Substituted pyrazine compounds, pharmaceutical compositions comprising the same and uses thereof

Abstract

The present application belongs to the field of pharmaceutical chemistry, and relates to substituted pyrazine compounds, pharmaceutical compositions containing the same and uses thereof. Specifically, the present application relates to a compound having the 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

[0001] Citation of relevant applications

[0002] This invention claims priority to Chinese patent applications filed on June 22, 2020, entitled "Substituted pyrazine compounds, pharmaceutical compositions comprising the same, and uses thereof", with application number 202010576572.X, and filed on November 27, 2020, entitled "Substituted pyrazine compounds, pharmaceutical compositions comprising the same, and uses thereof", with application number 202011359022.9, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention belongs to the field of medicinal chemistry and relates to a method for use as SHP2 ( s rc h omology 2 domain-containing phosphotyrosine p hosphatase 2 The substituted pyrazine compounds that inhibit SHP2, pharmaceutical compositions comprising such compounds, and their medicinal use for the prevention and / or treatment of SHP2-related diseases. Background Technology

[0004] SHP2 is a gene derived from PTPN11 ( p rotein t yrosine p hosphatase n onreceptor 11 SHP2 encodes protein tyrosine phosphatases (PTPs), which are intracellular non-receptor members of the PTPs family. They catalyze the dephosphorylation of tyrosine residues in proteins. SHP2 possesses two SH2 ( s rc h omology 2 SHP2 contains two SH2 domains (N-terminal N-SH2 and C-terminal 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 autoinhibited, with N-SH2 binding to PTP, thereby inhibiting phosphatase activity. However, in the presence of growth factors, cytokines, or inflammatory factors, such as PDGF (… p latelet- d erived g rowth f actor) and FGF ( f ibroblast ggrowth f Under the stimulation of growth factors (such as EGF, PDGF, etc.), SHP2 phosphorylates tyrosine residues Tyr542 (Y542) and Tyr580 (Y580) and binds to N-SH2, so that the catalytic active site of the PTP domain is exposed, thereby releasing the self-inhibition state and activating the PTP activity of SHP2, thereby triggering the signal transduction cascade initiated by tyrosine phosphorylation.

[0005] SHP2 is widely expressed in the human body and is involved in multiple signaling pathways such as Ras-Erk, PI3K-Akt, Jak-Stat, Met, FGFR, EGFR and NF-kB, thereby regulating physiological functions such as cell proliferation, differentiation, migration and apoptosis. Activated mutants of SHP2 are associated with the occurrence of various diseases, such as Noonan syndrome, breast cancer, melanoma, etc. Overexpression of SHP2 increases the risk of chronic myeloid leukemia, mastocytosis, malignant glioma, lung cancer and breast cancer, etc., suggesting that SHP2 has a wide range of effects in different types of cancer and different stages of cancer development. Therefore, it is necessary to use SHP2 inhibitors to prevent and / or treat cancer and other related diseases.

[0006] At present, it has been found that pyrimidinone, pyrazine, carboxylic acid, quinone, quinoline and indole compounds have the function of inhibiting SHP2 activity (for example, see WO2018013597A1), but there is still an urgent need in the art for new SHP2 inhibitors, especially SHP2 inhibitors with high activity and other excellent properties. SUMMARY

[0007] Problem to be solved by the invention

[0008] The present application is surprised to find a series of substituted pyrazine compounds through a large number of researches, which have high SHP2 inhibitory activity, and can be used as SHP2 inhibitors for preventing and / or treating SHP2 related diseases, especially tumor diseases, showing good application prospect.

[0009] Solution to the problem

[0010] In a first aspect, the present application provides a compound having the structure of formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled, metabolite or prodrug thereof, wherein

[0011]

[0012] X is selected from a chemical bond, S, O, NH and CH2;

[0013] R 1hydrogen, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, 3-6 membered heterocycloalkyl, and C 3-6 cycloalkyl, wherein said alkyl, heterocycloalkyl, and cycloalkyl are each optionally substituted with one or more substituents selected from halogen, hydroxyl, and amino;

[0014] R 2 hydrogen, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, 3-6 membered heterocycloalkyl, and C 3-6 cycloalkyl, wherein said alkyl, heterocycloalkyl, and cycloalkyl are each optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, amino;

[0015] A is selected from C 6-12 arylene, 5-12 membered heteroarylene, 3-12 membered heterocycloalkylene, and C 3-8 cycloalkylene, wherein said arylene, heteroarylene, heterocycloalkylene, and cycloalkylene are each optionally substituted with one or more R a substituents;

[0016] each R a is each independently selected from hydrogen, halogen, hydroxyl, -O-(C 1-6 alkyl), -O-(C 3-6 cycloalkyl), cyano, C 1-6 alkyl, C 3-6 alkyl, C 2-6 alkenyl, -S(=O) g -(C 1-6 alkyl), -S(=O) g NH2, amino, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, 3-12 membered heterocycloalkyl, C 6-10 aryl, and 5-12 membered heteroaryl, wherein said alkyl, cycloalkyl, alkenyl, heterocycloalkyl, aryl, and heteroaryl are each optionally substituted with one or more substituents selected from amino, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, halogen, cyano, oxo, hydroxyl, -O-(C 1-6 alkyl), -S(=O) g -(C 1-6 alkyl), and C 1-6 alkyl;

[0017] or, when X is NH or CH2, any one R aand X, together with the atom to which they are attached, form a 5-10 membered alicyclo, 5-10 membered heteroalicyclo, 5-6 membered heteroaromatic ring, or a phenyl ring, wherein each of said alicyclo, heteroalicyclo, heteroaromatic ring, and phenyl ring is optionally substituted with one or more substituents selected from amino, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, halo, cyano, oxo, hydroxy, -0-(C 1-6 alkyl), C 1-6 haloalkyl, and C 1-6 alkyl;

[0018] B is selected from -N(R b )-C(=0)-G-R d , -N(R b )-S(=0) g -G-R d , -N(R b )-C(=0)-N(R b )-G-R d , -N(R b )-S(=0) g -N(R b )-G-R d , -C(=0)-N(R b )-G-R d , -S(=0) g -N(R b )-G-R d , -S(=0) g -G-R d , -0-G-(3-10 membered heterocycloalkyl), -0-G-(C 3-6 cycloalkyl), -0-(C 3-6 cycloalkylene)-G-H, -0-(3-10 membered heterocycloalkylene)-G-H, -0-G-R d , -N(R b )-G-(3-10 membered heterocycloalkyl), -N(R b )-G-(C 3-6 cycloalkyl), -N(R b )-(C 3-6 cycloalkylene)-G-H, -N(R b )-(3-10 membered heterocycloalkylene)-G-H, -G-0-C(=0)-R b , -G-N(R b )-C(=0)-R b , -G-N(R b )-C(=0)-OR b , and wherein each of said heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxyl, amino, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, oxo, -O-(C 1-6 alkyl), C 1-6 haloalkyl, and C 1-6 alkyl, and B is not -O-(C 1-2 haloalkyl);

[0019] G is selected from the group consisting of C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-6 cycloalkylene, C 3-6 cycloalkenylene, 3-10 membered heterocycloalkenylene, and 3-10 membered heterocycloalkylene, wherein each of said alkylene, cycloalkylene, cycloalkenylene, heterocycloalkenylene, and heterocycloalkylene is optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, oxo, hydroxyl, cyano, amino, -OR b , -NHR b , -N(R b )2, -N(R b )-C(=O)-R b , -C(=O)-NH2, -C(=O)-N(R b )2, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 hydroxycycloalkyl, 3-10 membered haloheterocycloalkyl, 3-10 membered hydroxyheterocycloalkyl, and 3-10 membered heterocycloalkyl;

[0020] R b is selected from the group consisting of hydrogen, halogen, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 3-10 membered heterocycloalkenyl, and 3-10 membered heterocycloalkyl, wherein each of said alkyl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, and heterocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, oxo, hydroxyl, cyano, and amino;

[0021] C is selected from the group consisting of C 6-12 arylene, 5-12 membered heteroarylene, 3-12 membered heterocycloalkylene, C 3-12 cycloalkenylene, 3-12 membered heterocycloalkenylene, and C 3-8Cycloalkylene, wherein the arylene, heteroarylene, heterocyclic alkylene, cycloalkylene, heterocyclic alkenylene, and cycloalkylene are each optionally represented by one or more R c replace;

[0022] If it exists, each R c Each is independently selected from hydrogen, halogen, hydroxyl, -O-(C 1-6 alkyl), -O-(C 3-6 cycloalkyl), cyano, C 1-6 Alkyl, C 2-6 Alkenyl, -S (=O) g -(C 1-6 Alkyl group), -S (=O) g NH2, amino group, -NH(C) 1-6 alkyl) and -N(C) 1-6 Alkyl)2, wherein the alkyl and alkenyl groups are each optionally composed of one or more groups selected from amino, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group, halogen, cyano group, oxo group, hydroxyl group, -O-(C 1-6 Alkyl group), -S (=O) g -(C 1-6 alkyl) and C 1-6 Alkyl substituents;

[0023] Y is selected from C 1-6 Alkylene, C 3-6 Cycloalkylene, 3-6 membered heterocycloalkylene, C 3-6 Cycloalkylene, 3-6 membered heteroalkylene, C 6-10 aryl, 5-12 methyl aryl, C 2-6 alkenyl group, -S (=O) g -(C 1-6 Alkylene)-, -S(=O) g -N(R b )-、-C(=O)-(C 1-6 alkylene)-, -C(=O)-(C 3-6 -C(=O)-(3-6 membered heterocyclic alkyl)- and -C(=O)-, wherein the alkylene, heterocyclic alkyl, cycloalkylene, heterocyclic alkenyl and cycloalkylene are each optionally substituted by one or more substituents selected from halogens, oxo groups, hydroxyl groups and amino groups;

[0024] R d Selected from halogens, amino groups, hydroxyl groups, cyano groups, and -S (=O). g -(C 1-6 alkyl), -O-(C 1-6 alkyl), -O-(C 3-6cycloalkyl), -NH-(C 1-6 alkyl), -NH(C) 3-6 cycloalkyl), -N(C) 1-6 Alkyl)2、-NH-C(=O)-O-(C 1-6 alkyl), -N(C) 1-6 alkyl)-C(=O)-O-(C 1-6 Alkyl groups, -OC(=O)-NH2, -OC(=O)-NH(C 1-6 alkyl) and -N(C) 1-6 alkyl)-C(=O)-(C 1-6 Alkyl groups), wherein the alkyl and cycloalkyl groups are each optionally composed of one or more radicals selected from halogens, oxo groups, hydroxyl groups, amino groups, and -O-(C-yl groups). 1-6 Substitution of alkyl groups;

[0025] R 3 Selected from halogens, -OR z hydroxyl, cyano, -C(=O)-OR z -C(=O)-N(R) z 2. C 1-6 Alkyl, -(C 1-6 (alkylene)-R z -(C 1-6 (alkylene)-OR z -(C 1-6 alkylene)-OH, -(C 1-6 alkylene)-N(R z 2. C 3-6 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-12 Aryl, 5-12 heteroaryl, -S (=O) g -(C 1-6 alkyl), amino and -N(R) z )2, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, alkenyl, ynyl, heteroaryl, and aryl groups are each optionally selected from one or more halogens, cyano, oxo, -OR z hydroxyl group, -N(R) z )2、-NHR z amino, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, -C(=O)-OR z -C(=O)-N(R) z2. Substitution of -C(=O)-NH2 and nitro groups;

[0026] If it exists, each R z Each is independently selected from hydrogen, cyano, -C(=O)-(C 1-6 Alkyl), -C(=O)-(C 3-8 Cycloalkyl), -C(=O)-(3-8 membered heterocycloalkyl), C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-12 membered heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-12 aryl and 5-12 heteroaryl groups, wherein the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl and heteroaryl groups are each optionally composed of one or more groups selected from amino, halogen, cyano, oxo, nitro, hydroxyl, -O-(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups;

[0027] R 4 Selected from halogens, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C(=O)-R z 3-12 membered heterocyclic alkyl groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 aryl and 5-12 heteroaryl groups, wherein the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl and heteroaryl groups are each optionally composed of one or more groups selected from amino, halogen, cyano, hydroxyl, oxo, -O-(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups;

[0028] Or, R 3 and R 4 Together with the atoms attached thereto, they form a 4-8 membered alicyclic ring or a 4-8 membered heterocyclic ring, wherein the alicyclic ring and heterocyclic ring are each optionally bounded by one or more R 4a Replacement, or the alicyclic and heterocyclic rings are each optionally replaced with one or more C 6-10 Aromatic rings or 5-12-membered heterocyclic aromatic rings fused together, wherein the aromatic rings and heterocyclic aromatic rings are each optionally bound by one or more R 4a replace;

[0029] If it exists, each R 4a Each is independently selected from hydrogen, halogen, cyano, -C(=O)H, -C(=O)-(C 1-6 Alkyl), -C(=O)-(C 3-8 Cycloalkyl), -C(=O)-(3-8 membered heterocycloalkyl), -NH-C(=O)-(C 1-6 Alkyl), -NH-C(=O)-(C 3-8 Cycloalkyl), -NH-C(=O)- (3-8 membered heterocycloalkyl), oxo-group, C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, 3-12 membered heterocyclic alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-12 aryl and 5-12 heteroaryl groups, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocyclic alkenyl, heterocyclic alkyl, alkenyl, alkynyl, aryl, and heteroaryl groups are each optionally selected from one or more halogens, cyano, hydroxyl, -O-(C 1-6 Alkyl), C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups;

[0030] If it exists, each R 5 Each is independently selected from hydrogen, halogen, oxo group, cyano group, hydroxyl group, carboxyl group, -C(=O)-NH2, -C(=O)-O-(C 1-6 Alkyl), C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -S (=O) g -(C 1-6 Alkyl), 3-6 membered heterocyclic alkyl, C 6-10 aryl and 5-10 heteroaryl groups, wherein the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl and heteroaryl groups are each optionally composed of one or more groups selected from amino, hydroxyl, oxo, halogen, cyano, -O-(C 1-6 alkyl), -NH(C) 1-6 alkyl) and -N(C) 1-6 Substitution of alkyl group 2; or any two R groups 5 Together with the atoms bonded to it, they form C 3-10 Alicyclic rings or 4-12 membered heterocyclic rings;

[0031] g is 0, 1, or 2;

[0032] n can be 0, 1, 2, 3, 4, or 5.

[0033] In a second aspect, the present invention provides specific examples of compounds having the structure of Formula I, which include:

[0034] (1)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(2-(hydroxymethyl)pyrrolidine-1-yl)pyridin-4-ylthio)-5-methylpyrazin-2-yl)methanol;

[0035] (2)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(2-(hydroxymethyl)pyrrolidine-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0036] (3)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(2-(fluoromethyl)pyrrolidine-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0037] (4) 2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)pyrrolidine-2-yl)acetamide;

[0038] (5) 2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)pyrrolidine-2-yl)acetonitrile;

[0039] (6)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(2-(hydroxymethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0040] (7)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(2-(methoxymethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0041] (8) 2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-2-yl)acetonitrile;

[0042] (9)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(2-(methanesulfonylmethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0043] (10)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(2-(methylsulfonylmethyl)pyrrolidine-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0044] (11)2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)acetonitrile;

[0045] (12)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-(hydroxymethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0046] (13)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(2-(3-(aminomethyl)azacyclobutane-1-yl)-3-chloropyridin-4-ylthio)pyrazin-2-yl)methanol;

[0047] (14)2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)pyrrolidine-3-yl)acetonitrile;

[0048] (15)N-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-ylthio)-3-chloropyridin-2-yl)-2-cyanoacetamide;

[0049] (16)(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)piperidin-4-yl)methanol;

[0050] (17)(3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(3-chloro-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0051] (18)(3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(3-chloro-2-(2-(fluoromethyl)pyrrolidine-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0052] (19) 2-(1-(4-(5-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)acetonitrile;

[0053] (20)(3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(2-chloro-6-(2-(hydroxymethyl)azacyclobutane-1-yl)pyrimidin-3-ylthio)pyrazin-2-yl)methanol;

[0054] (21)(3-((S)-4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(2-(hydroxymethyl)pyrrolidine-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0055] (22)(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(fluoromethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)pyrrolidine-2-yl)methanol;

[0056] (23)(1-(4-(5-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-3-fluoro-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)pyrrolidine-2-yl)methanol;

[0057] (24)(4S)-4-amino-8-(5-(3-chloro-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyridin-4-ylthio)-3-(hydroxymethyl)pyrazin-2-yl)-2-cyclopropyl-2,8-diazaspiro[4.5]decane-3-one;

[0058] (25) 1-((4S)-4-amino-8-(5-(3-chloro-2-(2-(hydroxymethyl)pyrrolidine-1-yl)pyridin-4-ylthio)-3-(hydroxymethyl)pyrazin-2-yl)-2,8-diazaspiro[4.5]decane-2-yl) ethyl ketone;

[0059] (26)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(2-(hydroxymethyl)pyrrolidine-1-yl)pyrimidin-4-yl)-5-methylpyrazin-2-yl)methanol;

[0060] (27)(3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(2,3-dichloro-4-(3-(hydroxymethyl)azacyclobutane-1-yl)phenyl)-5-methylpyrazin-2-yl)methanol;

[0061] (28)(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)pyrrolidine-2-yl)methanol;

[0062] (29) 2-(1-(4-(5-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)pyrrolidine-2-yl)prop-2-ol;

[0063] (30)(3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(3-chloro-2-(3-(hydroxymethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0064] (31)(3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(2-(3-(aminomethyl)azacyclobutane-1-yl)-3-chloropyridin-4-ylthio)pyrazin-2-yl)methanol;

[0065] (32) 1-(4-(5-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-carboxamide;

[0066] (33)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-((S)-2-(hydroxymethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0067] (34)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(2-(2-(aminomethyl)pyrrolidine-1-yl)-3-chloropyridin-4-ylthio)pyrazin-2-yl)methanol;

[0068] (35)(3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(3-chloro-2-(3-(hydroxymethyl)pyrrolidin-1-yl)pyrimidin-4-yl)pyrazin-2-yl)methanol;

[0069] (36)(3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(3-chloro-2-(3-(hydroxymethyl)pyrrolidin-1-yl)pyrimidin-4-yl)-5-methylpyrazin-2-yl)methanol;

[0070] (37)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-(hydroxymethyl)pyrrolidine-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0071] (38)(1-(4-(5-(4-(1-amino-2-fluoroethyl)-4-methylpiperidin-1-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)pyrrolidine-2-yl)methanol;

[0072] (39)(1-(4-(5-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-3-fluoro-6-(hydroxymethyl)pyrazin-2-yl)-3-chloropyridin-2-yl)pyrrolidine-2-yl)methanol;

[0073] (40)(3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(3-chloro-2-(4-(hydroxymethyl)piperidin-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0074] (41) (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(3-chloro-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)-5-methylpyrazin-2-yl)methanol;

[0075] (42)N-(4-(5-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)-2-hydroxy-N,2-dimethylpropionamide;

[0076] (43)(3-(4-(1-amino-2-methoxyethyl)-4-methylpiperidin-1-yl)-6-(3-chloro-2-(2-(hydroxymethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0077] (44)(3-(4-(1-amino-2-methoxyethyl)-4-methylpiperidin-1-yl)-6-(3-chloro-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0078] (45)(3-(4-(1-amino-2-methoxyethyl)-4-methylpiperidin-1-yl)-6-(3-chloro-2-(3-(hydroxymethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0079] (46)(3-(4-(1-aminoethyl)-4-fluoropiperidin-1-yl)-6-(3-chloro-2-(3-(hydroxymethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0080] (47) 1-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-2-yl)cyclopropionitrile;

[0081] (48)3-(4-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)piperazin-1-yl)-3-oxopropionitrile;

[0082] (49) 1-((4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yloxy)methyl)cyclopropanol;

[0083] (50)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3,6-dichloro-2-(2-(hydroxymethyl)pyrrolidine-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0084] (51)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(2,3-dichloro-6-(2-(hydroxymethyl)pyrrolidine-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0085] (52)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(5-chloro-2-(2-(hydroxymethyl)pyrrolidine-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0086] (53)(3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(2,3-dichloro-6-(2-(hydroxymethyl)pyrrolidin-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0087] (54)(3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(5-chloro-2-(2-(fluoromethyl)pyrrolidine-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0088] (55)2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)pyridin-2-yl)pyrrolidine-2-yl)acetonitrile;

[0089] (56)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(2-(3-(fluoromethyl)azacyclobutane-1-yl)pyrimidin-3-ylthio)pyrazin-2-yl)methanol;

[0090] (57)(3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(2-(3-(fluoromethyl)azacyclobutane-1-yl)pyrimidin-3-ylthio)pyrazin-2-yl)methanol;

[0091] (58) 1-((4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-ylamino)methyl)cyclopropanol;

[0092] (59)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(oxacyclobutane-3-ylmethoxy)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0093] (60)(3-((S)-5-amino-5,7-dihydrospiro[cyclopentano[b]pyridin-6,4′-piperidin]-1′-yl)-6-(2-(2-(2-(fluoromethyl)azacyclobutane-1-yl)pyridin-3-ylthio)pyrazin-2-yl)methanol;

[0094] (61)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-fluoro-2-(2-(fluoromethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0095] (62)(1-(3-(3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-ylthio)pyridin-2-yl)pyrrolidine-2-yl)methanol;

[0096] (63)2-(1-(3-(3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-ylthio)pyridin-2-yl)pyrrolidine-3-yl)acetonitrile;

[0097] (64)(5-amino-3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(2-(2-(2-(fluoromethyl)pyrrolidine-1-yl)pyridin-3-ylthio)pyrazin-2-yl)methanol;

[0098] (65)(1-(3-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-ylthio)pyridin-2-yl)pyrrolidine-3-yl)methanol;

[0099] (66)1-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)cyclopropanol;

[0100] (67)2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0101] (68)(S)-2-(1-(4-(5-(4-amino-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0102] (69)(S)-2-(1-(4-(5-(4-(1-amino-2-methoxyethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0103] (70)1-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)ethanol;

[0104] (71)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-(methoxymethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0105] (72)(R)-2-(1-(4-(5-(3-amino-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0106] (73)(S)-2-(1-(4-(5-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0107] (74) 2-(1-(4-(5-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0108] (75)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-(methylsulfonylmethyl)azacyclobutane-1-yl)pyridin-4-ylthio)-5-methylpyrazine-2-yl)methanol;

[0109] (76)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-(methylsulfonylmethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0110] (77)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-(hydroxymethyl)-3-methylazacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0111] (78)2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0112] (79)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-methyl-3-(methylsulfonylmethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0113] (80)2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)-2-methylpropionitrile;

[0114] (81)3-((4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)-3-methylpyrazine-2-ylthio)-3-chloropyridin-2-ylamino)methyl)oxacyclobutane-3-ol;

[0115] (82)2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0116] (83)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-(methoxymethyl)-3-methylazacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0117] (84) 2-(1-(4-(5-(4-(1-amino-2-fluoroethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0118] (85)2-(1-(4-(3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0119] (86)(1-(4-(3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)pyrrolidine-2-yl)methanol;

[0120] (87)(3S,4S)-8-(6-amino-5-(3-chloro-2-(3-(methanesulfonylmethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine;

[0121] (88)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-fluoro-3-(hydroxymethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0122] (89)(S)-2-(1-(4-(5-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidin]-1′-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0123] (90)2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-fluoropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0124] (91)(S)-2-(1-(4-(5-(7-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidin]-1′-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0125] (92)(S)-2-(1-(4-(5-(5-amino-5,7-hydrospiro[cyclopentanol[c]pyridin-6,4′-piperidin]-1′-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0126] (93)(S)-2-(1-(4-(5-(4-amino-2-chloro-4,6-dihydrospiro[cyclopentadieno[d]thiazo-5,4′-piperidin]-1′-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0127] (94)(S)-2-(1-(4-(5-(4-amino-4,6-dihydrospiro[cyclopentadieno[d]thiazo-5,4′-piperidin]-1′-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0128] (95)(S)-2-(1-(4-(5-(4-amino-4,6-dihydrospiro[cyclopentadieno[d]oxazol-5,4′-piperidin]-1′-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0129] (96)(S)-2-(1-(4-(5-(6-amino-4,6-dihydrospiro[cyclopentadieno[d]oxazol-5,4′-piperidin]-1′-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0130] (97)(R)-2-(1-(4-(5-(3-amino-5-fluoro-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0131] (98)(R)-2-(1-(4-(5-(3-amino-5-fluoro-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-fluoropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0132] (99)(R)-2-(1-(4-(5-(3-amino-6-fluoro-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0133] (100)(R)-2-(1-(4-(5-(3-amino-6-fluoro-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-fluoropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0134] (101)(R)-2-(1-(4-(5-(3-amino-3H-spiro[furano[2,3-b]pyridin-2,4′-piperidin]-1′-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0135] (102)(S)-2-(1-(4-(5-(7-amino-5,7-dihydrospiro[cyclopentadieno[c]pyridin-6,4′-piperidin]-1′-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0136] (103)(S)-2-(1-(4-(5-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidin]-1′-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0137] (104)(S)-2-(1-(4-(5-(5-amino-5,7-dihydrospiro[cyclopentadieno[c]pyridin-6,4′-piperidin]-1′-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0138] (105)(S)-2-(1-(4-(5-(7-amino-5,7-dihydrospiro[cyclopentadiene[b]pyridin-6,4′-piperidin]-1′-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0139] (106)(R)-2-(1-(4-(5-(3-amino-3H-spiro[furano[2,3-b]pyridin-2,4′-piperidin]-1′-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0140] (107)(R)-2-(1-(4-(5-(3-amino-5-fluoro-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0141] (108)(R)-2-(1-(4-(5-(3-amino-6-fluoro-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0142] (109)(S)-2-(1-(4-(5-(4-amino-2-chloro-4,6-dihydrospiro[cyclopentadieno[d]thiazolyl-5,4′-piperidin]-1′-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0143] (110)(S)-2-(1-(4-(5-(4-amino-4,6-dihydrospiro[cyclopentadieno[d]thiazolyl-5,4′-piperidin]-1′-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0144] (111)(S)-2-(1-(4-(5-(4-amino-4,6-dihydrospiro[cyclopentadieno[d]oxazol-5,4′-piperidin]-1′-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0145] (112)(S)-2-(1-(4-(5-(6-amino-4,6-dihydrospiro[cyclopentadieno[d]oxazol-5,4′-piperidin]-1′-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0146] (113)(S)-2-(1-(4-(3-amino-5-(7-amino-5,7-dihydrospiro[cyclopentadieno[c]pyridin-6,4′-piperidin]-1′-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0147] (114)(S)-2-(1-(4-(3-amino-5-(7-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidin]-1′-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0148] (115)(S)-2-(1-(4-(3-amino-5-(5-amino-5,7-hydrospiro[cyclopentanol[b]pyridin-6,4′-piperidin]-1′-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0149] (116)(S)-2-(1-(4-(3-amino-5-(5-amino-5,7-dihydrospiro[cyclopentadieno[c]pyridin-6,4′-piperidin]-1′-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0150] (117)(S)-2-(1-(4-(3-amino-5-(4-amino-2-chloro-4,6-dihydrospiro[cyclopentadieno[d]thiazolyl-5,4′-piperidin]-1′-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0151] (118)(S)-2-(1-(4-(3-amino-5-(4-amino-4,6-dihydrospiro[cyclopentadiene[d]thiazolyl-5,4′-piperidin]-1′-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0152] (119)(R)-2-(1-(4-(3-amino-5-(3-amino-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0153] (120)(R)-2-(1-(4-(3-amino-5-(3-amino-5-fluoro-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0154] (121)(R)-2-(1-(4-(5-(4-amino-8-azabispiro[2.1.5.2]dodecane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0155] (122)(S)-2-(1-(4-(5-(1-amino-2,2-difluoro-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0156] (123)(S)-2-(1-(4-(5-(4-amino-8-aza-12-oxabispiro[2.1.5.2]dodecane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0157] (124)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-(fluoromethyl)-3-(hydroxymethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0158] (125)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-(fluoromethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0159] (126)1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)-3-(hydroxymethyl)azacyclobutane-3-carboxylonitrile;

[0160] (127)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-ethyl-3-(hydroxymethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol;

[0161] (128)2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(fluoromethyl)pyrazin-2-ylthio)-3-fluoropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0162] (129)2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-5-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0163] (130)2-(1-(5-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-6-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0164] (131)2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-ylthio)-3-fluoropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0165] (132)(R)-2-(1-(4-(3-amino-5-(4-amino-8-azabispiro[2.1.5.2]dodecane-8-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0166] (133)(S)-2-(1-(4-(3-amino-5-(1-amino-2,2-difluoro-8-azaspiro[4.5]decane-8-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0167] (134)(S)-2-(1-(4-(3-amino-5-(4-amino-8-aza-12-oxabispiro[2.1.5.2]dodecane-8-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0168] (135)(1-(4-(3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)-3-(fluoromethyl)azacyclobutane-3-yl)methanol;

[0169] (136)(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-(fluoromethyl)-3-(hydroxymethyl)azacyclobutane-1-yl)pyridin-4-ylthio)-5-methylpyrazine-2-yl)methanol;

[0170] (137)2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)pyrimidin-2-yl)azacyclobutane-3-yl)prop-2-ol;

[0171] (138)(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)-3-fluoroazacyclobutane-3-yl)methanol;

[0172] (139)2-(1-(4-(5-(4-amino-8-azabispiro[2.1.5.2]dodecane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol; and

[0173] (140)(S)-2-(1-(4-(5-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidin]-1′-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol.

