate Reference Example 1.

Step 1: Synthesis of 2,2,2-trichloroethyl 9-(5-bromopyrazin-2-yl)-1-((tert-butyloxycarbonyl)amino)-3,9-diazapyridinium[5.5]undecane-3-carboxylate

At room temperature, 2,5-dibromopyrazine (300 mg, 1.261 mmol) was dissolved in DMSO (10 mL), N,N-diisopropylethylamine (244 mg, 0.840 mmol) and 2,2,2-trichloroethyl-1-((tert-butyloxycarbonyl)amino)-3,9-diazapyridine [5.5] undecane-3-carboxylate (673 mg, 1.513 mmol) were added, the reaction temperature was raised to 80 ° C, the reaction was allowed to react for 1 h, cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (2X10 mL). The organic phase was washed twice with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. Column chromatography purification (methanol/dichloromethane = 1:20) gave 300 mg of a yellow solid with a yield of 75%. MS (ESI) m/z: 602.4 [M+H] ⁺ .

Step 2: Synthesis of tert-butyl (9-(5-bromopyrazin-2-yl)-3,9-diazo[5.5]undec-1-yl)carbamate

At room temperature, 2,2,2-trichloroethyl 9-(5-bromopyrazin-2-yl)-1-((tert-butyloxycarbonyl)amino)-3,9-diazapyridine[5.5]undecane-3-carboxylate (300 mg, 0.498 mmol) was dissolved in THF (2 mL), TBAF (2 mL) was added, and the mixture was stirred at room temperature for 1 h under nitrogen protection, dried by spin drying, and purified by column chromatography (methanol/dichloromethane=1:20) to obtain 260 mg of a yellow solid, yield: 80%. MS (ESI) m/z: 427.3 [M+H] ⁺ . Step 3: Synthesis of tert-butyl (9-(5-bromopyrazin-2-yl)-3-(thiazol-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate.

At room temperature, tert-butyl (9-(5-bromopyrazin-2-yl)-3,9-diazolyl[5.5]undecane-1-yl)carbamate (160 mg, 0.380 mmol) was dissolved in DMSO (2 mL), DIEA (74 mg, 0.570 mmol) and 2-bromothiazole (74 mg, 0.450 mmol) were added, the temperature was raised to 80 degrees Celsius under nitrogen protection, stirred for 16 hours, cooled to room temperature, water (20 mL) was added, and extracted with ethyl acetate (2×10 mL). The organic phase was washed twice with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. Purification by column chromatography (methanol/dichloromethane=1:20) gave 80 mg of a yellow solid, yield: 30%. MS (ESI) m/z: 510.4 [M+H] ⁺ .

Step 4: Synthesis of tert-butyl (9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3-(thiazol-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate

At room temperature, tert-butyl (9-(5-bromopyrazin-2-yl)-3-(thiazol-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (80 mg, 0.200 mg), sodium 4-chloro-2-methyl-2H-indazole-5-thiolate (44 mg, 0.200 mmol), DIEA (65 mg, 0.500 mmol), (dba)3Pd2 (20 mg, 0.020 mmol), Xantphos (23 mg, 0.04 mmol), dioxane (10 mL) were added to the reaction bottle in sequence, and nitrogen was replaced 3 times. The reaction solution was heated to 95 ° C and stirred for 16 h. LCMS detected that the raw material reacted completely. The reaction solution was directly spin-dried, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to obtain 50 mg of yellow solid, yield: 60%. MS (ESI) m/z: 628.1 [M+H] ⁺ .

Step 5: Synthesis of 9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3-(thiazol-2-yl)-3,9-diazaspiro[5.5]undecane-1-amine

Tert-butyl (9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3-(thiazol-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (50 mg, 0.080 mmol) was dissolved in a mixed solvent of EA (5 ml) and HCl/EA (5 ml) and stirred for 1 h. LCMS detected that the reaction of the raw material was complete. The reaction solution was directly spin-dried. The crude oil was dissolved in methanol (100 ml), washed with saturated sodium bicarbonate solution, and the organic phase was dried and spin-dried. The crude product was purified by silica gel preparation plate (dichloromethane: methanol = 10: 1) to obtain 20 mg of the final product. Yield: 60%. ¹ H NMR (400MHz, DMSO-d6) δ8.46(s,1H),8.28(s,1H),8.11(s,1H),7.53(d,J＝8.9Hz,1H),7.13(d,J＝3.6Hz,1H),7.06(d,J＝9.0Hz,1H),6.82–6.73(m,20H),4.1 7(s,3H),4.02(d,J＝13.8Hz,2H),3.56(d,J＝3.8Hz,2H ),3.26–3.14(m,5H),3.07(dd,J＝12.5,8.4Hz,1H),2.60(dd,J＝8.3,4.0Hz,2H),2.10(dt,J＝13.4,4.4Hz,1H),1.95(td,J＝13.2,12.7,3.7Hz,2H),1.66–1 .58(m,4H),1.42–1.20(m,6H).MS(ESI)m/z:527.4[M+H] ⁺ .

Example 19: Synthesis of 9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3-(4-methylthiazol-2-yl)-3,9-diazaspiro[5.5]undecane-1-amine (I-19)

Synthesis of tert-butyl (9-(5-bromopyrazin-2-yl)-3,9-diazolyl[5.5]undecane-1-yl)carbamate Reference Example 1.

Step 1: Synthesis of tert-butyl (9-(5-bromopyrazin-2-yl)-3-(4-methylthiazol-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate.

At room temperature, tert-butyl (9-(5-bromopyrazin-2-yl)-3,9-diazolyl[5.5]undecane-1-yl)carbamate (100 mg, 0.230 mmol) was dissolved in DMSO (2 mL), DIEA (74 mg, 0.570 mmol) and 2-bromo-4-methylthiazole (50 mg, 0.280 mmol) were added, the temperature was raised to 80 degrees Celsius under nitrogen protection, stirred for 16 hours, cooled to room temperature, water (20 mL) was added, and extracted with ethyl acetate (2×10 mL). The organic phase was washed twice with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. Purification by column chromatography (methanol/dichloromethane=1:20) gave 30 mg of a yellow solid, yield: 30%. MS (ESI) m/z: 523.8 [M+H] ⁺ .

Step 2: Synthesis of tert-butyl (9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3-(4-methylthiazol-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate

At room temperature, tert-butyl (9-(5-bromopyrazin-2-yl)-3-(4-methylthiazol-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (30 mg, 0.060 mmol), sodium 4-chloro-2-methyl-2H-indazole-5-thiolate (15 mg, 0.07 mmol), DIEA (20 mg, 0.150 mmol), (dba)3Pd2 (5.5 mg, 0.006 mmol), Xantphos (6.6 mg, 0.011 mmol), and dioxane (10 mL) were added to the reaction bottle in sequence, and nitrogen was replaced 3 times. The reaction solution was heated to 90°C and stirred for 16 h. LCMS detected that the raw material reacted completely. The reaction solution was directly spin-dried, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to obtain 20 mg of yellow solid, with a yield of 60%. MS (ESI) m/z: 642.3 [M+H] ⁺ .

Step 5: Synthesis of 9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3-(4-methylthiazol-2-yl)-3,9-diazaspiro[5.5]undecane-1-amine

Tert-butyl (9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3-(4-methylthiazol-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (20 mg, 0.030 mmol) was dissolved in a mixed solvent of EA (5 ml) and HCl/EA (5 ml) and stirred for 1 h. LCMS detected that the raw material was completely reacted. The reaction solution was directly spin-dried. The crude oil was dissolved in methanol (100 ml), washed with saturated sodium bicarbonate solution, and the organic phase was dried and spin-dried. The crude product was purified on a silica gel preparation plate (dichloromethane: methanol = 10: 1) to obtain 2 mg of the final product. The yield was 60%. MS (ESI) m/z: 541.5 [M+H] ⁺ .

Example 20: Synthesis of 1-(1-amino-9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazapyridin[5.5]undecane-3-yl)ethan-1-one (I-20)

Synthesis of tert-butyl (9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazolyl[5.5]undecane-1-yl)carbamate Reference Example 1.

Step 1: Synthesis of tert-butyl (3-acetyl-9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazo[5.5]undec-1-yl)carbamate

At room temperature, tert-butyl (9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazolyl[5.5]undecane-1-yl)carbamate (150 mg, 0.300 mmol) was dissolved in DCM (2 mL), N,N-diisopropylethylamine (58 mg, 0.450 mmol) and acetic anhydride (36 mg, 0.360 mmol) were added, the reaction temperature was cooled to -20 ° C, the reaction was allowed to react for 10 min, cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (2×10 mL). The organic phase was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to give 200 mg of a yellow solid crude product, which was directly used in the next step.

Step 2: Synthesis of 1-(1-amino-9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazapyridin[5.5]undec-3-yl)ethan-1-one

At room temperature, tert-butyl (3-acetyl-9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazo[5.5]undecane-1-yl)carbamate (200 mg, 0.355 mmol) was dissolved in EA (2 mL), HCl/EA (2 mL) was added, and the mixture was stirred at room temperature for 1 h under nitrogen protection, and then dried by rotation. Aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (2×10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotation. The mixture was purified by column chromatography (methanol/dichloromethane= ¹ :20) to obtain 12 mg of a white solid with a yield of 44%. NMR (400MHz, DMSO-d6) δ8.43(s,1H),8.28(s,1H),7.65(d,J＝5.4Hz,1H),6.33(s,2H),5.80(d,J＝5.4Hz,1H),4.04(dd,J＝19.3,14.2Hz,2H),3.53–3.42(m,3H ),3.10–3.00(m,3H),2.58–2.53(m,1H),2.00(s,3H),1.95–1.80(m,2H),1.70–1.50(m,3H),1.32(dt,J＝14.6,7.5Hz,2H),0.93(t,J＝7.3Hz,1H).MS( ESI)m/z:448.5[M+H] ⁺ .

Example 21: Synthesis of 1-amino-9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-N,N-dimethyl-3,9-diazaspiro[5.5]undecane-3-carboxamide (I-21)

Synthesis of tert-butyl (9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazolyl[5.5]undecane-1-yl)carbamate Reference Example 1.

Step 1: Synthesis of tert-butyl (9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-(dimethylcarbamoyl)-3,9-diazapyridin[5.5]undec-1-yl)carbamate

At room temperature, tert-butyl (9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazolyl[5.5]undec-1-yl)carbamate (150 mg, 0.300 mmol) was dissolved in DCM (2 mL), N,N-diisopropylethylamine (58 mg, 0.450 mmol) and dimethylcarbamoyl chloride (38.7 mg, 0.360 mmol) were added, the reaction temperature was cooled to -20 ° C, the reaction was reacted for 10 min, cooled to room temperature, water (20 mL) was added, and extracted with ethyl acetate (2X10 mL), the organic phase was washed twice with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to give 200 mg of yellow solid crude product, which was directly used in the next step.

Step 2: Synthesis of 1-amino-9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-N,N-dimethyl-3,9-diazaspiro[5.5]undecane-3-carboxamide

At room temperature, tert-butyl (9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-(dimethylcarbamoyl)-3,9-diazapyridin[5.5]undec-1-yl)carbamate (200 mg, 0.355 mmol) was dissolved in EA (2 mL), HCl/EA (2 mL) was added, and the mixture was stirred at room temperature for 1 h under nitrogen protection, and dried by rotation. Aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (2×10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotation. The mixture was purified by column chromatography (methanol/dichloromethane=1:20) to give 22 mg of a white solid, with a yield of 60%. ¹ H NMR (400MHz, DMSO-d6) δ8.44(s,1H),8.28(s,1H),7.65(d,J＝5.4Hz,1H),6.33(s,2H),5.80(d,J＝5.3Hz,2H),4.05(dd,J＝13.2,5.0Hz,2H),3.38–2.98(m ,7H),2.75(s,6H),2.04–1.94(m,2H),1.88(td,J＝14.0,4.1Hz,2H),1.50–1.33(m,2H),1.23(m,1H).MS(ESI)m/z:477.5[M+H] ⁺ .

Example 22: Synthesis of 1-amino-9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazapyridine[5.5]undecane-3-carboxylic acid methyl ester (I-22)

Synthesis of tert-butyl (9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazolyl[5.5]undecane-1-yl)carbamate Reference Example 1.

Step 1: Synthesis of methyl 9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-1-((tert-butoxycarbonyl)amino)-3,9-diazapyridin[5.5]undecane-3-carboxylate

At room temperature, tert-butyl (9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazolyl[5.5]undecane-1-yl)carbamate (150 mg, 0.300 mmol) was dissolved in DCM (2 mL), N,N-diisopropylethylamine (58 mg, 0.450 mmol) and methyl chloroformate (12.3 mg, 0.360 mmol) were added, the reaction temperature was cooled to -20 ° C, the reaction was allowed to react for 10 min, cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (2×10 mL). The organic phase was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to give 200 mg of a yellow solid crude product, which was directly used in the next step.

Step 2: Synthesis of methyl 1-amino-9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazapyrido[5.5]undecane-3-carboxylate

At room temperature, methyl 9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-1-((tert-butoxycarbonyl)amino)-3,9-diazapyridine[5.5]undecane-3-carboxylate (200 mg, 0.355 mmol) was dissolved in EA (2 mL), HCl/EA (2 mL) was added, and the mixture was stirred at room temperature for 1 h under nitrogen protection, and dried by rotation. Aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (2×10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotation. The mixture was purified by column chromatography (methanol/dichloromethane=1:20) to give 10 mg of a white solid, with a yield of 44%. 1H NMR (400MHz, DMSO-d6) δ8.45(s,1H),8.29(dd,J＝47.4,1.3Hz,1H),7.63(d,J＝5.4Hz,1H),6.33(s,2H),5.81(d,J＝5.4Hz,1H),4.10–3.96(m,2H),3.60(s ,3H),3.18–3.14(m,4H),2.85(m,1H),2.03–1.23(m,6H),0.95-0.91(m,2H).MS(ESI)m/z:464.4[M+H] ⁺ .

Example 23: Synthesis of 1-(1-amino-9-(5-((2-chloro-3-((S)-3-methoxypyrrolidin-1-yl)phenyl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-3-yl)ethan-1-one (I-23)

Synthesis of tert-butyl (3-acetyl-3,9-diazaspiro[5.5]undecane-1-yl)carbamate Reference Example 1.

Step 1: Synthesis of (S)-1-(3-bromo-2-chlorophenyl)-3-methoxypyrrolidine

At room temperature, 1-bromo-2-chloro-3-fluorobenzene (1.73 g, 8.24 mmol), (S)-3-methoxypyrrolidine (1.00 g, 9.89 mmol), DIEA (1.60 g, 12.36 mmol) were added to a single-mouth bottle in sequence and dissolved with DMSO (10 mL), protected by nitrogen, and reacted at 120°C for 16 h. The mixture was cooled, diluted with water, extracted with DCM, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (EA/PE system) to obtain 0.80 g of a colorless transparent liquid with a yield of 33%.

Step 2: Synthesis of methyl (S)-3-((2-chloro-3-(3-methoxypyrrolidin-1-yl)phenyl)thio)propanoate

At room temperature, (S)-1-(3-bromo-2-chlorophenyl)-3-methoxypyrrolidine (0.08 g, 2.76 mmol), methyl 3-mercaptopropionate (0.66 g, 5.52 mmol), DIEA (1.07 g, 8.28 mmol), Pd ₂ (dba) ₃ (0.26 g, 0.28 mmol), Xantphos (0.08 g, 0.14 mmol) were added to a single-mouth bottle in sequence, and dissolved with 1,4-dioxane (30 mL), and the reaction was terminated at 90° C. for 16 h under nitrogen protection. The mixture was cooled and concentrated to obtain a pale yellow oily crude product, which was purified by column chromatography (EA/PE system) to obtain 1.05 g of a pale yellow solid crude product.

Step 3: Synthesis of (S)-2-chloro-3-(3-methoxypyrrolidin-1-yl)benzenethiol sodium

At room temperature, (S)-methyl 3-((2-chloro-3-(3-methoxypyrrolidin-1-yl)phenyl)thio)propanoate (1.05 g, 3.18 mmol) was added to a single-mouth bottle in sequence, and dissolved with methanol (4 mL) and THF (4 mL). Under nitrogen protection, sodium methoxide (0.34 g, 6.37 mmol) was added at 0°C and the reaction was terminated at room temperature for 16 h. Concentration was performed to obtain 2.00 g of a yellow solid, which was directly used for the next step without purification.

Step 4: Synthesis of (S)-2-chloro-5-((2-chloro-3-(3-methoxypyrrolidin-1-yl)phenyl)thio)pyrazine

At room temperature, sodium (S)-2-chloro-3-(3-methoxypyrrolidin-1-yl)benzenethiol (0.30 g, 0.81 mmol), 2-bromo-5-chloropyrazine (0.24 g, 1.22 mmol), DIEA (0.31 g, 2.43 mmol), Pd ₂ (dba) ₃ (0.07 g, 0.08 mmol), Xantphos (0.02 g, 0.04 mmol) were added to a single-mouth bottle in sequence, and dissolved with 1,4-dioxane (10 mL), and nitrogen was protected and the reaction was terminated at 90° C. for 2 h. The mixture was cooled and concentrated to obtain a pale yellow oily crude product, which was purified by column chromatography (EA/PE system) to obtain 0.45 g of a yellow solid, with a three-step yield of 46%.

Step 5: Synthesis of tert-butyl (3-acetyl-9-(5-((2-chloro-3-((S)-3-methoxypyrrolidin-1-yl)phenyl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate

At room temperature, (S)-2-chloro-5-((2-chloro-3-(3-methoxypyrrolidin-1-yl)phenyl)thio)pyrazine (0.10 g, 0.28 mmol), (3-acetyl-3,9-diazaspiro[5.5]undecane-1-yl)carbamic acid tert-butyl ester (0.11 g, 0.34 mmol), DIEA (0.06 g, 0.42 mmol) were added to a single-mouth bottle in sequence and dissolved with DMSO (5 mL), nitrogen was protected, and the reaction was terminated at 80°C for 16 h. After cooling, the mixture was diluted with water to precipitate an off-white solid, which was filtered and dried to obtain 0.20 g of a crude product, which was directly carried out to the next step without purification.

Step 6: Synthesis of 1-(1-amino-9-(5-((2-chloro-3-((S)-3-methoxypyrrolidin-1-yl)phenyl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-3-yl)ethan-1-one

At room temperature, tert-butyl (3-acetyl-9-(5-((2-chloro-3-((S)-3-methoxypyrrolidin-1-yl)phenyl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (0.20 g, 0.28 mmol) was added to a single-necked bottle in sequence, and dissolved with DCM (2 mL) and TFA (2 mL). The reaction was terminated at room temperature for 2 h. Concentration gave a brown oily crude product, which was purified by column chromatography (MeOH (0.1% NH ₄ OH)/DCM system) to give 0.14 g of a light yellow solid, with a two-step yield of 94%. ¹ HNMR(400MHz,DMSO-d ₆ )δ8.41(s,1H),8.22(s,1H),7.05(t,J＝8.0Hz,1H),6.81(d,J＝8.2Hz,1H),6.30(d,J＝7.8Hz,1H),3.66–3.49(m,4H),3.34–3.27(m,5H),3.25(s,3H),3.22–3.15(m,3H),2.79(d,J＝13.0Hz,1H),2.03(d,J＝3.7Hz,3H),2.00–1.78(m,4H),1.68–1.34(m,5H).MS(ESI)m/z:531.5[M+H] ⁺ .

