Nitrogen-containing heterocyclic compound and use thereof

Abstract

Provided in the present disclosure is a nitrogen-containing heterocyclic compound having a new structure, a preparation method therefor and the pharmaceutical use thereof, which provides a new direction for the development of PCSK9 inhibitor drugs. Test results indicate that the compound of the present disclosure exhibits a relatively high affinity for PCSK9 proteins, can significantly reduce LDL-C, and can be used for treating and / or preventing cardiovascular diseases associated with dyslipidemia. In addition, in-vivo pharmacokinetic experiments indicate that the compound of the present disclosure exhibits good pharmacokinetic properties.

Description

A nitrogen-containing heterocyclic compound and its uses

[0001] Citation of relevant applications

[0002] This disclosure claims priority to two Chinese patent applications filed on October 31, 2024, entitled "A Nitrogen-Containing Heterocyclic Compound and Its Use Thereof," application number 202411540175.1, and on April 21, 2025, entitled "A Nitrogen-Containing Heterocyclic Compound and Its Use Thereof," application number 202510501306.3, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure relates to the field of pharmaceutical technology, and more specifically, to a class of nitrogen-containing heterocyclic compounds, their preparation methods, and their pharmaceutical uses. Background Technology

[0004] High levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor for atherosclerosis and coronary heart disease. Currently, statins are the primary first-line drugs for lowering LDL-C. However, statins can be intolerable to some patients, or the desired effect may not be achieved after treatment with tolerated doses. Combining non-statin drugs (such as ezetimibe, a cholesterol absorption inhibitor) with statins can further lower LDL-C by 15-20%. Literature indicates that PCSK9 inhibitors combined with statins are more effective in lowering LDL-C and can also overcome common statin side effects (such as muscle pain).

[0005] PCSK9, short for Proprotein Convertase Subtilisin / Kexin type 9, is the 9th member of the subtilisin family of proprotein convertases and a protein closely related to cholesterol regulation. It was first reported in 2003. PCSK9 is primarily synthesized in the liver and contains three unique domains that play important roles in its biological function and intracellular transport. PCSK9 expression is regulated by various factors, such as SREBP2 (cholesterol regulatory element-binding protein 2). One of its main functions is the interaction between PCSK9 and the low-density lipoprotein receptor (LDLR). By binding to LDLR, it promotes the degradation of LDLR within hepatocytes, thereby reducing the amount of LDLR on the hepatocyte surface, affecting LDL-C clearance, and potentially leading to elevated LDL-C levels in the blood, increasing the risk of cardiovascular disease. In addition to affecting LDLR, PCSK9 may also regulate other proteins associated with LDLR family members, such as ApoER2 (apolipoprotein E2 receptor) and VLDLR (very low-density lipoprotein receptor), as well as other cell surface proteins such as CD36 and ACE2.

[0006] PCSK9 may play a key role in a variety of diseases, including cardiovascular disease, liver disease, infectious and autoimmune diseases, as well as neurocognitive impairment and cancer. Particularly in cardiovascular disease, PCSK9 increases disease risk by affecting cholesterol uptake. Furthermore, PCSK9 levels are significantly correlated with cholesterol, oxidized low-density lipoprotein (ox-LDL), and triglycerides.

[0007] Since the discovery of PCSK9 in 2003, various PCSK9 inhibitors have been developed and approved for marketing, including monoclonal antibodies (such as Evolocumab, Alirocumab, and Tafolecimab) and siRNAs (such as Inclisiran). These inhibitors reduce LDL-C levels in the blood by lowering PCSK9 levels, increasing the number of LDLRs on the surface of hepatocytes, and improving LDL-C clearance, demonstrating the potential to significantly reduce LDL-C and potentially reduce the risk of cardiovascular events. To date, there are no marketed oral small-molecule PCSK9 inhibitors. Two products (MK0616 and AZD0780) have shown relatively active clinical progress, while other small-molecule products have not disclosed significant clinical data in the past three years. Therefore, the development of orally administered PCSK9 inhibitors is of great research value and application potential. Summary of the Invention

[0008] A first aspect of this disclosure provides a compound of formula (IA), a stereoisomer, a tautomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0009] in,

[0010] Ring A is a 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups;

[0011] R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C respectively. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, -N(C) 1-6 Alkyl)2, -N(C 3-6 2-cycloalkyl-NHC 1-6 Alkyl and -NHC 3-6 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, -N(C) 1-6 Alkyl)2, -N(C 3-6 2-cycloalkyl-NHC 1-6 Alkyl or -NHC 3-6 The cycloalkyl group may be optionally substituted by one, two or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl and cyano groups;

