Tricyclic compounds, pharmaceutical compositions comprising the same and uses thereof

Abstract

The present application belongs to the field of pharmaceutical chemistry, and relates to a tri-cyclic compound, a pharmaceutical composition containing the same and use thereof. Specifically, the present application relates to a compound having a structure of Formula I, which exhibits good SHP2 inhibitory activity and can be used as an efficient SHP2 inhibitor for preventing and / or treating SHP2 related diseases.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to a tricyclic compound used as an inhibitor of SHP2 (src homology 2 domain-containing phosphotyrosine phosphatase 2), pharmaceutical compositions comprising the same, and their use in the prevention and / or treatment of SHP2 enzyme-related diseases (also referred to herein as "SHP2 phosphatase-related diseases" or "SHP2-related diseases"). Background Technology

[0002] SHP2 is a protein tyrosine phosphatase (PTP) encoded by the gene PTPN11 (protein tyrosine phosphatase nonreceptor 11). It is an intracellular non-receptor member of the PTP family, catalyzing the dephosphorylation of tyrosine residues in proteins. SHP2 possesses two N-terminal SH2 (Src homology 2) domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail rich in proline groups and tyrosine phosphorylation sites. These two SH2 domains control the subcellular localization and functional regulation of SHP2. In the inactive state, SHP2 is in a self-inhibitory state; the N-SH2 domain binds to the PTP, inhibiting phosphatase activity. However, under stimulation by growth factors, cytokines, or inflammatory factors, such as platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF), tyrosine residues Tyr542 and Tyr580 are phosphorylated and bound to N-SH2, exposing the catalytically active site of the PTP domain. This releases the self-inhibitory state, activates the PTP activity of SHP2, and triggers a signal transduction cascade initiated by tyrosine phosphorylation.

[0003] SHP2 is widely expressed in the human body and participates in multiple signaling pathways, including Ras-Erk, PI3K-Akt, Jak-Stat, Met, FGFR, EGFR, and NF-κB, thereby regulating physiological functions such as cell proliferation, differentiation, migration, and apoptosis. Activating mutants of SHP2 are associated with the development of various diseases, such as Noonan syndrome, breast cancer, and melanoma. Overexpression of SHP2 increases the risk of cancers such as chronic myeloid leukemia, mastocytosis, malignant glioma, lung cancer, and breast cancer, suggesting that SHP2 plays a broad role in different types of cancer and different stages of cancer development. Therefore, it is necessary to use SHP2 phosphatase inhibitors to prevent and / or treat cancer and other diseases.

[0004] Currently, compounds such as pyrimidinones, pyrazines, carboxylic acids, quinones, quinolines, and indoles have been found to inhibit SHP2 activity (e.g., see WO2018013597A1), but there is still a great need in the field for new SHP2 inhibitors, especially those with high activity and other excellent properties. Summary of the Invention

[0005] The problem the invention aims to solve

[0006] Through extensive research, this invention has surprisingly discovered a series of tricyclic compounds with high SHP2 inhibitory activity. These compounds, as SHP2 inhibitors, can be used to prevent and / or treat SHP2-related diseases, especially tumors, demonstrating promising application prospects.

[0007] Solution for solving the problem

[0008] In a first aspect, the present invention provides a compound having the structure of Formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug thereof:

[0009]

[0010] in,

[0011] L1 is selected from single bonds and S;

[0012] Q is selected from CH and N;

[0013] Each R1 is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, -O-(C 1-6 alkyl), -O-(C 3-6 cycloalkyl), C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -C(=O)-C1-6 Alkyl, -C(=O)-OC 1-6 Alkyl group, -C(=O)-NH-C 1-6 Alkyl, -NH-C(=O)-OC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl groups and -S(=O)2-C 3-6 Cycloalkyl; the alkyl, cycloalkyl and heterocycloalkyl groups are each optionally separated by one or more groups selected from hydroxyl, halogen, cyano and -O-(C 1-6 Substitution of alkyl groups;

[0014] U, V, and W are each independently selected from single bonds, -CH2-, -O-, -N(R2)-, -OCH2-, -N(R2)CH2-, -C(=O)-, -N(R2)C(=O)-, and -OC(=O)-;

[0015] R2 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -C(=O)-C 1-6 Alkyl groups and -C(=O)-OC 1-6 Alkyl groups, wherein the alkyl, cycloalkyl, and heterocycloalkyl groups are each optionally substituted with one or more radicals selected from hydroxyl, halogen, cyano, C6, hydroxyl, cycloalkyl ... 1-6 Alkyl and -O-(C 1-6 Substitution of alkyl groups;

[0016] Ring A is a 5-10 membered heteroaromatic ring or a 3-6 membered heteroester ring;

[0017] Each R3 is independently selected from hydrogen, halogen, C. 1-6 Alkyl, amino, cyano, -C(=O)-NH2, -NH-C(=O)-OC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl groups and -S(=O)2-C 3-6 Cycloalkyl; the alkyl group and the cycloalkyl group are each optionally separated by one or more groups selected from hydroxyl, halogen, cyano and -O-(C 1-6 Substitution of alkyl groups;

[0018] Ring B is a 4-16 member nitrogen-containing heterocycle;

[0019] Each R4 group is independently selected from hydrogen, amino, halogen, cyano, hydroxyl, oxo, -O-(C) 1-6 alkyl), -O-(C 3-6 cycloalkyl), C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 6-10 Aryl, 5-10 heteroaryl, -C 1-6 Alkylene-C 3-6 cycloalkyl, -C 1-6 Alkylene (3-6 membered heterocyclic alkyl), -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-6 Cycloalkyl, -C(=O)-(3-6 membered heterocycloalkyl), -C(=O)-OC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 3-6 Cycloalkyl and -S(=O)2-(3-6-membered heterocycloalkyl); the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl and heteroaryl groups are each optionally surrounded by one or more elements selected from hydroxyl, halogen, cyano, amino, -O-(C 1-6 Alkyl), -O-(halogenated C) 1-6 Alkyl), -O- (3-6 membered heterocyclic alkyl), -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 3-6 cycloalkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Substitution with cycloalkyl, 3-6 membered heterocyclic alkyl and oxo groups;

[0020] m and n are each independently selected from 0, 1, and 2;

[0021] p is selected from 0, 1, 2, and 3.

[0022] Secondly, the present invention provides the following compounds or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites, or prodrugs:

[0023] (1) 4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-6,6a,7,8-tetrahydro-9H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-9-one;

[0024] (2) 4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-6a,7-dihydro-6H,9H-oxazolo[3,4-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0025] (3) 4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0026] (4) 4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-8-methyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0027] (5) 4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-8-isopropyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0028] (6) 4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-8-cyclopropyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0029] (7) 4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-8-(2-methoxyethyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0030] (8) 4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-8-(2-hydroxyethyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0031] (9) 4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-8-(2-hydroxy-2-methylpropyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0032] (10)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-8-((1-hydroxycyclopropyl)methyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0033] (11)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-8-(2-methoxy-2-methylpropyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0034] (12)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-8-((1-methoxycyclopropyl)methyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0035] (13)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-6,6a,7,8-tetrahydro-9H-pyridano[3,2-b]pyrrolo[1,2-d][1,4]oxazin-9-one;

[0036] (14) 4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-6a,7-dihydro-6H,9H-oxazolo[3,4-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0037] (15)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0038] (16)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-8-methyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0039] (17)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-8-isopropyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyridano[3,2-b][1,4]oxazin-9-one;

[0040] (18)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-8-cyclopropyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyridano[3,2-b][1,4]oxazin-9-one;

[0041] (19)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-8-(2-methoxyethyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0042] (20)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-8-(2-hydroxyethyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0043] (21)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-8-(2-hydroxy-2-methylpropyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0044] (22)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-8-((1-hydroxycyclopropyl)methyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyridano[3,2-b][1,4]oxazin-9-one;

[0045] (23)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-8-(2-methoxy-2-methylpropyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0046] (24) 4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-8-((1-methoxycyclopropyl)methyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyridano[3,2-b][1,4]oxazin-9-one;

[0047] (25) 4-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-6,6a,7,8-tetrahydro-9H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-9-one;

