Spirocyclic compounds and uses thereof

Abstract

Provided is a class of compounds represented by formula (I), or prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof. The compounds have SHP2 kinase inhibitory effects and can be used to treat and / or prevent diseases, disorders and conditions mediated by SHP2 activity, such as tumors, cancer, cancer metastasis, cardiovascular diseases, immune disorders or visual disorders.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the rights and priority of Chinese invention patent applications No. 202110557549.0 and No. 202111000088.3 filed with the State Intellectual Property Office of the People's Republic of China on May 21, 2021 and August 27, 2021, respectively, the entire contents of which are hereby incorporated by reference into this application in their entirety. Technical Field

[0003] The present application relates to the field of medical technology, and in particular, to a class of novel compounds having SHP2 inhibitory activity and their use in treating and preventing diseases, disorders and conditions mediated by SHP2 activity, such as hyperproliferative diseases. Background Art

[0004] SHP2 (Src homology-2domain) is encoded by protein tyrosine phosphatase nonreceptor type 11 (PTP nonreceptor 11, PTPN11) and catalyzes protein tyrosine dephosphorylation reactions. It is generally believed that the N-terminus of SHP2 contains two SH2 domains, including N-src homology 2 domain (SH2) and C-SH2, and the C-terminus contains a catalytic PTP domain. In the unactivated state, SHP2 is in an autoinhibitory state, and N-SH2 and C-PTP bind to each other to inhibit phosphatase activity. In the presence of extracellular stimuli, they bind to related receptors and activate multiple downstream signaling pathways, such as Ras / MAPK, PI3K / AKT and other signal transduction pathways, regulating cell proliferation, differentiation, apoptosis and survival.

[0005] Literature has revealed (Eur J Med Genet. 2015.58:509; WO2018013597) that germline mutations of PTPN11 and SHP2 have been associated with a variety of human diseases, such as Noonan syndrome (NS), Leopard Syndrome, and a variety of malignant tumors (leukemia, etc.). Revolution Medicines' research has also shown that SHP2 plays an important role in the carcinogenic growth and survival signals of some common cancers.

[0006] In addition, studies have shown (Sci Adv. 2020, 6(5):eaay4458) that programmed death 1 (PD-1) is also involved in mediating and activating SHP2. In cancer, PD-1 inhibits T cell stimulation and mediates immune escape. After stimulation, PD-1 is phosphorylated at its immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM), then binds to SHP2 and initiates T cell inactivation. Therefore, SHP2 inhibitors can stimulate adaptive and innate immune activity in the tumor microenvironment and have the potential to restore anti-tumor immune responses that have been silenced by cancer cells.

[0007] In view of the above, there is a great need for compounds that are useful as SHP2 inhibitors for the treatment and prevention of diseases, disorders and conditions mediated through SHP2 activity. Summary of the invention

[0008] The present application provides a class of SHP2 inhibitor compounds with novel structures, and also provides the use of such compounds or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof for treating diseases, disorders and conditions mediated by SHP2 activity.

[0009] In one aspect, the present application provides a compound represented by formula (I), or a prodrug, tautomer, stereoisomer, solvate, isotope derivative or a pharmaceutically acceptable salt thereof, which has the following structure:

[0010]

[0011] in,

[0012] X is selected from O, CH 2 , NH or S;

[0013] L is selected from N or CH;

[0014] G is selected from a bond or S;

[0015] A is selected from CH or N;

[0016] R 3 are independently selected from: optionally substituted 8-12 membered heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted 5-14 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, -COOH, -COCH 3 、-COOCH 3 、-CONH 2 , C 1-6 Alkyl, C 1-6Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 substituted by a substituent of an aryl group or a 5-12-membered heteroaryl group;

[0017] R 1 are independently selected from hydrogen, deuterium or amino;

[0018] R 2 are independently selected from hydrogen, halogen, cyano, -CONH 2 、-COR 5 、-COOR 5 , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, wherein R 5 are independently selected from hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C 6-10 Aryl, optionally substituted 5-10 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable sites of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0019] Y is independently selected from N or CR 4 ;

[0020] R 4 are independently selected from hydrogen, halogen, hydroxy, amino, cyano, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable positions of the substituted group are independently selected from halogen, hydroxyl, amino, cyano, C 1～6 Alkyl, C 1-6 Alkoxy substituted;

[0021] R 6 independently selected from hydrogen or deuterium;

[0022] The "oxo group" refers to two H groups at the same substitution position being replaced by the same O group to form a double bond;

[0023] The heteroatoms in the heterocycloalkyl group, heteroaryl group and heterocyclic group are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0024] In one embodiment of the present application, a compound represented by formula (I), or a prodrug, tautomer, stereoisomer, solvate, isotope derivative or a pharmaceutically acceptable salt thereof is provided, which has the following structure:

[0025]

[0026] in,

[0027] X is selected from O, CH 2 , NH or S;

[0028] L is selected from N or CH;

[0029] G is selected from a bond or S;

[0030] A is selected from CH or N;

[0031] R 3 It is amino group;

[0032] R 1 are independently selected from hydrogen, amino or deuterium;

[0033] R 2 independently selected from halogen, cyano, -CONH 2 、-COR 5 、-COOR 5 , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, wherein R 5 are independently selected from hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C 6-10 Aryl, optionally substituted 5-10 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable sites of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0034] Y is independently selected from N or CR 4 ;

[0035] R 4 are independently selected from hydrogen, halogen, hydroxy, amino, cyano, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6Alkoxy, the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently selected from halogen, hydroxyl, amino, cyano, C 1～6 Alkyl, C 1-6 Alkoxy substituted;

[0036] R 6 independently selected from hydrogen or deuterium;

[0037] The "oxo group" refers to two H groups at the same substitution position being replaced by the same O group to form a double bond;

[0038] The heteroatoms in the heterocycloalkyl group, heteroaryl group and heterocyclic group are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0039] In another embodiment of the present application, a compound represented by formula (I), or a prodrug, tautomer, stereoisomer, solvate, isotope derivative or a pharmaceutically acceptable salt thereof is provided, which has the following structure:

[0040]

[0041] in,

[0042] X is selected from O, CH 2 , NH or S;

[0043] L is selected from N or CH;

[0044] G is selected from a bond or S;

[0045] A is selected from CH or N;

[0046] R 3 are independently selected from: amino, optionally substituted 8-12 membered heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted 5-14 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, -COOH, -COCH 3 、-COOCH 3 、-CONH 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 substituted by a substituent of an aryl group or a 5-12-membered heteroaryl group;

[0047] R 1 are independently selected from hydrogen, deuterium or amino;

[0048] R 2 are independently selected from hydrogen, halogen, cyano, -CONH 2 、-COR 5 、-COOR 5 , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, wherein R 5 are independently selected from hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C 6-10 Aryl, optionally substituted 5-10 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable sites of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0049] Y is independently selected from N or CR 4 ;

[0050] R 4 are independently selected from hydrogen, halogen, hydroxy, amino, cyano, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, cyano, C 1～6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0051] R 6 independently selected from hydrogen or deuterium;

[0052] The "oxo group" refers to two H groups at the same substitution position being replaced by the same O group to form a double bond;

[0053] The heteroatoms in the heterocycloalkyl group, heteroaryl group and heterocyclic group are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0054] In yet another embodiment of the present application, R 6 For deuterium.

[0055] In another embodiment of the present application, a compound represented by formula (I-1), or a prodrug, tautomer, stereoisomer, solvate, isotope derivative or a pharmaceutically acceptable salt thereof is provided, which has the following structure:

[0056]

[0057] in,

[0058] X is selected from O, CH 2 , NH or S;

[0059] L is selected from N or CH;

[0060] G is selected from a bond or S;

[0061] A is selected from CH or N;

[0062] R 3 are independently selected from optionally substituted 8-12 membered heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted 5-14 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable sites of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, -COOH, -COCH 3 、-COOCH 3 、-CONH 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 substituted by a substituent of an aryl group or a 5-12-membered heteroaryl group;

[0063] R 1 are independently selected from hydrogen, deuterium or amino;

[0064] R 2 are independently selected from hydrogen, halogen, cyano, -CONH 2 、-COR 5 、-COOR 5 , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, wherein R 5 are independently selected from hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C 6-10Aryl, optionally substituted 5-10 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable sites of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0065] Y is independently selected from N or CR 4 ;

[0066] R 4 are independently selected from hydrogen, halogen, hydroxy, amino, cyano, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, cyano, C 1～6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0067] The "oxo group" refers to two H groups at the same substitution position being replaced by the same O group to form a double bond;

[0068] The heteroatoms in the above heterocycloalkyl, heteroaryl and heterocyclic groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4;

[0069] Where the compound is not:

[0070]

[0071] In another embodiment of the present application, a compound having a structure as shown in formula (I-1-1), or a prodrug, tautomer, stereoisomer, solvate, isotope derivative or a pharmaceutically acceptable salt thereof is provided.

[0072]

[0073] Among them, G, A, Y, R 1 , R 2 , R 3 The definitions of X and L are the same as those of the compound represented by formula (I) or formula (I-1) above in this application.

[0074] In certain embodiments of the present application, provided are compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1), or prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein the R 3 It is amino.

[0075] In certain embodiments of the present application, provided are compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1), or prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein the R 3 are independently selected from: optionally substituted 8-12 membered heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted 5-14 membered heteroaryl.

[0076] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 3 are independently selected from: optionally substituted 8-12 membered bicyclic heterocyclic group, optionally substituted C 6-10 Aryl, optionally substituted 5-14 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, -COOH, -COCH 3 、-COOCH 3 、-CONH 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 The aryl group or the 5- to 12-membered heteroaryl group may be substituted by a substituent of the aryl group or the 5- to 12-membered heteroaryl group.

[0077] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 3 are independently selected from optionally substituted 8-10 membered bicyclic heterocyclic groups, optionally substituted C 6-8 Aryl, optionally substituted 5-10 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, -COOH, -COCH 3 、-COOCH 3 、-CONH 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 The aryl group or the 5- to 12-membered heteroaryl group may be substituted by a substituent of the aryl group or the 5- to 12-membered heteroaryl group.

[0078] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 3are independently selected from optionally substituted 8-10 membered bicyclic heterocyclic groups, optionally substituted C 6-8 Aryl, optionally substituted 5-10 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, oxo, cyano, -CONH 2 , C 1-6 The alkyl group is substituted with an alkyl substituent.

[0079] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 3 are independently selected from optionally substituted 10-membered bicyclic heterocyclyl, optionally substituted C 6-8 Aryl, optionally substituted 5-10 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from hydroxyl, oxo, cyano, -CONH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl substituents, wherein the heteroatoms in the heterocyclic group and the heteroaryl group are independently selected from O, N or S, and the number of heteroatoms is 1, 2 or 3.

[0080] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 3 are independently selected from optionally substituted C 6-8 Aryl, optionally substituted 5-6 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, oxo, cyano, -CONH 2 , C 1-6 The heteroaryl group is substituted by a substituent of an alkyl group, wherein the heteroatoms in the heteroaryl group are independently selected from O, N or S, and the number of heteroatoms is 1 or 2.

[0081] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 3 independently selected from optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substitutable positions of the substituted group is independently selected from cyano, -CONH 2 , methyl substituents, wherein the heteroatoms in the heteroaryl group are independently selected from O, N or S, and the number of heteroatoms is 1 or 2.

[0082] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 3 Independently selected from: optionally substituted C 6-10 Aryl, optionally substituted 5-14 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, -COOH, -COCH 3 、-COOCH 3 、-CONH 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 The aryl group or the 5- to 12-membered heteroaryl group may be substituted by a substituent of the aryl group or the 5- to 12-membered heteroaryl group.

[0083] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 3 independently selected from optionally substituted 5-10 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, oxo, cyano, -CONH 2 , C 1-6 The alkyl group is substituted with an alkyl substituent.

[0084] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 3 independently selected from optionally substituted 5-6 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, cyano, -CONH 2 , C 1-6 The heteroaryl group is substituted by a substituent of an alkyl group, wherein the heteroatoms in the heteroaryl group are independently selected from O, N or S, and the number of heteroatoms is 1 or 2.

[0085] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 3 independently selected from optionally substituted 5-6 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, cyano, -CONH 2 , C 1-3The heteroaryl group is substituted by a substituent of an alkyl group, wherein the heteroatoms in the heteroaryl group are independently selected from O, N or S, and the number of heteroatoms is 1 or 2.

[0086] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 3 independently selected from optionally substituted 5-membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from hydroxyl, cyano, -CONH 2 , methyl substituents, wherein the heteroatoms in the heteroaryl group are independently selected from O, N or S, and the number of heteroatoms is 1 or 2.

[0087] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 3 Independently selected from the following optionally substituted structures:

[0088]

[0089] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 3 Independently selected from the following optionally substituted structures:

[0090]

[0091] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 3 Independently selected from the following optionally substituted structures:

[0092]

[0093] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 3 are independently selected from amino, optionally substituted

[0094] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 3 Independently selected from optionally substituted

[0095] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), the compound of formula (I-1-1) 3Independently selected from the following structures:

[0096]

[0097] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 3 Independently selected from the following structures:

[0098]

[0099] In certain embodiments of the present application, provided are compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1)) or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof, wherein R 2 independently selected from halogen, cyano, -CONH 2 、-COR 5 、-COOR 5 , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, wherein R 5 are independently selected from hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C 6-10 Aryl, optionally substituted 5-10 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable sites of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted with an alkoxy substituent.

[0100] In certain embodiments of the present application, provided are compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1)) or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof, wherein R 2 are independently selected from hydrogen, halogen, cyano, -CONH 2 、-COR 5 、-COOR 5 , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 3-10Cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxy, amino, nitro, oxo, cyano, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted with an alkoxy substituent.

[0101] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 2 are independently selected from hydrogen, halogen, cyano, -CONH 2 、-COR 5 、-COOR 5 , optionally substituted C 1-4 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted with an alkoxy substituent.

[0102] In certain specific embodiments of the present application, in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1), R 2 independently selected from halogen, cyano, -CONH 2 、-COR 5 、-COOR 5 , is selected from hydroxyl, C 1-6 C substituted with one or more substituents of alkoxy and halogen 1-4 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl.

[0103] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 2 independently selected from halogen, cyano, -CONH 2 、-COR 5 、-COOR 5 , hydroxy substituted C 1-4 Alkyl, C 2-6 Alkenyl, C 3-6 In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), the compound of formula (I-1-1)2 are independently selected from halogen, -COR 5 、-COOR 5 , hydroxy substituted C 1-4 Alkyl, C 2-6 alkenyl or 3-6 membered heterocycloalkyl; or, R 2 are independently selected from halogen, -COR 5 、-COOR 5 , C 2-6 alkenyl or 3-6 membered heterocycloalkyl; or, R 2 Independently selected from -COR 5 or -COOR 5 or, R 2 For-COR 5 or R 2 -COOR 5 , wherein preferably, R 5 C 3-6 Cycloalkyl or C 1-6 Alkyl, preferably C 3-4 Cycloalkyl or C 1-3 Alkyl, such as cyclopropyl, methyl; or, R 2 Independently selected from -CO(C 1-6 alkyl); or, R 2 Independently selected from -CO(C 1-3 alkyl).

[0104] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 5 are independently selected from hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted with an alkoxy substituent.

[0105] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 5 are independently selected from hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable sites of the substituted group is independently selected from halogen, hydroxyl, amino, C 1-6The alkyl group is substituted with an alkyl substituent.

[0106] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 5 are independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; further, R 5 Independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl; or R 5 Independently selected from C 1-3 An alkyl group, such as a methyl group.

[0107] In certain embodiments of the present application, provided are compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1), or prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein R 2 independently selected from halogen, cyano, -CONH 2 、-CO-(C 1-3 alkyl), -CO-(C 3-6 Cycloalkyl), -COO-(C 1-3 Alkyl), -COO-(C 3-6 Cycloalkyl), -CH 2 OH, -CH 2 CH 2 OH, -CH(OH)CH 3 , C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl.

[0108] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 2 are independently selected from halogen, -CO-(C 1-3 alkyl), -CO-(C 3-6 Cycloalkyl), -COO-(C 1-3 Alkyl), -COO-(C 3-6 Cycloalkyl), -CH 2 OH, C 2-4 Alkenyl, 3-6 membered heterocycloalkyl.

[0109] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 2 independently selected from halogen, -C(O)CH 3 、-C(O)-(cyclopropane), -C(O)OCH3 、-C(O)O-(cyclopropane)、-CH 2 OH, vinyl, oxetane.

[0110] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 2 are independently selected from hydrogen, fluorine, -C(O)CH 3 、-C(O)OCH 3 、-CH 2 OH, -CH=CH 2 ,

[0111] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 2 independently selected from fluorine, -C(O)CH 3 、-C(O)OCH 3 、-CH=CH 2 ,

[0112] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 2 Independently selected from -C(O)CH 3 or -C(O)OCH 3 .

[0113] In certain embodiments of the present application, R in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) 2 -C(O)CH 3 .

[0114] In certain preferred embodiments of the present application, there is provided a compound of formula (I), a compound of formula (I-1), a compound of formula (I-1-1), or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein R 1 are independently selected from hydrogen, amino; preferably, R 1 are independently selected from amino groups.

[0115] In one embodiment of the present application, a compound having a structure shown in formula (I-2) or a prodrug, tautomer, stereoisomer, solvate, isotope derivative or a pharmaceutically acceptable salt thereof is provided.

[0116]

[0117] Among them, R 1Independently selected from deuterium or amino, preferably amino;

[0118] R 2 are independently selected from cyano, -CONH 2 、-COR 5 、-COOR 5 , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, wherein R 5 are independently selected from hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C 6-10 Aryl, optionally substituted 5-10 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable sites of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0119] R 6 is hydrogen or deuterium, preferably deuterium;

[0120] X, L, G, A, and Y are as defined in the compound of formula (I) or formula (I-1) above.

[0121] In one embodiment of the present application, a compound as shown in formula (I-2) or a prodrug, tautomer, stereoisomer, solvate, isotope derivative or a pharmaceutically acceptable salt thereof is provided, wherein R 2 are independently selected from hydrogen, halogen, cyano, -CONH 2 、-COR 5 、-COOR 5 , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxy, amino, nitro, oxo, cyano, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted with an alkoxy substituent.

[0122] In one embodiment of the present application, R in the compound represented by formula (I-2) 2are independently selected from cyano, -CONH 2 、-COR 5 、-COOR 5 , optionally substituted C 1-4 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted with an alkoxy substituent.

[0123] In another embodiment of the present application, R in the compound represented by formula (I-2) 2 are independently selected from cyano, -CONH 2 、-COR 5 、-COOR 5 , hydroxy substituted C 1-4 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl.

[0124] In another embodiment of the present application, R in the compound of the structure represented by formula (I-2) or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof 2 are independently selected from cyano, -CONH 2 、-COR 5 、-COOR 5 , unsubstituted C 2-6 Alkyl, substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxy, amino, nitro, oxo, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; or

[0125] R 2 are independently selected from cyano, -CONH 2 、-COR 5 、-COOR 5 , substituted C 1-6 Alkyl, optionally substituted C 2-6Alkenyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; or

[0126] R 2 are independently selected from cyano, -CONH 2 、-COR 5 、-COOR 5 , is selected from hydroxyl, halogen and C 1 -C 3 One or more substituents in the alkoxy group replace the C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; or

[0127] When R 1 When it is deuterium, R 2 Selected from -CO-(C 3-6 Cycloalkyl), -COOR 5 , optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxy, amino, nitro, oxo, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; or

[0128] When R 1 When it is deuterium, R 2 Selected from -CO-(C 3-6 Cycloalkyl), -COOR 5 , optionally substituted C 2-6 Alkenyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; or

[0129] When R 1 When it is deuterium, R 2Selected from -CO-(C 3-6 Cycloalkyl), -COOR 5 , C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl.

[0130] In one embodiment of the compound of the structure represented by formula (I-2) of the present application, when R 1 When it is deuterium, R 2 It may be a halogen.

[0131] In certain embodiments of the present application, in the compound having the structure shown in formula (I-2) or its prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt, R 1 It can be hydrogen; R 2 are independently selected from halogen, -CO-(C 3 -C 6 Cycloalkyl), -COOR 5 , optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxy, amino, nitro, oxo, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; or

[0132] R 1 It can be hydrogen; R 2 are independently selected from halogen, -CO-(C 3 -C 6 Cycloalkyl), -COOR 5 , optionally substituted C 2-6 Alkenyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; or

[0133] R 1 It can be hydrogen; R 2 are independently selected from halogen, -CO-(C 3 -C 6 Cycloalkyl), -COOR 5 , C 2-6Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl.

[0134] In one embodiment of the present application, R in the compound represented by the above formula (I-2) 5 are independently selected from hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted with an alkoxy substituent.

