Heterocyclic compounds that inhibit SHP2 activity, methods for their preparation and use

Abstract

The present invention relates to heterocyclic compounds that inhibit SHP2 activity, their preparation and use, represented by general formula I. The compounds of the present invention can effectively treat diseases or conditions or disease states mediated by SHP2. [Formula 1] JPEG2024517965000053.jpg3877

Description

[Technical field]

[0001] The present invention relates to compounds capable of inhibiting SHP2 activity. In particular, the present invention relates to heterocyclic compounds that inhibit SHP2 activity, methods for their preparation, pharmaceutical compositions containing such compounds, methods of treating SHP2-mediated diseases or conditions using such compounds or compositions, and the use of such compounds or compositions in the manufacture of medicaments. [Background technology]

[0002] SHP2 (Src-homology containing phosphatase 2) is a non-receptor protein tyrosine phosphatase encoded by PTPN11. Structurally, SHP2 consists of two Src-homology-2 domains (i.e., N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. In the resting state, the SHP2 molecule is maintained in an inactivated, autoinhibited conformation by the interaction of amino acid residues in the N-SH2 domain with the PTP domain. Upon stimulation by cytokines, growth factors, etc., SHP2 exposes the catalytic site and becomes catalytically active.

[0003] SHP2 is widely expressed in various tissue cells and is involved in intracellular signaling processes via signaling pathways such as Ras-MAPK, JAK-STAT, and PI3K-AKT, and plays an important role in various cellular functions such as cell proliferation, differentiation, migration, and cell cycle maintenance.

[0004] High activation of SHP2 catalytic function due to germline and somatic mutations in PTPN11 has been identified in patients with congenital disorders such as Noonan syndrome and Leopard syndrome, and hematological malignancies such as juvenile myelomonocytic leukemia, myelodysplastic syndrome, B-cell acute lymphoblastic leukemia / lymphoma, and acute granulocytic leukemia. In addition, activating mutations in PTPN11 are also present in various solid cancers such as lung cancer, colon cancer, melanoma, medulloblastoma, and hepatoma. SHP2 also plays an important role in PD-1 / PD-L1-mediated tumor immune evasion.

[0005] Therefore, activation or upregulation of SHP2 protein in human tumors and other diseases represents an ideal target for the development of innovative therapeutics. The compounds of the present invention fill a need for small molecules that inhibit SHP2 activity. Summary of the Invention

[0006] One object of the present invention is to provide heterocyclic compounds capable of inhibiting SHP2 activity.

[0007] Another object of the present invention is to provide a pharmaceutical composition comprising said heterocyclic compound.

[0008] It is another object of the present invention to provide methods of treating diseases or conditions associated with abnormal activity of SHP2 using such compounds or compositions.

[0009] It is another object of the present invention to provide a use of said compound or composition in the manufacture of a medicament for the treatment of a disease or condition associated with abnormal activity of SHP2.

[0010] According to one aspect of the present invention, there is provided a compound represented by general formula I, a pharmacologically acceptable salt thereof, an enantiomer, a diastereomer, an atropisomer, a racemate, a crystal polymorph, a solvate or an isotopically labeled compound thereof. [ka] In formula I, R1 is selected from the group consisting of hydrogen, -NH2, -OH, -CN, halogen, C1-C4 alkyl group, C1-C4 haloalkyl group, and C3-C6 cycloalkyl group; R2 is hydrogen, C1-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, C3-C8 cycloalkyl groups, 3-10 membered heterocyclic groups, C6-C 10 aryl groups, and 5-10 membered heteroaryl groups; 10 Alkyl groups, C1-C 10 Haloalkyl groups, C3-C8 cycloalkyl groups, 3-10 membered heterocycloalkyl groups, C6-C 10 The aryl group and the 5- to 10-membered heteroaryl group further comprise 1 to 5 -NR 10 R 11 , -OR 10 , -CN, halogen, C1-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, C3-C8 cycloalkyl groups, 3-10 membered heterocyclic groups, -C(=O)R 10 , -C(=O)OR 10 , -C(=O)NR 10 R 11 , -S(=O)2R 10 , -S(=O)2NR 10 R 11 , -NR 10 C(=O)R 11 R 10 and R 11 are each independently selected from the group consisting of hydrogen, a C1-C4 alkyl group, and a C3-C7 cycloalkyl group; R3 is selected from the group consisting of hydrogen, halogen, C1-C4 alkyl group, C3-C8 cycloalkyl group, C1-C4 alkoxy group, and C1-C4 haloalkyl group; R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 7bare each independently selected from the group consisting of hydrogen, -NH2, -OH, halogen, a carbonyl group, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C3-C8 cycloalkyl group, and a C1-C4 alkylamino group; R8 and R9 are each independently selected from the group consisting of -NH2, -OH, -CN, -COOH, halogen, a C1-C4 alkyl group, a C1-C4 alkoxy group, and a C1-C4 alkylamino group; the C1-C4 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of -NH2, -OH, and -CN; Or, R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a , R 7b and R8, taken together with the carbon atom to which they are attached, form a 5-6 membered saturated or unsaturated ring; Alternatively, R8 and R9 together with the carbon atom to which they are attached form a 3-7 membered saturated or unsaturated ring, preferably the 3-7 membered saturated or unsaturated ring is selected from the group consisting of 1 to 3 independently selected from N, O, C(=O), S(=O) m and m=1 or 2; the saturated or unsaturated ring may be substituted with 1 to 3 substituents selected from the group consisting of -NH2, -OH, -CN, halogen, a C1-C4 alkyl group, a C1-C4 alkoxy group, and a C1-C4 alkylamino group; p is 0 or 1; q is 0 or 1; X is S or absent; Y is CR 12 or N; R 12 is hydrogen, -NH2, -CN, halogen, C1-C4 alkyl group, -OR 13 , C3-C8 cycloalkyl group, 3-10 membered heterocyclic group, -C(=O)R 13 , -C(=O)OR 13 , -C(=O)NR 13 R14 , -S(=O)2NR 13 R 14 , -S(=O)2R 13 R 13 , R 14 are each independently selected from the group consisting of hydrogen, a C1-C4 alkyl group, and a C3-C6 cycloalkyl group; Z1 is N or CR 15 and; Z2 is N or CR 16 and; Z3, N or CR 17 and; R 15 , R 16 , R 17 are each independently hydrogen, -CN, halogen, or -C(=O)R 18 , -C(=O)OR 18 , -C(=O)NR 18 R 19 , -NR 18 R 19 , -NR 18 C(=O)R 19 , -NR 18 C(=O)OR 19 , -OC(=O)R 18 , -OC(=O)NR 18 R 19 , -OR 18 , -S(=O)2NR 18 R 19 , -S(=O)2R 18 , C1-C4 alkyl group, C3-C8 cycloalkyl group, 3-10 membered heterocyclic group, C6-C 10 aryl groups, and 5- to 10-membered heteroaryl groups; 18 , R 19 are each independently selected from the group consisting of hydrogen, a C1-C4 alkyl group, and a C3-C8 cycloalkyl group; R 15 From R 19 The C1-C4 alkyl group, the C3-C8 cycloalkyl group, R 15 From R 17 The 3-10 membered heterocyclic group, C6-C 10The aryl group and the 5- to 10-membered heteroaryl group may be further substituted with 1 to 3 substituents each independently selected from the group consisting of -NH2, -OH, -CN, halogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, and a C1-C4 alkoxy group.

[0011] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising one or more selected from the group consisting of the above-mentioned compound, its pharmacologically acceptable salt, enantiomer, diastereomer, atropisomer, racemate, crystalline polymorph, solvate and isotopically labeled compound, and a pharmacologically acceptable carrier.

[0012] According to another aspect of the present invention, there is provided a method for treating a disease or condition mediated by SHP2 with the above-mentioned compound, a pharmacologically acceptable salt, enantiomer, diastereomer, atropisomer, racemate, polymorph, solvate or isotopically labeled compound thereof, or a pharmaceutical composition as described above.

[0013] According to another aspect of the invention, there is provided the use of the above compound, a pharmacologically acceptable salt, enantiomer, diastereomer, atropisomer, racemate, polymorph, solvate or isotopically labelled compound or the above pharmaceutical composition in the manufacture of a medicament for treating a disease or condition or disease state mediated by SHP2. Effect of the Invention

[0014] The compounds of the present invention can effectively treat diseases or conditions or disease states mediated by SHP2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] According to one embodiment of the present invention, there is provided a compound represented by general formula I, a pharmacologically acceptable salt, enantiomer, diastereomer, atropisomer, racemate, crystal polymorph, solvate or isotopically labeled compound thereof. [ka] In formula I, R1 is selected from the group consisting of hydrogen, -NH2, -OH, -CN, halogen, C1-C4 alkyl group, C1-C4 haloalkyl group, and C3-C6 cycloalkyl group; R2 is hydrogen, C1-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, C3-C8 cycloalkyl groups, 3-10 membered heterocyclic groups, C6-C 10 aryl groups, and 5-10 membered heteroaryl groups; 10 Alkyl groups, C1-C 10 Haloalkyl groups, C3-C8 cycloalkyl groups, 3-10 membered heterocycloalkyl groups, C6-C 10 The aryl group and the 5- to 10-membered heteroaryl group further comprise 1 to 5 -NR 10 R 11 , -OR 10 , -CN, halogen, C1-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, C3-C8 cycloalkyl groups, 3-10 membered heterocyclic groups, -C(=O)R 10 , -C(=O)OR 10 , -C(=O)NR 10 R 11 , -S(=O)2R 10 , -S(=O)2NR 10 R 11 , -NR 10 C(=O)R 11 R 10 and R 11 are each independently selected from the group consisting of hydrogen, a C1-C4 alkyl group, and a C3-C7 cycloalkyl group; R3 is selected from the group consisting of hydrogen, halogen, C1-C4 alkyl group, C3-C8 cycloalkyl group, C1-C4 alkoxy group, and C1-C4 haloalkyl group; R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R7a and R 7b are each independently selected from the group consisting of hydrogen, -NH2, -OH, halogen, a carbonyl group, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C3-C8 cycloalkyl group, and a C1-C4 alkylamino group; R8 and R9 are each independently selected from the group consisting of -NH2, -OH, -CN, -COOH, halogen, a C1-C4 alkyl group, a C1-C4 alkoxy group, and a C1-C4 alkylamino group; the C1-C4 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of -NH2, -OH, and -CN; Or, R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a , R 7b and R8, taken together with the carbon atom to which they are attached, form a 5-6 membered saturated or unsaturated ring; Alternatively, R8 and R9 together with the carbon atom to which they are attached form a 3-7 membered saturated or unsaturated ring, preferably the 3-7 membered saturated or unsaturated ring is selected from the group consisting of 1 to 3 independently selected from N, O, C(=O), S(=O) m and m=1 or 2; the saturated or unsaturated ring may be substituted with 1 to 3 substituents selected from the group consisting of -NH2, -OH, -CN, halogen, a C1-C4 alkyl group, a C1-C4 alkoxy group, and a C1-C4 alkylamino group; p is 0 or 1; q is 0 or 1; X is S or absent; Y is CR 12 or N; R 12 is hydrogen, -NH2, -CN, halogen, C1-C4 alkyl group, -OR 13 , C3-C8 cycloalkyl group, 3-10 membered heterocyclic group, -C(=O)R 13 , -C(=O)OR 13, -C(=O)NR 13 R 14 , -S(=O)2NR 13 R 14 , -S(=O)2R 13 R 13 , R 14 are each independently selected from the group consisting of hydrogen, a C1-C4 alkyl group, and a C3-C6 cycloalkyl group; Z1 is N or CR 15 and; Z2 is N or CR 16 and; Z3, N or CR 17 and; R 15 , R 16 , R 17 are each independently hydrogen, -CN, halogen, or -C(=O)R 18 , -C(=O)OR 18 , -C(=O)NR 18 R 19 , -NR 18 R 19 , -NR 18 C(=O)R 19 , -NR 18 C(=O)OR 19 , -OC(=O)R 18 , -OC(=O)NR 18 R 19 , -OR 18 , -S(=O)2NR 18 R 19 , -S(=O)2R 18 , C1-C4 alkyl group, C3-C8 cycloalkyl group, 3-10 membered heterocyclic group, C6-C 10 aryl groups, and 5- to 10-membered heteroaryl groups; 18 , R 19 are each independently selected from the group consisting of hydrogen, a C1-C4 alkyl group, and a C3-C8 cycloalkyl group; R 15 From R 19 The C1-C4 alkyl group, the C3-C8 cycloalkyl group, R 15 From R 17 The 3-10 membered heterocyclic group, C6-C 10The aryl group and the 5- to 10-membered heteroaryl group may be further substituted with 1 to 3 substituents each independently selected from the group consisting of -NH2, -OH, -CN, halogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, and a C1-C4 alkoxy group.