[0048] (26) 4-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-6a,7-dihydro-6H,9H-oxazolo[3,4-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0049] (27) 4-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0050] (28) 4-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-8-methyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0051] (29) 4-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-8-isopropyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0052] (30)4-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-8-cyclopropyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0053] (31)4-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-8-(2-methoxyethyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0054] (32)4-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-8-(2-hydroxyethyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0055] (33)4-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-8-(2-hydroxy-2-methylpropyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0056] (34) 4-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-8-((1-hydroxycyclopropyl)methyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0057] (35)4-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-8-(2-methoxy-2-methylpropyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0058] (36)4-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-8-((1-methoxycyclopropyl)methyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0059] (37)4-((3-amino-5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-6,6a,7,8-tetrahydro-9H-pyridano[3,2-b]pyrrolo[1,2-d][1,4]oxazin-9-one;

[0060] (38) 4-((3-amino-5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-6a,7-dihydro-6H,9H-oxazolo[3,4-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0061] (39)4-((3-amino-5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0062] (40) 4-((3-amino-5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-8-methyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0063] (41) 4-((3-amino-5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-8-isopropyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0064] (42) 4-((3-amino-5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-8-cyclopropyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0065] (43) 4-((3-amino-5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-8-(2-methoxyethyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyridano[3,2-b][1,4]oxazin-9-one;

[0066] (44) 4-((3-amino-5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-8-(2-hydroxyethyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0067] (45) 4-((3-amino-5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-8-(2-hydroxy-2-methylpropyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0068] (46) 4-((3-amino-5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-8-((1-hydroxycyclopropyl)methyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0069] (47) 4-((3-amino-5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-8-(2-methoxy-2-methylpropyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyridano[3,2-b][1,4]oxazin-9-one;

[0070] (48) 4-((3-amino-5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-8-((1-methoxycyclopropyl)methyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyridano[3,2-b][1,4]oxazin-9-one;

[0071] (49)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-6,6a,7,8-tetrahydro-9H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-9-one;

[0072] (50)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-6a,7-dihydro-6H,9H-oxazolo[3,4-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0073] (51)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0074] (52)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-8-methyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0075] (53)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-8-isopropyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0076] (54)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-8-cyclopropyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0077] (55)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-8-(2-methoxyethyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0078] (56)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-8-(2-hydroxyethyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0079] (57)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-8-(2-hydroxy-2-methylpropyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0080] (58)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-8-((1-hydroxycyclopropyl)methyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0081] (59)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-8-(2-methoxy-2-methylpropyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0082] (60)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-8-((1-methoxycyclopropyl)methyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0083] (61)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-6,6a,7,8-tetrahydro-9H-pyridano[3,2-b]pyrrolo[1,2-d][1,4]oxazin-9-one;

[0084] (62)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-6a,7-dihydro-6H,9H-oxazolo[3,4-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0085] (63)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0086] (64)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-8-methyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyridano[3,2-b][1,4]oxazin-9-one;

[0087] (65)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-8-isopropyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0088] (66)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-8-cyclopropyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyridano[3,2-b][1,4]oxazin-9-one;

[0089] (67)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-8-(2-methoxyethyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0090] (68)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-8-(2-hydroxyethyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0091] (69)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-8-(2-hydroxy-2-methylpropyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyridano[3,2-b][1,4]oxazin-9-one;

[0092] (70)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-8-((1-hydroxycyclopropyl)methyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyridano[3,2-b][1,4]oxazin-9-one;

[0093] (71)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-8-(2-methoxy-2-methylpropyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyridano[3,2-b][1,4]oxazin-9-one;

[0094] (72)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-8-((1-methoxycyclopropyl)methyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyridano[3,2-b][1,4]oxazin-9-one;

[0095] (73)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-yl)thio)-6,6a,7,8-tetrahydro-9H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-9-one;

[0096] (74)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-yl)thio)-6a,7-dihydro-6H,9H-oxazolo[3,4-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0097] (75)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-yl)thio)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0098] (76)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-yl)thio)-8-methyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0099] (77)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-yl)thio)-8-isopropyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0100] (78)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-yl)thio)-8-cyclopropyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0101] (79)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-yl)thio)-8-(2-methoxyethyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0102] (80)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-yl)thio)-8-(2-hydroxyethyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0103] (81)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-yl)thio)-6,6a,7,8-tetrahydro-9H-pyridano[3,2-b]pyrrolo[1,2-d][1,4]oxazin-9-one;

[0104] (82)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-yl)thio)-6a,7-dihydro-6H,9H-oxazolo[3,4-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0105] (83)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-yl)thio)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0106] (84)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-yl)thio)-8-methyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyridano[3,2-b][1,4]oxazin-9-one;

[0107] (85)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-yl)thio)-8-isopropyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyridano[3,2-b][1,4]oxazin-9-one;

[0108] (86)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-yl)thio)-8-cyclopropyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyridano[3,2-b][1,4]oxazin-9-one;

[0109] (87)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-yl)thio)-8-(2-methoxyethyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyridano[3,2-b][1,4]oxazin-9-one;

[0110] (88)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-yl)thio)-8-(2-hydroxyethyl)-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyridano[3,2-b][1,4]oxazin-9-one;

[0111] (89)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio))-6,6a,7,8-tetrahydro-9H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazin-9-one;

[0112] (90)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio))-6a,7-dihydro-6H,9H-oxazolo[3,4-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0113] (91)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio))-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0114] (92)4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)imidazo[1,2-c]pyrimidin-8-yl)thio))-8-methyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0115] (93)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)imidazo[1,2-c]pyrimidin-8-yl)thio))-6,6a,7,8-tetrahydro-9H-pyridano[3,2-b]pyrrolo[1,2-d][1,4]oxazin-9-one;

[0116] (94)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)imidazo[1,2-c]pyrimidin-8-yl)thio))-6a,7-dihydro-6H,9H-oxazolo[3,4-d]pyrido[3,2-b][1,4]oxazin-9-one;

[0117] (95)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)imidazo[1,2-c]pyrimidin-8-yl)thio))-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one; and

[0118] (96)4-((5-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4'-piperidin]-1'-yl)imidazo[1,2-c]pyrimidin-8-yl)thio))-8-methyl-6,6a,7,8-tetrahydro-9H-imidazo[1,5-d]pyrido[3,2-b][1,4]oxazin-9-one.

[0119] Thirdly, the present invention provides a pharmaceutical composition comprising at least one compound having the structure of Formula I, Formula II, Formula III or Formula III-1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0120] Fourthly, the present invention provides the use of compounds having the structure of Formula I, Formula II, Formula III or Formula III-1, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites or prodrugs or pharmaceutical compositions thereof in the preparation of medicaments for the prevention and / or treatment of SHP2 phosphatase-related diseases.

[0121] Fifthly, the present invention provides compounds having the structure of Formula I, Formula II, Formula III or Formula III-1, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites or prodrugs or pharmaceutical compositions thereof, for the prevention and / or treatment of SHP2 phosphatase-related diseases.

[0122] In a sixth aspect, the present invention provides a method for preventing and / or treating SHP2 phosphatase-related diseases, the method comprising administering to an individual in need an effective amount of a compound having the structure of Formula I, Formula II, Formula III or Formula III-1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug or pharmaceutical composition thereof.

[0123] In a seventh aspect, the present invention provides a combined method for preventing and / or treating SHP2 phosphatase-related diseases, the combined method comprising the method for preventing and / or treating SHP2 phosphatase-related diseases and additional treatment methods, the additional treatment methods including radiotherapy, chemotherapy, immunotherapy, or a combination thereof.

[0124] The effects of the invention

[0125] This invention provides a novel tricyclic compound that can serve as a highly active SHP2 inhibitor and achieve at least one of the following technical effects:

[0126] (1) High inhibitory activity against SHP2;

[0127] (2) Excellent physicochemical properties (such as solubility, physical and / or chemical stability);

[0128] (3) Excellent pharmacokinetic properties (such as good bioavailability, appropriate half-life and duration of action);

[0129] (4) Excellent safety (lower toxicity and side effects, wider therapeutic window). Detailed Implementation

[0130] General terms and definitions

[0131] Unless otherwise defined, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by those skilled in the art.

[0132] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other elements or method steps not listed. Those skilled in the art will understand that the foregoing term “comprising” encompasses the meaning of “consisting of.”

[0133] The term "one or more species" or similar expression "at least one species" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more species.