[0012] Ring B is a 5-12 membered heterocyclic group, C 6-10 Aryl or 5-12 heteroaryl groups;

[0013] R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C, respectively. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 5-6 membered heterocyclic, aryl, and 5-6 membered heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6Alkylthio, C 3-6 The cycloalkyl, 5-6 membered heterocyclic, aryl, or 5-6 membered heteroaryl groups are optionally substituted by one, two, or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, and cyano groups; or two R groups attached to the same atom. b The linkage forms a 3-6 membered cycloalkyl group or a 4-6 membered heterocyclic group, wherein the 3-6 membered cycloalkyl group or the 4-6 membered heterocyclic group is optionally composed of 1, 2 or 3 groups selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy and halogenated C 1-4 The substituents of the alkylthio group are replaced;

[0014] Ring C is C 5-6 Cycloalkyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; the C 5-6 Cycloalkyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl groups are optionally surrounded by 1, 2, or 3 groups selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy and halogenated C 1-4 The substituents of the alkylthio group are replaced;

[0015] R c Selected from hydrogen, deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, and C, respectively. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy and halogenated C 1-4 Alkylthio;

[0016] x is 0, 1, 2, 3 or 4;

[0017] y is 0, 1, 2, 3 or 4;

[0018] p can be 0, 1, 2, 3, or 4.

[0019] This disclosure provides a compound of formula (I), its stereoisomers, tautomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof:

[0020] in,

[0021] Ring A is a 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups;

[0022] R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C respectively. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 alkylthio and C 3-6 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 alkylthio or C 3-6 The cycloalkyl group may be optionally substituted by one, two or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl and cyano groups;

[0023] Ring B is a 5-12 membered heterocyclic group, C 6-10 Aryl or 5-12 heteroaryl groups;

[0024] R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C, respectively. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 5-6 membered heterocyclic, aryl, and 5-6 membered heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 The cycloalkyl, 5-6 membered heterocyclic, aryl, or 5-6 membered heteroaryl groups are optionally substituted by one, two, or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, and cyano groups; or two R groups attached to the same atom. b The linkage forms a 3-6 membered cycloalkyl group or a 4-6 membered heterocyclic group, wherein the 3-6 membered cycloalkyl group or the 4-6 membered heterocyclic group is optionally composed of 1, 2 or 3 groups selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy and halogenated C1-4 The substituents of the alkylthio group are replaced;

[0025] Ring C is C 5-6 Cycloalkyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; the C 5-6 Cycloalkyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl groups are optionally surrounded by 1, 2, or 3 groups selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy and halogenated C 1-4 The substituents of the alkylthio group are replaced;

[0026] R c Selected from hydrogen, deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, and C, respectively. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy and halogenated C 1-4 Alkylthio;

[0027] x is 0, 1, 2, 3 or 4;

[0028] y is 0, 1, 2, 3 or 4;

[0029] p can be 0, 1, 2, 3, or 4.

[0030] In one embodiment of this disclosure, ring A is C. 6-10 Aryl or 5-10 heteroaryl compounds.

[0031] In one embodiment of the present invention, ring A is phenyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, 5-membered 6-membered bicyclic heteroaryl, 6-membered 5-membered bicyclic heteroaryl, 5-membered 5-membered bicyclic heteroaryl, or 6-membered 6-membered bicyclic heteroaryl.

[0032] In one embodiment of the present invention, ring A is a 5-membered monocyclic heteroaryl, a 6-membered monocyclic heteroaryl, a 5-membered 6-membered bicyclic heteroaryl, or a 6-membered 5-membered bicyclic heteroaryl.

[0033] In one embodiment of the present invention, ring A is a 6-membered monocyclic heteroaryl, a 5-membered 6-membered bicyclic heteroaryl, or a 6-membered 5-membered bicyclic heteroaryl.

[0034] In one specific embodiment of this disclosure, ring A is

[0035] In one specific embodiment of this disclosure, ring A is

[0036] In one specific embodiment of this disclosure, ring A is

[0037] In one specific embodiment of this disclosure, ring A is In one specific embodiment of this disclosure, ring A is

[0038] In one specific embodiment of this disclosure, ring A is

[0039] In one specific embodiment of this disclosure, ring A is

[0040] In one specific embodiment of this disclosure, ring A is

[0041] In one embodiment of this disclosure, R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C respectively. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 alkylthio and C 3-6 cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 alkylthio or C 3-6 The cycloalkyl group may be optionally replaced by one, two or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl and cyano.

[0042] In one embodiment of this disclosure, R a The groups are selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, and cyclopropyl, respectively, wherein the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, or cyclopropyl groups are optionally substituted by one, two, or three substituents selected from deuterium and halogen.