Example 24: Synthesis of 1-(1-amino-9-(5-((3-chloro-2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazapyridin[5.5]undecane-3-yl)ethan-1-one (I-24)

Synthesis of tert-butyl (3-acetyl-3,9-diazaspiro[5.5]undecane-1-yl)carbamate Reference Example 1.

Step 1: Synthesis of 1-methyl-3-(tributylstannyl)-1H-pyrazole

At room temperature, 3-bromo-1-methyl-1H-pyrazole (3.00 g, 18.63 mmol), hexabutyl ditin (10.80 g, 18.63 mmol), tetrakistriphenylphosphine palladium (1.08 g, 0.93 mmol) were added to a single-mouth bottle in sequence and dissolved with toluene (20 mL), nitrogen was protected, and the reaction was terminated at 110°C for 5 h. Concentration and column chromatography (EA/PE system) purification gave 1.80 g of a colorless transparent liquid with a yield of 26%.

Step 2: Synthesis of methyl 3-((2,3-dichloropyridin-4-yl)thio)propanoate

At room temperature, 2,3-dichloro-4-iodopyridine (1.00 g, 3.65 mmol), methyl 3-mercaptopropionate (0.53 g, 4.38 mmol), DIEA (1.42 g, 10.95 mmol), Pd ₂ (dba) ₃ (0.34 g, 0.37 mmol), Xantphos (0.11 g, 0.18 mmol) were added to a single-mouth bottle in sequence, and dissolved with 1,4-dioxane (30 mL), and the mixture was protected by nitrogen and reacted at 100° C. for 2 h to terminate. The mixture was cooled and concentrated to obtain a pale yellow oily crude product, which was purified by column chromatography (EA/PE system) to obtain 1.30 g of a pale yellow solid crude product.

Step 3: Synthesis of methyl 3-((3-chloro-2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)thio)propanoate

At room temperature, methyl 3-((2,3-dichloropyridin-4-yl)thio)propanoate (1.30 g, 4.88 mmol), 1-methyl-3-(tributylstannyl)-1H-pyrazole (1.80 g, 4.88 mmol), and tetrakistriphenylphosphine palladium (0.28 g, 0.24 mmol) were added to a single-mouth bottle in sequence and dissolved in xylene (30 mL), protected by nitrogen, and reacted at 150° C. for 5 h to terminate. Concentration and purification by column chromatography (EA/PE system) gave 0.25 g of a yellow oil with a two-step yield of 22%.

Step 4: Synthesis of sodium 3-chloro-2-(1-methyl-1H-pyrazol-3-yl)pyridine-4-thiolate

At room temperature, methyl 3-((3-chloro-2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)thio)propanoate (0.25 g, 0.81 mmol) was added to a single-mouth bottle in sequence, and dissolved with methanol (3 mL) and THF (3 mL). Under nitrogen protection, sodium methoxide (0.09 g, 1.61 mmol) was added at 0°C and the reaction was terminated at room temperature for 16 h. Concentration was performed to obtain 0.30 g of a yellow solid, which was directly used for the next step without purification.

Step 5: Synthesis of 2-chloro-5-((3-chloro-2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)thio)pyrazine

At room temperature, sodium 3-chloro-2-(1-methyl-1H-pyrazol-3-yl)pyridine-4-thiolate (0.30 g, 0.81 mmol), 2-bromo-5-chloropyrazine (0.24 g, 1.22 mmol), DIEA (0.31 g, 2.43 mmol), Pd ₂ (dba) ₃ (0.07 g, 0.08 mmol), Xantphos (0.02 g, 0.04 mmol) were added to a single-mouth bottle in sequence, and dissolved with 1,4-dioxane (10 mL), and nitrogen was protected and the reaction was terminated at 90° C. for 2 h. The mixture was cooled and concentrated to obtain a pale yellow oily crude product, which was purified by column chromatography (EA/PE system) to obtain 0.20 g of a yellow solid, with a two-step yield of 74%.

Step 6: Synthesis of tert-butyl (3-acetyl-9-(5-((3-chloro-2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate

At room temperature, 2-chloro-5-((3-chloro-2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)thio)pyrazine (0.10 g, 0.29 mmol), (3-acetyl-3,9-diazaspiro[5.5]undecane-1-yl)carbamic acid tert-butyl ester (0.12 g, 0.38 mmol), DIEA (0.08 g, 0.58 mmol) were added to a single-mouth bottle in sequence and dissolved with DMSO (5 mL), nitrogen was protected, and the reaction was terminated at 80°C for 16 h. Cool, dilute with water, extract with EA, wash with water, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a pale yellow oily crude product, which was purified by column chromatography (MeOH/DCM system) to obtain 0.20 g of a yellow oily crude product.

Step 7: Synthesis of 1-(1-amino-9-(5-((3-chloro-2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazapyridin[5.5]undecane-3-yl)ethan-1-one

At room temperature, tert-butyl (3-acetyl-9-(5-((3-chloro-2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate (0.20 g, 0.29 mmol) was added to a single-mouth bottle in sequence, and dissolved with DCM (2 mL) and TFA (2 mL). The reaction was terminated at room temperature for 2 h. Concentration gave a brown oily crude product, which was purified by column chromatography (MeOH (0.1% NH ₄ OH)/DCM system) to give 0.09 g of a light yellow solid, with a two-step yield of 91%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.38 (s, 1H), 8.26 (s, 1H), 8.20 (d, J = 5.0Hz, 1H), 7.90 (d, J = 2.3Hz, 1H), 7.55 (d, J = 5.1Hz, 1H), 6.94 (d, J = 2.3Hz, 1H), 4.09–4.00 ( m,2H),3.96(s,3H),3.69–3.41(m,5H),2.77–2.66(m,1H),2.03(s,3H),1.96–1.81(m,2H),1.68–1.30(m,5H).MS(ESI)m/z:513.5[M+H] ⁺ .

Example 25: Synthesis of 1-(1-amino-9-(5-((2-chloro-3-((R)-3-methoxypyrrolidin-1-yl)phenyl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-3-yl)ethan-1-one (I-25)

Synthesis of tert-butyl (3-acetyl-3,9-diazaspiro[5.5]undecane-1-yl)carbamate Reference Example 1.

Step 1: Synthesis of tert-butyl (3-acetyl-9-(5-((2-chloro-3-((R)-3-methoxypyrrolidin-1-yl)phenyl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate

At room temperature, (R)-2-chloro-5-((2-chloro-3-(3-methoxypyrrolidin-1-yl)phenyl)thio)pyrazine (0.09 g, 0.25 mmol), (3-acetyl-3,9-diazaspiro[5.5]undecane-1-yl)carbamic acid tert-butyl ester (0.10 g, 0.33 mmol), DIEA (0.06 g, 0.50 mmol) were added to a single-mouth bottle in sequence and dissolved with DMSO (5 mL), nitrogen protection, and the reaction was terminated at 80°C for 16 h. Cool, dilute with water, extract with EA, wash with water, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 0.28 g of crude product, which was directly carried out to the next step without purification.

Step 2: Synthesis of 1-(1-amino-9-(5-((2-chloro-3-((R)-3-methoxypyrrolidin-1-yl)phenyl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-3-yl)ethan-1-one

At room temperature, tert-butyl (3-acetyl-9-(5-((2-chloro-3-((R)-3-methoxypyrrolidin-1-yl)phenyl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (0.28 g, 0.25 mmol) was added to a single-necked bottle in sequence, and dissolved with DCM (4 mL) and TFA (3 mL). The reaction was terminated at room temperature for 2 h. Concentration gave a brown oily crude product, which was purified by column chromatography (MeOH (0.1% NH ₄ OH)/DCM system) to give 0.11 g of a yellow solid, with a two-step yield of 83%. ¹ HNMR(400MHz, DMSO-d ₆ )δ8.41(s,1H),8.22(s,1H),7.05(t,J＝8.0Hz,1H),6.81(d,J＝8.2Hz,1H),6.29(d,J＝7.8Hz,1H),3.65–3.50(m,4H),3.34–3.27(m, 5H),3.24(s,3H),3.22–3.15(m,3H),2.81–2.72(m,1H),2.02(s,3H),1.99–1.75(m,4H),1.65–1.30(m,5H).MS(ESI)m/z:531.6[M+H] ⁺ .

Example 26: Synthesis of 1-(1-amino-9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-2-morpholinone-1-one (I-28)

Synthesis of tert-butyl (3-acetyl-3,9-diazaspiro[5.5]undec-1-yl)carbamate Reference Example 1. Synthesis of tert-butyl (9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate Reference Example 1.

Step 1: Synthesis of tert-butyl (9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3-(2-acetylmorpholino)-3,9-diazaspiro[5.5]undec-1-yl)carbamate

At room temperature, tert-butyl (9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate (0.10 g, 0.18 mmol), morpholin-4-ylacetic acid (0.05 g, 0.36 mmol), HATU (0.14 g, 0.36 mmol), DIEA (0.05 g, 0.36 mmol), and DMF (2 mL) were added to the bottle in sequence. The reaction was carried out at room temperature for 12 h. LCMS detected that the reaction of the raw material was complete. The reaction solution was filtered, the filtrate was spin-dried, and column chromatography (ACN/H ₂ O system) was performed to obtain 0.05 g of a yellow solid, with a yield of 42%. MS (ESI) m/z: 671.2 [M+H] ⁺ .

Step 2: Synthesis of 1-(1-amino-9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-3-yl)-2-morpholin-1-one

At room temperature, tert-butyl (9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3-(2-acetylmorpholine)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (0.04 g, 0.06 mmol) and 4N methanolic hydrochloric acid solution (4 mL) were added to the bottle in sequence. The reaction was carried out at room temperature for 4 h. LCMS detected that the reaction of the raw materials was complete. Sodium carbonate solution was added to the reaction solution until the pH was greater than 9. The reaction solution was filtered, the filtrate was spin-dried, and column chromatography (ACN/H ₂ O system) was performed to obtain 0.01 g of a yellow solid. Yield: 30%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.48(s,1H),8.30(d,J＝1.5Hz,1H),8.12(d,J＝1.4Hz,1H),7.56–7.52(m,1H),7.07(d,J＝9.0Hz,1H),4.19(s,3H),4.05–3.89(m,3H),3.71–3.51(m, 8H),3.24–3.05(m, 4H),2.73–2.64(m,2H),2.41(d,J＝5.1Hz,3H),2.01(q,J＝7.0,6.5Hz,2H),1.86(d,J＝13.9Hz,1H),1.58(d,J＝6.1Hz,2H),1.47(d,J＝6.6Hz,2H).MS(ESI)m /z:571.2[M+H] ⁺ .

Example 27: Synthesis of 3-(1-amino-9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-3-yl)-3-oxopropionitrile (I-29)

Synthesis of tert-butyl (9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate Reference Example 1.

Step 1: Synthesis of tert-butyl (9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3-(2-cyanoacetyl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate

At room temperature, tert-butyl (9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate (0.10 g, 0.18 mmol), cyanoacetic acid (0.03 g, 0.36 mmol), HATU (0.14 g, 0.36 mmol), DIEA (0.05 g, 0.36 mmol), and DCM (2 mL) were added to the bottle in sequence. The reaction was carried out at room temperature for 12 h. LCMS detected that the raw material reacted completely. The reaction solution was filtered, the filtrate was spin-dried, and column chromatography (ACN/H ₂ O system) was performed to obtain 0.06 g of yellow solid, with a yield of 54%. MS (ESI) m/z: 611.2 [M+H] ⁺ .

Step 2: Synthesis of 3-(1-amino-9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-3-yl)-3-oxopropionitrile

At room temperature, tert-butyl (9-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)pyrazine-2-yl)-3-(2-cyanoacetyl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (0.05 g, 0.09 mmol) and 4N hydrochloric acid methanol solution (4 mL) were added to the bottle in sequence. The reaction was carried out at room temperature for 4 hours. LCMS detected that the raw material reacted completely. Sodium carbonate solution was added to the reaction solution until the pH was greater than 9. The reaction solution was filtered, the filtrate was dried by spin drying, and column chromatography (ACN/H ₂ O system) was performed to obtain 0.003 g of yellow solid. Yield: 8%. MS (ESI) m/z: 511.2 [M+H] ⁺ .

Example 28: Synthesis of 1-(1-amino-9-(5-(3-chloro-2-morpholinylpyridin-4-yl)thiopyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-3-yl)ethan-1-one (I-30)

Synthesis of tert-butyl (3-acetyl-3,9-diazaspiro[5.5]undecane-1-yl)carbamate Reference Example 1.

Step 1: Synthesis of 4-(4-bromo-3-chloropyridin-2-yl)morpholine

At room temperature, 2,4-dibromo-3-chloropyridine (1.0 g, 3.62 mmol) and N,N-diisopropylethylamine (2.2 g, 18.4 mmol) were dissolved in dimethyl sulfoxide (16 mL), and then morpholine (322 mg, 3.62 mmol) was added. The reaction solution was reacted at 80°C for 12 hours, and the reaction solution was washed with water (50 mL x3), extracted with ethyl acetate (60 mL x3), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. Purification by column chromatography (ethyl acetate/petroleum ether = 1:3) gave 500 mg of a yellow oil. MS (ESI) m/z: 279.0 [M+H] ⁺ .

Step 2: Synthesis of methyl 3-((3-chloro-2-morpholinylpyridin-4-yl)thio)propanoate

At room temperature, 4-(4-bromo-3-chloropyridin-2-yl)morpholine (500mg, 1.80mmol), methyl 3-mercaptopropionate (475mg, 3.95mmmol), tris(dibenzylideneacetone)dipalladium(0) (324mg, 0.36mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (211mg, 0.36mmol) and N,N-diisopropylethylamine (1.16g, 8.99mmol) were dissolved in dioxane (5mL), the reaction temperature was raised to 100 degrees, the reaction was allowed to react for 5 hours, the mixture was concentrated and dried, and the mixture was purified by column chromatography (EA/PE=1:3) to obtain 530mg of a yellow oil. MS (ESI) m/z: 317.1 [M+H] ⁺ .

Step 3: Synthesis of sodium 3-chloro-2-morpholinopyridine-4-thioate

At room temperature, methyl 3-((3-chloro-2-morpholinylpyridin-4-yl)thio)propanoate (530 mg, 1.68 mmol) was dissolved in methanol (6 mL), and sodium methoxide (190 mg, 3.42 mmol) was added. The mixture was stirred at room temperature for 12 hours and directly dried for the next step without purification to obtain 1.2 g of yellow powder. MS (ESI) m/z: 230.0 [M+H] ⁺ .

Step 4: Synthesis of 4-(3-chloropyrazin-2-yl)thiopyridine-2-morpholine

At room temperature, 3-chloro-2-morpholinylpyridine-4-thioate sodium (1.2 g, 4.76 mmol), 2-bromo-5-chloropyrazine (1.1 g, 5.71 mmol), tris(dibenzylideneacetone)dipalladium (0) (860 mg, 0.95 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (551 mg, 0.95 mmol) and N,N-diisopropylethylamine (3.0 g, 23.8 mmol) were dissolved in dioxane (15 mL), the reaction temperature was raised to 90 degrees, the reaction was allowed to react for 4 hours, the mixture was concentrated and dried, and the mixture was purified by column chromatography (EA/PE=1:5) to obtain 450 mg of a yellow solid. MS (ESI) m/z: 343.9 [M+H] ⁺ .

Step 5: Synthesis of tert-butyl (3-acetyl-9-(5-((3-chloro-2-morpholinylpyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate

At room temperature, 4-(3-chloropyrazin-2-yl)thiopyridine-2-morpholine (100 mg, 0.29 mmol), (3-acetyl-3,9-diazaspiro[5.5]undecane-1-yl)carbamic acid tert-butyl ester (133 mg, 0.43 mmol) and N,N-diisopropylethylamine (375 mg, 2.9 mmol) were dissolved in dimethyl sulfoxide (4 mL). Under nitrogen protection, the temperature was raised to 80 degrees for 15 hours, cooled to room temperature, water (20 mL) was added, and extracted with ethyl acetate (10 mL x 3). The organic phase was washed twice with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. 400 mg of yellow oil was obtained by column chromatography purification (methanol/dichloromethane = 1:10). MS (ESI) m/z: 618.2 [M+H] ⁺ .

Step 6: Synthesis of 1-(1-amino-9-(5-(3-chloro-2-morpholinylpyridin-4-yl)thiopyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-3-yl)ethan-1-one

At room temperature, tert-butyl (3-acetyl-9-(5-((3-chloro-2-morpholinylpyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate (120 mg, 0.19 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated aqueous sodium bicarbonate at 0°C, extracted with dichloromethane, concentrated, and purified by TLC (methanol/dichloromethane=1:10) to give 25 mg of a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.48 (s, 1H), 8.32 (s, 1H), 7.98 (d, J = 5.3Hz, 1H), 6.29 (d, J = 5.3Hz, 1H), 4.09–4.01 (m, 2H), 3.74 (t, J = 4.6Hz, 5H), 3.66–3.50 (m, 4H),3.22(t,J＝4.5Hz,5H),2.77(t,J＝8.2Hz,1H),2.03(d,J＝3.3Hz,3H),2.0 2–1.94(m,1H),1.94–1.75(m,2H),1.67–1.34(m,5H).MS(ESI)m/z:518.2[M+ H] ⁺ .

Example 29: Synthesis of 9-(8-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(5-fluoropyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-1-amine (I-38)

Synthesis of tert-butyl (9-(8-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate Reference Example 1.

Step 1: Synthesis of tert-butyl (9-(8-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(5-fluoropyrimidin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate

At room temperature, tert-butyl (9-(8-((2-amino-3-chloropyridin-4-yl)sulfanyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (0.05 g, 0.09 mmol), 2-chloro-5-fluoro-pyrimidine (0.02 g, 0.18 mmol), DIEA (0.12 g, 0.92 mmol), and DMSO (1 mL) were added to the reaction bottle in sequence, and the mixture was reacted at 80° C. for 2 h under a nitrogen atmosphere. LCMS detected that the raw material reaction was complete. Water (5 ml) and ethyl acetate (10 ml*2) were added to the reaction solution, and the organic phase was washed with water, dried, and spin-dried. The crude product was subjected to column chromatography (MeOH/DCM system) to obtain 0.03 g of a yellow solid with a yield of 51%. MS (ESI) m/z: 642.2 [M+H] ⁺ .