[0134] When used to modify a numerical value or range, the term "about" refers to the numerical value or range and the range of error acceptable to those skilled in the art, such as ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, etc., which usually means within ±10%, preferably within ±5%, and more preferably within ±2%.

[0135] When the lower and upper limits of a numerical range are disclosed, any numerical value falling within that range and any included range are specifically disclosed. In particular, each range of values ​​disclosed herein (in the form of “about a to b,” or equivalently, “approximately a to b,” or equivalently, “about ab”) should be understood to represent each numerical value and range encompassed within a wider range. For example, the expression “C…” 1-6 "This should be understood as encompassing any subrange and each point value, such as C." 2-5 C 3-4 C 1-2 C 1-3 C 1-4 C 1-5And so on, as well as C1, C2, C3, C4, C5, C6, etc. For example, the expression "3-10 yuan" should be understood as encompassing any sub-range and each point value within it, such as 3-4 yuan, 3-5 yuan, 3-6 yuan, 3-7 yuan, 3-8 yuan, 3-9 yuan, 4-5 yuan, 4-6 yuan, 4-7 yuan, 4-8 yuan, 5-7 yuan, 5-8 yuan, 6-7 yuan, etc., and 3, 4, 5, 6, 7, 8, 9, 10 yuan, etc.

[0136] When used alone or in combination with other groups in this document, "single bond" refers to a chemical bond connecting atoms to atoms, atoms to groups of atoms, or groups of atoms to groups of atoms, including (but not limited to) covalent bonds, ionic bonds, coordinate bonds, metallic bonds, and hydrogen bonds. In medicinal chemistry or organic chemistry, the term "single bond" usually refers to a covalent bond.

[0137] When used alone or in combination with other groups in this document, the term "alkyl" refers to a saturated, straight-chain or branched hydrocarbon group. The term "C"... 1-6 "Alkyl" refers to a saturated, straight-chain or branched hydrocarbon group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms). For example, "C 1-6 "alkyl" can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl, etc.

[0138] When used alone or in combination with other groups in this document, the term "alkylene" refers to a saturated, straight-chain or branched divalent hydrocarbon group. The term "C 1-6 "Alkylene" refers to a saturated, straight-chain or branched divalent hydrocarbon group having 1-6 carbon atoms. This includes, but is not limited to, methylene, ethylene, propylene, or butylene.

[0139] When used alone or in combination with other groups herein, the term "cycloalkyl" or "alicyclic" refers to a saturated or partially saturated, aliphatic monocyclic or polycyclic (such as bicyclic) hydrocarbon group; for example, monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutene, cyclopentene, cyclohexene; or bicyclic, including spirocyclic, fused or bridged systems (such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl or bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.). For example, the term "C 3-6 "Cycloalkyl" refers to a cycloalkyl group having 3 to 6 (e.g., 3, 4, 5 or 6) cyclic carbon atoms.

[0140] When used alone or in combination with other groups herein, the term "heterocyclic alkyl" or "heterocyclic ring" refers to a saturated or partially saturated, aliphatic monocyclic or polycyclic (such as bicyclic) group containing at least one cyclic heteroatom selected from N, O, P, and S, which may be substituted with 0 to 3 oxo groups; preferably, the number of cyclic heteroatoms is 1, 2, 3, or 4. For example, a 3-6 membered heterocyclic alkyl refers to a heterocyclic alkyl having 3-6 (e.g., 3, 4, 5, or 6) cyclic atoms, and at least one of them being a heteroatom. Specific examples include oxetane, oxetane butane, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, homopiperazinyl, sulfolane, etc.

[0141] When used alone or in combination with other groups herein, the term "4-16 membered nitrogen-containing heterocycle" refers to a monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) group having 4-16 (suitably 6-16, more preferably 6-10) cyclic atoms, saturated or partially unsaturated, wherein at least one cyclic atom is a nitrogen atom, and optionally contains one or more (e.g., 1 or 2) cyclic heteroatoms selected from N, O, P, and S, with the remainder being carbon atoms. The individual rings in the system can be saturated or partially saturated aliphatic ring systems (e.g., alicyclic or heteroaliphatic rings) or aromatic ring systems (e.g., aromatic or heteroaromatic rings). Additionally, the system may optionally be substituted with one or more substituents as described herein, said substituents being selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -C 1-6 Alkylene-C 3-6 cycloalkyl, -C 1-6 Alkylene (3-6 membered heterocyclic alkyl), -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-6 Cycloalkyl, -C(=O)-(3-6 membered heterocycloalkyl), -C(=O)-OC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 3-6 Cycloalkyl, -S(=O)2- (3-6 membered heterocyclic alkyl), etc. The term also covers cases where the cyclic carbon atom is optionally present in the form of a carbonyl group, and the cyclic sulfur atom is optionally present in the form of a sulfoxide group (-S(=O)-) or a sulfone group (-S(=O)2-). Specific examples include... wait.

[0142] When used alone or in combination with other groups in this document, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon double bond. The term "C"... 2-6"Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2-6 carbon atoms (e.g., 2, 3, 4, 5, or 6 carbon atoms) and at least one carbon-carbon double bond. For example, "C 2-6 "Alkenyl" can be vinyl, propenyl, butenyl, etc.

[0143] When used alone or in combination with other groups in this document, the term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon triple bond. The term "C 2-6 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2-6 carbon atoms (e.g., 2, 3, 4, 5, or 6 carbon atoms) and at least one carbon-carbon triple bond. For example, "C 2-6 "Alynyl" can be ethynyl, propynyl, butynyl, etc.

[0144] When used alone or in combination with other groups in this document, the term "halogen" refers to F, Cl, Br, or I. Accordingly, the term "halogenation" refers to the action or state of substitution with a "halogen".

[0145] When used alone or in combination with other groups in this document, the term "halogenated alkyl" refers to a group in which one or more hydrogen atoms in an alkyl group are replaced by a halogen. The term "halogenated C" refers to a group in which one or more hydrogen atoms in an alkyl group are replaced by a halogen. 1-6 "Alkyl" refers to a C-aryl group that is optionally substituted with one or more (e.g., 1-3) halogens. 1-6 Alkyl groups. Those skilled in the art will understand that when there are more than one halogen substituent, the halogens can be the same or different, and can be located on the same or different carbon atoms. Specific examples include -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2Cl, or -CH2CH2CF3, etc.

[0146] When used alone or in combination with other groups in this document, the term "aryl" or "aromatic ring" refers to an aromatic all-carbon monocyclic or fused polycyclic (e.g., bicyclic) hydrocarbon group or ring having a conjugated π-electron system. The term "C" 6-10 "Aryl" refers to an aryl group containing 6-10 cyclic carbon atoms. Specific examples include phenyl and naphthyl.

[0147] When used alone or in combination with other groups herein, the term "heteroaryl" or "heteroary ring" refers to an aromatic monocyclic or fused polycyclic (e.g., bicyclic) group or ring system having a conjugated π-electron system, wherein one or more (e.g., 1, 2, or 3) cyclic atoms are heteroatoms selected from N, O, P, and S, and the remaining cyclic atoms are carbon atoms. The term "5-10-membered heteroaryl" refers to a heteroaryl containing 5-10 (e.g., 5, 6, 7, 8, 9, or 10) cyclic atoms, and at least one of them is a heteroatom. Specific examples include thiophene, furanyl, pyrrole, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc.; the term also covers cases where the heteroaryl or heteroary ring may optionally be further fused to other aryl or heteroaryl rings to form a fused ring system. Specific examples include... wait.

[0148] When used alone or in combination with other groups in this document, the term "cyano" refers to the -CN group.

[0149] When used alone or in combination with other groups in this document, the term "amino" refers to the -NH2 group.

[0150] When used alone or in combination with other groups in this document, the term "hydroxyl" refers to the -OH group.

[0151] When used alone or in combination with other groups in this document, the term "carbonyl" refers to the -C(=O)- group.

[0152] When used alone or in combination with other groups in this document, the term "oxo" or "=O" refers to a group that, together with the carbon atom to which it is attached, forms a carbonyl group (-C(=O)-).