[0135] In one embodiment of the present application, R in the compound represented by the above formula (I-2) 5 are independently selected from hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, amino, C 1-6 The alkyl group is substituted with an alkyl substituent.

[0136] In one embodiment of the present application, R in the compound represented by the above formula (I-2) 5 are independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl.

[0137] In one embodiment of the present application, R in the compound represented by the above formula (I-2) 5 Independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl; or R 5 C 1-3 Alkyl; or R 5 C 3-6 Cycloalkyl.

[0138] In one embodiment of the present application, a compound as shown in formula (I-2) or a prodrug, tautomer, stereoisomer, solvate, isotope derivative or a pharmaceutically acceptable salt thereof is provided, wherein R 2 are independently selected from cyano, -CONH 2 、-CO-(C 1-3 alkyl), -CO-(C 3-6 Cycloalkyl), -COO-(C 1-3Alkyl), -COO-(C 3-6 Cycloalkyl), -CH 2 OH, -CH 2 CH 2 OH, -CH(OH)CH 3 , C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl;

[0139] Preferably, R 2 Independently selected from -CO-(C 1-3 alkyl), -CO-(C 3-6 Cycloalkyl), -COO-(C 1-3 Alkyl), -COO-(C 3-6 Cycloalkyl), -CH 2 OH, C 2-4 Alkenyl, 3-6 membered heterocycloalkyl;

[0140] More preferably, R 2 Independently selected from -C(O)CH 3 、-C(O)-(cyclopropane), -C(O)OCH 3 、-C(O)O-(cyclopropane)、-CH 2 OH, vinyl, oxetane;

[0141] More preferably, R 2 Independently selected from -C(O)CH 3 、-C(O)OCH 3 、-CH 2 OH, -CH=CH 2 ,

[0142] More preferably, R 2 Independently selected from -C(O)CH 3 、-C(O)OCH 3 、-CH=CH 2 ,

[0143] In one embodiment of the present application, a compound as shown in formula (I-2) or a prodrug, tautomer, stereoisomer, solvate, isotope derivative or a pharmaceutically acceptable salt thereof is provided, wherein R 2 Independently selected from -CO-(C 1-6 Alkyl), -COO-(C 1-6 alkyl);

[0144] Preferably, R 2 Independently selected from -CO-(C 1-3Alkyl), -COO-(C 1-3 alkyl);

[0145] More preferably, R 2 Independently selected from -C(O)CH 3 、-C(O)OCH 3 ;

[0146] More preferably, R 2 Independently selected from -C(O)CH 3 .

[0147] In one embodiment of the present application, a compound as shown in formula (I-2) or a prodrug, tautomer, stereoisomer, solvate, isotope derivative or a pharmaceutically acceptable salt thereof is provided, wherein L is selected from CH, and X is selected from O;

[0148] Preferably, L is selected from CH, X is selected from O, and G is selected from S.

[0149] In one embodiment of the present application, a compound as shown in formula (I-2) or a prodrug, tautomer, stereoisomer, solvate, isotope derivative or a pharmaceutically acceptable salt thereof is provided, wherein R 1 are independently selected from amino, R 2 Independently selected from -CO-(C 1-6 Alkyl), -COO-(C 1-6 alkyl), L is selected from CH, and X is selected from O.

[0150] In one embodiment of the present application, a compound as shown in formula (I-2) or a prodrug, tautomer, stereoisomer, solvate, isotope derivative or a pharmaceutically acceptable salt thereof is provided, wherein R 1 are independently selected from amino, R 2 Independently selected from -CO-(C 1-6 Alkyl), -COO-(C 1-6 alkyl), L is selected from CH, R 6 are independently selected from deuterium;

[0151] Preferably, R 1 are independently selected from amino, R 2 Independently selected from -CO-(C 1-3 Alkyl), -COO-(C 1-3 Alkyl), R 6 is selected from deuterium, L is selected from CH, X is selected from O, and G is selected from S.

[0152] In certain embodiments of the present application, provided are compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1), compounds of formula (I-2), or prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein X is selected from O or CH 2 ; Preferably, X is selected from O.

[0153] In certain embodiments of the present application, provided are compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1), compounds of formula (I-2), or prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein the compounds have a structure as shown in formula (IA), (IB), (I-1-A), (I-1-B), (I-2-A), or (I-2-B):

[0154]

[0155] Among them, L, G, A, Y, R 1 , R 2 , R 3 , R 6 The definition is the same as that of the compound represented by formula (I), formula (I-1) or formula (I-2) in the present application.

[0156] In certain embodiments of the present application, provided are compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1), compounds of formula (I-2), or prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein L is selected from CH.

[0157] In certain embodiments of the present application, provided is a compound (compound of formula (I), compound of formula (I-1), compound of formula (I-1-1), compound of formula (I-2)) or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative or a pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (I-A1), (I-1-A1) or (I-2-A1):

[0158]

[0159]

[0160] Among them, G, A, Y, R 1 , R 2 , R 3 , R 6 The definition is the same as that of the compound represented by formula (I), formula (I-1) or formula (I-2) in the present application.

[0161] In certain embodiments of the present application, the compound has a structure as shown in formula (I-A2), (I-A3), (I-2-A2) or (I-2-A3):

[0162]

[0163] Among them, G, A, Y, R 1 , R 2 , R 3 The definition is the same as that of the compound represented by formula (I), formula (I-1) or formula (I-2) in the present application.

[0164] In certain embodiments of the present application, provided are compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1), compounds of formula (I-2), or prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein the compound has a structure as shown in formula (I-Ba):

[0165]

[0166] Among them, G, A, Y, R 1 , R 2 , R 3 The definition is the same as that of the compound represented by formula (I), formula (I-1) or formula (I-2) in the present application.

[0167] In certain embodiments of the present application, provided is a compound (a compound of formula (I), a compound of formula (I-1), a compound of formula (I-1-1), a compound of formula (I-2)) or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (I-B1), formula (I-1-B1) or formula (I-2-B1):

[0168]

[0169] Among them, G, A, Y, R 2 , R 3 , R 6 The definition is the same as that of the compound represented by formula (I), formula (I-1) or formula (I-2) in the present application.

[0170] In certain embodiments of the present application, the compound has a structure as shown in formula (I-B2), (I-B3), formula (I-2-B2) or formula (I-2-B3):

[0171]

[0172] Among them, G, A, Y, R2 , R 3 The definition is the same as that of the compound represented by formula (I), formula (I-1) or formula (I-2) in the present application.

[0173] In certain embodiments of the present application, provided are compounds (compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1), compounds of formula (I-2), compounds of formula (I-A1), compounds of formula (I-1-A1), compounds of formula (I-2-A1), compounds of formula (I-A2), compounds of formula (I-A3), compounds of formula (I-2-A2), compounds of formula (I-2-A3), compounds of formula (I-B1), compounds of formula (I-1-B1), compounds of formula (I-2-B1) ) compound, formula (I-B2) compound, formula (I-B3) compound, formula (I-2-B2) compound, formula (I-2-B3) compound, formula (IA) compound, formula (IB) compound, formula (I-1-A) compound, formula (I-1-B) compound, formula (I-2-A) compound, formula (I-2-B) compound, formula (I-Ba) compound) or its prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt, wherein G is selected from S.

[0174] In certain embodiments of the present application, provided are compounds (compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1), compounds of formula (I-2), compounds of formula (I-A1), compounds of formula (I-1-A1), compounds of formula (I-2-A1), compounds of formula (I-A2), compounds of formula (I-A3), compounds of formula (I-2-A2), compounds of formula (I-2-A3), compounds of formula (I-B1), compounds of formula (I-1-B1), compounds of formula (I-2-B1) ) compound, compound of formula (I-B2), compound of formula (I-B3), compound of formula (I-2-B2), compound of formula (I-2-B3), compound of formula (IA), compound of formula (IB), compound of formula (I-1-A), compound of formula (I-1-B), compound of formula (I-2-A), compound of formula (I-2-B), compound of formula (I-Ba)) or its prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein A is selected from CH.

[0175] In certain embodiments of the present application, provided are compounds (compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1), compounds of formula (I-2), compounds of formula (I-A1), compounds of formula (I-1-A1), compounds of formula (I-2-A1), compounds of formula (I-A2), compounds of formula (I-A3), compounds of formula (I-2-A2), compounds of formula (I-2-A3), compounds of formula (I-B1), compounds of formula (I-1-B1), compounds of formula (I-2-B1) ) compound, compound of formula (I-B2), compound of formula (I-B3), compound of formula (I-2-B2), compound of formula (I-2-B3), compound of formula (IA), compound of formula (IB), compound of formula (I-1-A), compound of formula (I-1-B), compound of formula (I-2-A), compound of formula (I-2-B), compound of formula (I-Ba)) or its prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein A is selected from N.

[0176] In certain embodiments of the present application, provided are compounds (compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1), compounds of formula (I-2), compounds of formula (I-A1), compounds of formula (I-1-A1), compounds of formula (I-2-A1), compounds of formula (I-A2), compounds of formula (I-A3), compounds of formula (I-2-A2), compounds of formula (I-2-A3), compounds of formula (I-B1), compounds of formula (I-1-B1), compounds of formula (I-2-B1) ) compound, formula (I-B2) compound, formula (I-B3) compound, formula (I-2-B2) compound, formula (I-2-B3) compound, formula (IA) compound, formula (IB) compound, formula (I-1-A) compound, formula (I-1-B) compound, formula (I-2-A) compound, formula (I-2-B) compound, formula (I-Ba) compound) or its prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt, wherein Y is selected from CR 4 ; or A is CH and Y is CR 4 ; or A is N and Y is CR 4 ; or A is N and Y is N.

[0177] In certain embodiments of the present application, provided are compounds (compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1), compounds of formula (I-2), compounds of formula (I-A1), compounds of formula (I-1-A1), compounds of formula (I-2-A1), compounds of formula (I-A2), compounds of formula (I-A3), compounds of formula (I-2-A2), compounds of formula (I-2-A3), compounds of formula (I-B1), compounds of formula (I-1-B1), compounds of formula (I-2- B1) compound, (I-B2) compound, (I-B3) compound, (I-2-B2) compound, (I-2-B3) compound, (IA) compound, (IB) compound, (I-1-A) compound, (I-1-B) compound, (I-2-A) compound, (I-2-B) compound, (I-Ba) compound) or its prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt, wherein R 4 are independently selected from hydrogen, halogen, hydroxy, amino, cyano, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substitutable sites of the substituted group is independently replaced by a substituent selected from halogen, hydroxyl, and amino.

[0178] In one embodiment of the present application, wherein R 4 are independently selected from hydrogen, halogen, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino; further preferably, wherein R 4 are independently selected from hydrogen, fluorine, chlorine, amino, cyano, methyl, methoxy; further preferably, wherein R 4 Selected from chlorine.

[0179] In one embodiment of the present application, X in the compound of formula (I) is selected from O or CH 2 ; L is CH; G is S; A is selected from CH or N; R 3 are independently selected from: amino, optionally substituted 8-12 membered heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted 5-14 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from hydroxyl, oxo, cyano, -CONH 2 or C 1-6 Alkyl is substituted by a substituent; R 1 R is independently selected from hydrogen, deuterium, and amino; 2 Independently selected fromhalogen 、-COR 5 、-COOR 5 , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted 3-10 membered heterocycloalkyl; wherein R 5 Independently selected from unsubstituted C 1-6 Alkyl or unsubstituted C 3-6 Cycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, C 1-6 Alkoxy is substituted by a substituent; Y is independently selected from N or CR 4 ; R 4 is halogen; R 6 are independently selected from hydrogen, deuterium; or

[0180] X is selected from O or CH 2 ; L is CH; G is S; A is selected from CH or N; R 3 are independently selected from: amino, optionally substituted 8-10 membered bicyclic heterocyclic group, optionally substituted C 6 or C 10 Aryl, optionally substituted 5-6 membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from hydroxyl, oxo, cyano, -CONH 2 or C 1-6 Alkyl is substituted by a substituent; R 1 R is independently selected from hydrogen, deuterium, and amino; 2 Independently selected from halogen 、-COR 5 、-COOR 5 , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted 3-6 membered heterocycloalkyl; wherein R 5 Independently selected from unsubstituted C 1-6 Alkyl or unsubstituted C 3-6 Cycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, C 1-6 Alkoxy is substituted by a substituent; Y is independently selected from N or CR 4 ; R 4 is halogen; R 6 are independently selected from hydrogen or deuterium; or

[0181] X is selected from O or CH 2; L is CH; G is S; A is selected from CH or N; R 3 Independently selected from: amino, C 1-6 alkyl optionally substituted 5-6 membered heteroaryl; R 1 R is independently selected from hydrogen, deuterium, and amino; 2 are independently selected from halogen, -COR 5 、-COOR 5 , optionally substituted C 2-6 alkenyl, optionally substituted 3-6 membered heterocycloalkyl; wherein R 5 Independently selected from unsubstituted C 1-6 Alkyl or unsubstituted C 3-6 Cycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from halogen, hydroxyl, C 1-6 Alkoxy is substituted by a substituent; Y is independently selected from N or CR 4 ; R 4 is halogen; R 6 are independently selected from hydrogen, deuterium; or

[0182] X is selected from O or CH 2 ; L is CH; G is S; A is selected from CH or N; R 3 Independently selected from: amino, C 1-6 alkyl optionally substituted 5-6 membered heteroaryl; R 1 R is independently selected from hydrogen, deuterium, and amino; 2 are independently selected from halogen, -COR 5 、-COOR 5 , unsubstituted C 2-6 alkenyl, unsubstituted 3-6 membered heterocycloalkyl; wherein R 5 Independently selected from unsubstituted C 1-6 Alkyl or unsubstituted C 3-6 Cycloalkyl; Y is independently selected from N or CR 4 ; R 4 is halogen; R 6 are independently selected from hydrogen, deuterium; or

[0183] X is selected from O or CH 2 ; L is CH; G is S; A is selected from CH or N; R 3 Independently selected from: amino, C 1-4 alkyl optionally substituted 5-membered heteroaryl; R 1 R is independently selected from hydrogen, deuterium, and amino; 2 Independently selected from -COR 5 or -COOR 5 ; Among them, R 5 Independently selected from unsubstituted C1-4 Alkyl or unsubstituted C 3-6 Cycloalkyl; Y is independently selected from N or CR 4 ; R 4 is halogen, such as Cl or F, preferably Cl; R 6 are independently selected from hydrogen, deuterium; or

[0184] X is selected from O or CH 2 ; L is CH; G is S; when A is CH, Y is CR 4 ; R 4 is halogen, such as Cl or F, preferably Cl; or when A is N, Y is independently selected from N or CR 4 ; R 4 is halogen, such as Cl or F, preferably Cl; R 3 Independently selected from: amino, C 1-2 alkyl (eg, methyl) optionally substituted 5-membered heteroaryl; R 1 R is independently selected from hydrogen, deuterium, and amino; 2 Independently selected from -COR 5 or -COOR 5 ; Among them, R 5 Independently selected from unsubstituted C 1-2 Alkyl (eg, methyl) or unsubstituted C 3-4 Cycloalkyl (eg, cyclopropyl); R 6 are independently selected from hydrogen or deuterium.

[0185] In certain embodiments of the present application, the compounds of formula (I), formula (I-1), formula (I-1-1), formula (I-2), formula (I-A1), formula (I-1-A1), formula (I-2-A1), formula (I-A2), formula (I-A3), formula (I-2-A2), formula (I-2-A3), formula (I-B1), formula (I-1-B1), formula (I-2-B1), formula (I-B2), formula (I-B3), formula (I-2-B2), formula (I-2-B3), formula (IA), formula (IB), formula (I-1-A), formula (I-1-B), formula (I-2-A), formula (I-2-B), and formula (I-Ba) described above do not include the following compounds:

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193] On the other hand, the present application provides a compound represented by formula (II), or a prodrug, tautomer, stereoisomer, solvate, isotope derivative or a pharmaceutically acceptable salt thereof, which has the following structure:

[0194]

[0195] in,

[0196] Each R 1 are independently selected from hydrogen, deuterium, halogen, -NH 2 、-NHR a 、-N(R a ) 2 、-CN、-OH、-NO 2 , oxo, =O, carboxyl, -C(O)-NH 2 、-C(O)-NHR a 、-C(O)R a 、-C(O)OR a , C 2-6 Alkenyl, C 2-6 Alkynyl, -C(O)-C(O)OR a -C 1-6 Alkoxy, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-10 Cycloalkyl, -C 1-6 Alkylene-N(R a 2. -C 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-C(O)-OR a , -C 1-6 Alkylene-(3-10 membered heterocyclic group), -C 1-6 Alkylene-(5-10 membered heteroaryl), -C 1-6 Alkylene-C(O)-N(R a ) 2 , -C 1-6 Alkylene-NR a -C(O)-N(R a ) 2 , -C 1-6Alkylene-NR a -C(O)-C 1-6 Alkyl, -C(O)-N(R a ) 2 、-C(O)-C(O)-N(R a 2. -C 3-10 carbocyclic group, -5-10 membered heteroaryl, -3-10 membered heterocyclic group, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl, -C(O)-C 6-14 Aryl, -C(O)-C 5-10 Heteroaryl, -C(O)OC 1-6 Alkyl, -C(O)-C 1-6 Alkylene-N(R a )2. -C(O)-NR a -(3-10 membered heterocyclyl), -C(O)-NR a -(3-10 membered heterocyclyl), -C(O)-(3-10 membered heterocyclyl), -OC 1-6 Alkylene-C(O)-OR a 、-OC 1-6 Alkylene-C(O)-N(R a ) 2 、-OC 1-6 Alkylene-N(R a ) 2 、-OC 3-10 Carbocyclic group, -O-(3-10 membered heterocyclic group), -NR a -C(O)-C 1-6 Alkyl, -NR a -C(O)-N(R a ) 2 、-NR a -C(O)-(5-10 membered heteroaryl), -NR a -C(O)-(5-10 membered heterocyclic group), -NR a -C(O)-C 3-8 Cycloalkyl, -NR a -C 1-6 Alkylene-N(R a ) 2 、-NR a -C 1-6 Alkylene-(3-10 membered heterocyclic group), -NR a -C 1-6 Alkylene-(5-10 membered heteroaryl), -NR a -SO 2 C 1-6 Alkyl, -SC 1-6Alkyl, -SON(R a ) 2 、-SO 2 N(R a ) 2 、-SO-C 1-6 Alkyl, -SO 2 -C 1-6 Alkyl, -PO(C 1-6 alkyl) 2 ,-PO(C 1-6 Alkoxy) 2 , -3-10 membered heterocyclyl, -5-14 membered aryl or -5-14 membered heteroaryl, each group independently optionally substituted;

[0197] Or two adjacent R 1 Cyclization to form C 6-10 aryl, 5-10 membered heteroaryl, 3-10 membered carbocyclyl or 3-10 membered heterocyclyl, each of which is independently optionally substituted;

[0198] or two adjacent R a are connected together to form a 5-14 membered aromatic ring, a 5-14 membered heteroaromatic ring, a 5-14 membered heterocyclic ring or a 5-14 membered carbocyclic ring, and each of the ring systems is independently optionally substituted;

[0199] Each R a are independently selected from hydrogen, deuterium, halogen, -NH 2 、-CN、-OH、-NO 2 , carboxyl, -C 1-6 Alkoxy, -C 1-6 alkyl, each group independently optionally substituted;

[0200] R 3 for deuterium;

[0201] R 2 Selected from: hydrogen, deuterium, halogen, -NH 2 、-CN、-OH、-NO 2 、-COOH、-NH-C 1-6 Alkyl, -N(C1-6 alkyl) 2 , -C 1-6 Alkoxy or -C 1-6 alkyl, and each group independently is optionally substituted or unsubstituted;

[0202] Each R 4 and R 5 are independently selected from hydrogen, deuterium, halogen, -NH 2 、-CN、-OH、-NO 2 、-COOH、-NH-C 1-6 Alkyl, -N(C1-6 alkyl) 2 , -C 1-6 Alkoxy or -C 1-6 alkyl, each group independently being optionally substituted or unsubstituted; or

[0203] R 4 and R 5 Together with the carbon atoms to which they are commonly attached, they form a 3-14 membered carbocyclic ring, a 3-14 membered heterocyclic ring, a 5-14 membered aromatic ring, a 5-14 membered heteroaromatic ring or C=NRb, and each of the ring systems is independently optionally substituted or unsubstituted;

[0204] W does not exist, -CH 2 -、-CH(R b )-、-C(R b ) 2 -、-C(O)-、-NH-、-NR b -or-O-;

[0205] Y is C, CH, -C(R b )-or N;

[0206] When Y is CH, -C(R b )- or N, its adjacent is a single bond; or when Y is C, its adjacent is a double bond;