Step 2: Synthesis of 9-(8-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(5-fluoropyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-1-amine

At room temperature, tert-butyl (9-(8-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(5-fluoropyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (0.03 g, 0.05 mmol) and 4N methanolic hydrochloric acid (1 mL) were added to the bottle in sequence. The reaction was carried out at room temperature for 2 h. LCMS detected that the raw material reacted completely. Sodium carbonate solution was added to the reaction solution until the pH was greater than 9. The reaction solution was filtered, the filtrate was spin-dried, and the preparative plate was separated (MeOH/DCM=10:1) to obtain 0.02 g of white solid with a yield of 80%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.46(d,J＝18.9Hz,3H),8.19(s,1H),7.56(d,J＝5.4Hz,1H),5.87(d,J＝5.4Hz,1H),4.82(d,J＝13.4Hz,2H),4.01–3.83(m,2H),3.6 9–3.55(m,3H),3.42–3.35(m,3H),2.71–2.65(m,1H),2.14–2.05(m,2H),1.84–1.71(m,2H),1.50–1.38(m,2H).MS(ESI)m/z:542.2[M+H] ⁺ .

Example 30: Synthesis of 9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-(methylsulfonyl)-3,9-diazaspiro[5.5]undecane-1-amine (I-31)

Synthesis of tert-butyl (9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate Reference Example 1.

Step 1: Synthesis of tert-butyl (9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-(methylsulfonyl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate

At room temperature, tert-butyl (9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate (0.05 g, 0.09 mmol) was dissolved in dichloromethane (2 mL), DIEA (0.02 g, 0.17 mmol) and methanesulfonyl chloride (0.01 g, 0.10 mmol) were added, and the mixture was reacted at room temperature for 1 h. Water was added to separate the mixture, and the organic phase was washed with water once, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was purified by column chromatography (methanol/dichloromethane=1:20) to obtain 0.03 g of pure product with a yield of 52%. MS (ESI) m/z: 661.2 [M+H] ⁺ . Step 2: Synthesis of 9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-(methylsulfonyl)-3,9-diazaspiro[5.5]undecane-1-amine

At room temperature, tert-butyl (9-(8-((4-chloro-2-methyl-2H-indazol-5-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-(methylsulfonyl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (0.03 g, 0.05 mmol) and 4N methanolic hydrochloric acid (1 mL) were added to the bottle in sequence. The reaction was carried out at room temperature for 2 h. LCMS detected that the raw material reacted completely. Sodium carbonate solution was added to the reaction solution until the pH was greater than 9. The reaction solution was filtered, the filtrate was spin-dried, and the preparative plate was separated (MeOH/DCM=10:1) to obtain 0.01 g of a white solid. The yield was 40%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.48(s,1H),7.80(d,J＝1.4Hz,1H),7.71(s,1H),7.58(s,1H),7.46(d,J＝9.0Hz,1H),7.00(d,J＝9.0Hz,1H),4.18(s,3H),3.73–3.64(m,2H),3.28–3 .10(m,6H),2.89(s,4H),2.76–2.71(m,1H),2.12–2.00(m,2H),1.85–1.77(m,1H),1.64(d,J＝13.9Hz,1H),1.51–1.42(m,2H).MS(ESI)m/z:561.2[M+H ] ⁺ Example 31: Synthesis of 9-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-(ethylsulfonyl)-3,9-diazaspiro[5.5]undecane-1-amine (I-32)

Synthesis of tert-butyl (9-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate Reference Example 1.

Step 1: Synthesis of tert-butyl (9-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-(ethylsulfonyl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate

At room temperature, tert-butyl (9-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate (0.05 g, 0.09 mmol) was dissolved in dichloromethane (2 mL), DIEA (0.02 g, 0.17 mmol) and ethylsulfonyl chloride (0.01 g, 0.10 mmol) were added, and the mixture was reacted at room temperature for 1 h. Water was added to separate the mixture, and the organic phase was washed with water once, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was purified by column chromatography (methanol/dichloromethane=1:20) to obtain 0.03 g of pure product with a yield of 52%. MS (ESI) m/z: 637.2 [M+H] ⁺ .

Step 2: Synthesis of 9-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-(ethylsulfonyl)-3,9-diazaspiro[5.5]undecane-1-amine

At room temperature, tert-butyl (9-(8-((2-amino-3-chloropyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-(ethylsulfonyl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate (0.03 g, 0.05 mmol) and 4N methanolic hydrochloric acid (1 mL) were added to the bottle in sequence. The reaction was carried out at room temperature for 2 h. LCMS detected that the raw material had reacted completely. Sodium carbonate solution was added to the reaction solution until the pH was greater than 9. The reaction solution was filtered, the filtrate was spin-dried, and the preparative plate was separated (MeOH/DCM=10:1) to obtain 0.02 g of white solid with a yield of 80%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.00(s,1H),7.83(s,1H),7.57–7.52(m,2H),6.29(s,2H),5.79(d,J＝5.5Hz,1H),3.78(d,J＝13.5Hz,2H),3.38–3.33(m,4H),3.22(t,J＝5.7Hz,2H), 3.13–3.00(m,4H),2.80–2.75(m,1H),2.09–1.99(m,2H),1.84–1.77(m,1H),1.65(d,J＝14.4Hz,1H),1.56–1.45(m,2H),1.24(d,J＝7.4Hz,3H).MS (ESI )m/z:537.2[M+H] ⁺ .

Example 32: Synthesis of 2-(1-amino-9-(5-(2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-3-yl)pyrimidine-5-carbonitrile (I-33)

Synthesis of tert-butyl (9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate Reference Example 1.

Step 1: Synthesis of tert-butyl (9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-(5-cyanopyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate

At room temperature, tert-butyl (9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate (0.06 g, 0.12 mmol), 2-chloro-5-cyanopyrimidine (0.02 g, 0.15 mmol), DIEA (0.08 g, 0.64 mmol) and DMSO (1 mL) were added to a bottle in sequence, reacted at 80°C for 5 h, water and ethyl acetate were added for separation, ethyl acetate was extracted once, the organic phase was washed once with water, dried over anhydrous sodium sulfate, filtered, spin-dried, and purified by column chromatography (methanol/dichloromethane=1:20) to obtain 0.04 g of pure product, yield: 55%. MS (ESI) m/z: 609.2 [M+H] ⁺ .

Step 2: Synthesis of 2-(1-amino-9-(5-(2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-3-yl)pyrimidine-5-carbonitrile

At room temperature, tert-butyl 9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazine-2-yl)-3-(5-cyanopyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (0.04 g, 0.06 mmol) and 4N methanol hydrochloric acid (1 mL) were added to the bottle in sequence. The reaction was carried out at room temperature for 2 h. LCMS detected that the raw material reacted completely. Sodium carbonate solution was added to the reaction solution until the pH was greater than 9. The reaction solution was filtered, the filtrate was spin-dried, and the preparative plate was separated (MeOH/DCM=10:1) to obtain 0.02 g of white solid with a yield of 60%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.72(s,2H),8.44(s,1H),8.29(s,1H),7.66(d,J＝5.4Hz,1H),6.32(s,2H),5.82(d,J＝5.4Hz,1H),4.15–4.03(m,4H),3.69–3 .66(m,1H),2.58(d,J＝4.4Hz,1H),2.10–1.95(m,4H),1.69–1.64(m,2H),1.50–1.30(m,5H).MS(ESI)m/z:509.2[M+H] ⁺ .

Example 33: Synthesis of 9-(5-((2-amino-3-chloropyrimidin-4-yl)thio)pyrazin-2-yl)-3-(5-morpholinopyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-1-amine (I-34)

Synthesis of tert-butyl (9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate Reference Example 1.

Step 1: Synthesis of 2-(benzyloxy)-5-bromopyrimidine

At room temperature, 5-bromo-2-chloropyrimidine (3.00 g, 15.51 mmol), benzyl alcohol (1.84 g, 17.06 mmol) and DMF (10 mL) were added into the bottle in sequence, and potassium tert-butoxide (2.82 g, 23.26 mmol) was added in batches. The mixture was reacted at room temperature for 2 h, and water was added. The mixture was filtered to obtain 2.10 g of pure product with a yield of 51%.

Step 2: Synthesis of 4-(2-(benzyloxy)pyrimidin-5-yl)morpholine

At room temperature, 2-(benzyloxy)-5-bromopyrimidine (1.80 g, 6.79 mmol), morpholine (1.77 g, 20.37 mmol), JohnPhos (0.20 g, 0.68 mmol), t-BuONa (1.30 g, 13.58 mmol), Pd ₂ (dba) ₃ (0.31 g, 0.34 mmol) and toluene (30 mL) were added to the bottle in sequence. The reaction was carried out at room temperature for 3 h. LCMS detected that the raw material reacted completely. The reaction solution was filtered, the filtrate was spin-dried and sanded, and column chromatography (EA/PE system) was performed to obtain 1.40 g of pure product. Yield: 76%. MS (ESI) m/z: 272.2 [M+H] ⁺ .

Step 3: Synthesis of 5-morpholinopyrimidin-2-ol hydrochloride

At room temperature, 4-(2-(benzyloxy)pyrimidin-5-yl)morpholine (1.40 g, 5.16 mmol) and 4N hydrochloric acid dioxane solution (10 mL) were added to the bottle in sequence. The reaction was carried out at 50°C for 2 h. LCMS detected that the raw material had reacted completely. The reaction solution was filtered and washed with ethyl acetate to obtain 1.00 g of pure product. The yield was 89%. MS (ESI) m/z: 182.1 [M+H] ⁺ .

Step 4: Synthesis of 4-(2-chloropyrimidin-5-yl)morpholine

At room temperature, 5-morpholinopyrimidine-2-ol hydrochloride (1.00 g, 4.59 mmol), N,N-diethylaniline (1.37 g, 9.19 mmol), acetonitrile (10 mL) and phosphorus oxychloride (1 mL) were added to the bottle in sequence. React at 80 °C for 5 h. LCMS detected that the raw material reacted completely. The reaction solution was spin-dried, ethyl acetate was added, poured into a sodium carbonate solution, the pH was adjusted to 8, the liquid was separated, washed with water, dried, spin-dried and sanded, and column chromatography (EA/PE system) was performed to obtain 0.50 g of pure product. Yield: 55%. MS (ESI) m/z: 200.1 [M+H] ⁺ .

Step 5: Synthesis of tert-butyl (9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-(5-morpholinopyrimidin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate

At room temperature, tert-butyl (9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (0.10 g, 0.20 mmol), 4-(2-chloropyrimidin-5-yl)morpholine (0.05 g, 0.24 mmol), DIEA (0.12 g, 0.92 mmol), and DMSO (1 mL) were added to the reaction flask in sequence, and the mixture was reacted at 80° C. for 2 h under a nitrogen atmosphere. LCMS detected that the raw material reaction was complete. Water (5 ml) and ethyl acetate (10 ml*2) were added to the reaction solution, and the organic phase was washed with water, dried, and spin-dried. The crude product was subjected to column chromatography (MeOH/DCM system) to obtain 0.05 g of a yellow solid with a yield of 38%. MS (ESI) m/z: 669.3 [M+H] ⁺ .

Step 6: Synthesis of 9-(5-((2-amino-3-chloropyrimidin-4-yl)thio)pyrazin-2-yl)-3-(5-morpholinopyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-1-amine

At room temperature, tert-butyl (9-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazine-2-yl)-3-(5-morpholinopyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (0.05 g, 0.07 mmol) and 4N methanolic hydrochloric acid (1 mL) were added to the bottle in sequence. The reaction was carried out at room temperature for 2 h. LCMS detected that the raw material reacted completely. Sodium carbonate solution was added to the reaction solution until the pH was greater than 9. The reaction solution was filtered, the filtrate was spin-dried, and column chromatography (MeOH/DCM system) was performed to obtain 0.03 g of a yellow solid. The yield was 71%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.44(s,1H),8.29(s,1H),8.18(s,2H),7.66(d,J＝5.4Hz,1H),6.34(s,2H),5.82(d,J＝5.4Hz,1H),4.17–4.09(m,2H),4.05–3.88(m,2H),3.73(t,J＝ 4.7Hz, 4H), 3.49–3.35 (m, 5H), 3.19 (t, J = 10.5Hz, 1H), 2.98 (t, J = 4.7Hz, 4H), 2.09–1.97 (m, 2H), 1.67 (s, 2H), 1.31 (d, J = 15.5Hz, 2H). MS (ESI) m/z: 569. 2

[M+H] ⁺ .

Example 34: Synthesis of N-(3-((5-(9-acetyl-7-amino-3,9-diazaspiro[5.5]undecane-3-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide (I-35)

Synthesis of tert-butyl (3-acetyl-9-(8-iodoimidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate Reference Example 1.

Step 1: tert-Butyl (3-acetyl-9-(8-((3-amino-2-chlorophenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate

At room temperature, tert-butyl (3-acetyl-9-(8-iodoimidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (0.22 g, 0.40 mmol), 3-amino-2-chlorobenzene sodium sulfate (0.11 g, 0.60 mmol), DIEA (0.10 g, 0.80 mmol), Pd ₂ (dba) ₃ (0.04 g, 0.04 mmol), Xantphos (0.01 g, 0.02 mmol) were added to a single-mouth bottle in sequence, and dissolved with 1,4-dioxane (10 mL), protected with nitrogen, and reacted at 90° C. for 21 h to terminate. The mixture was cooled and concentrated to obtain a pale yellow oily crude product, which was purified by column chromatography (EA/PE system) to obtain 0.23 g of a yellow solid with a yield of 98%.

Step 2: tert-Butyl (3-acetyl-9-(8-((2-chloro-3-(2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamido)phenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate

At room temperature, 2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ethyl ester (0.09 g, 0.39 mmol) and tert-butyl (3-acetyl-9-(8-((3-amino-2-chlorophenyl)sulfanyl)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (0.23 g, 0.39 mmol) were added to a single-mouth bottle in sequence and dissolved with xylene (3 mL) and DMSO (2 mL), and nitrogen was protected and the reaction was terminated at 140°C for 1 h. Cool, add petroleum ether, separate the liquids, discard the upper layer, and purify the DMSO layer by column chromatography (MeOH/DCM system) to obtain 0.20 g of a yellow solid with a yield of 66%.

Step 3: N-(3-((5-(9-acetyl-7-amino-3,9-diazaspiro[5.5]undec-3-yl)imidazo[1,2-c]pyrimidin-8-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide

At room temperature, tert-butyl (3-acetyl-9-(8-((2-chloro-3-(2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamido)phenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (0.20 g, 0.26 mmol) was added to a single-mouth bottle in sequence, and dissolved in DCM (3 mL), TFA (2 mL) was added, nitrogen protection was applied, and the reaction was terminated at room temperature for 0.5 h. Concentration and purification by reverse phase system (acetonitrile/water (0.1% ammonia water), 5%-95%) were performed to obtain 50 mg of a white solid with a yield of 28%. MS (ESI) m/z: 678.6 [M+H] ⁺ .

Example 35: Synthesis of 1-(1-amino-9-(5-((2-chloro-3-((R)-3-methoxypyrrolidin-1-yl)phenyl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-3-yl)ethan-1-one (I-36)

Synthesis of tert-butyl (3-acetyl-3,9-diazaspiro [5.5] undecane-1-yl) carbamate Reference Example 1.

Step 1: tert-Butyl (3-acetyl-9-(5-((2-chloro-3-(2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamido)phenyl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate

At room temperature, N-(2-chloro-3-((5-chloropyrazin-2-yl)thio)phenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide (0.30 g, 0.65 mmol), tert-butyl(3-acetyl-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (0.24 g, 0.78 mmol), DIEA (0.17 g, 1.30 mmol) were added to a single-mouth bottle in sequence and dissolved with DMSO (5 mL), protected with nitrogen, and reacted at 90° C. for 16 h to terminate. After cooling, the mixture was purified by reverse phase system (acetonitrile/water, 5%-95%) to obtain 0.25 g of a light yellow solid with a yield of 52%.

Step 2: N-(3-((5-(9-acetyl-7-amino-3,9-diazaspiro[5.5]undec-3-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide

At room temperature, tert-butyl (3-acetyl-9-(5-((2-chloro-3-(2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamido)phenyl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate (0.10 g, 0.16 mmol) was added to a single-mouth bottle in sequence, and dissolved in DCM (2 mL), and TFA (1 mL) was added, nitrogen protection, and the reaction was terminated at room temperature for 0.5 h. Concentration and purification by reverse phase system (acetonitrile/water (0.1% ammonia water), 5%-95%) were performed to obtain 50 mg of a white solid with a yield of 58%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ13.10(s,1H),8.39(d,J＝10.5Hz,1H),8.29–8.19(m,2H),7.26(t,J＝8.1Hz,1H),6.61(d,J＝8.0Hz,1H),4.61(t,J＝5.7Hz,1H),4.10–3.96(m,2H),3.79 (t,J=6.1 Hz,1H),3.75–3.67(m,1H),3.52–3.41(m,7H),2.73–2.67(m,2H),2.01(s,3H),1.92–1.74(m,7H),1.64–1.55(m,2H),1.49–1.34(m,2H).MS(ESI)m/z :639.6[M+H] ⁺ .

Example 36: Synthesis of 1-(1-amino-9-(5-((2-chloro-3-((R)-3-methoxypyrrolidin-1-yl)phenyl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-3-yl)ethan-1-one (I-37)

Synthesis of (1-(1-amino-3,9-diazaspiro[5.5]undecane-3-yl)ethane-1-one Reference Example 1.

Step 1: N-(3-((5-(9-acetyl-7-amino-3,9-diazaspiro[5.5]undec-3-yl)-3-aminopyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide

At room temperature, N-((3-((3-amino-5-chloropyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide (0.10 g, 0.21 mmol), 1-(1-amino-3,9-diazaspiro[5.5]undecane-3-yl)ethane-1-one (0.07 g, 0.31 mmol), DIEA (0.05 g, 0.42 mmol) were added to a single-mouth bottle in sequence and dissolved with DMSO (3 mL), protected by nitrogen, and reacted at 90°C for 16 h. After cooling, the product was purified by reverse phase system (acetonitrile/water, 5%-95%) to obtain 8 mg of a light yellow solid with a yield of 6%. MS (ESI) m/z: 654.6 [M+H] ⁺ .

Example 37: Synthesis of 1-(1-amino-9-(5-((2-chloro-3-((1-methyl-1H-pyrazol-3-yl)ethynyl)phenyl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-3-yl)ethan-1-one (II-6)

Synthesis of tert-butyl (3-acetyl-3,9-diazaspiro[5.5]undecane-1-yl)carbamate Reference Example 1.

Step 1: Synthesis of ((3-bromo-2-chlorophenyl)ethynyl)trimethylsilane

At room temperature, 1,3-dibromo-2-chlorobenzene (1.0 g, 3.17 mmol) was dissolved in tetrahydrofuran (10 mL), and then trimethylsilane (0.34 g, 3.48 mmol), cuprous iodide (0.06 mg, 0.32 mmol), bistriphenylphosphine palladium dichloride (0.22 g, 0.32 mmol), and triethylamine (3.2 g, 31.7 mmol) were added. The reaction solution was reacted at 70°C under nitrogen protection for 1 hour. The reaction solution was directly filtered, the filtrate was spin-dried, and purified by column chromatography (ethyl acetate/petroleum ether=0:1) to obtain 1.2 g of yellow oil, MS (ESI) m/z: 288.2 [M+H] ⁺ .