[0174] Thirdly, the present invention provides a pharmaceutical composition comprising at least one compound having a structure of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, IVc, IVd, Va, Vb, or Vc, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers and / or one or more additional pharmaceutically active ingredients.

[0175] Fourthly, the present invention provides a medicine comprising:

[0176] a) Container;

[0177] b) at least one compound having the structure of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, IVc, IVd, Va, Vb, or Vc, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite, or prodrug or pharmaceutical composition thereof, located in the container; and

[0178] c) Optional packaging and / or instructions.

[0179] Fifthly, the present invention provides compounds having the structure of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, IVc, IVd, Va, Vb, or Vc, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope-labeled substances, metabolites, or prodrugs thereof, or pharmaceutical compositions thereof, or pharmaceutical products thereof, used as SHP2 inhibitors for the prevention and / or treatment of diseases or conditions (especially cancer) at least partially mediated by SHP2.

[0180] In a sixth aspect, the present invention provides the use of a compound having the structure of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, IVc, IVd, Va, Vb or Vc, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug, or the pharmaceutical composition thereof, or the pharmaceutical product thereof, as an SHP2 inhibitor.

[0181] In a seventh aspect, the present invention provides the use of compounds having the structure of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, IVc, IVd, Va, Vb or Vc, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope labels, metabolites or prodrugs thereof, or said pharmaceutical compositions, or said pharmaceutical products, in the preparation of a medicament for the prevention and / or treatment of diseases or conditions (especially cancer) at least partially mediated by SHP2.

[0182] Eighthly, the present invention provides a method for preventing and / or treating at least partially SHP2-mediated diseases or conditions (especially cancer), comprising the steps of: administering a preventive and / or therapeutically effective amount of a compound having the structure of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, IVc, IVd, Va, Vb, or Vc, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite, or prodrug, or the pharmaceutical composition thereof, or the pharmaceutical product thereof, to an individual in need thereof.

[0183] In a ninth aspect, the present invention provides a combined method for preventing and / or treating diseases or conditions (especially cancer) at least partially mediated by SHP2, comprising:

[0184] a) The methods described for the prevention and / or treatment of diseases or conditions (especially cancer) at least partially mediated by SHP2; and

[0185] b) Additional methods.

[0186] Effects of the invention

[0187] This invention provides a novel substituted pyrazine compound that can act as a highly active SHP2 inhibitor and achieve at least one of the following technical effects:

[0188] (1) High inhibitory activity against SHP2;

[0189] (2) Excellent pharmacokinetic properties (such as good bioavailability, appropriate half-life and duration of action);

[0190] (3) Excellent safety (lower toxicity and side effects, wider therapeutic window). Attached Figure Description

[0191] Figure 1 The in vivo efficacy comparison of the positive compound and the compound of Example 12 in the KYSE-520 cell xenograft model is shown.

[0192] Figure 2 The in vivo efficacy comparison of the positive compound and the compound of Example 12 in the NCI-H358 cell xenograft model is shown. Detailed Implementation

[0193] General terms and definitions

[0194] Unless otherwise defined, the terms used herein have the same meaning as commonly understood by those skilled in the art. The technical intent used herein refers to technology commonly understood in the art, including variations or equivalent substitutions that are obvious to those skilled in the art. While the following terms are readily understood by those skilled in the art, they are set forth below to better explain the invention.

[0195] The terms “comprising,” “including,” “having,” or “involving,” and their other variations herein, refer to inclusive or open-ended collection concepts and do not exclude other unlisted elements or method steps. Those skilled in the art will understand that the foregoing terms such as “comprising” encompass the meaning of “consisting of.”

[0196] The term "one or more species" or similar expression "at least one species" refers to, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more species.

[0197] When the lower and upper limits of a numerical range are disclosed, any value or subrange falling within that range is specifically disclosed. In particular, each numerical range of parameters disclosed herein (e.g., in the form of "about a to b", or equivalently "approximately a to b", or equivalently "about ab") should be understood to encompass every value and subrange therein. For example, "C..." 1-6 "This should be understood as encompassing any subrange and every 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, "3-10 yuan" should be understood as encompassing any sub-range and each point value, 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., as well as 3, 4, 5, 6, 7, 8, 9, 10 yuan, etc.

[0198] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention that is substantially non-toxic to organisms. Pharmaceutically acceptable salts generally include (but are not limited to) salts formed by the reaction of the compounds of the present invention with pharmaceutically acceptable inorganic / organic acids / acidic amino acids or inorganic / organic / basic amino acids; such salts are also known as acid addition salts or base addition salts. Suitable examples of acid addition salts include (but are not limited to) acetates. For a review of suitable salts, see, for example, Jusiak, Soczewinski, et al., Remington's Pharmaceutical Sciences [M], Mack Publishing Company, 2005 and Stahl, Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use [M], Wiley-VCH, 2002. Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0199] The term "pharmaceutically acceptable ester" refers to an ester that is substantially non-toxic to organisms and hydrolyzes in vivo to form the compound of the present invention or its salt. Pharmaceutically acceptable esters generally include (but are not limited to) esters formed from the compounds of the present invention and pharmaceutically acceptable carboxylic acids or sulfonic acids; such esters are also known as carboxylic acid esters or sulfonate esters. Additionally, the compounds of the present invention may themselves be esters.

[0200] The term "isomer" refers to compounds that have the same molecular weight due to having the same number and type of atoms, but different spatial arrangements or configurations of atoms.

[0201] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that, due to having at least one chiral element (including a chiral center, chiral axis, chiral plane, etc.), has a perpendicular asymmetric plane, thereby enabling the rotation of plane-polarized light. Since the compounds of this invention contain asymmetric centers and other chemical structures that may lead to stereoisomerism, this invention also includes these stereoisomers and mixtures thereof. Because the compounds of this invention (or pharmaceutically acceptable salts thereof) comprise asymmetric carbon atoms, they can exist as single stereoisomers, racemates, or mixtures of enantiomers and diastereomers. Typically, these compounds can be prepared in racemic form. However, if desired, such compounds can be prepared or isolated to obtain pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched with single stereoisomers (purity ≥99%, ≥98%, ≥97%, ≥96%, ≥95%, ≥90%, ≥85%, ≥80%, ≥75%, ≥70%, ≥65%, or ≥60%). As described below, the single stereoisomers of the compounds are prepared from optically active starting materials containing the desired chiral center, or by preparing a mixture of enantiomeric products followed by separation or resolution, for example, by converting to a mixture of diastereomers followed by separation or recrystallization, chromatographic treatment, using chiral resolving reagents, or by direct separation of the enantiomers on a chiral chromatographic column. Starting compounds with specific stereochemistry are commercially available or can be prepared according to the methods described below and then resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that are mirror images of each other. The term "diastereomer" or "diastereomer" refers to optical isomers that are not mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (i.e., an equimolar mixture of two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal parts of a single enantiomer. Unless otherwise stated, all stereoisomers of the compounds of this invention are within the scope of this invention.

[0202] Solid lines are used in this article. solid wedge Or virtual wedge The covalent chemical bonds of the compounds of the present invention are depicted. When solid lines are used to depict bonds to chiral atoms, it indicates that all possible stereoisomers at that chiral atom are included (e.g., specific enantiomers, racemic mixtures, etc.). When solid or dashed wedges are used to depict bonds to chiral atoms, it indicates the presence of the shown stereoisomers. Unless otherwise specified, the stereoisomers of the compounds of the present invention may encompass specific enantiomers, diastereomers, racemic mixtures, or mixtures thereof in any proportion.

[0203] The term "tautomer" (or "tautomer form") 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 for the tautomer. For example, proton tautomers (or proton transfer tautomers) include (but are not limited to) interconversions via proton transfer, such as keto-enol isomerization, imine-enamine isomerization, amide-imine alcohol isomerization, nitroso-oxime isomerization, etc. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0204] The term "polymorph" (or "polymorphic form") refers to the solid crystalline form of a compound or complex. Those skilled in the art can obtain polymorphs of molecules using many known methods. These methods include (but are not limited to) melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation. Furthermore, well-known techniques can be used to detect, classify, and identify polymorphs, including (but not limited to) differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), single-crystal X-ray diffraction (SCXRD), solid-state nuclear magnetic resonance (NMR), infrared spectroscopy (IR), Raman spectroscopy, and scanning electron microscopy (SEM). This invention covers all possible crystalline forms or polymorphs of the compounds of this invention, which can be a single polymorph or a mixture of multiple polymorphs in any proportion.

[0205] The term "solvent" refers to a substance formed by the combination of a compound of the present invention (or a pharmaceutically acceptable salt thereof) with at least one solvent molecule through non-covalent intermolecular forces. The compounds of the present invention may exist as solvates, containing a polar solvent as an element of the crystal structure. The amount of polar solvent may be stoichiometric or non-stoichiometric.

[0206] The term "isotope-labeled compound" refers to a derivative compound formed by replacing specific atoms in the compounds of this invention with their isotopic atoms. Unless otherwise indicated, the compounds of this invention include various isotopes of H, C, N, O, F, P, S, and Cl, such as... 2 H(D), 3 H(T), 13 C 14 C 13 N、 15 N、 17 O、 18 O、 18 F, 31 P, 32 P, 34 S,35 S, 36 S, 37 Cl and 125 I. For example, 12 C can be 13 C or 14 C substitution; 1 H can be 2 H(D, deuterium) or 3 H(T, tritium) substitution; 16 O can be 18 O substitution, etc.

[0207] The term "metabolite" refers to a derivative compound formed after the compounds of the present invention are metabolized, for example, by reactions such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, or enzymatic hydrolysis. Further information on metabolism can be found in Goodman and Gilman's: The Pharmacological Basis of Therapeutics [M], McGraw-Hill International Editions, 1996. This invention covers all possible metabolite forms of the compounds of the present invention, i.e., substances formed in the body of an individual who has taken the compounds of the present invention. Metabolites of the compounds can be identified by techniques known in the art, and their activity can be characterized experimentally.

[0208] The term "prodrug" refers to a derived compound that, upon administration to an individual, can directly or indirectly provide the compounds of the present invention. Particularly preferred derived compounds or prodrugs are those that, upon administration to an individual, can improve the bioavailability of the compounds of the present invention (e.g., greater absorption into the bloodstream) or promote the delivery of the parent compound to its site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are known in the art, see, for example, T. Higuchi, V. Stella, Pro-drugs as Novel Drug Delivery Systems [J], American Chemical Society, Vol. 14, 1975. Furthermore, the present invention also covers compounds of the present invention containing a protecting group. In any process of preparing the compounds of the present 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 present invention. This can be achieved by conventional protecting groups, such as those described in TW Greene, PGM Wuts, Protective Groups in Organic Synthesis [M], John Wiley & Sons, 2006. These protective bases can be removed at appropriate subsequent stages using methods known in the art.

[0209] The term "chemical bond" refers to the strong force that binds two or more adjacent atoms (or ions) together within a pure molecule or crystal, mainly including covalent bonds, ionic bonds, metallic bonds, and coordinate bonds. Unless otherwise stated, the chemical bonds in the compounds of this invention existing in free form are mostly covalent bonds.

[0210] When used alone or in combination with other groups in this document, the term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group. For example, the term "C" as used herein... 1-6 "Alkyl" refers to an alkyl group (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, etc.) having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms), optionally substituted by one or more (e.g., 1 to 3) substituents described herein (e.g., when substituted by a halogen, the group is "C"). 1-6 "Halogenated alkyl groups", such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, -CH2CH2CF3, etc.; if substituted with a hydroxyl group, this group is "C". 1-6 Hydroxyalkyl groups, such as -CH2OH, -CH2CH2OH, -CH(OH)CH3, etc.

[0211] When used alone or in combination with other groups in this document, the term "alkylene" refers to a straight-chain or branched divalent saturated aliphatic hydrocarbon group to which the two groups (or segments) are attached can be attached to the same carbon atom or different carbon atoms. For example, the term "C" as used herein... 1-6 "Alkylene" refers to an alkylene group having 1-6 carbon atoms (such as methylene, 1,1-ethylene, 1,2-ethylene, 1,2-propylene, 1,3-butylene, etc.), which is optionally substituted by one or more (e.g., 1-3) substituents described herein (where the substituent is "C" when halogenated). 1-6 "Halogenide groups", such as -CF2-, -C2F4-, -CHF-, etc.

[0212] When used alone or in combination with other groups herein, the term "cycloalkyl" refers to a monocyclic or polycyclic (e.g., bicyclic) alkyl group (e.g., monocyclic cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.; or bicyclic cycloalkyl, including fused rings, bridged rings, or spirocyclic rings, such as decahydronaphthyl, bicyclic [2.2.1]heptyl, spiro [4.5]decyl, etc.). For example, the term "C" as used herein... 3-6 "Cycloalkyl" refers to a cycloalkyl group having 3-6 cyclic carbon atoms, which is optionally substituted by one or more (e.g., 1-3) substituents described herein (e.g., when substituted by a halogen, the group is "C"). 1-6 "Halocycloalkyl", such as 2-fluorocyclopropyl, 3-chlorocyclobutyl, 4-bromocyclohexyl, etc.; if substituted with a hydroxyl group, this group is "C". 1-6 "Hydroxycycloalkyl", such as 2-hydroxycyclopropyl, 3-hydroxycyclobutyl, 4-hydroxycyclohexyl, etc.

[0213] When used alone or in combination with other groups in this document, the term "cycloalkylene" refers to a monocyclic or polycyclic (e.g., bicyclic) divalent alkyl group to which the two groups (or segments) are attached can be attached to the same cyclic carbon atom or different cyclic carbon atoms. For example, the term "C" as used herein... 3-6 "Cycloalkylene" refers to a cycloalkylene group having 3-6 cyclic carbon atoms, which is optionally substituted by one or more (e.g., 1-3) substituents described herein (e.g., ...). ).

[0214] When used alone or in combination with other groups herein, the term "heterocyclic alkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (e.g., bicyclic) group having one or more carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) and one or more (e.g., 1, 2, 3, or 4) heteroatoms, each independently selected from N, O, P, and S, for example, having a total of 3-15 (preferably 3-8, more preferably 3-6) ring atoms. The term also covers cases where the C, N, and / or P atoms in the ring can be substituted with oxo groups (=O) and / or the S atom in the ring can be substituted with one or two oxo groups (=O). The ring system in a heterocyclic alkyl group can be a fused ring, a bridged ring, or a spiro ring system. If the valence requirements are met, a heterocyclic alkyl group can be linked to other groups (or segments) through any one carbon atom or heteroatom in the ring. For example, the term “3-6 membered heterocyclic alkyl” as used herein refers to a heterocyclic alkyl group having 3-6 ring atoms (including one or more heteroatoms) which is optionally substituted by one or more (e.g., 1 to 3) substituents described herein (such as ethylene oxide, cyclothioethylene, cycloazaethylene, azacyclic butyl, oxacyclic butyl, thiocyclic butyl, tetrahydrofuranyl, dioxacyclic pentyl, tetrahydrothiophenyl, pyrrolyl, pyrrolidone, imidazolyl). The group can be substituted with alkyl, pyrazolyl, tetrahydropyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,4-thiaoxyl, 1,4-dioxane, 1,4-dithiaalkyl, piperazine, trioxane, trithiaalkyl, thiazine, etc.; when substituted with halogens, the group is a "3-6-membered halocyclic heterocyclic alkyl", such as 3-fluoropyrrolidine-1-yl, etc.; when substituted with hydroxyl groups, the group is a "3-6-membered hydroxycyclic heterocyclic alkyl", such as 4-hydroxytetrahydrofuran-2-yl, etc.).

[0215] When used alone or in combination with other groups herein, the term "heterocyclic alkylene" refers to a monocyclic or polycyclic (e.g., bicyclic) divalent group having one or more carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) and one or more (e.g., 2, 3, or 4) heteroatoms, each independently selected from N, O, P, and S, to which the two groups (or segments) are attached may be attached to the same cyclic carbon atom or separately to a cyclic carbon atom and a cyclic heteroatom (e.g., N or P atom). For example, the term "3-10-membered heterocyclic alkylene" as used herein refers to a heterocyclic alkylene having 3-10 ring atoms (including one or more heteroatoms) optionally substituted by one or more (e.g., 1-3) substituents described herein (e.g., ...). ).

[0216] When used alone or in combination with other groups herein, the term "heterocyclic alkenyl" refers to a monocyclic or polycyclic (e.g., bicyclic) group having one or more carbon-carbon double bonds, wherein the ring has one or more carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) and one or more (e.g., 1, 2, 3, or 4) heteroatoms, each independently selected from N, O, P, and S, for example, having a total of 3-15 (preferably 3-8, more preferably 3-6) ring atoms. The term also covers cases where the C, N, and / or P atoms in the ring can be substituted with oxo groups (=O) and / or the S atom in the ring can be substituted with one or two oxo groups (=O). The ring system in a heterocyclic alkenyl can be a fused ring, a bridged ring, or a spiro ring system. If the valence requirements are met, the heterocyclic alkenyl can be linked to other groups (or segments) through any one carbon atom or heteroatom in the ring. For example, the term “3-6 membered heterocyclic alkenyl” as used herein refers to a heterocyclic alkyl group having 3-6 ring atoms (including one or more heteroatoms) which is optionally substituted by one or more (e.g., 1 to 3) substituents described herein.

[0217] When used alone or in combination with other groups herein, the term "heterocyclic alkenyl" refers to a monocyclic or polycyclic (e.g., bicyclic) divalent group having one or more carbon-carbon double bonds, wherein the ring has one or more carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) and one or more (e.g., 1, 2, 3, or 4) heteroatoms, each independently selected from N, O, P, and S, for example, having a total of 3-15 (preferably 3-8, more preferably 3-6) ring atoms. The term also covers cases where the C, N, and / or P atoms in the ring can be substituted with oxo groups (=O) and / or the S atom in the ring can be substituted with one or two oxo groups (=O).

[0218] When used alone or in combination with other groups in this document, the term "aryl" refers to a monocyclic or fused-ring aromatic hydrocarbon group having a conjugated π-electron system. For example, the term "C" as used herein... 6-12 "Aryl" refers to an aryl group having 6-12 carbon atoms (such as phenyl, naphthyl, etc.), which is optionally substituted by one or more substituents described herein (such as C... 1-6 Alkyl-substituted tolyl groups, halogen-substituted chlorophenyl groups, etc.

[0219] When used alone or in combination with other groups in this document, the term "arylene" refers to a monocyclic or fused-ring divalent aromatic hydrocarbon group having a conjugated π-electron system. For example, the term "C" as used herein... 6-10 "Arylene" refers to an arylene group having 6-10 carbon atoms, which is optionally substituted with one or more substituents described herein (e.g., C10, C20, C30, C40, C50, C60, C7 ... 1-6Alkyl-substituted tolyne, halogen-substituted chlorophenyl, etc.

[0220] When used alone or in combination with other groups herein, the term "heteroaryl" refers to an aromatic group having a monocyclic or fused ring with a conjugated π-electron system, having one or more carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms) and one or more (e.g., 1, 2, 3, or 4) heteroatoms each independently selected from N, O, P, and S, for example, having a total of 5-12 (preferably 5-10, more preferably 5, 6, 9, or 10) ring atoms. If valence requirements are met, the heterocyclic alkyl group can be attached to the parent molecule moiety via any one ring atom. If valence requirements are met, the heteroaryl group can be attached to other groups (or segments) via any one carbon atom or heteroatom (e.g., N atom) in the ring. Furthermore, the heteroaryl group may optionally be further fused with benzene. For example, the term "5-12-membered heteroaryl" as used herein refers to a heteroaryl group having 5-12 ring atoms (such as furanyl, thiophene, pyrrole, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, benzofuranyl, isobenzofuranyl, benzothiophene, isobenzothiophene, indole, isoindoleyl or its benzo derivatives, etc.), which is optionally substituted by one or more substituents described herein (e.g., by C...). 1-6 Alkyl-substituted methylpyridinyl, halogen-substituted chloropyridinyl, etc.

[0221] When used alone or in combination with other groups herein, the term "heteroaryl" refers to a monocyclic or fused-ring divalent aromatic group having a conjugated π-electron system, having one or more carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms) and one or more (e.g., 1, 2, 3, or 4) heteroatoms, each independently selected from N, O, P, and S, for example, having a total of 5-12 (preferably 5-10, more preferably 5, 6, 9, or 10) ring atoms. For example, the term "5-12-membered heteroaryl" as used herein refers to a heteroaryl having 5-12 ring atoms, optionally substituted by one or more substituents described herein (e.g., substituted by C... 1-6 Alkyl-substituted Replaced by halogen wait).

[0222] When used alone or in combination with other groups herein, the term "alkenyl" refers to a straight-chain or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds. For example, the term "C" as used herein... 2-6"Alkenyl" refers to an alkenyl group (such as vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, etc.) having 2-6 carbon atoms and one, two, or three (preferably one) carbon-carbon double bonds, which is optionally substituted by one or more (e.g., 1-3) substituents described herein.

[0223] When used alone or in combination with other groups in this document, the term "alkenyl" refers to a straight-chain or branched divalent aliphatic hydrocarbon group having one or more carbon-carbon double bonds, to which the two groups (or segments) may be attached, either to the same carbon atom or to different carbon atoms. For example, the term "C" as used herein... 2-6 "Alkenyl" refers to alkenyl groups having 2-6 carbon atoms (e.g., alkenyl groups). (etc.), which may be optionally substituted by one or more (e.g., 1-3) substituents described herein.

[0224] When used alone or in combination with other groups herein, the term "cycloalkenyl" refers to an alkenyl group (e.g., monocyclic cycloalkenyl, such as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, etc.) having one or more carbon-carbon double bonds. For example, the term "C" as used herein... 3-6 "Cycloalkenyl" refers to a cycloalkenyl group having 3-6 cyclic carbon atoms, which is optionally substituted by one or more (e.g., 1-3) substituents described herein (e.g., ...). ).

[0225] When used alone or in combination with other groups herein, the term "cycloene-alkenyl" refers to a divalent alkenyl group of a monocyclic or polycyclic (e.g., bicyclic) ring having one or more carbon-carbon double bonds, to which the two groups (or segments) are attached may be attached to the same cyclic carbon atom or to different cyclic carbon atoms. For example, the term "C" as used herein... 3-6 "Isocyclic alkenyl" refers to an isocyclic alkenyl group having 3-6 cyclic carbon atoms, which is optionally substituted by one or more (e.g., 1-3) substituents described herein (e.g., ...). ).

[0226] When used alone or in combination with other groups herein, the term "alkynyl" refers to a straight-chain or branched aliphatic hydrocarbon group having one or more carbon-carbon triple bonds. For example, the term "C" as used herein... 2-6"Alynyl" refers to an alkynyl group having 2-6 carbon atoms and one, two, or three (preferably one) carbon-carbon triple bonds (such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.), which is optionally substituted by one or more (e.g., 1-3) substituents described herein.

[0227] When used alone or in combination with other groups in this document, the term "acetylenic" refers to a straight-chain or branched divalent aliphatic hydrocarbon group having one or more carbon-carbon triple bonds, wherein the two groups (or segments) to which it is attached are respectively attached to different carbon atoms. For example, the term "C" as used herein... 2-6 "Imyynyl" refers to an ynyl group having 2-6 carbon atoms (e.g., (etc.), which may be optionally substituted by one or more (e.g., 1-3) substituents described herein.

[0228] When used alone or in combination with other groups in this document, the term "alicyclic" or "aliphatic ring" refers to aliphatic hydrocarbon ring systems that are monocyclic or polycyclic (including fused rings, bridged rings, and spirocyclic rings, such as bicyclic rings), including cycloalkanes, cycloalkenes, and cycloalkynes.

[0229] When used alone or in combination with other groups in this document, the term "heterocyclic ring" or "heterocyclic hydrocarbon ring" refers to a monocyclic or polycyclic aliphatic hydrocarbon ring system (including fused rings, bridged rings, and spirocyclic rings, such as bicyclic rings) having one or more carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) and one or more heteroatoms (e.g., 1, 2, 3, or 4) each independently selected from N, O, P, and S, including heterocyclic alkanes, heterocyclic alkenes, and heterocyclic alkynes.

[0230] When used alone or in combination with other groups in this document, the term "aromatic ring" or "aromatic hydrocarbon ring" refers to a monocyclic or polycyclic (e.g., bicyclic) aromatic hydrocarbon ring system.

[0231] When used alone or in combination with other groups in this document, the term “heteroaromatic ring” or “heteroaromatic ring” refers to a monocyclic or polycyclic (e.g., bicyclic) aromatic hydrocarbon ring system having one or more carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8 or 9) and one or more (e.g., 1, 2, 3 or 4) heteroatoms each independently selected from N, O, P and S.

[0232] When used alone or in combination with other groups in this document, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0233] When used alone or in combination with other groups in this document, the term "hydroxyl" refers to -OH.

[0234] When used alone or in combination with other groups in this document, the term "cyano" refers to -CN.

[0235] When used alone or in combination with other groups in this document, the term "nitro" refers to -NO2.

[0236] When used alone or in combination with other groups in this document, the term "amino" refers to -NH2.

[0237] When used alone or in combination with other groups in this document, the term "oxo" refers to =O.

[0238] As used herein, the term "independently" means that at least two groups (or segments) in a structure with the same or similar value ranges can have the same or different meanings under specific circumstances. For example, if substituent X and substituent Y are independently hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl, then when substituent X is hydrogen, substituent Y can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl; similarly, when substituent Y is hydrogen, substituent X can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl.

[0239] The term "substitution" and its other variant forms herein refer to the replacement of one or more (e.g., 1, 2, 3, or 4) atoms or groups of atoms (e.g., hydrogen atoms) on a specified atom with other equivalents, provided that the replacement does not exceed the normal valence of the specified atom or group of atoms in the present case and results in the formation of a stable compound. If an atom or group of atoms is described as "optionally substituted," it may or may not be substituted. Unless otherwise stated, the linking sites of substituents herein may be derived from any suitable position of the substituent. When the linking bond in a substituent is shown as a chemical bond passing through two atoms connected to each other in the ring system, it indicates that the substituent may be linked to any one of the cyclic atoms in the ring system.

[0240] General formula compounds

[0241] This invention provides a compound of formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite, or prodrug thereof, wherein...