[0207] Each R b are independently selected from hydrogen, deuterium, halogen, -NH 2 、-CN、-OH、-C 1-6 Alkoxy or -C 1-6 alkyl, and each group independently is optionally substituted or unsubstituted;

[0208] A is selected from: unsubstituted or optionally substituted with one or more R 1 substituted aryl, heteroaryl, cycloalkyl, and heterocyclyl groups;

[0209] B is selected from: unsubstituted or optionally substituted with one or more R 1 substituted aryl, heteroaryl, cycloalkyl, and heterocyclyl groups;

[0210] C is absent, unsubstituted or optionally replaced by one or more R 1 substituted aryl, heteroaryl, cycloalkyl, and heterocyclyl groups;

[0211] When C does not exist, Y 1 and Y 2 Each independently selected from -C(R 1 ) 2 -、-C(R d )2 -、-NR d -、-NR 1 - and O; when In When it represents a single bond, Y 1 Yes-C(R 1 ) 2 -、-C(R d ) 2 -、-NR d -、-NR 1 - or O, and Y 2 Yes-C(R 1 ) 2 -、-C(R d ) 2 -、-NR d -、-NR 1 - or O; or, when In When Y represents a double bond, 1 Yes CR 1 , CR d or N, and Y 2 Yes CR 1 , CR d or N;

[0212] When C is an aromatic ring, a heteroaromatic ring, a cycloalkyl ring or a heterocycloalkyl ring; when In When it represents a single bond, Y 1 Yes CR d , CR 1 or N, and Y 2 Yes CR d or N; or, when In When Y represents a double bond, 1 is C, and Y 2 It is C;

[0213] Each L 1 and L 2 Independently selected from: covalent bond, -S-, -S(O)-, -S(O) 2 -、-O-、-C(O)-、-CO-NR d -、-NR d -、-NR d -C(O)-、-NR d -C(O)-NR d -、-C(O)O-、-NR d SO 2 -、-C(R d ) 2 -、-SO 2NR d -and

[0214] Each R d are independently selected from hydrogen, deuterium, halogen, -NH 2 、-CN、-OH、-NO 2 , -COOH, -CO-C 1-6 Alkyl, -COO-C 1-6 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkoxy, -C 1-6 Alkoxy or -C 1-6 alkyl, and each group independently is optionally substituted or unsubstituted;

[0215] --- indicates whether the key exists or not; and

[0216] i)---Indicates that when the key does not exist, X does not exist either;

[0217] ii) --- indicates that a bond exists, X is CH 2 ;

[0218] Each m, n and q are independently selected from 0, 1, 2, 3 or 4; when m is 0, W is directly connected with Y 2 connected;

[0219] The above substitutions are independently selected from -OH, halogen, unsubstituted C 1-6 Alkyl, -NH 2 、-NO 2 , unsubstituted -COC 1-6 Alkyl, -CN, =O, -COOH, -COCH 3 -、-COOCH 3 -、-CONH 2 , unsubstituted C 3-10 Cycloalkyl, unsubstituted -NH-C 1-6 Alkyl, unsubstituted -N(C 1-6 Alkyl)(C 1-6 Alkyl), unsubstituted -NH-C 3-6 Cycloalkyl, unsubstituted -N(C 3-6 Cycloalkyl)(C 3-6 cycloalkyl), unsubstituted 3-10 membered heterocycloalkyl, unsubstituted C 6-14 one or more substituents in an aryl or unsubstituted 5-12 membered heteroaryl group;

[0220] The substituent "oxo" or "=O" means that two hydrogen atoms at the same substitution position are replaced by oxygen atoms;

[0221] The heteroatoms in the above heterocycloalkyl, heteroaryl and heterocyclic group are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0222] In one embodiment of the present application, in the compound represented by formula (II), A is an optionally substituted or unsubstituted 3-14-membered cycloalkyl, 3-14-membered heterocycloalkyl, 5-14-membered aryl or 5-14-membered heteroaryl; preferably an optionally substituted or unsubstituted 5-12-membered cycloalkyl, 5-12-membered heterocycloalkyl, 5-12-membered aryl or 5-12-membered heteroaryl; further preferably an optionally substituted or unsubstituted 6-10-membered cycloalkyl, 6-10-membered heterocycloalkyl, 6-10-membered aryl or 6-10-membered heteroaryl; further preferably an optionally substituted or unsubstituted 6-10-membered aryl or 6-10-membered heteroaryl; further preferably an optionally substituted or unsubstituted 6-10-membered aryl or 6-10-membered heteroaryl; Substituted or unsubstituted phenyl, 8-10 membered polycyclic aryl, 5-6 membered monocyclic heteroaryl or 8-10 membered polycyclic heteroaryl; further preferably optionally substituted or unsubstituted phenyl, 8-10 membered fused ring aryl, 8-10 membered bridged ring aryl, 8-10 membered spirocyclic aryl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused ring heteroaryl, 8-10 membered bridged ring heteroaryl or 8-10 membered spirocyclic heteroaryl; further preferably optionally substituted or unsubstituted phenyl, 8-10 membered fused ring aryl, 5-6 membered monocyclic heteroaryl or 8-10 membered fused ring heteroaryl; wherein each of the above heteroaryl or heterocycle contains 1, 2 or 3 heteroatoms independently selected from N, O or S;

[0223] Further preferably, A is selected from the following optionally substituted or unsubstituted groups:

[0224]

[0225] Further preferably, A is selected from the following optionally substituted or unsubstituted groups:

[0226]

[0227] Further preferably, A is selected from the following optionally substituted or unsubstituted groups:

[0228]

[0229] Further preferably, A is selected from the following optionally substituted or unsubstituted groups:

[0230]

[0231] wherein the substitution is by one or more R 1 replace;

[0232] Indicates that L 2 are connected.

[0233] In one embodiment of the compound represented by formula (II) of the present application, the L 2 Selected from: covalent bond, -S-, -S(O)-, -S(O) 2 -、-O-、-C(O)-、-NR d -and-C(R d ) 2 -; preferably a covalent bond, -S-, -O- and -NR d -; further preferably a covalent bond and -S-.

[0234] In one embodiment of the compound represented by formula (II) of the present application, B is an optionally substituted or unsubstituted 3-14-membered cycloalkyl, 3-14-membered heterocycloalkyl, 5-14-membered aryl or 5-14-membered heteroaryl; preferably an optionally substituted or unsubstituted 5-12-membered cycloalkyl, 5-12-membered heterocycloalkyl, 5-12-membered aryl or 5-12-membered heteroaryl; further preferably an optionally substituted or unsubstituted 6-10-membered cycloalkyl, 6-10-membered heterocycloalkyl, 6-10-membered aryl or 6-10-membered heteroaryl; further preferably an optionally substituted or unsubstituted 6-10-membered aryl or 6-10-membered heteroaryl; further preferably an optionally substituted or unsubstituted phenyl, 8-10 membered polycyclic aryl, 5-6 membered monocyclic heteroaryl or 8-10 membered polycyclic heteroaryl; further preferably optionally substituted or unsubstituted phenyl, 8-10 membered fused ring aryl, 8-10 membered bridged ring aryl, 8-10 membered spirocyclic aryl, 5-6 membered monocyclic heteroaryl, 8-10 membered fused ring heteroaryl, 8-10 membered bridged ring heteroaryl or 8-10 membered spirocyclic heteroaryl; further preferably optionally substituted or unsubstituted phenyl, 8-10 membered fused ring aryl, 5-6 membered monocyclic heteroaryl or 8-10 membered fused ring heteroaryl; wherein each of the above heteroaryl or heterocycle contains 1, 2 or 3 heteroatoms independently selected from N, O or S;

[0235] Further preferably, B is selected from the following optionally substituted or unsubstituted groups:

[0236]

[0237] in,

[0238] Each Y 3 Each independently selected from C(R 1 ) 2 , CR 1 NR 1 , N, S and O;

[0239] Each Y 4 Each independently selected from CR 1 and NR 1 ;

[0240] when When it represents a single bond, Y 3 is C(R 1 ) 2 NR 1 , S and O, and Y 4 Yes CR 1 or N; or, when

[0241] When Y represents a double bond, 3 Yes CR 1 or N, and Y 4 It is C;

[0242] wherein the substitution is by one or more R 1 replace;

[0243] Indicates that L 1 and L 2 are connected.

[0244] In one embodiment of the compound represented by formula (II) of the present application, B is selected from a monocyclic ring such as substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted thiazole, substituted or unsubstituted pyridone, substituted or unsubstituted pyrimidone, substituted or unsubstituted pyridazinone, or the like; or a binary or ternary cyclic or condensed ring system formed by a substituted or unsubstituted pyridine ring, pyrazine ring, pyridazine ring, pyrimidine ring, thiazole ring, pyridone ring, pyrimidone ring, pyridazinone ring, or the like and a substituted or unsubstituted imidazole, substituted or unsubstituted triazole, substituted or unsubstituted pyrazole, substituted or unsubstituted indazole, substituted or unsubstituted oxazole, or the like;

[0245] Preferably, B is selected from the following optionally substituted or unsubstituted groups:

[0246]

[0247] Further preferably, B is selected from the following optionally substituted or unsubstituted groups:

[0248]

[0249] More preferably

[0250] wherein the substitution is by one or more R 1 replace.

[0251] In one embodiment of the compound represented by formula (II) of the present application, the L 1 Selected from: covalent bond, -S(O) 2 -、-CO-NR d -、-NR d-C(O)-, -C(O)O-, -NR d SO 2 -、-SO 2 NR d -and Preferably, it is a covalent bond, -S(O) 2 -、-CO-NR d -or-NR d -C(O)-; more preferably a covalent bond.

[0252] In one embodiment of the compound represented by formula (II) of the present application, Y is CH or N, and is a single bond; preferably N, and For a single key.

[0253] In one embodiment of the compound represented by formula (II) of the present application, W is -CH 2 -、-CH(R b )-、-C(R b ) 2 - or -O-; preferably -CH 2 -or-O-.

[0254] In one embodiment of the compound represented by formula (II) of the present application, the ring C is absent, unsubstituted or optionally replaced by one or more R 1 substituted 5-14-membered aryl, 5-14-membered heteroaryl, 5-14-membered carbocyclyl or 5-14-membered heterocyclyl; preferably, the ring C is absent, unsubstituted or optionally replaced by one or more R 1 substituted 5-12-membered aryl, 5-12-membered heteroaryl, 5-12-membered carbocyclyl or 5-12-membered heterocyclyl; further preferably, the ring C is absent, unsubstituted or optionally replaced by one or more R 1 substituted 5-10 membered aryl, 5-10 membered heteroaryl, 5-10 membered carbocyclyl or 5-10 membered heterocyclyl; further preferably, the ring C is absent, unsubstituted or optionally replaced by one or more R 1 substituted 6-10 membered aryl, 5-10 membered heteroaryl, 5-10 membered carbocyclyl or 5-10 membered heterocyclyl; further preferably, the ring C is absent, unsubstituted or optionally replaced by one or more R 1 substituted 6-10 membered monocyclic aryl, 6-10 membered fused ring aryl, 5-10 membered monocyclic heteroaryl, 5-10 membered fused ring heteroaryl, 5-7 membered monocyclic carbocyclic group, 7-10 membered fused ring carbocyclic group, 5-7 membered monocyclic heterocyclic group or 7-10 membered fused ring heterocyclic group; further preferably, the ring C is absent, unsubstituted or optionally replaced by one or more R 1Substituted phenyl, naphthyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, 7-membered monocyclic heteroaryl, 8-membered fused ring heteroaryl, 9-membered fused ring heteroaryl, 10-membered fused ring heteroaryl, 5-membered carbocyclyl, 6-membered carbocyclyl, 7-membered carbocyclyl, 8-membered fused ring carbocyclyl, 9-membered fused ring carbocyclyl, 10-membered fused ring carbocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered fused ring heterocyclyl, 9-membered fused ring heterocyclyl or 10-membered fused ring heterocyclyl; wherein each of the above heteroaryl or heterocycle contains 1, 2 or 3 heteroatoms independently selected from N, O or S;

[0255] Further preferably, the ring C is absent, or is selected from being unsubstituted or optionally substituted with one or more R 1 Substituted with the following groups:

[0256] Preferably, it is unsubstituted or optionally substituted with one or more R 1 Substituted with the following groups:

[0257] More preferably, it is unsubstituted or optionally substituted with one or more R 1 Substituted with the following groups:

[0258] More preferably, it is unsubstituted or optionally substituted with one or more R 1 Substituted with the following groups:

[0259]

[0260] in, Indicates a single bond or a double bond.

[0261] In one embodiment of the compound represented by formula (II) of the present application, when In When it represents a single bond, Y 1 Yes-CR d -or-N-, and Y 2 Yes-CR d -or-N-.

[0262] In one embodiment of the compound represented by formula (II) of the present application, when ring C is absent, Y 1 and Y 2 Each is independently -C(R 1 ) 2 -or-C(R d ) 2 -.

[0263] In one embodiment of the compound represented by formula (II) of the present application, each R 1 are independently selected from hydrogen, deuterium, halogen, -N(R a )2 、-CN、-OH、-NO 2 , oxo, =O, carboxyl, -C 1-6 Alkoxy, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-8 Cycloalkyl, -C 1-6 Alkylene-N(R a ) 2 , -C 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-C(O)-OR a , -C 1-6 Alkylene-(3-10 membered heterocyclic group), -C 1-6 Alkylene-(5-10 membered heteroaryl), -C 1-6 Alkylene-C(O)-N(R a ) 2 , -C 1-6 Alkylene-NR a -C(O)-C 1-6 Alkyl, -C(O)-N(R a ) 2 、-C(O)-C(O)-N(R a ) 2 , -C 3-10 carbocyclic group, -5-10 membered heteroaryl, -3-10 membered heterocyclic group, -C(O)-C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)-C 1-6 Alkylene-N(R a ) 2 、-C(O)-NR a -(3-10 membered heterocyclyl), -C(O)-NR a -(3-10 membered heterocyclyl), -C(O)-(3-10 membered heterocyclyl), -OC 1-6 Alkylene-C(O)-OR a 、-OC 3-10 Carbocyclic group, -O-(3-10 membered heterocyclic group), -NR a -C(O)-C 1-6 Alkyl, -NR a -C(O)-(5-10 membered heteroaryl), -NR a -C(O)-C 3-8 Cycloalkyl, -NR a -C 1-6 Alkylene-N(R a ) 2 、-NR a -C1-6 Alkylene-(3-10 membered heterocyclic group), -NR a -C 1-6 Alkylene-(5-10 membered heteroaryl), -NR a -S(O) 2 C 1-6 Alkyl, -S(O)-N(R a ) 2 、-S(O) 2 -N(R a ) 2 , -3-10 membered heterocyclyl or -5-10 membered heteroaryl; preferably, each R 1 Independently selected from -H, -F, -Cl, -Br, -NH 2 、-N(CH 3 ) 2 , -CN, -OH, oxo, =O, carboxyl, methoxy, ethoxy, methyl, ethyl, isopropyl, tert-butyl, -CH 2 NH 2 、-CH 2 CH 2 OCH 3 、-CH 2 -C(O)OH, -CH 2 NH-C(O)-NHCH 3 、-C(O)-NH 2 、-C(O)-N(CH 3 ) 2 , -C(O)-NHOH, -C(O)-NHCH 2 CH 2 OH, -C(O)-CH 3 、-C(O)O-CH 3 、-S(O) 2 -NH 2 、-NHS(O) 2 CH 3 、-NH-C(O)-CH 3 、-NH-C(O)-NHCH 3 ,

[0264]

[0265] Among them, each of the above R 1 are optionally substituted with 1, 2 or 3 -F, -Cl, -NH 2 , -OH, oxo, =O, methyl, ethyl or propyl;

[0266] or two adjacent R aare connected together to form a 5-14 membered aromatic ring, a 5-14 membered heteroaromatic ring, a 5-14 membered heterocyclic ring or a 5-14 membered carbocyclic ring, and each of the ring systems is independently optionally substituted; preferably, two adjacent R a are connected together to form a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, a 5-10 membered heterocyclic ring or a 5-10 membered carbocyclic ring, and each of the ring systems is independently optionally substituted;

[0267] or R a and R b Together with the atoms to which they are commonly attached, they form a 3-14-membered aromatic ring, a 3-14-membered heteroaromatic ring, a 3-14-membered heterocyclic ring or a 3-14-membered carbocyclic ring; and each of the ring systems is independently optionally substituted; preferably, R a and R b Together with the atoms to which they are commonly attached, they form a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, a 5-10 membered heterocyclic ring or a 5-10 membered carbocyclic ring; and each of said ring systems is independently optionally substituted;

[0268] Each R a are independently selected from hydrogen, deuterium, halogen, -NH 2 、-CN、-OH、-NO 2 , carboxyl, -C 1-6 Alkoxy, -C 1-6 alkyl; each group is independently optionally substituted; preferably, each R a are independently selected from hydrogen, deuterium, halogen, -NH 2 、-CN、-OH、-C 1-6 Alkoxy, -C 1-6 Alkyl; each group independently is optionally substituted.

[0269] In one embodiment of the compound represented by formula (II) of the present application, R on the B ring 1 are independently selected from hydrogen, deuterium, amino, halogen, cyano, -CONH 2 、-COR 6 、-COOR 6 , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl; preferably hydrogen, halogen, amino, cyano, -CONH 2 、-COR 6 、-COOR 6 , optionally substituted C 1-4 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 3-6Cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl; further preferably halogen, cyano, -CONH 2 、-COR 6 、-COOR 6 , hydroxy substituted C 1-4 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; wherein R 6 are independently selected from hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted C 6-10 Aryl, optionally substituted 5-10 membered heteroaryl; preferably, R 6 are independently selected from hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl; further preferably, R 5 are independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl;

[0270] The optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable positions of the substituted group is independently selected from -OH, halogen, -NH 2 、-NO 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)-C 1-6 Alkyl, -NH-C 3-6 Cycloalkyl, -N(C 3～6 Cycloalkyl)-C 3～6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6～14 substituted by a substituent of an aryl or 5-10 membered heteroaromatic ring group; preferably substituted by a substituent selected from halogen, hydroxyl, amino, nitro, oxo, cyano, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted with an alkoxy substituent.

[0271] In one embodiment of the compound represented by formula (II) of the present application, R on ring A 1 are independently selected from optionally substituted 8-12 membered heterocyclyl, optionally substituted C 6-10Aryl, optionally substituted 5-14 membered heteroaryl; the optional substitution means that the hydrogen on the substituted group is not replaced or the hydrogen on one or more substitutable sites of the substituted group is independently selected from halogen, hydroxyl, amino, nitro, oxo, cyano, -COOH, -COCH 3 、-COOCH 3 、-CONH 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 substituted by a substituent of an aryl group or a 5-12-membered heteroaryl group;

[0272] In one embodiment of the compound represented by formula (II) of the present application, R on the C ring 1 are independently selected from hydrogen, halogen, -NH 2 、-NHR 7 、-N(R 7 ) 2 、-CN、-NO 2 ,=O,-C(O)-OR 7 、-C(O)-NH 2 、-CO-NHR 7 、-CO-N(R 7 ) 2 、-C(O)R 7 、-COOH、-OH、-SC 1-6 Alkyl, -SOC 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1～6 Alkoxy; wherein R 7 Each independently is C 1～6 Alkyl; the "substituted" means that the substituents are independently selected from one or more -OH, halogen, C 1-6 Alkyl, -NH 2 、-NO 2 、-COCH 3 In the case of a group consisting of -CN and =O, when the substituent is "=O", it means that two hydrogen atoms at the same substitution position are substituted by oxygen atoms.

[0273] In one embodiment of the compound represented by formula (II) of the present application, R 2 Selected from: hydrogen, deuterium, halogen, -NH 2 、-OH、-NH-C 1-6 Alkyl, -N(C 1-6 alkyl) 2 , -C1-6 Alkoxy or -C 1-6 alkyl, and each group is independently optionally substituted or unsubstituted; preferably hydrogen, deuterium, halogen, -NH 2 、-OH、-C 1-3 Alkoxy or -C 1-3 Alkyl, and each group is independently optionally substituted or unsubstituted; further preferably hydrogen, -NH 2 or -OH, and each group is independently optionally substituted or unsubstituted; further preferably -NH 2 .

[0274] In one embodiment of the compound represented by formula (II) of the present application, each R 4 and R 5 are independently selected from hydrogen, deuterium, halogen, -NH 2 、-CN、-OH、-C 1-6 Alkoxy or -C 1-6 alkyl, and each group is independently optionally substituted or unsubstituted; preferably, each R 4 and R 5 are independently selected from hydrogen, deuterium, halogen, -NH 2 、-CN、-OH、-C 1-3 Alkoxy or -C 1-3 alkyl, and each group is independently optionally substituted or unsubstituted; further preferably, each R 4 and R 5 are independently selected from hydrogen, halogen, -OH, -CH 3 or -OCH 3 ; Further preferably, R 4 and R 5 All are hydrogen.