Step 2: Synthesis of 1-bromo-2-chloro-3-ethynylbenzene

At room temperature, ((3-bromo-2-chlorophenyl)ethynyl)trimethylsilane (1.2 g, 4.16 mmol) was dissolved in methanol (20 mL), potassium carbonate (1.15 g, 8.32 mmol) was added, and the mixture was stirred at room temperature for 30 mins under nitrogen protection. The reaction solution was washed with water (60 mL x 3), extracted with ethyl acetate (80 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain 1.0 g of a yellow oil.

Step 3: Synthesis of 3-((3-bromo-2-chlorophenyl)ethynyl)-1-methyl-1H-pyrazole

At room temperature, 1-bromo-2-chloro-3-ethynylbenzene (1.0 g, 4.64 mmol) was dissolved in tetrahydrofuran (10 mL), and then 3-iodo-1-methylpyrazole (1.06 g, 5.11 mmol), cuprous iodide (88 mg, 0.46 mmol), bistriphenylphosphine palladium dichloride (0.33 g, 0.46 mmol), triethylamine (4.68 g, 46.4 mmol) were added. The reaction solution was reacted at 70 ° C under nitrogen protection for 1 hour. The reaction solution was directly filtered, the filtrate was spin-dried, and purified by column chromatography (ethyl acetate/petroleum ether = 1:3) to obtain 0.27 g of a yellow oil.

Step 4: Synthesis of methyl 3-((2-chloro-3-((1-methyl-1H-pyrazol-3-yl)ethynyl)phenyl)thio)propanoate

At room temperature, 3-((3-bromo-2-chlorophenyl)ethynyl)-1-methyl-1H-pyrazole (0.27 g, 0.91 mmol) was dissolved in dioxane (10 mL), and then methyl 3-mercaptopropionate (0.17 g, 1.37 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.08 g, 0.09 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.11 g, 0.18 mmol) and N,N-diisopropylethylamine (0.24 g, 1.82 mmol) were added. The reaction temperature was raised to 100° C. and reacted for 5 hours. The mixture was concentrated and dried, and purified by column chromatography (EA/PE=1:1) to obtain 0.25 g of a yellow solid, MS (ESI) m/z: 335.2[M+H] ⁺ .

Step 5: Synthesis of potassium 2-chloro-3-((1-methyl-1H-pyrazol-3-yl)ethynyl)phenylthio

At room temperature, methyl 3-((2-chloro-3-((1-methyl-1H-pyrazol-3-yl)ethynyl)phenyl)thio)propanoate (0.25 g, 0.74 mmol) was dissolved in methanol (10 mL), and potassium tert-butoxide (91 mg, 0.81 mmol) was added. The mixture was stirred at room temperature for 30 min, and directly spin-dried for the next step without purification to obtain 300 mg of a yellow powder, MS (ESI) m/z: 248.1 [M+H] ⁺ .

Step 6: Synthesis of 2-chloro-5-((3-chloro-2-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)thio)pyrazine

At room temperature, potassium 2-chloro-3-((1-methyl-1H-pyrazol-3-yl)ethynyl)phenylthioate (300 mg, 1.21 mmol), 2-bromo-5-chloropyrazine (0.35 g, 1.82 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.08 g, 0.12 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (0.14 mg, 0.24 mmol) and N,N-diisopropylethylamine (0.31 g, 2.42 mmol) were dissolved in dioxane (10 mL), the reaction temperature was raised to 90 degrees, the reaction was allowed to react for 3 hours, the mixture was concentrated and dried, and the mixture was purified by column chromatography (EA/PE=1:2) to obtain 0.25 g of a yellow solid, MS (ESI) m/z: 361.8 [M+H] ⁺ .

Step 7: Synthesis of tert-butyl (3-acetyl-9-(5-((2-chloro-3-((1-methyl-1H-pyrazol-3-yl)ethynyl)phenyl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-1-yl)carbamate

At room temperature, 2-chloro-5-(3-chloro-2-(1-methylpyrazol-3-yl)ethynyl)pyridin-4-yl)thiopyrazine (100 mg, 0.28 mmol), (3-acetyl-3,9-diazaspiro[5.5]undec-1-yl)carbamic acid tert-butyl ester (100 mg, 0.33 mmol) and N,N-diisopropylethylamine (0.05 g, 0.42 mmol) were dissolved in dimethyl sulfoxide (10 mL). Under nitrogen protection, the temperature was raised to 80 degrees for 2 hours, cooled to room temperature, water (40 mL) was added, and extracted with ethyl acetate (50 mL x 3). The organic phase was washed twice with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. Purification by column chromatography (methanol/dichloromethane = 1:10) gave 57 mg of a yellow oil, MS (ESI) m/z: 636.8 [M+H] ⁺ .

Step 8: Synthesis of 1-(1-amino-9-(5-((2-chloro-3-((1-methyl-1H-pyrazol-3-yl)ethynyl)phenyl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undecane-3-yl)ethan-1-one

At room temperature, tert-butyl (3-acetyl-9-(5-((2-chloro-3-((1-methyl-1H-pyrazol-3-yl)ethynyl)phenyl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate (57 mg, 0.09 mmol) was dissolved in EA (4 mL), HCl/EA (4 mL) was added, stirred at room temperature for 1 hour, directly concentrated, and purified by column chromatography (methanol/dichloromethane = ^1:10 ) to obtain 33 mg of a light yellow solid. NMR (400MHz, DMSO-d6) δ8.40(s,1H),8.27(s,1H),7.80(s,1H),7.46(d,J＝7.6Hz,1H),7.26(t,J＝7.9Hz,1H),6.88(d,J＝8.1Hz,1H),6.56(s,1H),4.02(t,J＝1 5.5Hz,2 H), 3.88 (s, 3H), 3.74-3.62 (m, 2H), 3.19 (d, J = 40.4 Hz, 4H), 2.63 (d, J = 31.2 Hz, 1H), 2.00 (s, 3H), 1.84 (d, J = 16.5 Hz, 1H), 1.73-1.15 (m, 5H). MS (ESI) m/z: 536.7 [M+H] ⁺ . Example 38: Synthesis of 1-(1-amino-9-(5-(3-chloro-2-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-3-yl)ethan-1-one (II-7)

Synthesis of tert-butyl (3-acetyl-3,9-diazaspiro[5.5]undecane-1-yl)carbamate Reference Example 1.

Step 1: Synthesis of 4-bromo-3-chloro-2-(trimethylsilyl)ethynyl)pyridine

At room temperature, 2,4-dibromo-3-chloropyridine (7.0 g, 25.8 mmol) was dissolved in tetrahydrofuran (70 mL), and then trimethylsilane (2.79 g, 28.38 mmol), cuprous iodide (491 mg, 2.58 mmol), bistriphenylphosphine palladium dichloride (1.81 g, 2.58 mmol), and triethylamine (26.0 g, 258.0 mmol) were added. The reaction solution was reacted at 70°C under nitrogen protection for 1 hour. The reaction solution was directly filtered, the filtrate was spin-dried, and purified by column chromatography (ethyl acetate/petroleum ether=0:1) to obtain 6.0 g of a yellow oil, MS (ESI) m/z: 288.64 [M+H] ⁺ .

Step 2: Synthesis of 4-bromo-3-chloro-2-ethynylpyridine

At room temperature, 4-bromo-3-chloro-2-(trimethylsilyl)ethynyl)pyridine (6.0 g, 20.7 mmol) was dissolved in methanol (40 mL), potassium fluoride (2.4 g, 41.4 mmol) was added, and the mixture was stirred at room temperature for 30 mins under nitrogen protection. The reaction solution was washed with water (60 mL x 3), extracted with ethyl acetate (80 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain 4.4 g of a yellow oil.

Step 3: Synthesis of 4-bromo-3-chloro-2-(1-methylpyrazol-3-yl)ethynyl)pyridine

At room temperature, 4-bromo-3-chloro-2-ethynylpyridine (4.4 g, 20.3 mmol) was dissolved in tetrahydrofuran (40 mL), and then 3-iodo-1-methylpyrazole (4.64 g, 22.33 mmol), cuprous iodide (387 mg, 2.03 mmol), bistriphenylphosphine palladium dichloride (1.4 g, 2.03 mmol), triethylamine (20.0 g, 203.0 mmol) were added. The reaction solution was reacted at 70 ° C under nitrogen protection for 1 hour. The reaction solution was directly filtered, the filtrate was spin-dried, and purified by column chromatography (ethyl acetate/petroleum ether = 1:3) to obtain 2.9 g of a yellow oil.

Step 4: Synthesis of methyl 3-(3-chloro-2-(1-methylpyrazol-3-yl)ethynyl)pyridin-4-ylthio)propanoate

At room temperature, 4-bromo-3-chloro-2-(1-methylpyrazol-3-yl)ethynyl)pyridine (2.9 g, 9.8 mmol) was dissolved in dioxane (30 mL), and then methyl 3-mercaptopropionate (2.59 g, 21.56 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.7 g, 1.96 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (1.1 g, 1.96 mmol) and N,N-diisopropylethylamine (6.3 g, 49.0 mmol) were added. The reaction temperature was raised to 100° C. and reacted for 5 hours. The mixture was concentrated and dried, and purified by column chromatography (EA/PE=1:1) to obtain 2.16 g of a yellow solid, MS (ESI) m/z: 336.1[M+H] ⁺ .

Step 5: Synthesis of sodium 3-chloro-2-(1-methylpyrazol-3-yl)ethynyl)pyridine-4-thioate

At room temperature, methyl 3-(3-chloro-2-(1-methylpyrazol-3-yl)ethynyl)pyridin-4-ylthio)propanoate (2.16 g, 6.43 mmol) was dissolved in methanol (20 mL), and sodium methoxide (765 mg, 14.15 mmol) was added. The mixture was stirred at room temperature for 12 hours, and directly dried for the next step without purification to obtain 4.0 g of a yellow powder, MS (ESI) m/z: 248.7 [M+H] ⁺ .

Step 6: Synthesis of 2-chloro-5-(3-chloro-2-(1-methylpyrazol-3-yl)ethynyl)pyridin-4-yl)thiopyrazine

At room temperature, sodium 3-chloro-2-(1-methylpyrazol-3-yl)ethynyl)pyridine-4-thioate (4.0 g, 7.38 mmol), 2-bromo-5-chloropyrazine (1.7 g, 8.8 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.0 g, 1.47 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (850 mg, 1.47 mmol) and N,N-diisopropylethylamine (4.15 g, 32.2 mmol) were dissolved in dioxane (20 mL), the reaction temperature was raised to 90 degrees, the reaction was allowed to react for 3 hours, the mixture was concentrated and dried, and the mixture was purified by column chromatography (EA/PE=1:2) to obtain 1.44 g of a yellow solid, MS (ESI) m/z: 363.2 [M+H] ⁺ .

Step 7: Synthesis of tert-butyl (3-acetyl-9-(5-((3-chloro-2-((1-methylpyrazol-3-yl)ethynyl)pyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate

At room temperature, 2-chloro-5-(3-chloro-2-(1-methylpyrazol-3-yl)ethynyl)pyridin-4-yl)thiopyrazine (400 mg, 1.1 mmol), (3-acetyl-3,9-diazaspiro[5.5]undec-1-yl)carbamic acid tert-butyl ester (445 mg, 1.43 mmol) and N,N-diisopropylethylamine (1.42 g, 11.0 mmol) were dissolved in dimethyl sulfoxide (6 mL). Under nitrogen protection, the temperature was raised to 80 degrees for 15 hours, cooled to room temperature, water (40 mL) was added, and extracted with ethyl acetate (50 mL x 3). The organic phase was washed twice with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. Column chromatography purification (methanol/dichloromethane = 1:10) gave 600 mg of a yellow oil, MS (ESI) m/z: 637.5 [M+H] ⁺ .

Step 8: Synthesis of 1-(1-amino-9-(5-(3-chloro-2-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-3-yl)ethan-1-one

At room temperature, tert-butyl (3-acetyl-9-(5-((3-chloro-2-((1-methylpyrazol-3-yl)ethynyl)pyridin-4-yl)thio)pyrazin-2-yl)-3,9-diazaspiro[5.5]undec-1-yl)carbamate (600 mg, 0.97 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature for 1 hour, directly concentrated, and purified by column chromatography (methanol/dichloromethane=1:10) to obtain 415 mg of a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.48(s,1H),8.35(s,1H),8.27(d,J＝5.3Hz,1H),7.85(d,J＝2.2Hz,1H),6.72(d,J＝5.3Hz,1H),6.66(d,J＝2.3Hz,1H),4.07(dt,J＝13.9,6.9Hz,2H),3. 92(s,3H),3.52–3.42(m,4H),3.21(dd, J＝13.6,7.0Hz,1H),3.08(dd,J＝13.3,8.1Hz,1H),2.57(dd,J＝7.3,3.4Hz,1H),2.01(s,3H),1.88(ddd,J＝26.7,13.5,8.2Hz,2H),1.76–1.51(m,3H),1.49– 1.20(m,3H).MS(ESI)m/z:537.5[M+H] ⁺ .

Example 39: Synthesis of (1-(5-((3-chloro-2-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methanamine (II-1)

Synthesis of 2-chloro-5-((3-chloro-2-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)thio)pyrazine Reference Example 38.

Step 1: Synthesis of (4-methylpiperidin-4-yl)methanamine

At room temperature, add tert-butyl 4-(aminomethyl)-4-methylpiperidine-1-carboxylate (0.25 g, 1.09 mmol) and 4N hydrochloric acid methanol solution (4 mL) into the bottle in sequence. React at room temperature for 4 hours. LCMS detected that the raw material reacted completely. Add sodium carbonate solution to the reaction solution until the pH is greater than 9. Filter the reaction solution, spin dry the filtrate, and directly use the crude product for the next step.

Step 2: Synthesis of (1-(5-((3-chloro-2-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methanamine

At room temperature, (4-methylpiperidin-4-yl)methylamine (0.30 g, crude), 2-chloro-5-((3-chloro-2-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)thio)pyrazine (0.08 g, 0.23 mmol), DIEA (0.30 g, 2.30 mmol), and DMSO (1 mL) were added to the reaction bottle in sequence, and reacted at 80° C. for 4 h under nitrogen atmosphere. LCMS detected that the raw material reacted completely. The crude product was purified by column chromatography (ACN/H ₂ O system) to obtain 0.32 g of a yellow solid.

¹ H NMR (400MHz, DMSO-d6) δ8.49 (s, 1H), 8.34 (s, 1H), 8.27 (d, J = 5.3Hz, 1H), 7.85 (d, J = 2.3Hz, 1H), 6.72(d,J＝5.4Hz,1H),6.66(d,J＝2.2Hz,1H),3.96-3.88(m,2H),3.91(s,3H),3.49–3.43(m,2H),2.44 (s,2H),1.56–1.22(m,6H),0.95(s,3H).MS(ESI)m/z:454.2[M+H] ⁺ .

Example 40: Synthesis of (R)-1'-(5-((3-chloro-2-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)thio)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]-3-amine (II-2)

Synthesis of 2-chloro-5-((3-chloro-2-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)thio)pyrazine Reference Example 38.

Step 1: Synthesis of (R)-1'-(5-((3-chloro-2-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)thio)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-amine

At room temperature, (R)-3H-spiro[benzofuran-2,4'-piperidin]-3-amine (0.04 g, 0.20 mmol), 2-chloro-5-((3-chloro-2-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)thio)pyrazine (0.07 g, 0.20 mmol), DIEA (0.26 g, 2.00 mmol), and DMSO (1 mL) were added to the reaction bottle in sequence, and reacted at 80° C. for 4 h under nitrogen atmosphere. LCMS detected that the raw material reacted completely. The crude product was purified by column chromatography (ACN/H ₂ O system) to obtain 0.82 g of a yellow solid, with a yield of 79%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.59 (s, 1H), 8.39 (s, 1H), 8.28 (d, J = 5.4Hz, 1H), 7.86 (s, 1H), 7.34 (d, J = 7.4Hz, 1H), 7.16 (t, J = 7.8Hz, 1H), 6.89 (d, J = 7.4Hz, 1H) ,6.81–6.75(m,2H),6.66(s,1H),4.33(s,2H),4.12(s,1H),3.91(s,3H),3.48(d,J＝11.9Hz,2H),2.01–1.74(m,6H).MS(ESI)m/z:530.2[M+H] ⁺ Example 41: Synthesis of (3S, 4S)-8-(6-amino-5-(2-chloro-3-(1-methylpyrazol-3-yl)ethynyl)phenylthiopyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine (II-3)

Step 1: Synthesis of (3-bromo-2-chlorophenyl)ethynyl)trimethylsilane

At room temperature, 1-bromo-2-chloro-3-iodobenzene (1.2 g, 3.78 mmol) was dissolved in tetrahydrofuran (15 mL), and then trimethylsilane (408 mg, 4.16 mmol), cuprous iodide (72 mg, 0.38 mmol), bistriphenylphosphine palladium dichloride (265 mg, 0.38 mmol), triethylamine (3.82 g, 37.8 mmol) were added. The reaction solution was reacted at 70 ° C under nitrogen protection for 1 hour. The reaction solution was directly filtered, the filtrate was spin-dried, and purified by column chromatography (ethyl acetate/petroleum ether = 0: 1) to obtain 1.1 g of colorless oil.

Step 2: Synthesis of 1-bromo-2-chloro-3-ethynylbenzene

At room temperature, (3-bromo-2-chlorophenyl)ethynyl)trimethylsilane (1.1 g, 3.82 mmol) was dissolved in methanol (12 mL), potassium fluoride (444 mg, 7.64 mmol) was added, and the mixture was stirred at room temperature for 1 hour under nitrogen protection. The reaction solution was washed with water (30 mL x 3), extracted with ethyl acetate (40 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain 750 mg of a brown oil.

Step 3: Synthesis of 3-(3-bromo-2-chlorophenyl)ethynyl)-1-methylpyrazole

At room temperature, 1-bromo-2-chloro-3-ethynylbenzene (750 mg, 3.48 mmol) was dissolved in tetrahydrofuran (10 mL), and then 3-iodo-1-methylpyrazole (796 mg, 3.83 mmol), cuprous iodide (67 mg, 0.35 mmol), bistriphenylphosphine palladium dichloride (244 mg, 0.35 mmol), and triethylamine (3.51 g, 34.8 mmol) were added. The reaction solution was reacted at 70°C under nitrogen protection for 2 hours. The reaction solution was directly filtered, the filtrate was spin-dried, and purified by column chromatography (ethyl acetate/petroleum ether=1:3) to obtain 500 mg of a brown oil, MS (ESI) m/z: 296.8 [M+H] ⁺ .

Step 4: Synthesis of methyl 3-(2-chloro-3-(1-methylpyrazol-3-yl)ethynyl)phenylthio)propanoate

At room temperature, 3-(3-bromo-2-chlorophenyl)ethynyl)-1-methylpyrazole (500 mg, 1.69 mmol) was dissolved in dioxane (8 mL), and then methyl 3-mercaptopropionate (447 mg, 3.72 mmol), tris(dibenzylideneacetone)dipalladium(0) (154 mg, 0.17 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (195 mg, 0.34 mmol) and N,N-diisopropylethylamine (1.1 g, 8.45 mmol) were added. The reaction temperature was raised to 100° C. and the reaction was carried out for 15 hours. The mixture was concentrated and dried, and purified by column chromatography (EA/PE=1:1) to obtain 310 mg of a brown oil, MS (ESI) m/z: 334.9 [M+H] ⁺ .