[0242]

[0243] X is selected from chemical bonds, S, O, NH and CH2;

[0244] R 1 Selected from hydrogen, hydroxyl, halogen, amino, C 1-6 Alkyl, 3-6 membered heterocyclic alkyl and C 3-6Cycloalkyl, wherein the alkyl group, heterocycloalkyl group and cycloalkyl group are each optionally substituted by one or more substituents selected from halogens, hydroxyl groups and amino groups;

[0245] R 2 Selected from hydrogen, hydroxyl, amino, cyano, halogen, C 1-6 Alkyl, 3-6 membered heterocyclic alkyl and C 3-6 Cycloalkyl, wherein the alkyl group, heterocycloalkyl group and cycloalkyl group are each optionally substituted by one or more substituents selected from halogen, oxo, hydroxy and amino groups;

[0246] A is selected from C 6-12 arylene, 5-12-membered heteroarylene, 3-12-membered heterocycloalkyl and C 3-8 Cycloalkylene, wherein the arylene, heteroarylene, heterocycloalkylene, and cycloalkylene are each optionally represented by one or more R a replace;

[0247] If it exists, each R a Each is independently selected from hydrogen, halogen, hydroxyl, -O-(C 1-6 alkyl), -O-(C 3-6 cycloalkyl), cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 Alkenyl, -S (=O) g -(C 1-6 Alkyl group), -S (=O) g NH2, amino group, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl) 2, 3-12 membered heterocyclic alkyl, C 6-10 aryl and 5-12-membered heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, heterocycloalkyl, aryl and heteroaryl groups are each optionally composed of one or more groups selected from amino, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group, halogen, cyano group, oxo group, hydroxyl group, -O-(C 1-6 Alkyl group), -S (=O) g -(C 1-6 alkyl) and C 1-6 Alkyl substituents;

[0248] Alternatively, when X is NH or CH2, any R a Together with X and the atoms attached thereto, they form a 5-10 membered alicyclic ring, a 5-10 membered heterocyclic ring, a 5-6 membered heteroaromatic ring, or a benzene ring, wherein each of the alicyclic ring, heterocyclic ring, heteroaromatic ring, and benzene ring is optionally composed of one or more atoms selected from amino, -NH(C) 1-6 alkyl), -N(C) 1-6Alkyl group, halogen, cyano group, oxo group, hydroxyl group, -O-(C 1-6 Alkyl), C 1-6 Halogenated alkyl groups and C 1-6 Alkyl substituents;

[0249] B is selected from -N(R) b )-C(=O)-GR d -N(R) b )-S(=O) g -GR d -N(R) b )-C(=O)-N(R b )-GR d -N(R) b )-S(=O) g -N(R b )-GR d -C(=O)-N(R) b )-GR d -S (=O) g -N(R b )-GR d -S (=O) g -GR d -OG-(3-10 membered heterocyclic alkyl), -OG-(C 3-6 cycloalkyl), -O-(C 3-6 -O-(3-10 membered heterocyclic alkylene)-GH, -OGR d -N(R) b -G-(3-10 membered heterocyclic alkyl), -N(R) b )-G-(C 3-6 cycloalkyl), -N(R) b )-(C 3-6 Cycloalkylene)-GH, -N(R) b )-(3-10-membered heterocyclic alkylene)-GH, -GOC(=O)-R b -GN(R) b )-C(=O)-R b -GN(R) b )-C(=O)-OR b and The heterocyclic alkyl, heterocyclic alkylene, cycloalkyl, and cycloalkylene groups are each optionally composed of one or more elements selected from hydrogen, halogen, hydroxyl, amino, and -NH(C). 1-6 alkyl), -N(C) 1-6 Alkyl group, oxo group, -O-(C 1-6 Alkyl), C 1-6 Halogenated alkyl groups and C1-6 The alkyl group is substituted, and B is not -O-(C 1-2 (halogenated alkyl);

[0250] G is selected from C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-6 Cycloalkylene, C 3-6 Cycloalkenyl, 3-10-membered heterocyclic alkenyl, and 3-10-membered heterocyclic alkyl, wherein the alkylene, cycloalkylene, cycloalkenyl, heterocyclic alkenyl, and heterocyclic alkyl are each optionally composed of one or more elements selected from hydrogen, halogen, oxo, hydroxyl, cyano, amino, -OR b -NHR b -N(R) b )2、-N(R b )-C(=O)-R b , -C(=O)-NH2, -C(=O)-N(R b 2. C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Substituents of hydroxycycloalkyl, 3-10-membered halocycloalkyl, 3-10-membered hydroxycycloalkyl and 3-10-membered heterocycloalkyl;

[0251] R b Selected from hydrogen, halogen, amino, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 3-10-membered heterocyclic alkenyl and 3-10-membered heterocyclic alkyl, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocyclic alkenyl and heterocyclic alkyl are each optionally substituted by one or more substituents selected from hydrogen, halogen, oxo, hydroxyl, cyano and amino.

[0252] C is selected from C 6-12 arylene, 5-12-membered heteroarylene, 3-12-membered heterocycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocyclic cycloalkenyl and C 3-8 Cycloalkylene, wherein the arylene, heteroarylene, heterocyclic alkylene, cycloalkylene, heterocyclic alkenylene, and cycloalkylene are each optionally represented by one or more R c replace;

[0253] If it exists, each R c Each is independently selected from hydrogen, halogen, hydroxyl, -O-(C 1-6 alkyl), -O-(C 3-6cycloalkyl), cyano, C 1-6 Alkyl, C 2-6 Alkenyl, -S (=O) g -(C 1-6 Alkyl group), -S (=O) g NH2, amino group, -NH(C) 1-6 alkyl) and -N(C) 1-6 Alkyl)2, wherein the alkyl and alkenyl groups are each optionally composed of one or more groups selected from amino, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group, halogen, cyano group, oxo group, hydroxyl group, -O-(C 1-6 Alkyl group), -S (=O) g -(C 1-6 alkyl) and C 1-6 Alkyl substituents;

[0254] Y is selected from C 1-6 Alkylene, C 3-6 Cycloalkylene, 3-6 membered heterocycloalkylene, C 3-6 Cycloalkylene, 3-6 membered heteroalkylene, C 6-10 aryl, 5-12 methyl aryl, C 2-6 alkenyl group, -S (=O) g -(C 1-6 Alkylene)-, -S(=O) g -N(R b )-、-C(=O)-(C 1-6 alkylene)-, -C(=O)-(C 3-6 -C(=O)-(3-6 membered heterocyclic alkyl)- and -C(=O)-, wherein the alkylene, heterocyclic alkyl, cycloalkylene, heterocyclic alkenyl and cycloalkylene are each optionally substituted by one or more substituents selected from halogens, oxo groups, hydroxyl groups and amino groups;

[0255] R d Selected from halogens, amino groups, hydroxyl groups, cyano groups, and -S (=O). g -(C 1-6 alkyl), -O-(C 1-6 alkyl), -O-(C 3-6 cycloalkyl), -NH-(C 1-6 alkyl), -NH(C) 3-6 cycloalkyl), -N(C) 1-6 Alkyl)2、-NH-C(=O)-O-(C 1-6 alkyl), -N(C) 1-6 alkyl)-C(=O)-O-(C 1-6Alkyl groups, -OC(=O)-NH2, -OC(=O)-NH(C 1-6 alkyl) and -N(C) 1-6 alkyl)-C(=O)-(C 1-6 Alkyl groups), wherein the alkyl and cycloalkyl groups are each optionally composed of one or more radicals selected from halogens, oxo groups, hydroxyl groups, amino groups, and -O-(C-yl groups). 1-6 Substitution of alkyl groups;

[0256] R 3 Selected from halogens, -OR z hydroxyl, cyano, -C(=O)-OR z -C(=O)-N(R) z 2. C 1-6 Alkyl, -(C 1-6 (alkylene)-R z -(C 1-6 (alkylene)-OR z -(C 1-6 alkylene)-OH, -(C 1-6 alkylene)-N(R z 2. C 3-6 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-6 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-12 Aryl, 5-12 heteroaryl, -S (=O) g -(C 1-6 alkyl), amino and -N(R) z )2, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, alkenyl, alkynyl, aryl, and heteroaryl groups are each optionally selected from one or more halogens, cyano, oxo, -OR z hydroxyl group, -N(R) z )2、-NHR z amino, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, -C(=O)-OR z -C(=O)-N(R) z 2. Substitution of -C(=O)-NH2 and nitro groups;

[0257] If it exists, each R z Each is independently selected from hydrogen, cyano, -C(=O)-(C 1-6 Alkyl), -C(=O)-(C 3-8Cycloalkyl), -C(=O)-(3-8 membered heterocycloalkyl), C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-12 membered heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-12 aryl and 5-12 heteroaryl groups, wherein the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl and heteroaryl groups are each optionally composed of one or more groups selected from amino, halogen, cyano, oxo, nitro, hydroxyl, -O-(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups;

[0258] R 4 Selected from halogens, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C(=O)-R z 3-12 membered heterocyclic alkyl groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 aryl and 5-12 heteroaryl groups, wherein the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl and heteroaryl groups are each optionally composed of one or more groups selected from amino, halogen, cyano, hydroxyl, oxo, -O-(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups;

[0259] Or, R 3 and R 4 Together with the atoms attached thereto, they form a 4-8 membered alicyclic ring or a 4-8 membered heterocyclic ring, wherein the alicyclic ring and heterocyclic ring are each optionally bounded by one or more R 4a Replacement, or the alicyclic and heterocyclic rings are each optionally replaced with one or more C 6-10 Aromatic rings or 5-12-membered heterocyclic aromatic rings fused together, wherein the aromatic rings and heterocyclic aromatic rings are each optionally bound by one or more R 4a replace;

[0260] If it exists, each R 4a Each is independently selected from hydrogen, halogen, cyano, -C(=O)H, -C(=O)-(C 1-6 Alkyl), -C(=O)-(C 3-8Cycloalkyl), -C(=O)-(3-8 membered heterocycloalkyl), -NH-C(=O)-(C 1-6 Alkyl), -NH-C(=O)-(C 3-8 Cycloalkyl), -NH-C(=O)- (3-8 membered heterocycloalkyl), oxo-group, C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-12 aryl and 5-12 heteroaryl groups, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocyclic alkenyl, heterocyclic alkyl, alkenyl, alkynyl, aryl, and heteroaryl groups are each optionally selected from one or more halogens, cyano, hydroxyl, -O-(C 1-6 Alkyl), C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Substitution of aryl and 5-10 heteroaryl groups;

[0261] If it exists, each R 5 Each is independently selected from hydrogen, halogen, oxo group, cyano group, hydroxyl group, carboxyl group, -C(=O)-NH2, -C(=O)-O-(C 1-6 Alkyl), C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 Alkyne group, -S (=O) g -(C 1-6 Alkyl), 3-6 membered heterocyclic alkyl, C 6-10 aryl and 5-10 heteroaryl groups, wherein the alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl and heteroaryl groups are each optionally composed of one or more groups selected from amino, hydroxyl, oxo, halogen, cyano, -O-(C 1-6 alkyl), -NH(C) 1-6 alkyl) and -N(C) 1-6 Substitution of alkyl group 2; or any two R groups 5 Together with the atoms bonded to it, they form C 3-10 Alicyclic rings or 4-12 membered heterocyclic rings;

[0262] g is 0, 1, or 2;

[0263] n can be 0, 1, 2, 3, 4, or 5.

[0264] In some embodiments of the present invention, X in the compound of Formula I above is selected from chemical bonds and S; preferably, X is S.

[0265] In some embodiments of the present invention, R in the compound of Formula I described above... 1 Selected from hydrogen, hydroxyl, halogen, amino, C 1-6 Alkyl and C 3-6 cycloalkyl; preferably, R 1 Selected from hydrogen, halogen, amino and C 1-6 Alkyl groups (e.g., hydrogen, halogen, and C) 1-6 Alkyl); more preferably, R 1 Selected from hydrogen, fluorine, amino, and methyl; more preferably, R 1 Selected from hydrogen, fluorine, and methyl.

[0266] In some embodiments of the present invention, R in the compound of Formula I described above... 2 Selected from hydrogen, hydroxyl, halogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein the alkyl group and the cycloalkyl group are each optionally substituted with one or more substituents selected from halogens and hydroxyl groups; preferably, R2 is selected from hydrogen, hydroxyl, fluorine, hydroxymethyl (-CH2OH), and fluoromethyl (-CH2F); more preferably, R 2 Selected from hydrogen, hydroxymethyl, and fluoromethyl; more preferably, R 2 It is a hydroxymethyl group.

[0267] In some embodiments of the present invention, A in the compound of Formula I is selected from C. 6-12 arylene and 5-12-membered heteroarylene, wherein the arylene and heteroarylene are each optionally surrounded by one or more R a Substitution; preferably, A is selected from phenylene, pyridylene, and pyrimidinylene, wherein the phenylene, pyridylene, and pyrimidinylene are each optionally replaced by one or more R a Substitution; more preferably, A is selected from phenylene and pyridylene, wherein the phenylene and pyridylene are each optionally substituted with one or more R a replace.

[0268] In some embodiments of the present invention, multiple Rs exist simultaneously in Formula I. a Each R a Each is independently selected from hydrogen, halogen, hydroxyl, -O-(C 1-3 alkyl), -O-(C 3-6 cycloalkyl), cyano, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, amino, -NH(C 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -S (=O) g -(C 1-3 Alkyl groups and -S (=O) gNH2; preferably, each R a Each is independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, methoxy, cyclopropoxy, cyano, methyl, ethyl, n-propyl, isopropyl, difluoromethoxy, trifluoromethoxy, trifluoromethyl, difluoromethyl, cyclopropyl, pyrrolyl, morpholinyl, amino, methylamino, dimethylamino, methylthio, methanesulfonyl, and aminosulfonyl; more preferably, each R a Each is independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, pyrrolyl, morpholinyl, amino, methylamino, and dimethylamino; more preferably, each R a Each is independently selected from fluorine, chlorine, bromine, cyano, methyl, and amino.

[0269] In some embodiments of the present invention, X in Formula I is NH or CH2 and multiple R are present simultaneously. a Any R a Together with X and the atoms connected thereto, they form a 5-7 membered alicyclic ring or a 5-7 membered heterocyclic ring, preferably a 5-6 membered alicyclic ring or a 5-6 membered heterocyclic ring, wherein each of the alicyclic and heterocyclic rings is optionally formed by one or more atoms selected from amino, fluorine, chlorine, cyano, oxo, hydroxyl, -O-(C 1-3 Alkyl), C 1-3 Halogenated alkyl groups and C 1-3 The alkyl groups are substituted, preferably each of which is optionally substituted by one or more substituents selected from amino, fluorine, chlorine, oxo, hydroxyl, methoxy and methyl groups.

[0270] In some embodiments of the present invention, X in Formula I is NH and multiple R are present simultaneously. a Any R a Together with X and the atoms attached to it, it forms a morpholine ring.

[0271] In some embodiments of the present invention, B in the compound of formula I above is selected from -N(R) b )-C(=O)-GR d -N(R) b )-S(=O)2-GR d -OG-(3-10 membered heterocyclic alkyl), -OG-(C 3-6 cycloalkyl), -O-(C 3-6 -O-(3-10 membered heterocyclic alkylene)-GH, -OGR d -N(R) b -G-(3-10 membered heterocyclic alkyl), -N(R) b )-G-(C 3-6 cycloalkyl), -N(R) b )-(C 3-6Cycloalkylene)-GH, -N(R) b )-(3-10-membered heterocyclic alkylene)-GH, -GOC(=O)-R b -GN(R) b )-C(=O)-R b -GN(R) b )-C(=O)-OR b and The heterocyclic alkyl, heterocyclic alkylene, cycloalkyl, and cycloalkylene groups are each optionally composed of one or more elements selected from hydrogen, halogen, hydroxyl, amino, and -NH(C). 1-6 alkyl), -N(C) 1-6 Alkyl group, oxo group, -O-(C 1-6 Alkyl), C 1-6 Halogenated alkyl groups and C 1-6 The alkyl group is substituted, and B is not -O-(C 1-2 (Halogenated alkyl); preferably, B is selected from -N(R) b )-C(=O)-GR d -OG- (3-10 membered heterocyclic alkyl groups), -OGR d -N(R) b -G-(3-10 membered heterocyclic alkyl), -N(R) b )-G-(C 3-6 cycloalkyl), -N(R) b )-(C 3-6 Cycloalkylene)-GH, -N(R) b )-(3-10-membered heterocyclic alkylene)-GH, -GOC(=O)-R b and The heterocyclic alkyl, heterocyclic alkylene, cycloalkyl, and cycloalkylene groups are each optionally composed of one or more elements selected from hydrogen, halogen, hydroxyl, amino, and -NH(C). 1-6 alkyl), -N(C) 1-6 Alkyl group, oxo group, -O-(C 1-6 Alkyl), C 1-6 Halogenated alkyl groups and C 1-6 The alkyl group is substituted, and B is not -O-(C 1-2 (Halogenated alkyl groups).

[0272] In some embodiments of the present invention, B in the compound of formula I above comprises G, wherein G is selected from C. 1-6 Alkylene, C 3-6 Cycloalkylene and 3-6-membered heterocyclic alkylene, wherein each of the alkylene, cycloalkylene and heterocyclic alkylene is optionally composed of one or more radicals selected from hydrogen, fluorine, oxo, hydroxyl, cyano, -OR b C 1-6Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 The hydroxyalkyl groups are substituted, preferably each optionally substituted with one or more substituents selected from hydrogen and fluorine; preferably, G is C. 1-3 Alkylene, wherein the alkylene is optionally radically formed by one or more radicals selected from hydrogen, fluorine, oxo, hydroxyl, cyano, -OR b C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 The hydroxyalkyl group is substituted, preferably optionally substituted with one or more substituents selected from hydrogen and fluorine.

[0273] In some embodiments of the present invention, B in the compound of formula I above contains R. b R b Selected from hydrogen, fluorine, chlorine, amino, C 1-3 Alkyl, cyclopropyl, and 3-6 membered heterocyclic alkyl groups, wherein each of the alkyl and heterocyclic alkyl groups is optionally substituted by one or more substituents selected from hydrogen, fluorine, oxo, hydroxyl, and cyano.

[0274] In some embodiments of the present invention, B in the compound of formula I above comprises C, wherein C is selected from 3-6 membered heterocyclic alkyl groups and C24. 3-6 Cycloalkylene, wherein the heterocyclic alkylene and the cycloalkylene are each optionally influenced by one or more R c Substitution; preferably, C is selected from pyridinealkyl, azapyridinebutylalkyl, piperidinyl, and piperazineyl, wherein the pyridinealkyl, azapyridinebutylalkyl, piperidinyl, and piperazineyl are each optionally replaced by one or more R c replace.

[0275] In some embodiments of the present invention, multiple Rs are simultaneously present in B of the compound of formula I described above. c Each R c Each is independently selected from hydrogen, fluorine, cyano, methyl, ethyl, fluoromethyl, hydroxymethyl, and hydroxy; preferably, each R c Each is independently selected from hydrogen, fluorine, and hydroxyl.

[0276] In some embodiments of the present invention, B in the compound of formula I above comprises Y, where Y is selected from C. 1-3 Alkylene, C 3-6 Cycloalkylene, 3-6 membered heterocycloalkylene, C 2-6 alkenyl group, -C(=O)-(C 1-3 alkylene)-, -C(=O)-(C 3-6The alkylene group is selected from -C(=O)-(3-6 membered heterocyclic alkylene group)- and -C(=O)-, wherein each of the alkylene group, heterocyclic alkylene group, and alkylene group is optionally substituted with one or more substituents selected from fluorine, hydroxyl, and amino groups; preferably, Y is selected from -CH2-, -CH(CH3)-, -C(CH3)2-, cyclopropylene group, and -C(=O)-CH2-, wherein each of the -CH2-, -CH(CH3)-, -C(CH3)2-, cyclopropylene group, and -C(=O)-CH2- is optionally substituted with one or more substituents selected from fluorine, hydroxyl, and amino groups.

[0277] In some embodiments of the present invention, B in the compound of formula I above contains R. d R d Selected from fluorine, amino, hydroxyl, cyano, -S(=O)2-(C 1-6 alkyl), -O-(C 1-6 Alkyl), -NH-C(=O)-O-(C 1-6 Alkyl groups, -OC(=O)-NH2, -OC(=O)-NH(C 1-6 alkyl) and -N(C) 1-6 alkyl)-C(=O)-(C 1-6 Alkyl group), wherein the alkyl group is optionally radically formed by one or more radicals selected from fluorine, chlorine, oxo, hydroxyl, and -O-(C). 1-6 Alkyl) substituents; preferably, R d The group is selected from fluorine, amino, hydroxyl, cyano, -S(=O)2-CH3, -O-CH3, -NH-C(=O)-O-CH3 and -OC(=O)-NH2, wherein -S(=O)2-CH3, -O-CH3 and -NH-C(=O)-O-CH3 are each optionally replaced by one or more groups selected from fluorine, chlorine, oxo, hydroxyl and -O-(C 1-6 Alkyl groups are substituted.

[0278] In some embodiments of the present invention, B in the compound of Formula I is selected from... -NH-C(=O)-CH2-CN and -N(CH3)-C(=O)-C(CH3)2-OH; preferably, B is selected from... -NH-C(=O)-CH2-CN and -N(CH3)-C(=O)-C(CH3)2-OH.

[0279] In some embodiments of the present invention, R in the compound of Formula I described above... 3 and R 4 Not interconnected, R3 Selected from fluorine, chlorine, bromine, -OR z hydroxyl, cyano, C 1-6 Alkyl, -(C 1-4 (alkylene)-R z -(C 1-4 (alkylene)-OR z C 3-6 Cycloalkyl, 3-8 membered heterocyclic alkyl (e.g., 3-6 membered heterocyclic alkyl), C 2-4 alkenyl, C 2-4 Alkynyl, phenyl, and 5-6-membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, phenyl, and heteroaryl groups are each optionally composed of one or more groups selected from fluorine, chlorine, cyano, oxo, -OR z hydroxyl group, -N(R) z )2、-NHR z amino, C 1-4 Alkyl, C 3-6 Substituents of cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, and 5-6-membered heteroaryl groups; preferably, R 3 Selected from fluorine, chlorine, -OR z , hydroxyl, cyano, methyl, ethyl, -CH2-R z -CH2-OR z Cyclopropyl, oxacyclobutyl, -CH2CH=CH2, -CH=CH2, -CH2C≡CH, -C≡CH, pyridinyl, pyrimidinyl, oxazolyl, thiazolyl, pyridazinyl, and thiophene, wherein the pyridinyl, pyrimidinyl, oxazolyl, thiazolyl, pyridazinyl, and thiophene groups are each optionally selected from one or two groups selected from fluorine, chlorine, cyano, and -OR. z hydroxyl group, -N(R) z )2、-NHR z Substitution of amino and pyrazolyl groups; more preferably, R 3 Selected from fluorine, chlorine, hydroxyl, cyano, methyl, ethyl, cyclopropyl, oxadiazolyl, pyridinyl, pyrimidinyl, oxazolyl, thiazolyl, pyridazinyl, pyrazolyl, and thiophene; more preferably, R 3 Selected from fluorine, chlorine, methyl, ethyl, cyclopropyl, and oxetane; more preferably, R 3 Selected from fluorine and methyl.

[0280] In some embodiments of the present invention, R in the compound of formula I is... 3 Contains multiple R z Each R z Each is independently selected from cyano, C 1-4 Alkyl, C 3-6Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, benzyl, and 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl, benzyl, and heteroaryl groups are each optionally composed of one or more groups selected from amino, fluorine, chlorine, cyano, oxo, hydroxyl, -O-(C 1-3 Alkyl), methyl, ethyl, difluoromethyl, trifluoromethyl, C 3-6 Substituents of cycloalkyl and phenyl groups; preferably, each R z Each of the following groups is independently selected from cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino, piperazine, oxazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, aziridine, phenyl, benzyl, pyrrolyl, furanyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyrazine, pyrimidinyl, and pyridinyl, wherein the piperazine, aziridine, phenyl, pyrrolyl, furanyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyrazine, pyrimidinyl, and pyridinyl groups are each optionally substituted by one or two substituents selected from fluorine, chlorine, cyano, hydroxyl, methoxy, methyl, and ethyl.

[0281] In some embodiments of the present invention, R in the compound of Formula I described above... 3 and R 4 Not interconnected, R 4 Selected from halogens, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C(=O)-R z 3-12 membered heterocyclic alkyl groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-12 aryl and 5-12 heteroaryl groups, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are each optionally composed of one or more groups selected from amino, fluorine, chlorine, cyano, hydroxyl, oxo, -O-(C 1-3 Alkyl), methyl, ethyl, difluoromethyl, trifluoromethyl and C 3-6 Cycloalkyl substituents; preferably, R 4 The group is selected from fluorine, chlorine, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, ethylene oxide, oxacyclobutane, phenyl, pyrrolyl, furanyl, thiophene, imidazolyl, oxazolyl, thiazolyl, pyrazole, pyridinyl, pyridinyl, pyridinyl, and pyrimidinyl, wherein the phenyl, pyrrolyl, furanyl, thiophene, imidazolyl, oxazolyl, thiazolyl, pyrazole, pyridinyl, pyridinyl, and pyrimidinyl groups are each optionally substituted by one or more substituents selected from amino, fluorine, chlorine, cyano, hydroxyl, methoxy, methyl, ethyl, difluoromethyl, and trifluoromethyl; more preferably, R 4Selected from fluorine, chlorine, methyl, ethyl, isopropyl, cyclopropyl, methoxymethyl, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, cyanomethyl, hydroxymethyl, 2-methylfuranyl, thiazolyl, pyridyl, and pyrimidinyl; more preferably, R 4 Selected from methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, fluoroethyl, cyanomethyl, and hydroxymethyl; more preferably, R 4 It is selected from methyl, fluoromethyl, fluoroethyl, methoxymethyl, cyanomethyl, and hydroxymethyl.

[0282] In some embodiments of the present invention, R in the compound of Formula I described above... 3 With R 4 Interconnected, R 3 and R 4 And when the atoms connected to it form a ring, Choose from any of the following:

[0283] The following are preferred:

[0284] Where m is 0, 1, or 2;

[0285] Preferably, R 3 and R 4 And when the atoms connected to it form a ring, Choose from any of the following:

[0286] The following are preferred:

[0287] Where m is 0, 1, or 2;

[0288] More preferably, R 3 and R 4 And when the atoms connected to it form a ring, Choose from any of the following:

[0289] The following are preferred:

[0290]

[0291] In some embodiments of the present invention, R 3 and R 4 Together with the atoms connected to it, it forms a structure containing multiple R atoms. 4a The ring system, each R 4a Each is independently selected from hydrogen, fluorine, chlorine, cyano, -C(=O)H, -C(=O)-(C 1-6 Alkyl), -C(=O)-(C 3-8 Cycloalkyl), -C(=O)- (3-8 membered heterocycloalkyl), oxoyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-12 membered heterocycloalkyl, C 2-6 alkenyl and C 2-6 Alkynyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, alkenyl and alkynyl groups are each optionally composed of one or more groups selected from halogen, cyano, hydroxyl, -O-(C 1-6 alkyl) and C 1-6 Alkyl substituents; preferably, each R 4a Each group is independently selected from hydrogen, fluorine, chlorine, oxo, methyl, acetyl, and cyclopropyl, wherein the methyl and cyclopropyl groups are each optionally replaced by one or more groups selected from halogen, cyano, hydroxyl, -O-(C 1-6 alkyl) and C 1-6 Alkyl substituents.

[0292] In some embodiments of the present invention, the compound of formula I above simultaneously contains a plurality of R. 5 And any two R 5 They are not interconnected, each R 5 Each is independently selected from hydrogen, fluorine, chlorine, oxo, cyano, -C(=O)-O-(C 1-4 alkyl) and C 1-3 Alkyl groups, wherein each alkyl group is optionally substituted with one or more substituents selected from amino, hydroxyl, oxo, and halogen groups; preferably, each R 5 Each is independently selected from hydrogen, fluorine, chlorine, cyano, methyl, and -C(=O)-O-CH3; more preferably, each R 5 Each is independently selected from hydrogen, fluorine, and methyl; more preferably, each R 5 Both are hydrogen.

[0293] In some embodiments of the present invention, the compound of formula I above simultaneously contains a plurality of R. 5 Any two R atoms that are not connected to the same atom 5 Together with the atoms bonded to it, they form C 4-8 Alicyclic or 4-8 membered heterocyclic alicyclic rings, preferably C 4-6 Alicyclic rings or 4-6 membered nitrogen-containing heterocyclic rings, or any two R atoms connected to the same atom5 Together with the atoms bonded to it, they form C 3-6 Alicyclic or 3-6 membered heterocyclic alicyclic rings, preferably cyclopropane rings.

[0294] In some embodiments of the present invention, g is 0 or 2.

[0295] In some embodiments of the present invention, n is 0, 1, 2 or 3; preferably, n is 0, 1 or 2.

[0296] In some embodiments of the present invention, the compound of formula I has a structure as shown in formula IIa or IIb, wherein

[0297]

[0298] A, B, R 3 and R 4 As defined above.

[0299] In some embodiments of the present invention, the compound of formula I has a structure as shown in formula IIIa or IIIb, wherein

[0300]

[0301] A, B, R 3 and R 4 As defined above.

[0302] In some embodiments of the present invention, the compounds of formula I described above have structures as shown in formulas IVa, IVb, IVc, or IVd, wherein

[0303]

[0304] A, B, R 3 and R 4 As defined above.

[0305] In some embodiments of the present invention, the compound of formula I has a structure as shown in formula Va, formula Vb or formula Vc, wherein

[0306]

[0307] A, B, R 3 and R 4 As defined above.