[0016] According to one embodiment of the invention, the compound of general formula I is selected from the group consisting of compounds of formula Ia: [ka] In formula Ia, R1 is selected from the group consisting of hydrogen, -NH2, a C1-C4 alkyl group, and a C1-C4 haloalkyl group; R2 is hydrogen, C1-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, C3-C8 cycloalkyl groups, 3-10 membered heterocyclic groups, C6-C 10 aryl groups, and 5-10 membered heteroaryl groups; 10 Alkyl groups, C1-C 10 Haloalkyl groups, C3-C8 cycloalkyl groups, 3-10 membered heterocycloalkyl groups, C6-C 10 The aryl group and the 5- to 10-membered heteroaryl group further comprise 1 to 5 -NR 10 R 11 , -OR 10 , -CN, halogen, C1-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, C3-C8 cycloalkyl groups, 3-10 membered heterocyclic groups, -C(=O)R 10 , -C(=O)OR 10 , -C(=O)NR 10 R 11 , -S(=O)2R 10 , -S(=O)2NR 10 R 11 , -NR 10 C(=O)R 11 R 10 and R 11are each independently selected from the group consisting of hydrogen, a C1-C4 alkyl group, and a C3-C7 cycloalkyl group; R3 is selected from the group consisting of hydrogen, a C1-C4 alkyl group, or a halogen; R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are each independently selected from the group consisting of hydrogen, -NH2, -OH, halogen, a carbonyl group, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C3-C8 cycloalkyl group, and a C1-C4 alkylamino group; R8 and R9 are each independently selected from the group consisting of -NH2, -OH, -CN, -COOH, halogen, a C1-C4 alkyl group, a C1-C4 alkoxy group, and a C1-C4 alkylamino group; the C1-C4 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of -NH2, -OH, and -CN; Alternatively, R8 and R9 together with the carbon atom to which they are attached form a 3-7 membered saturated or unsaturated ring, preferably the 3-7 membered saturated or unsaturated ring is selected from the group consisting of 1 to 3 independently selected from N, O, C(=O), S(=O) m and m=1 or 2; the saturated or unsaturated ring may be substituted with 1 to 3 substituents selected from the group consisting of -NH2, -OH, -CN, halogen, a C1-C4 alkyl group, a C1-C4 alkoxy group, and a C1-C4 alkylamino group; p is 0 or 1; q is 0 or 1; Y is CR 12 or N; R 12 is hydrogen, -NH2, -CN, halogen, C1-C4 alkyl group, -OR 13 , C3-C8 cycloalkyl group, 3-10 membered heterocyclic group, -C(=O)R 13 , -C(=O)OR 13 , -C(=O)NR 13 R14 , -S(=O)2NR 13 R 14 , -S(=O)2R 13 R 13 , R 14 are each independently selected from the group consisting of hydrogen, a C1-C4 alkyl group, and a C3-C6 cycloalkyl group; Z1 is N or CR 15 and; Z2 is N or CR 16 and; Z3, N or CR 17 and; R 15 , R 16 , R 17 are each independently hydrogen, -CN, halogen, a C1-C4 alkyl group, a C3-C8 cycloalkyl group, a 3-10 membered heterocyclic group, a C6-C 10 aryl groups, and 5-10 membered heteroaryl groups; the C1-C4 alkyl groups, C3-C8 cycloalkyl groups, 3-10 membered heterocyclic groups, C6-C 10 The aryl group and the 5- to 10-membered heteroaryl group may be further substituted with 1 to 3 substituents each independently selected from the group consisting of -NH2, -OH, -CN, halogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, and a C1-C4 alkoxy group.

[0017] According to one embodiment of the present invention, the compound of general formula I is selected from the group consisting of compounds of formula Ib: [ka] In formula Ib, R1 is selected from the group consisting of hydrogen, -NH2, methyl, and trifluoromethyl; R2 is hydrogen, C1-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, C3-C8 cycloalkyl groups, 3-10 membered heterocyclic groups, C6-C 10 aryl groups, and 5-10 membered heteroaryl groups; 10 Alkyl groups, C1-C10 Haloalkyl groups, C3-C8 cycloalkyl groups, 3-10 membered heterocycloalkyl groups, C6-C 10 The aryl group and the 5- to 10-membered heteroaryl group further comprise 1 to 5 -NR 10 R 11 , -OR 10 , -CN, halogen, C1-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, C3-C8 cycloalkyl groups, 3-10 membered heterocyclic groups, -C(=O)R 10 , -C(=O)OR 10 , -C(=O)NR 10 R 11 , -S(=O)2R 10 , -S(=O)2NR 10 R 11 , -NR 10 C(=O)R 11 R 10 and R 11 are each independently selected from the group consisting of hydrogen and a C1-C4 alkyl group; R 4a , R 4b , R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are each independently selected from the group consisting of hydrogen, -NH2, -OH, halogen, a carbonyl group, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C3-C8 cycloalkyl group, and a C1-C4 alkylamino group; R8 and R9 are each independently selected from the group consisting of -NH2, -OH, -CN, -COOH, halogen, a C1-C4 alkyl group, a C1-C4 alkoxy group, and a C1-C4 alkylamino group; the C1-C4 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of -NH2, -OH, and -CN; Alternatively, R8 and R9 together with the carbon atom to which they are attached form a 3-7 membered saturated or unsaturated ring, preferably the 3-7 membered saturated or unsaturated ring is selected from the group consisting of 1 to 3 independently selected from N, O, C(=O), S(=O) mand m=1 or 2; the saturated or unsaturated ring may be substituted with 1 to 3 substituents selected from the group consisting of -NH2, -OH, -CN, halogen, a C1-C4 alkyl group, a C1-C4 alkoxy group, and a C1-C4 alkylamino group; Y is CR 12 or N; R 12 is selected from the group consisting of hydrogen, -CN, and halogen; Z1 is N or CR 15 and; R 15 is hydrogen, -CN, halogen, C1-C4 alkyl group, C3-C8 cycloalkyl group, 3-10 membered heterocyclic group, C6-C 10 aryl groups, and 5-10 membered heteroaryl groups; the C1-C4 alkyl groups, C3-C8 cycloalkyl groups, 3-10 membered heterocyclic groups, C6-C 10 The aryl group and the 5- to 10-membered heteroaryl group may be further substituted with 1 to 3 substituents each independently selected from the group consisting of -NH2, -OH, -CN, halogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, and a C1-C4 alkoxy group.

[0018] According to one embodiment of the present invention, the compound of general formula I is selected from the group consisting of compounds of formula Ic: [ka] In formula Ic, R1 is selected from the group consisting of hydrogen, -NH2; R2 is hydrogen, C1-C 10 Alkyl groups, C3-C8 cycloalkyl groups, 3-10 membered heterocyclic groups, C6-C 10 aryl groups, and 5-10 membered heteroaryl groups; 10 Alkyl groups, C3-C8 cycloalkyl groups, 3-10 membered heterocycloalkyl groups, C6-C 10 The aryl group and the 5- to 10-membered heteroaryl group further comprise 1 to 5 -NR 10 R11 , -OR 10 , -CN, halogen, C1-C3 alkyl group, C3-C6 cycloalkyl group, -C(=O)R 10 , -C(=O)OR 10 , -C(=O)NR 10 R 11 , -S(=O)2R 10 , -S(=O)2NR 10 R 11 , -NR 10 C(=O)R 11 R 10 and R 11 are each independently selected from the group consisting of hydrogen and a C1-C4 alkyl group; R8 and R9 are each independently selected from the group consisting of -NH2, -OH, -CN, -COOH, halogen, a C1-C4 alkyl group, a C1-C4 alkoxy group, and a C1-C4 alkylamino group; the C1-C4 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of -NH2 and -OH; Alternatively, R8 and R9 together with the carbon atom to which they are attached form a 3-7 membered saturated or unsaturated ring, preferably the 3-7 membered saturated or unsaturated ring is selected from the group consisting of 1 to 3 independently selected from N, O, C(=O), S(=O) m and m=1 or 2; the saturated or unsaturated ring may be substituted with 1 to 3 substituents selected from the group consisting of -NH2, -OH, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C1-C4 alkylamino group, and halogen; Y is CH or N; Z1 is N or CR 15 and; R 15 is selected from the group consisting of hydrogen, -CN, a C1-C4 alkyl group, a C3-C8 cycloalkyl group, and a 3-10 membered heterocyclic group.

[0019] According to one embodiment of the invention, the compound of general formula I is selected from the group consisting of compounds of formula Id: [ka] In formula Id: R2 is hydrogen, C1-C 10 Alkyl groups, C3-C8 cycloalkyl groups, 3-10 membered heterocyclic groups, C6-C 10 aryl groups, and 5-10 membered heteroaryl groups; 10 Alkyl groups, C3-C8 cycloalkyl groups, 3-10 membered heterocycloalkyl groups, C6-C 10 The aryl group, the 5- to 10-membered heteroaryl group, further comprises 1 to 2 -NR 10 R 11 , -OR 10 , -CN, halogen, C1-C3 alkyl group, C3-C6 cycloalkyl group, -C(=O)R 10 , -C(=O)OR 10 , -C(=O)NR 10 R 11 , -S(=O)2R 10 , -S(=O)2NR 10 R 11 , -NR 10 C(=O)R 11 R 10 and R 11 are each independently selected from the group consisting of hydrogen and a C1-C4 alkyl group; Z1 is N or CR 15 and; R 15 is selected from the group consisting of hydrogen, -CN, a C1-C4 alkyl group, a C3-C8 cycloalkyl group, and a 3-10 membered heterocyclic group; V, [ka] It is.

[0020] According to one embodiment of the present invention, the compound of general formula I is selected from the group consisting of compounds of formula Ie: [ka] In formula Ie: R2 is C1-C 10 Alkyl groups, C3-C8 cycloalkyl groups, 3-10 membered heterocyclic groups, C6-C 10 aryl groups, and 5-10 membered heteroaryl groups; 10 Alkyl groups, C3-C8 cycloalkyl groups, 3-10 membered heterocycloalkyl groups, C6-C 10 The aryl group and the 5-10 membered heteroaryl group may be further substituted with 1 to 2 substituents selected from the group consisting of halogen, a C1-C3 alkyl group, and a C3-C6 cycloalkyl group; Z1 is N or CR 15 and; R 15 is selected from the group consisting of hydrogen, a C1-C4 alkyl group, and a C3-C8 cycloalkyl group.

[0021] According to one embodiment of the present invention, the compound represented by the general formula I is selected from the group consisting of the following compounds: [ka] [ka]

[0022] According to one embodiment of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of the above-mentioned compound, its pharmacologically acceptable salt, enantiomer, diastereomer, atropisomer, racemate, crystal polymorph, solvate, or isotope-labeled compound, and a pharmacologically acceptable carrier.

[0023] According to one embodiment of the invention, there is provided the use of the above-described compound, a pharmacologically acceptable salt, enantiomer, diastereomer, atropisomer, racemate, polymorph, solvate or isotopically labeled compound thereof, or the above-described pharmaceutical composition, in the manufacture of a medicament for treating a disease, disorder or disease state mediated by SHP2.

[0024] According to one embodiment of the invention, the disease or condition or disease state is selected from the group consisting of Noonan syndrome, Leopard syndrome, leukemia, neuroblastoma, liver cancer, medulloblastoma, squamous cell carcinoma of the head and neck, melanoma, breast cancer, esophageal cancer, head and neck tumors, gastric cancer, lung cancer, colon cancer, anaplastic large cell lymphoma and glioblastoma.

[0025] According to one embodiment of the invention, the disease or condition or disease state is selected from the group consisting of non-small cell lung cancer, esophageal cancer and head and neck tumors.

[0026] Furthermore, the leukemia is acute myeloid leukemia (AML) and the lung cancer is non-small cell lung cancer (NSCLC).

[0027] According to one embodiment of the present invention, there is provided use of the above-mentioned compound, a pharmacologically acceptable salt, enantiomer, diastereomer, atropisomer, racemate, crystal polymorph, solvate or isotopically labeled compound thereof, or the above-mentioned pharmaceutical composition in the manufacture of a medicament as an SHP2 inhibitor.

[0028] According to one embodiment of the present invention, there is provided a method for treating and / or preventing a disease, condition or disease state mediated by SHP2, comprising administering to a patient a therapeutically effective dose of one or more selected from the group consisting of the above-mentioned compounds, their pharmacologically acceptable salts, enantiomers, diastereomers, atropisomers, racemates, crystalline polymorphs, solvates and / or isotopically labeled compounds, or the above-mentioned pharmaceutical composition. EXAMPLES

[0029] The following examples are only used to illustrate and explain the technical solutions of the present invention, and do not limit the scope of the present invention. The compounds of the present invention can be synthesized in a similar manner by referring to the preparation methods in the following examples.

[0030] Synthesis of intermediate M-1-4 [ka]

[0031] (a) 2-Amino-3-bromo-6-chloropyrazine (3 g, 14.39 mmol) and tert-butyl dicarbonate (15.71 g, 71.96 mmol) were dissolved in 50 mL of dichloromethane, and 4-dimethylaminopyridine (879 mg, 7.20 mmol) was added to the above reaction system at room temperature and refluxed for 2 h. The solvent was evaporated with an evaporator, and the residue was isolated by column chromatography to obtain intermediate M-1-1. 1 H NMR (400 MHz, chloroform-d) δ 8.34(s, 1H), 1.42(s, 18H).

[0032] (b) Intermediate M-1-1 (1 g, 2.45 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decan-4-amine hydrochloride (714 mg, 2.94 mmol), and potassium phosphate (2.59 g, 12.23 mmol) were dispersed in 20 mL of N-methylpyrrolidinone and reacted at 130°C for 6 h. The reaction system was cooled to room temperature, saturated saline was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated. The residue was isolated by column chromatography to obtain the crude product of intermediate M-1-2. HPLC-MS: [M+H] + =542.36 / 544.02.

[0033] (c) Intermediate M-1-2 crude product (300 mg, 0.55 mmol) was dissolved in 10 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added to the above system at room temperature. The reaction was carried out at room temperature for 2 hours, and the solvent was evaporated using an evaporator. The residue was isolated by column chromatography to obtain intermediate M-1-3. HPLC-MS: [M+H] + =342.10 / 344.08.