Step 5: Synthesis of sodium 2-chloro-3-(1-methylpyrazol-3-yl)ethynyl)benzenethiol

At room temperature, methyl 3-(2-chloro-3-(1-methylpyrazol-3-yl)ethynyl)phenylthio)propanoate (310 mg, 0.93 mmol) was dissolved in methanol (6 mL), and sodium methoxide (111 mg, 2.05 mmol) was added. The mixture was stirred at room temperature for 12 hours and directly spin-dried for the next step without purification to obtain 800 mg of a yellow oil. MS (ESI) m/z: 247.7 [M+H] ⁺ .

Step 6: Synthesis of 6-chloro-3-(2-chloro-3-(1-methylpyrazol-3-yl)ethynyl)phenylthio)pyrazin-2-amine

At room temperature, sodium 2-chloro-3-(1-methylpyrazol-3-yl)ethynyl)benzenethiol (800 mg, 1.14 mmol), 2-amino-3-bromo-6-chloropyrazine (277 mg, 1.33 mmol), tris(dibenzylideneacetone)dipalladium(0) (200 mg, 0.23 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (128 mg, 0.23 mmol) and N,N-diisopropylethylamine (737 mg, 5.7 mmol) were dissolved in dioxane (10 mL), the reaction temperature was raised to 90 degrees, the reaction was allowed to react for 3 hours, the mixture was concentrated and dried, and the mixture was purified by column chromatography (EA/PE=1:2) to obtain 280 mg of a yellow oil, MS (ESI) m/z: 377.0 [M+H] ⁺ .

Step 7: Synthesis of (3S,4S)-8-(6-amino-5-(2-chloro-3-(1-methylpyrazol-3-yl)ethynyl)phenylthiopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

At room temperature, 6-chloro-3-(2-chloro-3-(1-methylpyrazol-3-yl)ethynyl)phenylthio)pyrazine-2-amine (100 mg, 0.26 mmol), 3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride (96 mg, 0.38 mmol) and N,N-diisopropylethylamine (171 mg, 1.33 mmol) were dissolved in dimethyl sulfoxide (2 mL). Under nitrogen protection, the temperature was raised to 90 degrees for 15 hours, cooled to room temperature, and purified by column chromatography (acetonitrile/water = 27%) to obtain 32 mg of brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.34(s,2H),7.82(d,J＝2.2Hz,1H),7.64(s,1H),7.41(dd,J＝7.7,1.5Hz,1H),7.24(t,J＝7.9Hz,1H),6.64(dd,J＝8.0,1.5Hz,1H),6.57(d,J＝2.3Hz,1H), 6.17(s,2H),4.12–4 .07(m,1H),3.89(s,3H),3.21–3.71(d,J＝8.5Hz,2H),3.31(m,4H),2.98(d,J＝5.1Hz,1H),1.75–1.62(m,2H),1.57–1.46(m,2H),1.11(d,J＝6.4Hz,3H) .MS(ESI)m/z:510.5[M+H] ⁺ .

Example 42: Synthesis of (3S,4S)-8-(5-((2-chloro-3-((1-methyl-1H-pyrazol-3-yl)ethynyl)phenyl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine (II-5)

Synthesis of 2-chloro-5-((3-chloro-2-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)thio)pyrazine Reference Example 38.

Step 1: Synthesis of ((3S,4S)-8-(5-((2-chloro-3-((1-methyl-1H-pyrazol-3-yl)ethynyl)phenyl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine

At room temperature, 2-chloro-5-((2-chloro-3-((1-methyl-1H-pyrazol-3-yl)ethynyl)phenyl)thio)pyrazine (0.10 g, 0.28 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride (0.08 g, 0.33 mmol), DIEA (0.18 g, 1.38 mmol) and DMSO (1 mL) were added to the bottle in sequence, and the mixture was reacted at 80° C. for 5 h. The reaction solution was directly purified by reverse phase column chromatography (acetonitrile/water system) and freeze-dried to obtain 0.09 g of pure product with a yield of 66%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.44(d,J＝1.4Hz,1H),8.28(d,J＝1.3Hz,1H),7.82(d,J＝2.2Hz,1H),7.48(dd,J＝7.7,1.4Hz,1H),7.27(t,J＝7.9Hz,1H),6.90(dd,J＝8.1,1.4Hz,1H),6.58 (d,J＝2.3Hz,1H),4.07( p,J＝6.3Hz,1H),3.94-3.86(m,2H),3.89(s,3H),3.68(d,J＝8.4Hz,1H),3.52–3.40(m,3H),2.92(d,J＝5.1Hz,1H),1.81–1.34(m,6H),1.09(d,J＝6.4Hz, 3H).MS(ESI)m/z:495.4[M+H] ⁺ .

Example 43: Synthesis of (3S,4S)-8-(5-((3-chloro-2-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)thio)pyrazol-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine (II-8)

Synthesis of 2-chloro-5-((3-chloro-2-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)thio)pyrazine Reference Example 38.

Step 1: (3S,4S)-8-(5-((3-chloro-2-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)thio)pyrazol-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine

At room temperature, 2-chloro-5-((3-chloro-2-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)thio)pyrazine (0.10 g, 0.28 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride (0.07 g, 0.41 mmol), DIEA (0.18 g, 1.40 mmol) and DMSO (1 mL) were added to the bottle in sequence, and the mixture was reacted at 80°C for 5 h. The reaction solution was directly purified by reverse phase column chromatography (acetonitrile/water system) and freeze-dried to obtain 0.06 g of pure product with a yield of 44%. ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.51(s,1H),8.35(s,1H),8.27(d,J＝5.3Hz,1H),7.85(d,J＝2.2Hz,1H),6.73(d,J＝5.3Hz,1H),6.66(d,J＝2.2Hz,1H),4.11–4.05(m,1H),3.98-3.89( m,2H),3.91(s,3H),3.69(d,J＝8.4Hz,1H),3.55–3.45(m,3H),2.93(d,J＝5.1Hz,1H),1.84–1.34(m,6H),1.09(d,J＝6.4Hz,3H).MS(ESI)m/z:496.2[M+H] ⁺ .

Example 44: Synthesis of (3S,4S)-8-(6-amino-5-(3-chloro-2-(1-methylpyrazol-3-yl)ethynylpyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine (II-4)

Synthesis of sodium 3-chloro-2-(1-methylpyrazol-3-yl)ethynyl)pyridine-4-thioate Reference Example 38.

Step 1: Synthesis of 6-chloro-3-(3-chloro-2-(1-methylpyrazol-3-yl)ethynyl)pyridin-4-ylthio)pyrazin-2-amine

At room temperature, sodium 3-chloro-2-(1-methylpyrazol-3-yl)ethynyl)pyridine-4-thioate (600 mg, 1.65 mmol), 2-amino-3-bromo-6-chloropyrazine (413 mg, 1.98 mmol), tris(dibenzylideneacetone)dipalladium(0) (300 mg, 0.33 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (191 mg, 0.33 mmol) and N,N-diisopropylethylamine (1.06 g, 8.25 mmol) were dissolved in dioxane (10 mL), the reaction temperature was raised to 90 degrees, the reaction was allowed to react for 3 hours, the mixture was concentrated and dried, and purified by column chromatography (EA/PE=1:1) to obtain 300 mg of a yellow oil, MS (ESI) m/z: 377.2 [M+H] ⁺ .

Step 2: Synthesis of 3S,4S)-8-(6-amino-5-(3-chloro-2-(1-methylpyrazol-3-yl)ethynylpyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

At room temperature, 6-chloro-3-(3-chloro-2-(1-methylpyrazol-3-yl)ethynyl)pyridin-4-ylthio)pyrazin-2-amine (120 mg, 0.27 mmol), 3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine hydrochloride (100 mg, 0.38 mmol) and N,N-diisopropylethylamine (200 mg, 1.38 mmol) were dissolved in dimethyl sulfoxide (2 mL). Under nitrogen protection, the temperature was raised to 90 degrees for 3 hours, cooled to room temperature, and purified by column chromatography (acetonitrile/water = 26%) to obtain 28 mg of brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.33(s,1H),8.26(d,J＝5.3Hz,1H),7.85(d,J＝2.2Hz,1H),7.68(s,1H),6.65(d,J＝2.2Hz,1H),6.56(d,J＝5.2Hz,1H),6.29(s,2H),4.12–4.08(m,1H), 3.91(s,3H),3.53(d,J＝8.6Hz,2H),3.21–3.31(m,4H),3.01(d,J＝5.0Hz,1H),1.75–1.64(m,2H),1.58–1.48(m,2H),1.11(d,J＝6.4Hz,3H).MS(ESI)m/z :511.2[M+H] ⁺ .

Using a similar preparation method as above, the following compounds can be prepared:

serial number Mass spectrometry dataMS(ESI)m/z serial number Mass spectrometry dataMS(ESI)m/z I-39 532.22[M+H] ⁺ . I-40 532.22[M+H] ⁺ . II-9 496.16[M+H] ⁺ . II-11 507.17[M+H] ⁺ . II-12 509.16[M+H] ⁺ . II-13 494.15[M+H] ⁺ . II-14 440.13[M+H] ⁺ . II-15 494.15[M+H] ⁺ . II-16 412.10[M+H] ⁺ . II-17 412.10[M+H] ⁺ . II-18 493.15[M+H] ⁺ . II-19 493.15[M+H] ⁺ . II-20 513.12[M+H] ⁺ . II-22 556.25[M+H] ⁺ . II-23 499.20[M+H] ⁺ . II-24 513.18[M+H] ⁺ . II-25 527.16[M+H] ⁺ . II-26 487.16[M+H] ⁺ . II-27 543.19[M+H] ⁺ . II-28 556.22[M+H] ⁺ . II-29 501.18[M+H] ⁺ . II-30 561.19[M+H] ⁺ . II-31 547.17[M+H] ⁺ . II-32 533.16[M+H] ⁺ . II-33 533.16[M+H] ⁺ . II-34 578.15[M+H] ⁺ . II-35 578.15[M+H] ⁺ . II-36 561.18[M+H] ⁺ . II-37 545.18[M+H] ⁺ . II-38 546.18[M+H] ⁺ . II-39 533.16[M+H] ⁺ . II-40 534.18[M+H] ⁺ . II-41 535.17[M+H] ⁺ . II-42 519.20[M+H] ⁺ . II-43 539.19[M+H] ⁺ . II-44 540.19[M+H] ⁺ . II-45 539.19[M+H] ⁺ . II-46 535.17[M+H] ⁺ . II-47 536.17[M+H] ⁺ . II-48 520.20[M+H] ⁺ . II-49 540.19[M+H] ⁺ . II-50 541.18[M+H] ⁺ . II-51 540.19[M+H] ⁺ . II-52 480.19[M+H] ⁺ . II-53 476.22[M+H] ⁺ . II-54 542.11[M+H] ⁺ . II-55 462.20[M+H] ⁺ . II-56 562.18[M+H] ⁺ . II-57 509.19[M+H] ⁺ . II-58 573.20[M+H] ⁺ . II-59 580.23[M+H] ⁺ . II-60 607.19[M+H] ⁺ . II-61 571.21[M+H] ⁺ . II-62 596.21[M+H] ⁺ . II-63 496.16[M+H] ⁺ . II-64 517.24[M+H] ⁺ . II-65 542.24[M+H] ⁺ . II-66 553.25[M+H] ⁺ . II-67 560.28[M+H] ⁺ . II-68 546.18[M+H] ⁺ . II-69 550.17[M+H] ⁺ . II-70 562.17[M+H] ⁺ . II-71 546.18[M+H] ⁺ . II-72 546.18[M+H] ⁺ . II-73 547.17[M+H] ⁺ .

Example 45: Synthesis of 6-amino-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-((3-chloro-2-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)thio)-3-methylpyrimidin-4(3H)-one (II-50)

Step 1: Synthesis of 6-amino-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-3-methylpyrimidin-4(3H)-one

At room temperature, 6-amino-3-methyluracil (0.80 g, 5.67 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro [4.5] decane-4-amine dihydrochloride (1.65 g, 6.80 mmol), Carter condensation agent (5.01 g, 11.34 mmol), DBU (4.31 g, 28.34 mmol) and DMF (3 mL) were added to the reaction bottle in sequence and reacted at room temperature for 12 h. LCMS detected that the raw material reacted completely. The reaction solution was directly reversed (MeCN/water system) to obtain 0.90 g of white solid, yield: 54%. MS (ESI) m/z: 294.2 [M+H] ⁺ .

Step 2: Synthesis of 6-amino-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-iodo-3-methylpyrimidin-4(3H)-one

At room temperature, 6-amino-2-((3S, 4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-3-methylpyrimidin-4(3H)-one (0.90 g, 3.07 mmol) and DMF (5 mL) were added to the reaction bottle in sequence. NIS (0.83 g, 3.68 mmol) was added at 0°C and the reaction was naturally restored to room temperature for 2 h. LCMS detected that the raw material reaction was complete. Water and ethyl acetate were added for separation, ethyl acetate was extracted twice, washed once with water, dried and spin-dried, and sanded. Column chromatography (MeOH/DCM system) was performed to obtain 1.0 g of white solid with a yield of 78%. MS (ESI) m/z: 420.1 [M+H] ⁺ .

Step 3: Synthesis of 6-amino-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-5-((3-chloro-2-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)thio)-3-methylpyrimidin-4(3H)-one

At room temperature, sodium 3-chloro-2-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridine-4-thiolate (0.23 g, 0.86 mmol), 6-amino-2-((3S, 4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-iodo-3-methylpyrimidin-4(3H)-one (0.30 g, 0.72 mmol), cuprous iodide (0.03 g, 0.14 mmol), TMEDA (0.02 g, 0.14 mmol), potassium phosphate (0.46 g, 2.15 mmol) and dioxane (10 mL) were added to the reaction bottle in sequence, and reacted at 90° C. for 12 h under nitrogen atmosphere. LCMS detected that the raw material reaction was complete. The reaction solution was directly spin-dried and sanded, and column chromatography (MeOH/DCM system) was performed to obtain 0.15 g of white solid, yield: 39%. MS (ESI) m/z: 541.5 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.24(d,J＝5.3Hz,1H),7.85(s,1H),6.87(s,2H),6.77(d,J＝5.3Hz,1H) ,6.65(d,J＝2.5Hz,1H),4.06(t,J＝6.2Hz,1H),3.91(s,3H),3.66(d,J＝8.5Hz,1H),3.49(d,J＝ 8.4Hz,2 H),3.29(s,4H),3.12(t,J＝11.1Hz,1H),3.04(t,J＝11.2Hz,1H),2.92(d,J＝5.0Hz,1H),1.84(t, J＝11.0Hz,1H),1.71(d,J＝9.8Hz,1H),1.63–1.55(m,2H),1.09(d,J＝6.3Hz,3H).

Example 46: Synthesis of (3S,4S)-8-(5-((3-chloro-2-((1-methyl-1H-indazol-3-yl)ethynyl)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine (II-38)

Synthesis of sodium 3-chloro-2-(1-methylpyrazol-3-yl)ethynyl)pyridine-4-thioate Reference Example 38.

Step 1: Synthesis of 3-((4-bromo-3-chloropyridin-2-yl)ethynyl)-1-methyl-1H-indazole

At room temperature, 4-bromo-3-chloro-2-ethylpyridine (0.60 g, 2.78 mmol), 3-iodo-1-methyl-1H-indole (0.72 g, 2.78 mmol), (PPh ₃ ) ₂ PdCl ₂ (0.09 g, 0.14 mmol), CuI (0.03 g, 0.14 mmol), TEA (2.81 g, 27.80 mmol), and tetrahydrofuran (10 mL) were added to the bottle in sequence. The reaction was carried out at 95°C for 12 h. LCMS detected that the raw material reacted completely. The reaction solution was filtered, the filtrate was spin-dried and sanded, and column chromatography (EA/PE system) was performed to obtain 0.47 g of brown oil, with a yield of 49%. MS (ESI) m/z: 345.9 [M+H] +.

Step 2: Synthesis of methyl 3-((3-chloro-2-((1-methyl-1H-indazol-3-yl)ethynyl)pyridin-4-yl)thio)propanoate

At room temperature, 3-((4-bromo-3-chloropyridin-2-yl)ethynyl)-1-methyl-1H-indazole (0.40 g, 1.15 mmol), methyl 3-mercaptopropionate (0.17 g, 1.38 mmol), Pd ₂ (dba) ₃ (0.05 g, 0.06 mmol), XantPhos (0.07 g, 0.12 mmol), DIEA (0.45 g, 3.45 mmol), and dioxane (10 mL) were added to the bottle in sequence. The reaction was carried out at 95°C for 6 h. LCMS detected that the raw material reacted completely. The reaction solution was filtered, the filtrate was spin-dried and sanded, and column chromatography (EA/PE system) was performed to obtain 0.25 g of brown solid, with a yield of 56%. MS (ESI) m/z: 386.1 [M+H] ⁺ .

Step 3: Synthesis of sodium 3-chloro-2-((1-methyl-1H-indazol-3-yl)ethynyl)pyridine-4-thiolate

At room temperature, methyl 3-((3-chloro-2-((1-methyl-1H-indazol-3-yl)ethynyl)pyridin-4-yl)thio)propanoate (0.25 g, 0.64 mmol), potassium tert-butoxide (0.15 g, 1.30 mmol), and MeOH (10 mL) were added to the bottle in sequence. The reaction was carried out at room temperature for 2 h. LCMS detected that the raw material reacted completely. The reaction solution was spin-dried and the crude product was directly used for the next step.

Step 4: Synthesis of 3-((3-chloro-4-((5-chloropyrazin-2-yl)thio)pyridin-2-yl)ethynyl)-1-methyl-1H-indazole

At room temperature, sodium 3-chloro-2-((1-methyl-1H-indazol-3-yl)ethynyl)pyridine-4-thiolate (0.20 g, 0.62 mmol), 2-bromo-5-chloropyrazine (0.12 g, 0.62 mmol), Pd ₂ (dba) ₃ (0.03 g, 0.03 mmol), XantPhos (0.04 g, 0.06 mmol), DIEA (0.24 g, 1.86 mmol), and dioxane (5 mL) were added to the bottle in sequence. The reaction was carried out at 95°C for 6 h. LCMS detected that the raw material reacted completely. The reaction solution was filtered, the filtrate was spin-dried and sanded, and column chromatography (EA/PE system) was performed to obtain 0.07 g of yellow solid, with a two-step yield of 27%. MS (ESI) m/z: 411.0 [M+H] ⁺ .

Step 5: Synthesis of (3S,4S)-8-(5-((3-chloro-2-((1-methyl-1H-indazol-3-yl)ethynyl)pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine

At room temperature, 3-((3-chloro-4-((5-chloropyrazin-2-yl)thio)pyridin-2-yl)ethynyl)-1-methyl-1H-indazole (0.06 g, 0.15 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine (0.11 g, 0.45 mmol), DIEA (0.19 g, 1.47 mmol), and DMSO (3 mL) were added to the reaction bottle in sequence, and the mixture was reacted at room temperature for 24 h under a nitrogen atmosphere. LCMS detected that the raw material reaction was complete. Water (5 ml) and ethyl acetate (10 ml*2) were added to the reaction solution, and the organic phase was washed with water, dried, and spin-dried. The crude product was subjected to column chromatography (MeOH/DCM system) to obtain 0.04 g of a yellow solid with a yield of 50%. MS (ESI) m/z: 546.2 [M+H] ⁺ .

