HK40079444B - Spiro compound and the use of the same - Google Patents

Description

Spirocyclic compounds and their uses

Cross-references to related applications

This application claims the benefit 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 incorporated herein by reference.

Technical Field

This application relates to the field of pharmaceutical technology, and more specifically, to a class of novel compounds having SHP2 inhibitory activity and their use in the treatment and prevention of diseases, symptoms and conditions mediated by SHP2 activity, such as hyperproliferative diseases.

Background Technology

SHP2 (Src homology-2 domain) is encoded by the protein tyrosine phosphatase nonreceptor 11 (PTP nonreceptor 11, PTPN11), catalyzing the dephosphorylation of proteins. It is generally believed that the N-terminus of SHP2 contains two SH2 domains, including the N-src homology-2 domain (SH2) and the C-SH2 domain, while the C-terminus contains a catalytically active PTP domain. In the inactive state, SHP2 is autoinhibited, with N-SH2 and C-PTP binding to inhibit phosphatase activity. However, in the presence of extracellular stimuli, these domains bind to relevant receptors, activating multiple downstream signaling pathways, including Ras/MAPK and PI3K/AKT pathways, regulating cell proliferation, differentiation, apoptosis, and survival.

Literature reports (Eur J Med Genet. 2015. 58:509; WO2018013597) that germline mutations in PTPN11 and SHP2 have been identified as associated with a variety of human diseases, such as Noonan syndrome (NS), leopard syndrome, and various malignancies (leukemia, etc.). Research by Revolution Medicines also indicates that SHP2 plays an important role in oncogenic growth and survival signaling in some common cancers.

Furthermore, research (Sci Adv. 2020, 6(5):eaay4458) indicates that programmed death 1 (PD-1) also participates in mediating and activating SHP2. In cancer, PD-1 inhibits T cell stimulation and mediates immune escape. Upon stimulation, PD-1 is phosphorylated at its immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM), and then binds to SHP2, initiating 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 silenced by cancer cells.

In view of this, there is an urgent need for compounds that can be used as SHP2 inhibitors to treat and prevent diseases, symptoms and conditions mediated by SHP2 activity.

Summary of the Invention

This application provides a class of novel SHP2 inhibitor compounds, and also provides the use of such compounds or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or pharmaceutically acceptable salts thereof for the treatment of SHP2-mediated diseases, symptoms and conditions.

On the one hand, this application provides a compound of formula (I), or a prodrug, tautomer, stereoisomer, solvate, isotope derivative, or pharmaceutically acceptable salt thereof, having the following structure:

in,

X is selected from O, _CH₂ , NH, or S;

L is selected from N or CH;

G is selected from either bond or S;

A is selected from CH or N;

R ₃ is independently selected from: optionally substituted 8-12-membered heterocyclic groups, optionally substituted C _6-10 aryl groups, optionally substituted 5-14-membered heteroaryl groups, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent 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 heterocyclic alkyl, C _6-10 aryl, and 5-12-membered heteroaryl groups;

_R1 is independently selected from hydrogen, deuterium, or amino;

_R2 is independently selected from hydrogen, halogen, cyano, _-CONH2 , _-COR5 , _-COOR5 , optionally substituted _C1-6 alkyl, optionally substituted _C2-6 alkenyl, optionally substituted _C2-6 ynyl, optionally substituted _C3-10 cycloalkyl, optionally substituted 3-10 heterocyclic alkyl, wherein _R5 is independently selected from hydrogen, optionally substituted _C1-6 alkyl, optionally substituted _C3-6 cycloalkyl, optionally substituted 3-6 heterocyclic alkyl, optionally substituted _C6-10 aryl, optionally substituted 5-10 heteroaryl, wherein optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, nitro, oxo, cyano, _C1-6 alkyl, _C1-6 alkoxy;

Y is independently selected from N or CR ₄ ;

_R4 is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, optionally substituted _C1-6 alkyl, optionally substituted _C1-6 alkoxy, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or one or more substituted sites of the substituted group are independently substituted by halogen, hydroxyl, amino, cyano, _C1-6 alkyl, _C1-6 alkoxy.

_R6 is independently selected from hydrogen or deuterium;

The term "oxo group" refers to a double bond formed when two H atoms at the same substitution site are replaced by the same O atom.

The heteroatoms in the heterocyclic alkyl, heteroaryl, and heterocyclic groups are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4.

In one embodiment of this application, a compound of formula (I), or a prodrug, tautomer, stereoisomer, solvate, isotope derivative, or pharmaceutically acceptable salt thereof, is provided having the following structure:

in,

X is selected from O, _CH₂ , NH, or S;

L is selected from N or CH;

G is selected from either bond or S;

A is selected from CH or N;

_R3 is an amino group;

_R1 is independently selected from hydrogen, amino, or deuterium;

_R2 is independently selected from halogen, cyano, _-CONH2 , _-COR5 , _-COOR5 , optionally substituted _C1-6 alkyl, optionally substituted _C2-6 alkenyl, optionally substituted _C2-6 ynyl, optionally substituted _C3-10 cycloalkyl, optionally substituted 3-10 heterocyclic alkyl, wherein _R5 is independently selected from hydrogen, optionally substituted _C1-6 alkyl, optionally substituted _C3-6 cycloalkyl, optionally substituted 3-6 heterocyclic alkyl, optionally substituted _C6-10 aryl, optionally substituted 5-10 heteroaryl, wherein optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, nitro, oxo, cyano, _C1-6 alkyl, _C1-6 alkoxy;

Y is independently selected from N or CR ₄ ;

_R4 is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, optionally substituted _C1-6 alkyl, optionally substituted _C1-6 alkoxy, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or one or more substituted sites of the substituted group are independently substituted by halogen, hydroxyl, amino, cyano, _C1-6 alkyl, _C1-6 alkoxy.

_R6 is independently selected from hydrogen or deuterium;

The term "oxo group" refers to a double bond formed when two H atoms at the same substitution site are replaced by the same O atom.

The heteroatoms in the heterocyclic alkyl, heteroaryl, and heterocyclic groups are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4.

In another embodiment of this application, a compound of formula (I), or a prodrug, tautomer, stereoisomer, solvate, isotope derivative, or pharmaceutically acceptable salt thereof, is provided having the following structure:

in,

X is selected from O, _CH₂ , NH, or S;

L is selected from N or CH;

G is selected from either bond or S;

A is selected from CH or N;

R ₃ is independently selected from: amino, optionally substituted 8-12-membered heterocyclic groups, optionally substituted C _6-10 aryl groups, optionally substituted 5-14-membered heteroaryl groups, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent 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 heterocyclic alkyl, C _6-10 aryl, 5-12-membered heteroaryl groups;

_R1 is independently selected from hydrogen, deuterium, or amino;

_R2 is independently selected from hydrogen, halogen, cyano, _-CONH2 , _-COR5 , _-COOR5 , optionally substituted _C1-6 alkyl, optionally substituted _C2-6 alkenyl, optionally substituted _C2-6 ynyl, optionally substituted _C3-10 cycloalkyl, optionally substituted 3-10 heterocyclic alkyl, wherein _R5 is independently selected from hydrogen, optionally substituted _C1-6 alkyl, optionally substituted _C3-6 cycloalkyl, optionally substituted 3-6 heterocyclic alkyl, optionally substituted _C6-10 aryl, optionally substituted 5-10 heteroaryl, wherein optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, nitro, oxo, cyano, _C1-6 alkyl, _C1-6 alkoxy;

Y is independently selected from N or CR ₄ ;

_R4 is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, optionally substituted _C1-6 alkyl, optionally substituted _C1-6 alkoxy, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen at one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, cyano, _C1-6 alkyl, _C1-6 alkoxy.

_R6 is independently selected from hydrogen or deuterium;

The term "oxo group" refers to a double bond formed when two H atoms at the same substitution site are replaced by the same O atom.

The heteroatoms in the heterocyclic alkyl, heteroaryl, and heterocyclic groups are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4.

In yet another embodiment of this application, _R6 is deuterium.

In another embodiment of this application, a compound of formula (I-1), or a prodrug, tautomer, stereoisomer, solvate, isotope derivative, or pharmaceutically acceptable salt thereof, is provided having the following structure:

in,

X is selected from O, _CH₂ , NH, or S;

L is selected from N or CH;

G is selected from either bond or S;

A is selected from CH or N;

R ₃ is independently selected from optionally substituted 8-12-membered heterocyclic groups, optionally substituted C _6-10 aryl groups, and optionally substituted 5-14-membered heteroaryl groups, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent 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 heterocyclic alkyl, C _6-10 aryl, and 5-12-membered heteroaryl groups;

_R1 is independently selected from hydrogen, deuterium, or amino;

_R2 is independently selected from hydrogen, halogen, cyano, _-CONH2 , _-COR5 , _-COOR5 , optionally substituted _C1-6 alkyl, optionally substituted _C2-6 alkenyl, optionally substituted _C2-6 ynyl, optionally substituted _C3-10 cycloalkyl, optionally substituted 3-10 heterocyclic alkyl, wherein _R5 is independently selected from hydrogen, optionally substituted _C1-6 alkyl, optionally substituted _C3-6 cycloalkyl, optionally substituted 3-6 heterocyclic alkyl, optionally substituted _C6-10 aryl, optionally substituted 5-10 heteroaryl, wherein optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, nitro, oxo, cyano, _C1-6 alkyl, _C1-6 alkoxy;

Y is independently selected from N or CR ₄ ;

R ₄ is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, optionally substituted _C1-6 alkyl, optionally substituted _C1-6 alkoxy, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen at one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, cyano, _C1-6 alkyl, _C1-6 alkoxy.

The term "oxo group" refers to a double bond formed when two H atoms at the same substitution site are replaced by the same O atom.

The heteroatoms in the aforementioned heterocyclic alkyl, heteroaryl, and heterocyclic groups are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4;

The compound in question is not:

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

The definitions of G, A, Y, _R1 , _R2 , _R3 , X and L are the same as those for the compounds shown in formula (I) or formula (I-1) above in this application.

In certain embodiments of this application, compounds of formula (I), formula (I-1), formula (I-1-1), or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives, or pharmaceutically acceptable salts thereof are provided, wherein _R3 is an amino group.

In certain embodiments of this application, compounds of formula (I), formula (I-1), formula (I-1-1), or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof are provided, wherein the _R3 is independently selected from: optionally substituted 8-12-membered heterocyclic groups, optionally substituted _C6-10 aryl groups, and optionally substituted 5-14-membered heteroaryl groups.

In certain embodiments of this application, _R3 in compounds of formula (I), formula (I-1), and formula (I-1-1) is independently selected from: optionally substituted 8-12-membered bicyclic heterocyclic groups, optionally substituted _C6-10 aryl groups, and optionally substituted 5-14-membered heteroaryl groups, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, nitro, oxo, cyano, -COOH, _-COCH3 , _-COOCH3 , _-CONH2 , _C1-6 alkyl, _C1-6 alkoxy, _C3-10 cycloalkyl, 3-10-membered heterocyclic alkyl, _C6-10 aryl, and 5-12-membered heteroaryl groups.

In certain embodiments of this application, _R3 in compounds of formula (I), formula (I-1), and formula (I-1-1) is independently selected from optionally substituted 8-10-membered bicyclic heterocyclic groups, optionally substituted _C6-8 aryl groups, and optionally substituted 5-10-membered heteroaryl groups, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, nitro, oxo, cyano, -COOH, _-COCH3 , _-COOCH3 , _-CONH2 , _C1-6 alkyl, _C1-6 alkoxy, _C3-10 cycloalkyl, 3-10-membered heterocyclic alkyl, _C6-10 aryl, and 5-12-membered heteroaryl groups.

In certain embodiments of this application, _R3 in the compound of formula (I), formula (I-1), and formula (I-1-1) is independently selected from optionally substituted 8-10 membered bicyclic heterocyclic groups, optionally substituted _C6-8 aryl groups, and optionally substituted 5-10 membered heteroaryl groups, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, oxo, cyano, _-CONH2 , and _C1-6 alkyl.

In certain embodiments of this application, _R3 in the compound of formula (I), formula (I-1), and formula (I-1-1) is independently selected from optionally substituted 10-membered bicyclic heterocyclic groups, optionally substituted _C6-8 aryl groups, and optionally substituted 5-10-membered heteroaryl groups, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from hydroxyl, oxo, cyano, _-CONH2 , methyl, ethyl, n-propyl, isopropyl, and n-butyl, wherein the heteroatom in the heterocyclic group or heteroaryl group is independently selected from O, N, or S, and the number of heteroatoms is 1, 2, or 3.

In certain embodiments of this application, _R3 in the compound of formula (I), formula (I-1), and formula (I-1-1) is independently selected from optionally substituted _C6-8 aryl groups and optionally substituted 5-6 heteroaryl groups, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, oxo, _cyano , -CONH2, and _C1-6 alkyl groups, wherein the heteroatom in the heteroaryl group is independently selected from O, N, or S, and the number of heteroatoms is one or two.

In certain embodiments of this application, _R3 in the compound of formula (I), formula (I-1), and formula (I-1-1) is independently selected from optionally substituted phenyl groups or optionally substituted 5-6 heteroaryl groups, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from cyano, _-CONH2 , or methyl, wherein the heteroatom in the heteroaryl group is independently selected from O, N, or S, and the number of heteroatoms is one or two.

In certain embodiments of this application, _R3 in the compounds of formula (I), formula (I-1), and formula (I-1-1) is independently selected from: optionally substituted _C6-10 aryl groups, optionally substituted 5-14 heteroaryl groups, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, nitro, _{oxo, cyano} , -COOH, -COCH3, _-COOCH3 , _-CONH2 , _C1-6 alkyl, _C1-6 alkoxy, _C3-10 cycloalkyl, 3-10 heterocyclic alkyl, _C6-10 aryl, and 5-12 heteroaryl groups.

In certain embodiments of this application, _R3 in the compound of formula (I), formula (I-1), and formula (I-1-1) is independently selected from optional substituted 5-10 heteroaryl groups, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, oxo, cyano, _-CONH2 , and _C1-6 alkyl.

In certain embodiments of this application, _R3 in the compound of formula (I), formula (I-1), and formula (I-1-1) is independently selected from optionally substituted 5-6-membered heteroaryl groups, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, cyano, _-CONH2 , and _C1-6 alkyl, wherein the heteroatom in the heteroaryl group is independently selected from O, N, or S, and the number of heteroatoms is one or two.

In certain embodiments of this application, _R3 in the compound of formula (I), formula (I-1), and formula (I-1-1) is independently selected from optionally substituted 5-6-membered heteroaryl groups, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, cyano, _-CONH2 , and _C1-3 alkyl, wherein the heteroatom in the heteroaryl group is independently selected from O, N, or S, and the number of heteroatoms is one or two.

In certain embodiments of this application, _R3 in the compound of formula (I), formula (I-1), and formula (I-1-1) is independently selected from optional substituted 5-membered heteroaryl groups, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from hydroxyl, cyano, _-CONH2 , and methyl, wherein the heteroatom in the heteroaryl group is independently selected from O, N, or S, and the number of heteroatoms is one or two.

In certain embodiments of this application, _R3 in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) is independently selected from the following structures with optional substitutions:

In certain embodiments of this application, _R3 in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) is independently selected from the following structures with optional substitutions:

In certain embodiments of this application, _R3 in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) is independently selected from the following structures with optional substitutions:

In certain embodiments of this application, _R3 in the compound of formula (I), formula (I-1), and formula (I-1-1) is independently selected from amino groups, optionally substituted groups.

In certain embodiments of this application, _R3 in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) is independently selected from optionally substituted compounds.

In certain embodiments of this application, _R3 in the compounds of formula (I), formula (I-1), and formula (I-1-1) is independently selected from the following structures:

In certain embodiments of this application, _R3 in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) is independently selected from the following structures:

In certain embodiments of this application, compounds of formula (I), formula (I-1), formula (I-1-1) or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof are provided, wherein _R2 is independently selected from halogens, cyano groups, -CONH2, _-COR5 , _-COOR5 , optionally substituted _C1-6 alkyl _groups , optionally substituted C2-6 alkenyl groups, optionally substituted _C2-6 ynyl groups, optionally substituted _C3-10 cycloalkyl groups, optionally substituted 3-10 heterocyclic alkyl groups, wherein _R5 is independently selected from hydrogen, optionally substituted _C1-6 alkyl groups, optionally substituted C3-6 cycloalkyl groups, optionally substituted 3-6 heterocyclic alkyl groups, optionally substituted _C1-6 alkyl groups, optionally substituted C2-6 alkenyl groups, optionally substituted _C3-10 cycloalkyl groups, optionally substituted C3-10 heterocyclic alkyl groups, optionally substituted C3-10 cyclo ... _6-10 aryl, optionally substituted 5-10 heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, nitro, oxo, cyano, _C1-6 alkyl, _C1-6 alkoxy.

In certain embodiments of this application, compounds of formula (I), formula (I-1), formula (I-1-1) or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof are provided, wherein _R2 is independently selected from hydrogen, halogen, cyano, _-CONH2 , _-COR5 , _-COOR5 , optionally substituted _C1-6 alkyl, optionally substituted _C2-6 alkenyl, optionally substituted _C3-10 cycloalkyl, optionally substituted 3-10 heterocyclic alkyl, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen at one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, nitro, oxo, cyano, _C1-6 alkyl, _C1-6 alkoxy.

In certain embodiments of this application, _R2 in the compound of formula (I), formula (I-1), and formula (I-1-1) is independently selected from hydrogen, halogen, cyano, _-CONH2 , _-COR5 , _-COOR5 , optionally substituted _C1-4 alkyl, optionally substituted _C2-6 alkenyl, optionally substituted _C3-6 cycloalkyl, and optionally substituted 3-6 heterocyclic alkyl, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen at one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, nitro, oxo, cyano, _C1-6 alkyl, and _C1-6 alkoxy.

In certain specific embodiments of this application, in the compounds of formula (I), formula (I-1), and formula (I-1-1), _R2 is independently selected from halogen, cyano, -CONH2, _-COR5 , _-COOR5 , _C1-4 alkyl, _C2-6 alkenyl, _C3-6 cycloalkyl, or 3-6 heterocyclic alkyl groups substituted with one or more substituents selected from _hydroxyl , _C1-6 alkoxy, and halogen.

In certain embodiments of this application, _R2 in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) is independently selected from halogen, cyano, _-CONH2 , _-COR5 , _-COOR5 , hydroxy-substituted _C1-4 alkyl, _C2-6 alkenyl, _C3-6 cycloalkyl, and 3-6 membered heterocyclic alkyl. In certain embodiments of this application, _R2 in the compound of formula (I), formula (I-1), and formula (I-1-1) is independently selected from halogen, _-COR5 , _-COOR5 , hydroxylated _C1-4 alkyl, _C2-6 alkenyl, or 3-6-membered heterocyclic alkyl; or, _R2 is independently selected from halogen, -COR5, _-COOR5 , _C2-6 alkenyl, or _3-6 -membered heterocyclic alkyl; or, _R2 is independently selected from _-COR5 or _-COOR5 ; or, _R2 is _-COR5 or _R2 is _-COOR5 , wherein preferably, _R5 is _C3-6 cycloalkyl or _C1-6 alkyl, preferably _C3-4 cycloalkyl or _C1-3 alkyl, such as cyclopropyl or methyl; or, _R2 is independently selected from -CO ( _C1-6 alkyl); or, _R2 is independently selected from -CO (C1-6 alkyl). _1-3 alkyl groups).