[0153] When used alone or in combination with other groups herein, the terms “substituted” and “substituted” mean that one or more (e.g., 1, 2, 3, or 4) hydrogen atoms on the specified atom are replaced by other atoms or groups, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound. If described as “optionally substituted by…”, then it may be (1) unsubstituted or (2) substituted. If described as “optionally substituted by one or more of the substituents in the list,” then one or more hydrogen atoms may be (1) unsubstituted or (2) substituted by at least one independently selected substituent. If described as “each independently selected from” or “each independently being,” then the multiple substituents used for substitution may be selected independently of each other. Unless otherwise specified, the connection point of a substituent may come from any suitable position of the substituent. When the bond of a substituent is shown as a bond connecting two atoms through the ring, it indicates that such a substituent may be connected to any suitable cyclizing atom in the ring.

[0154] The term "pharmaceutically acceptable salt" includes both its acid addition salts and base addition salts. Suitable acid addition salts are formed by acids that form pharmaceutically acceptable salts. Specific examples include hydrochlorides, acetates, aspartates, benzoates, bicarbonates / carbonates, glucono-p-glucose, gluconates, nitrates, palmitates, and other similar salts. Suitable base addition salts are formed by bases that form pharmaceutically acceptable salts. Specific examples include aluminum salts, arginine salts, choline salts, magnesium salts, and other similar salts. For a review of suitable salts, see, for example, "Remington's Pharmaceutical Sciences," Mack Publishing Company, Easton, Pa., (2005); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use," Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0155] The term "ester" includes physiologically hydrolyzable esters (compounds of the present invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). Alternatively, the compounds of the present invention may themselves be esters.

[0156] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can be produced. Geometric isomers (cis / trans) may also exist for a particular structure. Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. The scope of the present invention covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0157] Solid lines may be used in this article. solid wedge Or virtual wedge Depict the chemical bonds of the compounds of the present invention. Solid lines indicate the inclusion of all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.). Solid or dashed wedges indicate the presence of the specific stereoisomers shown. When present in racemic mixtures, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry.

[0158] This invention also covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0159] The present invention also covers all possible solvates (preferably hydrates) of the compounds of the present invention, which contain polar solvents, particularly such as water, methanol or ethanol, as structural elements of the lattice of the compounds.

[0160] This invention also covers all possible N-oxides of the compounds of this invention. Since nitrogen requires available lone pairs of electrons to be oxidized to oxides, not all nitrogen-containing heterocycles are capable of forming N-oxides. Those skilled in the art will recognize nitrogen-containing heterocycles capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxy acids (such as peracetic acid and m-chloroperoxybenzoic acid), hydrogen peroxide, alkyl hydrogen peroxide (such as tert-butyl hydrogen peroxide), sodium perborate, and diethylene oxide (such as dimethyldiethylene oxide). Methods for preparing N-oxides have been extensively described and reviewed in the literature, for example, see T.L. Gilchrist, Comprehensive Organic Synthesis, vol.7, pp. 748-750 (AR. Katritzky and A.J. Boulton, Eds., Academic Press); and G.W. H. Heeseman and E.S. G. Wierstiuk, Advances in Heterocyclic Chemistry, vol.22, pp.390-392 (AR. Katritzky and A.J. Boulton, Eds., Academic Press).

[0161] This invention also covers all possible isotopic labels for the compounds of this invention. Suitable examples include isotopes of hydrogen (e.g., D and T); isotopes of carbon (e.g., ... 13 C and 14 C); isotopes of chlorine (e.g.) 37 Cl); isotopes of iodine (e.g., Cl); 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes ... 32 P); and isotopes of sulfur (e.g. 34 S).

[0162] This invention also covers metabolites of the compounds of this invention, i.e., substances formed in the body after administration of the compounds of this invention. For example, the oxidized, reduced, hydrolyzed, amidated, deamidated, esterified, and enzymatically hydrolyzed forms of the administered compounds. Metabolites of the compounds can be identified using techniques known in the art, and their activity can be characterized using methods known in the art.

[0163] This invention also covers prodrugs of the compounds of this invention, i.e., derivatives of the compounds of this invention that may themselves lack or have weak pharmacological activity, which, when administered to an individual, can be converted into the compounds of this invention having the desired activity. Typically, prodrugs are derivatives of specific functional groups in the compound that are readily converted in vivo. Further information about prodrugs can be found in “Pro-drugs as Novel Delivery Systems”, Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella).

[0164] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention. The above process can be achieved using conventional protecting groups, for example, those described in TW Greene & P. ​​GMWuts, *Protective Groups in Organic Synthesis*, John Wiley & Sons, 2006. The protecting group can be removed at an appropriate subsequent stage using methods known in the art.

[0165] The term "effective dose" (e.g., "therapeutic effective dose" or "preventive effective dose") refers to the amount of active ingredient that, when applied, will achieve the desired effect to a certain extent, such as relieving one or more symptoms of a treated condition or preventing the occurrence of a condition or its symptoms.

[0166] The term "individual" includes humans or non-human animals. Exemplary human individuals include human individuals suffering from diseases (such as those described herein, also referred to as "patients") and normal human individuals. In this invention, "non-human animals" includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals (e.g., non-human primates, livestock, and / or domesticated animals, such as sheep, dogs, cats, cows, pigs, etc.).

[0167] The compounds of the present invention

[0168] This invention provides compounds of formula I or thereof, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites, or prodrugs thereof:

[0169]

[0170] in,

[0171] L1 is selected from single bonds and S;

[0172] Q is selected from CH and N;

[0173] Each R1 is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, -O-(C 1-6 alkyl), -O-(C 3-6 cycloalkyl), C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6 Alkyl group, -C(=O)-NH-C 1-6 Alkyl, -NH-C(=O)-OC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl groups and -S(=O)2-C 3-6 Cycloalkyl; the alkyl, cycloalkyl and heterocycloalkyl groups are each optionally separated by one or more groups selected from hydroxyl, halogen, cyano and -O-(C 1-6 Substitution of alkyl groups;

[0174] U, V, and W are each independently selected from single bonds, -CH2-, -O-, -N(R2)-, -OCH2-, -N(R2)CH2-, -C(=O)-, -N(R2)C(=O)-, and -OC(=O)-;

[0175] R2 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -C(=O)-C 1-6 Alkyl groups and -C(=O)-OC 1-6 Alkyl groups, wherein the alkyl, cycloalkyl, and heterocycloalkyl groups are each optionally substituted with one or more radicals selected from hydroxyl, halogen, cyano, C6, hydroxyl, cycloalkyl ... 1-6 Alkyl and -O-(C 1-6 Substitution of alkyl groups;

[0176] Ring A is a 5-10 membered heteroaromatic ring or a 3-6 membered heteroester ring;

[0177] Each R3 is independently selected from hydrogen, halogen, C. 1-6 Alkyl, amino, cyano, -C(=O)-NH2, -NH-C(=O)-OC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl groups and -S(=O)2-C 3-6 Cycloalkyl; the alkyl group and the cycloalkyl group are each optionally separated by one or more groups selected from hydroxyl, halogen, cyano and -O-(C 1-6 Substitution of alkyl groups;

[0178] Ring B is a 4-16 member nitrogen-containing heterocycle;

[0179] Each R4 group is independently selected from hydrogen, amino, halogen, cyano, hydroxyl, oxo, -O-(C) 1-6 alkyl), -O-(C 3-6 cycloalkyl), C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5-10 heteroaryl, -C 1-6 Alkylene-C 3-6 cycloalkyl, -C 1-6 Alkylene (3-6 membered heterocyclic alkyl), -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-6 Cycloalkyl, -C(=O)-(3-6 membered heterocycloalkyl), -C(=O)-OC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 3-6 Cycloalkyl and -S(=O)2-(3-6-membered heterocycloalkyl); the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl and heteroaryl groups are each optionally surrounded by one or more elements selected from hydroxyl, halogen, cyano, amino, -O-(C 1-6 Alkyl), -O-(halogenated C) 1-6 Alkyl), -O- (3-6 membered heterocyclic alkyl), -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 3-6 cycloalkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Substitution with cycloalkyl, 3-6 membered heterocyclic alkyl and oxo groups;

[0180] m and n are each independently selected from 0, 1, and 2;

[0181] p is selected from 0, 1, 2, and 3.

[0182] In some implementations, L1 is selected from single bonds and S, with S being preferred.

[0183] In some implementations, Q is selected from CH and N, with N being preferred.