[0034] (d) Intermediate M-1-3 (80 mg, 0.23 mmol) was dissolved in 10 mL of dichloromethane, and tert-butyl dicarbonate (102 mg, 0.47 mmol) was added to the above system and stirred at room temperature for 48 h. The solvent was evaporated using an evaporator, and the residue was isolated by column chromatography to obtain intermediate M-1-4. HPLC-MS: [M+H] + =442.23 / 444.16. 1 H NMR (400MHz, methanol-d4) δ 7.17(s,1H),4.28-4.19(m,1H),3.98-3.91(m,1H),3.71(d,J=8.7Hz,1H), 3.68-3.34(m,5H),1.83-1.49(m,4H),1.45(s,9H),1.14(d,J=6.3Hz,3H).

[0035] Synthesis of intermediate M-2-2 [ka]

[0036] (a) 2-Chloro-3-fluoroaniline (3g, 20.61mmol) was dissolved in 50mL DMF, and cesium carbonate (10.07g, 30.92mmol) and tert-butyl mercaptan (6.97mL, 61.83mmol) were added to the above system, and the reaction was carried out at 120℃ for 36h. The reaction system was cooled to room temperature, 150mL of saturated saline was added, and the mixture was extracted with ethyl acetate (100mL*3), and the ethyl acetate layer was combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated. The residue was isolated by column chromatography to obtain intermediate M-2-1. 1H NMR (400MHz, chloroform-d) δ 7.04 (dd, J = 7.6, 2.0Hz, 1H), 7.01 (t, J = 7.6Hz, 1H), 6.77 (dd, J = 7.5, 2.0Hz, 1H), 4.16 (s, 2H), 1.33 (s, 9H). (b) Intermediate M-2-1 (3g, 13.91mmol) was dissolved in 30mL concentrated hydrochloric acid, and an aqueous solution of sodium nitrite (1.15g, 16.69mmol) was added to the above system at 0°C. After 30min, an aqueous solution of potassium iodide (4.62g, 27.81mmol) was added to the above system and reacted for 30min. The reaction system was returned to room temperature, saturated saline was added, extracted with ethyl acetate, and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated. The residue was isolated by column chromatography to obtain intermediate M-2-2. 1 H NMR (400 MHz, chloroform-d) δ 7.86 (dd, J = 7.8, 1.5 Hz, 1H), 7.62 (dd, J = 7.8, 1.5 Hz, 1H), 6.91 (t, J = 7.8 Hz, 1H), 1.34 (s, 9H).

[0037] Synthesis of intermediate M-3-1 [ka]

[0038] 2,3-Dichloro-4-iodopyridine (5g, 18.25mmol) and diisopropylethylamine (9.07mL, 54.74mmol) were dissolved in 50mL 1,4-dioxane, Pd2(dba)3 (826mg, 0.91mmol) and Xantphos (1.06g, 1.82mmol) were added to the above system, the atmosphere was replaced with argon, and a dioxane solution of ethyl 3-mercaptopropionate (2.08Ml, 16.42mmol) was slowly added dropwise at 100°C, and after the addition was completed, the reaction was continued for 2h. The solvent was evaporated with an evaporator, and the residue was isolated by column chromatography to obtain intermediate M-3-1. HPLC-MS: [M+H] + =279.79 / 281.68 / 283.62. 1H NMR (400 MHz, chloroform-d) δ 8.15 (d, J = 5.3 Hz, 1H), 7.03 (d, J = 5.3 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.25 (t, J = 7.4 Hz, 2H), 2.74 (t, J = 7.4 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H).

[0039] Example 1 [ka]

[0040] (a) Intermediate M-2-2 (300 mg, 0.92 mmol) and N-methyl-4-ethynylpyrazole (117 mg, 1.10 mmol) were dissolved in a mixed solvent of Et3N / DMF (5 mL / 10 mL), and Pd(PPh3)2Cl2 (64 mg, 0.092 mmol) and CuI (35 mg, 0.18 mmol) were added to the above system, argon was substituted, and the reaction was carried out at 80°C for 2 h. The reaction solution was cooled to room temperature, 50 mL of saturated saline was added, and the mixture was extracted three times with ethyl acetate (30 mL*3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated. The residue was isolated by column chromatography to obtain intermediate M-4-1. HPLC-MS: [M+H] + =304.90 / 306.74. 1 H NMR (400 MHz, chloroform-d) δ 7.67 (s, 1H), 7.61 (s, 1H), 7.58 (dd, J = 7.7, 1.7 Hz, 1H), 7.51 (dd, J = 7.7, 1.7 Hz, 1H), 7.18 (t, J = 7.7 Hz, 1H), 3.92 (s, 3H), 1.34 (s, 9H).

[0041] (b) Intermediate M-4-1 (200 mg, 0.66 mmol) was dissolved in 15 mL of super dry toluene, and AlCl3 (351 mg, 2.62 mmol) was added to the above system at room temperature. After 30 min, silica gel was added and the sample was stirred. The crude product of intermediate M-4-2 was obtained by isolating the product by column chromatography. HPLC-MS: [M+H] + =248.84 / 250.67.

[0042] (c) Intermediate M-4-2 (34 mg, 0.14 mmol), M-1-4 (50 mg, 0.11 mmol), and diisopropylethylamine (56 μL, 0.34 mmol) were dissolved in 2 mL of 1,4-dioxane, and Pd2(dba)3 (10 mg, 0.011 mmol) and Xantphos (13 mg, 0.023 mmol) were added to the above system, purged with argon, and subjected to a microwave reaction at 130 °C for 2 h. The solvent was evaporated using an evaporator, and the residue was isolated by column chromatography to obtain intermediate M-4-3. HPLC-MS: [M+H] + =610.32 / 612.11.

[0043] (d) Intermediate M-4-3 was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added to the above system at room temperature. The reaction was carried out at room temperature for 2 h, and the solvent was evaporated using an evaporator. The residue was isolated by column chromatography to obtain ZB-S-82. HPLC-MS: [M+H] + =510.05 / 511.89. 1 H NMR (400MHz, methanol-d4) δ 7.89(s,1H),7.66(s,1H),7.56(s,1H),7.29(dd,J=7.9,1.5Hz,1H),7.10( t,J=7.9Hz,1H),6.64(dd,J=7.9,1.5Hz,1H),4.28-4.19(m,1H),4.11-3.97 (m,2H),3.91(s,3H),3.87(d,J=8.7Hz,1H),3.72(d,J=8.7Hz,1H),3.39-3. 20(m,2H),3.03(d,J=4.9Hz,1H),1.86-1.59(m,4H),1.22(d,J=6.5Hz,3H).

[0044] Example 2 [ka]

[0045] (a) Intermediate M-2-2 (300 mg, 0.92 mmol) and 3-ethynylpyridine (114 mg, 1.10 mmol) were dissolved in a mixed solvent of Et3N / DMF (5 mL / 10 mL), and Pd(PPh3)2Cl2 (64 mg, 0.092 mmol) and CuI (35 mg, 0.18 mmol) were added to the above system, argon was substituted, and the reaction was carried out at 80°C for 2 h. The reaction solution was cooled to room temperature, 50 mL of saturated saline was added, and the mixture was extracted three times with ethyl acetate (30 mL*3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated. The residue was isolated by column chromatography to obtain intermediate M-5-1. HPLC-MS: [M+H] + =301.90 / 303.74. 1 H NMR(400MHz,chloroform-d) δ 8.82-8.78(m,1H),8.57(dd,J=4.9,1.7Hz,1H),7.85(dt,J=7.9,1.9Hz,1H),7.65(dd,J=7.7,1.7Hz,1 H),7.58(dd,J=7.7,1.7Hz,1H),7.30(ddd,J=7.9,4.9,0.9Hz,1H),7.23(t,J=7.7Hz,1H),1.36(s,9H).

[0046] (b) Intermediate M-5-1 (200 mg, 0.66 mmol) was dissolved in 15 mL of super dry toluene, and AlCl3 (351 mg, 2.62 mmol) was added to the above system at room temperature. After 30 minutes, silica gel was added and the sample was stirred. The crude product of intermediate M-5-2 was obtained by isolating the product by column chromatography. HPLC-MS: [M+H] + =245.79 / 247.63.

[0047] (c) Intermediate M-5-2 (33 mg, 0.14 mmol), M-1-4 (50 mg, 0.11 mmol), and diisopropylethylamine (56 μL, 0.34 mmol) were dissolved in 2 mL of 1,4-dioxane, and Pd2(dba)3 (10 mg, 0.011 mmol) and Xantphos (13 mg, 0.023 mmol) were added to the above system, purged with argon, and subjected to a microwave reaction at 130 °C for 2 h. The solvent was evaporated using an evaporator, and the residue was isolated by column chromatography to obtain intermediate M-5-3. HPLC-MS: [M+H] + =607.27 / 609.06.

[0048] (d) Intermediate M-5-3 was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added to the above system at room temperature. The reaction was carried out at room temperature for 2 h, and the solvent was evaporated using an evaporator. The residue was isolated by column chromatography to obtain ZB-S-83. HPLC-MS: [M+H] + =507.10 / 508.89. 1 H NMR (400MHz, methanol-d4) δ 8.73(dd,J=2.1,0.9Hz,1H),8.56(dd,J=5.0,1.7Hz,1H),8.01(dt,J=7.9,1.9Hz,1H) ,7.59(s,1H),7.50(ddd,J=8.0,5.0,1.0Hz,1H),7.42(dd,J=7.9,1.5Hz,1H),7.17(t ,J=7.9Hz,1H),6.73(dd,J=7.9,1.5Hz,1H),4.33-4.08(m,3H),3.94(d,J=8.9Hz,1H) ,3.81(d,J=8.9Hz,1H),3.38-3.10(m,3H),1.88-1.62(m,4H),1.27(d,J=6.5Hz,3H).

[0049] Example 3 [ka]

[0050] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and 3-ethynylpyridine (162 mg, 1.57 mmol) were dissolved in 30 mL of a mixed solvent of 1,4-dioxane / diisopropylamine (20 mL / 10 mL), and Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-6-1. HPLC-MS: [M+H] + =346.94 / 348.77. 1 H NMR(400MHz,chloroform-d) δ 9.12-8.78(m,1H),8.76-8.50(m,1H),8.38(d,J=5.1Hz,1H),7.92(d,J=7.9Hz,1H),7.42-7.28(m,1H),7.08 (d,J=5.1Hz,1H),4.20(q,J=7.2Hz,1H),3.27(t,J=7.4Hz,2H),2.76(t,J=7.4Hz,2H),1.29(t,J=7.2Hz,2H).

[0051] (b) Intermediate M-6-1 (200 mg, 0.58 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (78 mg, 0.69 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated with an evaporator to obtain intermediate M-6-2. This was used in the next step without purification. HPLC-MS: [M+H] + =246.71 / 266.98.

[0052] (c) Intermediate M-6-2 (165 mg, 0.57 mmol), 2-amino-3-bromo-6-chloropyrazine (100 mg, 0.48 mmol), and potassium phosphate (203 mg, 0.96 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (27 mg, 0.14 mmol) and phenanthroline (52 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-6-3. HPLC-MS: [M+H] + =373.88 / 375.86 / 377.99.

[0053] (d) Intermediate M-6-3 (60 mg, 0.16 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (CAS: 2055761-19-6, 47 mg, 0.19 mmol), and diisopropylethylamine (264 μL, 1.60 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 ° C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography to obtain ZB-S-84. HPLC-MS: [M + H] + =508.11 / 509.90. 1 H NMR (400MHz, methanol-d4) δ 8.83-8.76(m,1H),8.61(dd,J=4.9,1.6Hz,1H),8.19(d,J=5.4Hz,1H),8.13-8.04(m,1H),7.64(s,1H),7.53(dd,J=8.0,4.9Hz,1H),6.68(d, J=5.4Hz,1H),4.34-4.13(m,3H),3.94(d,J=8.9Hz,1H),3.82(d,J=8.9Hz,1H),3.34-3.11(m,3H),1.87-1.62(m,4H),1.28(d,J=6.5Hz,3H).

[0054] Example 4 [ka]

[0055] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and N-methyl-4-ethynylpyrazole (167 mg, 1.57 mmol) were dissolved in 30 mL of 1,4-dioxane / diisopropylamine (20 mL / 10 mL) mixed solvent, Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, the atmosphere was replaced with argon, and the reaction was carried out at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-7-1. HPLC-MS: [M+H] + =349.98 / 351.82. 1 H NMR(400MHz,chloroform-d) δ 8.32(d,J=5.3Hz,1H),7.72(s,1H),7.66(s,1H),7.01(d,J=5.3Hz,1H),4.19(q,J=7.1H z,2H),3.92(s,3H),3.25(t,J=7.4Hz,2H),2.74(t,J=7.4Hz,2H),1.28(t,J=7.1Hz,3H).

[0056] (b) Intermediate M-7-1 (200 mg, 0.57 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (77 mg, 0.69 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated using an evaporator to obtain intermediate M-7-2. This was used in the next step without purification. HPLC-MS: [M+H] + =249.85 / 251.69.

[0057] (c) Intermediate M-7-2 (165 mg, 0.57 mmol), 2-amino-3-bromo-6-chloropyrazine (100 mg, 0.48 mmol), and potassium phosphate (203 mg, 0.96 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (27 mg, 0.14 mmol) and phenanthroline (52 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-7-3. HPLC-MS: [M+H] + =376.93 / 378.76 / 380.70.