In certain embodiments of this application, _R5 in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) is independently selected from hydrogen, optionally substituted _C1-6 alkyl, optionally substituted _C3-6 cycloalkyl, and optionally substituted 3-6 heterocyclic alkyl, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, nitro, oxo, cyano, _C1-6 alkyl, and _C1-6 alkoxy.

In certain embodiments of this application, _R5 in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) is independently selected from hydrogen, optionally substituted _C1-6 alkyl, optionally substituted _C3-6 cycloalkyl, and optionally substituted 3-6 heterocyclic alkyl, wherein optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen at one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, and _C1-6 alkyl.

In some embodiments of this application, _R5 in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) is independently selected from hydrogen, _C1-6 alkyl, _C3-6 cycloalkyl, and 3-6 heterocyclic alkyl; further, _R5 is independently selected from _C1-3 alkyl and _C3-6 cycloalkyl; or _R5 is independently selected from _C1-3 alkyl, such as methyl.

In certain embodiments of this application, compounds of formula (I), formula (I-1), formula (I-1-1), or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof are provided, wherein _R2 is independently selected from halogens, cyano groups, _-CONH2 , -CO-( _C1-3 alkyl), -CO-( _C3-6 cycloalkyl), -COO-( _C1-3 alkyl), -COO-( _C3-6 cycloalkyl), _-CH2OH , _-CH2CH2OH , -CH(OH) _CH3 , _C2-6 alkenyl, _C3-6 cycloalkyl, and _3-6 membered heterocyclic alkyl groups.

In certain embodiments of this application, _R2 in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) is independently selected from halogens, -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, and 3-6 membered heterocyclic alkyl.

In some embodiments of this application, _R2 in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) is independently selected from halogens, -C(O) _CH3 , -C(O)-(cyclopropane), -C(O) _OCH3 , -C(O)O-(cyclopropane), _-CH2OH , vinyl, and oxetane.

In certain embodiments of this application, _R2 in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) is independently selected from hydrogen, fluorine, -C(O) _CH3 , -C(O) _OCH3 , _-CH2OH , -CH= _CH2 ,

In certain embodiments of this application, _R2 in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) is independently selected from fluorine, -C(O) _CH3 , -C(O) _OCH3 , -CH= _CH2 ,

In some embodiments of this application, _R2 in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) is independently selected from -C(O) _CH3 or -C(O) _OCH3 .

In some embodiments of this application, _R2 in the compound of formula (I), the compound of formula (I-1), and the compound of formula (I-1-1) is -C(O) _CH3 .

In certain preferred embodiments of this application, compounds of formula (I), formula (I-1), formula (I-1-1), or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives, or pharmaceutically acceptable salts thereof are provided, wherein _R1 is independently selected from hydrogen and amino; preferably, _R1 is independently selected from amino.

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

_R1 is independently selected from deuterium or amino, preferably amino;

_R2 is independently selected from cyano, _-CONH2 , _-COR5 , _-COOR5 , optionally substituted _C1-6 alkyl, optionally substituted _C2-6 alkenyl, optionally substituted _C2-6 ynyl, optionally substituted C3-10 cycloalkyl, optionally substituted _3-10 heterocyclic alkyl, wherein _R5 is independently selected from hydrogen, optionally substituted _C1-6 alkyl, optionally substituted _C3-6 cycloalkyl, optionally substituted 3-6 heterocyclic alkyl, optionally substituted _C6-10 aryl, optionally substituted 5-10 heteroaryl, wherein optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, nitro, oxo, cyano, _C1-6 alkyl, _C1-6 alkoxy;

R ₆ is hydrogen or deuterium, preferably deuterium;

X, L, G, A, and Y are defined as described in the compounds of formula (I) or formula (I-1) of this application.

In one embodiment of this application, a compound of formula (I-2) or a prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof is provided, wherein _R2 is independently selected from hydrogen, halogen, cyano, _-CONH2 , _-COR5 , _-COOR5 , optionally substituted _C1-6 alkyl, optionally substituted _C2-6 alkenyl, optionally substituted _C3-10 cycloalkyl, optionally substituted 3-10 heterocyclic alkyl, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, nitro, oxo, cyano, _C1-6 alkyl, _C1-6 alkoxy.

In one embodiment of this application, _R2 in the compound represented by formula (I-2) is independently selected from cyano, _-CONH2 , _-COR5 , _-COOR5 , optionally substituted _C1-4 alkyl, optionally substituted _C2-6 alkenyl, optionally substituted _C3-6 cycloalkyl, optionally substituted 3-6 heterocyclic alkyl, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxy, amino, nitro, oxo, cyano, _C1-6 alkyl, _C1-6 alkoxy.

In yet another embodiment of this application, _R2 in the compound represented by formula (I-2) is independently selected from cyano, _-CONH2 , _-COR5 , _-COOR5 , hydroxy-substituted _C1-4 alkyl, _C2-6 alkenyl, _C3-6 cycloalkyl, and 3-6 membered heterocyclic alkyl.

In another embodiment of this application, _R2 in the compound of formula (I-2) or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof is independently selected from cyano, _-CONH2 , _-COR5 , _-COOR5 , unsubstituted _C2-6 alkyl, substituted _C1-6 alkyl, optionally substituted _C2-6 alkenyl, optionally substituted _C2-6 ynyl, optionally substituted _C3-10 cycloalkyl, optionally substituted 3-10 heterocyclic alkyl, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen at one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, nitro, oxo, cyano, _C1-6 alkyl, _C1-6 alkoxy; or

_R2 is independently selected from cyano, _-CONH2 , _-COR5 , _-COOR5 , substituted _C1-6 alkyl, optionally substituted _C2-6 alkenyl, optionally substituted _C3-6 cycloalkyl, optionally substituted 3-6 heterocyclic alkyl, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen at one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxy, amino, nitro, oxo, cyano, _C1-6 alkyl, _C1-6 alkoxy; or

_R2 is independently selected from cyano, _-CONH2 , _-COR5 , _-COOR5 , _C1-6 alkyl, _C2-6 alkenyl, _C3-6 cycloalkyl, _3-6 heterocyclic alkyl groups substituted with one or more substituents selected from hydroxyl, halogen, and C1- _C3 alkoxy; or

When _R1 is deuterium, _R2 is selected from -CO- ( _C3-6 cycloalkyl), -COOR ₅ , optionally substituted _C2-6 alkenyl, optionally substituted _C2-6 ynyl, optionally substituted _C3-10 cycloalkyl, optionally substituted 3-10 heterocyclic alkyl, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen at one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, nitro, oxo, cyano, _C1-6 alkyl, _C1-6 alkoxy; or

When _R1 is deuterium, _R2 is selected from -CO- ( _C3-6 cycloalkyl), -COOR ₅ , optionally substituted _C2-6 alkenyl, optionally substituted _C3-6 cycloalkyl, optionally substituted 3-6 heterocyclic alkyl, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen at one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, nitro, oxo, cyano, _C1-6 alkyl, _C1-6 alkoxy; or

When _R1 is deuterium, _R2 is selected from -CO- ( _C3-6 cycloalkyl), _-COOR5 , _C2-6 alkenyl, _C3-6 cycloalkyl, and 3-6 heterocyclic alkyl.

In one embodiment of the compound with the structure shown in formula (I-2) of this application, when _R1 is deuterium, _R2 can be a halogen.

In certain embodiments of this application, in compounds having the structure shown in formula (I-2) or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof, _R1 may be hydrogen; _R2 is independently selected from halogens, -CO- ( _C3 - _C6 cycloalkyl), _-COOR5 , optionally substituted _C2-6 alkenyl, optionally substituted _C2-6 ynyl, optionally substituted _C3-10 cycloalkyl, optionally substituted 3-10 heterocyclic alkyl, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen at one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogens, hydroxyl, amino, nitro, oxo, cyano, _C1-6 alkyl, _C1-6 alkoxy; or

_R1 can be hydrogen; _R2 is independently selected from halogen, -CO- ( _C3 - _C6 cycloalkyl), _-COOR5 , optionally substituted _C2-6 alkenyl, optionally substituted _C3-6 cycloalkyl, optionally substituted 3-6 membered heterocyclic alkyl, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen at one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, nitro, oxo, cyano, _C1-6 alkyl, _C1-6 alkoxy; or

_R1 can be hydrogen; _R2 is independently selected from halogen, -CO- ( _C3 - _C6 cycloalkyl), _-COOR5 , _C2-6 alkenyl, _C3-6 cycloalkyl, 3-6 heterocyclic alkyl.

In one embodiment of this application, _R5 in the compound represented by formula (I-2) above is independently selected from hydrogen, optionally substituted _C1-6 alkyl, optionally substituted _C3-6 cycloalkyl, optionally substituted 3-6 membered heterocyclic alkyl, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, nitro, oxo, cyano, _C1-6 alkyl, _C1-6 alkoxy.

In one embodiment of this application, _R5 in the compound represented by formula (I-2) above is independently selected from hydrogen, optionally substituted _C1-6 alkyl, optionally substituted _C3-6 cycloalkyl, optionally substituted 3-6 heterocyclic alkyl, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, _C1-6 alkyl.

In one embodiment of this application, _R5 in the compound represented by formula (I-2) above is independently selected from hydrogen, _C1-6 alkyl, _C3-6 cycloalkyl, and 3-6 heterocyclic alkyl.

In one embodiment of this application, _R5 in the compound represented by formula (I-2) above is independently selected from _C1-3 alkyl, _C3-6 cycloalkyl; or _R5 is _C1-3 alkyl; or _R5 is _C3-6 cycloalkyl.

In one embodiment of this application, a compound of formula (I-2) or a prodrug thereof, tautomer, stereoisomer, solvate, isotope derivative thereof or a pharmaceutically acceptable salt thereof is provided, wherein _R2 is independently selected from cyano, _-CONH2 , -CO-( _C1-3 alkyl), -CO-( _C3-6 cycloalkyl), -COO-( _C1-3 alkyl), -COO-( _C3-6 cycloalkyl ₎ , _-CH2OH , -CH2CH2OH, -CH(OH) _CH3 , _C2-6 alkenyl, _C3-6 cycloalkyl, _3-6 membered heterocyclic alkyl;

Preferably, _R2 is independently selected from -CO-( _C1-3 alkyl), -CO-( _C3-6 cycloalkyl), -COO-( _C1-3 alkyl), -COO-( _C3-6 cycloalkyl), _-CH2OH , _C2-4 alkenyl, and 3-6 membered heterocyclic alkyl;

More preferably, _R2 is independently selected from -C(O) _CH3 , -C(O)-(cyclopropane), -C(O) _OCH3 , -C(O)O-(cyclopropane), _-CH2OH , vinyl, oxetane;

More preferably, _R2 is independently selected from -C(O) _CH3 , -C(O) _OCH3 , _-CH2OH , -CH= _CH2 ,

More preferably, _R2 is independently selected from -C(O) _CH3 , -C(O) _OCH3 , -CH= _CH2 ,

In one embodiment of this application, a compound of formula (I-2) or a prodrug thereof, a tautomer, a stereoisomer, a solvate, an isotope derivative thereof or a pharmaceutically acceptable salt thereof is provided, wherein _R2 is independently selected from -CO-( _C1-6 alkyl) and -COO-( _C1-6 alkyl);

Preferably, _R2 is independently selected from -CO- ( _C1-3 alkyl) and -COO- ( _C1-3 alkyl);

More preferably, _R2 is independently selected from -C(O) _CH3 and -C(O) _OCH3 ;

More preferably, _R2 is independently selected from -C(O) _CH3 .

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

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

In one embodiment of this application, a compound of formula (I-2) or a prodrug thereof, tautomer, stereoisomer, solvate, isotope derivative thereof or a pharmaceutically acceptable salt thereof is provided, wherein _R1 is independently selected from amino, _R2 is independently selected from -CO- ( _C1-6 alkyl) or -COO- ( _C1-6 alkyl), L is selected from CH, and X is selected from O.

In one embodiment of this application, a compound of formula (I-2) or a prodrug thereof, a tautomer, a stereoisomer, a solvate, an isotope derivative thereof or a pharmaceutically acceptable salt thereof is provided, wherein _R1 is independently selected from amino, _R2 is independently selected from -CO- ( _C1-6 alkyl) and -COO- ( _C1-6 alkyl), L is selected from CH, and _R6 is independently selected from deuterium;

Preferably, _R1 is independently selected from amino, _R2 is independently selected from -CO-( _C1-3 alkyl) or -COO-( _C1-3 alkyl), _R6 is selected from deuterium, L is selected from CH, X is selected from O, and G is selected from S.

In certain embodiments of this application, compounds of formula (I), formula (I-1), formula (I-1-1), formula (I-2), or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives, or pharmaceutically acceptable salts thereof are provided, wherein X is selected from O or _CH2 ; preferably, X is selected from O.

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

Wherein, L, G, A, Y, _R1 , _R2 , _R3 , and _R6 are defined as those of the compounds shown in formula (I), formula (I-1), or formula (I-2) above in this application.

In certain embodiments of this application, compounds of formula (I), formula (I-1), formula (I-1-1), formula (I-2), or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives, or pharmaceutically acceptable salts thereof are provided, wherein L is selected from CH.

In certain embodiments of this application, compounds (compound of formula (I), compound of formula (I-1), compound of formula (I-1-1), compound of formula (I-2)) or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof are provided, wherein the compounds have a structure as shown in formula (I-A1), (I-1-A1) or (I-2-A1):

Wherein, G, A, Y, _R1 , _R2 , _R3 , and _R6 are defined as those of the compounds shown in formula (I), formula (I-1), or formula (I-2) above in this application.

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

Wherein, G, A, Y, _R1 , _R2 , and _R3 are defined as those of the compounds shown in formula (I), formula (I-1), or formula (I-2) above in this application.

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

Wherein, G, A, Y, _R1 , _R2 , and _R3 are defined as those of the compounds shown in formula (I), formula (I-1), or formula (I-2) above in this application.

In certain embodiments of this application, compounds (compound of formula (I), compound (I-1), compound (I-1-1), compound (I-2)) or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof are provided, wherein the compounds have a structure as shown in formula (I-B1), formula (I-1-B1) or formula (I-2-B1):

Wherein, G, A, Y, _R2 , _R3 , and _R6 are defined as those of the compounds shown in formula (I), formula (I-1), or formula (I-2) above in this application.

In some embodiments of this application, the compound has a structure as shown in formula (I-B2), (I-B3), (I-2-B2), or (I-2-B3):

Wherein, G, A, Y, _R2 , and _R3 are defined as those of the compounds shown in formula (I), formula (I-1), or formula (I-2) of this application.

In certain embodiments of this application, compounds of formula (I), (I-1), (I-1-1), (I-2), (I-A1), (I-1-A1), (I-2-A1), (I-A2), (I-A3), (I-2-A2), (I-2-A3), (I-B1), (I-1-B1), and (I-2-B1) are provided. The compound, or a compound of formula (I-B2), formula (I-B3), formula (I-2-B2), formula (I-2-B3), formula (I-A), formula (I-B), formula (I-1-A), formula (I-1-B), formula (I-2-A), formula (I-2-B), formula (I-Ba), or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof, wherein G is selected from S.

In certain embodiments of this application, compounds of formula (I), (I-1), (I-1-1), (I-2), (I-A1), (I-1-A1), (I-2-A1), (I-A2), (I-A3), (I-2-A2), (I-2-A3), (I-B1), (I-1-B1), and (I-2-B1) are provided. Compounds, compounds of formula (I-B2), (I-B3), (I-2-B2), (I-2-B3), (I-A), (I-B), (I-1-A), (I-1-B), (I-2-A), (I-2-B), (I-2-B), (I-Ba), or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein A is selected from CH.

In certain embodiments of this application, compounds of formula (I), (I-1), (I-1-1), (I-2), (I-A1), (I-1-A1), (I-2-A1), (I-A2), (I-A3), (I-2-A2), (I-2-A3), (I-B1), (I-1-B1), and (I-2-B1) are provided. Compounds, compounds of formula (I-B2), (I-B3), (I-2-B2), (I-2-B3), (I-A), (I-B), (I-1-A), (I-1-B), (I-2-A), (I-2-B), (I-2-B), (I-Ba), or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein A is selected from N.

In certain embodiments of this application, compounds of formula (I), (I-1), (I-1-1), (I-2), (I-A1), (I-1-A1), (I-2-A1), (I-A2), (I-A3), (I-2-A2), (I-2-A3), (I-B1), (I-1-B1), and (I-2-B1) are provided. The compound, or a compound of 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), formula (I-Ba), or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof, wherein Y is selected from _CR4 ; or A is CH and Y is _CR4 ; or A is N and Y is _CR4 ; or A is N and Y is N.

In certain embodiments of this application, compounds of formula (I), (I-1), (I-1-1), (I-2), (I-A1), (I-1-A1), (I-2-A1), (I-A2), (I-A3), (I-2-A2), (I-2-A3), (I-B1), (I-1-B1), and (I-2-A3) are provided. B1) compounds of formula (I-B2), (I-B3), (I-2-B2), (I-2-B3), (IA), (IB), (I-1-A), (I-1-B), (I-2-A), (I-2-B), (I-2-B), (I-Ba) compounds, or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein _R4 is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, optionally substituted _C1-6 alkyl, optionally substituted _C1-6 alkoxy, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen at one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, or amino.

In one embodiment of this application, _R4 is independently selected from hydrogen, halogen, amino, cyano, _C1-6 alkyl, _C1-6 alkoxy, and _C1-6 alkylamino; more preferably, _R4 is independently selected from hydrogen, fluorine, chlorine, amino, cyano, methyl, and methoxy; and more preferably, _R4 is selected from chlorine.