[0184] In some embodiments, when at least one R1 is present, each R1 is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, -O-(C 1-3 alkyl), -O-(C 3-6 cycloalkyl), C 1-3 Alkyl, C 3-6Cycloalkyl and 3-6 membered heterocyclic alkyl; preferably, each R1 is independently selected from hydrogen, fluorine, chlorine, cyano, methyl and amino; more preferably, R1 is hydrogen.

[0185] In some embodiments, U, V, and W are each independently selected from single bonds, -CH2-, -O-, -N(R2)-, and -C(=O)-; preferably, U, V, and W are each independently selected from -CH2-, -O-, and -N(R2)-; more preferably, It is one of the following structures:

[0186] In some implementation schemes, when R2 is present, R2 is selected from hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups; each of the alkyl, cycloalkyl, and heterocyclic alkyl groups is optionally separated by one or more groups selected from hydroxyl, halogen, cyano, C 1-3 Alkyl and -O-(C 1-6 The alkyl group is substituted with a substituent; preferably, R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, isobutyl, cyclopropyl, and cyclopropylmethyl; each of the methyl, ethyl, n-propyl, isopropyl, isobutyl, cyclopropyl, and cyclopropylmethyl groups is optionally substituted with one or more substituents selected from hydroxy, fluorine, chlorine, cyano, methyl, and methoxy; more preferably, R2 is selected from hydrogen, methyl, 2-hydroxyethyl, 2-methoxyethyl, isopropyl, 2-hydroxy-2-methylpropyl, 2-methoxy-2-methylpropyl, cyclopropyl, (1-hydroxycyclopropyl)methyl, and (1-methoxycyclopropyl)methyl.

[0187] In some embodiments, ring A is a 6-9 member heteroaromatic ring or a 5-6 member heteroester ring; preferably, ring A is a 6-membered heteroaromatic ring, a 9-membered heteroaromatic ring or a 6-membered heteroester ring; more preferably, ring A is a 6-membered heteroaromatic ring or a 9-membered heteroaromatic ring.

[0188] In some implementations, when at least one R3 is present, each R3 is independently selected from hydrogen, halogen, C. 1-6 Alkyl, amino, cyano, and -C(=O)-NH2; the alkyl group is optionally substituted with one or more substituents selected from hydroxyl, halogen, and cyano; preferably, each R3 is independently selected from hydrogen, methyl, ethyl, -CH2-OH, -CH2F, -CH2CHF2, -CH2CH2F, -C(=O)-NH2, and amino; more preferably, each R3 is independently selected from hydrogen, methyl, -CH2-OH, and amino.

[0189] In some implementations, ring A has one of the following structures: R3 is defined as in Equation I; preferably, ring A is...

[0190] In some embodiments, ring B is a 6-16 member nitrogen-containing heterocycle, and each R4 is independently selected from hydrogen, amino, C 1-6 Alkyl, -C 1-6 Alkylene-C 3-6 cycloalkyl, -C 1-6 Alkylene (3-6 membered heterocyclic alkyl), -C(=O)-C 1-6 Alkyl groups and -S(=O)2-C 1-6 Alkyl; the alkyl, cycloalkyl and heterocycloalkyl groups are each optionally selected by one or more (e.g., 1, 2, 3 or 4) from hydroxyl, halogen, cyano, amino, -O-(C 1-6 Alkyl), -O-(halogenated C) 1-6 Alkyl group), -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Substitution of cycloalkyl and 3-6 membered heterocyclic alkyl groups; preferably, ring B is a 6-16 membered nitrogen-containing heterocycle, and each R4 is independently selected from -CH3, -NH2, -CH2NH2, -CH(NH2)CH3, -CH(NH2)CH2OCH3, -CH(NH2)CH2F, -CH(NH2)CH2CN, -CH(NH2)CH2OH, -CH(NH2)CH(CH3)OH, -CH(NH2)CH(CH3)OCH3, -CH(NH2)C(CH3)2OCH3, -CH(NH2)CH2OCHF2, -CH(NH2)CH2S(=O)2CH3, -CH2F, -CH2OCH2F, -CH2OCHF2 and More preferably, ring B is a 6-16 member nitrogen-containing heterocycle, and each R4 is independently selected from -NH2, -CH2F, -CH2OCH2F, -CH2OCHF2 and -CH3.

[0191] In some implementation schemes, It is one of the following structures:

[0192] R5 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -C 1-6 Alkylene-C 3-6 cycloalkyl, -C 1-6 Alkylene (3-6 membered heterocyclic alkyl), -C(=O)-C 1-6 Alkyl, -C(=O)-C3-6 Cycloalkyl, -C(=O)-(3-6 membered heterocycloalkyl), -C(=O)-OC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 3-6 Cycloalkyl and -S(=O)2-(3-6-membered heterocycloalkyl); each of the alkyl, cycloalkyl and heterocycloalkyl groups is optionally separated by one or more groups selected from hydroxyl, halogen, cyano, -O-(C 1-6 Alkyl), C 2-6 alkenyl, C 2-6 Substitution of alkynyl and oxo groups;

[0193] Preferably, It is one of the following structures:

[0194] More preferably, for

[0195] In some embodiments, the compound of formula I has the structure shown in formula II:

[0196]

[0197] in,

[0198] X1 is selected from -O-, -CH2- and -N(R5)-;

[0199] Each R4 is independently selected from C 1-6 Alkyl and amino groups, wherein the alkyl group is optionally separated by one or more groups selected from hydroxyl, halogen, cyano, -O-(C 1-6 Alkyl), -O-(halogenated C) 1-6 Alkyl group), -S(=O)2-C 1-6 Alkyl, C 3-6 Substitution with cycloalkyl, 3-6 membered heterocyclic alkyl and oxo groups;

[0200] R5 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -C 1-6 Alkylene-C 3-6 cycloalkyl, -C 1-6 Alkylene (3-6 membered heterocyclic alkyl), -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-6 Cycloalkyl, -C(=O)-(3-6 membered heterocycloalkyl), -C(=O)-OC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C3-6 Cycloalkyl and -S(=O)2-(3-6 membered heterocyclic alkyl); each of the alkyl, cycloalkyl and heterocyclic alkyl groups is optionally separated by one or more radicals selected from hydroxyl, halogen, cyano, oxo, -O-(C 1-6 Alkyl), C 2-6 alkenyl and C 2-6 Substitution of the alkynyl group;

[0201] Rings A, U, V, W, L1, Q, R1, R3, m, n, and p are defined as in Equation I.

[0202] In some implementations, X1 is -O-.

[0203] In some embodiments, the compound of formula I has the structure shown in formula III:

[0204]

[0205] in,

[0206] X3, X4, X5, and X6 are each independently selected from CR4 and N;

[0207] X2 is selected from -O-, -CH2-, -CF2-, -CHF, -N(R5)-, -C(=O-) and

[0208] Ring D is C 3-6 Cycloalkylene groups; the cycloalkylene groups are optionally radicalized by one or more groups selected from hydroxyl, halogen, cyano, amino, -O-(C 1-6 Alkyl), -O-(halogenated C) 1-6 Substitution of alkyl groups and -O- (3-6 membered heterocyclic alkyl groups);

[0209] R5 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -C 1-6 Alkylene-C 3-6 cycloalkyl, -C 1-6 Alkylene (3-6 membered heterocyclic alkyl), -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-6 Cycloalkyl, -C(=O)-(3-6 membered heterocycloalkyl), -C(=O)-OC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 3-6 Cycloalkyl and -S(=O)2-(3-6 membered heterocyclic alkyl); each of the alkyl, cycloalkyl and heterocyclic alkyl groups is optionally separated by one or more radicals selected from hydroxyl, halogen, cyano, oxo, -O-(C 1-6 Alkyl), C2-6 alkenyl and C 2-6 Substitution of the alkynyl group;

[0210] Rings A, U, V, W, L1, Q, R1, R3, R4, m, and n are defined as in Equation I.

[0211] In some implementations, at least one of X3, X4, X5 and X6 is N, and X2 is -CH2-.

[0212] In some embodiments, the above-mentioned compound of formula III has the structure shown in formula III-1:

[0213]

[0214] Among them, rings A, U, V, W, L1, Q, R1, R3, R4, m, n and p are defined as in Equation III.

[0215] Those skilled in the art will understand that this invention covers compounds obtained by any combination of the various embodiments. Embodiments obtained by combining technical features or preferred technical features from one embodiment with technical features or preferred technical features from another embodiment are also included within the scope of this invention.