1H NMR (400MHz, DMSO-d6) δ8.53(s,1H),8.38(s,1H),8.33(d,J＝5.4Hz,1H),7.88–7.79(m,2H),7.55(t, J＝7.8Hz,1H),7.36(t,J＝7.5Hz,1H),6.78(d,J＝5.3Hz,1H),4.17(s,4H),3 .96(s,2H),3.71(d,J＝8.5Hz,1H),3.55–3.46(m,3H),2.96(d,J＝4.6Hz,1H),1.78(d,J＝12.9Hz, 1H),1.69(s,1H),1.60(s,1H),1.54(s,1H),1.25(s,2H),1.11(d,J=6.4Hz,3H).

Example 47: Synthesis of (3S,4S)-8-(8-((2-chloro-3-((1-methyl-1H-pyrazol-3-yl)ethynyl)phenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine (II-41)

Synthesis of (3S, 4S)-8-(8-iodo-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-amine Reference Example 45.

Step 1: Synthesis of (3S,4S)-8-(8-((2-chloro-3-((1-methyl-1H-pyrazol-3-yl)ethynyl)phenyl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

At room temperature, sodium 2-chloro-3-((1-methyl-1H-pyrazol-3-yl)ethynyl)benzenethiocarboxylate (0.40 g, 1.48 mmol), (3S,4S)-8-(8-iodo-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-amine (0.61 g, 1.48 mmol), Pd ₂ (dba) ₃ (0.14 g, 0.15 mmol), Xantphos (0.09 g, 0.15 mmol), DIEA (0.57 g, 4.43 mmol) and dioxane (10 mL) were added to a reaction bottle in sequence, and the mixture was reacted at 95° C. for 2 h under a nitrogen atmosphere. The reaction of the raw materials was complete as detected by LCMS. The reaction solution was directly spin-dried and sanded, and then subjected to column chromatography (MeOH/DCM system) to obtain 0.474 g of a white solid, with a yield of 60%. MS (ESI) m/z: 535.5 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.40 (s, 1H), 8.00 (s, 1H), 7.82 (t, J = 1.6Hz, 1H), 7.45 (d, J = 7.6Hz, 1H) ,7.17(t,J＝7.9Hz,1H),6.89(d,J＝8.1Hz,1H),6.59(d,J＝1.8Hz,1H),4.12–4.07(m,1H),3.90(s, 3 H),3.88–3.84(m,2H),3.70(d,J＝8.5Hz,1H),3.64–3.51(m,3H),2.98(d,J＝5.0Hz,1H),1.97(t,J ＝11.0Hz,1H),1.86–1.80(m,1H),1.71–1.62(m,2H),1.11(d,J＝6.2Hz,3H).

Example 48: Synthesis of (3S,4S)-8-(8-((2-chloro-3-((1-methyl-1H-pyrazol-3-yl)ethynyl)phenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine (II-40)

Synthesis of (3S, 4S)-8-(8-iodoimidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine Reference Example 45.

Step 1: Synthesis of (3S,4S)-8-(8-((2-chloro-3-((1-methyl-1H-pyrazol-3-yl)ethynyl)phenyl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine

At room temperature, sodium 2-chloro-3-((1-methyl-1H-pyrazol-3-yl)ethynyl)benzenesulfonate (0.20 g, 0.74 mmol), (3S, 4S)-8-(8-iodoimidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine (0.31 g, 0.74 mmol), Pd ₂ (dba) ₃ (0.04 g, 0.04 mmol), XantPhos (0.02 g, 0.04 mmol), DIEA (0.29 g, 2.22 mmol), and dioxane (5 mL) were added to the bottle in sequence. The reaction was carried out at 95°C for 6 h. LCMS detected that the raw material reacted completely. The reaction solution was filtered, the filtrate was spin-dried and sanded, and column chromatography (MeOH/DCM system) was performed to obtain 0.24 g of yellow solid, with a yield of 56%. MS (ESI) m/z: 534.5 [M+H] ⁺ .

1H NMR (400MHz, DMSO-d6) δ8.03(s,1H),7.86(d,J＝13.8Hz,1H),7.83(d,J＝2.2Hz,1H),7.57(s,1H),7.43 (d,J＝7.6Hz,1H),7.15(t,J＝7.8Hz,1H),6.76(d,J＝8.1Hz,1H),6.59(d,J＝2.2Hz,1H),4.12–4.0 7(m,1H),3.90(s,2H),3.70(t,J＝9.6Hz,3H),3.52(dd,J＝12.2,8.4Hz,2H),3.47–3.35(m,3H),3.00 –2.95(m,1H),1.97(d,J＝11.8Hz,1H),1.90–1.79(m,2H),1.74–1.63(m,2H),1.10(t,J＝5.9Hz,3H).

Example 49: Synthesis of (3S,4S)-8-(3-chloro-2-(1-methylpyrazol-3-yl)ethynyl)pyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (II-46)

Step 1: Synthesis of 2-chloro-N-(2,2-dimethoxyethyl)-5-iodopyrimidin-4-amine

At room temperature, 2,4-dichloro-5-iodopyrimidine (20.00 g, 0.073 mol) and aminoacetaldehyde dimethyl acetal (15.30 g, 0.15 mol) were dissolved in ethanol (260 mL), cooled to 0°C, triethylamine (14.73 g, 0.15 mol) was added dropwise, and the temperature was raised to an external temperature of 35°C. A large amount of white solid was generated. The suspension was stirred overnight and concentrated under reduced pressure. Water (150 mL) was added to the concentrate, and it was extracted three times with dichloromethane (150 mL). The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 22.20 g of a crude product, which was directly used in the next step. The yield was 89%.

Step 2: Synthesis of 8-iodoimidazole[1,2-c]pyrimidin-5-ol

At room temperature, 2-chloro-N-(2,2-dimethoxyethyl)-5-iodopyrimidine-4-amine (21.20 g, 0.06 mol) was slowly added to concentrated sulfuric acid (130 mL), the reaction temperature was raised to 65°C, the reaction was allowed to react for 2 hours, and the reaction solution was slowly added to a large amount of ice cubes. The pH value of the solution was adjusted to 6 with a 4M aqueous sodium hydroxide solution. A large amount of light yellow solid precipitated, which was filtered. The solid was slurried with methanol (20 ml) for 3 hours, filtered, and vacuum dried to obtain 10.30 g of a light yellow solid with a yield of 64%.

Step 3: Synthesis of 5-chloro-8-iodoimidazole[1,2-c]pyrimidine

At room temperature, 8-iodoimidazole [1,2-c] pyrimidine-5-ol (7.34 g, 0.03 mmol) was slowly added to a mixed solution of cyclopentane sulfone (21 ml) and phosphorus oxychloride (73 mL), and diisopropylethylamine (14 mL) was slowly added dropwise. The reaction solution was heated to 110 ° C. and reacted overnight. The next day, it was spin-dried and slowly added dropwise with a saturated aqueous solution of sodium bicarbonate to adjust the pH to > 7. It was extracted twice with ethyl acetate (200 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (ethyl acetate, petroleum ether = 1:9-1:4) to obtain 3.19 g of a light yellow solid with a yield of 41%.

Step 4: Synthesis of (3S,4S)-8-(8-iodoimidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-amine

5-Chloro-8-iodoimidazole[1,2-c]pyrimidine (1.00 g, 3.58 mmol), 3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine (0.96 g, 3.94 mmol), N,N-diisopropylethylamine (2.77 g, 21.47 mmol) were dissolved in dimethyl sulfoxide (3 mL), and reacted at 20° C. for 2 hours under nitrogen protection. After the reaction was complete, the mixture was concentrated and directly purified by directional column chromatography (acetonitrile/water=37%:63%) to obtain 1.40 g of white solid with a yield of 95%.

Step 5: Synthesis of potassium 3-chloro-2-(1-methylpyrazol-3-yl)ethynyl)pyridine-4-thioate

At room temperature, methyl 3-(3-chloro-2-(1-methylpyrazol-3-yl)ethynyl)pyridin-4-ylthio)propanoate (0.55 g, 1.64 mmol) and potassium tert-butoxide (0.37 g, 3.28 mmol) were dissolved in tetrahydrofuran (5 mL) and reacted at room temperature for 2 hours under nitrogen protection. The mixture was dried by rotation to obtain a yellow solid crude product, which can be directly used in the next step.

Step 6: Synthesis of (3S,4S)-8-(3-chloro-2-(1-methylpyrazol-3-yl)ethynyl)pyridin-4-yl)thio)imidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

At room temperature, potassium 3-chloro-2-(1-methylpyrazol-3-yl)ethynyl)pyridine-4-thioate (0.38 g, 1.33 mmol), (3S,4S)-8-(8-iodoimidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxo-8-azaspiro[4.5]decan-4-amine (0.50 g, 1.20 mmol), trisdibenzylideneacetone dipalladium (0.06 g, 0.06 mmol), Xantphos (0.07 g, 0.12 mmol), N,N-diisopropylethylamine (0.47 g, 3.63 mmol), dispersed in 1,4-dioxane (15 mL), replaced with nitrogen 3 times, heated to 100 ° C for reaction, concentrated and dried, and directly purified by reverse column chromatography to obtain the product as a white solid of 0.13 g, with a yield of 20%, MS (ESI) m/z: 535.4 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.16 (d, J = 5.4, 2.0 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 6.0 Hz, 2H) ,7.58(s,1H),6.76–6.68(m,1H),6.68–6.65(m,1H),4.15–4.01(m,1H),3.92(s,3H),3.81–3.74(m,1H) ,3.7 1(d,J＝8.4Hz,2H),3.53(d,J＝8.5Hz,1H),3.51–3.38(m,2H),2.97(d,J＝5.0Hz,1H),2.05–1.90(m ,1H),1.90–1.79(m,1H),1.77–1.55(m,2H),1.34(s,2H),1.11(d,J＝6.4,1.9Hz,3H).

Example 50: Synthesis of (3S,4S)-8-(3-chloro-2-(1-methylpyrazol-3-yl)ethynyl)pyridin-4-yl)thio)[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine (II-47)

Step 1: Synthesis of 2-chloro-4-hydrazino-5-iodopyrimidine

At room temperature, 2,4-dichloro-5-iodopyrimidine (20.00 g, 72.76 mmol) was dissolved in ethanol (200 mL), cooled to 0°C, and hydrazine hydrate (10.93 g, 218.29 mmol) was added under temperature control. After the addition, the temperature was raised to room temperature and reacted for 2 hours. After the reaction was completed, the filter cake was filtered, and the filter cake was rinsed with ethanol (50 ml). The filter cake was concentrated and dried under reduced pressure to obtain 20.90 g of crude product, which was directly used in the next step with a yield of 106%.

Step 2: Synthesis of 5-chloro-8-iodo-[1,2,4]triazolo[4,3-c]pyrimidine

At room temperature, 2-chloro-4-hydrazino-5-iodopyrimidine (10.90 g, 40.30 mmol) and trimethyl orthoformate (70 ml) were added to the reaction flask, and the reaction temperature was raised to reflux for 2 hours. After the reaction was completed, it was cooled to room temperature, and water (100 ml) and ethyl acetate (100 ml) were added to the reaction solution for separation. The organic phase was washed twice with saturated brine, dried and desolventized, and PE/EA system column chromatography was used to obtain 6.55 g of the product, with a yield of 30%.

Step 3: Synthesis of (3S,4S)-8-(8-iodo-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-methyl-2-oxo-8-azaspiro[4.5]dec-4-amine

At room temperature, 8-iodoimidazole [1,2-c] pyrimidin-5-ol (1.00 g, 3.57 mmol), (3S, 4S) -3-methyl-2-oxo-8-azaspiro [4.5] decan-4-amine hydrochloride (0.95 g, 3.92 mmol), DIEA (2.77 g, 21.40 mmol) and DMSO (5 ml) were added to the reaction bottle and stirred at room temperature for 4 hours. After the reaction was completed, reverse column chromatography (water/acetonitrile system) was used to obtain 0.45 g of the product, with a yield of 30%.

Step 4: Synthesis of (3S,4S)-8-(8-((3-chloro-2-((1-methyl-1H-pyrazol-3-yl)ethynyl)pyridin-4-yl)thio)-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

At room temperature, potassium 3-chloro-2-(1-methylpyrazol-3-yl)ethynyl)pyridine-4-thioate (0.34 g, 1.20 mmol), (3S,4S)-8-(8-iodo-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-methyl-2-oxo-8-azaspiro[4.5]decan-4-amine (0.45 g, 1.09 mmol), Pd ₂ (dba) ₃ (0.05 g, 0.06 mmol), xantphos (0.06 g, 0.11 mmol), DIEA (0.42 g, 3.26 mmol), dispersed in 1,4-dioxane (15 mL), replaced with nitrogen 3 times, heated to 100 ° C for reaction, concentrated and dried after the reaction, and directly purified by reverse column chromatography to obtain the product as a white solid of 0.276 g, with a yield of 40%, MS (ESI) m/z: 536.4 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ )δ9.44(s,1H),8.19(d,J＝5.3Hz,1H),8.06(s,1H),7.86(s,1H),6.86(d,J＝5.3Hz,1H),6.67(s,1H),4.19–4.02(m,1H),4.01–3.85(m,5H),3.78–3.6 6(m,1H),3.67–3.61(m,1H),3.59–3.52(m,2H),3.05–2.99(m,1H),2.02–1.92(m,1H),1.89–1.81(m,1H),1.79–1.69(m,1H),1.67–1.58(m,1H),1 .13(d,J＝6.4Hz,3H).

Test Example 1: NCI-H358 cell activity test

NCI-H358 cell culture: Culture conditions: RPMI1640 medium + 10% FBS + 1% sodium pyruvate, 37°C, 5% CO ₂ . Plating: Pour off the cell culture supernatant, wash twice with 2mL PBS, add 1mL 0.25% trypsin solution, digest for 3min, add an equal volume of complete medium to terminate digestion, transfer to a centrifuge tube, and centrifuge at 800rpm for 5min. Resuspend with complete medium and count cells. Dilute with medium containing 0.65% methylcellulose (complete medium: 2.6% methylcellulose = 3:1) and adjust the final cell concentration to 15,000 cells/mL. Then inoculate the cells into a 96-well plate, 100μL per well, and culture in an incubator overnight. Dosing: Weigh the compound sample and add DMSO to make a 10mM stock solution. Perform gradient dilutions with DMSO, and then dilute with culture medium to twice the concentration of the drug to be tested. Each group of drug solution was added to a 96-well plate, 100 μL per well, n=3 for each drug concentration, and negative wells (n=6) and blank wells (n=3) were set up at the same time. The 96-well plate was cultured in an incubator for 7 days. CCK8 reagent was added to the 96-well plate, 20 μL per well, and then placed in an incubator for 4 hours. The absorbance of the solution was measured at a wavelength of 450 nm using an ELISA reader. The proliferation inhibition rate was calculated, and the half-maximal inhibitory concentration IC ₅₀ value was calculated using Graphpad Prism 6.0 software.

Among them, SHP099 was purchased from the manufacturer MCE, Catalog No: HY-116009 Batch # 41869, and the structural formula is as follows:

RMC-4550, purchased from manufacturer MCE, Catalog No: HY-100388 Batch # 37191, SHP099, structural formula is as follows:

Compound No. H358 cell IC ₅₀ (μM) I-17 0.21 I-26 0.93 I-27 0.12 I-35 0.08 I-36 0.07 I-37 0.08 II-3 0.13 II-5 0.05 II-7 0.02 II-8 0.01 II-38 0.65 II-40 0.08 II-41 0.07 II-46 0.02 II-47 0.06 II-50 0.02 SHP099 >5 RMC-4550 0.42

Conclusion: The compounds of the present invention have significant H358 cell inhibitory activity, most of the compounds have activities close to or stronger than the positive drug RMC-4550, and all the compounds have activities stronger than the positive drug SHP099.

Test Example 2: In vivo efficacy test

NCI-H358 cells were cultured (culture conditions: RPMI1640 medium + 10% FBS + 1% sodium pyruvate, 37°C, 5% CO ₂ ), and the cells that were subcultured to the logarithmic growth phase were collected and transferred into centrifuge tubes and centrifuged at 800rpm for 5min. The cell density was adjusted to 3*10 ⁷ cells/mL on the day of inoculation. Inoculation: The inoculation site was the right shoulder blade of the experimental animal, and the inoculation density was 3*10 ⁶ cells/100μL/mouse. Administration: When the average tumor volume reached 80-150mm ³ , the animals were randomly divided into groups according to the tumor volume, and the coefficient of variation of the tumor volume CV did not exceed 1/3 of the average volume. The day of grouping was defined as D0 day, and administration began on the day of grouping. The weight of the mice was measured before administration, and the administration was carried out according to the weight of the day. Experimental observation and data collection: After cell inoculation, the effect of tumor on the normal behavior of animals was routinely monitored every week. The specific contents include the activity of experimental animals, food and water intake, weight gain or loss, eyes, fur and other abnormalities. After the start of drug administration, mice were weighed and administrated every day, and tumor volume was measured twice a week. The tumor volume was calculated as follows: tumor volume (mm ³ ) = 0.52 × tumor long diameter (mm) × tumor short diameter (mm) ² . At the end of the experiment, the following indicators were analyzed: tumor growth curve, mouse weight curve, tumor weight, and the excised tumors were arranged according to groups and photographed uniformly to calculate the tumor volume inhibition rate TGI.

TGI _TV (relative tumor volume inhibition rate) calculation formula:

V _nt : tumor volume of mouse numbered n on day t;

V _n0 : tumor volume of mouse numbered n on day 0;

RTV _n : relative tumor volume of mouse numbered n on day t;

mean RTV _treat : mean RTV of the treatment group;

mean RTV _vehicle : the mean RTV value of the Vehicle group;

The experimental results of tumor volume and mouse body weight of each group of animals are expressed as mean ± standard error (Mean ± SEM). All data were analyzed using GraphPad Prism 6.0. P < 0.05 was considered to be significantly different.

Table 3 Tumor growth inhibition rate

Conclusion: As shown in Figure 1 and Table 3, compounds I-20 and II-8 have a clear inhibitory effect on tumor volume compared with the H358 cell model group.

Example 3: Mouse PK test

The mice were weighed and dosed. About 50 μL of whole blood was collected from the orbital venous plexus at 5 min, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration, and EDTA-K ₂ was used for anticoagulation. The blood samples were centrifuged at 4000 rpm for 10 min at 4 ° C, and 20 μL of supernatant plasma samples were taken into EP tubes and immediately stored in a -80 ° C refrigerator for analysis. 10 μL of plasma samples were transferred to a 96-well plate and 250 μL of acetonitrile (including internal standard) was added to precipitate proteins. Centrifuge at 4000 rpm/min in a 4 ° C centrifuge for 20 minutes. The transferred supernatant was injected into LC MS/MS to detect the drug concentration. The data was processed by Thermo LC Quan software, and the standard curve was established by the internal standard method. The theoretical standard curve concentration was the horizontal axis and the peak area ratio was the vertical axis (test compound peak area/internal standard peak area). The sample concentration was calculated by the standard curve. The pharmacokinetic parameters were calculated by WinNonlin 8.2 software.