In one embodiment of this application, in the compound of formula (I), X is selected from O or _CH2 ; L is CH; G is S; A is selected from CH or N; _R3 is independently selected from: amino, optionally substituted 8-12-membered heterocyclic group, optionally substituted _C6-10 aryl, optionally substituted 5-14-membered heteroaryl, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from hydroxyl, oxo, cyano, _-CONH2 or _C1-6 alkyl; _R1 is independently selected from hydrogen, deuterium, amino; _R2 is independently selected from halogen , _-COR5 , _-COOR5 , optionally substituted _C1-6 alkyl, optionally substituted _C2-6 alkenyl, optionally substituted 3-10-membered heterocyclic alkyl; wherein, _R5 is independently selected from unsubstituted _C1-6 alkyl or unsubstituted C _3-6 cycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen at one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogens, hydroxyl groups, and _C1-6 alkoxy groups; Y is independently selected from N or _C4 ; _R4 is a halogen; _R6 is independently selected from hydrogen and deuterium; or

X is selected from O or _CH2 ; L is CH; G is S; A is selected from CH or N; _R3 is independently selected from: amino, optionally substituted 8-10 membered bicyclic heterocyclic group, optionally substituted _C6 or _C10 aryl, 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 substituted sites of the substituted group is independently substituted by a substituent selected from hydroxyl, oxo, cyano, _-CONH2 or _C1-6 alkyl; _R1 is independently selected from hydrogen, deuterium, amino; _R2 is independently selected from halogen , _-COR5 , _-COOR5 , optionally substituted _C1-6 alkyl, optionally substituted _C2-6 alkenyl, optionally substituted 3-6 membered heterocyclic alkyl; wherein, _R5 is independently selected from unsubstituted _C1-6 alkyl or unsubstituted C _3-6 cycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen at one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogens, hydroxyl groups, and _C1-6 alkoxy groups; Y is independently selected from N or _C4 ; _R4 is a halogen; _R6 is independently selected from hydrogen or deuterium; or

X is selected from O or _CH2 ; L is CH; G is S; A is selected from CH or N; _R3 is independently selected from: amino, 5-6-membered heteroaryl group optionally substituted with _C1-6 alkyl; _R1 is independently selected from hydrogen, deuterium, amino; _R2 is independently selected from halogen, _-COR5 , _-COOR5 , optionally substituted _C2-6 alkenyl, optionally substituted 3-6-membered heterocyclic alkyl; wherein _R5 is independently selected from unsubstituted _C1-6 alkyl or unsubstituted _C3-6 cycloalkyl, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or the hydrogen at one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, _C1-6 alkoxy; Y is independently selected from N or _C4 ; _R4 is halogen; _R6 is independently selected from hydrogen, deuterium; or

X is selected from O or _CH₂ ; L is CH; G is S; A is selected from CH or N; _R₃ is independently selected from: amino, 5-6-membered heteroaryl group optionally substituted with C₁ _-6 alkyl; _R₁ is independently selected from hydrogen, deuterium, amino; _R₂ is independently selected from halogen, _-COR₅ , _-COOR₅ , unsubstituted C₂ _-6 alkenyl, unsubstituted 3-6-membered heterocyclic alkyl; wherein, _R₅ is independently selected from unsubstituted C₁ _-6 alkyl or unsubstituted C₃ _-6 cycloalkyl; Y is independently selected from N or _CR₄ ; _R₄ is halogen; _R₆ is independently selected from hydrogen, deuterium; or

X is selected from O or _CH₂ ; L is CH; G is S; A is selected from CH or N; _R₃ is independently selected from: amino, 5-membered heteroaryl group optionally substituted with C₁ _-4 alkyl; _R₁ is independently selected from hydrogen, deuterium, amino; _R₂ is independently selected from _-COR₅ or _-COOR₅ ; wherein _R₅ is independently selected from unsubstituted C₁ _-4 alkyl or unsubstituted C₃ _-6 cycloalkyl; Y is independently selected from N or _CR₄ ; _R₄ is a halogen, such as Cl or F, preferably Cl; _R₆ is independently selected from hydrogen, deuterium; or

X is selected from O or _CH2 ; L is CH; G is S; when A is CH, Y is _CR4 ; _R4 is a halogen, such as Cl or F, preferably Cl; or when A is N, Y is independently selected from N or _CR4 ; _R4 is a halogen, such as Cl or F, preferably Cl; _R3 is independently selected from: amino, 5-membered heteroaryl group optionally substituted with _C1-2 alkyl (e.g., methyl); _R1 is independently selected from hydrogen, deuterium, amino; _R2 is independently selected from _-COR5 or _-COOR5 ; wherein _R5 is independently selected from unsubstituted _C1-2 alkyl (e.g., methyl) or unsubstituted _C3-4 cycloalkyl (e.g., cyclopropyl); _R6 is independently selected from hydrogen or deuterium.

In certain embodiments of this application, compounds of formula (I), (I-1), (I-1-1), (I-2), (I-A1), (I-1-A1), (I-2-A1), (I-A2), (I-A3), (I-2-A2), (I-2-A3), (I-B1), and (I-) are described above. Compounds of formula (I-B1), (I-2-B1), (I-B2), (I-B3), (I-2-B2), (I-2-B3), (I-A), (I-B), (I-1-A), (I-1-B), (I-2-A), (I-2-B), and (I-Ba) do not include the following compounds:

On the other hand, this application provides a compound of formula (II), or a prodrug, tautomer, stereoisomer, solvate, isotope derivative, or pharmaceutically acceptable salt thereof, having the following structure:

in,

Each _R1 is independently selected from hydrogen, deuterium, halogen, _-NH2 , _-NHRa , -N( _Ra ) ₂ , -CN, -OH, -NO2, _oxo , =O, carboxyl, -C(O) _-NH2 , -C(O) _-NHRa , -C(O) _Ra , -C(O) _ORa , _C2-6 alkenyl, _C2-6 alkynyl, -C(O)-C(O) _ORa , _-C1-6 alkoxy, _-C1-6 alkyl, _-C1-6 haloalkyl, _{-C3-10 cycloalkyl, -C1-6 alkylene} -N( _Ra )2, _-C1-6 alkylene- _OC1-6 alkyl, _-C1-6 alkylene-C(O) _-ORa , _-C1-6 alkylene-(3-10 heterocyclic), -C _1-6 alkylene-(5-10 heteroaryl), -C _1-6 alkylene-C(O)-N( _Ra ) ₂ , -C _1-6 alkylene-NR _a -C(O)-N( _Ra ) ₂ , -C _1-6 alkylene-NR _a -C(O)-C _1-6 alkyl, -C(O)-N( _Ra ) ₂ , -C(O)-C(O)-N( _Ra ) 2, -C _3-10 carbocyclic, -5-10 heteroaryl, -3-10 heterocyclic, -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(Ra ₎ )2、-C(O)-NR _a- (3-10-membered heterocyclic group), -C(O)-NR _a- (3-10-membered heterocyclic group), -C(O)-(3-10-membered heterocyclic group), -OC _1-6 alkylene-C(O)-OR _a , -OC _1-6 alkylene-C(O)-N( _Ra ) ₂ , -OC _1-6 alkylene-N( _Ra ) 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( _Ra ) ₂ , -NR _a -C(O)-(5-10-membered heteroaryl group), -NR _a -C(O)-(5-10-membered heterocyclic group), -NR _a -C(O)-C _3-8 cycloalkyl, -NR _a -C _1-6 alkylene-N( _Ra ) ₂ , -NRa _{- C1-6} alkylene-(3-10-membered heterocyclic group), _-NRa - _C1-6 alkylene-(5-10-membered heteroaryl group), _-NRa -SO2C1-6 alkyl, _-SC1-6 alkyl, -SON( _Ra ) ₂ , -SO2N( _Ra ) ₂ , -SO _{-C1-6 alkyl} , -SO2 _{- C1-6} alkyl, -PO( _C1-6 alkyl) ₂ , -PO( _C1-6 alkoxy) ₂ , -3-10 _- membered heterocyclic group, -5-14-membered aryl or -5-14-membered heteroaryl, each group being independently and optionally substituted _;

Alternatively, two adjacent _R1 groups may cyclize to form a _C6-10 aryl, a 5-10 heteroaryl, a 3-10 carbocyclic, or a 3-10 heterocyclic group, with each group being independently and optionally substituted.

Or two adjacent _Ra are connected together to form a 5-14 membered aromatic ring, a 5-14 membered heteroaromatic ring, a 5-14 membered heterocycle, or a 5-14 membered carbon ring, and each ring system is independently and optionally substituted.

Each _Ra is independently selected from hydrogen, deuterium, halogen, _-NH2 , -CN, -OH, _-NO2 , carboxyl, _-C1-6 alkoxy, _-C1-6 alkyl, and each group is independently and optionally substituted;

_R3 is deuterium;

_R2 is selected from: hydrogen, deuterium, halogen, _-NH2 , -CN, -OH, _-NO2 , -COOH, -NH- _C1-6 alkyl, -N(C1-6 alkyl) ₂ , _-C1-6 alkoxy or _-C1-6 alkyl, and each group is independently and optionally substituted or unsubstituted;

Each _R4 and _R5 is independently selected from hydrogen, deuterium, halogen, _-NH2 , -CN, -OH, _-NO2 , -COOH, -NH- _C1-6 alkyl, -N( _C1-6 alkyl) ₂ , _-C1-6 alkoxy, or _-C1-6 alkyl, and each group is independently and optionally substituted or unsubstituted; or

_R4 and _R5 together with the carbon atoms they are connected to form 3-14 membered carbon rings, 3-14 membered heterocycles, 5-14 membered aromatic rings, 5-14 membered heteroaromatic rings or C=NRb, and each ring system is independently and optionally substituted or not substituted.

W represents non-existent, _-CH2- , -CH( _Rb )-, -C( _Rb ) _2- , -C(O)-, -NH-, _-NRb- , or -O-;

Y is C, CH, -C( _Rb )- or N;

When Y is CH, -C( _Rb )- or N, its adjacent bonds are single bonds; or when Y is C, its adjacent bonds are double bonds.

Each _Rb is independently selected from hydrogen, deuterium, halogen, _-NH2 , -CN, -OH, _-C1-6 alkoxy or _-C1-6 alkyl, and each group is independently optionally substituted or unsubstituted;

A is selected from: aryl, heteroaryl, cycloalkyl and heterocyclic groups that are unsubstituted or optionally substituted with one or more _R1s ;

B is selected from: aryl, heteroaryl, cycloalkyl and heterocyclic groups that are unsubstituted or optionally substituted with one or more _R1s ;

C represents an aryl, heteroaryl, cycloalkyl, or heterocyclic group that is absent, unsubstituted, or optionally substituted by one or more _{R1 groups} ;

When C is absent, _Y1 and _Y2 are each independently selected from -C( _R1 ) _2- , -C( _Rd ) _2- , _-NRd- , _-NR1- , and O; when one of them represents a single bond, _Y1 is -C( _R1 ) _2- , -C( _Rd ) _2- , -NRd-, _-NR1- , or O, and _Y2 is -C( _R1 ) _2- , -C( _Rd ) _2- , _-NRd- , _-NR1- , or O; or, when one of them represents a double bond, _Y1 is _CR1 , _CRd , or N, _{and Y2} is _CR1 , _CRd , or N.

When C is an aromatic ring, heteroaromatic ring, cycloalkyl or heterocycloalkyl; when represents a single bond, _Y1 is CR _d , CR ₁ or N, and _Y2 is CR _d or N; or, when represents a double bond, _Y1 is C and _Y2 is C.

Each _L1 and _L2 is independently selected from: covalent bonds, -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 SO2-} , -C(R _d ) _2- , _{-SO 2 NR d-} and

Each R _d is 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 is independently optionally substituted or unsubstituted;

--- indicates whether the key exists or does not exist; and

i) --- indicates that if the key does not exist, X also does not exist;

ii)---Indicates that X is _CH2 when the bond exists;

Each m, n, and q is independently selected from 0, 1, 2, 3, or 4; when m is 0, W is directly connected to Y ₂ ;

The above substitutions are independently selected from one or more substituents selected from -OH, halogen, unsubstituted _C1-6 alkyl, _-NH2 , _-NO2 , unsubstituted _-COC1-6 alkyl, -CN, =O, -COOH, _-COCH3- , _-COOCH3- , _-CONH2 , unsubstituted _C3-10 cycloalkyl, unsubstituted -NH- _C1-6 alkyl, unsubstituted -N( _C1-6 alkyl)( _C1-6 alkyl), unsubstituted -NH- _C3-6 cycloalkyl, unsubstituted -N( _C3-6 cycloalkyl)( _C3-6 cycloalkyl), unsubstituted 3-10 membered heterocyclic alkyl, unsubstituted _C6-14 aryl, or unsubstituted 5-12 membered heteroaryl groups;

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

The heteroatoms in the aforementioned heterocyclic alkyl, heteroaryl, and heterocyclic groups are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4.

In one embodiment of this application, in the compound represented by formula (II), A is optionally substituted or unsubstituted 3-14-membered cycloalkyl, 3-14-membered heterocycloalkyl, 5-14-membered aryl, or 5-14-membered heteroaryl; preferably optionally substituted or unsubstituted 5-12-membered cycloalkyl, 5-12-membered heterocycloalkyl, 5-12-membered aryl, or 5-12-membered heteroaryl; more preferably optionally substituted or unsubstituted 6-10-membered cycloalkyl, 6-10-membered heterocycloalkyl, 6-10-membered aryl, or 6-10-membered heteroaryl; more preferably optionally substituted or unsubstituted 6-10-membered aryl or 6-10-membered heteroaryl; more preferably optionally substituted... The heteroaryl group or heterocycle may be substituted or unsubstituted, consisting of an 8-10 membered polycyclic aryl group, a 5-6 membered monocyclic heteroaryl group, or an 8-10 membered polycyclic heteroaryl group; more preferably, it may be optionally substituted or unsubstituted, consisting of an 8-10 membered fused-ring aryl group, an 8-10 membered bridged-ring aryl group, an 8-10 membered spirocyclic aryl group, a 5-6 membered monocyclic heteroaryl group, an 8-10 membered fused-ring heteroaryl group, an 8-10 membered bridged-ring heteroaryl group, or an 8-10 membered spirocyclic heteroaryl group; more preferably, it may be optionally substituted or unsubstituted, consisting of an 8-10 membered fused-ring aryl group, a 5-6 membered monocyclic heteroaryl group, or an 8-10 membered fused-ring heteroaryl group; wherein each of the above heteroaryl groups or heterocycles contains 1, 2, or 3 heteroatoms independently selected from N, O, or S;

More preferably, A is selected from the following groups, either substituted or unsubstituted:

More preferably, A is selected from the following groups, either substituted or unsubstituted:

More preferably, A is selected from the following groups, either substituted or unsubstituted:

More preferably, A is selected from the following groups, either substituted or unsubstituted:

Wherein, the substitution is being replaced by one or more R ₁ ;

This indicates a connection to _L2 .

In one embodiment of the compound shown in formula (II) of this application, the _L2 is selected from: covalent bond, -S-, -S(O)-, -S(O) _2- , -O-, -C(O)-, -NR _d- and -C(R _d ) _2- ; preferably covalent bond, -S-, -O- and -NR _d- ; more preferably covalent bond and -S-.

In one embodiment of the compound shown in formula (II) of this application, B is optionally substituted or unsubstituted 3-14-membered cycloalkyl, 3-14-membered heterocycloalkyl, 5-14-membered aryl, or 5-14-membered heteroaryl; preferably optionally substituted or unsubstituted 5-12-membered cycloalkyl, 5-12-membered heterocycloalkyl, 5-12-membered aryl, or 5-12-membered heteroaryl; more preferably optionally substituted or unsubstituted 6-10-membered cycloalkyl, 6-10-membered heterocycloalkyl, 6-10-membered aryl, or 6-10-membered heteroaryl; more preferably optionally substituted. Or unsubstituted phenyl, 8-10 membered polycyclic aryl, 5-6 membered monocyclic heteroaryl or 8-10 membered polycyclic heteroaryl; more 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; more 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 heterocycles contains 1, 2 or 3 heteroatoms independently selected from N, O or S;

More preferably, B is selected from the following groups, either substituted or unsubstituted:

in,

Each _Y3 is independently selected from C( _R1 ) ₂ , _CR1 , _NR1 , N, S, and O;

Each _Y4 is independently selected from _CR1 and _NR1 ;

When representing a single bond, _Y3 is C( _R1 ) ₂ , _NR1 , S, and O, and _Y4 is _CR1 or N; or, when

When representing a double bond, _Y3 is either _CR1 or N, and _Y4 is C;

Wherein, the substitution is being replaced by one or more R ₁ ;

This indicates that it is connected to _L1 and _L2 respectively.

In one embodiment of the compound shown in formula (II) of this application, B is selected from monocyclic compounds such as substituted or unsubstituted pyridine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted thiazole, substituted or unsubstituted pyridinone, substituted or unsubstituted pyrimidinone, substituted or unsubstituted pyridazinone; or binary or ternary fused-ring systems formed by substituted or unsubstituted pyridine rings, pyrazine rings, pyridazine rings, pyrimidine rings, thiazole rings, pyridinone rings, pyrimidinone rings, pyridazinone rings, etc., together with substituted or unsubstituted imidazole, substituted or unsubstituted triazole, substituted or unsubstituted pyrazole, substituted or unsubstituted indazole, substituted or unsubstituted oxazole, etc.

Preferably, B is selected from the following groups, either substituted or unsubstituted:

More preferably, B is selected from the following groups, either substituted or unsubstituted:

Further preferred

Wherein, the substitution is being replaced by one or more R ₁ .

In one embodiment of the compound shown in formula (II) of this application, _L1 is selected from: covalent bond, -S(O) _2- , -CO-NR _d- , -NR _d- C(O)-, -C(O)O-, -NR _{d SO2-} , _-SO2 NR _d- and preferably covalent bond, -S(O) _2- , -CO-NR _d- or -NR _d- C(O)-; more preferably covalent bond.

In one embodiment of the compound shown in formula (II) of this application, Y is CH or N and is a single bond; preferably N and is a single bond.

In one embodiment of the compound shown in formula (II) of this application, W is -CH ₂ -, -CH(R _b )-, -C(R _b ) ₂ - or -O-; preferably -CH ₂ - or -O-.

In one embodiment of the compound shown in formula (II) of this application, the ring C is a 5-14 aryl, 5-14 heteroaryl, 5-14 carbocyclic, or 5-14 heterocyclic group that is absent, unsubstituted, or optionally substituted with one or more _R1 groups; preferably, the ring C is a 5-12 aryl, 5-12 heteroaryl, 5-12 carbocyclic, or 5-12 heterocyclic group that is absent, unsubstituted, or optionally substituted with one or more _{R1 groups} ; more preferably, the ring C is a 5-10 aryl, 5-10 heteroaryl, 5-10 carbocyclic, or 5-10 heterocyclic group that is absent, unsubstituted, or optionally substituted with one or more R1 groups; more preferably, the ring C is a 5-10 aryl, 5-10 heteroaryl, 5-10 carbocyclic, or 5-10 heterocyclic group that is absent, unsubstituted, or optionally substituted with one or more R1 groups. _The ring C is a 6-10 substituted aryl, 5-10 heteroaryl, 5-10 carbocyclic, or 5-10 heterocyclic group; more preferably, the ring _C is a 6-10 monocyclic aryl, 6-10 fused-ring aryl, 5-10 monocyclic heteroaryl, 5-10 fused-ring heteroaryl, 5-7 monocyclic carbocyclic, 7-10 fused-ring carbocyclic, 5-7 monocyclic heterocyclic, or 7-10 fused-ring heterocyclic group that is absent, unsubstituted, or optionally substituted by one or more R 1; more preferably, the ring C is a 6-10 substituted monocyclic aryl, 5-10 fused-ring carbocyclic, or 5-7 monocyclic heterocyclic group that is absent, unsubstituted, or optionally substituted by one or more R 1. _1- substituted 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 carbocyclic, 6-membered carbocyclic, 7-membered carbocyclic, 8-membered fused-ring carbocyclic, 9-membered fused-ring carbocyclic, 10-membered fused-ring carbocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered fused-ring heterocyclic, 9-membered fused-ring heterocyclic, or 10-membered fused-ring heterocyclic; wherein each of the above heteroaryl or heterocycles contains 1, 2, or 3 heteroatoms independently selected from N, O, or S;

More preferably, the ring C is absent, or selected from the following groups that are unsubstituted or optionally substituted by one or more R ₁ groups:

Preferably, the following groups are unsubstituted or optionally substituted by one or more _R1 groups:

Further preferred are the following groups that are unsubstituted or optionally substituted by one or more _R1 groups:

Further preferred are the following groups that are unsubstituted or optionally substituted by one or more _R1 groups:

Here, represents a single bond or a double bond.