[0216] This invention provides the following compounds covered by Formula I, Formula II, Formula III, or Formula III-1, or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope labels, metabolites, or prodrugs:

[0217]

[0218]

[0219]

[0220] Pharmaceutical compositions, formulations and kits

[0221] The present invention provides a pharmaceutical composition comprising at least one compound covered by a compound of formula I, II, III or III-1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate (e.g., hydrate), N-oxide, isotope label, metabolite or prodrug.

[0222] In some embodiments, the pharmaceutical compositions of the present invention further comprise one or more pharmaceutically acceptable carriers.

[0223] The present invention further provides a method for preparing a pharmaceutical composition comprising combining at least one compound covered by a compound of formula I, II, III or III-1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug with one or more pharmaceutically acceptable carriers.

[0224] Accordingly, the present invention provides a pharmaceutical formulation comprising at least one compound of formula I, II, III or III-1 as an active ingredient, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite or prodrug or pharmaceutical composition thereof.

[0225] In some embodiments, the pharmaceutical formulation of the present invention is a solid formulation, a semi-solid formulation, a liquid formulation, or a gaseous formulation.

[0226] The present invention further provides an article of manufacture, for example, provided in the form of a kit. The article of manufacture of the present invention comprises: (a) a container; (b) at least one compound of formula I, II, III, or III-1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope label, metabolite, or prodrug or pharmaceutical composition thereof, located in said container; and (c) optionally, packaging and / or instructions for use. The instructions for use list information about the active pharmaceutical ingredient in the above-described article of manufacture, preferably specifically listing the indications for which the active pharmaceutical ingredient is approved for use. The instructions for use are on a printable material (e.g., paper, plastic, metal foil, adhesive paper, etc.) on which the required information can be formed (e.g., printed or coated).

[0227] Medical Use

[0228] The compounds of this invention exhibit strong inhibitory activity against SHP2 and can be used as SHP2 inhibitors. Therefore, this invention provides the use of compounds covered by Formula I, Formula II, Formula III, or Formula III-1, or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates (such as hydrates), N-oxides, isotope labels, metabolites, prodrugs, or pharmaceutical compositions for the prevention and / or treatment of SHP2-related diseases (or as SHP2 inhibitors).

[0229] The present invention further provides the use of compounds covered by Formula I, Formula II, Formula III or Formula III-1, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites or prodrugs or pharmaceutical compositions thereof in the preparation of medicaments for the prevention and / or treatment of SHP2-related diseases.

[0230] In addition, the present invention provides a method for preventing and / or treating SHP2-related diseases, comprising administering to an individual in need an effective amount of a compound covered by a compound of formula I, II, III or III-1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, metabolite or prodrug or pharmaceutical composition thereof.

[0231] In some implementations, SHP2-related diseases are diseases that are sensitive to or responsive to SHP2 phosphatase inhibition; preferably, SHP2-related diseases are tumor-related conditions, including (but not limited to) malignant solid tumors and hematologic malignancies, such as breast cancer, lung cancer, head and neck cancer, esophageal cancer, ovarian cancer, pancreatic cancer, etc., as well as leukemia, multiple myeloma, and lymphoma, etc.

[0232] In some implementation schemes, SHP2-related diseases are lung cancer or esophageal cancer.

[0233] This invention further provides a combined method for preventing and / or treating SHP2-related diseases, comprising the method of this invention for preventing and / or treating SHP2-related diseases and additional treatment methods, including (but not limited to) radiotherapy, chemotherapy, immunotherapy, or combinations thereof. The compounds or pharmaceutical compositions of this invention may be administered before, during, or after the additional treatment methods. The administration of the additional treatment methods and the administration of the compounds or pharmaceutical compositions of this invention may be performed simultaneously, closely linked, or at intervals, and the manner and order of administration may be selected and adjusted according to the specific treatment situation.

[0234] To make the objectives and technical solutions of this invention clearer, the embodiments of this invention are described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of this invention.

[0235] Unless otherwise specified, all reagents and instruments used in the following examples are commercially available products. Unless otherwise specified, all procedures were performed under standard conditions or conditions recommended by the manufacturer.

[0236] The meanings of the abbreviations used in this article are shown in the table below.

[0237]

[0238] The structures of the compounds described in the following examples were determined by nuclear magnetic resonance (NMR). 1 Determined by 1H-NMR and / or mass spectrometry (MS).

[0239] Nuclear magnetic resonance (NMR) 1 The H-NMR determination was performed using a Bruker 400MHz NMR spectrometer. The determination solvents were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), hexadeuterated dimethyl sulfoxide (DMSO-d6), or deuterated water (D2O). The internal standard was tetramethylsilane (TMS).

[0240] The abbreviations used in the nuclear magnetic resonance (NMR) data in the following examples have the following meanings:

[0241] s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, qd: quartet doublet, ddd: double double doublet, ddt: double double triplet, dddd: double double double doublet, m: multiplet, br: broad, J: coupling constant, Hz: Hertz, δ: chemical shift.

[0242] All chemical shift (δ) values ​​are given in parts per million (ppm).

[0243] The reaction was monitored using thin-layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS). The developing solvent or mobile phase system used included (but was not limited to) dichloromethane and methanol, n-hexane and ethyl acetate, and petroleum ether and ethyl acetate. The volume ratio of the solvent was adjusted according to the polarity of the compound, or by adding triethylamine, etc.

[0244] Thin-layer chromatography used GF 254 silica gel plates (0.4–0.5 nm) produced in Yantai.

[0245] Preparative high performance liquid chromatography (Prep-HPLC) was performed using a Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250×20mm column).

[0246] Column chromatography (CC) uses Qingdao Ocean 200-300 mesh silica gel as the stationary phase. The eluent system includes (but is not limited to) dichloromethane and methanol system and n-hexane and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.

[0247] Mass spectrometry (MS) measurements were performed using an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.

[0248] Unless otherwise specified, the reaction temperature in the following examples is room temperature (20–30°C).

[0249] Unless otherwise specified, the reagents used in the following examples were purchased from Acros Organics, Aldrich Chemical, Nanjing Yaoshi Technology, or Shanghai Shuya Pharmaceutical Technology, etc.

[0250] Preparation of intermediates

[0251] Example 1: Preparation of methyl 6-bromo-3-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazine-2-carboxylate (compound A1)

[0252]

[0253] Compound A1-1 (120.0 mg, 0.41 mmol), compound A1-0 (103.54 mg, 0.43 mmol), and DIPEA (314.46 mg, 2.43 mmol) were added to NMP (3 mL) and reacted at 25 °C for 12 hours. Then, Boc₂O (177.01 mg, 811.04 μmol) was added to the reaction mixture, and the reaction was continued at 25 °C for 2 hours. Water and ethyl acetate were added to extract the product. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by thin-layer chromatography to give compound A1 (162 mg, 82% yield).

[0254] Compounds A2, A3, and A4 were synthesized following the method described in Example 1 for preparing intermediates.

[0255]

[0256] Example 2: Preparation of 2-ethylhexyl 3-((3-((tert-butyldiphenylsilyl)oxy)methyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)thio)propionate (compound B1) and 2-ethylhexyl 3-((3-(hydroxymethyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)thio)propionate (compound B2)

[0257] Step 1: Preparation of methyl 2-((tert-Butoxycarbonyl)amino)-3-((tert-Butyldiphenylsilyl)oxy)propionate (compound B1-2).

[0258]

[0259] Compound B1-1 (3.00 g, 13.7 mmol) was dissolved in DCM (100 mL), and imidazole (1.86 g, 27.4 mmol) and TBDPSCl (1.72 g, 15.1 mmol) were added. The mixture was heated to 40 °C and stirred. After 4 hours of reaction, the reaction was monitored by TLC to indicate its completion. The reaction was quenched by adding saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound B1-2 (5.80 g), which was used directly for the next step without further purification.

[0260] Step 2: Preparation of (1-((tert-butyldiphenylsilyl)oxy)-3-hydroxypropyl-2-yl)carbamate tert-butyl ester (compound B1-3)

[0261]

[0262] Compound B1-2 (5.80 g, 12.7 mmol) was dissolved in EtOH (100 mL). Calcium chloride (7.05 g, 63.5 mmol) and sodium borohydride (2.41 g, 63.5 mmol) were added. After reacting for 2 hours, the reaction was monitored by TLC until it ended. The reaction was quenched by adding saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound B1-3 (4.70 g), which was used directly for the next step without further purification.