[0058] (d) Intermediate M-7-3 (65 mg, 0.17 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (CAS: 2055761-19-6, 50 mg, 0.21 mmol), and diisopropylethylamine (285 μL, 1.72 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 ° C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, and the mixture was extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography to obtain ZB-S-85. HPLC-MS: [M + H] + =511.16 / 513.00. 1 H NMR (400MHz, methanol-d4) δ 8.12(d,J=5.4Hz,1H),7.99(s,1H),7.74(s,1H),7.62(s,1H),6.60(d,J=5.4Hz,1H),4.31-4.19(m,1H),4.16-4.02(m,2H),3.93(s,3 H),3.89(d,J=8.7Hz,1H),3.74(d,J=8.7Hz,1H),3.42-3.21(m,2H),3.06(d,J=4.9Hz,1H),1.91-1.52(m,4H),1.23(d,J=6.4Hz,3H).

[0059] Example 5 [ka]

[0060] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and 4-ethynylpyridine (162 mg, 1.57 mmol) were dissolved in 30 mL of a mixed solvent of 1,4-dioxane / diisopropylamine (20 mL / 10 mL), and Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-8-1. HPLC-MS: [M+H] + =346.94 / 349.11. 1 H NMR(400MHz,chloroform-d) δ 8.72-8.55(m,2H),8.37(d,J=5.3Hz,1H),7.51-7.43(m,2H),7.09(d,J=5.3Hz,1H),4.1 9(q,J=7.1Hz,2H),3.26(t,J=7.4Hz,2H),2.75(t,J=7.4Hz,2H),1.28(t,J=7.1Hz,3H).

[0061] (b) Intermediate M-8-1 (200 mg, 0.58 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (78 mg, 0.69 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated with an evaporator to obtain intermediate M-8-2. This was used in the next step without purification. HPLC-MS: [M+H] + =246.85 / 249.03.

[0062] (c) Intermediate M-8-2 (165 mg, 0.57 mmol), 2-amino-3-bromo-6-chloropyrazine (100 mg, 0.48 mmol), and potassium phosphate (203 mg, 0.96 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (27 mg, 0.14 mmol) and phenanthroline (52 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-8-3. HPLC-MS: [M+H] + =373.88 / 375.77 / 377.65.

[0063] (d) Intermediate M-8-3 (59 mg, 0.16 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (CAS: 2055761-19-6, 46 mg, 0.19 mmol), and diisopropylethylamine (261 μL, 1.57 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 ° C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography to obtain ZB-S-86. HPLC-MS: [M + H] + =508.16 / 510.39. 1 H NMR(400MHz,DMSO-d6) δ 8.74-8.66(m,2H),8.30(d,J=5.3Hz,1H),7.68(s,1H),7.64-7.58(m,2H),6.62(d,J=5.3Hz,1H),6.31(s,2H),4.12-4.02(m,1H),3.94-3.7 9(m,2H),3.68(d,J=8.4Hz,1H),3.50(d,J=8.4Hz,1H),3.46-3.26(m,2H),2.93(d,J=5.0Hz,1H),1.80-1.41(m,4H),1.09(d,J=6.4Hz,3H).

[0064] Example 6 [ka]

[0065] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and cyclopropylacetylene (0.61 mL, 7.14 mmol) were dissolved in 30 mL of 1,4-dioxane / diisopropylamine (20 mL / 10 mL) mixed solvent, and Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-9-1. HPLC-MS: [M+H] + =309.88 / 311.67. 1 H NMR(400MHz,chloroform-d) δ 8.25(d,J=5.3Hz,1H),6.96(d,J=5.3Hz,1H),4.18(q,J=7.1Hz,2H),3.22(t,J=7.4Hz,2 H),2.72(t,J=7.4Hz,2H),1.57-1.49(m,1H),1.27(t,J=7.1Hz,3H),0.96-0.91(m,4H).

[0066] (b) Intermediate M-9-1 (200 mg, 0.65 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (87 mg, 0.77 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated with an evaporator to obtain intermediate M-9-2. This was used in the next step without purification.

[0067] (c) Intermediate M-9-2 (142 mg, 0.57 mmol), 2-amino-3-bromo-6-chloropyrazine (100 mg, 0.48 mmol), and potassium phosphate (203 mg, 0.96 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (27 mg, 0.14 mmol) and phenanthroline (52 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-9-3. HPLC-MS: [M+H] + =336.92 / 338.76 / 340.79.

[0068] (d) Intermediate M-9-3 (60 mg, 0.18 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (52 mg, 0.21 mmol), and diisopropylethylamine (294 μL, 1.78 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 ° C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, and extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography to obtain ZB-S-87. HPLC-MS: [M + H] + =471.18 / 473.29. 1 H NMR (400MHz, methanol-d4) δ 8.04(d,J=5.4Hz,1H),7.61(s,1H),6.55(d,J=5.4Hz,1H),4.30-4.19(m,1H),4.19-4.03(m,2H),3.89(d,J=8.8Hz,1H),3.75(d,J=8 .8Hz,1H),3.39-3.19(m,2H),3.10(d,J=4.8Hz,1H),1.88-1.53(m,4H),1.24(d,J=6.5Hz,3H),1.06-0.97(m,2H),0.93-0.84(m,2H).

[0069] Example 7 [ka]

[0070] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and 2-ethynylpyridine (162 mg, 1.57 mmol) were dissolved in 30 mL of a mixed solvent of 1,4-dioxane / diisopropylamine (20 mL / 10 mL), and Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-10-1. HPLC-MS: [M+H] + =346.94 / 349.11.

[0071] (b) Intermediate M-10-1 (200 mg, 0.58 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (78 mg, 0.69 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated with an evaporator to obtain intermediate M-10-2. This was used in the next step without purification. HPLC-MS: [M+H] + =246.85 / 249.03.

[0072] (c) Intermediate M-10-2 (164 mg, 0.57 mmol), 2-amino-3-bromo-6-chloropyrazine (100 mg, 0.48 mmol), and potassium phosphate (203 mg, 0.96 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (27 mg, 0.14 mmol) and phenanthroline (52 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-10-3. HPLC-MS: [M+H] + =373.88 / 375.77 / 377.80.

[0073] (d) Intermediate M-10-3 (40 mg, 0.11 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (31 mg, 0.13 mmol), and diisopropylethylamine (177 μL, 1.07 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 ° C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, and the mixture was extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography to obtain ZB-S-88. HPLC-MS: [M + H] + =508.11 / 510.14. 1 H NMR (400MHz, methanol-d4) δ 8.65-8.59(m,1H),8.20(d,J=5.4Hz,1H),7.93(td,J=7.8,1.8Hz,1H),7.81- 7.74(m,1H),7.64(s,1H),7.51(ddd,J=7.7,4.9,1.2Hz,1H),6.68(d,J=5.4Hz ,1H),4.34-4.19(m,3H),3.97(d,J=9.1Hz,1H),3.85(d,J=9.1Hz,1H),3.35( d,J=4.3Hz,1H),3.29-3.12(m,2H),1.89-1.63(m,4H),1.30(d,J=6.5Hz,3H).

[0074] Example 8 [ka]

[0075] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and 2-ethynylpyran (173 mg, 1.57 mmol) were dissolved in 30 mL of a mixed solvent of 1,4-dioxane / diisopropylamine (20 mL / 10 mL), and Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-11-1. HPLC-MS: [M+H] + =354.05 / 355.84. 1 H NMR(400MHz,chloroform-d) δ 8.29(d,J=5.3Hz,1H),7.01(d,J=5.3Hz,1H),4.19(q,J=7.2Hz,2H),3.97(ddd,J=11.7,6.3,3.6Hz,2H),3.59(ddd,J=11.4,7.9,3.1Hz,2H ),3.24(t,J=7.5Hz,2H),2.98(tt,J=8.2,4.2Hz,1H),2.73(t,J=7.5Hz,2H),2.01-1.89(m,2H),1.89-1.74(m,2H),1.28(t,J=7.2Hz,3H).

[0076] (b) Intermediate M-11-1 (250 mg, 0.71 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (95 mg, 0.85 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated with an evaporator to obtain intermediate M-11-2. This was used in the next step without purification. HPLC-MS: [M+H] + =253.91 / 255.75.

[0077] (c) Intermediate M-11-2 (168 mg, 0.57 mmol), 2-amino-3-bromo-6-chloropyrazine (100 mg, 0.48 mmol), and potassium phosphate (203 mg, 0.96 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (27 mg, 0.14 mmol) and phenanthroline (52 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-11-3. HPLC-MS: [M+H] + =380.99 / 382.98 / 384.86.

[0078] (d) Intermediate M-11-3 (70 mg, 0.18 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (53 mg, 0.22 mmol), and diisopropylethylamine (303 μL, 1.83 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 ° C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, and the mixture was extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography to obtain ZB-S-89. HPLC-MS: [M + H] + =514.25 / 516.37. 1 H NMR(400MHz,DMSO-d6) δ 8.18(d,J=5.2Hz,1H),7.67(s,1H),6.49(d,J=5.2Hz,1H),6.27(s,2H),4.15-4.0 7(m,1H),4.05-3.90(m,2H),3.86-3.78(m,2H),3.76(d,J=8.6Hz,1H),3.56(d,J= 8.6Hz,1H),3.54-3.45(m,2H),3.33-3.15(m,2H),3.10(d,J=5.0Hz,1H),3.03(tt ,J=8.5,4.2Hz,1H),1.93-1.83(m,2H),1.76-1.40(m,6H),1.13(d,J=6.4Hz,3H).

[0079] Example 9 [ka]

[0080] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and 1-Boc-4-ethynylpiperidine (330 mg, 1.57 mmol) were dissolved in 30 mL of a mixed solvent of 1,4-dioxane / diisopropylamine (20 mL / 10 mL), and Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-12-1. HPLC-MS: [M+H] + =453.02 / 454.81. 1 H NMR(400MHz,chloroform-d) δ 8.29(d,J=5.4Hz,1H),7.01(d,J=5.4Hz,1H),4.19(q,J=7.1Hz,2H),3.71(ddd,J=12.9,7.2,3.5Hz,3H),3.33(ddd,J=13.5,7.7,3.6Hz,2H),3.2 4(t,J=7.4Hz,2H),2.93(tt,J=7.6,4.0Hz,1H),2.73(t,J=7.4Hz,2H),1 .96-1.82(m,2H),1.81-1.68(m,2H),1.46(s,9H),1.28(t,J=7.1Hz,3H).

[0081] (b) Intermediate M-12-1 (300 mg, 0.66 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (89 mg, 0.79 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated with an evaporator to obtain intermediate M-12-2. This was used in the next step without purification.

[0082] (c) Intermediate M-12-2 (224 mg, 0.57 mmol), 2-amino-3-bromo-6-chloropyrazine (100 mg, 0.48 mmol), and potassium phosphate (203 mg, 0.96 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (27 mg, 0.14 mmol) and phenanthroline (52 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-12-3. HPLC-MS: [M+H] + =480.01 / 481.89 / 483.54.

[0083] (d) Intermediate M-12-3 (80 mg, 0.17 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (53 mg, 0.20 mmol), and diisopropylethylamine (276 μL, 1.67 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 ° C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, and the mixture was extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography to obtain M-12-4. HPLC-MS: [M + H] + =614.39 / 616.17.

[0084] (e) Intermediate M-12-4 was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added to the above system at room temperature. The reaction was carried out at room temperature for 2 h, and the solvent was evaporated using an evaporator. The residue was isolated by column chromatography to obtain ZB-S-90. HPLC-MS: [M+H] + =514.21 / 515.95. 1H NMR (400MHz, methanol-d4) δ 8.11(d,J=5.4Hz,1H),7.62(s,1H),6.63(d,J=5.4Hz,1H),4.29-4.20(m,1H),4.16-4.00(m,2H),3.88(d,J=8.7Hz,1H),3.73(d,J= 8.7Hz,1H),3.43-3.22(m,4H),3.19-3.01(m,4H),2.22-2.09(m,2H),2.00-1.88(m,2H),1.87-1.56(m,4H),1.23(d,J=6.5Hz,3H).

[0085] Example 10 [ka]

[0086] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and 5-ethynyl-1-methyl-1H-imidazole (167 mg, 1.57 mmol) were dissolved in 30 mL of 1,4-dioxane / diisopropylamine (20 mL / 10 mL) mixed solvent, and Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-13-1. HPLC-MS: [M+H] + =349.38 / 351.77. 1 H NMR(400MHz,chloroform-d) δ 8.35(d,J=5.3Hz,1H),7.55(br,2H),7.05(d,J=5.3Hz,1H),4.20(q,J=7.2Hz,2H) ,3.80(s,3H),3.27(t,J=7.4Hz,2H),2.75(t,J=7.4Hz,2H),1.29(t,J=7.2Hz,3H).

[0087] (b) Intermediate M-13-1 (200 mg, 0.57 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (77 mg, 0.69 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated with an evaporator to obtain intermediate M-13-2. This was used in the next step without purification.

[0088] (c) Intermediate M-13-2 (165 mg, 0.57 mmol), 2-amino-3-bromo-6-chloropyrazine (100 mg, 0.48 mmol), and potassium phosphate (203 mg, 0.96 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (27 mg, 0.14 mmol) and phenanthroline (52 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-13-3. HPLC-MS: [M+H] + =376.95 / 378.66 / 380.73.