In one embodiment of the compound shown in formula (II) of this application, when representing a single bond, _Y1 is -CR _d- or -N-, and _Y2 is -CR _d- or -N-.

In one embodiment of the compound shown in formula (II) of this application, when ring C is absent, _Y1 and _Y2 are each independently -C( _R1 ) _2- or -C( _Rd ) _2- .

In one embodiment of the compound shown in formula (II) of this application, each _R1 is independently selected from hydrogen, deuterium, halogen, -N( _Ra ) ₂ , -CN, -OH, -NO2, _oxo , ₌ O, carboxyl, -C1-6 alkoxy, _-C1-6 alkyl, _-C1-6 haloalkyl, _-C3-8 cycloalkyl, _-C1-6 alkylene-N( _Ra ) ₂ , _-C1-6 alkylene- _OC1-6 alkyl, _-C1-6 alkylene-C(O) _-ORa , _-C1-6 alkylene-( _3-10 -membered heterocyclic), -C1-6 alkylene-(5-10-membered heteroaryl), _-C1-6 alkylene-C(O)-N( _Ra ) ₂ , _-C1-6 alkylene-NRa, -C(O) _-C1-6 alkyl, _-C (O)-N(Ra _{) 2.} -C(O)-C(O)-N( _Ra ) _2. -C _3-10 carbocyclic, -5-10 heterocyclic, -3-10 heterocyclic, -C(O)-C _1-6 alkyl, -C(O)OC _1-6 alkyl, -C(O)-C _1-6 alkylene-N( _Ra ) _2. -C(O)-NR _a- (3-10 heterocyclic), -C(O) _- (3-10 heterocyclic), -OC _1-6 alkylene-C(O)-OR _a , -OC _3-10 carbocyclic, -O-(3-10 heterocyclic), -NR _a -C(O)-C _1-6 alkyl, -NR _a- C(O)-(5-10 heterocyclic), -NR _a -C(O)-C _3-8 cycloalkyl, -NRa _- C _1-6 alkylene-N( _Ra ) ₂ , -NRa _{- C 1-6} alkylene-(3-10 heterocyclic), -NRa-C _1-6 alkylene-(5-10 heteroaryl), -NRa- _S (O) _{2C 1-6} alkyl, -S(O)-N( _Ra ) ₂ , -S(O) ₂ -N( _Ra ) ₂ , -3-10 heterocyclic or -5-10 heteroaryl; preferably, each _R1 is independently selected from -H, -F, -Cl, -Br, _-NH2 , -N( _CH3 ) ₂ , -CN, -OH, oxo, =O, carboxyl, methoxy, ethoxy, _methyl , ethyl, _isopropyl , tert- _butyl , -CH2NH2 _{, -CH2CH2OCH3} , -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 ,

Each of the above _R1 is independently and optionally substituted by 1, 2 or 3 -F, -Cl, _-NH2 , -OH, oxo, =O, methyl, ethyl or propyl groups;

Alternatively, two adjacent Ra _rings may be 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 carbon ring, and each ring system may be independently and optionally substituted; preferably, two adjacent Ra _rings may be 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 carbon ring, and each ring system may be independently and optionally substituted.

Alternatively, _Ra and _Rb, together with the atoms they are connected to, form 3-14 membered aromatic rings, 3-14 membered heteroaromatic rings, 3-14 membered heterocycles, or 3-14 membered carbon rings; and each ring system is independently and optionally substituted; preferably, _Ra and _Rb, together with the atoms they are connected to, form 6-10 membered aromatic rings, 5-10 membered heteroaromatic rings, 5-10 membered heterocycles, or 5-10 membered carbon rings; and each ring system is independently and optionally substituted;

Each _Ra is independently selected from hydrogen, deuterium, halogen, _-NH₂ , -CN, -OH, _-NO₂ , carboxyl, -C₁ _-6 alkoxy, -C₁ _-6 alkyl; each group is independently and optionally substituted; preferably, each _Ra is independently selected from hydrogen, deuterium, halogen, _-NH₂ , -CN, -OH, -C₁ _-6 alkoxy, -C₁ _-6 alkyl; each group is independently and optionally substituted.

In one embodiment of the compound shown in formula (II) of this application, _R1 on ring B is independently selected from hydrogen, deuterium, amino, halogen, cyano, _-CONH2 , _-COR6 , _-COOR6 , optionally substituted _C1-6 alkyl, optionally substituted _C2-6 alkenyl, optionally substituted _C2-6 ynyl, optionally substituted C3-10 cycloalkyl, optionally substituted _3-10 heterocyclic alkyl; preferably hydrogen, halogen, amino, cyano, _-CONH2 , _-COR6 , _-COOR6 , optionally substituted _C1-4 alkyl, optionally substituted _C2-6 alkenyl, optionally substituted _C3-6 cycloalkyl, optionally substituted 3-6 heterocyclic alkyl; more preferably halogen, cyano, _-CONH2 , _-COR6 , _-COOR6 , hydroxyl-substituted _C1-4 alkyl, _C2-6 alkenyl, C _3-6 cycloalkyl, 3-6 heterocyclic alkyl; wherein, _R6 is independently selected from hydrogen, optionally substituted _C1-6 alkyl, optionally substituted _C3-6 cycloalkyl, optionally substituted 3-6 heterocyclic alkyl, optionally substituted _C6-10 aryl, optionally substituted 5-10 heteroaryl; preferably, _R6 is independently selected from hydrogen, optionally substituted _C1-6 alkyl, optionally substituted _C3-6 cycloalkyl, optionally substituted 3-6 heterocyclic alkyl; more preferably, _R5 is independently selected from hydrogen, _C1-6 alkyl, _C3-6 cycloalkyl, 3-6 heterocyclic alkyl;

The optional substitution refers to the situation where the hydrogen on the substituted group is not substituted or the hydrogen at one or more substituted sites of the substituted group is independently substituted by a substituent selected from -OH, halogen, _-NH2 , _-NO2 , _C1-6 alkyl, _C1-6 alkoxy, _C3-6 cycloalkyl, -NH- _C1-6 alkyl, -N( _C1-6 alkyl) _-C1-6 alkyl, -NH- _C3-6 cycloalkyl, -N( _C3-6 cycloalkyl) _{-C3-6 cycloalkyl, 3-6} membered heterocyclic alkyl, _C6-14 aryl or 5-10 membered heterocyclic cycloalkyl; preferably, it is substituted by a substituent selected from halogen, hydroxyl, amino, nitro, oxo, cyano, _C1-6 alkyl, _C1-6 alkoxy.

In one embodiment of the compound shown in formula (II) of this application, _R1 on ring A is independently selected from optionally substituted 8-12-membered heterocyclic groups, optionally substituted _C6-10 aryl groups, and optionally substituted 5-14-membered heteroaryl groups; wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that the hydrogen on one or more substituted sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxyl, amino, nitro, _oxo , _cyano , -COOH, -COCH3, -COOCH3, _-CONH2 , _C1-6 alkyl, _C1-6 alkoxy, _C3-10 cycloalkyl, 3-10-membered heterocyclic alkyl, _C6-10 aryl, and 5-12-membered heteroaryl groups;

In one embodiment of the compound shown in formula (II) of this application, _R1 on the C ring is independently selected from hydrogen, halogen, _-NH2 , _-NHR7 , -N( _R7 ) ₂ , -CN, _-NO2 , =O, -C(O) _-OR7 , -C(O) _-NH2 , -CO- _NHR7 , -CO-N( _R7 ) ₂ , -C(O) _R7 , -COOH, -OH, _-SC1-6alkyl , _-SOC1-6alkyl , -S(O) _2C1-6alkyl , substituted or unsubstituted _C1-6alkyl , substituted or unsubstituted _C1-6 alkoxy; wherein _{each R7} is independently _C1-6 alkyl; the term "substituted" means that the substituent is independently selected from _one or more -OH, halogen, _C1-6 alkyl, _-NH2 , _-NO2 , -COCH For groups with ₃ , -CN, and =O, the case where the substituent is "=O" means that two hydrogen atoms at the same substitution position are replaced by oxygen atoms.

In one embodiment of the compound shown in formula (II) of this application, _R2 is selected from: hydrogen, _deuterium , halogen, -NH2, -OH, -NH- _C1-6 alkyl, -N( _C1-6 alkyl) ₂ , _-C1-6 alkoxy, or _-C1-6 alkyl, and each group is independently optionally substituted or unsubstituted; preferably hydrogen, _deuterium , halogen, -NH2, -OH, _-C1-3 alkoxy, or _-C1-3 alkyl, and each group is independently optionally substituted or unsubstituted; more preferably hydrogen, _-NH2 , or -OH, and each group is independently optionally substituted or unsubstituted; more preferably _-NH2 .

In one embodiment of the compound shown in formula (II) of this application, each _R4 and _R5 is independently selected from hydrogen, deuterium, halogen, _-NH2 , -CN, -OH, _-C1-6 alkoxy, or _-C1-6 alkyl, and each group is independently optionally substituted or unsubstituted; preferably, each _R4 and _R5 is independently selected from hydrogen, deuterium, halogen, _-NH2 , -CN, -OH, _-C1-3 alkoxy, or _-C1-3 alkyl, and each group is independently optionally substituted or unsubstituted; more preferably, each _R4 and _R5 is independently selected from hydrogen, halogen, -OH, _-CH3 , or _-OCH3 ; more preferably, both _R4 and _R5 are hydrogen.

In one embodiment of the compound shown in formula (II) of this application, m is 0 or 1; q is 1; n is 1, 2 or 3; when m is 0, W is directly connected to Y ₂ .

In one embodiment of the compound shown in formula (II) of this application, --- indicates that the bond is not present.

In one embodiment of the compound shown in formula (II) of this application, the above-mentioned substitution is independently selected from one or more substituents selected from -OH, halogen, unsubstituted C1-6 alkyl, _-NH2 , _-NO2 , unsubstituted _-COC1-6 alkyl, -CN, =O, -C( _O )OH, -C(O) _-CH3- , -C(O) _OCH3- , -C(O)-NH2, unsubstituted _C3-10 cycloalkyl, unsubstituted -NH- _C1-6 alkyl, unsubstituted -N( _C1-6 alkyl) _{(C1-6 alkyl} ), unsubstituted -NH- _{C3-6 cycloalkyl, unsubstituted -N(C3-6} cycloalkyl)( _C3-6 cycloalkyl), unsubstituted 3-10 membered heterocyclic alkyl, unsubstituted _C6-14 aryl, or unsubstituted 5-12 membered heteroaryl groups; preferably -OH, halogen, unsubstituted _C1-6 alkyl, _-NH2 -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).

In one embodiment of the compound shown in formula (II) of this application, each _Rb is independently selected from hydrogen, deuterium, halogen, _-NH2 , -CN, -OH, _-C1-6 alkoxy or _-C1-6 alkyl; preferably hydrogen, deuterium, halogen, _-NH2 , -CN, -OH, _-C1-3 alkoxy or _-C1-3 alkyl.

In one embodiment of the compound shown in formula (II) of this application, each R _{_d} is independently selected from hydrogen, deuterium, halogen, -NH_₂, -CN, -OH, -NO_₂, -C(O)OH, -C(O) _-C1-6 alkyl, -C(O) _-OC1-6 alkyl, _-C1-6 alkylene- _OC1-6 alkoxy, _-C1-6 alkoxy, or _-C1-6 alkyl; preferably hydrogen, deuterium, halogen, -NH_₂ , -CN, -OH, -NO_₂, -C(O)OH, -C(O) _-C1-3 alkyl, -C(O) _-OC1-3 alkyl, _-C1-3 alkylene- _OC1-3 alkoxy, _-C1-3 alkoxy, or _-C1-3 alkyl; more preferably hydrogen, deuterium, halogen, -NH_₂, -CN, -OH, or -NO_₂. -C(O)OH, -C(O)-C _1-3alkyl , -C _1-3alkylene -OC _1-3alkoxy .

In certain embodiments of this application, the following compounds or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or pharmaceutically acceptable salts thereof are provided:

In certain preferred embodiments of this application, the following compounds or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or pharmaceutically acceptable salts thereof are provided:

In certain preferred embodiments of this application, the following compounds or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or pharmaceutically acceptable salts thereof are provided:

In certain preferred embodiments of this application, the following compounds or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or pharmaceutically acceptable salts thereof are provided:

This application also provides a main method for preparing the compound of formula (I) above, which can be used, for example, by the methods shown in the following synthesis scheme one and synthesis scheme two.

Synthesis Scheme 1

Where A, Y, G, X, L, _R1 , _R2 , _R3 and _R6 are as defined in the compound of formula (I),

I) Compounds I-1 and I-2 undergo a chemical transformation to yield compound I-3;

For example, using compounds I-1, I-2 and Ti(OEt) ₄ as basic raw materials, compound I-3 is obtained;

II) Compound I-3 undergoes a chemical transformation to yield compound I-4;

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

III) Compound I-4 undergoes a chemical transformation to yield compound I-5;

For example, compound I-4 yields compound I-5 under acidic conditions;

IV) Compound I-5 undergoes a chemical transformation to yield compound I-7;

For example, compound I-7 is obtained by reacting compounds I-5 and I-6 under alkaline conditions using compounds as basic raw materials.

V) Compound I-7 undergoes a chemical transformation to yield compound I-8;

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

VI) Compound I-8 undergoes a chemical transformation to yield compound I-9;

For example, compound I-9 can be obtained by using compounds I-8 and (Boc) _₂O as basic raw materials;

VII) Compound I-9 undergoes a chemical transformation to yield compound I-11;

Compound I-11 was obtained by reacting compounds I-9 and I-10 as basic raw materials under palladium catalysis and alkaline conditions.

Compound I-11 of formula (VIII) undergoes a chemical transformation to yield compound of general formula (I);

Compounds of general formula (I) are obtained by reacting compounds such as I-11 under acidic conditions.

Synthesis Scheme 2

Where A, Y, G, X, L, _R1 , _R2 , _R3 and _R6 are as defined in the compound of formula (I),

2-I) Compounds I-10 and I-6 undergo a chemical transformation to yield compound I-12;

For example, using compounds I-10 and I-6 as basic raw materials, compound I-12 was obtained under palladium catalysis and alkaline conditions;

2-II) Compounds I-12 and I-5 undergo chemical transformation to yield compound I-13;

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

Compound I-13 of formula (2-III) undergoes a chemical transformation to yield compound of general formula (I);

For example, compound I-13 yields compound of general formula (I) under acidic conditions.

This application also provides a pharmaceutical composition comprising (e.g., a therapeutically effective amount) the compounds described in this 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) Compounds of formula (I-2-B1), (I-B2), (I-B3), (I-2-B2), (I-2-B3), (II), (I-A), (I-B), (I-1-A), (I-1-B), (I-2-A), (I-2-B), (I-2-B), (I-Ba), or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof.

Furthermore, the pharmaceutical composition described in this application comprises the compounds described in this 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)). The compound of formula (I-B2), formula (I-B3), formula (I-2-B2), formula (I-2-B3), formula (II), formula (I-A), formula (I-B), formula (I-1-A), formula (I-1-B), formula (I-2-A), formula (I-2-B), formula (I-Ba), or its prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.

This application contains compounds of formula (I), (I-1), (I-1-1), (I-2), (I-A1), (I-1-A1), (I-2-A1), (I-A2), (I-A3), (I-2-A2), (I-2-A3), (I-B1), (I-1-B1), (I-2-B1), (I-B2), (I-B3), and (I-2... Compounds of formula (I-B2), (I-2-B3), (II), (I-A), (I-B), (I-1-A), (I-1-B), (I-2-A), (I-2-B), (I-Ba), or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof may be administered in pure form or as a suitable pharmaceutical composition by any acceptable route of administration of a medicament for similar use. The pharmaceutical compositions of this application may be prepared by combining the compounds described herein with suitable pharmaceutically acceptable excipients. The pharmaceutical compositions of this application may be formulated into solid, semi-solid, liquid, or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalers, gels, microspheres, and aerosols, etc. Generally, the above-mentioned pharmaceutical compositions can be prepared using conventional excipients in the pharmaceutical field and conventional preparation methods.

This application also provides, in another aspect, the compounds described in this 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)). Use of the following pharmaceutical compositions, including compounds of formula (I-2-B2), (I-2-B3), (II), (I-A), (I-B), (I-1-A), (I-1-B), (I-2-A), (I-2-B), (I-Ba), or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, in the preparation of medicaments for the prevention and/or treatment of diseases, symptoms, and conditions mediated by SHP2 activity.

Furthermore, in the uses provided in this application, the diseases, symptoms, and conditions mentioned are tumors, cancer metastases, cardiovascular diseases, immune disorders, or visual disorders.

Furthermore, in the uses provided in this application, the tumor includes solid tumors and hematologic tumors.

Furthermore, in the uses provided in this application, the solid tumor includes lung cancer, and the hematologic malignancy includes leukemia, preferably acute myeloid leukemia. In certain contexts within the art, the cancer may also be referred to as a malignant tumor.

On another front, this application provides a method for preventing and/or treating diseases, symptoms, and conditions mediated by SHP2 activity, comprising administering to an individual in need the compounds described in this 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-A ... Compound (B2), compound (I-2-B3), compound (I-A), compound (I-B), compound (I-1-A), compound (I-1-B), compound (I-2-A), compound (I-2-B), compound (I-Ba), compound (II), or its prodrug, tautomer, stereoisomer, solvate, isotope derivative, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of this application; preferably, the disease, symptom, and condition are tumors, cancer metastases, cardiovascular diseases, immune disorders, or visual disorders; more preferably, the tumors include solid tumors and hematologic malignancies; more preferably, the solid tumors include lung cancer, and the hematologic malignancies include leukemia, preferably acute myeloid leukemia.

On the other hand, this application provides compounds of formula (I), (I-1), (I-1-1), (I-2), (I-A1), (I-1-A1), (I-2-A1), (I-A2), (I-A3), (I-2-A2), (I-B1), (I-1-B1), (I-2-B1), (I-B2), (I-B3), (I-B3), (I-2-B2), (I-B3), (I-2-B2), (I-B3), (I-2-B2), and (I-B3) compounds for the prevention and/or treatment of diseases, symptoms, and conditions mediated by SHP2 activity. The invention may contain, but is not limited to, compounds of formula (I-2-B3), (II), (I-A), (I-B), (I-1-A), (I-1-B), (I-2-A), (I-2-B), (I-Ba), or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof; preferably, the disease, symptom, or condition is a tumor, cancer metastasis, cardiovascular disease, immune disorder, or visual disorder; more preferably, the tumor includes solid tumors and hematologic malignancies; more preferably, the solid tumor includes lung cancer, and the hematologic malignancies include leukemia, preferably acute myeloid leukemia.

Furthermore, in the uses or methods provided in this application, the compounds described in this 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-A2), compound of formula (I-B1), compound of formula (I-1-B1), compound of formula (I-2-B1), compound of formula (I-B2), ... The compound of formula (I-B3), formula (I-2-B2), formula (I-2-B3), formula (II), formula (I-A), formula (I-B), formula (I-1-A), formula (I-1-B), formula (I-2-A), formula (I-2-B), formula (I-Ba) or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of this application, may be used in combination with another, two or more compounds having antitumor activity.