Detection object: the compound of the present invention and the compound ZB-S-103 of CN114716448A, whose structural formula is as follows:

Conclusion: The compounds of the present invention have good oral bioavailability, which is beneficial to reduce gastrointestinal toxic side effects and increase drug exposure in vivo.

Test Example 4: SHP2 enzyme inhibition activity test

Weigh the compound sample and add DMSO to make a 10mM master solution, then dilute with DMSO. Add 50μL of the test compound to a 384-well dilution plate; use Echo to transfer 0.05μL of the diluted compound solution in each row to the 384 plate, with n=2 replicates; add 4μL of enzyme and 4μL of SHP-2 activated peptide working solution to the 384-well detection plate, centrifuge at 1000prm for 1min; incubate at 25℃ for 60min; add 2μL of substrate (DiFMUP) working solution to start the reaction, centrifuge at 1000prm for 1min; incubate at 25℃ for 30min; read the Ex360nm and Em460nm fluorescence signals with BMG; calculate the inhibition rate, and calculate the IC50 value using the formula Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)).

Table 4 SHP2 enzyme inhibition activity results

Compound No. Shp2 IC ₅₀ (nM) TNO-155 2.00 SHP099 25.8 I-17 0.58 I-27 0.79 I-35 0.52 I-37 1.08 II-5 0.80 II-6 1.17 II-7 0.31 II-8 0.42

It can be seen from the above table that the compounds of the present invention have good SHP2 enzyme inhibitory activity.

Claims (24)