[0089] (d) Intermediate M-13-3 (70 mg, 0.19 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (54 mg, 0.22 mmol), and diisopropylethylamine (307 μL, 1.85 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 °C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, and the mixture was extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography to obtain ZB-S-91. HPLC-MS: [M + H] + =511.16 / 512.85. 1H NMR(400MHz,DMSO-d6) δ 8.26(d,J=5.3Hz,1H),7.89(s,1H),7.68(s,1H),7.50(s,1H),6.55(d,J=5.3Hz,1H),6.30(s,2H),4.16-4.06(m,1H),4.03-3.89(m,2H),3. 77(s,3H),3.74(d,J=8.7Hz,1H),3.55(d,J=8.7Hz,1H),3.45-3.17(m,2H),3.07(d,J=5.0Hz,1H),1.86-1.38(m,4H),1.12(d,J=6.4Hz,3H).

[0090] Example 11 [ka]

[0091] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and 1-methyl-4-ethynyl-1H-imidazole (167 mg, 1.57 mmol) were dissolved in 30 mL of a mixed solvent of 1,4-dioxane / diisopropylamine (20 mL / 10 mL), and Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-14-1. HPLC-MS: [M+H] + =349.98 / 351.82. 1 H NMR(400MHz,chloroform-d) δ 8.32(d,J=5.3Hz,1H),7.49(s,1H),7.27(s,1H),7.01(d,J=5.3Hz,1H),4.19(q,J=7.1H z,2H),3.72(s,3H),3.25(t,J=7.4Hz,2H),2.74(t,J=7.4Hz,2H),1.28(t,J=7.1Hz,3H).

[0092] (b) Intermediate M-14-1 (220 mg, 0.63 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (85 mg, 0.75 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated with an evaporator to obtain intermediate M-14-2. This was used in the next step without purification.

[0093] (c) Intermediate M-14-2 (165 mg, 0.57 mmol), 2-amino-3-bromo-6-chloropyrazine (100 mg, 0.48 mmol), and potassium phosphate (203 mg, 0.96 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (27 mg, 0.14 mmol) and phenanthroline (52 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-14-3. HPLC-MS: [M+H] + =376.88 / 378.67 / 380.75.

[0094] (d) Intermediate M-14-3 (70 mg, 0.19 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (54 mg, 0.22 mmol), and diisopropylethylamine (307 μL, 1.85 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 ° C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, and the mixture was extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography to obtain ZB-S-92. HPLC-MS: [M + H] + =511.16 / 512.76.

[0095] Example 12 [ka]

[0096] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and 2-ethynylpyrazine (162 mg, 1.57 mmol) were dissolved in 30 mL of a mixed solvent of 1,4-dioxane / diisopropylamine (20 mL / 10 mL), and Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-15-1. HPLC-MS: [M+H] + =347.90 / 349.79. 1 H NMR(400MHz,chloroform-d) δ 8.86(d,J=1.5Hz,1H),8.64(dd,J=2.5,1.5Hz,1H),8.55(d,J=2.5Hz,1H),8.40(d,J=5.3Hz,1H),7.12(d, J=5.3Hz,1H), 4.20(q,J=7.2Hz,2H),3.28(t,J=7.4Hz,2H),2.76(t,J=7.4Hz,2H),1.29(t,J=7.2Hz,3H).

[0097] (b) Intermediate M-15-1 (120 mg, 0.34 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (47 mg, 0.41 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated with an evaporator to obtain intermediate M-15-2. This was used in the next step without purification.

[0098] (c) Intermediate M-15-2 (82 mg, 0.29 mmol), 2-amino-3-bromo-6-chloropyrazine (50 mg, 0.24 mmol), and potassium phosphate (101 mg, 0.48 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (14 mg, 0.072 mmol) and phenanthroline (26 mg, 0.14 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-15-3. HPLC-MS: [M+H] +=374.85 / 376.78 / 378.52.

[0099] (d) Intermediate M-15-3 (40 mg, 0.11 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (31 mg, 0.13 mmol), and diisopropylethylamine (176 μL, 1.06 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 ° C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, and the mixture was extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography to obtain ZB-S-93. HPLC-MS: [M + H] + =509.13 / 510.92. 1 H NMR (400MHz, methanol-d4) δ 8.91(d,J=1.5Hz,1H),8.69(dd,J=2.6,1.5Hz,1H),8.64(d,J=2.6Hz,1H), 8.22(d,J=5.3Hz,1H),7.63(s,1H),6.72(d,J=5.3Hz,1H),4.30-4.20(m,1H ),4.19-4.06(m,2H),3.90(d,J=8.7Hz,1H),3.76(d,J=8.7Hz,1H),3.41-3. 19(m,2H),3.11(d,J=4.8Hz,1H),1.87-1.62(m,4H),1.24(d,J=6.5Hz,3H).

[0100] Example 13 [ka]

[0101] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and 5-ethynyl-1-methyl-1H-pyrazole (167 mg, 1.57 mmol) were dissolved in 30 mL of 1,4-dioxane / diisopropylamine (20 mL / 10 mL) mixed solvent, Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, the atmosphere was replaced with argon, and the reaction was carried out at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-16-1. HPLC-MS: [M+H] + =349.93 / 351.77. 1 H NMR(400MHz,chloroform-d) δ 8.37(d,J=5.3Hz,1H),7.49(d,J=2.0Hz,1H),7.08(d,J=5.3Hz,1H),6.61(d,J=2.0Hz,1H),4.20( q,J=7.2Hz,2H),4.06(s,3H),3.27(t,J=7.4Hz,2H),2.76(t,J=7.4Hz,2H),1.29(t,J=7.2Hz,3H).

[0102] (b) Intermediate M-16-1 (140 mg, 0.40 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (54 mg, 0.48 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated with an evaporator to obtain intermediate M-16-2. This was used in the next step without purification.

[0103] (c) Intermediate M-16-2 (116 mg, 0.40 mmol), 2-amino-3-bromo-6-chloropyrazine (70 mg, 0.33 mmol), and potassium phosphate (142 mg, 0.67 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (19 mg, 0.100 mmol) and phenanthroline (36 mg, 0.201 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-16-3. HPLC-MS: [M+H] +=377.02 / 378.91 / 381.09.

[0104] (d) Intermediate M-16-3 (65 mg, 0.17 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (50 mg, 0.21 mmol), and diisopropylethylamine (285 μL, 1.72 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 ° C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, and the mixture was extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography to obtain ZB-S-94. HPLC-MS: [M + H] + =511.16 / 513.00. 1 H NMR(400MHz,DMSO-d6) δ 8.29(d,J=5.3Hz,1H),7.68(s,1H),7.59(d,J=2.1Hz,1H),6.79(d,J=2.1Hz,1H ),6.60(d,J=5.3Hz,1H),6.30(s,2H),4.15-4.05(m,1H),4.00(s,3H),3.99-3. 87(m,2H),3.73(d,J=8.6Hz,1H),3.53(d,J=8.6Hz,1H),3.43-3.20(m,2H),3.0 2(d,J=5.1Hz,1H),1.78-1.61(m,2H),1.60-1.41(m,2H),1.11(d,J=6.4Hz,3H).

[0105] Example 14 [ka]

[0106] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and 5-ethynyl-2-methyl-pyridine (184 mg, 1.57 mmol) were dissolved in 30 mL of 1,4-dioxane / diisopropylamine (20 mL / 10 mL) mixed solvent, and Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-17-1. HPLC-MS: [M+H] + =361.20 / 363.12.

[0107] (b) Intermediate M-17-1 (250 mg, 0.69 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (94 mg, 0.83 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated with an evaporator to obtain intermediate M-17-2. This was used in the next step without purification.

[0108] (c) Intermediate M-17-2 (172 mg, 0.57 mmol), 2-amino-3-bromo-6-chloropyrazine (100 mg, 0.48 mmol), and potassium phosphate (203 mg, 0.96 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (27 mg, 0.14 mmol) and phenanthroline (52 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-17-3. HPLC-MS: [M+H] + =387.89 / 389.73 / 391.90.

[0109] (d) Intermediate M-17-3 (70 mg, 0.17 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (53 mg, 0.22 mmol), and diisopropylethylamine (299 μL, 1.80 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 ° C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography to obtain ZB-S-95. HPLC-MS: [M + H] + =522.24 / 524.13.

[0110] Example 15 [ka]

[0111] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and 4-ethynyl-1-methyl-piperidine (194 mg, 1.57 mmol) were dissolved in 30 mL of 1,4-dioxane / diisopropylamine (20 mL / 10 mL) mixed solvent, and Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-18-1. HPLC-MS: [M+H] + =367.08 / 369.12.

[0112] (b) Intermediate M-18-1 (250 mg, 0.68 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (92 mg, 0.82 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated with an evaporator to obtain intermediate M-18-2. This was used in the next step without purification.

[0113] (c) Intermediate M-18-2 (175 mg, 0.57 mmol), 2-amino-3-bromo-6-chloropyrazine (100 mg, 0.48 mmol), and potassium phosphate (203 mg, 0.96 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (27 mg, 0.14 mmol) and phenanthroline (52 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-18-3. HPLC-MS: [M+H] + =394.12 / 396.07 / 398.13.

[0114] (d) Intermediate M-18-3 (80 mg, 0.20 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (59 mg, 0.24 mmol), and diisopropylethylamine (336 μL, 2.03 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 °C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, and the mixture was extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography to obtain ZB-S-96. HPLC-MS: [M + H] + =528.23 / 530.12.

[0115] Example 16 [ka]

[0116] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and 4-ethynyl-1-ethyl-piperidine (216 mg, 1.57 mmol) were dissolved in 30 mL of 1,4-dioxane / diisopropylamine (20 mL / 10 mL) mixed solvent, and Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-19-1. HPLC-MS: [M+H] + =381.02 / 383.11.

[0117] (b) Intermediate M-19-1 (300 mg, 0.79 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (107 mg, 0.95 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated with an evaporator to obtain intermediate M-19-2. This was used in the next step without purification.

[0118] (c) Intermediate M-19-2 (183 mg, 0.57 mmol), 2-amino-3-bromo-6-chloropyrazine (100 mg, 0.48 mmol), and potassium phosphate (203 mg, 0.96 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (27 mg, 0.14 mmol) and phenanthroline (52 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-19-3. HPLC-MS: [M+H] + =408.02 / 409.93 / 412.04.

[0119] (d) Intermediate M-19-3 (85 mg, 0.21 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (61 mg, 0.25 mmol), and diisopropylethylamine (345 μL, 2.08 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 °C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, and the mixture was extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography to obtain ZB-S-97. HPLC-MS: [M + H] + =542.33 / 544.21.

[0120] Example 17 [ka]

[0121] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and 4-ethynyl-1-isopropyl-piperidine (238 mg, 1.57 mmol) were dissolved in 30 mL of 1,4-dioxane / diisopropylamine (20 mL / 10 mL) mixed solvent, and Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-20-1. HPLC-MS: [M+H] + =395.21 / 397.12.

[0122] (b) Intermediate M-20-1 (270 mg, 0.79 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (93 mg, 0.82 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated with an evaporator to obtain intermediate M-20-2. This was used in the next step without purification.

[0123] (c) Intermediate M-20-2 (191 mg, 0.57 mmol), 2-amino-3-bromo-6-chloropyrazine (100 mg, 0.48 mmol), and potassium phosphate (203 mg, 0.96 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (27 mg, 0.14 mmol) and phenanthroline (52 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-20-3. HPLC-MS: [M+H] + =421.98 / 423.86 / 425.96.

[0124] (d) Intermediate M-20-3 (90 mg, 0.21 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (62 mg, 0.26 mmol), and diisopropylethylamine (353 μL, 2.13 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 ° C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, and the mixture was extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography to obtain ZB-S-98. HPLC-MS: [M + H] + =556.14 / 558.09.

[0125] Example 18 [ka]

[0126] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and 4-ethynyl-1-cyclopropyl-piperidine (235 mg, 1.57 mmol) were dissolved in 30 mL of 1,4-dioxane / diisopropylamine (20 mL / 10 mL) mixed solvent, and Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-21-1. HPLC-MS: [M+H] + =393.14 / 395.25.

[0127] (b) Intermediate M-21-1 (250 mg, 0.64 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (79 mg, 0.70 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated with an evaporator to obtain intermediate M-21-2. This was used in the next step without purification.

[0128] (c) Intermediate M-21-2 (190 mg, 0.57 mmol), 2-amino-3-bromo-6-chloropyrazine (100 mg, 0.48 mmol), and potassium phosphate (203 mg, 0.96 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (27 mg, 0.14 mmol) and phenanthroline (52 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-21-3. HPLC-MS: [M+H] + =420.11 / 422.07 / 424.13.

[0129] (d) Intermediate M-21-3 (75 mg, 0.18 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (52 mg, 0.21 mmol), and diisopropylethylamine (295 μL, 1.78 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 ° C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, and the mixture was extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography to obtain ZB-S-99. HPLC-MS: [M + H] + =554.19 / 556.05.

[0130] Example 19 [ka]

[0131] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and 3-ethynyl imidazole [1,2-b] pyridazine (225 mg, 1.57 mmol) were dissolved in 30 mL of 1,4-dioxane / diisopropylamine (20 mL / 10 mL) mixed solvent, Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, the atmosphere was replaced with argon, and the reaction was carried out at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-22-1. HPLC-MS: [M+H] + =387.14 / 389.05. 1H NMR(400MHz,DMSO-d6) δ 8.74(dd,J=4.4,1.5Hz,1H),8.44(d,J=5.3Hz,1H),8.32(s,1H),8.29(dd,J=9.2,1.5Hz,1H),7.48(d,J=5.3Hz,1H),7 .43(dd,J=9.2,4.4Hz,2H),4.11(q,J=7.1Hz,2H),3.34(d,J=7.0Hz,2H),2.78(t,J=7.0Hz,2H),1.20(t,J=7.1Hz,3H).