[0043] In one embodiment of this disclosure, R aThe groups are selected from hydrogen, deuterium, halogen, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, and cyclopropyl, respectively, wherein the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, or cyclopropyl groups are optionally substituted by one, two, or three substituents selected from deuterium and halogen.

[0044] In one embodiment of this disclosure, R a The groups are selected from hydrogen, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, and cyclopropyl, respectively, wherein the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, or cyclopropyl groups are optionally substituted by one, two, or three substituents selected from halogens.

[0045] In one embodiment of this disclosure, R a The groups are selected from hydrogen, F, Cl, Br, methyl, ethyl, methoxy, -OCHF2, -CF3 and cyclopropyl, respectively.

[0046] In one embodiment of this disclosure, R a They are selected from Cl, methyl, methoxy, -OCHF2, -CF3 and cyclopropyl, respectively.

[0047] In one embodiment of this disclosure, R a Selected from methylthio, -OCF3, and -N(C) respectively 1-3 Alkyl)2, -N(C 3-6 2-cycloalkyl-NHC 1-3 Alkyl and -NHC 3-6 Cycloalkyl.

[0048] In one embodiment of this disclosure, R a They are selected from methylthio, -OCF3 and -NH-cyclopropyl, respectively.

[0049] In one embodiment of this disclosure, when ring A is At that time, R a Selected from amino, hydroxyl, cyano, nitro, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkylthio, -N(C) 1-6 Alkyl)2, -N(C 3-6 2-cycloalkyl-NHC 1-6 Alkyl and -NHC 3-6 cycloalkyl, the C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkylthio, -N(C) 1-6 Alkyl)2, -N(C 3-62-cycloalkyl-NHC 1-6 Alkyl or -NHC 3-6 The cycloalkyl group may be optionally replaced by one, two or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl and cyano.

[0050] In one embodiment of this disclosure, when ring A is At that time, R a Selected from C respectively 2-6 alkenyl and C 2-6 alkynyl group, the C 2-6 alkenyl or C 2-6 The alkynyl group may be optionally replaced by one, two or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl and cyano.

[0051] In one embodiment of this disclosure, when ring A is At that time, R a The groups are selected from vinyl and ethynyl groups, respectively, and the vinyl or ethynyl group is optionally replaced by one, two or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl and cyano.

[0052] In one embodiment of this disclosure, when ring A is At that time, R a C respectively 1-6 Alkylthio, the C 1-6 The alkylthio group may be optionally replaced by one, two, or three substituents selected from deuterium and halogens.

[0053] In one embodiment of this disclosure, when ring A is At that time, R a They are methylthio and -SCHF2, respectively.

[0054] In one specific implementation of this disclosure, for

[0055] In one specific implementation of this disclosure, for

[0056] In one specific implementation of this disclosure, for

[0057] In one specific implementation of this disclosure, for

[0058] In one specific implementation of this disclosure, for

[0059] In one specific implementation of this disclosure, for

[0060] In one specific implementation of this disclosure, for

[0061] In one specific implementation of this disclosure, for

[0062] In one specific implementation of this disclosure, for

[0063] In one embodiment of this disclosure, ring B is a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group, a 7-membered monocyclic heterocyclic group, a 5-membered 6-membered bicyclic heterocyclic group, a 6-membered 5-membered bicyclic heterocyclic group, a 5-membered 5-membered bicyclic heterocyclic group, a 6-membered 6-membered bicyclic heterocyclic group, a 5-membered 7-membered bicyclic heterocyclic group, a 7-membered 5-membered bicyclic heterocyclic group, a 7-membered 6-membered bicyclic heterocyclic group, a 6-membered 7-membered bicyclic heterocyclic group, a phenyl group, a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group, a 5-membered 6-membered bicyclic heterocyclic group, a 6-membered 5-membered bicyclic heterocyclic group, a 5-membered 5-membered bicyclic heterocyclic group, a 6-membered 6-membered bicyclic heterocyclic group, a 5-membered 7-membered bicyclic heterocyclic group, a 7-membered 5-membered bicyclic heterocyclic group, a 7-membered 6-membered bicyclic heterocyclic group, or a 6-membered 7-membered bicyclic heterocyclic group.

[0064] In one embodiment of this disclosure, ring B is a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group, a 5-membered 6-membered bicyclic heterocyclic group, a 6-membered 5-membered bicyclic heterocyclic group, a 5-membered 5-membered bicyclic heterocyclic group, a 6-membered 6-membered bicyclic heterocyclic group, a 7-membered 6-membered bicyclic heterocyclic group, a 6-membered 7-membered bicyclic heterocyclic group, a phenyl group, a 5-membered monocyclic heteroaryl group, a 6-membered monocyclic heteroaryl group, a 5-membered 6-membered bicyclic heteroaryl group, a 6-membered 5-membered bicyclic heteroaryl group, a 5-membered 5-membered bicyclic heteroaryl group, a 6-membered 6-membered bicyclic heteroaryl group, a 7-membered 6-membered bicyclic heteroaryl group, or a 6-membered 7-membered bicyclic heteroaryl group.