[0308] In some embodiments of the present invention, the compounds of formula I described above have structures as shown in any one of formulas IIa-IIb, IIIa-IIIb, IVa-IVd, Va-Vc, wherein

[0309] A is selected from C 6-12arylene and 5-12-membered heteroarylene, wherein the arylene and heteroarylene are each optionally surrounded by one or more R a replace;

[0310] If it exists, each R a Each is independently selected from hydrogen, halogen, hydroxyl, -O-(C 1-3 alkyl), -O-(C 3-6 cycloalkyl), cyano, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, amino, -NH(C 1-3 alkyl), -N(C) 1-3 Alkyl group 2, -S (=O) g -(C 1-3 Alkyl groups and -S (=O) g NH2;

[0311] B is selected from -N(R) b )-C(=O)-GR d -N(R) b )-S(=O)2-GR d -OG-(3-10 membered heterocyclic alkyl), -OG-(C 3-6 cycloalkyl), -O-(C 3-6 -O-(3-10 membered heterocyclic alkylene)-GH, -OGR d -N(R) b -G-(3-10 membered heterocyclic alkyl), -N(R) b )-G-(C 3-6 cycloalkyl), -N(R) b )-(C 3-6 Cycloalkylene)-GH, -N(R) b )-(3-10-membered heterocyclic alkylene)-GH, -GOC(=O)-R b -GN(R) b )-C(=O)-R b -GN(R) b )-C(=O)-OR b and The heterocyclic alkyl, heterocyclic alkylene, cycloalkyl, and cycloalkylene groups are each optionally composed of one or more elements selected from hydrogen, halogen, hydroxyl, amino, and -NH(C). 1-6 alkyl), -N(C) 1-6 Alkyl group, oxo group, -O-(C 1-6 Alkyl), C 1-6 Halogenated alkyl groups and C 1-6 The alkyl group is substituted, and B is not -O-(C 1-2(halogenated alkyl);

[0312] G is selected from C 1-6 Alkylene, C 3-6 Cycloalkylene and 3-6-membered heterocyclic alkylene, wherein each of the alkylene, cycloalkylene and heterocyclic alkylene is optionally composed of one or more radicals selected from hydrogen, fluorine, oxo, hydroxyl, cyano, -OR b C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 The hydroxyalkyl groups are substituted, preferably each of which is optionally substituted by one or more substituents selected from hydrogen and fluorine;

[0313] R b Selected from hydrogen, fluorine, chlorine, amino, C 1-3 Alkyl, cyclopropyl and 3-6 membered heterocyclic alkyl groups, wherein each of the alkyl and heterocyclic alkyl groups is optionally substituted by one or more substituents selected from hydrogen, fluorine, oxo, hydroxy and cyano groups;

[0314] C is selected from 3-6 membered heterocyclic alkyl groups and C 3-6 Cycloalkylene, wherein the heterocyclic alkylene and the cycloalkylene are each optionally influenced by one or more R c replace;

[0315] If it exists, each R c Each is independently selected from hydrogen, fluorine, cyano, methyl, ethyl, fluoromethyl, hydroxymethyl, and hydroxy;

[0316] Y is selected from C 1-3 Alkylene, C 3-6 Cycloalkylene, 3-6 membered heterocycloalkylene, C 2-6 alkenyl group, -C(=O)-(C 1-3 alkylene)-, -C(=O)-(C 3-6 -C(=O)-(3-6 membered heterocyclic alkylene)- and -C(=O)-, wherein the alkylene, heterocyclic alkylene and alkylene are each optionally substituted by one or more substituents selected from fluorine, hydroxyl and amino;

[0317] R d Selected from fluorine, amino, hydroxyl, cyano, -S(=O)2-(C 1-6 alkyl), -O-(C 1-6 Alkyl), -NH-C(=O)-O-(C 1-6 Alkyl groups, -OC(=O)-NH2, -OC(=O)-NH(C 1-6 alkyl) and -N(C) 1-6 alkyl)-C(=O)-(C 1-6Alkyl group), wherein the alkyl group is optionally radically formed by one or more radicals selected from fluorine, chlorine, oxo, hydroxyl, and -O-(C). 1-6 Substitution of alkyl groups;

[0318] R 3 and R 4 When they are not connected to each other,

[0319] R 3 Selected from fluorine, chlorine, bromine, -OR z hydroxyl, cyano, C 1-6 Alkyl, -(C 1-4 (alkylene)-R z -(C 1-4 (alkylene)-OR z C 3-6 Cycloalkyl, 3-8 membered heterocyclic alkyl (e.g., 3-6 membered heterocyclic alkyl), C 2-4 alkenyl, C 2-4 Alkynyl, phenyl, and 5-6-membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, phenyl, and heteroaryl groups are each optionally composed of one or more groups selected from fluorine, chlorine, cyano, oxo, -OR z hydroxyl group, -N(R) z )2、-NHR z amino, C 1-4 Alkyl, C 3-6 Substitution of cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl groups;

[0320] If it exists, each R z Each is independently selected from cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, benzyl, and 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl, benzyl, and heteroaryl groups are each optionally composed of one or more groups selected from amino, fluorine, chlorine, cyano, oxo, hydroxyl, -O-(C 1-3 Alkyl), methyl, ethyl, difluoromethyl, trifluoromethyl, C 3-6 Substitution of cycloalkyl and phenyl groups;

[0321] R 4 Selected from halogens, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C(=O)-R z 3-12 membered heterocyclic alkyl groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-12aryl and 5-12 heteroaryl groups, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are each optionally composed of one or more groups selected from amino, fluorine, chlorine, cyano, hydroxyl, oxo, -O-(C 1-3 Alkyl), methyl, ethyl, difluoromethyl, trifluoromethyl and C 3-6 Substituents of cycloalkyl groups;

[0322] Or, R 3 and R 4 And when the atoms connected to it form a ring,

[0323] Choose from any of the following:

[0324]

[0325] The following are preferred:

[0326]

[0327] m is 0, 1, or 2;

[0328] If it exists, each R 4a Each is independently selected from hydrogen, fluorine, chlorine, cyano, -C(=O)H, -C(=O)-(C 1-6 Alkyl), -C(=O)-(C 3-8 Cycloalkyl), -C(=O)- (3-8 membered heterocycloalkyl), oxoyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-12 membered heterocycloalkyl, C 2-6 alkenyl and C 2-6 Alkynyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, alkenyl and alkynyl groups are each optionally composed of one or more groups selected from halogen, cyano, hydroxyl, -O-(C 1-6 alkyl) and C 1-6 Alkyl substituents.

[0329] In some embodiments of the present invention, the compounds of formula I described above have structures as shown in any one of formulas IIa-IIb, IIIa-IIIb, IVa-IVd, Va-Vc, wherein

[0330] A is selected from phenylene, pyridinyl, and pyrimidinyl, wherein the phenylene, pyridinyl, and pyrimidinyl groups are each optionally surrounded by one or more R groups. a replace;

[0331] If it exists, each R aEach is independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, methoxy, cyclopropoxy, cyano, methyl, ethyl, n-propyl, isopropyl, difluoromethoxy, trifluoromethoxy, trifluoromethyl, difluoromethyl, cyclopropyl, pyrrolyl, morpholinyl, amino, methylamino, dimethylamino, methylthio, methanesulfonyl, and aminosulfonyl;

[0332] B is selected from -N(R) b )-C(=O)-GR d -OG- (3-10 membered heterocyclic alkyl groups), -OGR d -N(R) b -G-(3-10 membered heterocyclic alkyl), -N(R) b )-G-(C 3-6 cycloalkyl), -N(R) b )-(C 3-6 Cycloalkylene)-GH, -N(R) b )-(3-10-membered heterocyclic alkylene)-GH, -GOC(=O)-R b and The heterocyclic alkyl, heterocyclic alkylene, cycloalkyl, and cycloalkylene groups are each optionally composed of one or more elements selected from hydrogen, halogen, hydroxyl, amino, and -NH(C). 1-6 alkyl), -N(C) 1-6 Alkyl group, oxo group, -O-(C 1-6 Alkyl), C 1-6 Halogenated alkyl groups and C 1-6 The alkyl group is substituted, and B is not -O-(C 1-2 (halogenated alkyl);

[0333] G is C 1-6 Alkylene, wherein the alkylene is optionally radically formed by one or more radicals selected from hydrogen, fluorine, oxo, hydroxyl, cyano, -OR b C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Hydroxyl alkyl substituents;

[0334] R b Selected from hydrogen, fluorine, chlorine, amino, C 1-3 Alkyl, cyclopropyl and 3-6 membered heterocyclic alkyl groups, wherein each of the alkyl and heterocyclic alkyl groups is optionally substituted by one or more substituents selected from hydrogen, fluorine, oxo, hydroxy and cyano groups;

[0335] C is selected from pyridinealkyl, azapyridinebutylalkyl, piperidinyl, and piperazineyl, wherein the pyridinealkyl, azapyridinebutylalkyl, piperidinyl, and piperazineyl are each optionally surrounded by one or more R. c replace;

[0336] If it exists, each R c Each is independently selected from hydrogen, fluorine, and hydroxyl;

[0337] Y is selected from -CH2-, -CH(CH3)-, -C(CH3)2-, cyclopropylene, and -C(=O)-CH2-, wherein -CH2-, -CH(CH3)-, -C(CH3)2-, cyclopropylene, and -C(=O)-CH2- are each optionally substituted by one or more substituents selected from fluorine, hydroxyl, and amino groups;

[0338] R d The group is selected from fluorine, amino, hydroxyl, cyano, -S(=O)2-CH3, -O-CH3, -NH-C(=O)-O-CH3 and -OC(=O)-NH2, wherein -S(=O)2-CH3, -O-CH3 and -NH-C(=O)-O-CH3 are each optionally replaced by one or more groups selected from fluorine, chlorine, oxo, hydroxyl and -O-(C 1-6 Substitution of alkyl groups;

[0339] R 3 and R 4 When they are not connected to each other,

[0340] R 3 Selected from fluorine, chlorine, -OR z , hydroxyl, cyano, methyl, ethyl, -CH2-R z -CH2-OR z Cyclopropyl, oxacyclobutyl, -CH2CH=CH2, -CH=CH2, -CH2C≡CH, -C≡CH, pyridinyl, pyrimidinyl, oxazolyl, thiazolyl, pyridazinyl, and thiophene, wherein the pyridinyl, pyrimidinyl, oxazolyl, thiazolyl, pyridazinyl, and thiophene groups are each optionally selected from one or two groups selected from fluorine, chlorine, cyano, and -OR. z hydroxyl group, -N(R) z )2、-NHR z Substitution of amino and pyrazol groups;

[0341] If it exists, each R zEach of the following groups is independently selected from cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino, piperazine, oxazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, aziridine, phenyl, benzyl, pyrrolyl, furanyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyrazine, pyrimidinyl, and pyridinyl, wherein the piperazine, aziridine, phenyl, pyrrolyl, furanyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyrazine, pyrimidinyl, and pyridinyl groups are each optionally substituted by one or two substituents selected from fluorine, chlorine, cyano, hydroxyl, methoxy, methyl, and ethyl.

[0342] R 4 Selected from fluorine, chlorine, methyl, ethyl, isopropyl, cyclopropyl, methoxymethyl, hydroxymethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, cyanomethyl, hydroxymethyl, 2-methylfuranyl, thiazolyl, pyridinyl, and pyrimidinyl;

[0343] Or, R 3 and R 4 And when the atoms connected to it form a ring,

[0344] Choose from any of the following:

[0345]

[0346] The following are preferred:

[0347] m is 0, 1, or 2;

[0348] If it exists, each R 4a Each group is independently selected from hydrogen, fluorine, chlorine, oxo, methyl, acetyl, and cyclopropyl, wherein the methyl and cyclopropyl groups are each optionally replaced by one or more groups selected from halogen, cyano, hydroxyl, -O-(C 1-6 alkyl) and C 1-6 Alkyl substituents.

[0349] In some embodiments of the present invention, the compounds of formula I described above have structures as shown in any one of formulas IIa-IIb, IIIa-IIIb, IVa-IVd, Va-Vc, wherein

[0350] A is selected from phenylene, pyridinyl, and pyrimidinyl, wherein the phenylene, pyridinyl, and pyrimidinyl groups are each optionally surrounded by one or more R groups. a replace;

[0351] If it exists, each R aEach is independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, pyrrolyl, morpholino, amino, methylamino, and dimethylamino;

[0352] B is selected from -NH-C(=O)-CH2-CN and -N(CH3)-C(=O)-C(CH3)2-OH;

[0353] R 3 and R 4 When they are not connected to each other,

[0354] R 3 The group is selected from fluorine, chlorine, hydroxyl, cyano, methyl, ethyl, cyclopropyl, oxetyl, pyridinyl, pyrimidinyl, oxazolyl, thiazolyl, pyridazinyl, pyrazolyl, and thiophene, with fluorine, chlorine, methyl, ethyl, cyclopropyl, and oxetyl being preferred.

[0355] R 4 Selected from methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, fluoroethyl, cyanomethyl, and hydroxymethyl;

[0356] Or, R 3 and R 4 And when the atoms connected to it form a ring,

[0357] Choose from any of the following:

[0358]

[0359] Any of the following:

[0360]

[0361] In other embodiments of the invention, the compounds of formula I described above have a structure as shown in any one of formulas IIa-IIb, IIIa-IIIb, IVa-IVd, Va-Vc, wherein

[0362] A is selected from phenylene, pyridinyl, and pyrimidinyl, wherein the phenylene, pyridinyl, and pyrimidinyl groups are each optionally surrounded by one or more R groups. a replace;

[0363] If it exists, each R a Each is independently selected from fluorine, chlorine, bromine, cyano, methyl, and amino groups;

[0364] B is selected from -NH-C(=O)-CH2-CN and -N(CH3)-C(=O)-C(CH3)2-OH;

[0365] The following are preferred: -NH-C(=O)-CH2-CN and -N(CH3)-C(=O)-C(CH3)2-OH;

[0366] R 3 and R 4 When they are not connected to each other,

[0367] R 3 Selected from fluorine and methyl;

[0368] R 4 Selected from methyl, fluoromethyl, fluoroethyl, cyanomethyl, hydroxymethyl, and methoxymethyl;

[0369] Or, R 3 and R 4 And when the atoms connected to it form a ring,

[0370] Choose from any of the following:

[0371]

[0372] The following are preferred:

[0373]

[0374] In some embodiments of the present invention, the compounds of formula I described above have structures as shown in any one of formulas IIa-IIb, IIIa-IIIb, IVa-IVd, Va-Vc, wherein

[0375] A is selected from 5-12-membered heteroaryl groups, wherein the heteroaryl group is optionally substituted with one or more halogens;

[0376] B is selected from

[0377] C is selected from 3-6 membered heterocyclic alkyl groups, wherein the heterocyclic alkyl group is optionally substituted with one or more fluorine, cyano, methyl or fluoromethyl groups;

[0378] Y is selected from C 1-3 Alkylene and -C(=O)-(C 1-3 alkylene);

[0379] R d Selected from fluorine, amino, hydroxyl, cyano, -S(=O)2-(C 1-6alkyl) and -O-(C 1-6 alkyl);

[0380] R 3 and R 4 When they are not interconnected, R 3 Selected from C 1-6 Alkyl, R 4 Selected from C 1-6 Alkyl group, wherein the alkyl group is optionally -O-(C 1-3 Alkyl) substitution;

[0381] Or, R 3 and R 4 And when the atoms connected to it form a ring, Selected from

[0382] m is 0, 1, or 2;

[0383] If it exists, each R 4a They are each independently selected from hydrogen and fluorine.

[0384] In some embodiments of the present invention, the compounds of formula I described above have structures as shown in any one of formulas IIa-IIb, IIIa-IIIb, IVa-IVd, Va-Vc, wherein

[0385] A is selected from pyridyl group, wherein the pyridyl group is optionally substituted with one or more chlorine groups;

[0386] B is selected from

[0387] C is selected from aziridine and pyridine, wherein each of the aziridine and pyridine is optionally substituted with one or more fluorine, cyano, methyl or fluoromethyl groups;

[0388] Y is selected from -CH2-, -CH(CH3)-, -C(CH3)2- and -C(=O)-CH2-;

[0389] R d Selected from fluorine, amino, hydroxyl, cyano, S(=O)2-CH3 and -O-CH3;

[0390] R 3 and R 4 When they are not interconnected, R 3 Selected from methyl, R 4 Selected from methyl, wherein the methyl group is optionally substituted with a methoxy group;

[0391] Or, R 3 and R 4 And when the atoms connected to it form a ring, Selected from

[0392] In some embodiments of the present invention, the compounds of formula I described above have structures as shown in any one of formulas IIa-IIb, IIIa-IIIb, IVa-IVd, Va-Vc, wherein

[0393] A is selected from pyridyl group, wherein the pyridyl group is optionally substituted with one or more chlorine groups;

[0394] B is selected from

[0395] R 3 and R 4 When they are not interconnected, R 3 Selected from methyl, R 4 Selected from methyl, wherein the methyl group is optionally substituted with a methoxy group;

[0396] Or, R 3 and R 4 And when the atoms connected to it form a ring, Selected from

[0397] In some embodiments of the present invention, the compound of formula I has a structure as shown in formula IIb, wherein

[0398] A is selected from 5-12-membered heteroaryl groups, wherein the heteroaryl group is optionally substituted with one or more halogens; preferably, A is selected from pyridyl groups, wherein the pyridyl group is optionally substituted with one or more chlorines;

[0399] B is selected from Where C is selected from 3-6 membered heterocyclic alkyl groups, and Y is selected from C 1-3 Alkylene, R d B is selected from hydroxyl groups; preferably, B is selected from...

[0400] R 3 and R 4 And the atoms connected to it form a ring, and Selected from

[0401] Those skilled in the art will understand that this invention covers compounds obtained by any combination of 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.

[0402] This invention provides the following compounds covered by compounds of formulas I, IIa, IIb, IIIa, IIIb, IVa, IVb, IVc, IVd, Va, Vb, and Vc:

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410] Process for the preparation of compounds

[0411] This invention provides two methods for preparing compounds of formula I;

[0412] Method 1 includes the following steps:

[0413] (1) Compound S-1 reacts with compound S-2 to generate compound M-1;

[0414]

[0415] (2) Compound M-1 reacts with compound S-3 to generate compound M-2;

[0416]

[0417] (3) Compound M-2 is deprotected and its functional groups are transformed to generate compound I;

[0418]

[0419] Method 2 includes the following steps:

[0420] (1) The compound of formula S-1 reacts with the compound of formula S-3 to generate the compound of formula M-3;

[0421]

[0422] (2) The compound of formula M-3 reacts with the compound of formula S-2, and then undergoes optional deprotection and functional group transformation to generate the compound of formula I;

[0423]

[0424] in

[0425] LG 1 and LG 2 Each is an independent halogen leaving group or a C that is optionally substituted with a halogen. 1-6 Alkyl sulfonate leaving groups (such as trifluoromethanesulfonate leaving groups); additionally, LG 2 It can also be a hydroxyl group;

[0426] R x It is hydrogen or a leaving group;

[0427] R f It is a group that is hydrogen, hydroxymethyl, fluoromethyl, or converted to hydroxymethyl or fluoromethyl through one or more steps of reaction;

[0428] PG 1 Protecting groups for hydrogen or amino groups (such as methyl, tert-butyloxycarbonyl, tert-butyldimethylsilyl, triisopropylsilyl, benzyl, and methoxymethyl, etc.);

[0429] The remaining groups are as defined above.

[0430] In some embodiments of the present invention, LG 1 It is a halogen leaving group (such as iodine or bromine).

[0431] In some embodiments of the present invention, LG 2 It is a halogen leaving group (such as bromine or chlorine) or a hydroxyl group.

[0432] In some embodiments of the present invention, R x It can be hydrogen, halogen, borate group, borate ester group, substituted silicon group, substituted metal group, or C optionally substituted with halogen. 1-6 Alkyl sulfonate group, preferably borate group or borate group.

[0433] In some embodiments of the present invention, R f It can be hydrogen, halogen (such as fluorine, chlorine, bromine or iodine), fluoromethyl or ester group (such as -C(=O)-OC2H5).

[0434] In some embodiments of the present invention, the reaction in step (1) above is carried out in the presence of a base. In some preferred embodiments of the present invention, the base is an inorganic base, such as potassium phosphate.

[0435] In other embodiments of the invention, the reaction in step (1) above is carried out in the presence of a condensing agent and a base. In some preferred embodiments of the invention, the base is an organic base, such as DIPEA. In other preferred embodiments of the invention, the condensing agent is BOP, HATU, or PyBOP, preferably BOP.

[0436] In some embodiments of the present invention, the reaction in step (2) above is carried out in the presence of a metal catalyst. In some preferred embodiments of the present invention, the metal catalyst is a palladium catalyst or a copper catalyst, such as tetrakis(triphenylphosphine)palladium, palladium acetate, tris(dibenzylacetone)palladium, [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride, 1,2-bis(diphenylphosphine)ethanepalladium dichloride and bis(triphenylphosphine)palladium dichloride, cuprous iodide, etc.

[0437] In some embodiments of the present invention, the functional group transformation in step (3) above includes (but is not limited to) the following reactions: 1) reduction reaction (using reagents such as LiBH4, DIBAL-H); 2) metal-catalyzed coupling reaction; 3) hydrolysis reaction.

[0438] In some embodiments of the present invention, the deprotection in step (3) is carried out under conditions of acid hydrolysis or catalytic hydrogenolysis in the presence of a metal catalyst. In some preferred embodiments of the present invention, the acid used for acid hydrolysis is an organic acid, preferably trifluoroformic acid. In other preferred embodiments of the present invention, the metal catalyst used for catalytic hydrogenation is palladium / carbon or palladium hydroxide / carbon.

[0439] Those skilled in the art should understand that, depending on the desired product structure, one or more steps in the above preparation method may be omitted, and the order of reaction steps may be appropriately adjusted, and protection / deprotection reaction steps may be added or omitted as needed.

[0440] Other compounds of the general formula of this invention can be synthesized by a similar method.

[0441] Pharmaceutical compositions

[0442] The term "pharmaceutical composition" refers to a composition that can be used as a medicine, comprising a pharmaceutically active ingredient (API) (or therapeutic agent) and optionally one or more pharmaceutically acceptable carriers, intended to facilitate administration to an organism, enhance the absorption of the active ingredient, and thereby exert its biological activity. The term "pharmaceutically acceptable carrier" refers to an excipient administered co-administered with a therapeutic agent, and which, to the extent of reasonable medical judgment, is suitable for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable carriers that can be used in this invention include (but are not limited to) a) diluents; b) lubricants; c) binders; d) disintegrants; e) absorbents, colorants, flavoring agents, and sweeteners; f) emulsifiers or dispersants; and / or g) agents that enhance the absorption of the compound.

[0443] The present invention provides a pharmaceutical composition comprising at least one compound of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, IVc, IVd, Va, Vb or Vc of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate (e.g. hydrate), isotope label, metabolite or prodrug thereof.

[0444] In some embodiments of the present invention, the above-described pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

[0445] In other embodiments of the invention, the pharmaceutical composition further comprises one or more additional pharmaceutically active ingredients (such as pharmaceutically active ingredients for the prevention and / or treatment of SHP2-related diseases).

[0446] In some preferred embodiments of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers and one or more additional pharmaceutically active ingredients (such as pharmaceutically active ingredients for the prevention and / or treatment of SHP2-related diseases).

[0447] In some embodiments of the invention, the above-described pharmaceutical compositions can act systemically and / or locally. For this purpose, they can be administered via suitable routes, such as parenteral, local, intravenous, oral, subcutaneous, intra-arterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular, inhalation, or any other method known to those skilled in the art. The above-described pharmaceutical compositions can be administered in combination with at least one other therapeutic agent that has a therapeutic effect on a disease or condition.

[0448] In some embodiments of the present invention, the above-described route of administration can be achieved through a suitable dosage form.

[0449] In some embodiments of the present invention, the pharmaceutical composition may comprise 0.01 mg to 1000 mg of at least one compound of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, IVc, IVd, Va, Vb or Vc of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate (e.g. hydrate), isotope label, metabolite or prodrug thereof.

[0450] The present invention also provides a method for preparing the above-described pharmaceutical composition or its corresponding formulation, comprising combining at least one compound of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, IVc, IVd, Va, Vb or Vc of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate (e.g., hydrate), isotope label, metabolite or prodrug, with one or more pharmaceutically acceptable carriers and / or one or more additional pharmaceutically active ingredients (e.g., pharmaceutically active ingredients for the prevention and / or treatment of SHP2-related diseases).

[0451] Pharmaceutical products

[0452] The term "medicine" refers to a combination product comprising a therapeutic agent, optionally other therapeutic agents, and optionally packaged and / or instructions.

[0453] The terms “pharmaceutical active ingredient,” “pharmaceutical active substance,” “pharmaceutical active agent,” or “therapeutic agent” refer to a chemical entity that can effectively prevent and / or treat a target disease or one or more of its symptoms.

[0454] This invention provides a medicine comprising:

[0455] a) Container;

[0456] b) at least one compound of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, IVc, IVd, Va, Vb, or Vc of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate (e.g., hydrate), isotope label, metabolite, or prodrug or pharmaceutical composition thereof, located in a container; and

[0457] c) Optional packaging and / or instructions.

[0458] The instructions for use list information about the active pharmaceutical ingredient or pharmaceutical composition in the aforementioned medicine, and preferably specifically list the indications for which the active pharmaceutical ingredient or pharmaceutical composition is approved for use. The instructions for use are made of printable material (such as paper, plastic, metal foil, adhesive paper, etc.) on which the necessary information can be formed (such as by printing or coating).

[0459] In some embodiments of the present invention, the above-mentioned pharmaceutical product may contain 0.01 mg to 1000 mg of at least one compound of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, IVc, IVd, Va, Vb or Vc of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate (such as hydrate), isotope label, metabolite or prodrug thereof.

[0460] The present invention also provides a method for preparing the above-mentioned pharmaceutical product, comprising combining at least one compound of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, IVc, IVd, Va, Vb or Vc of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate (such as hydrate), isotope label, metabolite or prodrug, or pharmaceutical composition thereof, with a container and optionally a packaging and / or instructions.

[0461] Medical use

[0462] The compounds of the present invention exhibit strong inhibitory activity against SHP2 and can be used as SHP2 inhibitors. Therefore, the present invention provides the use of compounds of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, IVc, IVd, Va, Vb, or Vc, or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates (such as hydrates), isotope-labeled substances, metabolites, or prodrugs, or pharmaceutical compositions, or pharmaceutical products, as SHP2 inhibitors.

[0463] In addition, the present invention also provides the use of compounds of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, IVc, IVd, Va, Vb or Vc of the present invention, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates (such as hydrates), isotope labels, metabolites or prodrugs, or pharmaceutical compositions, or pharmaceutical products thereof, in the preparation of medicaments for the prevention and / or treatment of diseases or conditions at least partially mediated by SHP2 (or SHP2-related diseases, SHP2 enzyme-related diseases or SHP2 phosphatase-related diseases, especially cancer).

[0464] The term "disease or condition mediated at least in part by SHP2 (or SHP2-related disease)" refers to a disease whose pathogenesis involves at least some factors related to SHP2, particularly diseases that are sensitive to or responsive to SHP2 phosphatase inhibition, including (but not limited to) neoplasms.

[0465] In some embodiments of the present invention, the aforementioned tumor-related diseases include (but are not limited to) breast cancer, colorectal cancer, colon cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer, and bronchioloalveolar carcinoma), prostate cancer, bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer, vulvar cancer, multiple myeloma, lymphoma, and leukemia, such as chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML).

[0466] Method of treatment

[0467] This invention provides a method for preventing and / or treating diseases (especially cancer) at least partially mediated by SHP2, comprising the steps of: administering a preventive and / or therapeutically effective amount of at least one compound of formula I, IIa, IIb, IIIa, IIIb, IVa, IVb, IVc, IVd, Va, Vb, or Vc of this invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate (e.g., hydrate), isotope label, metabolite, or prodrug, or pharmaceutical composition, or drug substance, to an individual in need of it.

[0468] The term "effective dose" refers to a dose that is sufficient to induce a biological or medical response in cells, tissues, organs, or an organism (e.g., an individual) and achieve the desired preventive and / or therapeutic effect. Dosing regimens can be adjusted to provide the best response. For example, it can be administered as a single dose, divided into fractions over time, or the dose can be proportionally reduced or increased as needed. It is understood that for any given individual, the specific dosing regimen should be adjusted as needed and with the professional judgment of the person administering the medication. Furthermore, it is important to distinguish between prophylactic and therapeutic use. In prophylactic use, relatively low doses are typically administered over a long period at relatively long intervals. In therapeutic use, relatively high doses are typically administered at relatively short intervals until disease progression is slowed or stopped, preferably until the individual shows partial or complete improvement in symptoms.

[0469] In this invention, suitable in vitro or in vivo assays are performed to determine the efficacy of compounds, pharmaceutical compositions, and / or drugs, and whether administration is suitable for treating an individual's disease or condition. Examples of these assays will be described in the non-limiting embodiments below. Typically, an effective amount of a compound sufficient to achieve preventive and / or therapeutic effects is from about 0.001 mg / kg body weight / day to about 10,000 mg / kg body weight / day.

[0470] The term "prevention" includes suppressing and delaying the onset of disease, and includes not only prevention before the disease develops, but also prevention of disease recurrence after treatment.