[0132] (b) Intermediate M-22-1 (250 mg, 0.65 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (87 mg, 0.78 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated with an evaporator to obtain intermediate M-22-2. This was used in the next step without purification.

[0133] (c) Intermediate M-22-2 (187 mg, 0.58 mmol), 2-amino-3-bromo-6-chloropyrazine (100 mg, 0.48 mmol), and potassium phosphate (203 mg, 0.96 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (27 mg, 0.14 mmol) and phenanthroline (52 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-22-3. HPLC-MS: [M+H] + =414.01 / 416.12 / 418.06.

[0134] (d) Intermediate M-22-3 (75 mg, 0.18 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (52 mg, 0.21 mmol), and diisopropylethylamine (295 μL, 1.78 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 ° C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, and the mixture was extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography and purified using ZB-S-100. 1 H NMR(400MHz,DMSO-d6) δ 8.74(dd,J=4.5,1.6Hz,1H),8.33(s,1H),8.31-8.27(m,2H),7.68(s,1H),7.43(dd,J= 9.2,4.5Hz,1H),6.59(d,J=5.3Hz,1H),6.29(s,2H),4.12-4.01(m,1H),3.93-3.80(m, 2H),3.68(d,J=8.4Hz,1H),3.49(d,J=8.4Hz,1H),3.46-3.27(m,2H),2.92(d,J=5.1Hz ,1H),1.79-1.68(m,1H),1.68-1.57(m,1H),1.57-1.42(m,2H),1.08(d,J=6.3Hz,3H).

[0135] Example 20 [ka]

[0136] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and 4-ethynyl-3,5-dimethylisoxazole (191 mg, 1.57 mmol) were dissolved in 30 mL of 1,4-dioxane / diisopropylamine (20 mL / 10 mL) mixed solvent, and Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-23-1. HPLC-MS: [M+H] + =365.06 / 367.11.

[0137] (b) Intermediate M-23-1 (250 mg, 0.69 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (92 mg, 0.82 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated with an evaporator to obtain intermediate M-23-2. This was used in the next step without purification.

[0138] (c) Intermediate M-23-2 (174 mg, 0.58 mmol), 2-amino-3-bromo-6-chloropyrazine (100 mg, 0.48 mmol), and potassium phosphate (203 mg, 0.96 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (27 mg, 0.14 mmol) and phenanthroline (52 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-23-3. HPLC-MS: [M+H] + =371.05 / 393.11 / 395.04.

[0139] (d) Intermediate M-23-3 (75 mg, 0.19 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (52 mg, 0.23 mmol), and diisopropylethylamine (317 μL, 1.91 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 ° C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, and the mixture was extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography to obtain ZB-S-101. HPLC-MS: [M + H] + =526.24 / 528.17. 1 H NMR(400MHz,DMSO-d6) δ 8.25(d,J=5.2Hz,1H),7.67(s,1H),6.57(d,J=5.3Hz,1H),6.28(s,2H) ,4.14-4.03(m,1H),3.98-3.81(m,2H),3.70(d,J=8.5Hz,1H),3.51(d,J =8.5Hz,1H),3.43-3.23(m,2H),2.97(d,J=5.0Hz,1H),2.56(s,3H),2.33(s,3H),1.79-1.59(m,2H),1.59-1.42(m,2H),1.10(d,J=6.4Hz,3H).

[0140] Example 21 [ka]

[0141] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and N-acetyl-4-ethynylpiperidine (238 mg, 1.57 mmol) were dissolved in 30 mL of a mixed solvent of 1,4-dioxane / diisopropylamine (20 mL / 10 mL), and Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-24-1. HPLC-MS: [M+H] + =395.15 / 397.10. 1 H NMR(400MHz,chloroform-d) δ 8.29(d,J=5.4Hz,1H),7.02(d,J=5.3Hz,1H),4.19(q,J=7.1Hz,2H),3.86-3.78(m,1H),3.76-3.67(m,1H),3.66-3.57(m,1H),3.47-3.36 (m,1H),3.24(t,J=7.4Hz,2H),3.02(tt,J=7.2,4.1Hz,1H),2.73(t,J=7.4Hz,2H),2.10(s,3H),1.98-1.75(m,4H),1.28(t,J=7.1Hz,3H).

[0142] (b) Intermediate M-24-1 (250 mg, 0.69 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (85 mg, 0.76 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated with an evaporator to obtain intermediate M-24-2. This was used in the next step without purification.

[0143] (c) Intermediate M-24-2 (191 mg, 0.56 mmol), 2-amino-3-bromo-6-chloropyrazine (100 mg, 0.48 mmol), and potassium phosphate (203 mg, 0.96 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (27 mg, 0.14 mmol) and phenanthroline (52 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-24-3. HPLC-MS: [M+H] + =422.07 / 4244.12 / 426.03.

[0144] (d) Intermediate M-24-3 (80 mg, 0.19 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (52 mg, 0.23 mmol), and diisopropylethylamine (317 μL, 1.91 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 ° C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, and the mixture was extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography to obtain ZB-S-102. HPLC-MS: [M + H] + =556.31 / 558.25. 1 H NMR(400MHz,DMSO-d6) δ 8.18(d,J=5.2Hz,1H),7.65(s,1H),6.51(d,J=5.2Hz,1H),6.24(s,2H),4. 13-4.00(m,1H),3.92-3.75(m,3H),3.70-3.61(m,2H),3.48(d,J=8.5Hz,1 H),3.44-3.19(m,4H),3.05(tt,J=8.1,4.0Hz,1H),2.90(d,J=5.1Hz,1H), 2.01(s,3H),1.97-1.78(m,2H),1.77-1.41(m,6H),1.08(d,J=6.4Hz,3H).

[0145] Example 22 [ka]

[0146] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and 3-ethynyl-1-methyl-1H-pyrazole (167 mg, 1.57 mmol) were dissolved in 30 mL of 1,4-dioxane / diisopropylamine (20 mL / 10 mL) mixed solvent, and Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-25-1. HPLC-MS: [M+H] + =349.94 / 351.79. 1 H NMR(400MHz,chloroform-d) δ 8.33(d,J=5.3Hz,1H),7.34(d,J=2.3Hz,1H),7.03(d,J=5.3Hz,1H),6.55(d,J=2.3Hz,1H),4.18( q,J=7.1Hz,2H),3.93(s,3H),3.24(t,J=7.4Hz,2H),2.73(t,J=7.4Hz,2H),1.27(t,J=7.1Hz,3H).

[0147] (b) Intermediate M-25-1 (140 mg, 0.40 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (54 mg, 0.48 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated with an evaporator to obtain intermediate M-25-2. This was used in the next step without purification.

[0148] (c) Intermediate M-25-2 (116 mg, 0.40 mmol), 2-amino-3-bromo-6-chloropyrazine (70 mg, 0.33 mmol), and potassium phosphate (142 mg, 0.67 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (19 mg, 0.100 mmol) and phenanthroline (36 mg, 0.201 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-25-3. HPLC-MS: [M+H] + =377.01 / 378.97 / 381.10.

[0149] (d) Intermediate M-25-3 (65 mg, 0.17 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (50 mg, 0.21 mmol), and diisopropylethylamine (285 μL, 1.72 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 ° C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, and the mixture was extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography to obtain ZB-S-103. HPLC-MS: [M + H] + =511.15 / 513.06. 1 H NMR(400MHz,Methanol-d4) δ 8.15(d,J=5.3Hz,1H),7.67(d,J=2.3Hz,1H),7.61(s,1H),6.65(d,J=5.3 Hz,1H),6.60(d,J=2.3Hz,1H),4.23(qd,J=6.4,4.9Hz,1H),4.12-3.99(m, 2H),3.94(s,3H),3.86(d,J=8.7Hz,1H),3.71(d,J=8.7Hz,1H),3.44-3.2 3(m,2H),3.01(d,J=5.0Hz,1H),1.87-1.59(m,4H),1.22(d,J=6.4Hz,3H).

[0150] Example 23 [ka]

[0151] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and 3-ethynyl-1-isopropyl-1H-pyrazole (211 mg, 1.57 mmol) were dissolved in 30 mL of 1,4-dioxane / diisopropylamine (20 mL / 10 mL) mixed solvent, and Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-26-1. HPLC-MS: [M+H] + =378.12 / 380.06. 1 H NMR(400MHz,chloroform-d) δ 8.31(d,J=5.3Hz,1H),7.73(s,1H),7.71(s,1H),7.00(d,J=5.3Hz,1H),4.50(hept,J=6.7Hz,1H),4.19(q ,J=7.1Hz,2H),3.25(t,J=7.4Hz,2H),2.74(t,J=7.4Hz,2H),1.51(d,J=6.7Hz,6H),1.27(t,J=7.1Hz,3H).

[0152] (b) Intermediate M-26-1 (150 mg, 0.40 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (53 mg, 0.48 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated with an evaporator to obtain intermediate M-26-2. This was used in the next step without purification.

[0153] (c) Intermediate M-26-2 (127 mg, 0.40 mmol), 2-amino-3-bromo-6-chloropyrazine (70 mg, 0.33 mmol), and potassium phosphate (142 mg, 0.67 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (19 mg, 0.100 mmol) and phenanthroline (36 mg, 0.201 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-26-3. HPLC-MS: [M+H] + =405.06 / 407.12 / 409.02.

[0154] (d) Intermediate M-26-3 (80 mg, 0.20 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (48 mg, 0.24 mmol), and diisopropylethylamine (327 μL, 1.97 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 °C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, and the mixture was extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography to obtain ZB-S-104. HPLC-MS: [M + H] + =539.19 / 541.21. 1 H NMR(400MHz,DMSO-d6) δ 8.31(s,1H),8.22(d,J=5.3Hz,1H),7.80(s,1H),7.66(s,1H),6.51(d,J=5.3Hz,1H),6. 27(s,2H),4.54(hept,J=6.7Hz,1H),4.12-3.99(m,1H),3.92-3.76(m,2H),3.67(d,J=8. 4Hz,1H),3.48(d,J=8.4Hz,1H),3.45-3.21(m,2H),2.90(d,J=5.1Hz,1H),1.79-1.67(m, 1H),1.67-1.57(m,1H),1.56-1.45(m,2H),1.43(d,J=6.7Hz,6H),1.08(d,J=6.4Hz,3H).

[0155] Example 24 [ka]

[0156] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and 3-ethynyl-1-ethyl-1H-pyrazole (189 mg, 1.57 mmol) were dissolved in 30 mL of 1,4-dioxane / diisopropylamine (20 mL / 10 mL) mixed solvent, and Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-27-1. HPLC-MS: [M+H] + =364.01 / 366.12. 1 H NMR(400MHz,chloroform-d) δ 8.31(d,J=5.3Hz,1H),7.72(s,1H),7.68(s,1H),7.00(d,J=5.3Hz,1H),4.22-4.13(m,4H), 3.24(t,J=7.4Hz,2H),2.73(t,J=7.4Hz,2H),1.49(t,J=7.3Hz,3H),1.27(t,J=7.1Hz,3H).

[0157] (b) Intermediate M-27-1 (150 mg, 0.41 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (56 mg, 0.49 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated with an evaporator to obtain intermediate M-27-2. This was used in the next step without purification.

[0158] (c) Intermediate M-27-2 (127 mg, 0.40 mmol), 2-amino-3-bromo-6-chloropyrazine (70 mg, 0.33 mmol), and potassium phosphate (142 mg, 0.67 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (19 mg, 0.100 mmol) and phenanthroline (36 mg, 0.201 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-27-3. HPLC-MS: [M+H] + =391.03 / 393.12 / 395.03.

[0159] (d) Intermediate M-27-3 (80 mg, 0.20 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (50 mg, 0.25 mmol), and diisopropylethylamine (339 μL, 2.04 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 ° C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, and the mixture was extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography to obtain ZB-S-105. HPLC-MS: [M + H] + =525.31 / 527.22. 1 H NMR(400MHz,DMSO-d6) δ 8.28(s,1H),8.22(d,J=5.3Hz,1H),7.80(s,1H),7.66(s,1H),6.51(d,J=5.3Hz,1H),6. 27(s,2H),4.17(q,J=7.3Hz,2H),4.10-4.02(m,1H),3.92-3.76(m,2H),3.67(d,J=8.4H z,1H),3.48(d,J=8.4Hz,1H),3.45-3.26(m,2H),2.90(d,J=5.1Hz,1H),1.77-1.67(m,1 H),1.66-1.56(m,1H),1.56-1.41(m,2H),1.39(t,J=7.3Hz,3H),1.08(d,J=6.4Hz,3H).

[0160] Example 25 [ka]

[0161] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and 3-ethynyl-1-cyclopropyl-1H-pyrazole (208 mg, 1.57 mmol) were dissolved in 30 mL of 1,4-dioxane / diisopropylamine (20 mL / 10 mL) mixed solvent, and Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-28-1. HPLC-MS: [M+H] + =376.12 / 378.06. 1 H NMR(400MHz,chloroform-d) δ 8.31(d,J=5.3Hz,1H),7.73(s,1H),7.69(s,1H),7.00(d,J=5.3Hz,1H),4.18(q,J=7.1Hz,2H),3.60(tt,J=7.4,3.8 Hz,1H),3.24(t,J=7.4Hz,2H),2.73(t,J=7.4Hz,2H),1.27(t,J=7.1Hz,3H),1.16-1.09(m,2H),1.08-1.01(m,2H).

[0162] (b) Intermediate M-28-1 (150 mg, 0.40 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (54 mg, 0.48 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated with an evaporator to obtain intermediate M-28-2. This was used in the next step without purification.