[0065] In one embodiment of this disclosure, ring B is a 6-membered monocyclic heterocyclic group, a 6-membered 5-membered bicyclic heterocyclic group, or a 6-membered 7-membered bicyclic heterocyclic group.

[0066] In one specific embodiment of this disclosure, ring B is

[0067] In one specific embodiment of this disclosure, ring B is

[0068] In one specific embodiment of this disclosure, ring B is

[0069] In one specific embodiment of this disclosure, ring B is

[0070] In one specific embodiment of this disclosure, ring B is

[0071] In one embodiment of this disclosure, R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C, respectively. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 3-6 Cycloalkyl, phenyl, and 5-6-membered heteroaryl groups, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 3-6 The cycloalkyl, phenyl, or 5-6-membered heteroaryl group is optionally substituted by one, two, or three substituents selected from deuterium, halogen, and cyano; or two R groups attached to the same atom. b Linkage forms a 3-6 membered cycloalkyl group, wherein the 3-6 membered cycloalkyl group is optionally surrounded by 1, 2, or 3 groups selected from deuterium, halogen, cyano, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl thiols, halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy and halogenated C 1-3 The substituents of the alkylthio group are replaced.

[0072] In one embodiment of this disclosure, R b The radicals are selected from hydrogen, deuterium, halogen, cyano, oxo, thio, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, cyclopropyl, phenyl, and 6-membered heteroaryl, wherein the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, cyclopropyl, phenyl, or 6-membered heteroaryl radicals are optionally substituted by 1, 2, or 3 substituents selected from halogens; or two R radicals attached to the same atom. b The links form 3-4 membered cycloalkyl groups, which are optionally replaced by 1, 2 or 3 substituents selected from deuterium, halogen, cyano, methyl and methoxy.

[0073] In one embodiment of this disclosure, R bThe radicals are selected from hydrogen, F, Cl, Br, cyano, oxo, methyl, ethyl, methoxy, ethoxy, cyclopropyl, and pyrimidinyl, respectively, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl, or pyrimidinyl radicals are optionally substituted by one, two, or three substituents selected from halogens; or two R radicals attached to the same atom. b The linker forms a cyclopropane, which is optionally substituted with one, two, or three substituents selected from halogens, methyl groups, and methoxy groups.

[0074] In one embodiment of this disclosure, R b The radicals are selected from hydrogen, F, Cl, Br, cyano, oxo, methyl, ethyl, methoxy, ethoxy, cyclopropyl, pyrimidinyl, -OCF3, and -CF3, or two R radicals attached to the same atom. b The link forms cyclopropane.

[0075] In one embodiment of this disclosure, R b They are selected from Cl, methyl, and methoxy, respectively.

[0076] In one specific implementation of this disclosure, for

[0077] In one specific implementation of this disclosure, for

[0078] In one specific implementation of this disclosure, for

[0079] In one specific implementation of this disclosure, for

[0080] In one specific implementation of this disclosure, for

[0081] In one specific implementation of this disclosure, for

[0082] In one specific implementation of this disclosure, for

[0083] In one embodiment of this disclosure, ring C is a 5-6 membered heterocyclic group, phenyl, or 5-6 membered heteroaryl; the 5-6 membered heterocyclic group, phenyl, or 5-6 membered heteroaryl group is optionally composed of 1, 2, or 3 groups selected from deuterium, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl thiols, halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy and halogenated C 1-3 The substituents of the alkylthio group are replaced.

[0084] In one embodiment of this disclosure, ring C is a 5-membered heterocyclic group or a 5-membered heteroaryl group; said 5-membered heterocyclic group or 5-membered heteroaryl group is optionally substituted by 1, 2 or 3 substituents selected from deuterium, halogen, cyano, methyl and methoxy.

[0085] In one specific implementation of this disclosure, for in This represents the bond connected to NH in formula (IA), formula (I), or formula (II). This represents the bond connected to ring B.

[0086] In one specific implementation of this disclosure, for in This represents the bond connected to NH in formula (IA), formula (I), or formula (II). This represents the bond connected to ring B.

[0087] In one specific implementation of this disclosure, for in This represents the bond connected to NH in formula (IA), formula (I), or formula (II). This represents the bond connected to ring B.