[0275] In one embodiment of the compound represented by formula (II) of the present application, m is 0 or 1; q is 1; n is 1, 2 or 3; when m is 0, W is directly combined with Y 2 connected.

[0276] In one embodiment of the compound represented by formula (II) of the present application, --- indicates that the bond does not exist.

[0277] In one embodiment of the compound represented by formula (II) of the present application, the above-mentioned substitution is independently selected from -OH, halogen, unsubstituted C1-6 alkyl, -NH 2 、-NO 2 , unsubstituted -COC 1-6 Alkyl, -CN, =O, -C(O)OH, -C(O)-CH 3 -、-C(O)OCH 3 -、-C(O)-NH2 , unsubstituted C 3～10 Cycloalkyl, unsubstituted -NH-C 1～6 Alkyl, unsubstituted -N(C 1～6 Alkyl)(C 1～6 Alkyl), unsubstituted -NH-C 3～6 Cycloalkyl, unsubstituted -N(C 3～6 Cycloalkyl)(C 3～6 cycloalkyl), unsubstituted 3-10 membered heterocycloalkyl, unsubstituted C 6～14 One or more substituents in an aryl or unsubstituted 5- to 12-membered heteroaryl group; preferably -OH, halogen, unsubstituted C 1-6 Alkyl, -NH 2 、-NO 2 , unsubstituted -COC 1-6 Alkyl, -CN, =O, -C(O)OH, -C(O)-CH 3 -、-C(O)OCH 3 -、-C(O)-NH 2 , unsubstituted -NH-C 1～6 Alkyl or unsubstituted -N(C 1～6 Alkyl)(C 1～6 alkyl).

[0278] In one embodiment of the compound represented by formula (II) of the present application, each R b are independently selected from hydrogen, deuterium, halogen, -NH 2 、-CN、-OH、-C 1-6 Alkoxy or -C 1-6 Alkyl; preferably hydrogen, deuterium, halogen, -NH 2 、-CN、-OH、-C 1-3 Alkoxy or -C 1-3 alkyl.

[0279] In one embodiment of the compound represented by formula (II) of the present application, each R d are independently selected from hydrogen, deuterium, halogen, -NH 2 、-CN、-OH、-NO 2 、-C(O)OH、-C(O)-C 1-6 Alkyl, -C(O)-OC 1-6 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkoxy, -C 1-6 Alkoxy or -C 1-6 Alkyl; preferably hydrogen, deuterium, halogen, -NH 2 、-CN、-OH、-NO 2、-C(O)OH、-C(O)-C 1-3 Alkyl, -C(O)-OC 1-3 Alkyl, -C 1-3 Alkylene-OC 1-3 Alkoxy, -C 1-3 Alkoxy or -C 1-3 Alkyl; more preferably hydrogen, deuterium, halogen, -NH 2 、-CN、-OH、-NO 2 、-C(O)OH、-C(O)-C 1-3 Alkyl, -C 1-3 Alkylene-OC 1-3 Alkoxy.

[0280] In certain embodiments of the present application, the following compounds or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof are provided:

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287] In certain preferred embodiments of the present application, the following compounds or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts are provided:

[0288]

[0289]

[0290] In certain preferred embodiments of the present application, the following compounds or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts are provided:

[0291]

[0292]

[0293] In certain preferred embodiments of the present application, the following compounds or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts are provided:

[0294]

[0295] On the other hand, the present application also provides a main method for preparing the compound of formula (I) above, which can be prepared by, for example, the method shown in the following Synthesis Scheme 1 and Synthesis Scheme 2.

[0296] Synthesis Scheme 1

[0297]

[0298] Among them, A, Y, G, X, L, R 1 , R 2 , R 3 and R 6 As defined in the compound of formula (I),

[0299] I) Compounds I-1 and I-2 are chemically converted to obtain compound I-3;

[0300] For example, compounds I-1, I-2 and Ti(OEt) 4 etc. as basic raw materials to obtain compound I-3;

[0301] II) Compound I-3 undergoes chemical conversion to obtain compound I-4;

[0302] For example, compound I-3 is used as a basic raw material in the presence of a reducing agent to react to obtain compound I-4;

[0303] III) Compound I-4 undergoes chemical conversion to obtain compound I-5;

[0304] For example, compound I-4 is subjected to acidic conditions to obtain compound I-5;

[0305] IV) Compound I-5 is chemically converted to obtain compound I-7;

[0306] For example, using compounds I-5 and I-6 as basic raw materials, compound I-7 can be obtained by reacting under alkaline conditions;

[0307] V) Compound I-7 is chemically converted to obtain compound I-8;

[0308] For example, compound I-7 is reacted under acidic conditions to obtain compound I-8;

[0309] VI) Compound I-8 is chemically converted to obtain compound I-9;

[0310] For example, compound I-8 and (Boc 2 O etc. as basic raw materials to obtain compound I-9;

[0311] VII) Compound I-9 is chemically converted to obtain compound I-11;

[0312] For example, using compounds I-9 and I-10 as basic raw materials, compound I-11 can be obtained under palladium catalysis and alkaline conditions.

[0313] VIII) chemically transforming compound I-11 to obtain a compound of formula (I);

[0314] For example, compound I-11 or the like is used as a basic raw material and reacts under acidic conditions to obtain a compound of general formula (I).

[0315] Synthesis Scheme 2

[0316]

[0317] Among them, A, Y, G, X, L, R 1 , R 2 , R 3 and R 6 As defined in the compound of formula (I),

[0318] 2-1) Compounds I-10 and I-6 are chemically converted to obtain compound I-12;

[0319] For example, using compounds I-10 and I-6 as basic raw materials, compound I-12 can be obtained under palladium catalysis and alkaline conditions;

[0320] 2-II) Compounds I-12 and I-5 are chemically converted to obtain compound I-13;

[0321] For example, using compounds I-12 and I-5 as basic raw materials, compound I-13 is obtained under palladium catalysis and alkaline conditions;

[0322] 2-III) Compound I-13 is chemically converted to obtain a compound of formula (I);

[0323] For example, compound I-13 is treated under acidic conditions to obtain a compound of formula (I).

[0324] On the other hand, the present application also provides a pharmaceutical composition comprising (for example, a therapeutically effective amount of) the compound described in the present application (a compound of formula (I), a compound of formula (I-1), a compound of formula (I-1-1), a compound of formula (I-2), a compound of formula (I-A1), a compound of formula (I-1-A1), a compound of formula (I-2-A1), a compound of formula (I-A2), a compound of formula (I-A3), a compound of formula (I-2-A2), a compound of formula (I-2-A3), a compound of formula (I-B1), a compound of formula (I-1-B1) compound of formula (I-2-B1), compound of formula (I-B2), compound of formula (I-B3), compound of formula (I-2-B2), compound of formula (I-2-B3)), compound of formula (II), compound of formula (IA), compound of formula (IB), compound of formula (I-1-A), compound of formula (I-1-B), compound of formula (I-2-A), compound of formula (I-2-B), compound of formula (I-Ba)) or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof.

[0325] Further, the pharmaceutical composition described in the present application comprises the compound described in the present application (compound of formula (I), compound of formula (I-1), compound of formula (I-1-1), compound of formula (I-2), compound of formula (I-A1), compound of formula (I-1-A1), compound of formula (I-2-A1), compound of formula (I-A2), compound of formula (I-A3), compound of formula (I-2-A2), compound of formula (I-2-A3), compound of formula (I-B1), compound of formula (I-1-B1), compound of formula (I-2-B1) compound of formula (I-B2), compound of formula (I-B3), compound of formula (I-2-B2), compound of formula (I-2-B3)), compound of formula (II), compound of formula (IA), compound of formula (IB), compound of formula (I-1-A), compound of formula (I-1-B), compound of formula (I-2-A), compound of formula (I-2-B), compound of formula (I-Ba)) or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

[0326] The compounds of the present application (compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1), compounds of formula (I-2), compounds of formula (I-A1), compounds of formula (I-1-A1), compounds of formula (I-2-A1), compounds of formula (I-A2), compounds of formula (I-A3), compounds of formula (I-2-A2), compounds of formula (I-2-A3), compounds of formula (I-B1), compounds of formula (I-1-B1), compounds of formula (I-2-B1), compounds of formula (I-B2), compounds of formula (I-B3), compounds of formula (I- The administration of the compound of formula (I-2-B2), the compound of formula (I-2-B3), the compound of formula (II), the compound of formula (IA), the compound of formula (IB), the compound of formula (I-1-A), the compound of formula (I-1-B), the compound of formula (I-2-A), the compound of formula (I-2-B), the compound of formula (I-Ba)) or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or its pharmaceutically acceptable salt can be carried out in pure form or in the form of a suitable pharmaceutical composition by providing any acceptable mode of administration of drugs of similar use. The pharmaceutical composition of the present application can be prepared by combining the compound described in the present application with a suitable pharmaceutically acceptable excipient. The pharmaceutical composition of the present application can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc. Generally, the above-mentioned pharmaceutical composition can be prepared by conventional preparation methods using conventional excipients in the field of pharmaceutical preparations.

[0327] On the other hand, the present application also provides the compounds described in the present application (compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1), compounds of formula (I-2), compounds of formula (I-A1), compounds of formula (I-1-A1), compounds of formula (I-2-A1), compounds of formula (I-A2), compounds of formula (I-A3), compounds of formula (I-2-A2), compounds of formula (I-2-A3), compounds of formula (I-B1), compounds of formula (I-1-B1), compounds of formula (I-2-B1), compounds of formula (I-B2), compounds of formula (I-B3) Compounds of formula (I-2-B2), compounds of formula (I-2-B3)), compounds of formula (II), compounds of formula (IA), compounds of formula (IB), compounds of formula (I-1-A), compounds of formula (I-1-B), compounds of formula (I-2-A), compounds of formula (I-2-B), compounds of formula (I-Ba)) or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of the present application in the preparation of medicaments for preventing and / or treating diseases, disorders and conditions mediated by SHP2 activity.

[0328] Furthermore, in the uses provided in the present application, the diseases, disorders and conditions are tumors, cancer metastasis, cardiovascular diseases, immune disorders or visual disorders.

[0329] Furthermore, in the uses provided in the present application, the tumor includes solid tumors and hematological tumors.

[0330] Furthermore, in the use provided in the present application, the solid tumor includes lung cancer, the blood tumor includes leukemia, and the leukemia is preferably acute myeloid leukemia. In certain contexts in the art, the cancer may also be referred to as a malignant tumor.

[0331] In another aspect, the present application provides a method for preventing and / or treating diseases, disorders and conditions mediated by SHP2 activity, comprising administering to an individual in need thereof a compound described herein (a compound of formula (I), a compound of formula (I-1), a compound of formula (I-1-1), a compound of formula (I-2), a compound of formula (I-A1), a compound of formula (I-1-A1), a compound of formula (I-2-A1), a compound of formula (I-A2), a compound of formula (I-A3), a compound of formula (I-2-A2), a compound of formula (I-2-A3), a compound of formula (I-B1), a compound of formula (I-1-B1), a compound of formula (I-2-B1), a compound of formula (I-B2), a compound of formula (I-B3), a compound of formula (I-2 -B2) compound, compound of formula (I-2-B3), compound of formula (IA), compound of formula (IB), compound of formula (I-1-A), compound of formula (I-1-B), compound of formula (I-2-A), compound of formula (I-2-B), compound of formula (I-Ba), compound of formula (II)) or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts or pharmaceutical compositions of the present application; preferably, the diseases, disorders and conditions are tumors, cancer metastasis, cardiovascular diseases, immune disorders or visual disorders; more preferably, the tumors include solid tumors and hematological tumors; more preferably, the solid tumors include lung cancer, the hematological tumors include leukemia, and the leukemia is preferably acute myeloid leukemia.

[0332] On the other hand, the present application provides compounds described herein (compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1), compounds of formula (I-2), compounds of formula (I-A1), compounds of formula (I-1-A1), compounds of formula (I-2-A1), compounds of formula (I-A2), compounds of formula (I-A3), compounds of formula (I-2-A2), compounds of formula (I-2-A3), compounds of formula (I-B1), compounds of formula (I-1-B1), compounds of formula (I-2-B1), compounds of formula (I-B2), compounds of formula (I-B3), compounds of formula (I-2-B2)) for use in preventing and / or treating diseases, disorders, and conditions mediated by SHP2 activity. , compound of formula (I-2-B3)), compound of formula (II), compound of formula (IA), compound of formula (IB), compound of formula (I-1-A), compound of formula (I-1-B), compound of formula (I-2-A), compound of formula (I-2-B), compound of formula (I-Ba)) or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof or the pharmaceutical composition of the present application; preferably, the diseases, disorders and conditions are tumors, cancer metastasis, cardiovascular diseases, immune disorders or visual disorders; more preferably, the tumors include solid tumors and hematological tumors; more preferably, the solid tumors include lung cancer, the hematological tumors include leukemia, and the leukemia is preferably acute myeloid leukemia.

[0333] Furthermore, in the uses or methods provided by the present application, the compounds described in the present application (compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1), compounds of formula (I-2), compounds of formula (I-A1), compounds of formula (I-1-A1), compounds of formula (I-2-A1), compounds of formula (I-A2), compounds of formula (I-A3), compounds of formula (I-2-A2), compounds of formula (I-2-A3), compounds of formula (I-B1), compounds of formula (I-1-B1), compounds of formula (I-2-B1), compounds of formula (I-B2) , a compound of formula (I-B3), a compound of formula (I-2-B2), a compound of formula (I-2-B3)), a compound of formula (II), a compound of formula (IA), a compound of formula (IB), a compound of formula (I-1-A), a compound of formula (I-1-B), a compound of formula (I-2-A), a compound of formula (I-2-B), a compound of formula (I-Ba)) or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of the present application is used in combination with another, two or more compounds having tumor inhibitory activity.

[0334] On the other hand, the present application provides compounds described in the present application (compounds of formula (I), compounds of formula (I-1), compounds of formula (I-1-1), compounds of formula (I-2), compounds of formula (I-A1), compounds of formula (I-1-A1), compounds of formula (I-2-A1), compounds of formula (I-A2), compounds of formula (I-A3), compounds of formula (I-2-A2), compounds of formula (I-2-A3), compounds of formula (I-B1), compounds of formula (I-1-B1), compounds of formula (I-2-B2) 1) compound, compound of formula (I-B2), compound of formula (I-B3), compound of formula (I-2-B2), compound of formula (I-2-B3)), compound of formula (II), compound of formula (IA), compound of formula (IB), compound of formula (I-1-A), compound of formula (I-1-B), compound of formula (I-2-A), compound of formula (I-2-B), compound of formula (I-Ba)) or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof or the pharmaceutical composition of the present application.

[0335] definition

[0336] The terms "optional", "optionally", "optionally" or "arbitrarily" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0337] Unless otherwise specified, the term "optionally substituted" or "arbitrarily substituted" means that the group may be unsubstituted or substituted, wherein the substituents are independently selected from hydroxyl, halogen, amino, nitro, thiol, cyano, azido, oxo, carboxyl, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)-C 1-6 Alkyl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -C(O)NH-C 1-6 Alkyl, -NHC(O)-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 aryl, 5-12 membered heteroaryl group or more; wherein the C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 The aryl or 5-12 membered heteroaromatic ring group may be optionally selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl or C 1-6 The present invention is substituted by one or more alkoxy groups.

[0338] The term "oxo" refers to two hydrogen atoms at the same substitution position being replaced by the same oxygen atom to form a double bond, ie, =0.

[0339] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms (i.e., C 1-10 Alkyl), further preferably containing 1 to 8 carbon atoms (C 1-8 Alkyl), more preferably containing 1 to 6 carbon atoms (i.e. C 1-6 Alkyl), such as "C 1-6 "Alkyl" means that the group is an alkyl group and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1, 2, 3, 4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0340] Unless otherwise specified, the term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. The alkenyl group may contain 2 to 20 carbon atoms, preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms (i.e., C 2-10 Alkenyl), further preferably containing 2 to 8 carbon atoms (C 2-8 Alkenyl), more preferably containing 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), 2-5 carbon atoms (i.e. C 2-5 alkenyl), 2-4 carbon atoms (i.e. C 2-4 alkenyl), 2-3 carbon atoms (i.e. C 2-3 alkenyl), 2 carbon atoms (i.e. C 2 alkenyl), such as "C 2-6"Alkenyl" means that the group is an alkenyl group, and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl and 1,3-butadienyl, etc.

[0341] Unless otherwise specified, the term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. The alkynyl group may contain 2 to 20 carbon atoms, preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms (i.e., C 2-10 Alkynyl), further preferably containing 2 to 8 carbon atoms (C 2-8 Alkynyl), more preferably containing 2 to 6 carbon atoms (i.e. C 2-6 Alkynyl), 2-5 carbon atoms (i.e. C 2-5 Alkynyl), 2-4 carbon atoms (i.e. C 2-4 Alkynyl), 2-3 carbon atoms (i.e. C 2-3 Alkynyl), 2 carbon atoms (i.e. C 2 Alkynyl), such as "C 2-6 "Alkynyl" means that the group is an alkynyl group, and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl and 1-butynyl, etc.

[0342] Unless otherwise specified, the term "cycloalkyl", "carbocyclyl" or "carbocycle" refers to a monocyclic saturated aliphatic hydrocarbon group having a specified number of carbon atoms, containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (i.e., C 3-14 Cycloalkyl), preferably containing 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl), more preferably containing 3 to 10 carbon atoms (C 3-10 Cycloalkyl), preferably 3 to 7 carbon atoms (C 3-7 Cycloalkyl), 4-6 carbon atoms (C 4-6 Cycloalkyl), 5-6 carbon atoms (C 5-6 Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, etc. In some embodiments of the present application, "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group with a specific number of carbon atoms composed of carbon atoms and hydrogen atoms. In some embodiments of the present application, the cycloalkyl group also preferably contains 3-4 carbon atoms (C 3-4 Cycloalkyl), 3-5 carbon atoms (C 3-5 Cycloalkyl) or 4-5 carbon atoms (C 4-5 cycloalkyl).

[0343] Unless otherwise specified, the term "alkoxy" refers to -O-alkyl, and the alkyl is defined as above, i.e., contains 1-20 carbon atoms, preferably, contains 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably 1-8 carbon atoms, more preferably 1 to 6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, and the like.

[0344] Unless otherwise specified, the term "carboxyl" refers to a -COOH group. The term "halogen" or "halo" refers to F, Cl, Br, I. The term "haloalkyl" refers to an alkyl group as defined above in which one, two or more hydrogen atoms or all hydrogen atoms are replaced by halogen. Representative examples of haloalkyl include CCl 3 CF 3 , CHCl 2 , CH 2 Cl, CH 2 Br, CH 2 I. CH 2 CF 3 CF 2 CF 3 wait.