[0471] The term "treatment" refers to reversing, alleviating, or eliminating a targeted disease or symptom. A subject is considered successfully "treated" if, after receiving a therapeutic amount of a compound of the present invention or its pharmaceutically acceptable form, or a pharmaceutical composition of the present invention, at least one indicator and symptom of the subject shows observable and / or detectable relief and / or improvement. It is understood that treatment includes not only complete treatment but also the achievement of some biologically or medically relevant outcome without achieving complete treatment. Specifically, "treatment" means that a compound of the present invention or its pharmaceutically acceptable form, or a pharmaceutical composition of the present invention, can achieve at least one of the following effects: (1) inhibiting disease (i.e., preventing further development of pathology and / or symptomology) in animals experiencing or exhibiting disease pathology or symptomology; (2) improving disease (i.e., reversing pathology and / or symptomology) in animals experiencing or exhibiting disease pathology or symptomology.

[0472] The term "application" refers to the process of applying a pharmaceutically active ingredient (such as the compound of the present invention) or a pharmaceutical composition containing a pharmaceutically active ingredient (such as the pharmaceutical composition of the present invention) to an individual or its cells, tissues, organs, biological fluids, etc., so as to bring the pharmaceutically active ingredient or pharmaceutical composition into contact with the individual or its cells, tissues, organs, biological fluids, etc.

[0473] The term “needs” refers to the judgment of a physician or other caregiver regarding an individual’s need for or potential benefit from preventive and / or treatment processes, which is based on various factors within the physician’s or other caregiver’s area of ​​expertise.

[0474] The term "individual" (or subject) refers to a human or non-human animal. Individuals in this invention include individuals suffering from diseases and / or conditions (patients) and healthy individuals. Non-human animals in this invention include all vertebrates, such as non-mammals, such as birds, amphibians, reptiles, etc., and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0475] The present invention also provides a combined method for preventing and / or treating diseases or conditions (especially cancer) at least partially mediated by SHP2, comprising: a) the method of the present invention for preventing and / or treating diseases or conditions (especially cancer) at least partially mediated by SHP2; and b) additional therapies.

[0476] In some embodiments of the present invention, the additional therapies in the above-described combination methods include (but are not limited to) radiotherapy, chemotherapy, immunotherapy, or any combination thereof. The compounds, pharmaceutical compositions, or drugs of the present invention may be administered before, during, or after the administration of the additional therapies. The administration of the additional therapies and the administration of the compounds, pharmaceutical compositions, or drugs of the present invention may be performed simultaneously, closely linked, or at intervals; the manner and order of administration may be selected and adjusted according to the specific treatment situation.

[0477] 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.

[0478] Unless otherwise stated, all reagents or instruments used in the examples are commercially available conventional products. Unless otherwise specified, all procedures were performed under conventional conditions or conditions recommended by the manufacturer. The term "room temperature" as used herein refers to 20°C ± 5°C. When used to modify a numerical value or range, the term "about" as used herein means including the numerical value or range and a range of errors acceptable to those skilled in the art, such as ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, etc. Unless otherwise stated, concentrations are by weight, and proportions (including percentages) are by mole.

[0479] The meanings of the abbreviations in the conventional synthesis methods and in the examples and intermediate synthesis examples are shown in the table below.

[0480]

[0481] 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).

[0482] 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).

[0483] The abbreviations used in the nuclear magnetic resonance (NMR) data in the following examples have the following meanings:

[0484] 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.

[0485] All chemical shift (δ) values ​​are given in parts per million (ppm).

[0486] The reaction was monitored using thin-layer chromatography or liquid chromatography-mass spectrometry. The mobile phase system included (but was not limited to) dichloromethane-methanol system, n-hexane-ethyl acetate system and petroleum ether-ethyl acetate system. The volume ratio of the solvent could be adjusted according to the polarity of the compound, or by adding a small amount of triethylamine, etc.

[0487] Thin-layer chromatography was performed using GF 254 silica gel plates (0.4–0.5 nm, Yantai Jiangyou Silica Gel Development Co., Ltd.).

[0488] The preparative high performance liquid chromatography (HPLC) instrument used was a Shimadzu LC-8A preparative HPLC system (YMC, ODS, 250×20mm×5μm C18 column).

[0489] The mass spectrometry measurements were performed using an Agilent 6120B mass spectrometer with an electrospray ionization (ESI) source.

[0490] Column chromatography uses 200-300 mesh silica gel (Qingdao Ocean Chemical Co., Ltd.) as the stationary phase. The mobile phase system includes (but is not limited to) dichloromethane-methanol system and n-hexane-ethyl acetate system. The volume ratio of the solvent can be adjusted according to the different polarities of the compounds, or by adding a small amount of triethylamine, etc.

[0491] Unless otherwise stated, the reaction temperature in the following examples is room temperature (20–30°C).

[0492] Unless otherwise stated, the reagents used in the following examples were purchased from Acros Organics, Aldrich Chemical, Nanjing Yaoshi Technology, Shanghai Shuya Pharmaceutical Technology, etc.

[0493] Example 1: Preparation of ethyl 6-bromo-3-((3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-methylpyrazine-2-carboxylate (compound IM-1) and tert-butyl (3S,4S)-8-(5-bromo-3-(hydroxymethyl)-6-methylpyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-ylcarbamate (compound IM-7).

[0494]

[0495] Step 1: Preparation of ethyl 6-bromo-3-((3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-methylpyrazine-2-carboxylic acid (compound IM-1):

[0496] Compound A-1 (200 mg, 766.07 μmol), DMF (4 mL), compound A-2 (195.60 mg, 804.37 μmol), BOP (312.74 mg, 1.53 mmol), and DIPEA (594.04 mg, 4.60 mmol) were mixed and heated to 40 °C for 2 hours. After the reaction was complete, di-tert-butyl dicarbonate (250.79 mg, 1.15 mmol) was added, and the reaction was continued for another 2 hours. The mixture was extracted with water and ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by thin-layer chromatography to give compound IM-1 (290 mg, 73% yield).

[0497] Step 2: Preparation of (3S,4S)-8-(5-bromo-3-(hydroxymethyl)-6-methylpyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-ylcarbamate tert-butyl ester (compound IM-7):

[0498] Compound IM-1 (5.7 g, 11.74 mmol) was dissolved in CH₂Cl₂ (100 mL) and cooled to -78 °C. DIBAL-H (35.23 mL, 35.23 mmol) was slowly added, and the temperature was slowly raised to 0 °C, reacting for 10 minutes. After the reaction was complete, the temperature was lowered to -78 °C, and saturated sodium potassium tartrate aqueous solution (200 mL) was added. The reaction mixture was stirred for 2 hours after reaching room temperature, then separated by CH₂Cl₂ extraction. The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound IM-7 (2.16 g, yield 39%).

[0499] Example 2: Preparation of (S)-6-bromo-3-(1-(tert-butoxycarbonylamino)-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl)pyrazine-2-carboxylic acid methyl ester (compound IM-2).

[0500]

[0501] Compound 2-1 (300 mg, 1.01 mmol) was added to NMP (5 mL), followed by DIPEA (786.14 mg, 6.08 mmol), and then compound A-3 (215.34 mg, 1.06 mmol) was added in portions. The mixture was reacted at 25 °C for 6 hours. Then, di-tert-butyl dicarbonate (442.52 mg, 2.03 mmol) was added, and the mixture was reacted at 40 °C for 2 hours. After the reaction was complete, water (15 mL) was added, followed by extraction with ethyl acetate. The organic phase was concentrated to obtain the crude product, which was purified by column chromatography to give compound IM-2 (310 mg, yield 56%).

[0502] Fragment preparation example 1: Preparation of 2-fluoro-1-(4-methylpiperidin-4-yl)ethylamine (compound A-4).

[0503]

[0504] Step 1: Preparation of tert-butyl 4-(2-bromoacetyl)-4-methylpiperidine-1-carboxylic acid (compound B1-2):

[0505] Under nitrogen protection, compound B1-1 (5.00 g, 20.72 mmol) was added to THF (50 mL), the temperature was lowered to -78 °C, and LDA (2 M tetrahydrofuran solution, 34.19 mL) was added dropwise. After the addition was complete, the temperature was maintained and the mixture was stirred for 10 minutes. Then, TMSCl (7.43 g, 68.37 mmol) was added dropwise to the system, and the temperature was maintained at -78 °C. After the addition was complete, the mixture was stirred for 1 hour. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution, extracted twice with methyl tert-butyl ether, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain an oil. This oil was dissolved in THF (25 mL), sodium carbonate (4.39 g, 41.44 mmol) was added, the temperature was lowered to 0 °C, and NBS (4.06 g, 22.79 mmol) was added in portions. The temperature was then raised to 25 °C, and the reaction was carried out for 4 hours. After the reaction was completed, methyl tert-butyl ether and 10% sodium carbonate aqueous solution were added to the reaction solution. After stirring, the mixture was separated. The organic phase was washed once with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain compound B1-2 (6.60 g, yield 99%).

[0506] Step 2: Preparation of tert-butyl 4-(2-fluoroacetyl)-4-methylpiperidine-1-carboxylic acid (compound B1-3):

[0507] Compound B1-2 (6.60 g, 20.61 mmol), 18-crown-6 (6.86 g, 25.97 mmol), and anhydrous potassium fluoride (3.23 g, 55.65 mmol) were added to toluene (100 mL), and the mixture was heated to 85 °C and reacted for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, water was added to the system, the organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give crude compound B1-3 (4.68 g), which was used directly in the next reaction without purification.

[0508] Step 3: Preparation of 4-(1-(tert-butylsulfinamido)-2-fluoroethyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester (compound B1-4):

[0509] Compound B1-3 (4.68 g, 16.24 mmol) was dissolved in tetraisopropyl titanate (50 mL), and tert-butylsulfinamide (2.95 g, 24.36 mmol) was added. After purging with nitrogen, the mixture was heated to 90 °C and reacted for 5 hours. After cooling to room temperature, saturated sodium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, and concentrated under reduced pressure. The residue was dissolved in methanol (50 mL), and sodium borohydride (1.69 g, 44.67 mmol) was slowly added under ice bath conditions. The mixture was heated to 25 °C and reacted for 2 hours. After the reaction was complete, the mixture was cooled to 0 °C, and saturated ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried, concentrated under reduced pressure, and purified by column chromatography to give compound B1-4 (4.85 g, 80% yield).

[0510] Step 4: Preparation of 2-fluoro-1-(4-methylpiperidin-4-yl)ethylamine (compound A-4):

[0511] Compound B1-4 (0.30 g, 0.82 mmol) was dissolved in dioxane hydrochloride solution (4 M, 3 mL) and reacted at 25 °C for 2 hours. The reaction solution was concentrated to obtain crude compound A-4 hydrochloride (0.19 g), which was used directly in the next reaction without purification.

[0512] Fragment preparation example 2: Preparation of 2-methoxy-1-(4-methylpiperidin-4-yl)ethylamine (compound A-5).

[0513]

[0514] Step 1: Preparation of tert-butyl 4-methyl-4-(ethylene oxide-2-yl)piperidine-1-carboxylic acid (compound B2-2):

[0515] Under nitrogen protection, trimethyl sulfoxide (12.20 g, 55.4 mmol) was added to DMSO (50 mL), and the mixture was cooled to 0 °C with ice water. NaH (1.27 g, 55.4 mmol) was added in portions, and the mixture was kept at 10–20 °C for 0.5 hours. Then, 4-formyl-4-methylpiperidin-1-carboxylic acid tert-butyl ester (7.00 g, 30.8 mmol) was added in a single batch, and the mixture was kept at 10–20 °C for 4 hours. The mixture was then cooled to 0 °C with ice water, and water (150 mL) and ethyl acetate (200 mL) were added sequentially. The mixture was stirred for 10 minutes, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain crude compound B2-2 (5.37 g, crude yield 72%), which was used directly for the next step without further purification.

[0516] Step 2: Preparation of tert-butyl 4-(1-hydroxy-2-methoxyethyl)-4-methylpiperidine-1-carboxylic acid (compound B2-3):

[0517] Compound B2-2 (1.40 g, 5.80 mmol) was dissolved in MeOH (60 mL), and NaOMe (10.44 g, 58.0 mmol, 30% MeOH solution) was added. The mixture was then stirred at 40 °C for 5 h. LC-MS showed that the starting material had essentially disappeared. The mixture was cooled to room temperature, and the reaction was quenched with 1 N HCl. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound B2-3 (1.4 g, crude yield 88%). This crude compound was used directly for the next step without further purification.

[0518] Step 3: Preparation of tert-butyl 4-(2-methoxyacetyl)-4-methylpiperidine-1-carboxylic acid (compound B2-4):

[0519] Compound B2-3 (300 mg, 1.10 mmol) was dissolved in DCM (20 mL), sodium bicarbonate (277 mg, 3.30 mmol) and Dess-Martin reagent (710 mg, 1.65 mmol) were added, and the mixture was stirred at room temperature for 5 h. LC-MS showed that the starting material had essentially disappeared. The mixture was cooled to room temperature, and the reaction was quenched with saturated sodium sulfite solution. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound B2-4 (250 mg, crude yield 84%). This crude compound was used directly for the next step without further purification.

[0520] Step 4: Preparation of (Z)-4-(1-(oxime)-2-methoxyethyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester (compound B2-5):

[0521] Compound B2-4 (230 mg, 0.85 mmol) was dissolved in EtOH (10 mL), and hydroxylamine hydrochloride (118 mg, 1.70 mmol) and triethylamine (257 mg, 2.54 mmol) were added. The mixture was then stirred at 60 °C for 2 h. LC-MS showed that the starting material had essentially disappeared. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with 1 N hydrochloric acid solution, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound B2-5 (230 mg, crude yield 95%), which was used directly for the next step without further purification.

[0522] Step 5: Preparation of tert-butyl 4-(1-amino-2-methoxyethyl)-4-methylpiperidine-1-carboxylic acid (compound B2-6):

[0523] Compound B2-5 (230 mg, 0.85 mmol) was dissolved in MeOH (10 mL), and Raney nickel (94 mg, 1.61 mmol) was added. After three purgings with hydrogen balloons, the mixture was stirred at room temperature for 10 hours. LC-MS showed that the starting material had essentially disappeared. The mixture was filtered through diatomaceous earth, concentrated, and yielded crude compound B2-6 (200 mg, crude yield 91%), which was used directly for the next step without further purification.

[0524] Step 6: Preparation of 2-methoxy-1-(4-methylpiperidin-4-yl)ethylamine (compound A-5):

[0525] Compound B2-6 (200 mg, 0.73 mmol) was dissolved in DCM (10 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 1 hour. LCMS showed that the starting material had essentially disappeared. The solution was concentrated to obtain trifluoroacetate of crude compound A-5 (200 mg, crude product yield 95%), which was used directly for the next step without further purification.

[0526] Referring to the method of intermediate preparation Example 2, intermediate compounds IM-3, IM-4, IM-5, IM-6, IM-8, IM-9, IM-10, IM-11, IM-12, IM-13 and IM-14 were synthesized using the corresponding starting materials; referring to the method of intermediate preparation Example 1, intermediate compound IM-15 was synthesized using the corresponding starting materials.

[0527]

[0528] Example 1: Preparation of (3-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(2-hydroxymethyl)pyrrolidine-1-yl)pyridin-4-ylthio)-5-methylpyrazin-2-yl)methanol (compound 1).

[0529]

[0530] Step 1: Preparation of (1-(3-chloro-4-iodopyridin-2-yl)pyrrolidine-2-yl)methanol (compounds 1-2):

[0531] Compound 1-1 (1.00 g, 3.88 mmol), DMSO (12 mL), pyridinyl-2-ylmethanol (432.20 mg, 4.28 mmol), and K₂CO₃ (1.61 g, 11.65 mmol) were mixed and heated to 80 °C for 4 hours. After cooling to room temperature, 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 give crude compound 1-2 (1.29 g, 98% yield), which was used directly in the next reaction without purification.

[0532] Step 2: Preparation of 2-ethylhexyl 3-(3-chloro-2-(2-hydroxymethyl)pyrrolidone-1-yl)pyridin-4-ylthio)propionic acid (compounds 1-3):

[0533] Compounds 1-2 (0.50 g, 1.48 mmol), 2-ethylhexyl 3-mercaptopropionic acid (370.83 mg, 1.70 mmol), DIPEA (381.72 mg, 2.95 mmol), Xantphos (85.45 mg, 147.68 μmol), and Pd2(dba)3 (67.62 mg, 73.84 μmol) were added to dioxane (5 mL). The mixture was evacuated under vacuum and purged three times with nitrogen. The temperature was then raised to 100 °C and reacted for 4 hours. After cooling to room temperature, the solid was filtered off, the filtrate was concentrated, and 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 give crude compounds 1-3 (632.00 mg, 99% yield), which was used directly in the next reaction without purification.

[0534] Step 3: Preparation of sodium 3-chloro-2-(2-(hydroxymethyl)pyrrolidone-1-yl)pyridine-4-thiophenol (compounds 1-4):

[0535] Sodium ethoxide (20% ethanol solution, 0.35 mL) was added to a THF solution of compounds 1-3 (300 mg, 559.42 μmol) (5 mL), and the reaction was carried out at 25 °C for 1 hour. The reaction mixture was concentrated to remove most of the solvent, and dichloromethane (5 mL) was added. The mixture was stirred for 10 minutes, filtered, and the filter cake was dried to obtain crude compounds 1-4 (149.77 mg, 100% yield), which was used directly in the next reaction without purification.

[0536] Step 4: Preparation of ethyl 3-((3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(2-(hydroxymethyl)pyrrolidine-1-yl)pyridin-4-ylthio)-5-methylpyrazine-2-carboxylic acid (compounds 1-5):

[0537] Compound IM-1 (100.0 mg, 194.77 μmol), compounds 1-4 (143.40 mg, 428.50 μmol), CuI (37.09 mg, 194.77 μmol), 1,10-phenanthroline (35.10 mg, 194.77 μmol), and K3PO4 (124.03 mg, 584.31 μmol) were added to dioxane (5 mL), and the mixture was heated to 100 °C in a microwave reactor and reacted for 1.5 hours. After cooling to room temperature, insoluble matter was filtered off, and the filtrate was concentrated to obtain the crude product. The crude product was purified by thin-layer chromatography to obtain compound 1-5 (65.00 mg, yield 49.28%).

[0538] Step 5: Preparation of (3S,4S)-8-(5-(3-chloro-2-(2-hydroxymethyl)pyrrolidone-1-yl)pyridin-4-ylthio)-3-(hydroxymethyl)-6-methylpyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-ylcarbamate (compounds 1-6):

[0539] Compounds 1-5 (65 mg, 95.98 μmol) were dissolved in dichloromethane (2 mL), and DIBAL-H (1 M hexane solution, 0.67 mL) was slowly added at -25 °C. The reaction was maintained at this temperature for 1 hour. After the reaction was complete, dichloromethane (10 mL) and a saturated sodium potassium tartrate aqueous solution (5 mL) were added to the reaction solution, and the mixture was stirred for 2 hours. The product was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by thin-layer chromatography to obtain compounds 1-6 (42 mg, yield 68.89%).

[0540] Step 6: Preparation of trifluoroacetate of (3-((3S,4S)-4-amino-3-methyl-2-oxo-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(2-(hydroxymethyl)pyrrolidine-1-yl)pyridin-4-ylthio)-5-methylpyrazin-2-yl)methanol (compound 1):

[0541] Compounds 1-6 (42 mg, 66.12 μmol) were dissolved in a mixture of dichloromethane (1 mL) and TFA (150.78 mg, 1.32 mmol) and reacted at 25 °C for 1 hour. The solvent in the reaction solution was removed by concentration to obtain a crude product, which was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain trifluoroacetate of compound 1 (27.10 mg, yield 61%).

[0542] MS(ESI): m / z 535.0 [M+H] + .

[0543] 1 H-NMR (400MHz, DMSO-d6): δ7.92 (s, 3H), 7.80 (d, J=5.2Hz, 1H), 5.90 (d, J=5.2Hz, 1H), 4 .48(s, 2H), 4.43-4.40(m, 1H), 4.23-4.19(m, 1H), 3.92(m, 1H), 3.82(m, 2H), 3.70(d, J= 8.8Hz, 1H), 3.52 (dd, J=10.4, 3.6Hz, 1H), 3.46-3.36 (m, 2H), 3.23 (m, 1H), 3.08 (m, 2H), 2.42 (s, 3H), 2.07-1.98 (m, 1H), 1.96-1.67 (m, 6H), 1.61 (m, 1H), 1.22 (d, J=6.4Hz, 3H).

[0544] Example 2: Preparation of (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(2-hydroxymethyl)pyrrolidine-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol (compound 2).

[0545]

[0546] Step 1: Preparation of methyl 6-bromo-3-((3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-carboxylic acid (compound 2-2):

[0547] Compound 2-1 (120.0 mg, 0.41 mmol), compound A-2 (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, di-tert-butyl dicarbonate (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, the product was extracted, 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 2-2 (162 mg, 82% yield).

[0548] Steps 2 to 4: Preparation of (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(2-hydroxymethyl)pyrrolidine-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol (compound 2):

[0549] Except that in step 2, compound 2-2 was used instead of compound IM-1 in step 4 of Example 1, crude compound 2 was synthesized using a method similar to that described in steps 4 to 6 of Example 1. The crude compound was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain trifluoroacetate of compound 2.

[0550] MS(ESI): m / z 521.3 [M+H] + .

[0551] 1 H-NMR (400MHz, DMSO-d6): δ8.36 (s, 1H), 7.94 (s, 3H), 7.82 (d, J=5.2Hz, 1H), 6.07 (d, J=5. 2Hz, 1H), 4.52 (s, 2H), 4.44-4.39 (m, 1H), 4.23-4.20 (m, 1H), 3.89-3.81 (m, 3H), 3.70 (d, J= 8.8Hz, 1H), 3.51 (dd, J=10.4, 3.6Hz, 1H), 3.46-3.34 (m, 2H), 3.22 (m, 1H), 3.09 (m, 2H), 2. 07-1.99 (m, 1H), 1.96-1.79 (m, 4H), 1.78-1.67 (m, 2H), 1.60 (m, 1H), 1.22 (d, J=6.4Hz, 3H).

[0552] Example 3: Preparation of (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(3-chloro-2-(2-hydroxymethyl)pyrrolidine-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol (compound 17).

[0553]

[0554] Except that 1-(4-methylpiperidin-4-yl)ethylamine dihydrochloride (compound 3-0) was used instead of compound A-2 in the first step of Example 2, crude compound 17 was synthesized using a method similar to that described in steps one through four of Example 2. The crude compound was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain trifluoroacetate of compound 17.

[0555] MS(ESI): m / z 493.2 [M+H] + .

[0556] 1H-NMR (400MHz, DMSO-d6): δ8.35 (s, 1H), 7.83 (d, J=5.2Hz, 1H), 7.71 (s, 3H), 6.08 (d, J=5.2Hz , 1H), 4.53 (s, 2H), 4.46-4.40 (m, 2H), 3.84 (m, 3H), 3.53 (dd, J=10.4, 3.6Hz, 1H), 3.41-3.35 (m , 1H), 3.25-3.19(m, 2H), 3.18-3.13(m, 1H), 2.07-2.00(m, 1H), 1.97-1.88(m, 1H), 1.86-1.78( m, 1H), 1.76-1.68 (m, 1H), 1.65-1.53 ​​(m, 3H), 1.44 (m, 1H), 1.16 (d, J=6.4Hz, 3H), 1.03 (s, 3H).

[0557] Example 4: Preparation of (1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(fluoromethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)pyrrolidine-2-yl)methanol (compound 22).

[0558]

[0559] Step 1: Preparation of (3S,4S)-8-(5-bromo-3-(hydroxymethyl)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-ylcarbamate tert-butyl ester (compound 4-1):

[0560] Compound 2-2 (60 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL), and DIBAL-H (1 M hexane solution, 0.84 mL) was slowly added at -25 °C. The reaction was maintained at this temperature for 1 hour. After the reaction was complete, dichloromethane (10 mL) and saturated sodium potassium tartrate aqueous solution (5 mL) were added to the reaction solution, and the mixture was stirred for 2 hours. The product was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by thin-layer chromatography to obtain compound 4-1 (40 mg, yield 71%).

[0561] Step 2: Preparation of (3S,4S)-8-(5-bromo-3-(fluoromethyl)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-ylcarbamate tert-butyl ester (compound 4-2):

[0562] Compound 4-1 (40 mg, 87.46 μmol) was added to dichloromethane (4 mL), and DAST (28.19 mg, 174.92 μmol) was slowly added. The reaction was carried out at room temperature for 2 hours. The reaction solution was slowly poured into a mixture of saturated sodium bicarbonate aqueous solution (5 mL) and dichloromethane (5 mL), and the product was extracted. The organic phase was washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by thin-layer chromatography to obtain compound 4-2 (32 mg, 80% yield).

[0563] Step 3: Preparation of (3S,4S)-8-(5-(3-chloro-2-(2-hydroxymethyl)pyrrolidone-1-yl)pyridin-4-ylthio)-3-(fluoromethyl)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-ylcarbamate tert-butyl ester (compound 4-3):

[0564] Except that 4-2 is used in place of IM-1 in step four of Example 1 in this step, compound 4-3 is synthesized using a similar method to that described in step four of Example 1.

[0565] Step 4: Preparation of (1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(fluoromethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)pyrrolidine-2-yl)methanol (compound 22):

[0566] Compound 4-3 (20 mg, 0.03 mmol) was dissolved in a mixture of dichloromethane (1 mL) and TFA (1 mL) and reacted at 25 °C for 1 hour. The solvent in the reaction solution was removed by concentration to obtain a crude product, which was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain trifluoroacetate of compound 22 (5 mg, yield 24%).

[0567] MS(ESI): m / z 523.2 [M+H] + .

[0568] 1H-NMR (400MHz, CD3OD): δ8.41 (d, J=1.6Hz, 1H), 7.74 (d, J=6.0Hz, 1H), 6.28 (dd, J=6.0, 1.6H z, 1H), 5.47 (d, J=47.6Hz, 2H), 4.68-4.53 (m, 1H), 4.33-4.27 (m, 1H), 3.99-3.86 (m, 4H), 3.67 -3.61 (m, 2H), 3.56 (dd, J=11.2, 5.2Hz, 1H), 3.46 (d, J=4.0Hz, 1H), 3.27-3.14 (m, 3H), 2.22- 2.16 (m, 1H), 2.08-2.02 (m, 1H), 1.98-1.84 (m, 5H), 1.76-1.72 (m, 1H), 1.32 (d, J=6.4Hz, 3H).

[0569] Example 5: Preparation of 2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)acetonitrile (compound 11).

[0570]

[0571] Except that 3-cyanomethylazonium butane was used in the first step instead of 2-hydroxymethylpyrrolidine in the first step of Example 1, and compound 4-1 was used in the fourth step instead of compound IM-1 in the fourth step of Example 1, the crude product of compound 11 was synthesized by a method similar to that described in the first to fourth steps and the sixth step of Example 1. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous formic acid) to obtain the formate salt of compound 11.

[0572] MS(ESI): m / z 516.2 [M+H] + .

[0573] 1H-NMR (400MHz, CD3OD): δ8.53 (brs, 1H), 8.30 (s, 1H), 7.73 (d, J=5.6Hz, 1H), 6.14 (d, J=5 .6Hz, 1H), 4.67 (s, 2H), 4.41 (t, J=8.8Hz, 2H), 4.32-4.26 (m, 1H), 4.03-4.00 (m, 2H), 3.96 -3.94(m, 1H), 3.89-3.80(m, 3H), 3.39(d, J=4.0Hz, 1H), 3.20-3.08(m, 2H), 3.02-2.94(m , 1H), 2.83 (d, J=6.8Hz, 2H), 1.98-1.86 (m, 3H), 1.74-1.71 (m, 1H), 1.30 (d, J=6.4Hz, 3H).

[0574] Example 6: Preparation of (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-(hydroxymethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol (compound 12).

[0575]

[0576] Except that in the first step, 3-hydroxymethylazine hydrochloride was used instead of 2-hydroxymethylpyrrolidine in the first step of Example 1, and in the fourth step, compound 2-2 was used instead of compound IM-1 in the fourth step of Example 1, crude compound 12 was synthesized using a method similar to that described in the first to sixth steps of Example 1. The crude compound was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain trifluoroacetate of compound 12.

[0577] MS(ESI): m / z 507.2 [M+H] + .