1. A compound represented by formula (I), an isomer thereof, a deuterated compound thereof or a pharmaceutically acceptable salt thereof, Ring A is selected from 3-8 membered heterocyclic group, 6-13 membered bicyclic fused heterocyclic group, 8-21 membered polycyclic fused heterocyclic group, wherein the 3-8 membered heterocyclic group, 6-13 membered bicyclic fused heterocyclic group, 8-21 membered polycyclic fused heterocyclic group are unsubstituted or are independently substituted by C _1-6 alkyl; each R ₁ is independently selected from hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, 3-8 membered monocyclic group, 6-13 membered bicyclic condensed ring group, 8-21 membered polycyclic condensed ring group, 5-7 membered heteroaryl, -NR ₂ R ₃ , -S(O)R ₂ , -S(O)NR ₂ R ₃ , -NR ₂ S(O)NR ₂ R ₃ , -NR ₂ S(O)R ₃ , -S(O) ₂ R ₂ , -S(O) ₂ NR ₂ R ₃ , -NR ₂ S(O) ₂ R ₃ , -NR ₂ S(O) ₂ NR ₂ R ₃ , -C(O)R ₂ , -C(O)NR ₂ R ₃ , -NR ₃ C(O)R ₃ , -NR ₃ C(O)NR ₂ R ₃ , -CO ₂ R ₃ , the C _1-6 alkyl, halogenated C _1-6 alkyl, 3-8 membered monocyclic group, 6-13 membered bicyclic condensed ring group, 8-21 membered polycyclic condensed ring group, 5-7 membered heteroaryl group is unsubstituted or substituted by one to three groups independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, carboxyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halogenated C _1-6 alkoxy, 3-8 membered heterocyclic group, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 5-7 membered heteroaryl, phenyl; q is 0, 1, 2, or 3; Cy3 is selected from 3-8 membered heterocyclyl, 6-13 membered bicyclic condensed heterocyclyl, 5-7 membered heteroaryl, 8-13 membered bicyclic condensed heteroaryl, phenyl, 8-13 membered bicyclic condensed aryl, wherein the 3-8 membered heterocyclyl, 6-13 membered bicyclic condensed heterocyclyl, 5-7 membered heteroaryl, 8-13 membered bicyclic condensed heteroaryl, phenyl, 8-13 membered bicyclic condensed aryl is unsubstituted or substituted with 1-3 R _a3 ; Each R _a3 is independently selected from hydrogen, hydroxy, cyano, nitro, halogen, carboxyl, amino, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, C _1-6 alkylcarbonyl, aminocarbonyl, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl, hydroxyC _1-6 alkyl; Cy2 is selected from 3-8 membered heterocyclyl, 6-13 membered bicyclic fused heterocyclyl, 8-21 membered polycyclic fused heterocyclyl, 5-7 membered heteroaryl, phenyl, 8-13 membered bicyclic fused heteroaryl and 8-13 membered bicyclic fused aryl, wherein the 3-8 membered heterocyclyl, 6-13 membered bicyclic fused heterocyclyl, 8-21 membered polycyclic fused heterocyclyl, 5-7 membered heteroaryl, phenyl, 8-13 membered bicyclic fused heteroaryl and 8-13 membered bicyclic fused aryl are unsubstituted or substituted with 1-3 R _a2 ; each _Ra2 is independently selected from hydrogen, hydroxy, carboxyl, halogen, nitro, cyano, _C1-6 alkyl, halogenated _C1-6 alkyl, _C2-8 alkenyl, C2-8 alkynyl, _3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, _-OR4 , _-NR4R5 , _-SR4 , -S(O) _R4 , _-S (O)NR4R5, -NR4S(O) _NR4R5 , _-NR4S (O) _R5 , -S(O _{) 2R4 , -S} ( _O ) _2NR4R5 , _-NR4S ( _O ) _2R5 , -NR4S _{( O ) 2NR4R5} , _-C (O _{)R4 , -C} ( _O ) _NR4R5 , -NR ₄ C(O)R ₅ , -NR ₄ C(O)NR ₄ R ₅ , -CO ₂ R ₄ , wherein the C _1-6 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl is unsubstituted or substituted with one or more groups independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, carboxyl, C _1-6 alkyl, haloC _{1-6 alkyl, C 1-6 alkoxy} , haloC _1-6 alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkylamino, (C _1-6 alkyl) _2amino , C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkylcarbonyl, aminocarbonyl, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) _{2aminocarbonyl} ; R ₂ , R ₃ , R ₄ and R ₅ are independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, nitro, carboxyl, amino, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halogenated C _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic fused ring cycloalkyl, 6-13 bicyclic fused ring cycloalkenyl, 6-13 membered bicyclic fused ring heterocyclyl, the amino, C _1-6 alkyl, halogenated C _{1-6 alkyl, C 1-6 alkoxy} , C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halogenated C _1-6 alkoxy, C _{2-8 alkenyl, C 2-8} alkynyl, _2-8 membered alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic fused ring cycloalkyl, 6-13 bicyclic fused ring cycloalkenyl, 6-13 membered bicyclic fused ring heterocyclyl is unsubstituted or substituted with one or more groups independently selected from hydrogen, hydroxy, carboxyl, amino, nitro, cyano, C _1-6 alkyl, C _1-6 alkylamino, (C _1-6 alkyl) _2amino , C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkylcarbonyl, aminocarbonyl, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) _{2aminocarbonyl} , 3-8 membered heterocyclyl; m and n are independently 0 or 1; L is selected from a bond, C _2-8 alkynyl, -C(O)NH-, -CH ₂ -, -O-, C _2-8 alkynyl-C _1-6 alkyl, C _2-8 alkynyl-C _1-6 alkyl-carbonyl, C _2-8 alkenyl; B is selected from C _1-6 alkylamino, (C _1-6 alkyl) _2amino or Cy1; Cy1 is selected from 3-8 membered heterocyclyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 5-7 membered heteroaryl, phenyl, 8-13 membered bicyclic fused ring heteroaryl or 8-13 membered bicyclic fused ring heterocyclyl, wherein the 3-8 membered heterocyclyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 5-7 membered heteroaryl, phenyl, 8-13 membered bicyclic fused ring heteroaryl or 8-13 membered bicyclic fused ring heterocyclyl is unsubstituted or substituted by one to three groups independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, carboxyl, C _1-6 alkyl, halo-substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halo-substituted C _1-6 alkoxy, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl. 2. The compound according to claim 1, its isomer, deuterated compound or a pharmaceutically acceptable salt thereof, Ring A is selected from 3-8 membered heterocyclic group, 6-13 membered bicyclic fused heterocyclic group, 8-21 membered polycyclic fused heterocyclic group, wherein the 3-8 membered heterocyclic group, 6-13 membered bicyclic fused heterocyclic group, 8-21 membered polycyclic fused heterocyclic group are unsubstituted or are independently substituted by C _1-6 alkyl; each R ₁ is independently selected from hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, 3-8 membered monocyclic group, 6-13 membered bicyclic condensed ring group, 8-21 membered polycyclic condensed ring group, 5-7 membered heteroaryl, -NR ₂ R ₃ , -S(O)R ₂ , -S(O)NR ₂ R ₃ , -NR ₂ S(O)NR ₂ R ₃ , -NR ₂ S(O)R ₃ , -S(O) ₂ R ₂ , -S(O) ₂ NR ₂ R ₃ , -NR ₂ S(O) ₂ R ₃ , -NR ₂ S(O) ₂ NR ₂ R ₃ , -C(O)R ₂ , -C(O)NR ₂ R ₃ , -NR ₃ C(O)R ₃ , -NR ₃ C(O)NR ₂ R ₃ , -CO ₂ R ₃ , the C _1-6 alkyl, halogenated C _1-6 alkyl, 3-8 membered monocyclic group, 6-13 membered bicyclic condensed ring group, 8-21 membered polycyclic condensed ring group, 5-7 membered heteroaryl group is unsubstituted or substituted by one to three groups independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, carboxyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halogenated C _1-6 alkoxy, 3-8 membered heterocyclic group, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 5-7 membered heteroaryl, phenyl; q is 0, 1, 2, or 3; Cy3 is selected from 3-8 membered heterocyclyl, 6-13 membered bicyclic condensed heterocyclyl, 5-7 membered heteroaryl, 8-13 membered bicyclic condensed heteroaryl, phenyl, 8-13 membered bicyclic condensed aryl, wherein the 3-8 membered heterocyclyl, 6-13 membered bicyclic condensed heterocyclyl, 5-7 membered heteroaryl, 8-13 membered bicyclic condensed heteroaryl, phenyl, 8-13 membered bicyclic condensed aryl is unsubstituted or substituted with 1-3 R _a3 ; Each R _a3 is independently selected from hydrogen, hydroxy, cyano, nitro, halogen, carboxyl, amino, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, C _1-6 alkylcarbonyl, aminocarbonyl, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl, hydroxyC _1-6 alkyl; Cy2 is selected from 3-8 membered heterocyclyl, 6-13 membered bicyclic fused heterocyclyl, 8-21 membered polycyclic fused heterocyclyl, 5-7 membered heteroaryl, phenyl, 8-13 membered bicyclic fused heteroaryl and 8-13 membered bicyclic fused aryl, wherein the 3-8 membered heterocyclyl, 6-13 membered bicyclic fused heterocyclyl, 8-21 membered polycyclic fused heterocyclyl, 5-7 membered heteroaryl, phenyl, 8-13 membered bicyclic fused heteroaryl and 8-13 membered bicyclic fused aryl are unsubstituted or substituted with 1-3 R _a2 ; each _Ra2 is independently selected from hydrogen, hydroxy, carboxyl, halogen, nitro, cyano, _C1-6 alkyl, halogenated _C1-6 alkyl, _C2-8 alkenyl, C2-8 alkynyl, _3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, _-OR4 , _-NR4R5 , _-SR4 , -S(O) _R4 , _-S (O)NR4R5, -NR4S(O) _NR4R5 , _-NR4S (O) _R5 , -S(O _{) 2R4 , -S} ( _O ) _2NR4R5 , _-NR4S ( _O ) _2R5 , -NR4S _{( O ) 2NR4R5} , _-C (O _{)R4 , -C} ( _O ) _NR4R5 , -NR ₄ C(O)R ₅ , -NR ₄ C(O)NR ₄ R ₅ , -CO ₂ R ₄ , wherein the C _1-6 alkyl, C _2-8 alkenyl, C 2-8 alkynyl, _3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl is unsubstituted or substituted with one or more groups independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, carboxyl, C _1-6 alkyl, haloC _{1-6 alkyl, C 1-6 alkoxy} , haloC _1-6 alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkylamino, (C _1-6 alkyl) _2amino , C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkylcarbonyl, aminocarbonyl, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) _{2aminocarbonyl} ; R ₂ , R ₃ , R ₄ and R ₅ are independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, nitro, carboxyl, amino, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halogenated C _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic fused ring cycloalkyl, 6-13 bicyclic fused ring cycloalkenyl, 6-13 membered bicyclic fused ring heterocyclyl, the amino, C _1-6 alkyl, halogenated C _{1-6 alkyl, C 1-6 alkoxy} , C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halogenated C _1-6 alkoxy, C _{2-8 alkenyl, C 2-8} alkynyl, _2-8 membered alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic fused ring cycloalkyl, 6-13 bicyclic fused ring cycloalkenyl, 6-13 membered bicyclic fused ring heterocyclyl is unsubstituted or substituted with one or more groups independently selected from hydrogen, hydroxy, carboxyl, amino, nitro, cyano, C _1-6 alkyl, C _1-6 alkylamino, (C _1-6 alkyl) _2amino , C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkylcarbonyl, aminocarbonyl, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) _{2aminocarbonyl} , 3-8 membered heterocyclyl; m and n are independently 0 or 1; L is selected from a bond, C _2-8 alkynyl, -C(O)NH-, -CH ₂ -, -O-, C _2-8 alkynyl-C _1-6 alkyl, C _2-8 alkynyl-C _1-6 alkyl-carbonyl, C _2-8 alkenyl; B is selected from C _1-6 alkylamino, (C _1-6 alkyl) _2amino or Cy1; Cy1 is selected from 3-8 membered heterocyclyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 5-7 membered heteroaryl, phenyl, 8-13 membered bicyclic fused ring heteroaryl or 8-13 membered bicyclic fused ring heterocyclyl, wherein the 3-8 membered heterocyclyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 5-7 membered heteroaryl, phenyl, 8-13 membered bicyclic fused ring heteroaryl or 8-13 membered bicyclic fused ring heterocyclyl is unsubstituted or substituted by one to three groups independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, carboxyl, C _1-6 alkyl, halo-substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, halo-substituted C _1-6 alkoxy, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl; Provided that, (i) when L is alkynyl, n is 1, for Cy3 Cy2 When m is 1 and B is Cy1, Cy1 is not (ii) when L is an alkynyl group, n is 1, for Cy3 Cy2 When m is 1 and B is Cy1, Cy1 is not 3. The compound according to claim 2, its isomer, deuterated compound or a pharmaceutically acceptable salt thereof, Ring A is selected from a 5-6 membered nitrogen-containing heterocyclic group, a 6-12 membered nitrogen-containing bicyclic spiro heterocyclic group, and a 10-16 membered nitrogen-containing polycyclic spiro heterocyclic group, wherein the 5-6 membered nitrogen-containing heterocyclic group, the 6-12 membered nitrogen-containing bicyclic spiro heterocyclic group, and the 10-16 membered nitrogen-containing polycyclic spiro heterocyclic group are unsubstituted or are independently substituted by C _1-6 alkyl; each R ₁ is independently selected from hydrogen, C _1-6 alkyl, 5-6 membered nitrogen-containing heteroaryl, -S(O) ₂ R ₂ , -C(O)R ₂ , -C(O)NR ₂ R ₃ , -CO ₂ R ₃ , said C _1-6 alkyl, 5-6 membered nitrogen-containing heteroaryl is unsubstituted or substituted by one to three groups independently selected from hydrogen, halogen, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl and 3-8 membered nitrogen-containing heterocyclic group; q is 0 or 1; Cy3 is selected from a 5-6-membered nitrogen-containing heterocyclic group, a 5-6-membered nitrogen-containing heteroaryl group, an 8-13-membered nitrogen-containing bicyclic heteroaryl group or a phenyl group; the 5-6-membered nitrogen-containing heterocyclic group, the 5-6-membered nitrogen-containing heteroaryl group, the 8-13-membered nitrogen-containing bicyclic heteroaryl group or the phenyl group is unsubstituted or substituted with 1-3 R _a3 ; Each R _a3 is independently selected from hydrogen, amino, C _1-6 alkyl, hydroxy C _1-6 alkyl; Cy2 is selected from 5-6 membered nitrogen-containing heteroaryl, phenyl, 8-13 membered nitrogen-containing bicyclic heteroaryl, wherein the 5-6 membered nitrogen-containing heteroaryl, phenyl, 8-13 membered nitrogen-containing bicyclic heteroaryl is unsubstituted or substituted with 1-3 R _a2 ; Each R _a2 is independently selected from hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, -NR ₄ R ₅ ; _R2 , _R3 , _R4 and _R5 are independently selected at each occurrence from hydrogen, _C1-6 alkyl or halogenated _C1-6 alkyl, said _C1-6 alkyl or halogenated _C1-6 alkyl being unsubstituted or substituted with one or more groups independently selected from hydrogen, cyano, ( _C1-6 alkyl) _2amino or 3-8 membered nitrogen-containing heterocyclic group; m and n are independently 0 or 1; L is selected from a bond, C _2-8 alkynyl, -C(O)NH-, C _2-8 alkynyl-C _1-6 alkyl, C _2-8 alkynyl-C _1-6 alkyl-carbonyl; B is selected from C _1-6 alkylamino, (C _1-6 alkyl) _2amino or Cy1; Cy1 is selected from a 5-6 membered nitrogen-containing heterocyclic group, a 5-6 membered nitrogen-containing heteroaryl group, a phenyl group, an 8-13 membered nitrogen-containing bicyclic heterocyclic group or an 8-13 membered nitrogen-containing bicyclic heteroaryl group, wherein the 5-6 membered nitrogen-containing heterocyclic group, the _{5-6 membered nitrogen-containing heteroaryl group, the phenyl group, the 8-13 membered nitrogen-containing bicyclic heterocyclic group or the 8-13 membered nitrogen-containing bicyclic heteroaryl group is unsubstituted or substituted by one to three groups independently selected from hydrogen, hydroxyl, C 1-6} alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 alkylaminocarbonyl; Provided that, (i) when L is alkynyl, n is 1, for Cy3 Cy2 When m is 1 and B is Cy1, Cy1 is not (ii) when L is an alkynyl group, n is 1, for Cy3 Cy2 When m is 1 and B is Cy1, Cy1 is not 4. The compound according to claim 2, its isomer, deuterated compound or pharmaceutically acceptable salt thereof, having the structure shown in formula (II), L is selected from a bond, -C(O)NH-, -CH ₂ -, -O-; m and n are independently 0 or 1; R ₁ is selected from hydrogen, C _1-6 alkyl, 5-6 membered heteroaryl, -S(O) ₂ R ₂ , -C(O)R ₂ , -C(O)NR ₂ R ₃ , -CO ₂ R ₃ , -S(O) ₂ NR ₂ R ₃ , wherein the C _1-6 alkyl and 5-6 membered heteroaryl are unsubstituted or substituted with one to three groups independently selected from hydrogen, halogen, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, halo-substituted C _1-6 alkyl, halo-substituted C _1-6 alkoxy, 5-6 membered heterocyclyl, 5-6 membered cycloalkyl, 5-6 membered cycloalkenyl; _R2 and _R3 are independently selected at each occurrence from hydrogen, halogen, hydroxyl, cyano, nitro, carboxyl, amino, _C1-6 alkyl, halogenated _C1-6 alkyl, C1-6 alkoxy, _C1-6 alkylamino, ( _C1-6 alkyl) _2amino , halogenated _C1-6 alkoxy, wherein the _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylamino, ( _C1-6 alkyl) _2amino , halogenated _C1-6 alkoxy are unsubstituted or substituted _with one or more groups independently selected from hydrogen, cyano, 5-6 membered heterocyclyl, _C1-6 alkylamino, ( _C1-6 alkyl) _2amino ; Cy3 is selected from 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, wherein the 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl is unsubstituted or substituted with 1-3 R _a3 ; Each R _a3 is independently selected from hydrogen, amino, hydroxy, halogen, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, hydroxy C _1-6 alkyl; Cy2 is selected from 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, phenyl, wherein the 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, phenyl is unsubstituted or substituted with 1-3 R _a2 ; Each R _a2 is independently selected from hydrogen, hydroxy, carboxyl, halogen, nitro, cyano, amino, C _1-6 alkyl, halogenated C _1-6 alkyl; Cy1 is selected from 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocyclyl, wherein the 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocyclyl is unsubstituted or substituted by one to three groups independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, carboxyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl. 5. The compound according to claim 4, its isomer, deuterated compound or a pharmaceutically acceptable salt thereof, L is selected from a bond, -C(O)NH-; m and n are independently 0 or 1; R ₁ is selected from hydrogen, 5-6 membered nitrogen-containing heteroaryl, -S(O) ₂ R ₂ , -C(O)R ₂ , -C(O)NR ₂ R ₃ , -CO ₂ R ₃ , wherein the 5-6 membered nitrogen-containing heteroaryl is unsubstituted or substituted by one to three groups independently selected from hydrogen, halogen, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, 5-6 membered nitrogen-containing heterocyclic group; R ₂ and R ₃ are independently selected from hydrogen, C _1-6 alkyl at each occurrence, wherein the C _1-6 alkyl is unsubstituted or substituted by one or more groups independently selected from hydrogen, cyano, and 5-6-membered nitrogen-containing heterocyclic group; Cy3 is selected from a 6-membered nitrogen-containing heterocyclic group, a 6-membered nitrogen-containing heteroaryl group, or a 9-membered nitrogen-containing bicyclic heteroaryl group, wherein the 6-membered nitrogen-containing heterocyclic group, the 6-membered nitrogen-containing heteroaryl group, or the 9-membered nitrogen-containing bicyclic heteroaryl group is unsubstituted or substituted with 1-3 R _a3 groups; Each R _a3 is independently selected from hydrogen, amino, C _1-6 alkyl; Cy2 is selected from a 6-membered nitrogen-containing heteroaryl, a 9-membered nitrogen-containing bicyclic heteroaryl, or a phenyl group, wherein the 6-membered nitrogen-containing heteroaryl, the 9-membered nitrogen-containing bicyclic heteroaryl, or the phenyl group is unsubstituted or substituted with 1-3 R _a2 groups; Each R _a2 is independently selected from hydrogen, halogen, amino, C _1-6 alkyl; Cy1 is selected from a 5-6 membered nitrogen-containing heterocyclic group, a 5-6 membered nitrogen-containing heteroaryl group, and a 10 membered nitrogen-containing bicyclic heterocyclic group, wherein the 5-6 membered nitrogen-containing heterocyclic group, the 5-6 membered nitrogen-containing heteroaryl group, and the 10 membered nitrogen-containing bicyclic heterocyclic group are unsubstituted or substituted by one to three groups independently selected from hydrogen, hydroxyl, C _1-6 alkyl, and C _1-6 alkoxy. 6. The compound according to claim 5, its isomer, deuterated compound or a pharmaceutically acceptable salt thereof, L is selected from a bond, -C(O)NH-; m and n are independently 0 or 1; _R1 is selected from hydrogen, -S(O) ₂ CH ₃ , -C(O)CH ₃ , -C(O)N(CH ₃ ) ₂ , -CO ₂ CH ₃ , -S(O) ₂ CH ₂ CH ₃ , Cy3 is selected from Cy2 is selected from Cy1 is selected from 7. The compound according to claim 2, its isomer, deuterated compound or pharmaceutically acceptable salt thereof, having a structure represented by formula (III): L is selected from C _2-8 alkynyl, C _2-8 alkynyl-C _1-6 alkyl, C _2-8 alkynyl-C _1-6 alkyl-carbonyl, Ring A is selected from 4-6 membered heterocyclyl, 4-6 membered heterocyclyl-C _1-6 alkyl, 10-11 membered bicyclic spiro heterocyclyl, 14-15 membered polycyclic spiro heterocyclyl; R ₁ is selected from hydrogen, C _1-6 alkyl, 5-6 membered heteroaryl, -S(O) ₂ R ₂ , -C(O)R ₂ , -C(O)NR ₂ R ₃ , -CO ₂ R ₃ , -S(O) ₂ NR ₂ R ₃ , wherein the C _1-6 alkyl and 5-6 membered heteroaryl are unsubstituted or substituted with one to three groups independently selected from hydrogen, halogen, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, halo-substituted C _1-6 alkyl, halo-substituted C _1-6 alkoxy, 5-6 membered heterocyclyl, 5-6 membered cycloalkyl, 5-6 membered cycloalkenyl; _R2 and _R3 are independently selected at each occurrence from hydrogen, halogen, hydroxyl, cyano, nitro, carboxyl, amino, _C1-6 alkyl, halogenated _C1-6 alkyl, C1-6 alkoxy, _C1-6 alkylamino, ( _C1-6 alkyl) _2amino , halogenated _C1-6 alkoxy, wherein the _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylamino, ( _C1-6 alkyl) _2amino , halogenated _C1-6 alkoxy are unsubstituted or substituted _with one or more groups independently selected from hydrogen, cyano, 5-6 membered heterocyclyl, _C1-6 alkylamino, ( _C1-6 alkyl) _2amino ; Cy3 is selected from 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, wherein the 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl is unsubstituted or substituted with 1-3 R _a3 ; Each R _a3 is independently selected from hydrogen, hydroxy, amino, halogen, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, hydroxy C _1-6 alkyl; Cy2 is selected from 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, phenyl, wherein the 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, phenyl is unsubstituted or substituted with 1-3 R _a2 ; Each R _a2 is independently selected from hydrogen, hydroxy, carboxyl, halogen, nitro, cyano, amino, C _1-6 alkyl, halogenated C _1-6 alkyl; B is selected from C _1-6 alkylamino, (C _1-6 alkyl) _2amino or Cy1; Cy1 is selected from 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocyclyl, wherein the 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocyclyl is unsubstituted or substituted by one to three groups independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, carboxyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) _2amino , C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) _{2aminocarbonyl} ; Provided that, (i) when L is alkynyl, n is 1, for Cy3 Cy2 When m is 1 and B is Cy1, Cy1 is not (ii) when L is an alkynyl group, n is 1, for Cy3 Cy2 When m is 1 and B is Cy1, Cy1 is not 8. The compound according to claim 7, its isomer, deuterated compound or a pharmaceutically acceptable salt thereof, L is selected from C _2-8 alkynyl, C _2-8 alkynyl-C _1-6 alkyl, C _2-8 alkynyl-C _1-6 alkyl-carbonyl, Ring A is selected from 4-6 membered heterocyclyl, 4-6 membered heterocyclyl-C _1-6 alkyl, 10-11 membered bicyclic spiro heterocyclyl, 14-15 membered polycyclic spiro heterocyclyl; R ₁ is selected from hydrogen, C _1-6 alkyl, 5-6 membered heteroaryl, -S(O) ₂ R ₂ , -C(O)R ₂ , -C(O)NR ₂ R ₃ , -CO ₂ R ₃ , -S(O) ₂ NR ₂ R ₃ , wherein the C _1-6 alkyl and 5-6 membered heteroaryl are unsubstituted or substituted with one to three groups independently selected from hydrogen, halogen, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, halo-substituted C _1-6 alkyl, halo-substituted C _1-6 alkoxy, 5-6 membered heterocyclyl, 5-6 membered cycloalkyl, 5-6 membered cycloalkenyl; _R2 and _R3 are independently selected at each occurrence from hydrogen, halogen, hydroxyl, cyano, nitro, carboxyl, amino, _C1-6 alkyl, halogenated _C1-6 alkyl, C1-6 alkoxy, _C1-6 alkylamino, ( _C1-6 alkyl) _2amino , halogenated _C1-6 alkoxy, wherein the _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylamino, ( _C1-6 alkyl) _2amino , halogenated _C1-6 alkoxy are unsubstituted or substituted _with one or more groups independently selected from hydrogen, cyano, 5-6 membered heterocyclyl, _C1-6 alkylamino, ( _C1-6 alkyl) _2amino ; Cy3 is selected from 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, wherein the 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl is unsubstituted or substituted with 1-3 R _a3 ; Each R _a3 is independently selected from hydrogen, hydroxy, halogen, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, hydroxy C _1-6 alkyl; Cy2 is selected from 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, phenyl, wherein the 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, phenyl is unsubstituted or substituted with 1-3 R _a2 ; Each R _a2 is independently selected from hydrogen, hydroxy, carboxyl, halogen, nitro, cyano, amino, C _1-6 alkyl, halogenated C _1-6 alkyl; B is selected from C _1-6 alkylamino, (C _1-6 alkyl) _2amino or Cy1; Cy1 is selected from 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocyclyl, wherein the 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 8-10 membered bicyclic heteroaryl, 8-10 membered bicyclic heterocyclyl is unsubstituted or substituted by one to three groups independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxyl, carboxyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, C _1-6 alkylamino, (C _1-6 alkyl) ₂ amino, C _1-6 alkylaminocarbonyl, (C _1-6 alkyl) ₂ aminocarbonyl. 9. The compound according to claim 8, its isomer, deuterated compound or pharmaceutically acceptable salt thereof, L is selected from C _2-8 alkynyl, C _2-8 alkynyl-C _1-6 alkyl, C _2-8 alkynyl-C _1-6 alkyl-carbonyl, Ring A is selected from a 5-6 membered nitrogen-containing heterocyclic group, a 5-6 membered nitrogen-containing heterocyclic group-C _1-6 alkyl group, a 10-11 membered nitrogen-containing bicyclic spiro heterocyclic group, and a 14-15 membered nitrogen-containing polycyclic spiro heterocyclic group; R ₁ is selected from hydrogen, C _1-6 alkyl, 6-membered nitrogen-containing heteroaryl, -C(O)R ₂ ; R ₂ is selected from hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, the C _1-6 alkyl is unsubstituted or substituted by one or more groups independently selected from hydrogen, cyano, (C _1-6 alkyl) ₂ amino; Cy3 is selected from a 6-membered nitrogen-containing heteroaryl, a 6-membered nitrogen-containing heterocyclic group, or a 9-membered nitrogen-containing bicyclic heteroaryl, wherein the 6-membered nitrogen-containing heteroaryl, the 6-membered nitrogen-containing heterocyclic group, or the 9-membered nitrogen-containing bicyclic heteroaryl is unsubstituted or substituted with 1-3 R _a3 ; Each R _a3 is independently selected from hydrogen, C _1-6 alkyl, hydroxy C _1-6 alkyl; Cy2 is selected from a 6-membered nitrogen-containing heteroaryl group or a phenyl group, wherein the 6-membered nitrogen-containing heteroaryl group or the phenyl group is unsubstituted or substituted with 1-3 R _a2 groups; Each R _a2 is independently selected from hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl; B is selected from C _1-6 alkylamino, (C _1-6 alkyl) _2amino or Cy1; Cy1 is selected from a 5-6 membered nitrogen-containing heterocyclic group, a 5-6 membered nitrogen-containing heteroaryl group, a 9-membered nitrogen-containing bicyclic heteroaryl group, and a 9-membered nitrogen-containing bicyclic heterocyclic group, wherein the 5-6 membered nitrogen-containing heterocyclic group, the 5-6 membered nitrogen-containing heteroaryl group, the 9-membered nitrogen-containing bicyclic heteroaryl group, and the 9-membered nitrogen-containing bicyclic heterocyclic group are unsubstituted or substituted by one to three groups independently selected from hydrogen, C _1-6 alkyl, C _1-6 alkylamino, and C _1-6 alkylaminocarbonyl. 10. The compound according to claim 7, its isomer, deuterated compound or pharmaceutically acceptable salt thereof, L is C _2-8 alkynyl, C _2-8 alkynyl-C _1-6 alkyl, C _2-8 alkynyl-C _1-6 alkyl-carbonyl; Selected from R ₁ is selected from hydrogen, methyl, -C(O)CH ₃ , -C(O)CH ₂ CN, -C(O)CH ₂ N(CH ₃ ) ₂ , -C(O)CF ₃ ; Cy3 is selected from Cy2 is selected from Cy1 is selected from 11. The compound according to claim 9, its isomer, deuterated compound or pharmaceutically acceptable salt thereof, Selected from L is C _2-8 alkynyl; R ₁ is selected from hydrogen, C _1-6 alkyl, 6-membered nitrogen-containing heteroaryl, -C(O)R ₂ ; Cy3 is selected from a 6-membered nitrogen-containing heteroaryl group; Cy2 is selected from a 6-membered nitrogen-containing heteroaryl group or a phenyl group, wherein the 6-membered nitrogen-containing heteroaryl group or the phenyl group is unsubstituted or substituted with 1-3 R _a2 groups; Each R _a2 is independently selected from hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl; R ₂ is selected from hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, the C _1-6 alkyl is unsubstituted or substituted by one or more groups independently selected from hydrogen, cyano, (C _1-6 alkyl) ₂ amino; Cy1 is a 5-membered nitrogen-containing heteroaryl group, which is unsubstituted or substituted by a C _1-6 alkyl group. 12. The compound according to claim 7, its isomer, deuterated compound or pharmaceutically acceptable salt thereof, having the structure shown in formula (IV), L is selected from C _2-8 alkynyl, C _2-8 alkynyl-C _1-6 alkyl, C _2-8 alkynyl-C _1-6 alkyl-carbonyl, Cy3 is selected from 6-membered nitrogen-containing heteroaryl, 9-membered nitrogen-containing bicyclic heteroaryl, wherein the 6-membered nitrogen-containing heteroaryl, 9-membered nitrogen-containing bicyclic heteroaryl is unsubstituted or substituted with 1-3 R _a3 ; Each R _a3 is independently selected from hydrogen, C _1-6 alkyl, hydroxy C _1-6 alkyl; Cy2 is selected from a 6-membered nitrogen-containing heteroaryl group or a phenyl group, wherein the 6-membered nitrogen-containing heteroaryl group or the phenyl group is unsubstituted or substituted with 1-3 R _a2 groups; Each R _a2 is independently selected from hydrogen, halogen, C _1-6 alkyl; B is selected from C _1-6 alkylamino, (C _1-6 alkyl) _2amino or Cy1; Cy1 is selected from a 5-6 membered nitrogen-containing heterocyclic group, a 5-6 membered nitrogen-containing heteroaryl group, a 9-membered nitrogen-containing bicyclic heteroaryl group, and a 9-membered nitrogen-containing bicyclic heterocyclic group, wherein the 5-6 membered nitrogen-containing heterocyclic group, the 5-6 membered nitrogen-containing heteroaryl group, the 9-membered nitrogen-containing bicyclic heteroaryl group, and the 9-membered nitrogen-containing bicyclic heterocyclic group are unsubstituted or substituted by one to three groups independently selected from hydrogen, C _1-6 alkyl, C _1-6 alkylamino, and C _1-6 alkylaminocarbonyl. 13. The compound according to claim 7, its isomer, deuterated compound or pharmaceutically acceptable salt thereof, having the structure shown in formula (V), Selected from R ₁ is selected from C _1-6 alkyl, 6-membered nitrogen-containing heteroaryl, -C(O)R ₂ ; R ₂ is selected from hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, the C _1-6 alkyl is unsubstituted or substituted by one or more groups independently selected from hydrogen, cyano, (C _1-6 alkyl) ₂ amino; Cy2 is selected from a 6-membered nitrogen-containing heteroaryl group or a phenyl group, wherein the 6-membered nitrogen-containing heteroaryl group or the phenyl group is unsubstituted or substituted with 1-3 R _a2 groups; Each R _a2 is independently selected from hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl; Cy1 is selected from a 5-6 membered nitrogen-containing heterocyclic group, a 5-6 membered nitrogen-containing heteroaryl group, a 9-membered nitrogen-containing bicyclic heteroaryl group, and a 9-membered nitrogen-containing bicyclic heterocyclic group, wherein the 5-6 membered nitrogen-containing heterocyclic group, the 5-6 membered nitrogen-containing heteroaryl group, the 9-membered nitrogen-containing bicyclic heteroaryl group, and the 9-membered nitrogen-containing bicyclic heterocyclic group are unsubstituted or substituted by one to three groups independently selected from hydrogen, C _1-6 alkyl, C _1-6 alkylamino, and C _1-6 alkylaminocarbonyl. 14. The compound according to claim 10, its isomer, deuterated compound or pharmaceutically acceptable salt thereof, L is a C ₂ alkynyl group; for B is Cy1; Cy3 is selected from Cy2 is selected from Cy1 is selected from 15. The compound according to claim 10, its isomer, deuterated compound or pharmaceutically acceptable salt thereof, L is a C ₂ alkynyl group; for B is Cy1; Cy3 is selected from Cy2 is selected from Cy1 is selected from 16. The compound according to claim 10, its isomer, deuterated compound or a pharmaceutically acceptable salt thereof, L is a C ₂ alkynyl group; for B is Cy1; Cy3 is selected from Cy2 is selected from Cy1 is selected from 17. The compound according to claim 1, its isomer, deuterated compound or pharmaceutically acceptable salt thereof, having the following specific structure, 18. The compound according to claim 1, its isomer, deuterated compound or pharmaceutically acceptable salt thereof, having the following specific structure, 19. The compound according to claim 1, its isomer, deuterated compound or pharmaceutically acceptable salt thereof, having the following specific structure, 20. A pharmaceutical composition comprising the compound according to any one of claims 1 to 19, its isomer, deuterated compound or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and excipients. 21. Use of the compound according to any one of claims 1 to 19, its isomer, deuterated compound or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20 in the preparation of a medicament for treating and/or preventing diseases associated with abnormal SHP2 activity. 22. The use according to claim 21, wherein the disease is cancer. 23. The use according to claim 22, wherein the cancer comprises leukemia, neuroblastoma, melanoma, lung cancer, breast cancer, esophageal cancer, colon cancer, head and neck cancer and gastric cancer. 24. A method for treating and/or preventing a SHP2-related disease, comprising a therapeutically effective amount of the compound according to any one of claims 1 to 19, its isomer, deuterated compound or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20.