[0345] Unless otherwise specifically defined, the term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic non-aromatic substituent having ring carbon atoms and 1 to 4 ring heteroatoms, containing 3-20 ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. Preferably, it contains 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (i.e., 3-14-membered heterocyclyl), preferably contains 3 to 12 ring atoms (3-12-membered heterocyclyl), further preferably contains 3 to 10 ring atoms (3-10-membered heterocyclyl), or 3 to 8 ring atoms (3-8-membered heterocyclyl), or 3 to 6 ring atoms (3-6-membered heterocyclyl), or 4 to 6 ring atoms (4-6-membered heterocyclyl), or 5 to 6 ring atoms (5-6-membered heterocyclyl). The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2 or 3). Examples of monocyclic heterocyclic groups include oxirane, pyrrolidinyl, N-methylpyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, thiomorpholinyl and tetrahydrothienyl. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. "Heterocyclic group" can be a monocyclic ("monocyclic heterocyclic group") or a fused ("fused heterocyclic group" or "heterofused group"), bridged ("heterobridged group" or "bridged heterocyclic group") or spiro-fused ("heterospirocyclic group" or "spirocyclic heterocyclic group") ring system, such as a bicyclic system ("bicyclic heterocyclic group"), and can be saturated or partially unsaturated. The heterocyclic bicyclic system can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which the heterocyclyl ring as defined above is fused with one or more carbocyclyl groups, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring, or "heterocyclyl" also includes ring systems in which the heterocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, or cycloalkyl rings as defined above are fused with one or more heteroaryl groups, wherein the point of attachment is on the heterocyclyl or cycloalkyl ring, and in such cases, the number of members of the heterocyclyl ring system is the number of atoms in the ring system after fusion. In certain embodiments, each instance of heterocyclyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, aziridine, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.Exemplary 5-membered heterocyclic radicals containing 2 heteroatoms include, but are not limited to dioxolanyl, oxathiolanyl, dithiolanyl and oxazolidin-2-one. Exemplary 5-membered heterocyclic radicals containing 3 heteroatoms include, but are not limited to triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary 6-membered heterocyclic radicals containing 1 heteroatom include, but are not limited to piperidinyl, tetrahydropyranyl, dihydropyridinyl and thianyl. Exemplary 6-membered heterocyclic radicals containing 2 heteroatoms include, but are not limited to piperazinyl, morpholinyl, dithiolanyl and dioxanyl. Exemplary 6-membered heterocyclic radicals containing 3 heteroatoms include, but are not limited to triazacyclohexane, oxadiazinyl, thiadiazinyl, oxathiazinyl and dioxaazacyclohexane. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepane and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azocanyl, oxepane and thiecanyl. Fused to one C. 6 Exemplary 5-membered heterocyclyl groups on an aryl ring (also referred to herein as a 5,6-bicyclic heterocycle) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocycle) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0346] Unless otherwise specifically limited, "heterocycloalkyl" refers to a monocyclic, saturated "heterocyclyl" or "heterocycle" as defined above, with the ring atoms defined as above, i.e., containing 3 to 20 ring atoms ("3-20 membered heterocycloalkyl"), with the number of heteroatoms being 1 to 4 (1, 2, 3 or 4), preferably 1 to 3 (1, 2 or 3), wherein each heteroatom is independently selected from N, O or S. Preferably, the heterocycloalkyl group contains 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms ("3-12 membered heterocycloalkyl"), more preferably contains 3 to 10 ring atoms ("3-10 membered heterocycloalkyl"), even more preferably contains 3 to 8 ring atoms ("3-8 membered heterocycloalkyl"), even more preferably contains 4 to 7 ring atoms ("4-7 membered heterocycloalkyl"), even more preferably contains 5 to 10 ring atoms ("5-10 membered heterocycloalkyl"), even more preferably contains 5 to 6 ring atoms ("5-6 membered heterocycloalkyl"). In certain embodiments, each instance of heterocycloalkyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocycloalkyl") or substituted with one or more substituents (a "substituted heterocycloalkyl"). Some exemplary "heterocycloalkyl" groups are given in the "heterocyclyl" or "heterocycle" section above, and also include, but are not limited to, aziridine, oxirane, thiirane, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, oxanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxathiolanyl, oxazolidinyl, dioxanyl, dithiolanyl, thiazolidinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, and the like.

[0347] Unless otherwise specified, the term "aryl" or "aromatic ring group" means a monocyclic, bicyclic and tricyclic aromatic carbocyclic ring system containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms, preferably 6-10 carbon atoms, and the term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl or pyrenyl. Polycyclic aromatic groups include aromatic groups of condensed rings and bridged rings, and the explanation of condensed rings and bridged rings is similar to that of polycyclic heterocyclic groups.

[0348] Unless otherwise specifically limited, the term "heteroaryl" or "heteroaromatic ring group" means an aromatic monocyclic or polycyclic ring system containing 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 membered structures, or preferably 5-10 membered structures, or preferably 5-8 membered structures, more preferably 5-6 membered structures, wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3. Examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzopyridinyl, benzopyrimidinyl, benzo Pyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, etc. The polycyclic heteroaryl group includes condensed ring and bridged ring heteroaryl groups, and the explanation of condensed ring and bridged ring is similar to that of the polycyclic heterocyclic group.

[0349] When a substituent can be attached to more than one atom in a ring, the substituent may be bonded to any atom in the ring (including heteroatoms such as NH), e.g. It means that the connection site can be at any position on the benzene ring or the pyridine ring, or at any position on the benzene ring or the tetrahydrofuran ring.

[0350] Unless otherwise specifically defined, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts that are suitable for contact with mammalian tissues, especially human tissues, without excessive toxicity, irritation, allergic reactions, etc., and are commensurate with a reasonable benefit / risk ratio within the scope of reasonable medical judgment, such as amines, carboxylic acids and other types of medically acceptable salts of compounds are well known in the art. The salts can be prepared in situ during the final separation and purification of the compounds of the present application, or prepared separately by reacting the free base or free acid with a suitable reagent. The pharmaceutically acceptable salts of the present application include acid addition salts or base addition salts of the compounds described in the present application, which are obtained by reacting the compounds described in the present application with inorganic acids or organic acids and inorganic bases or organic bases well known to those skilled in the art.

[0351] Unless otherwise specifically defined, the term "isotopic derivative" means that the compounds of the present application may exist in an isotopically traced or enriched form, containing one or more atoms whose atomic mass or mass number is different from the atomic mass or mass number of the largest atom found in nature. Isotopes may be radioactive or non-radioactive isotopes. Isotopes commonly used as isotope labels are: hydrogen isotopes, 2 H and 3 H; Carbon isotope: 13 C and 14 C; Chlorine isotope: 35 Cl and 37 Cl; Fluorine isotope: 18 F; Iodine isotope: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotope: 15 O. 17 O and 18 O and sulfur isotopes 35 S. These isotope-labeled compounds can be used to study the distribution of drug molecules in tissues. 2 H and 13 C, because they are easy to label and detect, they are more widely used. Some heavy isotopes, such as deuterium ( 2 H) substitution can enhance metabolic stability, prolong half-life, thereby achieving the purpose of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds generally start from labeled starting materials and use known synthesis techniques to complete their synthesis in the same way as non-isotope-labeled compounds.

[0352] Unless otherwise specifically limited, the terms "solvate" and "solvate" mean a physical association of the present invention compound with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonds. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be separated. The solvent molecules in the solvate may exist in a regular arrangement and / or a disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" encompasses solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0353] Unless otherwise specifically defined, the term "stereoisomer" refers to a compound having the same chemical structure but different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformers (rotational isomers), geometric isomers (cis / trans) isomers, atropisomers, etc. Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and / or fractional crystallization based on the differences in the physical and chemical properties of the components.

[0354] Unless otherwise specifically limited, the term "tautomer" refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions through the reorganization of some bonding electrons.

[0355] Unless otherwise specified, the structural formulas described in the present application include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present application or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformational isomers) all fall within the scope of the present application.

[0356] Unless otherwise specifically defined, the term "prodrug" refers to a drug that is converted into a parent drug in vivo. Prodrugs are generally useful and can improve some determined, undesirable physical or biological properties. Physical properties are usually related to solubility (too high or insufficient lipid or water solubility) or stability, while problematic biological properties include too fast metabolism or poor bioavailability, which may itself be related to physicochemical properties. For example, they can be bioavailable by oral administration, while the parent cannot. Compared with the parent drug, the solubility of the prodrug in the pharmaceutical composition is also improved. An example of a prodrug, but not limited to this, can be any compound of the present application, which is administered as an ester ("prodrug") to facilitate transmission across the cell membrane, where water solubility is harmful to mobility, but once it enters the cell, water solubility is beneficial, which is then metabolically hydrolyzed into a carboxylic acid, i.e., an active entity. Another example of a prodrug can be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to display the active part.

[0357] Unless otherwise specifically limited, the term "treatment" encompasses any treatment of a disease, disorder or condition in a patient, including: (a) inhibiting the symptoms of the disease, disorder or condition, i.e., preventing its development; or (b) relieving the symptoms of the disease, disorder or condition, i.e., causing regression of the disease or symptoms; or (c) improving or eliminating the disease, disorder or condition or one or more symptoms associated with the disease.

[0358] Unless otherwise specifically limited, the term "therapeutically effective amount" means the amount of the compound of the present application that (i) treats a specific disease, disorder or condition, (ii) alleviates, improves or eliminates one or more symptoms of a specific disease, disorder or condition, or (iii) delays the onset of one or more symptoms of a specific disease, disorder or condition described herein. The amount of the compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0359] Unless otherwise specifically defined, the term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to an organism (e.g., human) and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. "Pharmaceutically acceptable excipients" may also refer to inert substances that are administered together with the active ingredient and are beneficial to the administration of the active ingredient, including but not limited to any glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or animals (e.g., livestock).

[0360] The beneficial effects of this application are:

[0361] The present application designs a class of novel compounds, which provide a new direction for the treatment of tumors, cancer, cancer metastasis, cardiovascular disease, immune disorders or visual disorders. The compounds of the present application have one or more of the following advantages: (1) strong SHP2 kinase inhibition; (2) higher exposure and good absorption; (3) no obvious inhibitory effect on hERG channels, and may have lower cardiac toxicity; (4) good tolerability and high drug safety; and (5) high in vivo tumor inhibition rate. In addition, the present application studies a specific synthesis method, which has a simple process, convenient operation, and is conducive to large-scale industrial production and application. DETAILED DESCRIPTION

[0362] The various aspects of the present application are further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present application and are not used to limit the scope of the various aspects described in the present application. If the experimental method of the specific conditions is not indicated in the embodiment, it is usually implemented according to conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used in this application have the same meaning as those familiar to professionals in the field. In addition, any method and material similar or equal to the recorded content can be applied to the present application method. The preferred implementation method and materials shown in this application are only for demonstration purposes.

[0363] Abbreviations used in the Preparative Examples, Examples, and elsewhere herein are:

[0364] DCM Dichloromethane

[0365] TEA Triethylamine

[0366] EA Ethyl acetate

[0367] DMSO Dimethyl sulfoxide

[0368] DMF N,N-Dimethylformamide

[0369] TFA Trifluoroacetic acid

[0370] DIPEA N,N-Diisopropylethylamine

[0371] Pd(dppf)Cl 2 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) chloride

[0372] Pd 2 (dba) 3 Tris(dibenzylideneacetone)dipalladium

[0373] Pd(PPh 3 ) 4 Tetrakis(triphenylphosphine)palladium(0)

[0374] XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0375] (Boc) 2 O Di-tert-butyl dicarbonate

[0376] NBS N-Bromosuccinimide

[0377] Dtbpy 4,4'-di-tert-butylbipyridine

[0378] DMA N,N-Dimethylacetamide

[0379] TBAI Tetrabutylammonium iodide

[0380] EDCI 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0381] Intermediate Preparation Example 1: 1-(5-amino-3-chloropyrazin-2-yl)ethanone (Intermediate 1)

[0382]

[0383] To a solution of 2-amino-5-bromo-6-chloropyrazine (20.0 g, 96.67 mmol, 1.0 eqv) in 1,4-dioxane (240 ml) were added tributyl(1-ethoxyvinyl)tin (52.36 g, 144.98 mmol, 1.5 eqv), CuI (1.84 g, 9.667 mmol, 0.1 eqv) and Pd(Ph 3 P) 2 Cl 2 (6.78 g, 9.667 mmol, 0.1 eqv), nitrogen protection, 100 ° C overnight reaction. Cool to room temperature, add silica gel to the reaction solution, concentrate to dryness under reduced pressure, and purify by column chromatography (n-hexane: EA = 10: 1 to 5: 1) to obtain 1-(5-amino-3-chloropyrazin-2-yl) ethanone (5.1 g, yield 31%). (ES, m / z): 171.97 [M+H] + .

[0384] Intermediate Preparation Example 2: 3-Chloro-5-((2,4-dimethoxybenzyl)amino)pyrazine-2-carboxylic acid methyl ester (Intermediate 2)

[0385]

[0386] Under nitrogen protection, CsF (8.36 g, 55.07 mmol, 3 eqv) was added to DMSO (40 mL) of 3,5-dichloropyrazine-2-carboxylic acid methyl ester (3.8 g, 18.36 mmol, 1 eqv) and 2,4-dimethoxybenzylamine (3.07 g, 18.36 mmol, 1 eqv), and then the temperature was raised to 75°C and reacted for 3 h; the temperature was lowered to room temperature, and the reaction solution was poured into water (200 ml) and EA (100 ml), separated, and the aqueous phase was extracted with EA (2×50 ml), and the organic phases were combined. The organic phase was washed with brine (100 ml), concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane: EA = 10:1 to 1:1) to obtain 3-chloro-5-((2,4-dimethoxybenzyl)amino)pyrazine-2-carboxylic acid methyl ester (4 g, yield 54.06%). (ES,m / z):338.1[M+H] + ; 1 H NMR (400 MHz, CDCl 3): δppm 7.82(s,1H)7.23(d,J=8.4Hz,1H)6.41-6.51(m,2H)5.66(br s,1H)4.55(d,J=5.6Hz,2H)3.94(s,3H)3.85(s,3H)3.81(s,3H).

[0387] Intermediate Preparation Example 3: 2-Chloro-3-(oxazol-2-yl)benzenethiol (Intermediate 3)

[0388]

[0389] Step a: 2-chloro-3-fluoroaniline (5.00 g, 33.663 mmol, 1 eqv), tert-butyl mercaptan (3.64 g, 40.396 mmol, 1.2 eqv), Cs 2 CO 3 (32.90g, 100.989mmol, 3eqv) in DMF (50ml) was reacted at 130℃ for 24h; cooled to room temperature, the reaction solution was poured into water (300ml), extracted with EA (2×300ml), the organic phases were combined, washed with brine (2×500ml), concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane:EA=100:1~20:1) to obtain 3-(tert-butylsulfanyl)-2-chloroaniline (7.0g, yield 94.46%). (ES,m / z):216[M+H] + .

[0390] Step b: Cool a solution of 3-(tert-butylsulfanyl)-2-chloroaniline (7.0 g, 32.55 mmol, 1 eqv) in concentrated hydrochloric acid (15 ml) to -10 to -5°C, add dropwise a solution of sodium nitrite (3.369 g, 48.83 mmol, 1.5 eqv) in water (105 ml), and keep the mixture warm for 30 min. At the same temperature, add dropwise a solution of potassium iodide (6.484 g, 39.06 mmol, 1.2 eqv) in water (6 5ml) solution, after the dropwise addition, the mixture was kept warm for 20min; ethyl acetate (100ml) and saturated sodium thiosulfate solution (100ml) were added to the reaction solution, stirred for 10min, separated, the aqueous phase was extracted with EA (2×50ml), and the organic phases were combined; the organic phase was washed with brine (100mL), concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane) to obtain tert-butyl (2-chloro-3-iodophenyl) sulfane (6.52g, yield 61.45%). 1 H-NMR (400MHz, DMSO-d6) δ7.99 (dd, J = 7.9, 1.5 Hz, 1H), 7.68 (dd, J = 7.7, 1.5 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 1.29 (s, 9H).

[0391] Step c: A solution of tert-butyl(2-chloro-3-iodophenyl)sulfane (6.5 g, 19.94 mmol, 1 eqv), oxazole (2.75 g, 39.88 mmol, 2 eqv), lithium tert-butoxide (1.92 g, 23.93 mmol, 1.2 eqv) and CuI (380 mg, 1.994 mmol, 0.1 eqv) in DMF (50 ml) was reacted at 140° C. for 2 h under nitrogen protection. The reaction was complete when detected by TLC. The temperature was lowered to room temperature, the reaction solution was poured into water (300 ml), extracted with EA (2×150 ml), the organic phases were combined, washed with brine (2×100 ml), and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane:EA=25:1-10:1) to obtain 2-(3-(tert-butylsulfanyl)-2-chlorophenyl)oxazole (3.12 g, yield 58.58%). (ES,m / z):267.93[M+H] + . 1 H-NMR (400MHz, CDCl 3 )δ7.91(dd,J=7.8,1.7Hz,1H),7.80(d,J=0.7Hz,1H),7.78(dd,J=7.7,1.7Hz,1H),7.36-7.31(m,2H),1.37(s,9H).

[0392] Step d: At 0°C, aluminum chloride (6.23 g, 46.72 mmol, 4 eqv) was added to a toluene (60 ml) solution of 2-(3-(tert-butylsulfanyl)-2-chlorophenyl)oxazole (3.12 g, 11.68 mmol, 1 eqv) and reacted at room temperature overnight; the temperature was lowered to 0°C, water (60 ml) was added dropwise, stirred for 30 min, and the liquids were separated; the aqueous phase was extracted with toluene (30 ml), and the organic phases were combined; the residue was concentrated under reduced pressure, and purified by column chromatography (n-hexane: EA = 20:1 to 5:1) to obtain 2-chloro-3-(oxazol-2-yl)benzenethiol (1.726 g, yield 70%). (ES, m / z): 211.89 [M+H] + .

[0393] Intermediate Preparation Examples 4-5:

[0394] Intermediates 4 to 5 were synthesized using the steps of Intermediate Preparation Example 3 and the following corresponding starting materials:

[0395]

[0396]

[0397] Intermediate Preparation Example 6: 2-Chloro-3-(pyrazin-2-yl)benzenethiol (Intermediate 6)

[0398]

[0399] Step a: Under nitrogen protection, tert-butyl (2-chloro-3-iodophenyl) sulfane (3.26 g, 10 mmol, 1 eqv), pyrazine-2-boronic acid (1.49 g, 12 mmol, 1.2 eqv), K 2 CO 3 (4.14 g, 30 mmol, 3 eqv) and Pd(dppf)Cl 2 A solution of (731.7 mg, 1 mmol, 0.1 eqv) in 1,4-dioxane (80 ml) and water (20 ml) was reacted at 100°C overnight; the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane:EA=50:1-25:1) to obtain 2-(3-(tert-butylsulfanyl)-2-chlorophenyl)pyrazine (1.21 g, yield 43.5%). (ES, m / z): 279.00[M+H] + .

[0400] Step b: At 0°C, aluminum chloride (2.32 g, 17.4 mmol, 4 eqv) was added in batches to a toluene (60 ml) solution of 2-(3-(tert-butylsulfanyl)-2-chlorophenyl)pyrazine (1.21 g, 4.35 mmol, 1 eqv), and the mixture was reacted at room temperature overnight; the temperature was lowered to 0°C, water (60 ml) was added dropwise, stirred for 30 min, and the mixture was separated; the aqueous phase was extracted with toluene (30 ml), and the organic phases were combined; the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane:EA=20:1-5:1) to obtain 2-chloro-3-(pyrazin-2-yl)benzenethiol (726 mg, yield 75.2%). (ES, m / z): 222.89 [M+H] + .

[0401] Intermediate Preparation Examples 7 to 9

[0402] Intermediates 7 to 9 were synthesized using the steps of Intermediate Preparation Example 6 and the following corresponding starting materials:

[0403]

[0404] Intermediate Preparation Example 10: 3-Chloro-2-(pyrazin-2-yl)pyridine-4-thiol (Intermediate 10)

[0405]

[0406] Step a: Under nitrogen protection, 2,3-dichloro-4-iodopyridine (2.00 g, 7.33 mmol, 1.00 eqv), 3-mercaptopropionic acid-2-ethyl-hexyl ester (2.07 g, 9.51 mmol, 1.3 eqv), DIPEA (2.862 g, 21.99 mmol, 3.00 eqv), Pd 2 (dba) 3 A solution of 1,4-dioxane (50 ml) and 1,4-dioxane (1.342 g, 1.466 mmol, 0.2 eqv) was stirred at 96 ° C for 8 h; the temperature was lowered to room temperature, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure; the residue was purified by column chromatography (n-hexane: EA = 20: 1) to obtain 2-ethyl-hexyl 3-(2-(2,3-dichloropyridin-4-yl)sulfanyl)propanoate (2.076 g, yield 78%). (ES, m / z): 364.06 [M+H] + .

[0407] Step b: Under nitrogen protection, 2-ethyl-hexyl 3-(2-(2,3-dichloropyridin-4-yl)sulfanyl)propanoate (666 mg, 1.834 mmol, 1.0 eqv), pyrazine-2-boronic acid (250 mg, 2.02 mmol, 1.1 eqv), Pd(dppf)Cl 2 (134mg, 0.183mmol, 0.1eqv) and potassium carbonate (760mg, 5.503mmol, 3eqv) in 1,4-dioxane (60mL) and water (10ml) were reacted at 96°C overnight; the temperature was lowered and the mixture was concentrated under reduced pressure. Water (200ml) and EA (100ml) were added to the residue, and the mixture was separated. The aqueous phase was extracted with EA (2×50ml) and the organic phases were combined; the organic phase was washed with brine (100ml) and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane:EA=30:1-10:1) to obtain 2-ethyl-hexyl 3-((3-chloro-2-(pyrazin-2-yl)pyridin-4-yl)sulfanyl)propanoate (637mg, yield 85.3%). (ES,m / z):408.15[M+H] + .

[0408] Step c: Under nitrogen protection, 2-ethyl-hexyl 3-((3-chloro-2-(pyrazin-2-yl)pyridin-4-yl)sulfanyl)propanoate (637 mg, 1.565 mmol, 1.0 eqv) and a methanol (60 ml) solution of NaOH (66 mg, 1.643 mmol, 1.05 eqv) were reacted at 50°C for 3 h; the temperature was lowered to about 0°C, 4M HCl / MeOH solution was added dropwise, the pH was adjusted to 3-4, the mixture was concentrated under reduced pressure, and column chromatography was performed for purification (n-hexane:EA=10:1-5:1) to obtain 3-chloro-2-(pyrazin-2-yl)pyridine-4-thiol (320 mg, yield 91.7%). (ES, m / z): 223.92 [M+H] + .