[0578] 1 H-NMR (400MHz, DMSO-d6): δ8.35 (s, 1H), 7.97 (s, 3H), 7.80 (d, J = 5.2Hz, 1H), 6.04 (d, J = 5.2Hz, 1H), 4.52 (s, 2H), 4.25-4.12 (m, 3H), 3.98 -3.65 (m, 8H), 3.56 (d, J=6.0Hz, 1H), 3.47-3.40 (m, 1H), 3.20-3.01 (m, 2H), 2.76-2.62 (m, 1H), 1.90-1.50 (m, 4H), 1.17 (d, J=6.4Hz, 3H).

[0579] Example 7: Preparation of (3-((S)-4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(2-(hydroxymethyl)pyrrolidine-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol (compound 21).

[0580]

[0581] Except that compound 7-1 was used in place of compound A-2 in the first step of Example 2, crude compound 21 was synthesized using a method similar to that described in steps one through four of Example 2. The crude compound was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain trifluoroacetate of compound 21.

[0582] MS(ESI): m / z 507.2 [M+H] + .

[0583] 1 H-NMR (400MHz, CD3OD): δ8.33 (s, 1H), 7.72 (d, J=6.0Hz, 1H), 6.28 (d, J=6.0Hz, 1H), 4.68 (s, 2H), 4.63-4.53 (m, 1H), 4.17 (dd, J=10.8, 5.6Hz , 1H), 4.02-3.81 (m, 6H), 3.71-3.50 (m, 4H), 3.27-3.19 (m, 1H), 3.18- 3.10 (m, 1H), 2.22-2.15 (m, 1H), 2.07-1.99 (m, 1H), 1.99-1.73 (m, 6H).

[0584] Example 8: Preparation of (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-(hydroxymethyl)pyrrolidine-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol (compound 37).

[0585]

[0586] Except that 3-hydroxymethylpyrrolidine was used in the first step instead of 2-hydroxymethylpyrrolidine in the first step of Example 1, and compound 2-2 was used in the fourth step instead of compound IM-1 in the fourth step of Example 1, crude compound 37 was synthesized using a method similar to that described in the first to sixth steps of Example 1. The crude compound was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous formic acid) to obtain the formate salt of compound 37.

[0587] MS(ESI): m / z 521.2 [M+H] + .

[0588] 1 H-NMR (400MHz, CD3OD): δ8.48 (brs, 1H), 8.30 (s, 1H), 7.72 (d, J=4.0Hz, 1H), 6.10 (d, J=4Hz, 1H), 4.67 (s, 2H), 4.32-4.21 (m, 1H), 3.97-3.94 (m, 1H), 3.92-3.78 (m, 3H), 3.7 4-3.65 (m, 3H), 3.62-3.50 (m, 3H), 3.42 (d, J=4Hz, 1H), 3.20-3.06 (m, 2H), 2.48-2.37 (m, 1H), 2.09-2.01 (m, 1H), 1.98-1.81 (m, 3H), 1.77-1.68 (m, 2H), 1.31 (d, J=8Hz, 3H).

[0589] Example 9: Preparation of (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-((S)-2-(hydroxymethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol (compound 33).

[0590]

[0591] Except that (S)-2-hydroxymethylazinebutane was used in the first step instead of 2-hydroxymethylpyrrolidine in the first step of Example 1, and compound 2-2 was used in the fourth step instead of compound IM-1 in the fourth step of Example 1, crude compound 33 was synthesized using a method similar to that described in the first to sixth steps of Example 1. The crude compound was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain trifluoroacetate of compound 33.

[0592] MS(ESI): m / z 507.1 [M+H] + .

[0593] 1H-NMR (400MHz, CD3OD): δ8.35 (s, 1H), 7.67 (d, J=6.4Hz, 1H), 6.31 (d, J=6.4Hz, 1H), 4.89-4.82 (m, 1H), 4.68 (s, 2H), 4.67-4.52m, 2H), 4.36-4.25 (m , 1H), 4.02-3.79 (m, 6H), 3.46 (d, J=4.0Hz, 1H), 3.25-3.07 (m, 2H), 2.54- 2.43 (m, 1H), 2.33-2.20 (m, 1H), 2.04-1.67 (m, 4H), 1.32 (d, J=6.4Hz, 3H).

[0594] Example 10: Preparation of 2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)pyrrolidine-3-yl)acetonitrile (compound 14).

[0595]

[0596] Except that 2-(pyrrolidone-3-yl)acetonitrile was used in the first step instead of 2-hydroxymethylpyrrolidine in the first step of Example 1, and compound 4-1 was used in the fourth step instead of compound IM-1 in Example 1, crude compound 14 was synthesized by a method similar to that described in the first to fourth and sixth steps of Example 1. The crude compound was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain trifluoroacetate of compound 14.

[0597] MS(ESI): m / z 530.2 [M+H] + .

[0598] 1 H-NMR (400MHz, DMSO-d6): δ8.35 (s, 1H), 7.95 (s, 3H), 7.82 (d, J = 5.2Hz, 1H), 6.07 (d, J = 5.2Hz, 1H), 4.52 (s, 2H), 4.23-4.18 (m, 1H), 3.91-3.82 ( m, 3H), 3.72-3.64 (m, 4H), 3.44-3.39 (m, 2H), 3.14-3.04 (m, 2H), 2.78-2 .69 (m, 2H), 2.14-2.06 (m, 1H), 1.85-1.59 (m, 6H), 1.22 (d, J=6.4Hz, 3H).

[0599] Example 11: Preparation of 2-(1-(5-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-6-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 130).

[0600]

[0601] Step 1: Preparation of 2-(1-(6-chloropyridin-2-yl)azacyclobutan-3-yl)prop-2-ol (compound 11-2):

[0602] 2,6-Dichloropyridine (800 mg, 5.41 mmol) was dissolved in DMSO (10 mL), and compound 12-0 (983.64 mg, 6.49 mmol) and potassium carbonate (2.24 g, 16.22 mmol) were added. The mixture was heated to 80 °C and reacted for 4 hours. After the reaction was completed as detected by LCMS, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, and concentrated to obtain crude compound 11-2 (1.06 g), which was used directly in the next reaction without purification.

[0603] Step 2: Preparation of 2-(1-(6-chloro-5-iodopyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 11-3):

[0604] Compound 11-2 (1.06 g, 4.68 mmol) was dissolved in acetonitrile (20 mL), and NIS (1.16 g, 5.14 mmol) was added. The reaction was carried out at 25 °C for 16 hours. After the reaction was completed by LCMS, the reaction solution was concentrated, and the crude product was purified by thin-layer chromatography to obtain compound 11-3 (700 mg, yield 42%).

[0605] Steps 3 to 7: Preparation of 2-(1-(5-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-6-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 130):

[0606] The crude product of compound 130 was synthesized using a method similar to steps two through six in Example 6. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate salt of compound 130.

[0607] MS(ESI): m / z 535.0 [M+H] + .

[0608] 1H-NMR (400MHz, DMSO-d6): δ7.94 (s, 3H), 7.72 (s, 1H), 7.71 (d, J=8.4Hz, 1H), 6.38 (d , J=8.4Hz, 1H), 4.46 (s, 2H), 4.29-4.11 (m, 1H), 3.97-3.86 (m, 4H), 3.82 (d, J=8.8Hz, 1H), 3.65 (d, J=8.8Hz, 1H), 3.63-3.56 (m, 3H), 2.97-2.81 (m, 2H), 2.72 (dt, J=14.8, 7 .6Hz, 1H), 1.91-1.65 (m, 3H), 1.62-1.51 (m, 1H), 1.20 (d, J=7.2Hz, 3H), 1.07 (s, 6H).

[0609] Example 12: Preparation of 2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 67).

[0610]

[0611] Step 1: Preparation of 2-(1-(3-chloro-4-iodopyridin-2-yl)azacyclobutan-3-yl)prop-2-ol (compound 12-1):

[0612] Compound 1-1 (25.0 g, 97.1 mmol), DMSO (200 mL), compound 12-0 (18.8 g, 111.7 mmol), and K2CO3 (40.3 g, 291.3 mmol) were mixed and heated to 80 °C for 4 hours. After cooling to room temperature, 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 give crude compound 12-1 (36.7 g), which was used directly in the next reaction without purification.

[0613] Step 2: Preparation of 2-ethylhexyl 3-(3-chloro-2-(3-(2-hydroxypropyl-2-yl)azacyclobutane-1-yl)pyridin-4-ylthio)propionate (compound 12-2):

[0614] Compound 12-1 (36.7 g, 93.68 mmol), 2-ethylhexyl 3-mercaptopropionic acid (24.6 g, 112.40 mmol), DIPEA (24.2 g, 187.4 mmol), Xantphos (542.0 mg, 0.94 mmol), and Pd2(dba)3 (428.9 mg, 0.47 mmol) were added to dioxane (300 mL). The mixture was evacuated under vacuum and purged three times with nitrogen. The mixture was then heated to 100 °C and reacted for 4 hours. After cooling to room temperature, the solid was filtered off, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography to give compound 12-2 (37.8 g, 86% yield).

[0615] Step 3: Preparation of sodium 3-chloro-2-(3-(2-hydroxypropyl-2-yl)azacyclobutan-1-yl)pyridine-4-thiophenol (compound 12-3):

[0616] Sodium methoxide (5.85 g, 30% methanol solution) was added to a THF (120 mL) solution of compound 12-2 (12.00 g, 27.1 mmol), and the reaction was carried out at 25 °C for 1 hour. The reaction mixture was concentrated to remove most of the solvent, and dichloromethane (100 mL) and petroleum ether (50 mL) were added. The mixture was stirred for 20 minutes, filtered, and the filter cake was dried under vacuum to obtain crude compound 12-3 (7.85 g), which was used directly in the next reaction without purification.

[0617] Step 4: Preparation of methyl 3-((3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-(2-hydroxypropyl-2-yl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazine-2-carboxylic acid (compound 12-4):

[0618] Compound 2-2 (5.00 g, 10.30 mmol), compound 12-3 (5.80 g, 20.60 mmol), CuI (0.98 g, 5.15 mmol), 1,10-phenanthroline (1.02 g, 5.15 mmol), and K3PO4 (4.37 g, 20.6 mmol) were added to dioxane (100 mL), and the mixture was heated to 100 °C and reacted for 3 hours. After cooling to room temperature, the insoluble matter was filtered off, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 12-4 (5.15 g, yield 71%).

[0619] Step 5: Preparation of (3S,4S)-8-(5-(3-(2-hydroxypropyl-2-yl)azacyclobutane-1-yl)pyridin-4-ylthio)-3-(hydroxymethyl)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-ylcarbamate tert-butyl ester (compound 12-5):

[0620] Compound 12-4 (5.15 g, 7.77 mmol) was dissolved in ethanol (80 mL), calcium chloride (3.45 g, 31.10 mmol) was added, and sodium borohydride (1.18 g, 31.10 mmol) was added in portions. The mixture was slowly heated to 35 °C and reacted for 3 hours. Water (50 mL) was slowly added, and the pH was adjusted to 7-8 with citric acid solution. Most of the ethanol was concentrated away, and the product was extracted with ethyl acetate (150 mL). The organic phase was concentrated to dryness to obtain the crude product, which was purified by column chromatography to give compound 12-5 (2.67 g, 51% yield).

[0621] Step 6: Preparation of 2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 67):

[0622] Compound 12-5 (40 mg, 0.06 mmol) was dissolved in dichloromethane (2 mL), and TFA (4 mL) was slowly added. The mixture was heated to 30 °C and reacted for 1 hour. The solvent in the reaction solution was removed by concentration to obtain a crude product. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% formic acid aqueous solution) to obtain compound 67.

[0623] MS(ESI): m / z 535.2 [M+H] + .

[0624] 1 H-NMR (400MHz, DMSO-d6) δ8.31 (s, 1H), 7.79 (d, J = 5.6Hz, 1H), 6.01 (d, J = 5.2Hz , 1H), 4.51 (s, 2H), 4.14-4.02 (m, 5H), 3.75-3.62 (m, 3H), 3.53 (d, J=8.4Hz, 1H) , 3.30-3.15(m, 2H), 3.00(d, J=5.2Hz, 1H), 2.62(p, J=7.6Hz, 1H), 1.90-1.79(m , 1H), 1.79-1.68 (m, 1H), 1.67-1.50 (m, 2H), 1.10 (d, J=6.4Hz, 3H), 1.05 (s, 6H).

[0625] Example 13: Preparation of (S)-2-(1-(4-(5-(4-amino-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 68).

[0626]

[0627] Except that compounds 12-3 were used in the first step instead of compounds 1-4 in the second step of Example 7, crude compound 68 was synthesized using a method similar to that described in the second to fourth steps of Example 7. The crude compound 68 was purified by Pre-TLC (MeOH / DCM = 1:5, V / V) to obtain compound 68.

[0628] MS(ESI): m / z 521.2 [M+H] + .

[0629] 1 H-NMR (400MHz, DMSO) δ8.33 (s, 1H), 7.79 (d, J=5.2Hz, 1H), 6.01 (d, J=5.2Hz, 1H), 5.51 (t, J=6. 0Hz, 1H), 4.51 (d, J=5.2Hz, 2H), 4.45 (s, 1H), 4.12-4.02 (m, 4H), 3.95 (dd, J=8.4, 6.4Hz, 1H), 3. 83-3.66 (m, 3H), 3.59 (d, J=8.4Hz, 1H), 3.30-3.28 (m, 1H), 3.21-3.10 (m, 2H), 3.06 (t, J=6.0Hz , 1H), 2.66-2.56(m, 1H), 1.81-1.74(m, 1H), 1.73-1.63(m, 1H), 1.52-1.42(m, 2H), 1.05(s, 6H).

[0630] Example 14: Preparation of (S)-2-(1-(4-(5-(4-(1-amino-2-methoxyethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 69).

[0631]

[0632] The crude product of compound 69 was synthesized using a method similar to that in Example 13. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate of compound 69.

[0633] MS(ESI): m / z 537.2 [M+H] + .

[0634] 1H-NMR (400MHz, DMSO) δ8.33 (s, 1H), 7.85 (br, 3H), 7.79 (d, J=5.6Hz, 1H), 6.01 (d, J=5.2Hz, 1H), 4.51 (s, 2H), 4.12-4.05 (m, 4H), 3.82-3.77 (m, 2H), 3.63 (dd, J=10.8 , 3.2Hz, 1H), 3.54-3.43 (m, 1H), 3.33 (s, 3H), 3.26-3.13 (m, 3H), 2.62 (p, J=7.6Hz , 1H), 1.76-1.62(m, 2H), 1.62-1.53(m, 1H), 1.53-1.41(m, 1H), 1.13-0.99(m, 9H).

[0635] Example 15: Preparation of 1-((4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-ylamino)methyl)cyclopropane-1-ol (compound 58).

[0636]

[0637] The crude product of compound 58 was synthesized using a method similar to that in Example 6. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate salt of compound 58.

[0638] MS(ESI): m / z 507.2 [M+H] + .

[0639] 1 H-NMR (400MHz, CD3OD): δ8.35 (s, 1H), 7.63 (d, J=6.4Hz, 1H), 6.24 (d, J=6.4Hz, 1H), 4.68 (s, 2H), 4.33-4.26 (m, 1H), 4.00-3.82 (m, 4H), 3.60 (s, 2H), 3.46 (d, J=4.4Hz, 1H), 3.27-3.14 (m, 2H), 2.01-1.67 (m, 4H), 1.32 (d, J=6.4Hz, 3H), 0.81-0.75 (m, 2H), 0.74-0.67 (m, 2H).

[0640] Example 16: Preparation of (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-(fluoromethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol (compound 125).

[0641]

[0642] The crude product of compound 125 was synthesized using a method similar to that in Example 6. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate of compound 125.

[0643] MS(ESI): m / z 509.2 [M+H] + .

[0644] 1 H-NMR (400MHz, DMSO-d6): δ 8.35 (s, 1H), 8.02 (s, 3H), 7.82 (d, J = 5.2Hz, 1H), 6.08 (d, J = 5.2Hz, 1H), 4.68 (d, J = 5.6Hz, 1H), 4.56 (d, J = 5.6Hz, 1H), 4.52 (s, 2H), 4.30-4.17 (m, 4H), 4.00-3.78 (m, 4H), 3.70 (d, J=9.2Hz, 1H), 3.48 -3.40 (m, 1H), 3.15-2.90 (m, 3H), 1.93-1.55 (m, 4H), 1.22 (d, J=6.4Hz, 3H).

[0645] Example 17: Preparation of 1-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)ethanol (compound 70).

[0646]

[0647] The crude product of compound 70 was synthesized using a method similar to that in Example 6. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate of compound 70.

[0648] MS(ESI): m / z 521.3 [M+H] + .

[0649] 1H-NMR (400MHz, DMSO-d6): δ8.34 (s, 1H), 7.95 (s, 3H), 7.80 (d, J = 5.6Hz, 1H), 6.03 (d, J = 5.6Hz, 1H), 4.52 (s, 2H), 4.25-4.18 (m, 1H), 4.17-4.10 (m, 2H), 4.08-4.01(m, 1H), 3.90-3.45(m, 7H), 3.15-3.01(m, 2H), 2.57-2.52 (m, 1H), 1.92-1.55 (m, 4H), 1.22 (d, J=6.4Hz, 3H), 1.02 (d, J=6.4Hz, 3H).

[0650] Example 18: Preparation of 2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)pyrrolidine-2-yl)acetonitrile (compound 5).

[0651]

[0652] The crude product of compound 5 was synthesized using a method similar to that in Example 5. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate of compound 5.

[0653] MS(ESI): m / z 530.2 [M+H] + .

[0654] 1 H-NMR (400MHz, DMSO-d6): δ8.37 (s, 1H), 7.98 (s, 3H), 7.88 (d, J=5.2Hz, 1H), 6.18 (d, J= 5.2Hz, 1H), 4.52 (s, 2H), 4.45-4.44 (m, 1H), 4.24-4.18 (m, 1H), 3.97-3.81 (m, 4H), 3.70 (d, J=9.2Hz, 1H), 3.43-3.37(m, 2H), 3.14-3.04(m, 2H), 2.89-2.78(m, 2H), 2.22-2.16( m, 1H), 2.06-1.95 (m, 1H), 1.89-1.74 (m, 5H), 1.63-1.59 (m, 1H), 1.20 (t, J=6.4Hz, 3H).

[0655] Example 19: Preparation of 2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)pyrrolidine-2-yl)acetamide (compound 4).

[0656]

[0657] Compound 5 (20 mg, 37.73 μmol) was dissolved in a mixture of dichloromethane (1 mL), water (0.5 mL), and TFA (80 mg, 0.69 mmol), and reacted at 35 °C for 2 hours. The solvent in the reaction solution was removed by concentration to obtain a crude product, which was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain trifluoroacetate of compound 4 (7.20 mg, yield 30%).

[0658] MS(ESI): m / z 548.1 [M+H] + .

[0659] 1 H-NMR (400MHz, DMSO-d6): δ8.36 (s, 1H), 7.94 (s, 3H), 7.86 (d, J=5.2Hz, 1H), 7.23 (s, 1H), 6. 79 (s, 1H), 6.10 (d, J=5.2Hz, 1H), 4.59-4.49 (m, 3H), 4.25-4.18 (m, 1H), 3.90-3.79 (m, 3H), 3 .763.69 (m, 3H), 3.46-3.44 (m, 1H), 3.36-3.32 (m, 1H), 3.14-3.04 (m, 2H), 2.55 (dd, J=14.0, 3.6Hz, 1H), 2.13-2.09 (m, 1H), 1.95-1.81 (m, 3H), 1.67-1.59 (m, 4H), 1.22 (d, J=6.4Hz, 3H).

[0660] Example 20: Preparation of (R)-2-(1-(4-(5-(3-amino-5-fluoro-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 97).

[0661]

[0662] The crude product of compound 97 was synthesized using a method similar to that in Example 13. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate of compound 97.

[0663] MS(ESI): m / z 586.9 [M+H] + .

[0664] 1 H-NMR (400MHz, DMSO-d6): δ8.54 (s, 3H), 8.38 (s, 1H), 7.80 (d, J=5.6Hz, 1H), 7.38 (dd, J= 8.0, 2.8Hz, 1H), 7.23 (td, J=8.8, 4.4Hz, 1H), 7.01 (dd, J=8.8, 4.4Hz, 1H), 6.05 (d, J=5.6 Hz, 1H), 4.77-4.69 (m, 1H), 4.56 (s, 2H), 4.20-4.02 (m, 5H), 3.98-3.85 (m, 2H), 3.41-3.2 7(m, 2H), 2.70-2.57(m, 1H), 2.16(t, J=13.2, 4.4Hz, 1H), 2.07-1.76(m, 3H), 1.05(s, 6H).

[0665] Example 21: Preparation of (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-(methoxymethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol (compound 71).

[0666]

[0667] The crude product of compound 71 was synthesized using a method similar to that in Example 5. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate of compound 71.

[0668] MS(ESI): m / z 521.2 [M+H] + .

[0669] 1H-NMR (400MHz, DMSO-d6): δ8.33 (s, 1H), 7.99 (s, 3H), 7.80 (d, J=5.6Hz, 1H), 6.06 (d, J=5.2Hz, 1H), 4.52 (s, 2H), 4.24-4.20 (m, 3H), 3.92-3.85 (m, 4H), 3.71-3.69 (s, 2H), 3 .51(d, J=6.8Hz, 2H), 3.45-3.41(m, 1H), 3.28(s, 3H), 3.14-3.03(m, 2H), 2.89-2.81(m , 1H), 1.88-1.83 (m, 2H), 1.76-1.73 (m, 1H), 1.63-1.60 (m, 1H), 1.22 (d, J=6.8Hz, 3H).

[0670] Example 22: Preparation of (R)-2-(1-(4-(5-(3-amino-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 72).

[0671]

[0672] The crude product of compound 72 was synthesized using a method similar to that in Example 13. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate of compound 72.

[0673] MS (ESI): m / z 569.2 [M+H] + .

[0674] 1 H-NMR (400MHz, DMSO-d6): δ8.44 (s, 3H), 8.38 (s, 1H), 7.80 (d, J=5.4Hz, 1H), 7.57 (d, J=7.4Hz , 1H), 7.38 (t, J=7.4Hz, 1H), 7.02 (dd, J=16.4, 8.0Hz, 2H), 6.05 (d, J=5.4Hz, 1H), 4.73-4.68 (m , 1H), 4.56 (s, 2H), 4.10 (d, J=7.6Hz, 4H), 3.97-3.92 (m, 1H), 3.45-3.43 (m, 2H), 3.33-3.30 (m, 1H), 2.66-2.60(m, 1H), 2.21-2.12(m, 1H), 2.05-1.89(m, 2H), 1.82-1.77(m, 1H), 1.05(s, 6H).

[0675] Example 23: Preparation of (S)-2-(1-(4-(5-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 73).

[0676]

[0677] The crude product of compound 73 was synthesized using a method similar to that in Example 13. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate of compound 73.

[0678] MS (ESI): m / z 567.3 [M+H] + .

[0679] 1 H-NMR (400MHz, DMSO-d6): δ8.35 (s, 1H), 8.23 ​​(s, 3H), 7.80 (d, J=5.4Hz, 1H), 7.51 (d, J=7. 2Hz, 1H), 7.40-7.29 (m, 3H), 6.03 (d, J=5.6Hz, 1H), 4.54 (s, 2H), 4.44-4.40 (m, 1H), 4.08 (d , J=7.6Hz, 4H), 4.01-3.95 (m, 1H), 3.87-3.84 (s, 1H), 3.29-3.19 (m, 2H), 3.17-3.13 (m, 1H) , 3.04-3.00 (m, 1H), 2.65-2.58 (m, 1H), 1.89-1.80 (m, 2H), 1.61-1.51 (m, 2H), 1.05 (s, 6H).

[0680] Example 24: Preparation of 2-(1-(4-(5-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 74).

[0681]

[0682] The crude product of compound 74 was synthesized using a method similar to that in Example 13. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate of compound 74.

[0683] MS(ESI): m / z 507.2 [M+H] + .

[0684] 1 H-NMR (400MHz, DMSO-d6): δ8.33 (s, 1H), 7.79 (d, J = 5.2Hz, 1H), 7.69 (s, 3H), 6.01 (d, J = 5.2Hz, 1H), 4.51 (s, 2H), 4.08 (d, J = 7.6Hz, 4H), 3.8 5-3.78 (m, 2H), 3.25-3.10 (m, 3H), 2.64-2.58 (m, 1H), 1.691.53 (m, 3H), 1.441.41 (m, 1H), 1.14 (d, J=6.8Hz, 3H), 1.05 (s, 6H), 1.01 (s, 3H).

[0685] Example 25: Preparation of (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-(methylsulfonylmethyl)azacyclobutane-1-yl)pyridin-4-ylthio)-5-methylpyrazine-2-yl)methanol (compound 75).

[0686]

[0687] The crude product of compound 75 was synthesized using a method similar to that in Example 5. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate of compound 75.

[0688] MS(ESI): m / z 583.1 [M+H] + .

[0689] 1 H-NMR (400MHz, CD3OD): δ7.64-7.58 (m, 1H), 6.11-6.08 (m, 1H), 4.72-4.60 (m, 4H), 4.41-4.27 (m, 3H), 4.01-3.83 (m, 4H), 3.58 (d, J=7.6Hz, 2H), 3. 45(d, J=4.0Hz, 1H), 3.41-3.33(m, 1H), 3.21-3.06(m, 2H), 3.01(s, 3H), 2 .48 (s, 3H), 2.03-1.87 (m, 3H), 1.74-1.71 (m, 1H), 1.32 (d, J=6.4Hz, 3H).

[0690] Example 26: Preparation of (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-(methylsulfonylmethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol (compound 76).

[0691]

[0692] The crude product of compound 76 was synthesized using a method similar to steps four and five of Example 5. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate of compound 76.

[0693] MS(ESI): m / z 569.0 [M+H] + .

[0694] 1 H-NMR (400MHz, CD3OD): δ8.32 (s, 1H), 7.66 (d, J=6.0Hz, 1H), 6.22 (d, J=6.0Hz , 1H), 4.66 (s, 2H), 4.62-4.58 (m, 2H), 4.32-4.25 (m, 3H), 3.97-3.84 (m, 4H), 3 .56(d, J=7.6Hz, 2H), 3.45(d, J=4.0Hz, 1H), 3.38-3.32(m, 1H), 3.20-3.07(m, 2H), 3.00 (s, 3H), 1.99-1.88 (m, 3H), 1.77-1.68 (m, 1H), 1.31 (d, J=6.5Hz, 3H).

[0695] Example 27: Preparation of (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-(hydroxymethyl)-3-methylazacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol (compound 77).

[0696]

[0697] The crude product of compound 77 was synthesized using a method similar to that in Example 5. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate of compound 77.

[0698] MS(ESI): m / z 521.1 [M+H] + .

[0699] 1H-NMR (400MHz, DMSO-d6): δ8.34 (s, 1H), 7.95 (s, 3H), 7.79 (d, J=5.6Hz, 1H), 6.0 3(d, J=5.2Hz, 1H), 4.52(s, 2H), 4.25-4.16(m, 1H), 4.03-4.00(m, 2H), 3.93-3.81 (m, 3H), 3.76-3.73 (m, 2H), 3.71-3.68 (m, 1H), 3.48-3.40 (m, 3H), 3.13-3.03 (m, 2H), 1.88-1.76(m, 2H), 1.76-1.71(m, 1H), 1.65-1.55(m, 1H), 1.22-1.21(m, 6H).

[0700] Example 28: Preparation of 2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 78).

[0701]

[0702] The crude product of compound 78 was synthesized using a method similar to steps four and five of Example 5. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% formic acid aqueous solution) to obtain compound 78.

[0703] MS (ESI): m / z 505.1 [M+H] + .

[0704] 1 H-NMR (400MHz, DMSO-d6): δ8.48(s, 1H), 8.29(s, 1H), 8.24(s, 1H), 7.78(d, J=5.2Hz, 1H), 5.92(d, J=5.2Hz, 1H), 4.12-4.03(m, 5H), 4.00-3.95(m, 2H), 3.75-3.70(m, 1H), 3.55-3.53(m, 1H), 3.37-3.34(m, 2H), 3.05-3.00(m, 1H) , 2.65-2.58 (m, 1H), 1.79-1.50 (m, 4H), 1.12 (d, J=6.4Hz, 3H), 1.05 (s, 6H).

[0705] Example 29: Preparation of (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-methyl-3-(methylsulfonylmethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol (compound 79).

[0706]

[0707] Step 1: Preparation of tert-butyl 3-methyl-3-(p-toluenesulfonyloxymethyl)-azacyclobutane-1-carboxylic acid (compound 29-2):

[0708] Compound 29-1 (1 g, 4.97 mmol) was dissolved in pyridine (10 mL), cooled to 0 °C, and TsCl (516 mg, 5.96 mmol) was added. After the addition was complete, the mixture was heated to 25 °C and reacted for 3 hours. After the reaction was complete, the reaction solution was quenched in water and extracted with dichloromethane. The organic phases were combined, dried, and concentrated to give the crude product. The crude product was purified by column chromatography to give compound 29-2 (900 mg, 48% yield).