Furthermore, this application provides compounds of formula (I), (I-1), (I-1-1), (I-2), (I-A1), (I-1-A1), (I-2-A1), (I-A2), (I-A3), (I-2-A2), (I-2-A3), (I-B1), (I-1-B1), (I-2-B1), and (I-2-B1) for inhibiting SHP2 activity. Compounds of formula (I-B2), (I-B3), (I-2-B2), (I-2-B3), (II), (I-A), (I-B), (I-1-A), (I-1-B), (I-2-A), (I-2-B), (I-2-B), (I-Ba), or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, as described in this application.

definition

The terms “optional,” “arbitrary,” “optionally,” or “arbitrarily” refer to events or conditions that are subsequently described but are not required to occur, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

Unless otherwise specified, "optional substitution" or "arbitrary substitution" means that the group can be unsubstituted or substituted, wherein the substituent is independently selected from one or more of the following groups: hydroxyl, halogen, amino, nitro, mercapto, cyano, azide, oxo, carboxyl, -C(O) _C1-6 alkyl, -C(O) _OC1-6 alkyl, -OC(O) _-C1-6 alkyl, -NH( _C1-6 alkyl), -N( _C1-6 alkyl)( _C1-6 alkyl), -C(O)NH- _C1-6 alkyl, -NHC(O) _-C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkyl, _C1-6 alkoxy, C3-10 cycloalkyl, _C3-10 cycloalkylsulfonyl, 3-10 heterocyclic alkyl, C6-14 aryl, and _5-12 heteroaryl groups; wherein the _C2-6 alkenyl, C3-6 cycloalkyl, C3-10 cycloalkylsulfonyl, _3-10 heterocyclic alkyl, C6-14 aryl, and 5-12 heteroaryl groups. The _2-6 alkynyl, _C1-6 alkyl, _C1-6 alkoxy, _C3-10 cycloalkyl, _C3-10 cycloalkylsulfonyl, 3-10 heterocyclic alkyl, _C6-14 aryl or 5-12 heterocyclic cycloalkyl may optionally be substituted with one or more selected from halogen, hydroxyl, amino, cyano, _C1-6 alkyl or _C1-6 alkoxy.

The term "oxo group" refers to a double bond formed when two hydrogen atoms at the same substitution position are replaced by the same oxygen atom, i.e., =O.

Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight-chain or branched group containing 1 to 20 carbon atoms, preferably containing 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms (i.e., _C1-10 alkyl), more preferably containing 1 to 8 carbon atoms ( _C1-8 alkyl), and more preferably containing 1 to 6 carbon atoms (i.e., _C1-6 alkyl). For example, " _C1-6 alkyl" means that the group is alkyl and the number of carbon atoms on 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.

Unless otherwise specified, the term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon atoms and hydrogen atoms, having at least one double bond. An alkenyl group may contain 2-20 carbon atoms, preferably 2, 3, 4, 5, 6, 7 _, 8, 9, or 10 carbon atoms (i.e., _C2-10 alkenyl), more preferably 2-8 carbon atoms ( _C2-8 alkenyl), and even more preferably 2-6 carbon atoms (i.e., _C2-6 alkenyl), 2-5 carbon atoms (i.e., _C2-5 alkenyl), 2-4 carbon atoms (i.e., C2-4 alkenyl), 2-3 carbon atoms (i.e., _C2-3 alkenyl), or 2 carbon atoms (i.e., _C2 alkenyl). For example, " _C2-6 alkenyl" means that the group is alkenyl and the number of carbon atoms on the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5, or 6). Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl.

Unless otherwise specified, the term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon atoms and hydrogen atoms, having at least one triple bond. The alkynyl group may contain 2-20 carbon atoms, preferably 2, 3, 4, 5, 6, 7 _, 8, 9, or 10 carbon atoms (i.e., _C2-10 alkynyl), more preferably 2-8 carbon atoms ( _C2-8 alkynyl), and even more preferably 2-6 carbon atoms (i.e., _C2-6 alkynyl), 2-5 carbon atoms (i.e., _C2-5 alkynyl), 2-4 carbon atoms (i.e., C2-4 alkynyl), 2-3 carbon atoms (i.e., _C2-3 alkynyl), or 2 carbon atoms (i.e., _C2 alkynyl). For example, " _C2-6 alkynyl" means that the group is alkynyl and the number of carbon atoms on 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.

Unless otherwise specified, the terms "cycloalkyl,""carbocyclic," or "carbocyclic" refer to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms, comprising 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, ₁₃ , or 14 carbon atoms (i.e., _C3-14 cycloalkyl), preferably comprising 3-12 carbon atoms (i.e., _C3-12 cycloalkyl), more preferably comprising 3-10 carbon atoms ( _C3-10 cycloalkyl), and even more preferably comprising 3-7 carbon atoms ( _C3-7 cycloalkyl), 4-6 carbon atoms ( _C4-6 cycloalkyl), or 5-6 carbon atoms (C5-6 cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, etc. In some embodiments of this application, "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms, composed of carbon atoms and hydrogen atoms. In some embodiments of this application, the cycloalkyl group preferably comprises 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).

Unless otherwise specified, the term "alkoxy" refers to -O-alkyl, which is defined as above, i.e., containing 1-20 carbon atoms, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably 1-8 carbon atoms, and even more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6). Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, etc.

Unless otherwise specified, the term "carboxyl" refers to the -COOH group. The terms "halogen" or "halogenated" refer to F, Cl, Br, and I. The term "halogenated alkyl" refers to an alkyl group as defined above in which one, two, or more, or all, of the hydrogen atoms are replaced by a halogen. Representative examples of halogenated alkyl _groups include _CCl₃ , _CF₃ , _CHCl₂ , _CH₂Cl , _CH₂Br , _CH₂I , _CH₂CF₃ , _CF₂CF₃ , _etc.

Unless otherwise specified, the term "heterocyclic group" or "heterocycle" refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic non-aromatic substituent having a ring carbon atom and 1 to 4 ring heteroatoms, comprising 3 to 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 comprises 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms (i.e., 3-14 membered heterocyclic groups), more preferably 3 to 12 ring atoms (3-12 membered heterocyclic groups), more preferably 3 to 10 ring atoms (3-10 membered heterocyclic groups), or 3 to 8 ring atoms (3-8 membered heterocyclic groups), or 3 to 6 ring atoms (3-6 membered heterocyclic groups), or 4 to 6 ring atoms (4-6 membered heterocyclic groups), or 5 to 6 ring atoms (5-6 membered heterocyclic groups). The heteroatoms are preferably 1-4, more preferably 1-3 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclic groups include ethylene oxide, pyrrolyl, N-methylpyrrolyl, pyrazolyl, imidazoyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, thiomorpholinyl, and tetrahydrothiopheneyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups. A "heterocyclic group" can be a monocyclic ("monocyclic heterocyclic group") or a fused ("fused heterocyclic group" or "heterofused-ring group"), bridged ("heterobridged ring group" or "bridged ring 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. A bicyclic heterocyclic system can include one or more heteroatoms in one or two rings. "Heterocyclic group" also includes a ring system in which the heterocyclic ring as defined above is fused with one or more carbocyclic groups, wherein the attachment point is on the carbocyclic or heterocyclic ring; or "heterocyclic group" also includes a ring system in which the heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, or a ring system in which a cycloalkyl ring as defined above is fused with one or more heteroaryl groups, wherein the attachment point is on the heterocyclic or cycloalkyl ring, and in such cases, the number of members in the heterocyclic ring system is the number of atoms in the fused ring system. In some embodiments, each example of a heterocyclic group is independently optionally substituted, for example, unsubstituted (an "unsubstituted heterocyclic group") or substituted with one or more substituents (an "substituted heterocyclic group"). Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirropropyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azahexacyclobutane, oxacyclobutane, and thiohexacyclobutane. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanecyclopentane, oxathiocyclopentane, dithiocyclopentane, and oxazolidinyl-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazine, morpholinyl, dithiocyclohexyl, and dioxazinanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazacyclohexyl, oxadiazine, thiadiazine, oxathiazine, and dioxazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxadiazine, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxadiazine, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused to a _C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocycle) include, but are not limited to, dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic 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.

Unless otherwise specified, "heterocyclic alkyl" refers to a monocyclic, saturated "heterocyclic group" or "heterocycle" as defined above, with the same definition of ring atoms as above, i.e., containing 3 to 20 ring atoms ("3-20 membered heterocyclic alkyl"), 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, it contains 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms (“3-12-membered heterocyclic alkyl”), more preferably 3 to 10 ring atoms (“3-10-membered heterocyclic alkyl”), even more preferably 3 to 8 ring atoms (“3-8-membered heterocyclic alkyl”), even more preferably 4 to 7 ring atoms (“4-7-membered heterocyclic alkyl”), even more preferably 5 to 10 ring atoms (“5-10-membered heterocyclic alkyl”), and even more preferably 5 to 6 ring atoms (“5-6-membered heterocyclic alkyl”). In some embodiments, each example of a heterocyclic alkyl group is independently optionally substituted, for example, unsubstituted (an “unsubstituted heterocyclic alkyl”) or substituted with one or more substituents (an “substituted heterocyclic alkyl”). The “heterocyclic group” or “heterocyclic” section above has given some exemplary “heterocyclic alkyl groups”, which also include, but are not limited to, azirrocyclopropane, oxacyclopropane, thiocyclopropane, azirrocyclobutane, oxacyclobutane, thiocyclobutane, tetrahydrofuranyl, oxacyclohexyl, piperidinyl, piperazineyl, morpholinyl, thiomorpholinyl, oxathiohexyl, oxazolidinyl, dioxane, dithiohexyl, thiazolyl, pyrrolidinyl, pyrazolyl, imidazolinyl, etc.

Unless otherwise specified, the term "aryl" or "aromatic ring group" refers to a monocyclic, bicyclic, or tricyclic aromatic carbocyclic system containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, preferably 6-10 carbon atoms. The term "aryl" may be used interchangeably with the term "aromatic ring." Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthraceneyl, phenanthryl, or pyreneyl. Polycyclic aryl groups include fused-ring and bridged-ring aryl groups, and the interpretation of fused-ring and bridged-ring is similar to that of polycyclic heterocyclic groups.

Unless otherwise specified, the term "heteroaryl" or "heteroary cycloyl" means an aromatic monocyclic or polycyclic system containing a 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14-membered structure, or preferably a 5-10-membered structure, or preferably a 5-8-membered structure, more preferably a 5-6-membered structure, wherein one, two, three or more ring atoms are heteroatoms and the remaining atoms are carbon atoms, the heteroatoms being independently selected from O, N or S, and the number of heteroatoms is preferably one, two or three. Examples of heteroaryl groups include, but are not limited to, furanyl, thiophene, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purine, indoleyl, isoindoleyl, indazoleyl, benzofuranyl, benzothiophene, benzopyridyl, benzopyrimidinyl, and benzo[] Pyrazinyl, benzimidazolyl, benzophthalazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, 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]pyridyl, etc. Polycyclic heteroaryl groups include fused-ring and bridged-ring heteroaryl groups; the explanations for fused-ring and bridged-ring groups are similar to those for polycyclic heteroaryl groups.

When a substituent can be attached to more than one atom on a ring, the substituent can bond to any atom on the ring (including heteroatoms, such as NH), for example, indicating that the attachment site can be at any position on the benzene ring or pyridine ring, or at any position on the benzene ring or tetrahydrofuran ring.

Unless otherwise specified, the terms "pharmaceutically acceptable salt" or "medicinal salt" refer to a salt suitable for contact with mammalian, particularly human, tissues without excessive toxicity, irritation, allergic reactions, etc., and in a manner commensurate with a reasonable benefit/risk ratio, within the limits of reasonable medical judgment. For example, medically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salts may be prepared in situ during the final separation and purification of the compounds described in this application, or solely by reacting a free base or free acid with a suitable reagent. The pharmaceutically acceptable salts of this application include acid addition salts or base addition salts of the compounds described in this application, obtained by reacting the compounds described in this application with inorganic or organic acids and inorganic or organic bases well known to those skilled in the art.

Unless otherwise specified, the term "isotope derivative" refers to compounds of this application that can exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weights or mass numbers differ from the atomic weights or mass numbers of the most abundant atoms found in nature. Isotopes can be radioactive or non-radioactive. Commonly used isotopes for labeling are: hydrogen isotopes, ^2H and ^3H ; carbon isotopes: ^13C and ^14C ; chlorine isotopes: ^35Cl and ^37Cl ; fluorine isotope: ^18F ; iodine isotopes: ^123I and ^125I ; nitrogen isotopes: ^13N and ^15N ; oxygen isotopes: ^15O , ^17O , and ^18O ; and sulfur isotope ^35S . These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. ^2H and ^13C , in particular, are more widely used due to their ease of labeling and detection. Substitution with certain heavy isotopes, such as deuterium ( ^2H ), can enhance metabolic stability and prolong half-life, thereby providing therapeutic advantages through dose reduction. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, just like non-isotope-labeled compounds.

Unless otherwise specified, the terms "solvent" or "solvent compound" refer to the physical association of the compound of this application with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. Solvent molecules in a solvate may be present in a regular and/or disordered arrangement. A solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvent compound" encompasses both 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.

Unless otherwise specified, the term "stereoisomer" refers to compounds that have the same chemical structure but differ in the spatial arrangement of their atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis/trans) isomers, and inhibited isomers. Any mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called proton transfer tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

Unless otherwise specified, the structural formulas described in this application include all isomers (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compound of this application or its enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers) are within the scope of this application.

Unless otherwise specified, the term "prodrug" refers to a drug that is converted into a parent drug in vivo. Prodrugs are generally useful because they can improve certain, undesirable physical or biological properties. Physical properties are usually related to solubility (excessive or insufficient lipid or water solubility) or stability, while problematic biological properties include metabolism that is too rapid or poor bioavailability, which may itself be related to physicochemical properties. For example, they can be bioavailable orally, whereas the parent drug cannot. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. An example of a prodrug, but not limited to this, can be any compound of this application administered as an ester ("prodrug") to facilitate transmembrane transport, where water solubility is detrimental to migration but beneficial once inside the cell, and which is subsequently metabolized and hydrolyzed into a carboxylic acid, the 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 exhibit the active moiety.

Unless otherwise specified, the term “treatment” covers any treatment of a patient’s disease, condition, or illness, including: (a) suppressing the symptoms of the disease, condition, or illness, i.e., preventing its development; or (b) alleviating the symptoms of the disease, condition, or illness, i.e., causing the disease or symptoms to subside; or (c) improving or eliminating the disease, condition, or illness or one or more symptoms associated with said disease.

Unless otherwise specified, the term "therapeutic effective amount" means the amount of the compound of this application used to treat a particular disease, condition, or illness; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or illness; or (iii) to delay the onset of one or more symptoms of a particular disease, condition, or illness described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the content of this disclosure.

Unless otherwise specified, the term "pharmaceuticalally acceptable excipient" means those excipients that do not cause significant irritation to an organism (e.g., human) and do not impair the biological activity and properties 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. "Pharmaceuticalally acceptable excipient" may also refer to inert substances that are administered co-administered with the active ingredient and facilitate the administration of the active ingredient, including but not limited to any flow aids, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers approved by the U.S. Food and Drug Administration for use in humans or animals (e.g., livestock).

The beneficial effects of this application are as follows:

This application designs a class of novel compounds, providing a new direction for the treatment of tumors, cancer, cancer metastasis, cardiovascular diseases, immune disorders, or visual disorders. The compounds of this application possess one or more of the following advantages: (1) strong SHP2 kinase inhibition; (2) high exposure and good absorption; (3) no significant inhibition of hERG channels, resulting in low cardiotoxicity; (4) good tolerability and high drug safety; and (5) high in vivo tumor inhibition rate. Furthermore, this application studies a specific synthetic method that is simple, convenient, and conducive to large-scale industrial production and application.

Detailed Implementation

The following specific embodiments further illustrate various aspects of this application. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the aspects described herein. Experimental methods without specific conditions specified in the embodiments are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as those familiar with the art. Furthermore, any methods and materials similar or equivalent to those described can be applied to the methods of this application. The preferred embodiments and materials shown in this application are for illustrative purposes only.

Preparation Examples, Examples, and other abbreviations used herein are:

DCM (Dichloromethane)

TEA (Triethylamine)

EA (ethyl acetate)

DMSO (Dimethyl sulfoxide)

DMF (dimethylformamide)

TFA (Trifluoroacetic acid)

DIPEA (N,N-diisopropylethylamine)

Pd(dppf) _Cl₂ 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride

_Pd2 (dba) _3tris (dibenzylacetone)dipalladium

Pd(PPh ₃ ) ₄ tetrakis(triphenylphosphine)palladium(0)

XantPhos 4,5-Bisdiphenylphosphine-9,9-Dimethyloxanthracene

(Boc) _₂O ditert-butyl dicarbonate

NBS (N-bromosuccinimide)

Dtbpy 4,4'-Di-tert-butylbipyridine

DMA (N,N-dimethylacetamide)

TBAI (Tetrabutylammonium iodide)

EDCI 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

Intermediate Preparation Example 1: 1-(5-amino-3-chloropyrazin-2-yl)acetone (Intermediate 1)

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), 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( _Ph₃P ) _₂Cl₂ (6.78 g, 9.667 _mmol , 0.1 eqv) were added, and the mixture was reacted overnight at 100 °C under nitrogen protection. After cooling to room temperature, silica gel was added to the reaction mixture, and the mixture was concentrated to dryness under reduced pressure. The solution was then purified by column chromatography (n-hexane:EA = 10:1–5:1) to give 1-(5-amino-3-chloropyrazin-2-yl)acetone (5.1 g, 31% yield). (ES,m/z):171.97[M+H] ⁺ .

Intermediate Preparation Example 2: Methyl 3-chloro-5-((2,4-dimethoxybenzyl)amino)pyrazine-2-carboxylate (Intermediate 2)

Under nitrogen protection, CsF (8.36 g, 55.07 mmol, 3 eqv) was added to 40 mL of DMSO containing methyl 3,5-dichloropyrazine-2-carboxylate (3.8 g, 18.36 mmol, 1 eqv) and 2,4-dimethoxybenzylamine (3.07 g, 18.36 mmol, 1 eqv). The mixture was then heated to 75 °C and reacted for 3 h. After cooling to room temperature, the reaction mixture was poured into water (200 mL) and EA (100 mL), and the mixture was separated. 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 give methyl 3-chloro-5-((2,4-dimethoxybenzyl)amino)pyrazine-2-carboxylate (4 g, yield 54.06%). (ES, m/z): 338.1[M+H] ⁺ ; ¹ H NMR (400MHz, 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).

Intermediate Preparation Example 3: 2-Chloro-3-(oxazol-2-yl)benzylthiol (Intermediate 3)

Step a: A solution of 2-chloro-3-fluoroaniline (5.00 g, 33.663 mmol, 1 eqv), tert- _butylthiol (3.64 g, 40.396 mmol, 1.2 eqv), and _Cs₂CO₃ (32.90 g, 100.989 mmol, 3 eqv) in DMF (50 mL) was reacted at 130 °C for 24 h. The mixture was cooled to room temperature, poured into water (300 mL), and extracted with EA (2 × 300 mL). The organic phases were combined, washed with brine (2 × 500 mL), concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane:EA = 100:1–20:1) to give 3-(tert-butylthioalkyl)-2-chloroaniline (7.0 g, yield 94.46%). (ES, m/z): 216 [M+H] ^⁺ .