[0409] Intermediate Preparation Example 11: (R)-2-methyl-N-((R)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)propane-2-sulfenamide (Intermediate 11)

[0410]

[0411] Steps a to b: Prepare Compound 8 from Compound 7 according to WO2021061706A1.

[0412] Step c: The product M11-2 (5.0 g, 12.238 mmol) was dissolved in DCM (90 ml), trifluoroacetic acid (30 ml) was added dropwise at 0°C, the mixture was reacted at room temperature for 3 h, and the mixture was concentrated under reduced pressure. Water (50 ml) was added to the residue, the pH was adjusted to 10 with 25% aqueous ammonia, the aqueous phase was extracted with a mixed solution of EA:THF=1:1 (60 ml×4), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (R)-2-methyl-N-((R)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)propane-2-sulfenamide (3.2 g). (ES, m / z): 309.10 [M+H] + .

[0413] Intermediate Preparation Example 11A: (R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidinyl]-1-yl)-2-methylpropane-2-sulfenamide (Intermediate 11A)

[0414]

[0415] A solution of (S)-tert-butyl 1-((R)-1,1-dimethylethylsulfonylamino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (48.00 g) and TFA (40 ml) in DCM (160 ml) was reacted at room temperature overnight; the reaction solution was concentrated under reduced pressure, EA (200 ml) and water (200 ml) were added to the residue, the pH was adjusted to 10 with 25% ammonia water, and the layers were separated; the aqueous phase was extracted with EA (100 ml×2), and the organic phases were combined; the organic phases were washed with water (100 ml) and brine (100 ml), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product of (R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfenamide (Intermediate 11A) (32 g). (ES,m / z):307.09[M+H] + .

[0416] Intermediate Preparation Example 12: (R)-tert-butyl (1'-(3-acetyl-6-amino-5-bromopyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamate (Intermediate 12)

[0417]

[0418] Step a: A solution of 1-(5-amino-3-chloropyrazin-2-yl)ethanone (266 mg, 1.555 mmol, 1.0 eqv), (R)-2-methyl-N-((R)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)propane-2-sulfinamide (575 mg, 1.866 mmol, 1.2 eqv) and DIPEA (603 mg, 4.6655 mmol, 3.0 eqv) in DMSO (10 ml) was reacted at 110° C. for 8 h; cooled to room temperature, water (50 ml) was added, extracted with EA (3×30 ml), and the organic phases were combined; the organic phases were washed with H 2 O (100 ml), washed with brine (100 ml), concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM: MeOH = 80: 1 to 50: 1) to obtain (R)-N-((R)-1'-(3-acetyl-6-aminopyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)-2-methylpropane-2-sulfenamide (321 mg, yield 46%). (ES, m / z): 444.16 [M+H] + .

[0419] Step b: To a reaction flask containing (R)-N-((R)-1'-(3-acetyl-6-aminopyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)-2-methylpropane-2-sulfenamide (321 mg, 0.724 mmol, 1.0 eqv) was added HCl / CH 3 OH solution (10 mL), stirred at room temperature for 4 h, and then the reaction solution was dried to obtain crude ((R)-1-(5-amino-3-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-yl)ethanone. (ES, m / z): 340.10 [M+H] + .

[0420] Step c: TEA (220 mg, 2.175 mmol, 3.0 eqv) was added to a solution of (R)-1-(5-amino-3-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-yl)ethanone (246 mg, 0.724 mmol, 1.0 eqv) in DCM (50 ml) at room temperature, followed by the addition of (Boc 2 O (316 mg, 1.448 mmol, 2.0 eqv), react at room temperature overnight. Water (50 ml) was added to the reaction solution, and the liquid was separated. The aqueous phase was extracted with DCM (20 ml × 2), and the organic phases were combined; and H 2 The combined organic phase was washed with 1,2-dihydro-1,4-dihydro-2-nitro-1-pyrazine (20 mL) and brine (20 mL), concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane:EA=5:1-1:5) to obtain tert-butyl (R)-(1'-(3-acetyl-6-aminopyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamate (221 mg, yield 69.5%). (ES, m / z): 440.15 [M+H] + .

[0421] Step d: At -15°C, NBS (94 mg, 0.528 mmol, 1.05 eqv) was added to a DCM (20 ml) solution containing tert-butyl (R)-(1'-(3-acetyl-6-aminopyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamate (221 mg, 0.503 mmol, 1.0 eqv), and the mixture was stirred at constant temperature for 10 min. The reaction solution was quenched by adding saturated sodium bicarbonate aqueous solution (10 ml), separated, the aqueous phase was extracted with DCM (10 ml×2), and the organic phases were combined; the organic phases were washed with H 2O (20 ml), washed with brine (20 ml), concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane:EA=5:1 to 1:1) to obtain (R)-(1'-(3-acetyl-6-amino-5-bromopyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamic acid tert-butyl ester (132 mg, yield 50.75%). (ES, m / z): 518.09 [M+H] + .

[0422] Intermediate Preparation Example 13: (R)-5-amino-6-bromo-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piperidinyl]-1'-yl)pyrazine-2-carboxylic acid methyl ester (Intermediate 13)

[0423]

[0424] Step a: 3-chloro-5-((2,4-dimethoxybenzyl)amino)pyrazine-2-carboxylic acid methyl ester (200 mg, 0.593 mmol, 1.0 eqv), (R)-2-methyl-N-((R)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)propane-2-sulfenamide (201 mg, 0.653 mmol, 1.1 eqv) and DIPEA (230 mg, 1.779 mmol, 3.0 eqv) in DMSO (10 ml) were reacted at 110° C. for 10 h; the mixture was cooled to room temperature, water (60 ml) and EA (60 ml) were added to the reaction solution, the solution was separated, the aqueous phase was extracted with EA (3×20 ml), and the organic phases were combined; the organic phase was purified by HPLC with H 2 O (100 ml), washed with brine (50 ml), concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA: MeOH = 80: 1 to 20: 1) to obtain 5-((2,4-dimethoxybenzyl)amino)-3-((R)-3-((R)-1,1-dimethylethylsulfonylamino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazine-2-carboxylic acid methyl ester (305 mg, yield 84.42%). (ES, m / z): 610.20 [M+H] + .

[0425] Step b: To 5-((2,4-dimethoxybenzyl)amino)-3-((R)-3-((R)-1,1-dimethylethylsulfonamido)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazine-2-carboxylic acid methyl ester (305 mg, 0.501 mmol, 1.0 eqv) was added CF 3COOH (6 ml), stirred at room temperature for 3 h, and then the reaction solution was dried to give crude 5-amino-3-((R)-3-((R)-1,1-dimethylethylsulfonylamino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazine-2-carboxylic acid methyl ester (230 mg). (ES, m / z): 460.15 [M+H] + .

[0426] Step c: To the crude methyl 5-amino-3-((R)-3-((R)-1,1-dimethylethylsulfonamido)-3H-spiro[benzofuran-2,4′-piperidinyl]-1′-yl)pyrazine-2-carboxylate (230 mg) was added HCl / CH 3 OH solution (10 mL), stirred at room temperature for 2 h, and then the reaction solution was dried to obtain crude (R)-5-amino-3-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazine-2-carboxylic acid methyl ester (178 mg). (ES, m / z): 356.11 [M+H] + .

[0427] Step d: TEA (253.3 mg, 2.505 mmol, 5.0 eqv) was added to a solution of (R)-5-amino-3-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazine-2-carboxylic acid methyl ester (178 mg, 0.501 mmol, 1.0 eqv) in DCM (20 ml) at room temperature, followed by the addition of (Boc 2 O (142 mg, 0.651 mmol, 1.3 eqv), react at room temperature overnight. Water (25 ml) was added to the reaction solution, and the liquid was separated. The aqueous phase was extracted with DCM (10 mL × 2), and the organic phases were combined; the organic phase was washed with H 2 O (20 ml), washed with brine (20 ml), concentrated under reduced pressure, and purified by silica gel column chromatography, with the eluent being DCM:MeOH = 100:1 to 20:1, to obtain (R)-5-amino-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piperidinyl]-1'-yl)pyrazine-2-carboxylic acid methyl ester (133 mg, yield 58.3%). (ES, m / z): 456.16 [M+H] + .

[0428] Step e: At -15°C, NBS (57 mg, 0.321 mmol, 1.1 eqv) was added to a DCM (30 ml) solution of (R)-5-amino-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazine-2-carboxylic acid methyl ester (133 mg, 0.292 mmol, 1.0 eqv) and the mixture was kept warm for 10 min. Saturated aqueous sodium bicarbonate solution (20 ml) was added to the reaction solution, the liquid was separated, the aqueous phase was extracted with DCM (10 ml×2), and the organic phases were combined; the organic phase was washed with H 2 O (20 ml), washed with brine (20 ml), concentrated under reduced pressure, purified by silica gel column chromatography, the eluent was n-hexane:EA = 5:1 to 1:2, to obtain (R)-5-amino-6-bromo-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazine-2-carboxylic acid methyl ester (100 mg, yield 64.3%). (ES, m / z): 534.09 [M+H] + .

[0429] Intermediate Preparation Example 14: (R)-6-bromo-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piperidinyl]-1'-yl)pyrazine-2-carboxylic acid methyl ester (Intermediate 14)

[0430]

[0431] Step a: A solution of 3,6-dibromopyrazine-2-carboxylic acid methyl ester (460 mg, 1.555 mmol, 1.0 eqv), (R)-2-methyl-N-((R)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)propane-2-sulfenamide (575 mg, 1.866 mmol, 1.2 eqv) and DIPEA (603 mg, 4.6655 mmol, 3.0 eqv) in DMSO (10 ml) was reacted at 110° C. for 6 h; cooled to room temperature, water (50 ml) was added, extracted with EA (3×30 ml), and the organic phases were combined; the organic phases were washed with H 2 O (100 ml), washed with brine (100 ml), concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM: MeOH = 100: 1 to 40: 1) to obtain 6-bromo-3-((R)-3-((R)-1,1-dimethylethylsulfonylamino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazine-2-carboxylic acid methyl ester (375 mg, yield 46.2%). (ES, m / z): 523.01 [M+H] + .

[0432] Step b: To 6-bromo-3-((R)-3-((R)-1,1-dimethylethylsulfonamido)-3H-spiro[benzofuran-2,4′-piperidinyl]-1′-yl)pyrazine-2-carboxylic acid methyl ester (375 mg, 0.718 mmol, 1.0 eqv) was added HCl / CH 3 OH solution (10 ml), stirred at room temperature for 4 hours, and then the reaction solution was dried to obtain crude (R)-3-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-6-bromopyrazine-2-carboxylic acid methyl ester. (ES, m / z): 419.02 [M+H] + .

[0433] Step c: TEA (218 mg, 2.155 mmol, 3.0 eqv) was added to a solution of (R)-3-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-6-bromopyrazine-2-carboxylic acid methyl ester (300 mg, 0.718 mmol, 1.0 eqv) in DCM (50 ml) at room temperature, and then (Boc) was added. 2 O (299 mg, 1.437 mmol, 2.0 eqv), react at room temperature overnight. Water (50 ml) was added to the reaction solution, and the liquid was separated. The aqueous phase was extracted with DCM (20 ml × 2), and the organic phases were combined; 2 The combined organic phase was washed with 1% 4-(4-nitro-2-nitro-2-yl)-1-nitro-2-ol (20 mL) and brine (20 mL), concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane:EA=5:1-1:5) to obtain (R)-6-bromo-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazine-2-carboxylic acid methyl ester (279 mg, yield 75%). (ES, m / z): 519.09 [M+H] + .

[0434] Intermediate Preparation Example 14A:

[0435] Intermediate 14A was synthesized using the steps of Intermediate Preparation Example 14 and the following corresponding starting materials:

[0436]

[0437] Intermediate Preparation Example 15: (R)-tert-butyl (1'-(3-acetyl-5-bromopyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamate (Intermediate 15)

[0438]

[0439] Step a: (R)-6-bromo-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piperidinyl]-1'-yl)pyrazine-2-carboxylic acid methyl ester (500 mg, 0.965 mmol, 1 eqv), LiOH. 2 A solution of 1H O (81 mg, 1.93 mmol, 2 eqv) in THF (10 ml) and water (10 ml) was reacted at room temperature overnight; the pH was adjusted to 3-4 with 1N HCl solution, and the mixture was concentrated under reduced pressure. Water (60 ml) and EA (60 ml) were added to the residue, and the phases were separated. The aqueous phase was extracted with EA (3×20 ml), and the organic phases were combined; the organic phase was purified by evaporation with H 2 O (100 ml), washed with brine (50 ml), concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM: MeOH = 80: 1 to 20: 1) to obtain (R)-6-bromo-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazine-2-carboxylic acid (440 mg, yield 90.45%). (ES, m / z): 505.02 [M+H] + .

[0440] Step b: Under nitrogen protection, to a solution of (R)-6-bromo-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piperidinyl]-1'-yl)pyrazine-2-carboxylic acid (400 mg, 0.793 mmol, 1 eqv) in anhydrous DMF (10 ml) at 0°C, methoxymethylamine (58 mg, 0.952 mmol, 1.2 eqv), EDCI (182.4 mg, 0.952 mmol, 1.2 eqv), HOBt (128.6 mg, 0.952 mmol, 1.2 eqv) and Et 3 N (160 mg, 1.586 mmol, 2 eqv), and then react at room temperature for 6 h; water (60 ml) and EA (60 ml) were added to the reaction, and the liquids were separated. The aqueous phase was extracted with EA (3 × 20 ml), and the organic phases were combined; the organic phase was washed with H 2 O (100 ml), washed with brine (50 ml), concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM: MeOH = 100: 1 to 25: 1) to obtain (R)-(1'-(5-bromo-3-(methoxy(methyl)carbamoyl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamic acid tert-butyl ester (227 mg, yield 52.32%). (ES, m / z): 548.10 [M+H] + .

[0441] Step c: Under nitrogen protection, methylmagnesium bromide (3.0M, 0.276ml, 2eqv) was added dropwise to a solution of (R)-(1'-(5-bromo-3-(methoxy(methyl)carbamoyl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamic acid tert-butyl ester (227mg, 0.415mmol, 1eqv) in anhydrous THF (10ml) at -78°C, and the temperature was naturally raised to 0°C for reaction for 2h; saturated NH 4 The reaction was quenched with Cl solution; water (60 ml) and EA (60 ml) were added to the reaction, the liquids were separated, the aqueous phase was extracted with EA (3 × 20 ml), and the organic phases were combined; the organic phases were treated with H 2 O (100 ml), washed with brine (50 ml), concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM: MeOH = 50: 1 to 20: 1) to obtain (R)-(1'-(3-acetyl-5-bromopyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamic acid tert-butyl ester (100 mg, yield 48%). (ES, m / z): 503.07 [M+H] + .

[0442] Intermediate Preparation Examples 15A to 15C:

[0443] Intermediates 15A to 15C were synthesized using the steps of Intermediate Preparation Example 15 and the following corresponding starting materials:

[0444]

[0445] Intermediate Preparation Example 16: 6-Chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)-5-(oxetan-3-yl)pyrazin-2-amine (Intermediate 16)

[0446]

[0447] Step a: Under nitrogen protection, 3-bromo-6-chloro-pyrazine-2-amine (5.00 g, 23.988 mmol, 1.00 equiv), 2-chloro-3-(oxazol-2-yl)benzenethiol (6.70 g, 28.786 mmol, 1.2 eqv), DIPEA (9.30 g, 71.963 mmol, 3.0 eqv), Pd 2 (dba) 3 .CHCl 3A solution of 1,4-dioxane (100 mL) and 2-(2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl]pyrazine-2-amine (intermediate M16-1) (5.86 g, yield 72.3%) was prepared by reacting 2-(2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)pyrazine-2-amine (0.62 g, 0.600 mmol, 0.025 eqv) and XantPhos (0.69 g, 1.199 mmol, 0.05 eqv) at 95°C overnight, cooling to room temperature, and filtering the reaction solution through diatomaceous earth. The filtrate was concentrated under reduced pressure; the residue was purified by column chromatography (n-hexane:EA=2:1) ​​to obtain 6-chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl]pyrazine-2-amine (intermediate M16-1) (5.86 g, yield 72.3%). (ES, m / z): 338.90 [M+H] + .

[0448] Step b: Under nitrogen protection, at 0°C, add 6-chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl]pyrazine-2-amine (5.50 g, 26.085 mmol, 1.00 eqv), K 2 CO 3 To a solution of 1.50 eqv (7.20 g, 52.17 mmol, 2.00 eqv) in MeOH (160 ml), add dropwise a solution of ICl (6.35 g, 39.128 mmol, 1.50 eqv) in DCM (160 ml), control the temperature to react for 2 h, and then react at room temperature overnight; add 500 ml of 10% Na 2 SO 3 The mixture was quenched, separated, and the aqueous phase was extracted with DCM (3×250 ml). The organic phases were combined; the organic phases were washed with saturated NaCl 250 ml, dried over anhydrous sodium sulfate, and concentrated under reduced pressure; 6-chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)-5-iodopyrazine-2-amine (Intermediate M16-2) (8.71 g, yield 72%) was obtained. (ES, m / z): 464.80 [M+H] + .

[0449] Step c: Replace nitrogen with dtbpy (551 mg, 1.832 mmol, 0.10 eqv) and DMA (200 ml), add NiBr 2.DME (724 mg, 1.832 mmol, 0.10 eqv), stirred at room temperature for 0.5 h; then 6-chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)-5-iodopyrazine-2-amine (8.5 g, 18.324 mmol, 1.00 eqv), 3-bromooxetane (5.624 g, 36.647 mmol, 2.00 eqv), TBAI (758.2 mg, 1.832 mmol) were added. mol, 0.10eqv), Zn (2.686g, 36.647mmol, 2.00eqv), under nitrogen protection, stirred at 75°C overnight; filtered through diatomaceous earth, the filtrate was poured into water (1000ml), extracted with EA (2×500ml), and the organic phases were combined; the organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (20-50% acetonitrile aqueous solution gradient elution, 0.1% NH 4 HCO 3 Modification) to give 6-chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)-5-(oxetan-3-yl)pyrazin-2-amine (810 mg, yield 11.22%). (ES, m / z): 394.92 [M+H] + .

[0450] Intermediate Preparation Example 17: 6-Chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)-5-vinylpyrazine-2-amine (Intermediate 17)

[0451]

[0452] Under nitrogen protection, 6-chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)-5-iodopyrazin-2-amine (197 mg, 0.425 mmol, 1 eqv), potassium vinyl trifluoroborate (116 mg, 0.85 mmol, 2 eqv), Pd(PPh 3 ) 4 (50mg, 0.0425mmol, 0.1eqv), potassium carbonate (176mg, 1.275mmol, 3eqv) were added to toluene (60ml), ethanol (30ml) and water (15ml), and the reaction was carried out at 80°C for 5h; the reaction solution was concentrated under reduced pressure, water (100ml) was added to the residue, and it was extracted with EA (2×50ml), and the organic phases were combined; the organic phases were washed with brine (50ml), concentrated under reduced pressure, and the residue was purified by column chromatography (CH 2 Cl 2 :CH 3OH=100:1), to give 6-chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)-5-vinylpyrazin-2-amine (101 mg, yield 65.3%). (ES, m / z): 364.93[M+H] + .

[0453] Intermediate Preparation Example 18: 4-(Oxazol-2-yl)pyrimidine-2-thiol (Intermediate 18)

[0454]

[0455] Step a: Under nitrogen protection, 2,4-diiodopyrimidine (7.96 g, 23.99 mmol, 1 eqv), methyl 3-mercaptopropionate (3.02 g, 25.19 mmol, 1.05 eqv), DIPEA (6.20 g, 47.97 mmol, 2 eqv), Pd(OAc) 2 (538.53mg, 2.40mmol, 0.1eqv) and Xantphos (2.08g, 3.60mmol, 0.15eqv) in 1,4-dioxane (160ml) were reacted at 95°C overnight; cooled to room temperature, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure; the residue was purified by column chromatography (n-hexane: EA = 100: 1 to 20: 1) to obtain methyl 3-((4-iodopyrimidin-2-yl)sulfanyl)propanoate (5g, yield 64.34%). (ES, m / z): 324.90 [M+H] + .