[0088] In one embodiment of this disclosure, R c Selected from hydrogen, deuterium, halogen, cyano, and C respectively 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl thiols, halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy and halogenated C 1-3 Alkylthio group.

[0089] In one embodiment of this disclosure, R cThey are selected from hydrogen, deuterium, halogen, cyano, methyl and methoxy, respectively.

[0090] In one embodiment of this disclosure, R c It is hydrogen.

[0091] In one specific implementation of this disclosure, for in This represents the bond connected to NH in formula (IA), formula (I), or formula (II). This represents the bond connected to ring B.

[0092] In one specific implementation of this disclosure, for in This represents the bond connected to NH in formula (IA), formula (I), or formula (II). This represents the bond connected to ring B.

[0093] In one specific implementation of this disclosure, for in This represents the bond connected to NH in formula (IA), formula (I), or formula (II). This represents the bond connected to ring B.

[0094] In one specific implementation of this disclosure, for in This represents the bond connected to NH in formula (IA), formula (I), or formula (II). This represents the bond connected to ring B.

[0095] In one specific implementation of this disclosure, for in This represents the bond connected to NH in formula (IA), formula (I), or formula (II). This represents the bond connected to ring B.

[0096] In one embodiment of this disclosure, x is 0, 1, 2 or 3.

[0097] In one embodiment of this disclosure, x is 0, 1, or 2.

[0098] In one embodiment of this disclosure, X is 0 or 1.

[0099] In one embodiment of this disclosure, X is 1.

[0100] In one embodiment of this disclosure, y is 0, 1, 2 or 3.

[0101] In one embodiment of this disclosure, y is 0 or 1.

[0102] In one embodiment of this disclosure, y is 0.

[0103] In one embodiment of this disclosure, p is 0 or 1.

[0104] In one embodiment of this disclosure, p is 0.

[0105] In one embodiment of this disclosure, the compound represented by formula (IA) or formula (I), its stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is further represented as shown in formula (II):

[0106] In formula (II), each substituent is as described in formula (IA) or formula (I).

[0107] Based on common knowledge in the field, the definitions of the above-mentioned groups or structural segments can be arbitrarily combined to obtain the preferred embodiments of this disclosure.

[0108] The compounds described in this disclosure are selected from:

[0109] or its stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0110] The compounds described in this disclosure are selected from:

[0111] or its stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0112] The object of this disclosure also includes providing a method for preparing compounds of the above general formula, their stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0113] The compound of the general formula can be prepared by a variety of methods, including but not limited to the following:

[0114] X1 is an amino protecting group, preferably selected from tert-butoxycarbonyl (Boc), benzyl (Bn) or 9-fluorenylmethoxycarbonyl (Fmoc); X2, X3 and X4 are independently selected from halogen, methyl mercapto, methanesulfonyl, borate, boric acid and trifluoromethanesulfonyl, preferably chlorine, bromine, iodine, methyl mercapto and boric acid.

[0115] Method a involves a substitution or coupling reaction under alkaline conditions; method b involves a halogenation reaction using a halogenating reagent; method c involves a substitution or coupling reaction under alkaline conditions; method d involves the removal of the amino protecting group under acidic, alkaline, or neutral conditions; and method e involves a substitution or coupling reaction under alkaline conditions.

[0116] This disclosure also provides a pharmaceutical composition comprising the compounds of this disclosure, their stereoisomers, tautomers, or mixtures thereof, or pharmaceutically acceptable salts thereof. Further, the pharmaceutical composition also comprises pharmaceutically acceptable excipients.

[0117] This disclosure also provides the use of the compounds of this disclosure, their stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for treating and / or preventing diseases mediated by PCSK9.

[0118] This disclosure also provides the use of the compounds of this disclosure, their stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of LDL-lowering drugs.

[0119] This disclosure also provides a method for preventing and / or treating diseases mediated by PCSK9, comprising administering to an individual in need (e.g., a patient) a preventive and / or therapeutically effective dose of a compound of this disclosure, its stereoisomers, tautomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this disclosure.

[0120] This disclosure also provides a method for lowering LDL, comprising administering an effective dose of a compound of this disclosure, its stereoisomers, tautomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this disclosure to an individual (e.g., a patient) who requires such treatment.

[0121] This disclosure also provides compounds of the disclosure, stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the disclosure, for the prevention and / or treatment of diseases mediated by PCSK9.

[0122] This disclosure also provides compounds of the disclosure, stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the disclosure, for lowering LDL.

[0123] In one embodiment of this disclosure, the diseases mediated by PCSK9 are selected from cardiovascular diseases, liver diseases, infectious and autoimmune diseases, neurocognitive disorders, and cancer.