[0263] Step 3: Preparation of 4-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(tert-butoxycarbonyl)-1,2,3-oxathiazoline-2-oxide (compound B1-4)

[0264]

[0265] Thionyl chloride (3.25 g, 27.4 mmol) was dissolved in acetonitrile (200 mL), and the solution was cooled to -40 °C. An acetonitrile solution (60 mL) of compound B1-3 (4.70 g, 10.9 mmol) was added dropwise. After 10 minutes, pyridine (3.03 g, 38.3 mmol) was added dropwise. The reaction was continued at -40 °C for 1 hour, then slowly heated to 0 °C. LC-MS analysis was performed to confirm the reaction was complete. The reaction was quenched by adding 1 N hydrochloric acid (20 mL), and the mixture was extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium bicarbonate solution (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound B1-4 (4.70 g), which was used directly in the next reaction.

[0266] Step 4: Preparation of 4-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(tert-butoxycarbonyl)-1,2,3-oxathiazoline-2,2-dioxide (compound B1-5)

[0267]

[0268] Compound B1-4 (4.70 g, 9.88 mmol) was dissolved in acetonitrile (200 mL) / water (100 mL), cooled to 0 °C, and then NaIO4 (3.17 g, 14.8 mmol) and RuCl3·H2O (22.3 mg, 0.99 mmol) were added. The mixture was reacted at 0 °C for 1 hour. After the reaction was detected by LC-MS, sodium thiosulfate solution was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound B1-5 (4.30 g), which was directly used in the next step of the reaction.

[0269] Step 5: Preparation of tert-butyl carbamate (compound B1-6)

[0270]

[0271] 2-Fluoropyridine-3-phenol (824.2 mg, 7.29 mmol) was dissolved in DMF (100 mL), and compound B1-5 (4.30 g, 8.75 mmol) and cesium carbonate (4.75 g, 14.6 mmol) were added. The mixture was heated to 80 °C and reacted for 2.5 hours. After the reaction was completed by LC-MS, water was added to the reaction solution, and the pH was adjusted to about 6 with 3N hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain compound B1-6 (3.51 g, total yield of 49% in five steps).

[0272] Step 6: Preparation of tert-butyl carbamate (compound B1-7)

[0273]

[0274] Compound B1-6 (2.80 g, 5.34 mmol) was dissolved in THF (200 mL), cooled to -78 °C, and LDA (2.0 MTHF solution, 9.34 mL) was added dropwise. After reacting at -78 °C for 1 hour, iodine (5.42 g, 21.35 mmol) in THF solution (50 mL) was added dropwise, and the reaction was carried out at -78 °C for 1 hour. After the reaction was completed by LC-MS, the reaction solution was added dropwise to a saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium sulfite solution, dried and concentrated to obtain crude compound B1-7 (3.4 g), which was directly used in the next reaction.

[0275] Step 7: Preparation of 1-((tert-butyldiphenylsilyl)oxy)-3-((2-fluoro-4-iodopyridin-3-yl)oxy)prop-2-amine (compound B1-8a) and 2-amino-3-((2-fluoro-4-iodopyridin-3-yl)oxy)prop-1-ol (compound B1-8b)

[0276]

[0277] Compound B1-7 (3.40 g, 5.23 mmol) was dissolved in DCM (150 mL), and TFA (7 mL) was added. After reacting at 25 °C for 15 hours, the reaction solution was concentrated to obtain a mixture of crude compounds B1-8a and B1-8b trifluoroacetates (3.47 g), which was directly used in the next step of the reaction.

[0278] Step 8: Preparation of 3-(((tert-butyldiphenylsilyl)oxy)methyl)-8-iodo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (compound B1-9a) and (8-iodo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-3-yl)methanol (compound B1-9b)

[0279]

[0280] A mixture of trifluoroacetates of compounds B1-8a and B1-8b (3.47 g) was dissolved in NMP (100 mL), potassium phosphate (4.43 g, 20.9 mmol) was added, and the mixture was heated to 110 °C for 1 hour. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude mixture of compounds B1-9a and B1-9b (2.50 g) was used directly in the next step of the reaction.

[0281] Step 9: Preparation of 2-ethylhexyl 3-((3-(((tert-butyldiphenylsilyl)oxy)methyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)thio)propionate (compound B1) and 2-ethylhexyl 3-((3-(hydroxymethyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)thio)propionate (compound B2)

[0282]

[0283] A mixture of compounds B1-9a and B1-9b (2.50 g) was dissolved in dioxane (50 mL), and DIPEA (2.05 g, 15.8 mmol), Xantphos (305.6 mg, 0.53 mmol), Pd2(dba)3 (151.8 mg, 0.53 mmol) and 2-ethylhexyl 3-mercaptopropionic acid (1.5 g, 6.86 mmol) were added. After nitrogen purging, the mixture was heated to 100 °C and reacted for 3 hours. After the reaction was completed, the reaction solution was filtered by LC-MS, washed with ethyl acetate, concentrated, and purified by column chromatography to obtain compounds B1 (1.39 g, 42% overall yield of four steps) and B2 (0.38 g, 21% overall yield of four steps).

[0284] Preparation of the compounds of the present invention

[0285] Example 1: Preparation of 4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-6a,7-dihydro-6H,9H-oxazolo[3,4-d]pyrido[3,2-b][1,4]oxazin-9-one (compound 50)

[0286] Step 1: Preparation of sodium 3-(((tert-butyldiphenylsilyl)oxy)methyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-8-thiophenol (compound 1-1)

[0287]

[0288] Compound B1 (900 mg, 1.01 mmol) was dissolved in THF (8 mL), and sodium ethoxide (237 mg, 1.32 mmol, 20% ethanol solution) was added. The mixture was reacted at 25 °C for half an hour. After the reaction was completed, the reaction solution was concentrated to obtain crude compound 1-1 (465 mg), which was directly used in the next reaction.

[0289] Step 2: Preparation of methyl 3-((3S,4S)-4-((tert-butyloxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-((3-(((tert-butyldiphenylsilyl)oxy)methyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)thio)pyrazine-2-carboxylate (compounds 1-2)

[0290]

[0291] Compound A1 (378 mg, 0.78 mmol) was dissolved in dioxane (10 mL), and compound 1-1 (465 mg, 1.01 mmol), cuprous iodide (223 mg, 1.17 mmol), 1,10-phenanthroline (232 mg, 1.17 mmol), and potassium phosphate (497 mg, 2.34 mmol) were added. After nitrogen purging, the mixture was heated to 110 °C and reacted for 3 hours. After the reaction was completed, ethyl acetate was added to the reaction solution, filtered, and the filtrate was concentrated and purified by thin-layer chromatography to obtain compound 1-2 (500 mg, yield 76%).

[0292] Step 3: Preparation of ((3S,4S)-8-(5-((3-(((tert-butyldiphenylsilyl)oxy)methyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)thio)-3-(hydroxymethyl)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate (compounds 1-3)

[0293]

[0294] Compounds 1-2 (300 mg, 0.36 mmol) were dissolved in EtOH (20 mL). Calcium chloride (594 mg, 5.35 mmol) and sodium borohydride (202 mg, 5.35 mmol) were added. After 2 hours of reaction, the reaction was monitored by TLC to indicate completion. The reaction was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compounds 1-3 (270 mg), which were used directly for the next step without further purification.

[0295] Step 4: Preparation of ((3S,4S)-8-(3-(hydroxymethyl)-5-((3-(hydroxymethyl)-3,4-dihydro-2H-pyridano[3,2-b][1,4]oxazin-8-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)tert-butyl carbamate (compounds 1-4)

[0296]

[0297] Compounds 1-3 (270 mg, 0.33 mmol) were dissolved in THF (10 mL). TBAF (0.83 mmol, 0.83 mL, 1 M THF solution) was added, and the reaction was carried out at room temperature for 2 hours. The reaction was then monitored by TLC until it ended. The solution was concentrated, and the crude product was purified by thin-layer chromatography to give compounds 1-4 (160 mg, yield 83%).