[0163] (c) Intermediate M-28-2 (126 mg, 0.40 mmol), 2-amino-3-bromo-6-chloropyrazine (70 mg, 0.33 mmol), and potassium phosphate (142 mg, 0.67 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (19 mg, 0.100 mmol) and phenanthroline (36 mg, 0.201 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-28-3. HPLC-MS: [M+H] + =403.05 / 405.11 / 407.09.

[0164] (d) Intermediate M-28-3 (80 mg, 0.20 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (50 mg, 0.25 mmol), and diisopropylethylamine (329 μL, 2.04 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 ° C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, and the mixture was extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography to obtain ZB-S-106. HPLC-MS: [M + H] + =537.21 / 539.16. 1 H NMR(400MHz,DMSO-d6) δ 8.32(s,1H),8.22(d,J=5.3Hz,1H),7.79(s,1H),7.66(s,1H),6.52(d,J=5.3Hz ,1H),6.27(s,2H),4.13-4.00(m,1H),3.91-3.74(m,3H),3.66(d,J=8.4Hz,1H), 3.48(d,J=8.4Hz,1H),3.45-3.26(m,2H),2.89(d,J=5.1Hz,1H),1.79-1.68(m,1 H),1.68-1.56(m,1H),1.56-1.41(m,2H),1.12-1.04(m,5H),1.02-0.95(m,2H).

[0165] Example 26 [ka]

[0166] (a) Intermediate M-3-1 (400 mg, 1.43 mmol) and N-methanesulfonyl-4-ethynylpiperidine (260 mg) were dissolved in 30 mL of 1,4-dioxane / diisopropylamine (20 mL / 10 mL) mixed solvent, and Pd(OAc)2 (32 mg, 0.14 mmol), Xphos (136 mg, 0.29 mmol), and CuI (54 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-30-1. HPLC-MS: [M+H] + =431.1.

[0167] (b) Intermediate M-30-1 (250 mg) was dissolved in 15 mL of anhydrous tetrahydrofuran, purged with argon, potassium tert-butoxide (85 mg, 0.76 mmol) was added to the above system at room temperature, reacted for 1 h, and the solvent was evaporated with an evaporator to obtain intermediate M-30-2. This was used in the next step without purification.

[0168] (c) Intermediate M-30-2 (190 mg), 2-amino-3-bromo-6-chloropyrazine (100 mg, 0.48 mmol), and potassium phosphate (203 mg, 0.96 mmol) were dispersed in 15 mL of 1,4-dioxane, and CuI (27 mg, 0.14 mmol) and phenanthroline (52 mg, 0.29 mmol) were added to the above system, purged with argon, and reacted at 90°C for 5 hours. The reaction solution was concentrated, and the residue was isolated by column chromatography to obtain intermediate M-30-3.

[0169] (d) Intermediate M-30-3 (80 mg), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4,5]decane-4-amine hydrochloride (52 mg, 0.23 mmol), and diisopropylethylamine (317 μL, 1.91 mmol) were dissolved in 10 mL DMSO, purged with argon, and reacted at 120 ° C for 10 h. The reaction solution was cooled to room temperature, 30 mL of saturated saline was added, extracted three times with ethyl acetate (20 mL * 3), and the ethyl acetate layers were combined. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was isolated by column chromatography to obtain ZB-S-107. HPLC-MS: [M + H] + =592.2.

[0170] Biological activity evaluation Example 10: Phosphatase Activity Inhibition Assay (IC 50 Assay). (a) Positive reference SHP099 was prepared according to the reported literature (J Med Chem 2016, 59(17), 7773-82.). Positive reference TNO155 was prepared according to the reported literature (J Med Chem 2020, 63(22), 13578-13594.).

[0171] (b) 6,8-difluoro-4-methylumbelliferone phosphate (DiFMUP) was used as the reaction substrate, and the reaction mixture (60 mM 3,3-4-(2-hydroxyethyl)-1-piperazinylethanesulfonic acid (HEPES) pH = 7.2, 75 mM NaCl, 75 mM KCl, 1 mM EDTA, 0.05% ... Tween-20, 5 mM dithiothreitol (DTT)) were co-incubated for 30-60 min to activate SHP2, and DMSO (1% (V / V) or compounds (10 μM-0.1 nM) were added to the mixture, followed by incubation at room temperature for 20 min. DiFMUP (25 μM, total reaction volume 50 μL) was added to initiate the reaction, and the fluorescence intensity of the reaction solution was detected (excitation light 355 nm, emission light 460 nm) using an Envision multifunctional microplate reader (PerkinElmer). Three replicate wells were set for each dose. The fluorescence value of the control well (DMSO) was taken as 100%, and the IC of the compounds of the present invention on SHP2 enzyme activity was calculated. 50 is shown in Table 1.

[0172] [Table 1]

[0173] Example 11 Cell proliferation inhibition assay (IC 50 Assay). (a) SHP099 and TNO155 were used as positive references.

[0174] (b) MV4-11 cells (10,000 cells / well) were seeded in a 96-well culture plate with 100 μL / well medium (IMDM containing 10% fetal bovine serum (FBS) from Gibco). After 6 hours of culture, the compounds of the present invention set at different concentrations were added. On the third day, 20 μL of MTS reagent (each purchased from Promega) was added to each well, and the absorbance value was measured according to the reagent's instructions (Promega). IC of the compounds of the present invention for MV4-11 cell proliferation inhibition 50 The values ​​are shown in Table 2.

[0175] [Table 2]

[0176] From the above results, it can be seen that most of the compounds of the present invention have activity 40 to 100 times stronger than that of the positive compound SHP099 and 5 to 40 times stronger than that of the clinical compound TNO155.

[0177] Example 12 Cellular protein kinase (p-ERK) phosphorylation inhibition assay The inhibition of intracellular protein kinase (ERK) phosphorylation level of compounds was assayed by AlphaLISA method. As the first step, cells were treated with compounds. The compounds to be tested were first diluted 5-fold with 100% DMSO, and 9 concentration gradients were set up. Next, MIAPaca-2 cells were seeded in a 96-well plate at a density of 40,000 cells per well in a volume of 80 μL per well. Then, 20 μL of DMSO or different concentrations of the compounds to be tested were added to each well, and two replicate wells were set for each concentration, and the final concentration of DMSO was controlled at 0.5%. As the first step, cells were lysed. After cells were treated for 2 hours, the medium was removed, the cells were washed three times with HBSS solution, and 50 μl of the newly set lysis buffer was added to each well, shaken, and left at room temperature for 10 minutes. In the third step, phosphorylated extracellular signal-regulated kinase (p-ERK) was detected using AphaLISA SureFire® UltraTM p-ERK 1 / 2 (Thr202 / Tyr204) kit (Perkin Elmer, ALSU-PERK-A500). 10 μL of the above lysate was transferred to a 384-well plate (Perkin Elmer, 6005350), and the phosphorylation level of extracellular signal-regulated kinase in the sample was detected according to the product's instructions. The signal was read using the AlphaScreen detector of Envision multifunctional microplate reader (PerkinElmer). Three replicate wells were set for each dose. The fluorescence value of the control well (DMSO) was set as 100%, and the IC of the compound of the present invention on SHP2 enzyme activity was calculated. 50 The results are shown in Table 1. The inhibition percentage (%) was calculated by the following formula: inhibition percentage (%)=(1-p-ERK signal of compound-treated cells / p-ERK signal of DMSO-treated cells)*100.

[0178] Results: The following table shows the IC of some compounds of the present invention. 50 The values ​​were shown. [Table 3]

[0179] These results show that the intracellular protein kinase phosphorylation (p-ERK) inhibitory activity of the selected compounds was significantly stronger than that of the positive compound TNO155.

Claims

1. A compound represented by general formula I, a pharmacologically acceptable salt thereof, an enantiomer, a diastereomer, an atropisomer, a racemate, a solvate or an isotopically labeled compound thereof, 【Chemistry 1】 In formula I, R １ is hydrogen, -NH ２ , -OH, -CN, halogen, C １ -C ４ Alkyl group, C １ -C ４ Haloalkyl group, C ３ -C ６ cycloalkyl groups; R ２ is hydrogen, C １ -C １０ Alkyl group, C １ -C １０ Haloalkyl group, C ３ -C ８ Cycloalkyl group, 3-10 membered heterocyclic group, C ６ -C １０ aryl groups, and 5- to 10-membered heteroaryl groups; １ -C １０ Alkyl group, C １ -C １０ Haloalkyl group, C ３ -C ８ Cycloalkyl groups, 3-10 membered heterocycloalkyl groups, C ６ -C １０ The aryl group, the 5- to 10-membered heteroaryl group, further comprises 1 to 5 -NR １０ R １１ , -OR １０ , -CN, halogen, C １ -C １０ Alkyl group, C １ -C １０ Haloalkyl group, C ３ -C ８ Cycloalkyl groups, 3-10 membered heterocyclic groups, -C(=O)R １０ , -C(=O)OR １０ , -C(=O)NR １０ R １１ , -S(=O) ２ R １０ , -S(=O) ２ N.R. １０ R １１ , -NR １０ C(=O)R １１ R may be substituted with a substituent selected from the group consisting of １０ and R １１ are each independently hydrogen, C １ -C ４ Alkyl group, C ３ -C ７ cycloalkyl groups; R ３ But hydrogen, halogen, C １ -C ４ Alkyl group, C ３ -C ８ Cycloalkyl group, C １ -C ４ Alkoxy group, C １ -C ４ haloalkyl groups; R ４ａ , R ４ｂ , R ５ａ , R ５ｂ , R ６ａ , R ６ｂ , R ７ａ and R ７ｂ are each independently hydrogen, -NH ２ , —OH, halogen, carbonyl group, C １ -C ４ Alkyl group, C １ -C ４ Alkoxy group, C ３ -C ８ Cycloalkyl group and C １ -C ４ alkylamino groups; R ８ and R ９ each independently represents -NH ２ , -OH, -CN, -COOH, halogen, C １ -C ４ Alkyl group, C １ -C ４ Alkoxy group, C １ -C ４ alkylamino groups; １ -C ４ The alkyl group has 1 to 3 -NH ２ , -OH, -CN; Or, R ４ａ , R ４ｂ , R ５ａ , R ５ｂ , R ６ａ , R ６ｂ , R ７ａ , R ７ｂ and R ８ any two groups selected from the group consisting of: Or, R ８ and R ９ form a 3-7 membered saturated or unsaturated ring together with the carbon atom to which they are attached, and the 3-7 membered saturated or unsaturated ring is independently selected from 1 to 3 N, O, C(=O), S(=O) ｍ and m=1 or 2; and the saturated or unsaturated ring may contain 1 to 3 -NH ２ , -OH, -CN, halogen, C １ -C ４ Alkyl group, C １ -C ４ Alkoxy group, C １ -C ４ may be substituted with a substituent selected from the group consisting of alkylamino groups; p is 0 or 1; q is 0 or 1; X is S or absent; Y is CR １２ or N; R １２ is hydrogen, -NH ２ , -CN, halogen, C １ -C ４ Alkyl group, -OR １３ , C ３ -C ８ Cycloalkyl groups, 3-10 membered heterocyclic groups, -C(=O)R １３ , -C(=O)OR １３ , -C(=O)NR １３ R １４ , -S(=O) ２ N.R. １３ R １４ , -S(=O) ２ R １３ R is selected from the group consisting of １３ , R １４ are each independently hydrogen, C １ -C ４ Alkyl group, C ３ -C ６ cycloalkyl groups; Z １ But N or CR １５ and Z ２ But N or CR １６ and Z ３ But N or CR １７ and R １５ , R １６ , R １７ are each independently hydrogen, -CN, halogen, or -C(=O)R １８ , -C(=O)OR １８ , -C(=O)NR １８ R １９ , -NR １８ R １９ , -NR １８ C(=O)R １９ , -NR １８ C(=O)OR １９ , -OC(=O)R １８ , -OC(=O)NR １８ R １９ , -OR １８ , -S(=O) ２ N.R. １８ R １９ , -S(=O) ２ R １８ , C １ -C ４ Alkyl group, C ３ -C ８ Cycloalkyl group, 3-10 membered heterocyclic group, C ６ -C １０ aryl groups, and 5- to 10-membered heteroaryl groups; １８ , R １９ are each independently hydrogen, C １ -C ４ Alkyl group, C ３ -C ８ cycloalkyl groups; R １５ From R １９ The above C １ -C ４ Alkyl group, C ３ -C ８ Cycloalkyl group, R １５ From R １７ The 3- to 10-membered heterocyclic group in ６ -C １０ The aryl group, the 5- to 10-membered heteroaryl group, further comprises 1 to 3 independently -NH ２ , -OH, -CN, halogen, C １ -C ４ Alkyl group, C ３ -C ６ Cycloalkyl group, C １ -C ４ may be substituted with a substituent selected from the group consisting of alkoxy groups; A compound, a pharmacologically acceptable salt thereof, an enantiomer, a diastereomer, an atropisomer, a racemate, a solvate or an isotopically labeled compound.