Step b: Cool the solution of 3-(tert-butylthioalkyl)-2-chloroaniline (7.0 g, 32.55 mmol, 1 eqv) in concentrated hydrochloric acid (15 ml) to -10 to -5 °C, and add sodium nitrite (3.369 g, 48.83 mmol, 1.5 eqv) in water (105 ml) dropwise. After the addition is complete, maintain the temperature for 30 min. At the same temperature, add potassium iodide (6.484 g, 39.06 mmol, 1.2 eqv) in water (6 ml) dropwise. Add 5 ml of solution, and after the addition is complete, keep the reaction at the specified temperature for 20 min. Add 100 ml of ethyl acetate and 100 ml of saturated sodium thiosulfate solution to the reaction solution, stir for 10 min, separate the layers, extract the aqueous phase with EA (2 × 50 ml), and combine the organic phases. Wash the organic phase with brine (100 mL), concentrate under reduced pressure, and purify the residue by column chromatography (n-hexane) to give tert-butyl(2-chloro-3-iodophenyl)thione (6.52 g, yield 61.45%). ^¹H -NMR (400 MHz, DMSO-d6) δ 7.99 (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).

Step c: A DMF (50 mL) solution of tert-butyl(2-chloro-3-iodophenyl)thione (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) was reacted at 140 °C for 2 h under nitrogen protection. The reaction was confirmed to be complete by TLC. The mixture was cooled to room temperature, and the reaction solution was poured into water (300 mL). It was extracted with EA (2 × 150 mL). The organic phases were combined, washed with brine (2 × 100 mL), concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane:EA = 25:1 to 10:1) to give 2-(3-(tert-butylthioalkyl)-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).

Step d: At 0°C, aluminum trichloride (6.23 g, 46.72 mmol, 4 eqv) was added to a toluene (60 mL) solution of 2-(3-(tert-butylthioalkyl)-2-chlorophenyl)oxazole (3.12 g, 11.68 mmol, 1 eqv), and the reaction was allowed to proceed overnight at room temperature. The mixture was then cooled to 0°C, water (60 mL) was added dropwise, and the mixture was stirred for 30 min. The liquid phase was separated, and the aqueous phase was extracted with toluene (30 mL). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane:EA = 20:1–5:1) to give 2-chloro-3-(oxazol-2-yl)benzylthiol (1.726 g, 70% yield). (ES, m/z): 211.89 [M+H] ⁺ .

Examples of intermediate preparation 4-5:

The steps for preparing Example 3 using intermediates and the following corresponding starting materials for synthesizing intermediates 4-5:

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

Step a: Under nitrogen protection, a solution of tert-butyl(2-chloro-3-iodophenyl)thione (3.26 g, 10 mmol, 1 eqv), pyrazine-2-boronic acid (1.49 g, 12 mmol, 1.2 eqv), _K₂CO₃ ( _4.14 g, 30 mmol, 3 eqv), and Pd(dppf) _Cl₂ (731.7 mg, 1 mmol, 0.1 eqv) in 1,4-dioxane (80 mL) and water (20 mL) was reacted overnight at 100 °C. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane:EA = 50:1 to 25:1) to give 2-(3-(tert-butylthioalkyl)-2-chlorophenyl)pyrazine (1.21 g, yield 43.5%). (ES, m/z): 279.00 [M+H] ^⁺ .

Step b: At 0°C, aluminum trichloride (2.32 g, 17.4 mmol, 4 eqv) was added dropwise to a toluene (60 mL) solution of 2-(3-(tert-butylthioalkyl)-2-chlorophenyl)pyrazine (1.21 g, 4.35 mmol, 1 eqv), and the reaction was allowed to proceed overnight at room temperature. The mixture was then cooled to 0°C, water (60 mL) was added dropwise, and the mixture was stirred for 30 min. The layers were 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 give 2-chloro-3-(pyrazin-2-yl)phenylthiol (726 mg, yield 75.2%). (ES, m/z): 222.89 [M+H] ⁺ .

Examples of intermediate preparation 7-9

The steps for preparing Example 6 using intermediates and the following corresponding starting materials for synthesizing intermediates 7-9:

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

Step a: Under nitrogen protection, 2,3-dichloro-4-iodopyridine (2.00 g, 7.33 mmol, 1.00 eqv), 2-ethylhexyl 3-mercaptopropionic acid (2.07 g, 9.51 mmol, 1.3 eqv), DIPEA (2.862 g, 21.99 mmol, 3.00 eqv), and _Pd₂ (dba) _₃ were added. A solution of 1,4-dioxane (50 mL) containing 1.342 g (1.466 mmol, 0.2 eqv) and XantPhos (1.696 g, 2.932 mmol, 0.4 eqv) was stirred at 96 °C for 8 h. The mixture was cooled to room temperature, 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 give 2-ethylhexyl 3-(2-(2,3-dichloropyridin-4-yl)thioalkyl)propionate (2.076 g, yield 78%). (ES, m/z): 364.06 [M+H] ⁺ .

Step b: Under nitrogen protection, 2-ethylhexyl 3-(2-(2,3-dichloropyridin-4-yl)thioalkyl)propionate (666 mg, 1.834 mmol, 1.0 eqv), pyrazine-2-boronic acid (250 mg, 2.02 mmol, 1.1 eqv), and Pd(dppf) _Cl₂ were added. A solution of 1,4-dioxane (60 mL) and potassium carbonate (760 mg, 5.503 mmol, 3 eqv) in 1,4-dioxane (60 mL) and water (10 mL) was reacted overnight at 96 °C. The mixture was cooled, concentrated under reduced pressure, and the residue was treated with water (200 mL) and EA (100 mL). The mixture was separated, and the aqueous phase was extracted with EA (2 × 50 mL). The organic phases were combined and washed with brine (100 mL). The residue was concentrated under reduced pressure, and purified by column chromatography (n-hexane:EA = 30:1–10:1) to give 2-ethylhexyl 3-((3-chloro-2-(pyrazin-2-yl)pyridin-4-yl)thioalkyl)propionate (637 mg, yield 85.3%). (ES, m/z): 408.15 [M+H] ⁺ .

Step c: Under nitrogen protection, a methanol (60 mL) solution of 2-ethyl-hexyl 3-((3-chloro-2-(pyrazin-2-yl)pyridin-4-yl)thioalkyl)propionate (637 mg, 1.565 mmol, 1.0 eqv) and NaOH (66 mg, 1.643 mmol, 1.05 eqv) was reacted at 50 °C for 3 h. The mixture was then cooled to approximately 0 °C, and 4 M HCl/MeOH solution was added dropwise to adjust the pH to 3–4. The solution was concentrated under reduced pressure and purified by column chromatography (n-hexane:EA = 10:1–5:1) to obtain 3-chloro-2-(pyrazin-2-yl)pyridin-4-thiol (320 mg, yield 91.7%). (ES, m/z): 223.92 [M+H] ⁺ .

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

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

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

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

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

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

Step a: A solution of 1-(5-amino-3-chloropyrazin-2-yl)acetone (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; the mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with EA (3 × 30 mL). The organic phases were combined; the organic phases were then subjected to H2 _... Washed with 100 ml of oxygen and 100 ml of brine, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH = 80:1 to 50:1) to give (R)-N-((R)-1'-(3-acetyl-6-aminopyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)-2-methylpropane-2-sulfinamide (321 mg, yield 46%). (ES, m/z): 444.16 [M+H] ⁺ .

Step b: Add 10 mL of HCl/CH₃OH solution 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 -sulfinamide (321 mg, 0.724 mmol, 1.0 eqv). After stirring at room temperature for 4 h, evaporate the reaction solution to dryness to obtain crude ((R)-1-(5-amino-3-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-yl) acetone. (ES, m/z): 340.10 [M+H] ^⁺ .

Step c: At room temperature, 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)acetone (246 mg, 0.724 mmol, 1.0 eqv) in DCM (50 ml), and then (Boc) _₂O (316 mg, 1.448 mmol, 2.0 eqv) was added. The reaction was allowed to proceed overnight at room temperature. Water (50 mL) was added to the reaction mixture, and the mixture was separated. The aqueous phase was extracted with DCM (20 mL × 2), and the organic phases were combined. The combined organic phases were washed with _H₂O (20 mL) and brine (20 mL), concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane:EA = 5:1 to 1:5) to give (R)-(1'-(3-acetyl-6-aminopyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamate tert-butyl ester (221 mg, yield 69.5%). (ES, m/z): 440.15 [M+H] ^⁺ .

Step d: At -15℃, NBS (94 mg, 0.528 mmol, 1.05 eqv) was added to a DCM (20 ml) solution containing (R)-(1'-(3-acetyl-6-aminopyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamate tert-butyl ester (221 mg, 0.503 mmol, 1.0 eqv), and the mixture was stirred at a constant temperature for 10 min. The reaction solution was quenched with saturated sodium bicarbonate aqueous solution (10 ml), separated, and the aqueous phase was extracted with DCM (10 ml × 2). The organic phases were combined and washed with _H₂O (20 ml) and brine (20 ml), concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane:EA = 5:1 to 1:1) to give (R)-(1'-(3-acetyl-6-amino-5-bromopyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)tert-butyl carbamate (132 mg, yield 50.75%). (ES, m/z): 518.09 [M+H] ^⁺ .

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

Step a: Methyl 3-chloro-5-((2,4-dimethoxybenzyl)amino)pyrazin-2-carboxylate (200 mg, 0.593 mmol, 1.0 eqv), (R)-2-methyl-N-((R)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)propane-2-sulfinamide (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, and water (60 mL) and EA (60 mL) were added to the reaction solution. The mixture was separated, and the aqueous phase was extracted with EA (3 × 20 mL). The organic phases were combined; the organic phases were then subjected to H₂ _... Washed with 100 ml of oxygen and 50 ml of saline, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EA:MeOH = 80:1 to 20:1) to give methyl 5-((2,4-dimethoxybenzyl)amino)-3-((R)-3-((R)-1,1-dimethylethylsulfinylamino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazine-2-carboxylic acid (305 mg, yield 84.42%). (ES, m/z): 610.20 [M+H] ⁺ .

Step b: CF3COOH (6 mL) was added to methyl 5-((2,4-dimethoxybenzyl)amino)-3-((R)-3-((R)-1,1-dimethylethylsulfinylamino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazine-2-carboxylate (305 mg, 0.501 mmol, 1.0 eqv) _. The mixture was stirred at room temperature for 3 h, and then the reaction solution was evaporated to dryness to obtain crude methyl 5-amino-3-((R)-3-((R)-1,1-dimethylethylsulfinylamino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazine-2-carboxylate (230 mg). (ES, m/z): 460.15 [M+H] ⁺ .

Step c: Add 10 mL of HCl/CH₃OH solution to crude (230 mg) methyl (R)-5-amino-3-((R)-3-((R)-1,1-dimethylethylsulfinylamino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazine- ₂ -carboxylate. After stirring at room temperature for 2 h, evaporate the reaction solution to dryness to obtain crude (R)-5-amino-3-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazine-2-carboxylate (178 mg). (ES, m/z): 356.11 [M+H] ^⁺ .

Step d: At room temperature, 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)pyrazin-2-carboxylic acid methyl ester (178 mg, 0.501 mmol, 1.0 eqv) in DCM (20 ml), followed by the addition of (Boc) _₂O (142 mg, 0.651 mmol, 1.3 eqv), and the reaction was allowed to proceed overnight at room temperature. Water (25 ml) was added to the reaction mixture, and the mixture was separated. The aqueous phase was extracted with DCM (10 mL × 2), and the organic phases were combined. The organic phase was washed with _H₂O (20 ml) and brine (20 ml), concentrated under reduced pressure, and purified by silica gel column chromatography with DCM:MeOH = 100:1 to 20:1 as the eluent, to give (R)-5-amino-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-carboxylic acid methyl ester (133 mg, yield 58.3%). (ES, m/z): 456.16 [M+H] ^⁺ .

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 reaction was maintained at this temperature for 10 min. The reaction mixture was added to a saturated sodium bicarbonate aqueous solution (20 ml), and the mixture was separated. The aqueous phase was extracted with DCM (10 ml × 2), and the organic phases were combined. The organic phase was washed with _H₂O (20 ml) and brine (20 ml), concentrated under reduced pressure, and purified by silica gel column chromatography with hexane:EA = 5:1 to 1:2 as the eluent, yielding (R)-5-amino-6-bromo-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-carboxylic acid methyl ester (100 mg, yield 64.3%). (ES, m/z): 534.09 [M+H] ^⁺ .

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

Step a: A solution of methyl 3,6-dibromopyrazine-2-carboxylate (460 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 6 h; the mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with EA (3 × 30 mL). The organic phases were combined; the organic phases were then subjected to H₂ _... Washed with 100 ml of oxygen and 100 ml of brine, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH = 100:1 to 40:1) to give methyl 6-bromo-3-((R)-3-((R)-1,1-dimethylethylsulfinylamino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-carboxylic acid (375 mg, yield 46.2%). (ES, m/z): 523.01 [M+H] ⁺ .

Step b: Add 10 ml of HCl/CH₃OH solution to methyl (375 mg, 0.718 mmol, 1.0 eqv) of 6-bromo-3-((R)-3-((R)-1,1-dimethylethylsulfinylamino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazine- ₂ -carboxylate. After stirring at room temperature for 4 h, evaporate the reaction solution to dryness to obtain crude (R)-3-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-6-bromopyrazine-2-carboxylate. (ES, m/z): 419.02 [M+H] ^⁺ .

Step c: At room temperature, 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), followed by the addition of (Boc) _₂O (299 mg, 1.437 mmol, 2.0 eqv), and the reaction was allowed to proceed overnight at room temperature. Add water (50 mL) to the reaction mixture, separate the layers, extract the aqueous phase with DCM (20 mL × 2), and combine the organic phases; wash the combined organic phases with _H₂O (20 mL) and brine (20 mL), concentrate under reduced pressure, and purify by silica gel column chromatography (n-hexane:EA = 5:1 to 1:5) to give (R)-6-bromo-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-carboxylic acid methyl ester (279 mg, yield 75%). (ES, m/z): 519.09 [M+H] ^⁺ .

Intermediate preparation example 14A:

The steps of preparing Example 14 using intermediates and the following corresponding starting materials for synthesizing intermediate 14A:

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

Step a: Methyl (R)-6-bromo-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-carboxylic acid (500 mg, 0.965 mmol, 1 eqv), LiOH· _H₂O (81 mg, 1.93 mmol, 2 eqv), THF (10 mL), and water (10 mL) were reacted overnight at room temperature. The pH was adjusted to 3–4 with 1 N HCl solution, and the mixture was concentrated under reduced pressure. Water (60 mL) and EA (60 mL) were added to the residue. The mixture was separated, and the aqueous phase was extracted with EA (3 × 20 mL). The organic phases were combined. The organic phases were then extracted with _H₂O. Washed with 100 ml of oxygen and 50 ml of brine, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH = 80:1 to 20:1) to give (R)-6-bromo-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-carboxylic acid (440 mg, yield 90.45%). (ES, m/z): 505.02 [M+H] ⁺ .

Step b: Under nitrogen protection and 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 3N (160 mg, 1.586 mmol, 2 eqv) were added to anhydrous DMF (10 mL) solution of (R)-6-bromo-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-carboxylic acid (400 mg, 0.793 mmol, 1 eqv), EDCI (182.4 mg, 0.952 mmol, 1.2 eqv), and Et _3N (160 mg, 1.586 mmol, 2 eqv) and added to the solution. The reaction was then carried out at room temperature for 6 h. Water (60 mL) and EA (60 mL) were added to the reaction mixture. The mixture was separated, and the aqueous phase was extracted with EA (3 × 20 mL). The organic phases were combined. The organic phases were then subjected to _H2O. Washed with 100 ml of oxygen and 50 ml of brine, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH = 100:1 to 25:1) to give (R)-(1'-(5-bromo-3-(methoxy(methyl)carbamoyl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamate tert-butyl ester (227 mg, yield 52.32%). (ES, m/z): 548.10 [M+H] ⁺ .

Step c: Under nitrogen protection, at -78°C, methyl magnesium bromide (3.0 M, 0.276 mL, 2 eqv) was added dropwise to an anhydrous THF (10 mL) solution of (R)-(1'-(5-bromo-3-(methoxy(methyl)carbamoyl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamate (227 mg, 0.415 mmol, 1 eqv), and the mixture was allowed to naturally warm to 0°C for 2 h. The reaction was quenched with saturated _NH₄Cl solution. Water (60 mL) and EA (60 mL) were added to the reaction mixture, and the mixture was separated. The aqueous phase was extracted with EA (3 × 20 mL), and the organic phases were combined. The organic phase was then extracted with _H₂. Washed with 100 ml of oxygen and 50 ml of saline, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH = 50:1 to 20:1) to give (R)-(1'-(3-acetyl-5-bromopyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamate tert-butyl ester (100 mg, yield 48%). (ES, m/z): 503.07 [M+H] ⁺ .

Examples of intermediate preparation 15A-15C:

The steps of preparing Example 15 using intermediates and the following corresponding starting materials for synthesizing intermediates 15A to 15C are as follows:

Intermediate Preparation Example 16: 6-Chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)thioalkyl)-5-(oxetane-3-yl)pyrazin-2-amine (Intermediate 16)

Step a: Under nitrogen protection, 3-bromo-6-chloro-pyrazin-2-amine (5.00 g, 23.988 mmol, 1.00 equiv), 2-chloro-3-(oxazol-2-yl)benzylthiol (6.70 g, 28.786 mmol, 1.2 eqv), DIPEA (9.30 g, 71.963 mmol, 3.0 eqv), and _Pd₂ (dba) _₃ ·CHCl₃ were added _. A solution of 1,4-dioxane (100 mL) containing 0.62 g (0.600 mmol, 0.025 eqv) and XantPhos (0.69 g, 1.199 mmol, 0.05 eqv) was reacted overnight at 95 °C. The mixture was then cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane:EA = 2:1) to give 6-chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)thioalkyl]pyrazin-2-amine (intermediate M16-1) (5.86 g, yield 72.3%). (ES, m/z): 338.90 [M+H] ⁺ .

Step b: Under nitrogen protection and at 0°C, add dropwise ICl (6.35 g, 39.128 mmol, 1.50 eqv) of DCM (160 ml) to a MeOH solution containing 6-chloro-3-((2-chloro- _3-( oxazol-2-yl)phenyl)thioalkyl]pyrazine- ₂ -amine (5.50 g, 26.085 mmol, 1.00 eqv) and K₂CO₃ (7.20 g, 52.17 mmol, 2.00 eqv). React for 2 hours at controlled temperature, then allow to react overnight at room temperature. Quench the reaction mixture with 500 ml of 10% _{Na₂SO₃ .} Separate the solutions, extract the aqueous phase with DCM (3 × 250 ml), and combine the organic phases. Separate the organic phases with saturated NaCl. Wash with 250 ml of water, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to give 6-chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)thioalkyl)-5-iodopyrazin-2-amine (intermediate M16-2) (8.71 g, 72% yield). (ES, m/z): 464.80 [M+H] ⁺ .