[0124] definition

[0125] Unless otherwise specified, the term "alkyl" refers to a straight-chain or branched monovalent saturated aliphatic hydrocarbon group, typically containing 1-20 carbon atoms, preferably 1-10 carbon atoms (i.e., C64-C ... 1-10 Alkyl groups, more preferably containing 1-8 carbon atoms (C64- ... 1-8 Alkyl groups, more preferably containing 1-6 carbon atoms (i.e., C64-C ... 1-6 Alkyl), for example, "C 1-6 "Alkyl" refers to a group that is alkyl and has 1 to 6 carbon atoms in its carbon chain (specifically, 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0126] Unless otherwise specified, the term "alkenyl" refers to a straight-chain or branched monovalent unsaturated aliphatic hydrocarbon group having at least one double bond, typically containing 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C64-C ... 2-10 Alkenyl), and more preferably containing 2-8 carbon atoms (i.e., C14-C24). 2-8 Alkenyl), more preferably containing 2-6 carbon atoms (i.e., C14-C2 ... 2-6 alkenyl), for example, "C 2-6 "Alkenyl" means that the group is alkenyl and the number of carbon atoms on the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl and 1,3-butadienyl.

[0127] Unless otherwise specified, the term "alkynyl" refers to a straight-chain or branched monovalent unsaturated aliphatic hydrocarbon group having at least one triple bond, typically containing 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C64-C ... 2-10 Alkyne group), further preferably containing 2-8 carbon atoms (i.e., C64-C ... 2-8 Alkyne group), more preferably containing 2-6 carbon atoms (i.e., C64-C ... 2-6 (Alkyne group), for example, "C 2-6"Alynyl" means that the group is alkynyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl and 1-butynyl.

[0128] Unless otherwise specified, the term "cycloalkyl" refers to a hydrocarbon group selected from cyclic hydrocarbon groups that do not contain unsaturated bonds, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused cycloalkyl, bridged cycloalkyl, or spirocycloalkyl. For example, a cycloalkyl group may contain 3 to 16 carbon atoms (such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4). Even further, for example, a cycloalkyl group may be selected from monocyclic groups containing 3 to 12 carbon atoms (such as 3 to 10, further such as 3 to 8, 3 to 6). Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Examples of bicyclic cycloalkyl groups include those having 5 to 12, further such as 7 to 12 or 5 to 10 ring atoms, such as fused bicyclics having [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems, or bridging bicyclics having bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane or bicyclic [3.2.2]nonane ring systems.

[0129] Unless otherwise specified, the term "heterocyclic group" refers to a cyclic group, saturated or partially unsaturated, monocyclic, bicyclic, or polycyclic, with a non-aromatic structure, typically containing 3-20 ring atoms, of which 1, 2, 3, or more ring atoms are N, O, or S, and the remaining ring atoms are C. Preferably, it contains 3-12 ring atoms, more preferably 3-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms. The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, pyranyl, etc. Bicyclic or polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0130] Unless otherwise specified, the term "alkoxy" refers to an "-O-alkyl" group, wherein the alkyl group is defined as above, i.e., containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, and even more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, etc.

[0131] Unless otherwise specified, the term "alkoxy" refers to the substitution of an oxygen atom in the above "alkoxy" with a sulfur atom.

[0132] Unless otherwise specified, the terms "halogen" or "halogenated" refer to F, Cl, Br, and I. The term "haloalkyl" refers to an alkyl group as defined above in which one, two, or more hydrogen atoms, or all hydrogen atoms, are replaced by a halogen. Representative examples of halogenated alkyl groups include -CCl3, -CF3, -CHCl2, -CH2Cl, -CH2Br, -CH2I, -CH2CF3, -CF2CF3, etc. The term "haloalkoxy" refers to an alkoxy group as defined above in which one, two, or more hydrogen atoms, or all hydrogen atoms, are replaced by a halogen. Representative examples of halogenated alkoxy groups include -OCCl3, -OCF3, -OCHCl2, -OCH2Cl, -OCHF2, -OCH2F, -OCH2CF3, -OCF2CF3, etc. The term "haloalkoxythio" refers to a "haloalkoxy" group in which the oxygen atom is replaced by a sulfur atom.

[0133] Unless otherwise specified, the term "aryl" refers to an aromatic carbocyclic system, typically containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms, preferably an aryl group containing 6-10 carbon atoms (i.e., C10). 6-10 Aryl), the term "aryl" may be used interchangeably with the term "aromatic ring". Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthraceneyl, phenanthrene, or pyrene.