[0298] Step 5: Preparation of ((3S,4S)-8-(3-(hydroxymethyl)-5-((9-oxo-6,6a,7,9-tetrahydrooxazolo[3,4-d]pyrido[3,2-b][1,4]oxazin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)tert-butyl carbamate (compounds 1-5)

[0299]

[0300] Compounds 1-4 (20 mg, 0.037 mmol) were dissolved in dichloromethane (5 mL). The mixture was cooled to 0°C in an ice-water bath, and triethylamine (11.2 mg, 0.11 mmol) and triphosgene (10.9 mg, 0.037 mmol) were added. After reacting in an ice-water bath for 1 hour, the reaction was monitored by TLC until it ended. The mixture was concentrated, and the crude product was purified by thin-layer chromatography to give compounds 1-5 (18 mg, yield 86%).

[0301] Step 6: Preparation of 4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(hydroxymethyl)pyrazin-2-yl)thio)-6a,7-dihydro-6H,9H-oxazolo[3,4-d]pyrido[3,2-b][1,4]oxazin-9-one (compound 50)

[0302]

[0303] Compounds 1-5 (18 mg, 0.032 mmol) were dissolved in DCM (1 mL), and TFA (0.3 mL) was added. The mixture was reacted at 25 °C for half an hour. After the reaction was completed, the reaction solution was concentrated by LC-MS to obtain the crude product. The crude product was purified by Prep-HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% formic acid aqueous solution) to obtain compound 50 (4 mg, yield 24%).

[0304] MS(ESI): m / z 501.0 [M+H] + .

[0305] 1 H-NMR (400MHz, DMSO): δ8.30(s,1H),7.82(d,J=5.2Hz,1H),6.60(d,J=5.2Hz,1H),5.54 (t,J=5.6Hz,1H),4.68–4.56(m,2H),4.51(d,J=5.6Hz,2H),4.42–4.32(m,1H),4.23–4. 12(m,2H),4.09(t,J=10.4Hz,1H),3.81–3.66(m,3H),3.60(d,J=8.8Hz,1H),3.20–3.08 (m,3H),1.88–1.75(m,2H),1.71–1.62(m,1H),1.61–1.52(m,1H),1.16(d,J=6.4Hz,3H).

[0306] Example 2: Preparation of 4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-6a,7-dihydro-6H,9H-oxazolo[3,4-d]pyrido[3,2-b][1,4]oxazin-9-one (compound 2)

[0307] Step 1: Preparation of sodium 3-(hydroxymethyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-8-thiophenol (compound 2-1)

[0308]

[0309] Compound B2 (120 mg, 0.22 mmol) was dissolved in THF (8 mL), and sodium ethoxide (51.4 mg, 0.29 mmol, 20% ethanol solution) was added. The mixture was reacted at 25 °C for half an hour. After the reaction was completed by TLC, the reaction solution was concentrated to obtain crude compound 2-1 (46 mg), which was directly used in the next step of the reaction.

[0310] Step 2: Preparation of ((3S,4S)-8-(5-((3-(hydroxymethyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)tert-butyl carbamate (compound 2-2)

[0311]

[0312] Compound A2 (80 mg, 0.19 mmol) was dissolved in dioxane (10 mL), and compound 2-1 (46 mg, 0.21 mmol), Xantphos (10.8 mg, 0.019 mmol), Pd2(dba)3 (17.1 mg, 0.019 mmol) and potassium phosphate (79.4 mg, 0.37 mmol) were added. After nitrogen purging, the mixture was heated to 110 °C and reacted for 3 hours. After the reaction was completed, ethyl acetate was added to the reaction solution, filtered, and the filtrate was concentrated and purified by thin-layer chromatography to obtain compound 2-2 (50 mg, yield 49%).

[0313] Steps 3 to 4: Preparation of 4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-6a,7-dihydro-6H,9H-oxazolo[3,4-d]pyrido[3,2-b][1,4]oxazin-9-one (compound 2)

[0314]

[0315] Except that in step 3, compound 2-2 was used instead of compounds 1-4 in step 5 of Example 1, crude compound 2 was synthesized using a method similar to that described in steps 5 to 6 of Example 1. The crude compound 2 was purified by Prep-HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous formic acid) to obtain compound 2.

[0316] MS(ESI): m / z 471.0 [M+H] +

[0317] 1H-NMR (400MHz, DMSO) δ8.47(s,1H),8.27(s,1H),7.80(d,J=5.2Hz,1H),6.44(d,J=5.2 Hz,1H),4.68–4.55(m,2H),4.41–4.32(m,1H),4.19(dd,J=8.8,6.0Hz,1H),4.13–4.03 (m,2H),3.97–3.84(m,2H),3.68(d,J=8.4Hz,1H),3.54–3.43(m,3H)),2.92(d,J=5.2H z,1H),1.80–1.72(m,1H),1.70–1.62(m,1H),1.58–1.46(m,2H),1.08(d,J=6.4Hz,3H).

[0318] Performance evaluation of the compounds of this invention

[0319] Experimental Example 1: In vitro enzyme activity inhibition assay of SHP2 (protein phosphatase)

[0320] (1) Test System

[0321] Phosphatase: Recombinant human PTPN11 full-length sequence protein (SHP2), active (SignalChem).

[0322] Substrate: 6,8-Difluoro-4-methylumbelliferyl ketone phosphate (DiFMUP) (Invitrogen)

[0323] Activating peptides: IRS1_pY1172(dPEG8)pY1222(BPS Bioscience)

[0324] Termination reagent: bpv(phen)(Abcam)

[0325] (2) Test parameters

[0326] SHP2 concentration: 0.5 nM; DiFMUP concentration: 200 μM; IRS-1 concentration: 0.5 μM; bpv: 160 μM

[0327] Buffer system: 60mM Hepes pH 7.2; 75mM NaCl; 75mM KCl; 0.05% P-20; 1mM EDTA; 5mM DTT

[0328] Compound incubation and enzyme activation time: 60 minutes at room temperature

[0329] Enzyme-substrate reaction time: 30 minutes at room temperature

[0330] Microplate reader parameters: BMG PHERAstar Fluorescence, excitation wavelength 340nm, emission wavelength 450nm

[0331] (3) Test Procedure

[0332] The mixture of the test compound and SHP2 was incubated with the activating peptide IRS-1 in a buffer system at room temperature for 60 minutes. The substrate DiFMUP was added to start the reaction. After incubation at room temperature for 30 minutes, bpv was added to terminate the reaction. The reaction plate was placed in a microplate reader, and the fluorescence value of each well in the plate was read using the endpoint method.

[0333] (4) Data processing

[0334] Using the solvent group (containing 0.5 nM SHP2, 200 μM DiFMUP, 0.5 μM IRS-1, 160 μM bpv, and 0.05% DMSO) as a negative control and the reaction buffer group (200 μM DiFMUP, 0.5 μM IRS-1, 160 μM bpv, and 0.05% DMSO) as a blank control, the relative inhibitory activity of each concentration group was calculated. The inhibition rate was calculated as: 100% - (fluorescence value of the test group - fluorescence value of the blank group) / (fluorescence value of the solvent group - fluorescence value of the blank group) * 100%. The half-maximal inhibitory concentration (IC50) of the compound was calculated based on the curve fitted using a four-parameter model. 50 ).

[0335] (5) Test Results

[0336] The inhibition of SHP2 activity by the compound was determined according to the above method, and the results are shown in Table 1 (where A represents IC50). 50 ≤50nM, B indicates IC 50 Between 50-100nM, C represents IC 50 ≥100nM).

[0337] Table 1. Results of SHP2 enzyme activity inhibition assay

[0338] Example <![CDATA[IC 50 (nM)]]> Example 1 A Example 2 A

[0339] (6) Conclusion

[0340] In the SHP2 enzymatic activity inhibition assay, the compounds of the present invention exhibited significant inhibitory activity.

[0341] The above embodiments do not limit the scope of this application in any way. In addition to those described herein, various modifications to the invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety.

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein Ring A is L1is S; Q is N; To To R1is hydrogen; each R3is independently selected from the group consisting of hydrogen and C 1-6 alkyl, said alkyl being optionally substituted with one or more hydroxyl groups; m is 1; n is 1 or 2.

2. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein, each R3is independently selected from hydrogen, methyl and -CH2-OH.

3. The following compounds or a pharmaceutically acceptable salt thereof, 4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

5. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 4 for the manufacture of a medicament for the prevention and / or treatment of a SHP2 related disease.

Images