Step c: Replace nitrogen with dtbpy (551 mg, 1.832 mmol, 0.10 eqv) and DMA (200 ml), add NiBr2 _· DME (724 mg, 1.832 mmol, 0.10 eqv), and stir at room temperature for 0.5 h; then add 6-chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)thioalkyl)-5-iodopyrazin-2-amine (8.5 g, 18.324 mmol, 1.00 eqv), 3-bromooxybutane (5.624 g, 36.647 mmol, 2.00 eqv), and TBAI (758.2 mg, 1.832 ml). 0.10 mol (eqv) and Zn (2.686 g, 36.647 mmol, 2.00 eqv) were reacted overnight at 75 °C under nitrogen protection with stirring. The mixture was filtered through diatomaceous earth, and the filtrate was poured into water (1000 ml) and extracted with EA ( ₂ × 500 ml). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by Prep-HPLC (gradient elution with 20-50% acetonitrile aqueous solution, modified with 0.1% _NH4HCO3 ) to give 6-chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)thioalkyl)-5-(oxetanebut-3-yl)pyrazin-2-amine (810 mg, yield 11.22%). (ES, m/z): 394.92 [M+H] ⁺ .

Intermediate Preparation Example 17: 6-Chloro-3-((2-Chloro-3-(oxazol-2-yl)phenyl)thioalkyl)-5-vinylpyrazine-2-amine (Intermediate 17)

Under nitrogen protection, 6-chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)thioalkyl)-5-iodopyrazin-2-amine (197 mg, 0.425 mmol, 1 eqv), potassium vinyltrifluoroborate (116 mg, 0.85 mmol, 2 eqv), Pd( _PPh3 ) ₄ (50 mg, 0.0425 mmol, 0.1 eqv), and potassium carbonate (176 mg, 1.275 mmol, 3 eqv) were added to toluene (60 mL), ethanol (30 mL), and water (15 mL), and reacted at 80 °C for 5 h. The reaction solution was concentrated under reduced pressure, and water (100 mL) was added to the residue. The residue was extracted with EA (2 × 50 mL), and the organic phases were combined. The organic phase was washed with brine (50 mL), concentrated under reduced pressure, and the residue was purified by _column chromatography ( _CH2Cl2 :CH3 _). OH = 100:1), yielding 6-chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)thioalkyl)-5-vinylpyrazine-2-amine (101 mg, yield 65.3%). (ES, m/z): 364.93 [M+H] ⁺ .

Intermediate Preparation Example 18: 4-(oxazol-2-yl)pyrimidin-2-thiol (Intermediate 18)

Step a: Under nitrogen protection, a solution of 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 (538.53 mg, 2.40 mmol, 0.1 eqv), and Xantphos (2.08 g, 3.60 mmol, 0.15 eqv) in 1,4-dioxane (160 ml) was reacted overnight at 95 °C. The mixture was cooled to room temperature, and the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane:EA = 100:1 to 20:1) to give methyl 3-((4-iodopyrimidin-2-yl)thioalkyl)propionate (5 g, yield 64.34%). (ES,m/z):324.90[M+H] ⁺ .

Step b: Under nitrogen protection, methyl 3-((4-iodopyrimidin-2-yl)thioalkyl)propionate (595 mg, 1.834 mmol, 1.0 eqv), oxazol-2-ylboronic acid (228 mg, 2.02 mmol, 1.1 eqv), and Pd(dppf) _Cl₂ were added. A solution of 1,4-dioxane (50 mL) and potassium carbonate (760 mg, 5.503 mmol, 3 eqv) in 1,4-dioxane (50 mL) and water (10 mL) was reacted overnight at 96 °C. The mixture was cooled, concentrated under reduced pressure, and the residue was treated with water (200 mL) and EA (100 mL). The mixture was separated, and the aqueous phase was extracted with EA (2 × 50 mL). The organic phases were combined and washed with brine (100 mL). The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane:EA = 30:1–10:1) to give methyl 3-((4-(oxazol-2-yl)pyrimidin-2-yl)thioalkyl)propionate (256 mg, yield 52.65%). (ES, m/z): 266 [M+H] ⁺ .

Step c: Under nitrogen protection, a methanol (10 mL) solution of methyl 3-((4-(oxazol-2-yl)pyrimidin-2-yl)thioalkyl)propionate (256 mg, 0.966 mmol, 1.0 eqv) and NaOH (40.6 mg, 1.014 mmol, 1.05 eqv) was reacted at 50 °C for 4 h; the temperature was lowered to approximately 0 °C, and 4 M HCl/MeOH solution was added dropwise to adjust the pH 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)pyrimidin-2-thiol (130 mg, yield 75.2%). (ES, m/z): 179.92 [M+H] ⁺ .

Examples of intermediate preparation 19-22

The steps for preparing Example 18 using intermediates and the following corresponding starting materials for synthesizing intermediates 19-22:

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

Steps a-b: Under nitrogen protection, Ti(OEt)₄ (100 ml) was added to a 2-MeTHF (40 ml) solution of 3-oxospiro[1-benzofuran-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester (10.00 g, 32.965 mmol, 1.00 eqv) and (R)-(+)-tert-butylsulfinamide (7.99 g, 65.93 mmol, ₂ eqv), and the reaction was carried out at 80 °C for 48 h; then the temperature was lowered to -5 °C, and NaBD₄ was added _. (1.66 g, 39.55 mmol, 1.2 eqv), reacted overnight at room temperature; cooled to 0 °C, methanol (30 ml) was added dropwise to the reaction solution, followed by water (1000 ml) and EA (1000 ml), stirred for 30 min, filtered, and the filtrate was separated; the organic phase was washed with brine (1000 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure; the residue was purified by column chromatography (n-hexane:EA = 6:1 to 2:1) to give M23-2 (10.5 g, yield 77.78%), (ES, m/z): 410.13 [M+H] ⁺ .

¹ H-NMR (600MHz, CDCl ₃ ) 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).

Step c: Dissolve M23-2 (10.5 g) in DCM (20 ml), add trifluoroacetic acid (20 ml) dropwise at 0 °C, react at room temperature for 6 h, concentrate under reduced pressure, add water (50 ml) to the residue, adjust pH to 10 with 25% ammonia, extract the aqueous phase with EA (50 ml × 3), combine the organic phases, dry with anhydrous sodium sulfate, concentrate under reduced pressure to obtain crude (R)-2-methyl-N-((R)-3-deuterium-spiro[benzofuran-2,4'-piperidin]-3-yl)propane-2-sulfinamide (M-23) (7.84 g), which was used directly in the next reaction without purification. (ES, m/z): 310.07 [M+H] ⁺ .

Intermediate preparation example 24:

The steps of preparing intermediate 23 and the corresponding starting materials for synthesizing intermediate 24 are as follows:

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

Steps ab: Under nitrogen protection, a solution of 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), and Pd( _Ph3P ) _2Cl2 (6.78 g, 9.667 mmol, 0.1 eqv) _in 1,4-dioxane (240 ml) was reacted overnight at 100 °C. The reaction was monitored by TLC until complete. Crude (R)-2-methyl-N-((R)-3-deuterium-spiro[benzofuran-2,4'-piperidin]-3-yl)propane-2-sulfinamide (M-23) (35.86 g, 115.987 mmol, 1.0 eqv) was added. A 2 eqv solution of 1,4-dioxane (200 mL) was added to the reaction mixture, followed by DIPEA (37.48 g, 289.97 mmol, 3.0 eqv). The reaction was carried out overnight at 100 °C. After cooling to room temperature, 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 give M25-1 (24.05 g, yield 56.01%). (ES, m/z): 445.07 [M+H] ⁺ .

Step c: At 0℃, NBS (11.563 g, 64.97 mmol, 1.2 eqv) was added to a DCM (250 ml) solution of M25-1 (24.05 g, 54.14 mmol, 1.0 eqv), and the reaction was allowed to proceed overnight at room temperature. Then, 10 ml of 4 M HCl/ _CH3OH solution was added and the mixture was stirred for 1 h. A saturated sodium bicarbonate aqueous solution (100 ml) was added to the reaction solution, and the mixture was separated. The aqueous phase was extracted with DCM (50 ml × 2), and the organic phases were combined. The organic phase was washed with _H2O (200 ml) and brine (200 ml), dried over anhydrous sodium sulfate, and filtered to obtain a crude DCM solution of M25-2, which was used directly in the next reaction without further treatment. (ES, m/z): 419.00 [M+H] ⁺ .

Step d: At 0℃, add (Boc) _₂O (14.2 g) to the DCM solution of M25-2 from step c, and add _Et₃N (10.96 g) dropwise. After the addition is complete, react overnight at room temperature. Add water (200 ml), separate the layers, extract the aqueous phase with DCM (100 ml × 2), and combine the organic phases. Wash the organic phase with _H₂O (200 ml) and brine (200 ml), concentrate to dryness under reduced pressure, and purify 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] ^⁺ .

Preparation Example 25A of Intermediate: Preparation of M-25A

The steps of preparing intermediate Example 25 and the following corresponding starting materials were used to synthesize intermediate M-25A:

Intermediate preparation example 26:

The steps of preparing Example 13 using intermediates and the following corresponding starting materials for synthesizing intermediate 26:

Intermediate Preparation Example 27: Preparation of M-27

Step a: Under nitrogen protection, a reaction solution of 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), and DIPEA (2.25 g, 7.34 mmol, 3 eqv) in 1,4-dioxane (60 mL) was reacted overnight at 97 °C. The mixture was then cooled, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EA:n-hexane = 1:3–2:1) to give M27-1 (3.00 g, 93% yield), (ES, m/z): 559.17 [M+H] ^⁺ .

Step b: Add NaOH (242 mg, 5.907 mmol, 1.1 eqv) to a MeOH (30 ml) solution of M27-1 (3.00 g, 5.37 mmol, 1.0 eqv), 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 1 N HCl, extract with EA (100 ml × 2), and combine the organic phases; wash the organic phase with _H2O (20 ml) and brine (20 ml), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain M-27 (1.33 g, yield 78.4%) (ES, m/z): 473.10 [M+H] ⁺ .

Examples of intermediate preparation 28-30:

The steps of preparing Example 27 using intermediates and the following corresponding starting materials for synthesizing intermediates 28-30:

The following are examples of the preparation of exemplary compounds of this application.

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)thioalkyl)pyrazin-2-yl)acetone (Compound 1)

Step a: Under nitrogen protection, tert-butyl carbamate (140 mg, 0.27 mmol, 1.0 eqv), 2-chloro-3-(oxazol-2-yl)benzylthiol (69 mg, 0.325 mmol, 1.2 eqv), DIPEA (123 mg, 0.954 mmol, 3.5 eqv), and _Pd2 (dba) ₃ were added. A solution of 1,4-dioxane (10 mL) containing 50 mg (0.054 mmol, 0.2 eqv) and Xantphos (63 mg, 0.109 mmol, 0.4 eqv) was reacted at 96 °C for 6 h. The mixture was then cooled to room temperature, silica gel was added, and the solution was purified by silica gel column chromatography (eluent: hexane:EA = 10:1 to 1:2) to give (R)-(1'-(3-acetyl-6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)thioalkyl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamate tert-butyl (152 mg, yield 86.85%). (ES, m/z): 649.14 [M+H] ⁺ .

Step b: Add trifluoroacetic acid (5 ml) to a solution of (R)-(1'-(3-acetyl-6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)thioalkyl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamate tert-butyl ester (152 mg) in dichloromethane (10 ml), and stir at room temperature for 3 h; concentrate the reaction solution under reduced pressure, add EA (50 ml) and water (50 ml) to the residue, adjust the pH to 10 with 25% ammonia, and separate the layers; extract the aqueous phase with EA (20 ml), and combine the organic phases; wash the organic phase with water (50 ml) and brine (50 ml), and concentrate under reduced pressure; purify the residue by _column chromatography ( _CH₂Cl₂ :CH₃ ₎ OH = 20:1 to 15:1), yielding (R)-1-(5-amino-3-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-6-((2-chloro-3-(oxazol-2-yl)phenyl)thioalkyl)pyrazin-2-yl)acetone (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).

Preparation Examples 2-15 and 11A:

Following the synthetic route and procedures of Preparation Example 1, compounds 2–15 and 11A were prepared using the corresponding intermediates as starting materials.

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)thioalkyl)pyrazine-2-carboxylic acid methyl ester (Compound 16)

Step a: Under nitrogen protection, methyl (R)-5-amino-6-bromo-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-carboxylic acid (144 mg, 0.27 mmol, 1.0 eqv), 2-chloro-3-(oxazol-2-yl)benzylthiol (69 mg, 0.324 mmol, 1.2 eqv), DIPEA (123 mg, 0.954 mmol, 3.5 eqv), and _Pd2 (dba) ₃ were added. A solution of 1,4-dioxane (20 mL) containing 50 mg, 0.054 mmol, 0.2 eqv and Xantphos (63 mg, 0.109 mmol, 0.4 eqv) was reacted at 96 °C for 6 h. The mixture was cooled to room temperature, silica gel was added, and the solution was purified by silica gel column chromatography (eluent: hexane:EA = 20:1 to 1:1) to give (R)-5-amino-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-6-(2-chloro-3-(oxazol-2-yl)phenyl)thioalkyl)pyrazine-2-carboxylic acid methyl ester (152 mg, yield 84.75%). (ES, m/z): 665.14 [M+H] ⁺ .

Step b: Add trifluoroacetic acid (5 ml) to a solution of (R)-5-amino-3-(3-((tert-butoxycarbonyl)amino)-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-6-(2-chloro-3-(oxazol-2-yl)phenyl)thioalkyl)pyrazine-2-carboxylic acid methyl ester (152 mg) in dichloromethane (20 ml), and stir at room temperature for 3 h; concentrate the reaction solution under reduced pressure, add EA (100 ml) and water (50 ml) to the residue, adjust the pH to 10 with 25% ammonia, and separate the layers; extract the aqueous phase with EA (20 ml), and combine the organic phases; wash the organic phase with water (50 ml) and brine (50 ml), dry with anhydrous sodium sulfate, and concentrate; purify the residue by _column chromatography ( _CH₂Cl₂ :CH₃ ₎ OH = 50:1 to 15:1), yielding (R)-5-amino-3-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-6-((2-chloro-3-(oxazol-2-yl)phenyl)thioalkyl)pyrazine-2-carboxylic acid methyl ester (118 mg, yield 91.4%). (ES, m/z): 565.10 [M+H] ⁺ .

Preparation Examples 17-20:

Following the synthetic route and procedures of Preparation Example 16, compounds 17–20 were prepared using the corresponding intermediates as starting materials.

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

Step a: A solution of 6-chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)thioalkyl)-5-(oxetane-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 mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with EA (3 × 50 mL). The organic phases were combined; the organic phases were then subjected to H2 _... Washed with 50 ml of oxygen and 50 ml of brine, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH = 100:1 to 25:1) to give (R)-N-((R)-1'-(6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)thioalkyl)-3-(oxacyclobut-3-yl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)-2-methylpropane-2-sulfinamide (677 mg, yield 65.31%). (ES, m/z): 667.11 [M+H] ⁺ .

Step b: Add HCl/CH3OH solution (60 mL) to (R)-N-((R)-1'-(6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)thioalkyl)-3-(oxacyclobut-3-yl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)-2-methylpropane- ₂ -sulfinamide (677 mg), react overnight at room temperature, concentrate the reaction solution under reduced pressure, add EA (50 mL) and water (50 mL) to the residue, adjust the pH to 9-10 with 25% ammonia, separate the layers; extract the aqueous phase with EA (20 mL), combine the organic phases; wash the organic phase with water (50 mL) and brine (50 mL), concentrate; purify the residue by _column chromatography ( _CH2Cl2 :CH3 ₎ OH = 20:1), yielding (R)-1'-(6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)thioalkyl)-3-(oxacyclobut-3-yl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]-3-amine (487 mg, yield 85.2%). (ES, m/z): 563.10 [M+H] ⁺ .

Preparation Example 22:

Following the synthetic route and procedures of Preparation Example 21, and using the corresponding intermediate as a starting material, compound 22 was prepared.

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

Step a: A solution of 6-chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)thioalkyl)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 overnight at 100 °C; the mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with EA (3 × 50 mL). The organic phases were combined; the organic phases were then subjected to H₂ _... Washed with 50 ml of oxygen and 50 ml of brine, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH = 80:1 to 25:1) to give (R)-N-((R)-1'-(6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)thioalkyl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)-2-methylpropane-2-sulfinamide (724 mg, yield 76.26%). (ES, m/z): 611.09 [M+H] ⁺ .

Step b: Add HCl/CH3OH solution (50 mL) to (R)-N-((R)-1'-(6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)thioalkyl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)-2-methylpropane- ₂ -sulfinamide (724 mg), react overnight at room temperature, concentrate the reaction solution under reduced pressure, add EA (50 mL) and water (50 mL) to the residue, adjust the pH to 9-10 with 25% ammonia, separate the layers; extract the aqueous phase with EA (20 mL), combine the organic phases; wash the organic phase with water (50 mL) and brine (50 mL), concentrate; purify the residue by _column chromatography ( _CH2Cl2 :CH3 ₎ OH = 30:1 to 15:1), yielding (R)-1'-(6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)thioalkyl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]-3-amine (557 mg, yield 92.75%). (ES, m/z): 507.03 [M+H] ⁺ .

Step c: Under nitrogen protection, at -15°C, add N-fluorobisbenzenesulfonamide (380 mg, 1.21 eqv) to a solution of (R)-1'-(6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)thioalkyl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]-3-amine (557 mg, 1.1 mmol, 1 eqv) in acetonitrile (100 ml). 1.1 eqv), after which the temperature was slowly raised to room temperature and the reaction was allowed to proceed overnight; the mixture was concentrated under reduced pressure and purified twice by Pre-TLC (DCM:MeOH = 15:1) to give (R)-1'-(6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)thioalkyl)-3-fluoropyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidine]-3-amine (109 mg, yield 18.9%). (ES, m/z): 525.09 [M+H] ⁺ .

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)thioalkyl)pyrazin-2-yl)acetone (compound 24)

Step a: Under nitrogen protection, tert-butyl 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), and _Pd2 (dba) ₃ were administered. A solution of 1,4-dioxane (10 mL) containing 50 mg, 0.054 mmol, 0.2 eqv and Xantphos (63 mg, 0.109 mmol, 0.4 eqv) was reacted at 96 °C for 6 h. The mixture was cooled to room temperature, silica gel was added, and the solution was purified by silica gel column chromatography (eluent: hexane:EA = 10:1 to 1:2) to give (R)-(1'-(3-acetyl-6-amino-5-((2-(oxazol-2-yl)pyrimidin-4-yl)thioalkyl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamate tert-butyl (126 mg, yield 75.74%). (ES, m/z): 617.14 [M+H] ⁺ .

Step b: Add trifluoroacetic acid (5 ml) to a solution of (R)-(1'-(3-acetyl-6-amino-5-((2-(oxazol-2-yl)pyrimidin-4-yl)thioalkyl)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamate (126 mg) in dichloromethane (5 ml), and stir at room temperature for 3 h; concentrate the reaction solution under reduced pressure, add EA (50 ml) and water (50 ml) to the residue, adjust the pH to 10 with 25% ammonia, and separate the layers; extract the aqueous phase with EA (20 ml), and combine the organic phases; wash the organic phase with water (50 ml) and brine (50 ml), and concentrate under reduced pressure; purify the residue _by column chromatography ( _CH₂Cl₂ :CH₃ ₎ OH = 20:1 to 15:1), yielding (R)-1-(5-amino-3-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)-6-((2-(oxazol-2-yl)pyrimidin-4-yl)thioalkyl)pyrazin-2-yl)acetone (97 mg, yield 91.9%). (ES, m/z): 517.10 [M+H] ⁺ .