[0134] Unless otherwise specified, the term "heteroaryl" refers to an aromatic cyclic system that typically contains a 5-16 member structure, or a 5-14 member structure, a 5-12 member structure, a 5-10 member structure, a 5-8 member structure, or a 5-6 member structure, consisting of a monocyclic, bicyclic, or polycyclic (e.g., tricyclic) ring structure, wherein one, two, three, or more ring atoms are heteroatoms and the remaining atoms are carbon atoms, wherein the heteroatoms are independently O, N, or S, and the number of heteroatoms is preferably one, two, or three. Examples of heteroaryl groups may include, but are not limited to, furanyl, thiophene, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrrole, pyrazolyl, imidazole, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purine, indoleyl, isoindoleyl, indazoleyl, benzofuranyl, benzothiophene, benzopyridyl, benzopyrimidinyl, and benzene. Pyrazinyl, benzimidazolyl, benziphthalazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, etc.

[0135] Unless otherwise specified, the term "amino" refers to the "-NH2" group.

[0136] Unless otherwise specified, the term "hydroxyl group" refers to the "-OH" group.

[0137] Unless otherwise specified, the term "thiol" refers to the "-SH" group.

[0138] Unless otherwise specified, the term "azido" refers to the "-N3" group.

[0139] Unless otherwise specified, the term "cyano" refers to the "-CN" group.

[0140] Unless otherwise specified, the term "nitro" refers to the "-NO2" group.

[0141] Unless otherwise specified, the term "oxo" refers to the "=O" group.

[0142] Unless otherwise specified, the term "thio-" refers to the "=S" group.

[0143] Unless otherwise specified, the term "carboxyl" refers to the "-C(=O)OH" group.

[0144] Unless otherwise specified, the terms "pharmaceutically acceptable salt" or "medicinal salt" refer to a salt that, within the bounds of reasonable medical judgment, is suitable for contact with the tissues of mammals, particularly humans, without excessive toxicity, irritation, allergic reactions, etc., and in a manner commensurate with a reasonable benefit / risk ratio. Medically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or solely by reacting a free base or free acid with a suitable reagent.

[0145] The compounds disclosed herein also include their "isotope derivatives." Unless otherwise specified, the term "isotope derivative" refers to compounds of this disclosure that can exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weights or mass numbers differ from the atomic weights or mass numbers of the most abundant atoms found in nature. Isotopes can be radioactive or non-radioactive isotopes. Commonly used isotopes for isotopic labeling include hydrogen isotopes. 2 H and 3 H; Carbon isotopes: 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially 3 H and 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (… 2 Substitution with H can enhance metabolic stability and prolong the half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, just like non-isotope-labeled compounds.

[0146] The compounds disclosed herein also include their solvates. Unless otherwise specified, the terms "solvate" or "solvent" refer to the physical association of a compound of this disclosure with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. Solvent molecules in a solvate may be present in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" encompasses both solution phases and separable solvates. Solvation methods are well known in the art.

[0147] Unless otherwise specified, the term "stereoisomer" refers to compounds having the same chemical structure but with different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and inhibited isomers. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0148] Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called proton transfer tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

[0149] Unless otherwise specified, the term "substitution" means that the hydrogen at the substituted site of the group is replaced by one or more substituents, preferably by one, two, or three substituents, wherein the substituents are preferably selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, nitro, amino, azide, oxo, carboxyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocyclic group, C 6-14 Aryl or 5-10 heteroaryl, wherein the C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocyclic group, C6-14 The aryl or 5-10 membered heteroaryl group may optionally be selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl and C 1-6 The alkoxy group is substituted by one or more substituents, wherein the oxo group refers to the two H atoms at the same substitution position being replaced by the same O atom to form a double bond.

[0150] The beneficial effects of this disclosure are as follows:

[0151] This disclosure presents a novel class of compounds, providing a new direction for the development of PCSK9 inhibitor drugs. Experimental results show that the disclosed compounds have a high affinity for PCSK9 protein, significantly reduce LDL-C, and can be used to treat and / or prevent cardiovascular diseases related to dyslipidemia. Furthermore, in vivo pharmacokinetic experiments demonstrate that the disclosed compounds possess favorable pharmacokinetic properties. Detailed Implementation

[0152] The present disclosure is further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the disclosure. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this disclosure. The preferred embodiments and materials shown herein are for illustrative purposes only.

[0153] The structures of the compounds disclosed herein were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or high-performance liquid chromatography (HPLC). The NMR determination was performed using a Bruker AVANCE III 600MHz instrument; the LC-MS was performed using an LCMS WATERS ACQUITY UPLC H-Class PLUS and / or SQD2 instrument; and the HPLC was performed using a WATERS e2695_2998 and / or an Agilent 1100 instrument.

[0154] The starting materials used in the embodiments of this disclosure are known and commercially available, or can be synthesized using methods known in the art.