[0709] Step 2: Preparation of tert-butyl 3-methyl-3-(methylthiomethyl)-azacyclobutane-1-carboxylic acid (compound 29-3):

[0710] Compound 29-2 (900 mg, 2.53 mmol) was dissolved in NMP (10 mL), and sodium methanethiol (355 mg, 5.06 mmol) was added at 20 °C. After the addition was complete, the mixture was heated to 70 °C and reacted for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phases were combined, dried, and concentrated to give crude compound 29-3 (600 mg), which was used directly in the next reaction without purification.

[0711] Step 3: Preparation of tert-butyl 3-methyl-3-(methylsulfonylmethyl)azacyclobutane-1-carboxylic acid (compound 29-4):

[0712] Compound 29-3 (600 mg, 2.07 mmol) was dissolved in DCM (20 mL) and cooled to 5 °C. m-CPBA (787 mg, 4.56 mmol) was added in portions. After the addition was complete, the mixture was allowed to rise naturally to room temperature for 4 hours. After the reaction was complete, 10 mL of 15% potassium carbonate aqueous solution was added and stirred for 5 minutes. After separation, the organic phase was washed with saturated brine, dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 29-4 (300 mg, 52% yield).

[0713] Step 4: Preparation of 3-methyl-3-(methylsulfonylmethyl)azacyclobutane (compound 29-5):

[0714] Compound 29-4 (300 mg, 1.14 mmol) was dissolved in DCM (2 mL), and TFA (1 mL) was added. The mixture was reacted at 20 °C for 1 hour. After the reaction was complete, the solvent was removed by concentration to obtain compound 29-5 (300 mg).

[0715] Steps 5 through 9: Preparation of (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-methyl-3-(methylsulfonylmethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol (compound 79).

[0716] Steps 5 through 9 were performed using a method similar to that in Example 5 to synthesize crude compound 79. The crude compound was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% formic acid aqueous solution) to obtain compound 79.

[0717] MS(ESI): m / z 583.2 [M+H] + .

[0718] 1 H-NMR (400MHz, DMSO-d6): δ8.32 (s, 1H), 7.81 (d, J=5.2Hz, 1H), 6.08 (d, J=5.2Hz, 1H), 4. 50 (s, 2H), 4.20 (d, J = 8.4Hz, 2H), 4.13-4.05 (m, 1H), 3.90 (d, J = 8.4Hz, 2H), 3.72-3.66 (m , 3H), 3.60 (s, 2H), 3.54 (d, J=8.8Hz, 1H), 3.27-3.15 (m, 2H), 3.04 (d, J=4.8Hz, 1H), 3.01 (m, 3H), 1.90-1.70 (m, 2H), 1.64-1.60 (m, 1H), 1.56-1.50 (m, 4H), 1.12 (d, J=6.4Hz, 3H).

[0719] Example 30: Preparation of 2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)-2-methylpropionitrile (compound 80).

[0720]

[0721] The crude product of compound 80 was synthesized using a method similar to that in Example 5. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% formic acid aqueous solution) to obtain compound 80.

[0722] MS(ESI): m / z 544.1 [M+H] + .

[0723] 1 H-NMR (400MHz, DMSO-d6): δ8.33 (s, 1H), 8.26 (s, 1H), 7.83 (d, J = 5.2Hz, 1H), 6.09 (d, J = 5.2Hz, 1 H), 5.56-5.49 (m, 1H), 4.51 (s, 2H), 4.29 (t, J=8.8Hz, 2H), 4.11-4.06 (m, 1H), 4.03-3.97 (m, 2H), 3.72-3.63(m, 3H), 3.52-3.50(m, 1H), 3.23-3.17(m, 2H), 2.96(d, J=5.2Hz, 1H), 2.82-2.75(m, 2 H), 1.87-1.79 (m, 1H), 1.76-1.68 (m, 1H), 1.62-1.49 (m, 2H), 1.29 (s, 6H), 1.09 (d, J=6.4Hz, 3H).

[0724] Example 31: Preparation of 3-((4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-ylthio)-3-chloropyridin-2-ylamino)methyl)oxecyclobutyl-3-ol (compound 81).

[0725]

[0726] The crude product of compound 81 was synthesized using a method similar to that in Example 5. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate of compound 81.

[0727] MS(ESI): m / z 537.1 [M+H] + .

[0728] 1H-NMR (400MHz, CD3OD): δ7.61 (d, J=7.2Hz, 1H), 6.23 (d, J=7.2Hz, 1H), 4.65 (s, 2H), 4.63-4.28 (m, 2H), 4.18-4.10 (m, 1H), 4.05-3.90 (m, 3H), 3.89 -3.84(m, 1H), 3.67-3.60(m, 3H), 3.50-3.43(m, 2H), 3.24-3.09(m, 2H), 2 .52 (s, 3H), 2.03-1.80 (m, 3H), 1.76-1.66 (m, 1H), 1.33 (d, J=6.8Hz, 3H).

[0729] Example 32: Preparation of 2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 82).

[0730]

[0731] The crude product of compound 82 was synthesized using a method similar to that in Example 13. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain trifluoroacetate of compound 82.

[0732] MS (ESI): m / z 549.3 [M+H] + .

[0733] 1 H-NMR (400MHz, DMSO-d6) δ7.94 (s, 3H), 7.77 (d, J = 5.4Hz, 1H), 5.85 (d, J = 5.4Hz , 1H), 4.48 (s, 2H), 4.24-4.18 (m, 1H), 4.09-4.07 (m, 4H), 3.96-3.81 (m, 3H), 3.7 0-3.68(m, 1H), 3.45-3.43(m, 1H), 3.12-3.02(m, 2H), 2.66-2.59(m, 1H), 2.41(s , 3H), 1.89-1.71 (m, 3H), 1.62-1.59 (m, 1H), 1.22 (d, J=6.4Hz, 3H), 1.05 (s, 6H).

[0734] Example 33: Preparation of (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-(methoxymethyl)-3-methylazacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol (compound 83).

[0735]

[0736] Step 1: Preparation of 3-chloro-4-iodo-2-(3-(methoxymethyl)-3-methylazacyclobutane-1-yl)pyridine (compound 33-1):

[0737] Compound 27-1 (0.30 g, 0.88 mmol) was dissolved in THF (3 mL), and NaH (70.89 mg, 1.77 mmol) was added. The mixture was reacted at 25 °C for 20 min, and then iodomethane (377.31 mg, 2.66 mmol) was added. The reaction was continued at 25 °C for 2 h. After the reaction was completed as detected by LCMS, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, concentrated, and purified by thin-layer chromatography to give compound 33-1 (100 mg, yield 32%).

[0738] Steps 2 to 6: Preparation of (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-(methoxymethyl)-3-methylazacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol (compound 83):

[0739] The crude product of compound 83 was synthesized using a method similar to steps two through six of Example 6. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% formic acid aqueous solution) to obtain compound 83.

[0740] MS(ESI): m / z 535.2 [M+H] + .

[0741] 1H-NMR (400MHz, CD3OD): δ8.27 (s, 1H), 7.68 (d, J=5.2Hz, 1H), 6.07 (d, J=5.2Hz, 1H ), 4.66 (s, 2H), 4.28-4.16 (m, 1H), 4.09 (d, J = 8.4Hz, 2H), 3.85 (dd, J = 8.4, 4.0Hz, 3 H), 3.77-3.63 (m, 3H), 3.41 (s, 2H), 3.39 (s, 3H), 3.29-3.12 (m, 2H), 3.03 (d, J=5.2 Hz, 1H), 1.99-1.81 (m, 2H), 1.77-1.65 (m, 2H), 1.31 (s, 3H), 1.22 (d, J=6.4Hz, 3H).

[0742] Example 34: Preparation of 2-(1-(4-(5-(4-(1-amino-2-fluoroethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 84).

[0743]

[0744] The crude product of compound 84 was synthesized using a method similar to that in Example 13. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate salt of compound 84.

[0745] MS(ESI): m / z 525.3 [M+H] + .

[0746] 1 H-NMR (400MHz, CD3OD): δ8.33 (s, 1H), 7.60 (d, J=5.6Hz, 1H), 6.22 (d, J=5.2Hz, 1H), 4.81-4.70 (m, 2H), 4.67 (s, 2H), 4.53- 4.33(m, 4H), 3.93-3.77(m, 2H), 3.51-3.37(m, 2H), 3.25-3.16(m, 1H), 2.88-2.73(m, 1H), 1.91-1.56(m, 4H), 1.19(m, 9H).

[0747] Example 35: Preparation of (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro

[45] decane-8-yl)-6-(3-chloro-2-(oxacyclobutane-3-ylmethoxy)pyridin-4-ylthio)pyrazin-2-yl)methanol (compound 59).

[0748]

[0749] The crude product of compound 59 was synthesized using a method similar to that in Example 5. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate salt of compound 59.

[0750] MS(ESI): m / z 508.1 [M+H] + .

[0751] 1 H-NMR (400MHz, CD3OD-d4): δ8.39 (s, 1H), 7.94 (d, J=7.2Hz, 1H), 6.90 (d, J=6.8Hz, 1H), 4.9 4-4.93 (m, 1H), 4.71-4.65 (m, 3H), 4.59 (dd, J=13.2, 4.2Hz, 1H), 4.42 (dd, J=13.6, 8.4Hz, 1 H), 4.34-4.27 (m, 1H), 4.01-3.86 (m, 4H), 3.77-3.71 (m, 2H), 3.46 (d, J=4.0Hz, 1H), 3.24-3 .10 (m, 2H), 2.72-2.66 (m, 1H), 2.02-1.87 (m, 3H), 1.76-1.73 (m, 1H), 1.32 (d, J=6.8Hz, 3H).

[0752] Example 36: Preparation of 2-(1-(4-(3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 85).

[0753]

[0754] Step 1: Preparation of 2-(1-(4-(3-amino-5-chloropyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 36-2):

[0755] Compound 36-1 (135 mg, 647.66 μmol), compound 12-3 (272.74 mg, 917.49 μmol), CuI (123.35 mg, 647.66 μmol), 1,10-phenanthroline (116.71 mg, 647.66 μmol), and K3PO4 (412.43 mg, 1.94 mmol) were added to dioxane (8 mL), and the mixture was heated to 105 °C in a microwave reactor and reacted for 2 hours. After cooling to room temperature, insoluble matter was filtered off, and the filtrate was concentrated to obtain the crude product. The crude product was purified by thin-layer chromatography to obtain compound 36-2 (130 mg, yield 52%).

[0756] Step 2: Preparation of 2-(1-(4-(3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 85):

[0757] Compound 36-2 (50 mg, 129.43 μmol), compound A-2 (63 mg, 258.87 μmol), and DIPEA (134 mg, 1.04 mmol) were added to DMF (3 mL), and the system was heated to 100 °C and reacted for 16 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% formic acid aqueous solution) to obtain compound 85 (8.10 mg, yield 11%).

[0758] MS(ESI): m / z 520.2 [M+H] + .

[0759] 1 H-NMR (400MHz, DMSO-d6): δ7.76 (d, J=5.6Hz, 1H), 7.63 (s, 1H), 6.14 (s, 2H), 5.84 (d, J=5.6Hz, 1H), 4.10-4.00 (m, 6H), 3.90-3.78 (m, 3H), 3. 67 (d, J=8.4Hz, 1H), 3.49 (d, J=8.4Hz, 1H), 2.92 (d, J=5.2Hz, 1H), 2.66-2.56 (m, 1H), 1.76-1.42 (m, 4H), 1.08 (d, J=6.8Hz, 3H), 1.05 (s, 6H).

[0760] Example 37: Preparation of (1-(4-(3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)pyrrolidine-2-yl)methanol (compound 86).

[0761]

[0762] The crude product of compound 86 was synthesized using a method similar to that in Example 36. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate of compound 86.

[0763] MS(ESI): m / z 506.1 [M+H] + .

[0764] 1 H-NMR (400MHz, DMSO-d6): δ7.98 (s, 3H), 7.80 (d, J=5.2Hz, 1H), 7.69 (s, 1H), 6.23 (s, 2H), 5.92 (d, J=5.2Hz , 1H), 4.46-4.39 (m, 1H), 4.25-4.18 (m, 2H), 4.16-4.12 (m, 1H), 3.88-3.80 (m, 2H), 3.69 (d, J=9.2Hz, 1H), 3. 52 (dd, J=10.4, 3.6Hz, 1H), 3.43-3.34 (m, 2H), 3.22 (dd, J=10.4, 7.2Hz, 1H), 3.13-3.00 (m, 2H), 2.08-1.99 (m, 1H), 1.97-1.89 (m, 1H), 1.86-1.78 (m, 1H), 1.70-1.67 (m, 4H), 1.57-1.54 (m, 1H), 1.22 (d, J=6.4Hz, 3H).

[0765] Example 38: Preparation of (3S,4S)-8-(6-amino-5-(3-chloro-2-(3-(methylsulfonylmethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine (compound 87).

[0766]

[0767] The crude product of compound 87 was synthesized using a method similar to that in Example 36. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% formic acid aqueous solution) to obtain compound 87.

[0768] MS(ESI): m / z 554.1 [M+H] + .

[0769] 1 H-NMR (400MHz, DMSO-d6): δ7.79 (d, J=5.2Hz, 1H), 7.63 (s, 1H), 6.14 (s, 2H), 5.91 (d, J=5.2Hz , 1H), 4.31 (t, J=8.4Hz, 2H), 4.10-4.03 (m, 1H), 4.03-3.96 (m, 2H), 3.87-3.79 (s, 2H), 3.66 (d, J=8.4Hz, 1H), 3.53-3.47(m, 3H), 3.43-3.38(m, 1H), 3.20-3.07(m, 2H), 2.98(s, 3H), 2.89(d, J=5.2Hz, 1H), 1.76-1.69 (m, 1H), 1.64-1.58 (m, 1H), 1.53-1.42 (m, 2H), 1.08 (d, J=6.4Hz, 3H).

[0770] Example 39: Preparation of (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-fluoro-3-(hydroxymethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol (compound 88).

[0771]

[0772] The crude product of compound 88 was synthesized using a method similar to that in Example 6. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% formic acid aqueous solution) to obtain compound 88.

[0773] MS(ESI): m / z 525.2 [M+H] + .

[0774] 1 H-NMR (400MHz, CD3OD): δ8.35 (s, 1H), 7.95 (s, 3H), 7.86 (d, J = 5.6Hz, 1H), 6.15 (d, J = 5.6Hz, 1H), 4.52 (s, 2H), 4.33 (d, J = 10.4Hz, 1H), 4.2 8 (d, J=10.4Hz, 1H), 4.24-4.10 (m, 4H), 3.9-3.60 (m, 6H), 3.48-3.38 (m, 1H), 3.17-3.30 (m, 2H), 1.92-1.55 (m, 4H), 1.22 (d, J=6.4Hz, 3H).

[0775] Example 40: Preparation of 2-(1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-fluoropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 90).

[0776]

[0777] The crude product of compound 90 was synthesized using a method similar to that in Example 6. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% formic acid aqueous solution) to obtain compound 90.

[0778] MS(ESI): m / z 519.1 [M+H] + .

[0779] 1 H-NMR (400MHz, DMSO-d6): δ8.23 (s, 1H), 7.61 (d, J=5.6Hz, 1H), 6.40-6.05 (m, 1H), 4.64 (s, 2H), 4.28-4.17 (m, 1H), 4.17-4.03 (m, 4H), 3.85 (d, J=8.8Hz, 1H), 3.71 (d, J =8.8Hz, 1H), 3.69-3.59 (m, 2H), 3.25-3.07 (m, 2H), 3.03 (d, J = 5.2Hz, 1H), 2.86-2.7 6 (m, 1H), 1.98-1.81 (m, 2H), 1.78-1.64 (m, 2H), 1.22 (d, J=6.8Hz, 3H), 1.18 (s, 6H).

[0780] Example 41: Preparation of (R)-2-(1-(4-(5-(3-amino-5-fluoro-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 107).

[0781]

[0782] The crude product of compound 107 was synthesized using a method similar to that in Example 13. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate of compound 107.

[0783] MS(ESI): m / z 557.0 [M+H] + .

[0784] 1 H-NMR (400MHz, DMSO-d6): δ8.59 (d, J=0.8Hz, 1H), 8.55 (s, 3H), 8.36 (d, J=0.8Hz, 1H), 7.80 (d, J =5.2Hz, 1H), 7.38 (dd, J=8.0, 2.8Hz, 1H), 7.23 (td, J=8.8, 2.8Hz, 1H), 7.01 (d, J=9.2, 4.4Hz, 1H) , 5.95 (d, J=5.2Hz, 1H), 4.77-4.65 (m, 1H), 4.60-4.51 (m, 1H), 4.46-4.36 (m, 1H), 4.08 (d, J=7.6H z, 4H), 3.42-3.25 (m, 2H), 2.70-2.55 (m, 1H), 2.10-1.94 (m, 2H), 1.90-1.76 (m, 2H), 1.05 (s, 6H).

[0785] Example 42: Preparation of (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-(fluoromethyl)-3-(hydroxymethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol (compound 124).

[0786]

[0787] Step 1: Preparation of 1-tert-butyl-3-methyl-3-(fluoromethyl)azacyclobutane-1,3-dicarboxylic acid ester (compound 42-2):

[0788] Compound 42-1 (450 mg, 1.93 mmol) was dissolved in DMF (5 mL), and potassium carbonate (533 mg, 3.86 mmol) and methyl iodide (411 mg, 2.89 mmol) were added. The reaction was carried out at 25 °C for 2 hours. The reaction was quenched by adding saturated ammonium chloride, extracted with ethyl acetate, and the organic phases were combined, dried, concentrated under reduced pressure, and purified by silica gel column chromatography to give compound 42-2 (345 mg, yield 72%).

[0789] Step 2: Preparation of tert-butyl 3-(fluoromethyl)-3-(hydroxymethyl)azacyclobutane-1-carboxylic acid (compound 42-3):

[0790] Compound 42-2 (320 mg, 1.29 mmol) was added to methanol (10 mL), followed by sodium borohydride (143 mg, 3.88 mmol). The reaction was carried out at 25 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, water was added to the system, the organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain crude compound 42-3 (280 mg), which was used directly in the next reaction without purification.

[0791] Step 3: Preparation of (3-(fluoromethyl)azacyclobutane-3-yl)methanol hydrochloride (compound 42-4):

[0792] Compound 42-3 (280 mg, 1.27 mmol) was dissolved in 4 M HCl / EA solution (5 mL) and reacted at 25 °C for 2 hours. The solvent was removed under reduced pressure to obtain crude compound 42-4 (210 mg), which was used directly in the next reaction without purification.

[0793] Steps 4 to 9: Preparation of (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(3-chloro-2-(3-(fluoromethyl)-3-(hydroxymethyl)azacyclobutane-1-yl)pyridin-4-ylthio)pyrazin-2-yl)methanol (compound 124):

[0794] The crude product of compound 124 was synthesized using a method similar to that described in steps one through six of Example 12. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate of compound 124.

[0795] MS (ESI): m / z 538.9 [M+H] + .

[0796] 1 H-NMR (400MHz, DMSO-d6): δ8.35 (s, 1H), 7.97 (brs, 3H), 7.81 (d, J=5.6Hz, 1H), 6.0 6(d, J=5.6Hz, 1H), 4.65(s, 1H), 4.53(s, 1H), 4.52(s, 2H), 4.25-4.17(m, 1H), 4.05- 3.78(m, 7H), 3.69(d, J=8.8Hz, 1H), 3.60(s, 2H), 3.38-3.34(m, 1H), 3.17-3.02(m, 2 H), 1.92-1.79 (m, 2H), 1.79-1.70 (m, 1H), 1.65-1.54 (m, 1H), 1.21 (d, J=6.8Hz, 3H).

[0797] Example 43: Preparation of (S)-2-(1-(4-(5-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidin]-1′-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 89).

[0798]

[0799] The crude product of compound 89 was synthesized using a method similar to that in Example 13. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate of compound 89.

[0800] MS(ESI): m / z 568.0 [M+H] + .

[0801] 1 H NMR (400MHz, DMSO) δ8.56 (dd, J=5.2, 1.6Hz, 1H), 8.44 (br, 3H), 8.36 (s, 1H), 7.96 (d, J=7 .6Hz, 1H), 7.80 (d, J=5.6Hz, 1H), 7.39 (dd, J=8.0, 5.2Hz, 1H), 6.05 (d, J=5.2Hz, 1H), 4.51 (s, 2H), 4.59-4.45 (m, 1H), 4.17-4.06 (m, 4H), 4.05-3.84 (m, 2H), 3.36-3.17 (m, 3H), 3.12 (d, J=17.2Hz, 1H), 2.68-2.57(m, 1H), 1.97-1.82(m, 2H), 1.67-1.50(m, 2H), 1.05(s, 6H).

[0802] Example 44: Preparation of (R)-2-(1-(4-(5-(3-amino-3H-spiro[furano[2,3-b]pyridin-2,4′-piperidin]-1′-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 101).

[0803]

[0804] The crude product of compound 101 was synthesized using a method similar to that in Example 13. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate of compound 101.

[0805] MS(ESI): m / z 570.0 [M+H] +.

[0806] 1 H-NMR (400MHz, DMSO-d6): δ8.60 (brs, 3H), 8.39 (s, 1H), 8.22 (dd, J=5.2, 1.6Hz, 1H), 7.97 (dd, J= 7.2, 1.2Hz, 1H), 7.80 (d, J=5.2Hz, 1H), 7.09 (dd, J=7.6, 5.2Hz, 1H), 6.06 (d, J=5.2Hz, 1H), 4.84-4 .73(m, 1H), 4.57(s, 2H), 4.20-4.10(m, 1H), 4.08(d, J=7.6Hz, 4H), 4.02-3.94(m, 1H), 3.44-3.28 (m, 2H), 2.70-2.57 (m, 1H), 2.25-2.12 (m, 1H), 2.08-1.90 (m, 2H), 1.90-1.77 (m, 1H), 1.05 (s, 6H).

[0807] Example 45: Preparation of (S)-2-(1-(4-(5-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidin]-1′-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 103).

[0808]

[0809] The crude product of compound 103 was synthesized using a method similar to that in Example 13. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate of compound 103.

[0810] MS(ESI): m / z 538.0 [M+H] + .

[0811] 1 H-NMR (400MHz, CD3OD): δ 8.64-8.54 (m, 1H), 8.41 (d, J = 1.2Hz, 1H), 8.33 (d, J = 1.2Hz, 1H), 7.98 (d, J = 7.6Hz, 1H), 7.59 (d, J = 6.4Hz, 1H), 7.42 (dd, J = 7.6, 5.2Hz, 1H), 6.14 (d, J=6.4Hz, 1H), 4.64-4.32 (m, 7H), 3.52-3.30 (m, 4 H), 2.88-2.78(m, 1H), 1.95-1.75(m, 3H), 1.74-1.65(m, 1H), 1.20(s, 6H).

[0812] Example 46: Preparation of (S)-2-(1-(4-(3-amino-5-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidin]-1′-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 115).

[0813]

[0814] The crude product of compound 115 was synthesized using a method similar to that in Example 36. The crude product was purified by Pre-TLC (MeOH / DCM = 1:5, V / V) to obtain compound 115.

[0815] MS(ESI): m / z 553.0 [M+H] + .

[0816] 1 H NMR (400MHz, DMSO) δ8.31 (d, J=4.0Hz, 1H), 7.77 (d, J=5.2Hz, 1H), 7.71-7.61 (m, 2H) , 7.21-7.13 (m, 1H), 6.15 (s, 2H), 5.86 (d, J=5.6Hz, 1H), 4.44 (s, 1H), 4.30-4.17 (m, 2 H), 4.12-3.99 (m, 4H), 3.89 (s, 1H), 3.22-3.06 (m, 3H), 2.75 (d, J=16.4Hz, 1H), 2.67 -2.56 (m, 1H), 1.82-1.62 (m, 2H), 1.57-1.48 (m, 1H), 1.18-1.07 (m, 1H), 1.05 (s, 6H).

[0817] Example 47: Preparation of 1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)-3-(hydroxymethyl)azacyclobutane-3-carboxylonitrile (compound 126).

[0818]

[0819] Except that in the first step, 3-(hydroxymethyl)azacyclobutane-3-carbamate was used instead of 2-hydroxymethylpyrrolidine in the first step of Example 1, and in the fourth step, compound 4-1 was used instead of compound IM-1 in the fourth step of Example 1, crude compound 126 was synthesized using a method similar to that described in the first to fourth and sixth steps of Example 1. The crude compound 126 was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate of compound 126.

[0820] MS(ESI): m / z 532.0 [M+H] + .

[0821] 1 H-NMR (400MHz, DMSO-d6): δ8.35 (s, 1H), 7.96 (s, 3H), 7.87 (d, J=5.6Hz, 1H), 6.18 (d , J=5.6Hz, 1H), 4.52 (s, 2H), 4.35 (d, J=8.4Hz, 2H), 4.22 (d, J=8.8Hz, 2H), 4.21-4.1 6 (m, 1H), 3.96-3.83 (m, 1H), 3.87 (d, J = 8.8Hz, 1H), 3.81 (s, 2H), 3.70 (d, J = 8.8Hz, 1 H), 3.50-3.40 (m, 1H), 3.16-3.01 (m, 2H), 1.92-1.55 (m, 4H), 1.22 (d, J=6.4Hz, 3H).

[0822] Example 48: Preparation of (1-(4-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)-3-fluoroazacyclobutane-3-yl)methanol (compound 138).

[0823]

[0824] The crude product of compound 138 was synthesized using a method similar to that in Example 13. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate of compound 138.

[0825] MS(ESI): m / z 495.0 [M+H] + .

[0826] 1H-NMR (400MHz, DMSO-d6): δ 8.53 (s, 1H), 8.33 (s, 1H), 7.95 (s, 3H), 7.84 (d, J = 5.6Hz, 1H) 6.04 (d, J = 5.2Hz, 1H), 4.33-4.10 (m , 7H), 3.91-3.88 (m, 1H), 3.73-3.68 (m, 3H), 3.23-3.14 (m, 3H), 1.79-1.69 (m, 3H), 1.60-1.57 (m, 1H), 1.21 (d, J=6.8Hz, 3H).

[0827] Example 49: Preparation of 2-(1-(4-(5-(4-amino-8-azabispiro[2.1.5.2]dodecane-8-yl)-6-(hydroxymethyl)pyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 139)

[0828]

[0829] The crude product of compound 139 was synthesized using a method similar to that in Example 13. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate salt of compound 139.

[0830] MS(ESI): m / z 545.0 [M+H] + .

[0831] 1 H-NMR (400MHz, DMSO-d6): δ8.34 (s, 1H), 7.78 (d, J=5.2Hz, 1H), 7.68 (brs, 3H), 6.01 (d, J= 5.2Hz, 1H), 4.52 (s, 2H), 4.07 (d, J=7.6Hz, 4H), 3.90-3.70 (m, 2H), 3.35-3.24 (m, 1H), 3.22 -3.12(m, 1H), 2.94-2.82(m, 1H), 2.66-2.58(m, 1H), 2.05-1.70(m, 6H), 1.66-1.50(m, 2H) , 1.05 (s, 6H), 1.00-0.90 (m, 1H), 0.84-0.73 (m, 1H), 0.64-0.53 (m, 1H), 0.53-0.45 (m, 1H).

[0832] Example 50: Preparation of (S)-2-(1-(4-(5-(5-amino-5,7-dihydrospiro[cyclopentadieno[b]pyridin-6,4′-piperidin]-1′-yl)-6-(hydroxymethyl)-3-methylpyrazin-2-ylthio)-3-chloropyridin-2-yl)azacyclobutane-3-yl)prop-2-ol (compound 140).

[0833]

[0834] The crude product of compound 140 was synthesized using a method similar to that in Example 13. The crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) to obtain the trifluoroacetate of compound 140.

[0835] MS(ESI): m / z 582.3 [M+H] + .

[0836] 1 H-NMR (400MHz, DMSO-d6): δ8.55 (d, J=4.8Hz, 1H), 8.38 (s, 3H), 7.93 (d, J=7.6Hz, 1H), 7. 77 (d, J=5.2Hz, 1H), 7.37 (dd, J=4.8Hz, 7.6Hz, 1H), 5.87 (d, J=5.2Hz, 1H), 4.50 (s, 3H), 4. 10(d, J=7.6Hz, 2H), 4.06-3.92(m, 2H), 3.28-3.20(m, 3H), 3.12-3.08(m, 1H), 2.66-2.59( m, 1H), 252-2.50 (m, 2H), 2.42 (s, 3H), 1.92-1.83 (m, 2H), 1.64-1.55 (m, 2H), 1.05 (s, 6H).