[0456] Step b: Under nitrogen protection, methyl 3-((4-iodopyrimidin-2-yl)sulfanyl)propanoate (595 mg, 1.834 mmol, 1.0 eqv), oxazol-2-ylboronic acid (228 mg, 2.02 mmol, 1.1 eqv), Pd(dppf)Cl 2 (134mg, 0.183mmol, 0.1eqv) and potassium carbonate (760mg, 5.503mmol, 3eqv) in 1,4-dioxane (50mL) and water (10ml) were reacted at 96°C overnight; the temperature was lowered and the mixture was concentrated under reduced pressure. Water (200ml) and EA (100ml) were added to the residue, and the mixture was separated. The aqueous phase was extracted with EA (2×50ml) and the organic phases were combined; the organic phase was washed with brine (100ml), concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane:EA=30:1~10:1) to obtain methyl 3-((4-(oxazol-2-yl)pyrimidin-2-yl)sulfanyl)propanoate (256mg, yield 52.65%). (ES,m / z):266[M+H] + .

[0457] Step c: Under nitrogen protection, methyl 3-((4-(oxazol-2-yl)pyrimidin-2-yl)sulfanyl)propanoate (256 mg, 0.966 mmol, 1.0 eqv) and a methanol (10 ml) solution of NaOH (40.6 mg, 1.014 mmol, 1.05 eqv) were reacted at 50°C for 4 h; the temperature was lowered to about 0°C, 4M HCl / MeOH solution was added dropwise, and the pH was adjusted to 3-4; silica gel was added and column chromatography was performed for purification (n-hexane:EA=10:1-5:1) to obtain 4-(oxazol-2-yl)pyrimidine-2-thiol (130 mg, yield 75.2%). (ES, m / z): 179.92 [M+H] + .

[0458] Intermediate Preparation Examples 19 to 22

[0459] Intermediates 19 to 22 were synthesized using the steps of Intermediate Preparation Example 18 and the following corresponding starting materials:

[0460]

[0461] Intermediate Preparation Example 23: (R)-2-methyl-N-((R)-3-deuterium-spiro[benzofuran-2,4'-piperidinyl]-3-yl)propane-2-sulfenamide (M-23)

[0462]

[0463] Steps a-b: Under nitrogen protection, Ti(OEt) was added to a solution of tert-butyl 3-oxospiro[1-benzofuran-2,4'-piperidine]-1'-carboxylate (10.00 g, 32.965 mmol, 1.00 eqv) and (R)-(+)-tert-butylsulfenamide (7.99 g, 65.93 mmol, 2 eqv) in 2-MeTHF (40 ml). 4 (100 ml), react at 80 ° C for 48 h; then cool to -5 ° C, add NaBD 4 (1.66 g, 39.55 mmol, 1.2 eqv), react at room temperature overnight; cool to 0°C, add methanol (30 ml) dropwise to the reaction solution, add water (1000 ml) and EA (1000 ml), stir for 30 min, filter, and separate the filtrate; wash the organic phase with brine (1000 ml), dry over anhydrous sodium sulfate, and concentrate under reduced pressure; the residue is purified by column chromatography (n-hexane: EA = 6:1 to 2:1) to obtain M23-2 (10.5 g, yield 77.78%), (ES, m / z): 410.13 [M+H] + .

[0464] 1 H-NMR (600MHz, CDCl3 )δ7.285-7.273(m,1H),7.250-7.224(m,1H),6.929-6.904(m,1H),6.817(d,J=7.8Hz,1H),4.086(br s,2H),3.673(s,1H),3.178(s,2H),2.011(s,1H),1.856(s,1H),1.770-1.748(m,1H),1.716-1.690(m,1H),1.465(s,9H),1.255(s,9H).

[0465] Step c: M23-2 (10.5 g) was dissolved in DCM (20 ml), trifluoroacetic acid (20 ml) was added dropwise at 0°C, the mixture was reacted at room temperature for 6 h, and the mixture was concentrated under reduced pressure. Water (50 ml) was added to the residue, the pH was adjusted to 10 with 25% aqueous ammonia, the aqueous phase was extracted with EA (50 ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (R)-2-methyl-N-((R)-3-deuterium-spiro[benzofuran-2,4'-piperidin]-3-yl)propane-2-sulfenamide (M-23) (7.84 g), which was used directly in the next step without purification. (ES, m / z): 310.07 [M+H] + .

[0466] Intermediate Preparation Example 24:

[0467] Intermediate 24 was synthesized using the steps of Intermediate Preparation Example 23 and the following corresponding starting materials:

[0468]

[0469] Intermediate Preparation Example 25: (R)-(1'-(3-acetyl-6-amino-5-bromopyrazin-2-yl)-3-deuterium-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamic acid tert-butyl ester (M-25)

[0470]

[0471] Step ab: Under nitrogen protection, 2-amino-5-bromo-6-chloropyrazine (20.0 g, 96.67 mmol, 1.0 eqv), tributyl(1-ethoxyvinyl)tin (52.36 g, 144.98 mmol, 1.5 eqv), CuI (1.84 g, 9.667 mmol, 0.1 eqv), Pd(Ph 3 P) 2 Cl 2(6.78 g, 9.667 mmol, 0.1 eqv) in 1,4-dioxane (240 ml) solution, react at 100 ° C overnight, TLC detection reaction is complete, (R)-2-methyl-N-((R)-3-deuterium-spiro[benzofuran-2,4'-piperidin]-3-yl)propane-2-sulfenamide (M-23) crude product (35.86 g, 115.987 mmol, 1. 2eqv) of 1,4-dioxane (200ml) was added to the reaction solution, and then DIPEA (37.48g, 289.97mmol, 3.0eqv) was added, and the reaction was carried out at 100°C overnight; the temperature was cooled to room temperature, and the mixture was concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (eluent: EA: n-hexane = 1:1 to 2:1) to obtain M25-1 (24.05g, yield 56.01%). (ES, m / z): 445.07[M+H] + .

[0472] Step c: To a solution of M25-1 (24.05 g, 54.14 mmol, 1.0 eqv) in DCM (250 ml) was added NBS (11.563 g, 64.97 mmol, 1.2 eqv) at 0°C, and the mixture was reacted overnight at room temperature, and then 4 M HCl / CH 3 OH solution (10 ml) was stirred for 1 h; saturated sodium bicarbonate aqueous solution (100 ml) was added to the reaction solution, the liquid was separated, the aqueous phase was extracted with DCM (50 ml × 2), and the organic phases were combined; the organic phase was washed with H 2 O (200 ml), washed with brine (200 ml), dried over anhydrous sodium sulfate, and filtered to obtain a DCM solution of crude M25-2, which was used directly in the next step without treatment. (ES, m / z): 419.00 [M+H] + .

[0473] Step d: At 0°C, add (Boc) to the DCM solution of M25-2 in step c 2 O (14.2 g), Et 3 N (10.96 g), after the addition, react at room temperature overnight; add water (200 ml), separate the layers, extract the aqueous phase with DCM (100 ml × 2), combine the organic phases; the organic phases are washed with H 2 O (200 ml), washed with brine (200 ml), concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (eluent: EA: n-hexane = 1:3 to 2:1) to obtain M-25 (16.43 g). (ES, m / z): 519.09 [M+H] + .

[0474] Intermediate Preparation Example 25A: Preparation of M-25A

[0475] Intermediate M-25A was synthesized using the steps of Intermediate Preparation Example 25 and the following corresponding starting materials:

[0476]

[0477] Intermediate Preparation Example 26:

[0478] Intermediate 26 was synthesized using the steps of Intermediate Preparation Example 13 and the following corresponding starting materials:

[0479]

[0480] Intermediate Preparation Example 27: Preparation of M-27

[0481]

[0482] Step a: Under nitrogen protection, M-25 (3.00 g, 5.78 mmol, 1.0 eqv), methyl 3-mercaptopropionate (1.04 g, 8.67 mmol, 1.5 eqv), Pd(OAc) 2 (250 mg, 1.16 mmol, 0.2 eqv), Xantphos (1.34 g, 2.31 mmol, 0.4 eqv), DIPEA (2.25 g, 7.34 mmol, 3 eqv) in 1,4-dioxane (60 ml) reaction solution, react at 97 ° C overnight. Cool down, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent EA: n-hexane = 1:3 to 2:1) to obtain M27-1 (3.00 g, yield 93%), (ES, m / z): 559.17 [M+H] + .

[0483] Step b: To a solution of M27-1 (3.00 g, 5.37 mmol, 1.0 eqv) in MeOH (30 ml), add NaOH (242 mg, 5.907 mmol, 1.1 eqv), and stir at 55 °C for 2 h; concentrate under reduced pressure, add water (100 ml) to the concentrate and mix, adjust the pH to 3-4 with 1N HCl, extract with EA (100 ml×2), and combine the organic phases; the organic phases are purified by purifying with H 2 O (20 ml), washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain M-27 (1.33 g, yield 78.4%) (ES, m / z): 473.10 [M+H] + .

[0484] Intermediate Preparation Examples 28-30:

[0485] Intermediates 28 to 30 were synthesized using the steps of Intermediate Preparation Example 27 and the following corresponding starting materials:

[0486]

[0487] The following are preparation examples of exemplary compounds of the present application.

[0488] Preparation Example 1: (R)-1-(5-amino-3-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-6-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)pyrazin-2-yl)ethanone (Compound 1)

[0489]

[0490] Step a: Under nitrogen protection, tert-butyl (R)-(1'-(3-acetyl-6-amino-5-bromopyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamate (140 mg, 0.27 mmol, 1.0 eqv), 2-chloro-3-(oxazol-2-yl)benzenethiol (69 mg, 0.325 mmol, 1.2 eqv), DIPEA (123 mg, 0.954 mmol, 3.5 eqv), Pd 2 (dba) 3 (50 mg, 0.054 mmol, 0.2 eqv) and Xantphos (63 mg, 0.109 mmol, 0.4 eqv) in 1,4-dioxane (10 mL) were reacted at 96°C for 6 h; the temperature was lowered to room temperature, silica gel was added to the reaction solution, and it was purified by silica gel column chromatography (eluent was n-hexane:EA=10:1-1:2) to obtain (R)-(1'-(3-acetyl-6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamic acid tert-butyl ester (152 mg, yield 86.85%). (ES, m / z): 649.14[M+H] + .

[0491] Step b: To a solution of (R)-(1'-(3-acetyl-6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamic acid tert-butyl ester (152 mg) in dichloromethane (10 ml) was added trifluoroacetic acid (5 ml) and stirred at room temperature for 3 h; the reaction solution was concentrated under reduced pressure, EA (50 ml) and water (50 ml) were added to the residue, the pH was adjusted to 10 with 25% ammonia water, and the layers were separated; the aqueous phase was extracted with EA (20 ml), and the organic phases were combined; the organic phase was washed with water (50 ml) and brine (50 ml), and concentrated under reduced pressure; the residue was purified by column chromatography (CH 2 Cl2 :CH 3 OH=20:1~15:1), to obtain (R)-1-(5-amino-3-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-6-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)pyrazin-2-yl)ethanone (120 mg, yield 93.4%). (ES, m / z): 549.10[M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ8.33.(s,1H),7.750(d,J=6.6Hz,1H),7.476(s,1H),7.4 16(t,J=7.8Hz,1H),7.321(d,J=7.2Hz,1H),7.148-7.060(m,4H),6.859(t,J=7.2Hz ,1H),6.772(d,J=7.2Hz,1H),4.105(s,1H),3.876-3.854(m,1H),3.762-3.740(m, 1H),3.309-3.290(m,1H),2.320(s,3H),2.033-1.985(m,3H),1.867-1.705(m,4H).

[0492] Preparation Examples 2 to 15 and 11A:

[0493] Referring to the synthetic route and operation of Preparation Example 1, compounds 2 to 15 and 11A were prepared using the corresponding intermediates as starting materials.

[0494]

[0495]

[0496]

[0497] Preparation Example 16: (R)-5-amino-3-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-6-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)pyrazine-2-carboxylic acid methyl ester (Compound 16)

[0498]

[0499] Step a: Under nitrogen protection, (R)-5-amino-6-bromo-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazine-2-carboxylic acid methyl ester (144 mg, 0.27 mmol, 1.0 eqv), 2-chloro-3-(oxazol-2-yl)benzenethiol (69 mg, 0.324 mmol, 1.2 eqv), DIPEA (123 mg, 0.954 mmol, 3.5 eqv), Pd 2 (dba) 3 A solution of (50 mg, 0.054 mmol, 0.2 eqv) and Xantphos (63 mg, 0.109 mmol, 0.4 eqv) in 1,4-dioxane (20 ml) was reacted at 96°C for 6 h; the temperature was lowered to room temperature, silica gel was added to the reaction solution, and the solution was purified by silica gel column chromatography (eluent was n-hexane:EA=20:1 to 1:1) to obtain (R)-5-amino-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piperidinyl]-1'-yl)-6-(2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)pyrazine-2-carboxylic acid methyl ester (152 mg, yield 84.75%). (ES, m / z): 665.14[M+H] + .

[0500] Step b: To a solution of (R)-5-amino-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piperidinyl]-1'-yl)-6-(2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)pyrazine-2-carboxylic acid methyl ester (152 mg) in dichloromethane (20 ml), trifluoroacetic acid (5 ml) was added and the mixture was stirred at room temperature for 3 h; the reaction solution was concentrated under reduced pressure, EA (100 ml) and water (50 ml) were added to the residue, the pH was adjusted to 10 with 25% aqueous ammonia, and the layers were separated; the aqueous phase was extracted with EA (20 ml), and the organic phases were combined; the organic phases were washed with water (50 ml) and brine (50 ml), dried over anhydrous sodium sulfate, and concentrated; the residue was purified by column chromatography (CH 2 Cl 2 :CH 3 OH=50:1~15:1), to obtain (R)-5-amino-3-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-6-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)pyrazine-2-carboxylic acid methyl ester (118 mg, yield 91.4%). (ES, m / z): 565.10[M+H] + .

[0501] Preparation Examples 17 to 20:

[0502] Referring to the synthetic route and operation of Preparation Example 16, compounds 17 to 20 were prepared using the corresponding intermediates as starting materials.

[0503]

[0504] Preparation Example 21: (R)-1'-(6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)-3-(oxetan-3-yl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-amine (Compound 21)

[0505]

[0506] Step a: A solution of 6-chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)-5-(oxetan-3-yl)pyrazin-2-amine (613 mg, 1.556 mmol, 1.0 eqv), (R)-2-methyl-N-((R)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)propane-2-sulfinamide (575 mg, 1.867 mmol, 1.2 eqv) and DIPEA (603 mg, 4.665 mmol, 3.0 eqv) in DMSO (10 ml) was reacted at 110° C. for 6 h; the temperature was cooled to room temperature, water (100 ml) was added, and the mixture was extracted with EA (3×50 ml), and the organic phases were combined; the organic phases were purified by HPLC with H 2 O (50 ml), washed with brine (50 ml), concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM: MeOH = 100: 1 to 25: 1) to obtain (R)-N-((R)-1'-(6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)-3-(oxetan-3-yl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)-2-methylpropane-2-sulfenamide (677 mg, yield 65.31%). (ES, m / z): 667.11 [M+H] + .

[0507] Step b: To (R)-N-((R)-1'-(6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)-3-(oxetan-3-yl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)-2-methylpropane-2-sulfenamide (677 mg) was added HCl / CH 3OH solution (60 mL), react at room temperature overnight, the reaction solution was concentrated under reduced pressure, EA (50 ml) and water (50 ml) were added to the residue, pH was adjusted to 9-10 with 25% ammonia water, and the liquid was separated; the aqueous phase was extracted with EA (20 ml), and the organic phases were combined; the organic phase was washed with water (50 ml) and brine (50 ml), and concentrated; the residue was purified by column chromatography (CH 2 Cl 2 :CH 3 OH=20:1), to obtain (R)-1'-(6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)-3-(oxetan-3-yl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-amine (487 mg, yield 85.2%). (ES, m / z): 563.10[M+H] + .

[0508] Preparation Example 22:

[0509] Referring to the synthetic route and operation of Preparation Example 21, Compound 22 was prepared using the corresponding intermediate as a starting material.

[0510]

[0511] Preparation Example 23: (R)-1'-(6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)-3-fluoropyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-amine (Compound 23)

[0512]

[0513] Step a: A solution of 6-chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)pyrazin-2-amine (526 mg, 1.556 mmol, 1.0 eqv), (R)-2-methyl-N-((R)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)propane-2-sulfinamide (575 mg, 1.867 mmol, 1.2 eqv) and DIPEA (603 mg, 4.665 mmol, 3.0 eqv) in DMSO (10 ml) was reacted at 100° C. overnight; the temperature was cooled to room temperature, water (100 ml) was added, and the mixture was extracted with EA (3×50 ml), and the organic phases were combined; the organic phases were purified by HPLC with H 2O (50 ml), washed with brine (50 ml), concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM: MeOH = 80: 1 to 25: 1) to obtain (R)-N-((R)-1'-(6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)-2-methylpropane-2-sulfenamide (724 mg, yield 76.26%). (ES, m / z): 611.09 [M+H] + .

[0514] Step b: To (R)-N-((R)-1'-(6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)-2-methylpropane-2-sulfenamide (724 mg) was added HCl / CH 3 OH solution (50 mL), react at room temperature overnight, the reaction solution was concentrated under reduced pressure, EA (50 ml) and water (50 ml) were added to the residue, pH was adjusted to 9-10 with 25% ammonia water, and the liquid was separated; the aqueous phase was extracted with EA (20 ml), and the organic phases were combined; the organic phase was washed with water (50 ml) and brine (50 ml), and concentrated; the residue was purified by column chromatography (CH 2 Cl 2 :CH 3 OH=30:1~15:1), to obtain (R)-1'-(6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-amine (557 mg, yield 92.75%). (ES, m / z): 507.03[M+H] + .

[0515] Step c: Under nitrogen protection, to a solution of (R)-1'-(6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-amine (557 mg, 1.1 mmol, 1 eqv) in acetonitrile (100 ml) at -15°C was added N-fluorobisbenzenesulfonamide (380 mg, 1.21 eqv, 1.1eqv), slowly warmed to room temperature after addition, reacted overnight; concentrated under reduced pressure, purified by two Pre-TLC (DCM:MeOH=15:1) to obtain (R)-1'-(6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)-3-fluoropyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]-3-amine (109 mg, yield 18.9%). (ES, m / z): 525.09[M+H]+ .

[0516] Preparation Example 24: (R)-1-(5-amino-3-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-6-((2-(oxazol-2-yl)pyrimidin-4-yl)sulfanyl)pyrazin-2-yl)ethanone (Compound 24)

[0517]

[0518] Step a: Under nitrogen protection, tert-butyl (R)-(1'-(3-acetyl-6-amino-5-bromopyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamate (140 mg, 0.27 mmol, 1.0 eqv), 2-(oxazol-2-yl)pyrimidine-4-thiol (58 mg, 0.325 mmol, 1.2 eqv), DIPEA (123 mg, 0.954 mmol, 3.5 eqv), Pd 2 (dba) 3 A solution of (50 mg, 0.054 mmol, 0.2 eqv) and Xantphos (63 mg, 0.109 mmol, 0.4 eqv) in 1,4-dioxane (10 mL) was reacted at 96°C for 6 h; the temperature was lowered to room temperature, silica gel was added to the reaction solution, and the solution was purified by silica gel column chromatography (eluent was n-hexane:EA=10:1-1:2) to obtain (R)-(1'-(3-acetyl-6-amino-5-((2-(oxazol-2-yl)pyrimidin-4-yl)sulfanyl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamic acid tert-butyl ester (126 mg, yield 75.74%). (ES, m / z): 617.14[M+H] + .

[0519] Step b: To a solution of (R)-(1'-(3-acetyl-6-amino-5-((2-(oxazol-2-yl)pyrimidin-4-yl)sulfanyl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamic acid tert-butyl ester (126 mg) in dichloromethane (5 ml) was added trifluoroacetic acid (5 ml) and stirred at room temperature for 3 h; the reaction solution was concentrated under reduced pressure, EA (50 ml) and water (50 ml) were added to the residue, the pH was adjusted to 10 with 25% ammonia water, and the layers were separated; the aqueous phase was extracted with EA (20 ml), and the organic phases were combined; the organic phase was washed with water (50 ml) and brine (50 ml), and concentrated under reduced pressure; the residue was purified by column chromatography (CH 2 Cl 2 :CH 3OH=20:1~15:1), to obtain (R)-1-(5-amino-3-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-6-((2-(oxazol-2-yl)pyrimidin-4-yl)sulfanyl)pyrazin-2-yl)ethanone (97 mg, yield 91.9%). (ES, m / z): 517.10[M+H] + .

[0520] Referring to the preparation process routes and operations of Intermediate Preparation Examples 1 to 22 and Preparation Examples 1 to 24, compounds 25 to 55 were prepared using 2,4-diiodopyrimidine and corresponding intermediates.