2. The compound represented by the general formula I is selected from the group consisting of compounds represented by the formula Ia: 【Chemistry 2】 In formula Ia, R １ is hydrogen, -NH ２ , C １ -C ４ Alkyl group, C １ -C ４ haloalkyl groups; R ２ is hydrogen, C １ -C １０ Alkyl group, C １ -C １０ Haloalkyl group, C ３ -C ８ Cycloalkyl group, 3-10 membered heterocyclic group, C ６ -C １０ aryl groups, and 5- to 10-membered heteroaryl groups; １ -C １０ Alkyl group, C １ -C １０ Haloalkyl group, C ３ -C ８ Cycloalkyl groups, 3-10 membered heterocycloalkyl groups, C ６ -C １０ The aryl group, the 5- to 10-membered heteroaryl group, further comprises 1 to 5 -NR １０ R １１ , -OR １０ , -CN, halogen, C １ -C １０ Alkyl group, C １ -C １０ Haloalkyl group, C ３ -C ８ Cycloalkyl groups, 3-10 membered heterocyclic groups, -C(=O)R １０ , -C(=O)OR １０ , -C(=O)NR １０ R １１ , -S(=O) ２ R １０ , -S(=O) ２ N.R. １０ R １１ , -NR １０ C(=O)R １１ R may be substituted with a substituent selected from the group consisting of １０ and R １１ are each independently hydrogen, C １ -C ４ Alkyl group, C ３ -C ７ cycloalkyl groups; R ３ is hydrogen, C １ -C ４ selected from the group consisting of alkyl groups and halogens; R ４ａ , R ４ｂ , R ５ａ , R ５ｂ , R ６ａ , R ６ｂ , R ７ａ and R ７ｂ are each independently hydrogen, -NH ２ , —OH, halogen, carbonyl group, C １ -C ４ Alkyl group, C １ -C ４ Alkoxy group, C ３ -C ８ Cycloalkyl group and C １ -C ４ alkylamino groups; R ８ and R ９ each independently represents -NH ２ , -OH, -CN, -COOH, halogen, C １ -C ４ Alkyl group, C １ -C ４ Alkoxy group, C １ -C ４ alkylamino groups; １ -C ４ The alkyl group has 1 to 3 -NH ２ , -OH, -CN; Or, R ８ and R ９ form a 3-7 membered saturated or unsaturated ring together with the carbon atom to which they are attached, and the 3-7 membered saturated or unsaturated ring is independently selected from 1 to 3 N, O, C(=O), S(=O) ｍ and m=1 or 2; and the saturated or unsaturated ring may contain 1 to 3 -NH ２ , -OH, -CN, halogen, C １ -C ４ Alkyl group, C １ -C ４ Alkoxy group, C １ -C ４ may be substituted with a substituent selected from the group consisting of alkylamino groups; p is 0 or 1; q is 0 or 1; Y is CR １２ or N; R １２ is hydrogen, -NH ２ , -CN, halogen, C １ -C ４ Alkyl group, -OR １３ , C ３ -C ８ Cycloalkyl groups, 3-10 membered heterocyclic groups, -C(=O)R １３ , -C(=O)OR １３ , -C(=O)NR １３ R １４ , -S(=O) ２ N.R. １３ R １４ , -S(=O) ２ R １３ R is selected from the group consisting of １３ , R １４ are each independently hydrogen, C １ -C ４ Alkyl group, C ３ -C ６ cycloalkyl groups; Z １ But N or CR １５ and Z ２ But N or CR １６ and Z ３ But N or CR １７ and R １５ , R １６ , R １７ are each independently hydrogen, -CN, halogen, C １ -C ４ Alkyl group, C ３ -C ８ Cycloalkyl group, 3-10 membered heterocyclic group, C ６ -C １０ aryl groups, and 5- to 10-membered heteroaryl groups; １ -C ４ Alkyl group, C ３ -C ８ Cycloalkyl group, 3-10 membered heterocyclic group, C ６ -C １０ The aryl group, the 5- to 10-membered heteroaryl group, further comprises 1 to 3 independently -NH ２ , -OH, -CN, halogen, C １ -C ４ Alkyl group, C ３ -C ６ Cycloalkyl group, C １ -C ４ may be substituted with a substituent selected from the group consisting of alkoxy groups; 2. The compound according to claim 1, or a pharmacologically acceptable salt, enantiomer, diastereomer, atropisomer, racemate, solvate or isotope-labeled compound thereof.

3. The compound represented by the general formula I is selected from the group consisting of compounds represented by the formula Ib: 【Chemistry 3】 In formula Ib, R １ is hydrogen, -NH ２ , methyl, and trifluoromethyl; R ２ is hydrogen, C １ -C １０ Alkyl group, C １ -C １０ Haloalkyl group, C ３ -C ８ Cycloalkyl group, 3-10 membered heterocyclic group, C ６ -C １０ aryl groups, and 5- to 10-membered heteroaryl groups; １ -C １０ Alkyl group, C １ -C １０ Haloalkyl group, C ３ -C ８ Cycloalkyl groups, 3-10 membered heterocycloalkyl groups, C ６ -C １０ The aryl group, the 5- to 10-membered heteroaryl group, further comprises 1 to 5 -NR １０ R １１ , -OR １０ , -CN, halogen, C １ -C １０ Alkyl group, C １ -C １０ Haloalkyl group, C ３ -C ８ Cycloalkyl groups, 3-10 membered heterocyclic groups, -C(=O)R １０ , -C(=O)OR １０ , -C(=O)NR １０ R １１ , -S(=O) ２ R １０ , -S(=O) ２ N.R. １０ R １１ , -NR １０ C(=O)R １１ R may be substituted with a substituent selected from the group consisting of １０ and R １１ are each independently hydrogen, C １ -C ４ alkyl groups; R ４ａ , R ４ｂ , R ５ａ , R ５ｂ , R ６ａ , R ６ｂ , R ７ａ and R ７ｂ are each independently hydrogen, -NH ２ , —OH, halogen, carbonyl group, C １ -C ４ Alkyl group, C １ -C ４ Alkoxy group, C ３ -C ８ Cycloalkyl group and C １ -C ４ alkylamino groups; R ８ and R ９ each independently represents -NH ２ , -OH, -CN, -COOH, halogen, C １ -C ４ Alkyl group, C １ -C ４ Alkoxy group, C １ -C ４ alkylamino groups; １ -C ４ The alkyl group has 1 to 3 -NH ２ , -OH, -CN; Or, R ８ and R ９ form a 3-7 membered saturated or unsaturated ring together with the carbon atom to which they are attached, and the 3-7 membered saturated or unsaturated ring is independently selected from 1 to 3 N, O, C(=O), S(=O) ｍ and m=1 or 2; and the saturated or unsaturated ring may contain 1 to 3 -NH ２ , -OH, -CN, halogen, C １ -C ４ Alkyl group, C １ -C ４ Alkoxy group, C １ -C ４ may be substituted with a substituent selected from the group consisting of alkylamino groups; Y is CR １２ or N; R １２ is selected from the group consisting of hydrogen, —CN, and halogen; Z １ But N or CR １５ and R １５ is hydrogen, -CN, halogen, C １ -C ４ Alkyl group, C ３ -C ８ Cycloalkyl group, 3-10 membered heterocyclic group, C ６ -C １０ aryl groups, and 5- to 10-membered heteroaryl groups; １ -C ４ Alkyl group, C ３ -C ８ Cycloalkyl group, 3-10 membered heterocyclic group, C ６ -C １０ The aryl group, the 5- to 10-membered heteroaryl group, further comprises 1 to 3 independently -NH ２ , -OH, -CN, halogen, C １ -C ４ Alkyl group, C ３ -C ６ Cycloalkyl group, C １ -C ４ may be substituted with a substituent selected from the group consisting of alkoxy groups; 2. The compound according to claim 1, or a pharmacologically acceptable salt, enantiomer, diastereomer, atropisomer, racemate, solvate or isotope-labeled compound thereof.

4. The compound represented by the general formula I is selected from the group consisting of compounds represented by the formula Ic: 【Chemistry 4】 In formula Ic, R １ is hydrogen, -NH ２ Selected from the group consisting of: R ２ is hydrogen, C １ -C １０ Alkyl group, C ３ -C ８ Cycloalkyl group, 3-10 membered heterocyclic group, C ６ -C １０ aryl groups, and 5- to 10-membered heteroaryl groups; １ -C １０ Alkyl group, C ３ -C ８ Cycloalkyl groups, 3-10 membered heterocycloalkyl groups, C ６ -C １０ The aryl group, the 5- to 10-membered heteroaryl group, further comprises 1 to 5 -NR １０ R １１ , -OR １０ , -CN, halogen, C １ -C ３ Alkyl group, C ３ -C ６ Cycloalkyl group, -C(=O)R １０ , -C(=O)OR １０ , -C(=O)NR １０ R １１ , -S(=O) ２ R １０ , -S(=O) ２ N.R. １０ R １１ , -NR １０ C(=O)R １１ R may be substituted with a substituent selected from the group consisting of １０ and R １１ are each independently hydrogen, C １ -C ４ alkyl groups; R ８ and R ９ each independently represents -NH ２ , -OH, -CN, -COOH, halogen, C １ -C ４ Alkyl group, C １ -C ４ Alkoxy group, C １ -C ４ alkylamino groups; １ -C ４ The alkyl group has 1 to 3 -NH ２ , -OH; Or, R ８ and R ９ form a 3-7 membered saturated or unsaturated ring together with the carbon atom to which they are attached, and the 3-7 membered saturated or unsaturated ring is independently selected from 1 to 3 N, O, C(=O), S(=O) ｍ and m=1 or 2; and the saturated or unsaturated ring may contain 1 to 3 -NH ２ , -OH, C １ -C ４ Alkyl group, C １ -C ４ Alkoxy group, C １ -C ４ may be substituted with a substituent selected from the group consisting of an alkylamino group and a halogen; Y is CH or N; Z １ But N or CR １５ and R １５ is hydrogen, -CN, C １ -C ４ Alkyl group, C ３ -C ８ cycloalkyl groups, and 3- to 10-membered heterocyclic groups; 2. The compound according to claim 1, or a pharmacologically acceptable salt, enantiomer, diastereomer, atropisomer, racemate, solvate or isotope-labeled compound thereof.

5. The compound represented by the general formula I is selected from the group consisting of compounds represented by the formula Id: 【Chemistry 5】 In formula Id, R ２ is hydrogen, C １ -C １０ Alkyl group, C ３ -C ８ Cycloalkyl group, 3-10 membered heterocyclic group, C ６ -C １０ aryl groups, and 5- to 10-membered heteroaryl groups; １ -C １０ Alkyl group, C ３ -C ８ Cycloalkyl groups, 3-10 membered heterocycloalkyl groups, C ６ -C １０ The aryl group and the 5- to 10-membered heteroaryl group further comprise one or two -NR １０ R １１ , -OR １０ , -CN, halogen, C １ -C ３ Alkyl group, C ３ -C ６ Cycloalkyl group, -C(=O)R １０ , -C(=O)OR １０ , -C(=O)NR １０ R １１ , -S(=O) ２ R １０ , -S(=O) ２ N.R. １０ R １１ , -NR １０ C(=O)R １１ R may be substituted with a substituent selected from the group consisting of １０ and R １１ are each independently hydrogen, C １ -C ４ alkyl groups; Z １ But N or CR １５ and R １５ is hydrogen, -CN, C １ -C ４ Alkyl group, C ３ -C ８ cycloalkyl groups, and 3- to 10-membered heterocyclic groups; V, 【Chemistry 6】 That is, 2. The compound according to claim 1, or a pharmacologically acceptable salt, enantiomer, diastereomer, atropisomer, racemate, solvate or isotope-labeled compound thereof.

6. The compound represented by the general formula I is selected from the group consisting of compounds represented by the formula Ie: 【Chemistry 7】 In formula Ie, R ２ But, C １ -C １０ Alkyl group, C ３ -C ８ Cycloalkyl group, 3-10 membered heterocyclic group, C ６ -C １０ aryl groups, and 5- to 10-membered heteroaryl groups; １ -C １０ Alkyl group, C ３ -C ８ Cycloalkyl groups, 3-10 membered heterocycloalkyl groups, C ６ -C １０ The aryl group, the 5- to 10-membered heteroaryl group may further comprise 1 to 2 halogens, C １ -C ３ Alkyl group, C ３ -C ６ may be substituted with a substituent selected from the group consisting of cycloalkyl groups; Z １ But N or CR １５ Selected from the group consisting of: R １５ is hydrogen, C １ -C ４ Alkyl group, C ３ -C ８ cycloalkyl groups, 2. The compound according to claim 1, or a pharmacologically acceptable salt, enantiomer, diastereomer, atropisomer, racemate, solvate or isotope-labeled compound thereof.

7. The compound represented by the general formula I is selected from the group consisting of the following compounds: 【Chemistry 8-1】 【Chemistry 8-2】 2. The compound according to claim 1, or a pharmacologically acceptable salt, enantiomer, diastereomer, atropisomer, racemate, solvate or isotope-labeled compound thereof.

8. A pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of the compound according to any one of claims 1 to 7, its pharmacologically acceptable salt, enantiomer, diastereomer, atropisomer, racemate, solvate, and isotope-labeled compound, and a pharmacologically acceptable carrier.

9. Use of a compound according to any one of claims 1 to 7, a pharmacologically acceptable salt, enantiomer, diastereomer, atropisomer, racemate, solvate or isotopically labeled compound thereof, or a pharmaceutical composition according to claim 8, in the manufacture of a medicament for treating a disease, condition or disease state mediated by SHP2.

10. The use according to claim 9, wherein the disease or condition or disease state is selected from the group consisting of Noonan syndrome, Leopard syndrome, leukemia, neuroblastoma, liver cancer, medulloblastoma, squamous cell carcinoma of the head and neck, melanoma, breast cancer, esophageal cancer, head and neck tumors, gastric cancer, lung cancer, colon cancer, anaplastic large cell lymphoma, glioblastoma and reproductive system tumors.

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