[0837] Synthesis of Comparative Compounds 1, 2 and TNO-155: Comparative Compounds 1, 2 and TNO-155 were synthesized according to the methods described in WO2019075265, WO2018013597 and WO2015107495, respectively.

[0838]

[0839] Experimental Example 1: In vitro enzyme activity inhibition assay of SHP2 (protein phosphatase).

[0840] 1. Test system:

[0841] Phosphatase: Recombinant human PTPN11 full-length sequence protein (SHP2), active (SignalChem);

[0842] Substrate: 6,8-Difluoro-4-methylumbelliferyl ketone phosphate (DiFMUP) (Invitrogen);

[0843] Activating peptides: IRS1_pY1172(dPEG8)pY1222(IRS1) (BPS Bioscience);

[0844] Termination reagent: bpv(phen)(bpv)(Abcam).

[0845] 2. Test parameters:

[0846] SHP2 concentration: 0.5 nM;

[0847] DiFMUP concentration: 200 μM;

[0848] IRS-1 concentration: 0.5 μM;

[0849] bpv concentration: 160 μM;

[0850] Buffer system: 60mM Hepes pH 7.2; 75mM NaCl; 75mM KCl; 0.05% surfactant P2O; 1mM EDTA; 5mM DTT.

[0851] Incubation time for compounds and enzymes: 60 minutes;

[0852] Enzyme-substrate reaction time: 30 minutes;

[0853] Microplate reader parameters: BMG PHERAstar fluorescent microplate reader, excitation wavelength 340nm, emission wavelength 450nm.

[0854] 3. Experimental Procedure:

[0855] Test group: The mixture of the test compound and phosphatase 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, and the mixture was incubated at room temperature for 30 minutes. Then, 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.

[0856] Negative group: The test compound was replaced with 0.05% DMSO aqueous solution, and the experimental method was the same as that of the test group.

[0857] Blank group: The test compound was replaced with 0.05% DMSO aqueous solution, and SHP2 was not added. The experimental method was the same as that of the test group.

[0858] 4. Data Processing:

[0859] Calculate the relative inhibitory activity for each concentration group: Inhibition rate (%) = 100% - (fluorescence value of test group - fluorescence value of blank group) / (fluorescence value of negative group - fluorescence value of blank group) × 100%. Calculate the half-maximal inhibitory concentration (IC50) of the compound based on the curve fitted by the four-parameter model. 50 ).

[0860] 5. Test Results:

[0861] The inhibitory effect of the compound on SHP2 activity was determined according to the above method, and the results are shown in Table 1.

[0862] Group IC 50 (nM) Group IC 50 (nM) Example 1 6.03 Example 25 7.00 Example 2 1.82 Example 26 0.70 Example 3 3.48 Example 27 4.10 Example 4 4.10 Example 28 2.45 Example 5 1.22 Example 29 1.68 Example 6 1.76 Example 30 4.00 Example 7 4.60 Example 32 3.70 Example 8 0.88 Example 33 4.10 Example 9 1.30 Example 37 2.40 Example 10 1.22 Example 38 5.30 Example 11 9.30 Example 39 1.40 Example 12 2.50 Example 40 4.13 Example 13 4.90 Example 41 8.40 Example 15 2.40 Example 42 10.19 Example 16 1.00 Example 43 2.60 Example 17 2.50 Example 44 2.49 Example 18 1.90 Example 45 4.10 Example 19 1.50 Example 46 2.60 Example 20 6.90 Example 47 3.20 Example 21 1.15 Example 48 2.20 Example 22 4.30 Example 49 2.30 Example 23 1.90 Example 50 4.84

[0863] 6. Conclusion:

[0864] In the SHP2 enzyme activity inhibition assay, the compounds of the present invention exhibited strong inhibitory activity.

[0865] Experimental Example 2: Assay on inhibition of proliferation activity of KYSE-520 cells (human esophageal squamous cell carcinoma cells).

[0866] 1. Test system:

[0867] Cells: KYSE-520 (JCRB Cell Bank);

[0868] Reagent kit: CellTiter- Promega luminescent cell viability assay kit.

[0869] 2. Test parameters:

[0870] Cell count: 1500 cells / well;

[0871] Plate-laying medium: KYSE-520: 1640 + 10% FBS;

[0872] Culture medium for drug administration: KYSE-520: 1640 + 10% FBS;

[0873] Compound incubation conditions: 37℃, 5% CO2;

[0874] Incubation period: 5 days;

[0875] Detection temperature: room temperature;

[0876] BMG PHERAstar FS detection of chemiluminescence.

[0877] 3. Experimental Procedure:

[0878] Cells were cultured in medium containing 10% fetal bovine serum at 37°C under 5% CO2 conditions. A suitable amount of cells was seeded into 96-well plates and cultured overnight to allow cell adhesion. The next day, the medium was removed, and complete medium containing pre-diluted compounds was added, and the plates were incubated at 37°C for 5 days. On the fifth day, the CellTiter assay reagent was added to each well. Chemiluminescence detection of the relative luminescence units (RLU) of each well.

[0879] 4. Data Processing:

[0880] CellTiter using cell-free culture medium Obtain background values. Cell viability (%) = (Sample RLU - Background RLU) / (Soluble RLU - Background RLU) × 100%, Maximum inhibition rate (%) = 100% - Cell viability 最大浓度 (%). The half-maximal inhibitory concentration (IC50) of the compound was calculated based on the curve fitted using the four-parameter model. 50 ).

[0881] 5. Test Results:

[0882] The inhibitory activity of the compound of the present invention on the proliferation of KYSE-520 cells was determined according to the above method, and the results are shown in Table 2.

[0883] Example number KYSE-520, IC 50 (μM) Example number KYSE-520, IC 50 (μM) Example 1 0.36 Example 21 0.11 Example 2 0.10 Example 22 0.05 Example 3 1.14 Example 23 0.14 Example 4 0.17 Example 26 0.03 Example 5 0.06 Example 27 0.06 Example 6 0.04 Example 29 0.04 Example 7 0.77 Example 33 0.09 Example 8 0.03 Example 39 0.02 Example 9 0.22 Example 42 0.10 Example 10 0.04 Example 43 0.04 Example 12 0.04 Example 44 0.05 Example 15 0.04 Example 45 0.21 Example 16 0.04 Example 46 0.07 Example 17 0.03 Example 47 0.04 Example 18 0.24 Example 48 0.64 Example 19 0.19 Example 49 0.27

[0884] 6. Conclusion:

[0885] The compounds of this invention exhibit strong cell proliferation inhibitory activity against KYSE-520 cells.

[0886] Experimental Example 3: Biochemical hERG Inhibition Assay.

[0887] 1. Test system:

[0888] Reagent kit: Predictor TM The hERG fluorescence polarization assay kit (ThermoFisher) contains:

[0889] Compound E4031 was used as a positive control;

[0890] hERG cell membrane;

[0891] Affinity tracers; and

[0892] hERG buffer.

[0893] 2. Test parameters:

[0894] hERG concentration: 1×;

[0895] Tracer concentration: 1 nM;

[0896] Incubation time: 2 hours;

[0897] Microplate reader parameters: BMG PHERAstar FS fluorescent microplate reader.

[0898] 3. Experimental Procedure:

[0899] Test group: Different concentrations of the test compound were added to microplates containing hERG cell membranes, and a tracer with high hERG affinity was added to each well. After incubating the microplates at 25°C for 2 hours, the changes in fluorescence polarization (excitation wavelength: 540 nm; emission wavelength: 590 nm) values ​​(mP) were detected using a multi-functional microplate reader.

[0900] Positive control group: The test compound was replaced with 30 μM compound E4031, and the experimental method was the same as that of the test group.

[0901] Blank control group: hERG buffer was used instead of the test compound, and no hERG cell membrane was added. The experimental method was the same as that of the test group.

[0902] 4. Data Processing:

[0903] Based on the data ratios, the percentage inhibition rate (%) of the compound of the present invention against hERG at different concentrations was calculated, and the half-maximal inhibitory concentration (IC50) of the compound was determined. 50 The range of ) is defined as follows: Percentage inhibition rate (%) = (1 - (mP of the test compound - mP of the positive control group) / (mP of the blank control group - mP of the positive control group)) × 100%.

[0904] 5. Test Results:

[0905] The inhibition of hERG by the compounds of the present invention was determined using the above method, and the results are shown in Table 3.

[0906] Example number IC 50 (μM) Example number IC 50 (μM) Example 2 ＞10 Example 27 ＞10 Example 4 ＞10 Example 28 ＞10 Example 7 ＞10 Example 29 ＞10 Example 9 ＞10 Example 30 ＞10 Example 12 ＞10 Example 39 ＞10 Example 13 ＞10 Example 40 ＞10 Example 15 ＞10 Example 42 ＞10 Example 18 ＞10 Example 46 ＞10 Example 19 ＞10 Example 47 ＞10 Example 25 ＞10 Example 48 ＞10 Example 26 ＞10

[0907] 6. Conclusion:

[0908] Test results show that the compound of this invention has low affinity for hERG and competes with affinity tracers for IC50. 50 Greater than 10 μM.

[0909] Experimental Example 4: Inhibition of proliferation activity of NCI-H358 cells (human non-small cell lung cancer cells).

[0910] 1. Test system:

[0911] Cells: NCI-H358 (Nanjing Kebai);

[0912] Reagent test kit: Promega luminescent cell viability assay kit.

[0913] 2. Test parameters:

[0914] Cell count: 1500 cells / well;

[0915] Plate-laying medium: NCI-H358: 1640 + 10% FBS;

[0916] Drug-treated culture medium: NCI-H358: 1640 + 10% FBS;

[0917] Compound incubation conditions: 37℃, 5% CO2;

[0918] Incubation period: 5 days;

[0919] Detection temperature: room temperature;

[0920] BMG PHERAstar FS detection of chemiluminescence.

[0921] 3. Experimental Procedure:

[0922] Cells were cultured in medium containing 10% fetal bovine serum at 37°C under 5% CO2 conditions. A suitable amount of cells was seeded into 96-well plates and cultured overnight to allow cell adhesion. The next day, the medium was removed, and complete medium containing pre-diluted compounds was added, and the plates were incubated at 37°C for 5 days. On the fifth day, the assay reagent was added to each well. Chemiluminescence detection of the relative luminescence units (RLU) of each well.

[0923] 4. Data Processing:

[0924] Using cell-free culture medium Obtain background values. Cell viability (%) = (Sample RLU - Background RLU) / (Soluble RLU - Background RLU) × 100%, Maximum inhibition rate (%) = 100% - Cell viability 最大浓度 (%). The half-maximal inhibitory concentration (IC50) of the compound was calculated based on the curve fitted using the four-parameter model. 50 ).

[0925] 5. Test Results:

[0926] The inhibitory activity of the compound of the present invention on the proliferation of NCI-H358 cells was determined according to the above method, and the results are shown in Table 4.

[0927] Example number NCI-H358, IC 50 (μM) Example number NCI-H358, IC 50 (μM) <!-- 94 -->]]> Example 2 0.040 Example 25 0.150 Example 5 0.034 Example 26 0.032 Example 6 0.074 Example 27 0.030 Example 12 0.018 Example 28 0.130 Example 13 0.260 Example 29 0.040 Example 15 0.040 Example 40 0.030 Example 17 0.039 Example 42 0.044 Example 19 0.220 Example 43 0.008 Example 21 0.030 Example 44 0.050 Example 22 0.031 Example 46 0.028 Example 23 0.005 Example 47 0.023

[0928] 6. Conclusion:

[0929] Test results show that the compound of the present invention has strong cell proliferation inhibitory activity against NCI-H358 cells.

[0930] Experimental Example 5: Biochemical CYP enzyme (cytochrome P450) inhibition test.

[0931] 1. Test system:

[0932] P450-Glo TM CYP1A2 Screening System, (Promega);

[0933] P450-Glo TM CYP2D6 Screening System, (Promega);

[0934] P450-Glo TM CYP3A4 Screening System, (Promega).

[0935] 2. Testing instruments:

[0936] BMG PHERAstar FS Luminescent.

[0937] 3. Test methods:

[0938] Perform the tests according to the kit instructions, as follows:

[0939] 3.1. Inhibition of CYP1A2:

[0940] Test group: Different concentrations of the test compound were added to the microplate. Luciferin-ME (100 μM), K3PO4 (100 mM) and CYP1A2 (0.01 pmol / μL) were added to each well. The plate was pre-incubated at room temperature for 10 min, then the NADPH regeneration system was added and the plate was reacted at room temperature for 30 min. Finally, an equal volume of detection buffer was added and the plate was incubated at room temperature for 20 min before chemiluminescence detection was performed.

[0941] Negative control group: The experimental method is the same as that of the test group, except that the test compound is not added.

[0942] Blank control group: The experimental method is the same as that of the test group, except that the test compound is not added, and CYP1A2 Membrance (0.01 pmol / μL) is used instead of CYP1A2.

[0943] 3.2. Inhibition of CYP2D6:

[0944] Test group: Different concentrations of the test compound were added to the microplate. Luciferin-MEEGE (3 μM), K3PO4 (100 mM) and CYP2D6 (5 nM) were added to each well. The plate was pre-incubated at room temperature for 10 min, then the NADPH regeneration system was added and the plate was reacted at 37 °C for 30 min. Finally, an equal volume of detection buffer was added and the plate was incubated at room temperature for 20 min before chemiluminescence detection was performed.

[0945] Negative control group: The experimental method is the same as that of the test group, except that the test compound is not added.

[0946] Blank control group: The experimental method is the same as that of the test group, except that the test compound is not added, and CYP2D6 Membrance (5nM) is used instead of CYP2D6.

[0947] 3.3. Inhibition of CYP3A4:

[0948] Test group: Different concentrations of the test compound were added to the microplate. Luciferin-IPA (3 μM), K3PO4 (100 mM) and CYP3A4 (2 nM) were added to each well. The plate was pre-incubated at room temperature for 10 min, then the NADPH regeneration system was added and the plate was reacted at room temperature for 30 min. Finally, an equal volume of detection buffer was added and the plate was incubated at room temperature for 20 min before chemiluminescence detection was performed.

[0949] Negative control group: The experimental method is the same as that of the test group, except that the test compound is not added.

[0950] Blank control group: The experimental method is the same as that of the test group, except that the test compound is not added, and CYP3A4 Membrance (2nM) is used instead of CYP3A4.

[0951] 4. Data Processing:

[0952] Percentage inhibition rate = (1 - (chemiluminescence signal value of the test compound concentration group - chemiluminescence signal value of the blank control group) / (chemiluminescence signal value of the negative control group - chemiluminescence signal value of the blank control group)) × 100%.

[0953] When the percentage inhibition rate is between 30% and 80%, the half-maximal inhibitory concentration (IC50) of the compound against the CYP enzyme is estimated according to the following formula. 50 ) or range: IC 50 =X×(1-percentage inhibition rate) / percentage inhibition rate, where X is the test concentration of the compound.

[0954] 5. Test Results:

[0955] The inhibition of the compounds of the present invention on three CYPs was determined according to the above method, and the results are shown in Table 5 below.

[0956] Table 5. Results of CYPs Inhibition Test

[0957]

[0958] 6. Conclusion:

[0959] The above results indicate that the compound of the present invention has no significant inhibitory effect on the three major CYP subtypes, suggesting that its potential drug interaction is relatively low, which is superior to that of the comparative compound 1.

[0960] Experimental Example 6: Pharmacokinetic (PK) Study of SD Rats.

[0961] The pharmacokinetic properties of Compound 12 and Comparative Compound 2 were investigated by intravenous (IV) and oral (PO) administration, respectively, to male SD rats. The IV and PO doses were 1 mg / kg and 5 mg / kg, respectively. The IV solution was 5% DMSO + 5% Solutol (polyethylene glycol 15-hydroxystearate) + 90% Saline (physiological saline), and the PO solution was 0.5% MC (sodium methylcellulose). Blood samples were collected at different time points after IV and PO administration. Blood was anticoagulated with EDTA-K2, centrifuged, and the resulting plasma samples were stored at -80°C.

[0962] Plasma samples were analyzed by LC-MS / MS after protein precipitation. Pharmacokinetic parameters were calculated using a non-compartmental model with WinNonlin 6.3 software, and the results are shown in Table 6 below.

[0963] Table 6. Pharmacokinetic parameters of the compounds in rat blood.

[0964]

[0965] Note: " / " indicates that the symbol does not exist.

[0966] Conclusion: Under the conditions of injection dose of 1 mg / kg and oral dose of 5 mg / kg, the compound of Example 12 of the present invention achieved a high exposure in rat plasma, which was much higher than that of control compound 2, and the clearance rate was much lower than that of control compound 2, thus exhibiting excellent pharmacokinetic properties.

[0967] Experimental Example 7: Pharmacokinetic (PK) Study in Balb / e Mice.

[0968] Pharmacokinetic characteristics of Compound 12, Comparative Compound 1, Comparative Compound 2, and TNO-155 were investigated by intravenous (IV) and oral (PO) administration to female Balb / c mice. The IV and PO doses were 1 mg / kg and 10 mg / kg, respectively. The solvent for IV was 5% DMSO + 5% Solutol + 90% Saline, and the solvent for PO was 0.5% MC (sodium methylcellulose). Blood samples were collected at different time points after IV and PO administration. Blood samples from the Compound 12, Comparative Compound 1, and Comparative Compound 2 test groups were anticoagulated with EDTA-K2 and stored at -80°C. Blood samples from the TNO-155 test group were anticoagulated with EDTA-K2, centrifuged, and stored at -80°C.

[0969] Blood or plasma samples were analyzed by LC-MS / MS after protein precipitation. Pharmacokinetic parameters were calculated using WinNonlin 6.3 software and a non-compartmental model; the results are shown in Table 7 below.

[0970] Table 7. Pharmacokinetic parameters of the compounds in blood of Balb / c mice

[0971]

[0972] Note: " / " indicates that the symbol does not exist.

[0973] Conclusion: The compound of Example 12 of this invention, at an injection dose of 1 mg / kg and an oral dose of 10 mg / kg, achieved high exposure, low clearance, and a long half-life in the systemic circulation of mice. Its overall properties were significantly superior to those of comparative compounds 1, 2, and TNO-155, demonstrating excellent pharmacokinetic properties.

[0974] Experimental Example 8: Pharmacokinetic (PK) Study of Beagle Dogs.

[0975] Pharmacokinetic characteristics of Compound 12, Comparative Compound 1, Comparative Compound 2, and TNO-155 were investigated by intravenous (IV) and oral (PO) administration to male beagle dogs. The IV and PO doses were 0.5 mg / kg and 2.5 mg / kg, respectively. The IV solvent was 5% DMSO + 5% Solutol + 90% Saline, and the PO solvent was 0.5% MC (sodium methylcellulose). Blood samples were collected at different time points after IV and PO administration. Blood was anticoagulated with EDTA-K2, centrifuged, and the resulting plasma samples were stored at -80°C.

[0976] Plasma samples were analyzed by LC-MS / MS after protein precipitation. Pharmacokinetic parameters were calculated using WinNonlin 6.3 software and a non-compartmental model; the results are shown in Table 8 below.

[0977] Table 8. Pharmacokinetic parameters of the compound in the blood of beagle dogs

[0978]

[0979] Note: " / " indicates that the symbol does not exist.

[0980] Conclusion: The compound of Example 12 of this invention achieved high exposure in beagle plasma at an injection dose of 0.5 mg / kg and an oral dose of 2.5 mg / kg, and exhibited a long half-life and low clearance rate. Its overall properties were superior to those of Comparative Compound 1, Comparative Compound 2 and TNO-155, demonstrating better pharmacokinetic properties.

[0981] Experimental Example 9: Tumor suppression experiment in KYSE-520 xenograft model.

[0982] 1. Experimental objective:

[0983] A CDX xenograft animal model was established by subcutaneously inoculating nu-nu mice with KYSE-520 cells. After tumor formation, the mice were orally administered once daily to evaluate the in vivo efficacy of different test compounds.

[0984] 2. Test reagents:

[0985]

[0986] 3. Test methods:

[0987] KYSE-520 cells were cultured in vitro in monolayers under the following conditions: RPMI 1640 medium supplemented with 10% fetal bovine serum, incubated at 37°C in a 5% CO2 incubator. Cells were passaged twice weekly after trypsin digestion. Cells were collected and counted when they reached the exponential growth phase. The KYSE-520 cell line cultured to the logarithmic growth phase was then prepared into a single-cell suspension (cells resuspended in PBS and mixed 1:1 with phenol red-free matrix gel, with a final cell density of 5 × 10⁶ cells / mL). 7 Each nude mouse was injected with 0.1 ml of the drug into the subcutaneous tissue of the right axilla to construct an esophageal cancer xenograft model. The tumor was allowed to grow to 130 mm. 3 Nude mice were randomly divided into 5 groups for drug administration, as shown in Table 9 (oral administration once a day for 21 days), with the solvent being 5% DMSO + 5% Solutol + 90% H2O.

[0988] Monitor the animals' health status and mortality daily. Routine checks include observing the effects of drug treatment on the animals' daily behavior, such as activity level, food (water) intake, physical appearance, or other abnormalities, and keep appropriate records.

[0989] Mice were weighed twice a week, and tumor volume was measured and recorded. The formula for calculating tumor volume (V) is: V = 1 / 2 × a × b. 2 , where a and b represent length and width, respectively. The volume of the mouse xenograft is as follows: Figure 1 As shown.

[0990] The tumor growth inhibition rate (TGI) of antitumor drugs was evaluated. When tumor regression did not occur, TGI (%) (tumor volume) = [1 - (TVt - TV0) / (CVt - CV0)] × 100%, where TV0 is the average tumor volume of the test compound group at the time of grouping, TVt is the average tumor volume of the test compound group t days after administration, CV0 is the average tumor volume of the solvent group at the time of grouping, and CVt is the average tumor volume of the solvent group t days after administration. When tumor regression occurred, TGI (%) (tumor volume) = 100% - (TVt - TV0) / TV0 × 100%.

[0991] 4. Test Results:

[0992] Table 9. Efficacy of the test compounds in the KYSE-520 cell xenograft model (calculated by tumor volume)

[0993]

[0994] Note: "-" indicates that the expression does not exist, and P < 0.05 indicates a significant difference compared to the solvent group.

[0995] 5. Experimental Conclusions:

[0996] The above data show that after 21 days of continuous oral administration, the compound of Example 12 of the present invention has a significant antitumor effect, which is superior to that of the positive compound TNO-155 administered at the same dose.

[0997] Experimental Example 10: Tumor suppression experiment in NCI-H358 xenograft model.

[0998] 1. Experimental objective:

[0999] A subcutaneous xenograft mouse model was constructed by subcutaneously inoculating human non-small cell lung cancer cells NCI-H358 into the right scapula of Balb / c-nu mice. After tumor formation, the mice were administered the drugs orally to evaluate the in vivo efficacy of different test compounds.

[1000] 2. Test reagents:

[1001]

[1002] 3. Test methods:

[1003] NCI-H358 cells were cultured in vitro in a monolayer using RPMI 1640 medium supplemented with 10% fetal bovine serum at 37°C and 5% CO2. Cells were passaged using trypsin-EDTA digestion 2-3 times per week. When the cells reached the exponential growth phase, they were collected, counted, and seeded.

[1004] Before tumor cells were inoculated, the experimental mice were individually tagged with special mouse-specific ear tags.

[1005] Each mouse was subcutaneously injected with 1×10⁻⁶ cells into the right scapula. 6 NCI-H358 cells (suspended in 0.1 ml PBS + Matrigel). The expected mean tumor volume on day 7 is ~200 mm. 3 Based on the measurement results on day 7, 30 mice with regular tumor shape and uniform volume were selected and randomly divided into 5 groups. They were then administered drugs according to the experimental protocol (the administration protocol is shown in Table 10 (lasting 21 days)), with the solvent being 5% DMSO + 5% Solutol + 90% H2O.

[1006] Mice were weighed three times a week, and tumor volume was measured and recorded. The formula for calculating tumor volume (V) is: V = 1 / 2 × a × b. 2 , where a and b represent length and width, respectively. The volume of the mouse xenograft is as follows: Figure 2 As shown.

[1007] The efficacy of antitumor drugs is evaluated using the tumor growth inhibition rate (TGI%), where, when tumor regression is not observed, TGI(%) (tumor volume) = [1 - (TV) / (tumor volume)] t -TV0) / (CV t -CV0)]×100%, where TV0 is the average tumor volume of the tested compound group at the time of grouping, and TV t CVt represents the average tumor volume of the test compound group on day t after drug administration; CV0 represents the average tumor volume of the solvent group at the time of grouping; CVt t The mean tumor volume in the solvent group is t days after drug administration; when tumor regression occurs, TGI (%) (tumor volume) = 100% - (TV) t -TV0) / TV0×100%.

[1008] If the tumor shrinks compared to its initial volume, i.e., V t When the value is less than V0, it is defined as partial tumor regression (PR); if the tumor disappears completely, it is defined as complete tumor regression (CR).

[1009] 4. Test Results:

[1010] Table 10. Efficacy of the test compounds in the NCI-H358 cell xenograft model (calculated by tumor volume)

[1011]

[1012] Note: "-" indicates non-existence; P < 0.05 indicates a significant difference compared to the solvent group; BID indicates twice daily; QD indicates once daily; mpk indicates mg / kg.

[1013] 5. Experimental Conclusions:

[1014] The above data show that after 21 days of continuous oral administration, the compound of Example 12 of the present invention has a significant antitumor effect, and its efficacy is superior to that of the positive compound TNO155 administered at the same or higher doses.

[1015] Experimental Example 11: Kinase Selectivity Test

[1016] 1. Purpose of the experiment: To assess the safety risks of the compounds of the present invention by conducting selectivity tests on multiple kinases.

[1017] 2. Testing Unit: ThermoFisher USA

[1018] 3. Testing methods: LanthaScreen binding, Z′-LYTE, Adapta

[1019] 4. Test targets: a total of 100 targets.

[1020]

[1021] 5. Experimental Conclusions:

[1022]

[1023] The results showed that TNO-155 had a strong inhibitory effect on the above 14 kinase targets, but a weak inhibitory effect on the remaining 86 targets; Example 12 had a weak inhibitory effect on all 100 kinase targets, indicating that Example 12 has good kinase selectivity and low safety risk.

[1024] In summary, this invention provides a series of highly active SHP2 phosphatase inhibitors with novel structures, which have demonstrated good efficacy in mouse KYSE-520 CDX and NCI-H358 CDX models and have great potential to be developed into drugs for tumor diseases.

[1025] In addition to the embodiments described herein, various modifications of 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 having the structure of Formula I or a pharmaceutically acceptable salt thereof, wherein, X is S; R 1 Selected from hydrogen, amino, and methyl; R 2 Selected from hydrogen and hydroxymethyl; A is a pyridyl group, which is optionally substituted with one or more fluorine and chlorine groups; B is C is selected from aziridine and pyridine, wherein each of the aziridine and pyridine is optionally substituted with one or more fluorine, cyano, methyl or fluoromethyl groups; Y is selected from -CH2-, -CH(CH3)-, -C(CH3)2- and -C(=O)-CH2-; R d Selected from fluorine, amino, hydroxyl, cyano, -S(=O)2-CH3 and -O-CH3; R 3 and R 4 And the atoms connected to it form rings, Selected from R 5 It is hydrogen; n is 1.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 2 It is a hydroxymethyl group.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, B is selected from 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in any one of formulas IIa-IIb, IVb, and Va. A, B, R 3 and R 4 As defined in claim 1.

5. The following compounds or their pharmaceutically acceptable salts:

6. A pharmaceutical composition comprising the compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

7. A medicine comprising: a) Container; b) at least one compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, located in the container; and c) Optional packaging and / or instructions.

8. Use of the compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 6, or the medicament of claim 7, in the preparation of a medicament for the prevention and / or treatment of at least part of a disease or condition mediated by SHP2.

9. The use according to claim 8, wherein, The disease or condition at least partially mediated by SHP2 is cancer.

10. The use according to claim 9, wherein, The cancers mentioned are selected from breast cancer, colorectal cancer, colon cancer, lung cancer, prostate cancer, bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer, vulvar cancer, multiple myeloma, lymphoma, and leukemia.

11. The use according to claim 10, wherein, The lung cancers mentioned are selected from small cell lung cancer, non-small cell lung cancer, and bronchioloalveolar carcinoma.

12. The use according to claim 10, wherein, The leukemia is selected from chronic lymphocytic leukemia, acute lymphocytic leukemia, and chronic myeloid leukemia.

Images