[0521]

[0522]

[0523]

[0524] Preparation Example 56: (R)-1-(5-amino-6-((2-amino-3-chloropyridin-4-yl)sulfanyl)-3-(3-amino-3-deuterio-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-yl)ethanone (Compound 56)

[0525]

[0526] Step a: Under nitrogen protection, M-27 (256 mg, 0.542 mmol, 1.0 eqv), 2-amino-3-chloro-4-iodopyridine (207 mg, 0.813 mmol, 1.5 eqv), Pd 2 (dba) 3 The reaction mixture was prepared by mixing a solution of 1,4-dioxane (20 ml) with (99 mg, 0.108 mmol, 0.2 eqv), Xantphos (125 mg, 0.217 mmol, 0.4 eqv), and DIPEA (245 mg, 1.897 mmol, 3.5 eqv) and the mixture was reacted at 97°C overnight. The reaction mixture was cooled and concentrated to dryness. Water (30 ml) was added to the concentrate, and the mixture was extracted with EA (20 ml × 2). The organic phases were combined. The organic phases were purified by HPLC. 2 O (20 ml), washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: n-hexane:EA=5:1-1:3) to obtain M56-1 (300 mg, yield 92%), (ES, m / z): 599.17 [M+H] + .

[0527] Step b: To a solution of M56-1 (300 mg, 0.501 mmol, 1.0 eqv) in DCM (5 ml) was added CF 3 COOH (5 ml), stirred at room temperature for 2 h, the reaction solution was spin-dried, water (30 ml) and EA (30 ml) were added to the residue, the pH was adjusted to 9-10 with 25% ammonia water, the liquid was separated, the aqueous phase was extracted with EA (20 ml × 2), and the organic phases were combined; the organic phase was extracted with H 2 O (20 ml), brine (20 ml), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: CH 2 Cl 2 :CH 3 OH=20:1~15:1), to obtain (R)-1-(5-amino-6-((2-amino-3-chloropyridin-4-yl)sulfanyl)-3-(3-amino-3-deuterium-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-yl)ethanone (200 mg, yield 80%) (ES, m / z): 499.10 [M+H] + . 1 H-NMR(600MHz,DMSO-d6)δ7.686(d,J=5.4Hz,1H),7.321(d,J=7.2Hz,1H),7.141(t,J=7.2H z,1H),7.081(s,2H),6.862(t,J=7.2Hz,1H),6.773(d,J=7.2Hz,1H),6.315(s,2H),5.887( d,J=5.4Hz,1H),3.882-3.860(m,1H),3.768-3.747(m,1H),3.372-3.330(m,1H),3.293-3. 286(m,1H),2.381(s,3H),2.029-1.980(m,2H),1.861-1.773(m,2H),1.727-1.704(m,1H).

[0528] Preparation Examples 56A, 57-59:

[0529] Referring to the synthetic route and operation of Preparation Example 56, compounds 56A, 57 to 59 were prepared using the corresponding intermediates as starting materials.

[0530]

[0531]

[0532] Preparation Example 60: Preparation of Compound 60

[0533]

[0534] Step a: Under nitrogen protection, M-25 (840 mg, 2.004 mmol, 1.0 eqv), 2-chloro-3-(oxazol-2-yl)benzenethiol (634 mg, 3.006 mmol, 1.5 eqv), DIPEA (906 mg, 7.014 mmol, 3.5 eqv), Pd 2 (dba) 3 (367 mg, 0.401 mmol, 0.2 eqv) and Xantphos (464 mg, 0.802 mmol, 0.4 eqv) in 1,4-dioxane (10 mL) were reacted at 96°C overnight; cooled to room temperature, silica gel was added to the reaction solution, and purified by silica gel column chromatography (eluent: n-hexane:EA=5:1-3:1) to obtain M60-1 (600 mg, yield 46%). (ES, m / z): 650.12 [M+H] + .

[0535] Step b: trifluoroacetic acid (5 ml) was added to a solution of M60-1 (600 mg, 0.924 mmol) in dichloromethane (15 ml), and the mixture was stirred at room temperature for 3 h; the reaction solution was concentrated under reduced pressure, EA (50 ml) and water (50 ml) were added to the residue, the pH was adjusted to 10 with 25% aqueous ammonia, and the layers were separated; the aqueous phase was extracted with EA (20 ml), and the organic phases were combined; the organic phase was washed with water (50 ml) and brine (50 ml), and concentrated under reduced pressure; the residue was purified by column chromatography (CH 2 Cl 2 :CH 3 OH=40:1~15:1), to obtain compound 60 (350 mg, yield 69%). (ES, m / z): 550.12[M+H] + .

[0536] Preparation Example 61:

[0537] Referring to the synthetic route and operation of Preparation Example 60, Compound 61 was prepared using the corresponding intermediate as the starting material.

[0538]

[0539]

[0540] Preparation Example 62:

[0541] Referring to the synthetic route and operation of Preparation Example 60, Compound 62 was prepared using the corresponding intermediate as the starting material.

[0542]

[0543] Note: Preparation of positive drug: Compound TW-45 (structure as follows) was prepared according to the preparation method of compound 45 in TW201840553A.

[0544]

[0545] The following describes the biological tests of the compounds of the present application.

[0546] Test Example 1: Test on the inhibitory effect on SHP2 enzyme

[0547] 1. Preparation of working buffer and compound preparation

[0548] Prepare working buffer 1x kinase buffer. Dilute the test compound to a stock concentration of 10mM with DMSO solvent. First dilute the test compound to an intermediate concentration of 1000μM, and then dilute it 3 times with DMSO. Therefore, the intermediate gradient dilution concentration of the test compound is: 1000μM, 3-fold dilution, 11 gradients. Using the Echo550 instrument, transfer 100nl of each concentration of the compound in the 384LDVecho plate to a new 384 enzyme-linked assay plate (corning, Cat#4514), ensuring that the final concentration of the test compound after adding 10μl of the reaction reagent is 10μM, 3-fold dilution, 11 gradients, 2 replicates. The final DMSO concentration is 1%. For both the negative control wells and the positive control wells, 100nl DMSO will be transferred.

[0549] 2. SHP2 enzymatic reaction steps

[0550] Use 1X enzyme buffer to prepare a mixture of 2X working SHP2 reagent (0.4nM) and 0.5μM SHP-2 activation peptide (BPSbioscience#79319-2). After incubating the above mixture at 25°C for 60 minutes, use a pipette to transfer 5μl of activated SHP2 kinase solution to the compound wells and Max control wells (Corning, #4514) of the compound plate. Then transfer 5μl of 1x kinase buffer to the Min control well. Centrifuge at 1000rpm for 30 seconds. Seal the plate and incubate the plate in a constant temperature incubator at 25°C for 30 minutes. Prepare DiFMUP (#D6567, Invitrogen) with 1x kinase buffer. TM) substrate solution, the concentration of which should be twice the final concentration of the experiment (DiFMUP final concentration: 10μM). Use an electric pipette to transfer 5μl of the prepared substrate solution to each well of the ELISA plate to start the reaction. Centrifuge at 1000rpm for 30 seconds. Seal the plate and incubate it in a constant temperature incubator at 25℃ for 60 minutes. Place the ELISA plate on the Spark machine and read the data at excitation / emission wavelengths of 358 / 455nm.

[0551] 3. Calculation method and test results:

[0552] The RLU values ​​were copied from Spark and the inhibition rate was calculated using the RLU values: inhibition rate = (maximum value - sample RLU) / (maximum value - minimum value) * 100, where "minimum value" refers to the RLU of the no enzyme control and "maximum value" refers to the RLU of the DMSO control. The data were fitted in XLFitexcel plugin version 5.4.0.8 to obtain IC 50 The results are shown in Table 1.

[0553] Table 1 Enzymatic effect test of the compounds of the present application on SHP2

[0554] Preparation Example No. Enzymology Preparation Example No. Enzymology Preparation Example No. Enzymology 1 A 22 A 58 A 8 A 23 A 59 A 16 A 24 A 60 A 19 A 56 A 61 A 21 A 57 A 62 A

[0555] Note: Compounds denoted as "A" have an IC less than or equal to 20 nM 50 value.

[0556] The above data show that the compounds of the present application have a strong inhibitory effect on SHP2 kinase.

[0557] Test Example 2: In vitro inhibition of proliferation of human acute myeloid leukemia MV-4-11 cells

[0558] 1. Test materials:

[0559] The human acute myeloid leukemia MV-4-11 cells used in the experiment were purchased from the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. The complete medium required for cell culture was IMDM (GIBCO) supplemented with 10% fetal bovine serum (GIBCO). The cells were incubated at 37°C and 5% CO 2 The test samples were cultured in an incubator. The reagents used in the experiment included dimethyl sulfoxide (purchased from Tianjin Komiou Chemical Reagent Co., Ltd.) and MTT (Shanghai Tebo Chemical Technology Co., Ltd., CAS. NO. 298-93-1). The test samples were sealed and stored at 4°C.

[0560] 2. Test methods and results:

[0561] Use dimethyl sulfoxide as solvent to fully dissolve the test substance and prepare a concentration of 5×10 -2mol / L storage solution, store the storage solution at -20℃. Use complete culture medium as diluent, gradient dilute the test substance to different concentrations for later use. In a 96-well culture plate, add 100μL / well (2×10 4 100 μL / well of the corresponding test substance of different concentrations were added to the complete medium suspension of MV-4-11 cells (number of cells / well). Eight concentrations of each test substance were set, and three replicate wells were set for each concentration. The cells were incubated at 37°C and 5% CO 2 After 72 hours of exposure to the test substance, 20 μL / well of MTT was added and the cells were cultured in an incubator at 37°C and 5% CO 2 Culture in an incubator for 4 hours, discard the supernatant, add 150 μL / well of dimethyl sulfoxide, shake and mix, and use a microplate reader to detect the OD value at a wavelength of 550 nm. The wells with only cell suspension without the test substance are control wells, and the wells with only complete culture medium are blank wells. The following formula is used to calculate the inhibition rate of cell growth:

[0562] Inhibition rate = (control well OD - test well OD) / (control well OD - blank well OD) * 100%. According to the inhibition rate of each concentration, the half inhibition concentration IC was calculated using SPSS software. 50 The results are shown in Table 2.

[0563] Table 2 Cell proliferation inhibition effect test of the compounds of the present application

[0564]

[0565] Note: Compounds denoted as "A" have an IC less than or equal to 20 nM 50 value.

[0566] The above data show that the compounds of the present application show good inhibitory activity in human acute myeloid leukemia cell proliferation inhibition test.

[0567] Test Example 3: In vitro inhibitory effect on proliferation of human lung adenocarcinoma NCI-H441 cells

[0568] 1. Test materials:

[0569] The human lung adenocarcinoma cells NCI-H441 used in the experiment were purchased from ATCC, and the complete medium required for cell culture was RPMI1640 Medium (GIBCO) supplemented with 10% fetal bovine serum (GIBCO). The cells were incubated at 37°C and 5% CO 2 The cells were cultured in an incubator. The reagents used in the experiment included dimethyl sulfoxide (purchased from Sigma), 3D Cell Viability assay kit (purchased from Promega), and the control substance TW-45 was obtained by self-production. The test substances were sealed and stored at 4°C.

[0570] 2. Test methods and results:

[0571] Use dimethyl sulfoxide as solvent to fully dissolve the test substance and prepare a concentration of 1×10 -2 mol / L storage solution, store the storage solution at -20℃. Use complete culture medium as diluent, gradient dilute the test substance to different concentrations for use (the final test concentration is 10000, 3333, 1111, 370, 123, 41, 13.7, 4.5, 1.5, 0.5nM). Incubate the cells at 37℃, 5% CO 2 Incubate in an incubator for 5 days. On the 5th day, add 30 μL of reagent (Celltiter Glo Assay Kit-3D) to each well and shake the plate on a plate shaker (protected from light) for 30 minutes. Incubate the plate at room temperature (protected from light) for 120 minutes. Record the chemiluminescence value with a multiplate reader.

[0572] Data analysis, stability check using VC and PC data. Inhibition percentage = 100-(Signal cmpd -Signal Ave-PC ) / (Signal Ave-VC -Signal Ave-PC ) × 100. LUM: chemiluminescent signal of each well, VC: average chemiluminescent signal of high quality control (wells containing 0.1% DMSO), PC: average chemiluminescent signal of low quality control (blank medium only).

[0573] GraphPad Prism 8 software was used to calculate the IC50 of the compound and draw the effect-dose curve: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope)). X: logarithm of cpd concentration Y: inhibition percentage:

[0574] The results are shown in Table 3.

[0575] Table 3 NCI-H441 cell proliferation inhibition effect test of the present compounds

[0576]

[0577] Note: Compounds denoted as "A" have an IC less than or equal to 20 nM 50 The compounds denoted as “B” have IC values ​​greater than 20 nM and less than 50 nM. 50 value.

[0578] The above data show that the compounds of the present application show good inhibitory activity in the human lung adenocarcinoma cell proliferation inhibition test.

[0579] Test Example 4: Pharmacokinetics test in mice

[0580] 1. Test method:

[0581] ICR mice were orally administered with the compound at 10 mg / kg or 20 mg / kg. Blood was collected from the mouse orbits at different time points (0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h) after administration. The collected whole blood was anticoagulated with sodium heparin and centrifuged at 3000 g to obtain mouse plasma samples. Methanol protein precipitation was used, and the drug concentration in mouse plasma after administration was determined by HPLC-MS / MS. The drug-time curve was drawn and the pharmacokinetic parameters were calculated. The pharmacokinetic behavior of the compound in mice after administration was described by non-compartmental statistical moment parameters.

[0582] 2. Test results:

[0583] The above-mentioned pharmacokinetic test was carried out on the compound of Preparation Example 1 and the compound of Preparation Example 56 of the present application. The test results showed that the compounds of the present application had a higher exposure amount in mice and were better absorbed.

[0584] Table 4 Results of pharmacokinetic experiments on the compounds of this application in mice

[0585]

[0586] Test Example 5: hERG Test

[0587] 1. Test method:

[0588] This test includes the following aspects:

[0589] hERG currents were recorded using the manual patch clamp technique in CHO-K1 cells stably expressing hERG channels;

[0590] The inhibition rate of each concentration was calculated based on the hERG tail current;

[0591] Each compound was tested at 5 concentrations and the IC 50 value;

[0592] Three cells were tested at each concentration;

[0593] A positive control drug.

[0594] The hERG current was recorded using the whole-cell patch clamp technique. The cell suspension was added to the cell trough and placed on an upright microscope stage. After the cells adhered to the wall, they were perfused with extracellular fluid at a flow rate of 1-2 mL / min. The glass microelectrode was pulled in two steps by a microelectrode puller, and its water resistance was 2-5 MΩ. After establishing the whole-cell recording, the clamping potential was maintained at -80 mV. When a voltage stimulus was given, the hERG tail current was elicited by depolarizing to +60 mV and then repolarizing to -50 mV. All recordings were performed after the current stabilized. Extracellular perfusion administration started with a low concentration, and each concentration was given for 5-10 minutes until the current stabilized before the next concentration was given. The half-maximal inhibitory concentration (IC 50 ) is obtained by best fitting the Logistic equation.

[0595] 2. Test results:

[0596] Table 5 hERG IC values ​​of compounds recorded on CHO-K1 stable cell line 50 value

[0597] Preparation Example No. <![CDATA[IC 50 (μM)]]> 1 A 56 A

[0598] Note: Compounds denoted as "A" have an IC greater than 10 μM 50 value.

[0599] The test results show that compounds No. 1 and No. 56 of the present application have no obvious inhibitory effect on the hERG channel within the detection concentration range of this test, which to a certain extent reflects that the compounds of the present application have lower cardiac toxicity and has positive significance for drug safety assessment.

[0600] Test Example 7: Mouse tolerance test

[0601] Test method:

[0602] Experimental animals: ICR mice, female, 5 weeks old

[0603] Solvent: 2% DMSO + 98% (0.5% MC), vortex thoroughly, and ultrasonicate to obtain a uniform suspension solution

[0604] Test method: Female ICR mice were divided into 4 groups according to their weight, with 5 mice in each group. The dosages were 50 mg / kg and 200 mg / kg respectively. The administration method was oral gavage, once a day, for 7 consecutive days. The dosage and results are shown in the table below.

[0605] Test results:

[0606] Table 6 Results of mouse tolerance test of the compounds of the present application (7 days)

[0607]

[0608] The test results showed that no death occurred in the compound No. 56 of the present application after 7 days of administration at 50 mg / kg and 200 mg / kg; the positive control compound TW-45 died 4 days after administration at 200 mg / kg, and all died on the 7th day. The maximum tolerated dose MTD of mice No. 56 was > 200 mg / kg, and TW-45 was < 200 mg / kg. It can be seen that the tolerance of the compound No. 56 of the present application in mice is significantly better than that of the positive control compound TW-45.

Claims

1. A compound as represented by formula (IA) or a deuterated derivative thereof or a pharmaceutically acceptable salt thereof, which has the following structure: in, L is selected from CH; G is selected from S; A is CH and Y is CR4; or A is N and Y is independently selected from N or CR4; R3 is R1 is independently selected from hydrogen or amino; R2 is independently selected from halogen, -COR5, -COOR5, unsubstituted C 2-6 alkenyl or unsubstituted 3-6 membered heterocycloalkyl, wherein R5 is independently selected from unsubstituted C 1-6 alkyl; R4 is independently selected from halogen; R6 is independently selected from hydrogen or deuterium; The heteroatoms in the heterocycloalkyl group are independently selected from O, N or S, and the number of the heteroatoms is 1.

2. The compound according to claim 1 or a deuterated derivative thereof or a pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (I-A2): in, G, A, R3, R1, R2 and Y are as defined in claim 1.

3. The compound according to claim 1 or a deuterated derivative thereof or a pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula (I-A3): in, G, A, R3, R1, R2 and Y are as defined in claim 1.

4. The compound according to any one of claims 1 to 3, or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R2 is independently selected from -COR5 or -COOR5.

5. A compound according to any one of claims 1 to 3 or a deuterated derivative thereof or a pharmaceutically acceptable salt thereof, wherein R2 is independently selected from halogen, -CO-(unsubstituted C 1-3 Alkyl), -COO-(unsubstituted C 1-3 Alkyl), unsubstituted C 2-4 alkenyl or unsubstituted 3-6 membered heterocycloalkyl.

6. The compound according to claim 5, or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R2 is independently selected from halogen, -C(O)CH3, -C(O)OCH3, vinyl or oxetanyl.

7. The compound according to claim 6, or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R2 is independently selected from fluorine, -C(O)CH3, -C(O)OCH3, -CH=CH2, 8. The compound according to any one of claims 1 to 3 and 6 to 7, or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R1 is an amino group.

9. The compound according to claim 4, or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R1 is an amino group. 10 . The compound according to claim 5 , or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is an amino group.

11. The compound according to any one of claims 1-3, 6-7 and 9-10, or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, wherein A is CH; or A is N and Y is N.

12. The compound according to any one of claims 1-3, 6-7 and 9-10, or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R4 is chlorine.

13. A compound as represented by formula (I-2-A) or a deuterated derivative thereof or a pharmaceutically acceptable salt thereof, which has the following structure: in, L is selected from CH; G is selected from S; A is selected from N; R1 is an amino group; R2 is independently selected from -COR5 or -COOR5, wherein R5 is independently selected from unsubstituted C 1-6 alkyl; Y is independently selected from CR4; R4 is independently selected from halogen; R6 is independently selected from hydrogen or deuterium.

14. The compound according to claim 13 or a deuterated derivative thereof or a pharmaceutically acceptable salt thereof, wherein the compound has one of the structures shown in formula (I-2-A2): wherein Y, G, A, R1 and R2 are as defined in claim 13.

15. The compound according to claim 13 or a deuterated derivative thereof or a pharmaceutically acceptable salt thereof, wherein the compound has one of the structures shown in formula (I-2-A3): wherein Y, G, A, R1 and R2 are as defined in claim 13.

16. The compound according to any one of claims 13 to 15, or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R5 is an unsubstituted C 1-3 alkyl.

17. The compound according to claim 16, or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R5 is an unsubstituted methyl group.

18. The compound according to any one of claims 13 to 15, or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R4 is chlorine.

19. The compound according to any one of claims 13 to 15, or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R5 is independently selected from unsubstituted methyl; and R4 is Cl.

20. A compound or a deuterated derivative thereof or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

21. A pharmaceutical composition comprising the compound according to any one of claims 1 to 20 or a deuterated derivative thereof or a pharmaceutically acceptable salt thereof.

22. Use of a compound according to any one of claims 1 to 20 or a deuterated derivative thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 21 in the preparation of a medicament for preventing and / or treating diseases, disorders and conditions mediated by SHP2 activity.

23. The use according to claim 22, wherein the disease, disorder or condition is a tumor, cancer metastasis, cardiovascular disease, immune disorder or visual disorder.

24. The use according to claim 23, wherein the tumor comprises solid tumors and hematological tumors.

25. The use according to claim 24, wherein the solid tumor comprises lung cancer, and the blood tumor comprises leukemia.

26. The use according to claim 25, wherein the leukemia is acute myeloid leukemia.

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