Following the preparation process routes and operations of intermediate preparation Examples 1-22 and 1-24, compounds 25-55 were prepared using 2,4-diiodopyrimidine and the corresponding intermediates.

Preparation Example 56: (R)-1-(5-amino-6-((2-amino-3-chloropyridin-4-yl)thioalkyl)-3-(3-amino-3-deuterium-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-yl)acetone (Compound 56)

Step a: Under nitrogen protection, react the _1,4 -dioxane (20 ml) reaction solution of M-27 (256 mg, 0.542 mmol, 1.0 eqv), 2-amino-3-chloro-4-iodopyridine (207 mg, 0.813 mmol, 1.5 eqv), Pd₂(dba) _₃ (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) overnight at 97°C; cool down, concentrate the reaction solution to dryness, add water (30 ml) to the concentrate, extract with EA (20 ml × 2), and combine the organic phases; the organic phases are then treated with _H₂. Wash with 20 ml of oxygen and 20 ml of saline solution, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by silica gel column chromatography (eluent: hexane:EA = 5:1 to 1:3) to obtain M56-1 (300 mg, yield 92%), (ES, m/z): 599.17 [M+H] ⁺ .

Step b: Add _CF3COOH (5 ml) to a DCM (5 ml) solution of M56-1 (300 mg, 0.501 mmol, 1.0 eqv), stir at room temperature for 2 h, then evaporate the reaction solution to dryness. Add water (30 ml) and EA (30 ml) to the residue, adjust the pH to 9-10 with 25% ammonia, separate the layers, extract the aqueous phase with EA (20 ml × 2), and combine the organic phases. Wash the organic phase with _H2O (20 ml) and brine (20 ml), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by silica gel column chromatography ( _eluent : _CH2Cl2 :CH3 _). OH = 20:1 to 15:1), yielding (R)-1-(5-amino-6-((2-amino-3-chloropyridin-4-yl)thioalkyl)-3-(3-amino-3-deuterium-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-yl)acetone (200 mg, 80% yield) (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).

Preparation Examples 56A, 57-59:

Following the synthetic route and procedures of Preparation Example 56, compounds 56A and 57–59 were prepared using the corresponding intermediates as starting materials.

Preparation Example 60: Preparation of Compound 60

Step a: Under nitrogen protection, a solution of M-25 (840 mg, 2.004 mmol, 1.0 eqv), 2-chloro-3-(oxazol-2-yl)benzylthiol (634 mg, 3.006 mmol, 1.5 eqv), DIPEA (906 mg, 7.014 mmol, 3.5 eqv), _Pd₂ (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) was reacted overnight at 96 °C. After cooling to room temperature, silica gel was added to the reaction solution, and purification was performed by silica gel column chromatography (eluent: hexane:EA = 5:1–3:1) to obtain M60-1 (600 mg, yield 46%). (ES, m/z): 650.12 [M+H] ^⁺ .

Step b: Add 5 ml of trifluoroacetic acid to a solution of M60-1 (600 mg, 0.924 mmol) in 15 ml of dichloromethane and stir at room temperature for 3 h; concentrate the reaction solution under reduced pressure, add 50 ml of EA and 50 ml of water to the residue, adjust the pH to 10 with 25% ammonia, and separate the layers; extract the aqueous phase with 20 ml of EA, and combine the organic phases; wash the organic phase with 50 ml of water and 50 ml of brine, and concentrate under reduced pressure; purify the residue by _column chromatography ( _CH₂Cl₂ : _CH₃OH = 40:1 to 15:1) to give compound 60 (350 mg, yield 69%). (ES, m/z): 550.12 [M+H] ^⁺ .

Preparation Example 61:

Following the synthetic route and procedures of Preparation Example 60, and using the corresponding intermediate as a starting material, compound 61 was prepared.

Preparation Example 62:

Following the synthetic route and procedures of Preparation Example 60, and using the corresponding intermediate as a starting material, compound 62 was prepared.

Note: Preparation of positive control drug: Compound TW-45 (structure shown below) was prepared according to the preparation method of compound 45 in TW201840553A.

The following describes the biological testing of the compounds in this application.

Experimental Example 1: Inhibition Effect Test on SHP2 Enzyme

1. Preparation of working buffer solution and compounds

Prepare working buffer 1x kinase buffer. Dilute the test compound to a storage concentration of 10 mM with DMSO. First, dilute the test compound to an intermediate concentration of 1000 μM, and then perform serial dilutions of 3-fold with DMSO. Therefore, the intermediate serial dilution concentrations of the test compound are: 1000 μM, 3-fold dilution, 11 gradients. Using an Echo 550 instrument, transfer 100 nmol of each concentration of the compound from the 384LDVecho plate to a new 384 ELISA plate (assay plate) (corning, Cat#4514), ensuring that the final concentration of the test compound after adding 10 μl of reaction reagent is 10 μM, 3-fold dilution, 11 gradients, 2 replicates. The final DMSO concentration is 1%. 100 nmol of DMSO will be transferred to both negative and positive control wells.

2. SHP2 enzymatic reaction steps

Prepare a mixture of 2X working SHP2 reagent (0.4 nM) and 0.5 μM SHP-2 activating peptide (BPSbioscience #79319-2) using 1X enzyme buffer. After incubating the mixture at 25°C for 60 minutes, transfer 5 μl of the activated SHP2 kinase solution to the compound wells and the Max control wells (Corning, #4514) of the ELISA plate using a pipette. Then transfer 5 μl of 1X kinase buffer to the Min control wells. Centrifuge at 1000 rpm for 30 seconds. Seal the plate and incubate it at 25°C for 30 minutes. Prepare a DiFMUP (#D6567, Invitrogen ^™ ) substrate solution using 1X kinase buffer at twice the final experimental concentration (DiFMUP final concentration: 10 μM). Transfer 5 μl of the prepared substrate solution to each well of the ELISA plate using a power pipette to initiate the reaction. Centrifuge at 1000 rpm for 30 seconds. Seal the plate and incubate it in a 25°C incubator for 60 minutes. Place the ELISA plate on a Spark microplate reader and read the excitation/emission wavelengths at 358/455 nm.

3. Calculation method and test results:

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 enzyme-free 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 the _IC50 values, and the results are shown in Table 1.

Table 1. Enzymatic efficacy test of the compound in this application against SHP2.

Preparation Example No. Enzymology Preparation Example No. Enzymology Preparation Example No. Enzymology 1 A twenty two A 58 A 8 A twenty three A 59 A 16 A twenty four A 60 A 19 A 56 A 61 A twenty one A 57 A 62 A

Note: Compounds designated as "A" have an _IC50 value of less than or equal to 20 nM.

The above data indicate that the compound of this application has a strong inhibitory effect on SHP2 kinase.

Experimental Example 2: In vitro inhibitory effect on the proliferation of human acute myeloid leukemia MV-4-11 cells

1. Experimental materials:

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 culture medium required for cell culture was IMDM (GIBCO), supplemented with 10% fetal bovine serum (GIBCO). Cells were cultured at 37°C in a 5% _CO2 incubator. Reagents used in the experiment included dimethyl sulfoxide (DMSO) (purchased from Tianjin Kemei Chemical Reagent Co., Ltd.) and MTT (Shanghai Teber Chemical Technology Co., Ltd., CAS No. 298-93-1). The test samples were sealed and stored at 4°C.

2. Experimental methods and results:

Using dimethyl sulfoxide (DMSO) as the solvent, the test substance was thoroughly dissolved to prepare a stock solution with a concentration of 5 × ^10⁻² mol/L, which was then stored at -20°C. The test substance was serially diluted to different concentrations using complete culture medium as the diluent. In a 96-well plate, 100 μL/well (2 × ^10⁴ cells/well) of MV-4-11 cell complete culture medium suspension was added, followed by 100 μL/well of the corresponding concentration of the test substance. Eight concentrations were prepared for each test substance, with three replicates per concentration. The plates were incubated at 37°C in a 5% _CO₂ incubator. After 72 hours of incubation, 20 μL/well of MTT was added, and the plates were incubated at 37°C in a 5% _CO₂ incubator for 4 hours. The supernatant was discarded, and 150 μL/well of DMSO was added. The plates were vortexed and the OD value was measured at 550 nm using a microplate reader. Wells containing only cell suspension and no test substance were designated as control wells, while wells containing only complete culture medium were designated as blank wells. The cell growth inhibition rate was calculated using the following formula:

Inhibition rate = (OD of control well - OD of test well) / (OD of control well - OD of blank well) * 100%. Based on the inhibition rate of each concentration, the half-maximum inhibitory concentration ( _IC50 ) was calculated using SPSS software. The results are shown in Table 2.

Table 2. Cell proliferation inhibition effect test of the compound in this application.

Note: Compounds designated as "A" have an _IC50 value of less than or equal to 20 nM.

The above data show that the compounds in this application all exhibit good inhibitory activity in the human acute myeloid leukemia cell proliferation inhibition assay.

Experimental Example 3: In vitro inhibitory effect on the proliferation of human lung adenocarcinoma NCI-H441 cells

1. Experimental materials:

Human lung adenocarcinoma cells NCI-H441 were purchased from ATCC. The complete culture medium required for cell culture was RPMI 1640 Medium (GIBCO), supplemented with 10% fetal bovine serum (GIBCO). Cells were cultured at 37°C in a 5% _CO2 incubator. Reagents used included dimethyl sulfoxide (DMSO) (Sigma), a 3D Cell Viability assay kit (Promega), and the control TW-45, which was prepared in-house. Test samples were stored sealed at 4°C.

2. Experimental methods and results:

The test substance was thoroughly dissolved in dimethyl sulfoxide (DMSO) to prepare a stock solution with a concentration of 1 × ^10⁻² mol/L, which was then stored at -20°C. The test substance was serially diluted to different concentrations using complete culture medium (final test concentrations were 10000, 3333, 1111, 370, 123, 41, 13.7, 4.5, 1.5, and 0.5 nM). Cells were cultured at 37°C in a 5% _CO₂ incubator for 5 days. On day 5, 30 μL of reagent (Celltiter Glo assay kit-3D) was added to each well, and the plate was shaken on a plate shaker (protected from light) for 30 minutes. The plate was then incubated at room temperature (protected from light) for 120 minutes. Chemiluminescence values were recorded using a multiplate reader.

Data analysis was performed using VC and PC data for stability checks. Inhibition percentage = 100 - (Signal _cmpd - Signal _{Ave - PC} ) / (Signal _{Ave - VC} - Signal _{Ave - PC} ) × 100. LUM: Chemiluminescence signal per well; VC: Average chemiluminescence signal of high-quality control wells (wells containing 0.1% DMSO); PC: Average chemiluminescence signal of low-quality control wells (blank medium only).

The IC50 of the compound was calculated and an effect-dose curve was plotted using GraphPad Prism 8 software: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC ₅₀ - X) * HillSlope)). X: Logarithm of cpd concentration; Y: Percentage of inhibition.

The results are shown in Table 3.

Table 3. Cell proliferation inhibition effect of the compound NCI-H441 in this application.

Note: Compounds designated as "A" have an IC ₅₀ value of less than or equal to 20 nM, and compounds designated as "B" have an IC ₅₀ value of greater than 20 nM and less than 50 nM.

The above data show that the compounds in this application exhibit good inhibitory activity in the human lung adenocarcinoma cell proliferation inhibition assay.

Experimental Example 4: Mouse Pharmacokinetic Study

1. Test method:

ICR mice were administered the compound by gavage at doses of 10 mg/kg or 20 mg/kg. Blood samples were collected from the orbital sinus at different time points after administration (0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h). The collected whole blood was anticoagulated with heparin sodium, and mouse plasma samples were obtained by centrifugation at 3000 g. Methanol protein precipitation was used, and the drug concentration in mouse plasma after administration was determined by HPLC-MS/MS. Drug-time curves were plotted, and pharmacokinetic parameters were calculated. The pharmacokinetic behavior of the compound in mice after administration was described by statistical moment parameters of a non-compartmental model.

2. Test Results:

The above-mentioned pharmacokinetic tests were conducted on the compounds of Preparation Example 1 and Preparation Example 56 of this application. The test results showed that the compounds of this application had high exposure levels in mice and good absorption.

Table 4 Results of mouse pharmacokinetic experiments of the compounds in this application.

Experimental Example 5: hERG Test

1. Test method:

This experiment includes the following aspects:

hERG currents were recorded in CHO-K1 cell lines that stably expressed hERG channels using manual patch-clamp technique.

The inhibition rate for each concentration was calculated based on the hERG tail current;

Five concentrations were tested for each compound, and the _IC50 value was calculated.

Three cells were tested for each concentration;

A positive control drug.

hERG currents were recorded using whole-cell patch-clamp technique. Cell suspension was added to a cell culture vessel and placed on the stage of an upright microscope. After cell adhesion, extracellular fluid was perfused at a flow rate of 1–2 mL/min. Glass microelectrodes were fabricated in two steps using a microelectrode stretcher, with a water resistance of 2–5 MΩ. After establishing whole-cell recordings, the clamping potential was maintained at -80 mV. Upon voltage stimulation, the voltage was depolarized to +60 mV, then repolarized to -50 mV to extract the hERG tail current. All recordings were performed after the current stabilized. Extracellular perfusion administration started with low concentrations, with each concentration administered for 5–10 min until the current stabilized before moving to the next concentration. The half-maximal inhibitory concentration ( _IC50 ) of the tested compounds was obtained by best fitting the Logistic equation.

2. Test Results:

Table 5. hERG _IC50 values of compounds recorded in CHO-K1 stable cell lines.

Preparation Example No. <![CDATA[IC₅₀(μM)]]> 1 A 56 A

Note: Compounds designated as "A" have an _IC50 value greater than 10 μM.

The experimental results show that compounds No. 1 and No. 56 of this application did not have a significant inhibitory effect on hERG channels within the detection concentration range of this experiment, which can reflect to a certain extent that the compounds of this application have low cardiotoxicity and has positive significance for drug safety assessment.

Experiment 7: Mouse Tolerance Test

Test method:

Experimental animals: Female ICR mice, 5 weeks old

Solvent: 2% DMSO + 98% (0.5% MC), vortex thoroughly, and sonicate to obtain a homogeneous suspension.

Experimental methods: Female ICR mice were divided into four groups of five mice each, based on their body weight. The dosages administered were 50 mg/kg and 200 mg/kg, respectively. Administration was by gavage once daily for seven consecutive days. The dosages and results are shown in the table below.

Experimental results:

Table 6. Results of mouse tolerance tests on the compounds in this application (7 days)

The experimental results showed that compound No. 56 of this application did not cause any deaths after 7 days of administration at 50 mg/kg and 200 mg/kg; the positive control compound TW-45 caused deaths after 4 days of administration at 200 mg/kg, and all mice died by day 7. The maximum tolerated dose (MTD) of mouse No. 56 was >200 mg/kg, while that of TW-45 was <200 mg/kg. Therefore, compound No. 56 of this application is significantly more tolerable in mice than the positive control compound TW-45.

Claims (26)

1. A compound of formula (I-A) or a deuterated derivative thereof or a pharmaceutically acceptable salt thereof, having the following structure: in, L is selected from CH; G is selected from S; A is CH and Y is CR ₄ ; or A is N and Y is independently selected from N or CR ₄ ; _R3 is _R1 is independently selected from hydrogen or amino; _R2 is independently selected from halogen, _-COR5 , _-COOR5 , unsubstituted _C2-6 alkenyl or unsubstituted 3-6 heterocyclic alkyl, wherein _R5 is independently selected from unsubstituted _C1-6 alkyl. _R4 is independently selected from halogens; _R6 is independently selected from hydrogen or deuterium; The heteroatom in the heterocyclic alkyl group is independently selected from O, N or S, and the number of 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 its deuterated derivative 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 1-3, or its deuterated derivative or its pharmaceutically acceptable salt, wherein _R2 is independently selected from -COR ₅ or -COOR ₅ . 5. The compound according to any one of claims 1-3, or its deuterated derivative or pharmaceutically acceptable salt thereof, wherein _R2 is independently selected from halogens, -CO- (unsubstituted _C1-3 alkyl), -COO- (unsubstituted _C1-3 alkyl), unsubstituted _C2-4 alkenyl or unsubstituted 3-6 membered heterocyclic alkyl. 6. The compound of claim 5 or its deuterated derivative or pharmaceutically acceptable salt thereof, wherein _R2 is independently selected from halogens, -C(O) _CH3 , -C(O) _OCH3 , vinyl or oxetane. 7. The compound according to claim 6, or its deuterated derivative 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 1-3 and 6-7, or its deuterated derivative or its pharmaceutically acceptable salt, wherein _R1 is an amino group. 9. The compound of claim 4 or its deuterated derivative or its pharmaceutically acceptable salt, wherein _R1 is an amino group. 10. The compound of claim 5 or its deuterated derivative or its pharmaceutically acceptable salt, wherein _R1 is an amino group. 11. The compound or its deuterated derivative or its pharmaceutically acceptable salt according to any one of claims 1-3, 6-7 and 9-10, wherein A is CH; or A is N and Y is N. 12. The compound or its deuterated derivative or its pharmaceutically acceptable salt according to any one of claims 1-3, 6-7 and 9-10, wherein _R4 is chlorine. 13. A compound of formula (I-2-A) or a deuterated derivative thereof or a pharmaceutically acceptable salt thereof, having 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 -COR ₅ or -COOR ₅ , wherein _R5 is independently selected from unsubstituted _C1-6 alkyl groups; Y is independently selected from CR ₄ ; _R4 is independently selected from halogens; _R6 is independently selected from hydrogen or deuterium. 14. The compound of claim 13 or its deuterated derivative 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 of claim 13 or its deuterated derivative 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 13-15, or a deuterated derivative thereof or a pharmaceutically acceptable salt thereof, wherein _R5 is an unsubstituted _C1-3 alkyl group. 17. The compound of claim 16 or its deuterated derivative or its pharmaceutically acceptable salt, wherein _R5 is an unsubstituted methyl group. 18. The compound according to any one of claims 13-15, or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, wherein _R4 is chlorine. 19. The compound according to any one of claims 13-15, or a deuterated derivative thereof or a pharmaceutically acceptable salt thereof, wherein _R5 is independently selected from an unsubstituted methyl group; 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 any one of the compounds of claims 1-20, a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof. 22. Use of the compound of any one of claims 1-20, its deuterated derivative or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 21 in the preparation of a medicament for the prevention and/or treatment of diseases, symptoms and conditions mediated by SHP2 activity. 23. The use according to claim 22, wherein the disease, symptom, and condition are tumors, cancer metastases, cardiovascular diseases, immune disorders, or visual disorders. 24. The use according to claim 23, wherein the tumor includes solid tumors and hematomas. 25. The use according to claim 24, wherein the solid tumor includes lung cancer, and the hematologic malignancy includes leukemia. 26. The use according to claim 25, wherein the leukemia is acute myeloid leukemia.