[0155] Abbreviations: DCM: dichloromethane; CDCl3: deuterated chloroform; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; PE: petroleum ether; EA: ethyl acetate; MeOH: methanol; CD3OD: deuterated methanol; THF: tetrahydrofuran; DIPEA: diisopropylethylamine; Pd / C: palladium on carbon; mCPBA: m-chloroperoxybenzoic acid; NIS: N-iodosuccinimide; RuPhos-Pd-G2: [2'-(amino)[1,1'-biphenyl]-2-yl][[2',6'-di(1-methylethoxy)[1,1'-biphenyl]-2-yl]dicyclohexylphosphine]palladium chloride.

[0156] Example 1: Synthesis of spiro[cyclopropane-1,3'-indoline]-2'-one

[0157] In a 100 mL three-necked flask, indoline-2-one (15.0 mmol), THF (30 mL), and DIPEA (30.0 mmol) were added. Under a nitrogen atmosphere, the system was cooled to -40 °C, and a 2.5 M n-butyllithium solution in n-hexane (27 mL) was added dropwise. The reaction was continued for 1 h. Then, the temperature was raised to 0 °C, and a 1,2-dibromoethane (45.0 mmol) THF solution (10 mL) was added dropwise. After the addition was complete, the reaction system was allowed to return to room temperature overnight. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated to dryness under reduced pressure. The concentrate was purified by column chromatography (PE:EA = 2:1, v / v) to give the target product (0.7 g). ESI-MS (m / z): 160.07 [M+H] + .

[0158] Intermediate Preparation Example 2: 3,4-Dihydrobenzo[f][1,4]thiazo -5(2H)-ketone 1,1-dioxide

[0159] 3,4-Dihydrobenzo[f][1,4]thiazolidinium oxide was added to a 100 mL reaction flask. -5(2H)-one (5.6 mmol), m-chloroperoxybenzoic acid (21.4 mmol), and DCM (10 mL) were reacted at room temperature for 1 h, and the reaction was confirmed to be complete by LCMS. The product was directly filtered to obtain the target product (0.61 g). ESI-MS (m / z): 212.03 [M+H] + .

[0160] Example 3 of intermediate preparation: 3-(4-methoxybenzyl)-2-(methanesulfonyl)-3H-imidazo[4,5-b]pyridine

[0161] Step 1: Preparation of 2-(methylthio)-3H-imidazo[4,5-b]pyridine

[0162] 1,3-Dihydro-2H-imidazo[4,5-b]pyridine-2-thione (3.0 mmol), iodomethane (3.3 mmol), potassium carbonate (6.0 mmol), and tetrahydrofuran (20 mL) were added to a reaction flask and reacted at room temperature for 2 h. After the reaction was confirmed to be complete, the solid was removed by filtration, and water and ethyl acetate were added. The mixture was separated, and the organic phase was washed once with water and once with saturated brine. The organic phase was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography to give the product (334 mg). ESI-MS (m / z): 166.03 [M+H] + .

[0163] Step 2: Preparation of 2-(methanesulfonyl)-3H-imidazo[4,5-b]pyridine

[0164] 2-(methylthio)-3H-imidazo[4,5-b]pyridine (2.0 mmol) was added to a reaction flask and dissolved in dichloromethane (10 mL). Then, m-chloroperoxybenzoic acid (4.4 mmol) was added, and the reaction was carried out at room temperature for 24 h. After confirming the reaction was complete, anhydrous sodium carbonate was added to adjust the pH to 9. The organic phase was concentrated to dryness under reduced pressure. The concentrate was purified by column chromatography to give the product (300 mg). ESI-MS (m / z): 198.02 [M+H] + .

[0165] Step 3: Preparation of 3-(4-methoxybenzyl)-2-(methanesulfonyl)-3H-imidazo[4,5-b]pyridine

[0166] 2-(methanesulfonyl)-3H-imidazo[4,5-b]pyridine (1.5 mmol) was added to a reaction flask and dissolved in dichloromethane (15 mL). The mixture was cooled to 0 °C in an ice bath, and triethylamine (3.0 mmol) and 4-methoxybenzyl chloride (1.7 mmol) were slowly added sequentially. The reaction was allowed to proceed at room temperature for 5 h after the addition was complete. Water and ethyl acetate were added, the mixture was stirred, and the layers were separated. The resulting organic phases were washed once with water and once with saturated brine. The organic phases were concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography to give the product (210 mg). ESI-MS (m / z): 318.08 [M+H] + .

[0167] Intermediate Preparation Example 4: ((1S,3S)-3-((4-iodofurano[2,3-c]pyridin-7-yl)amino)cyclopentyl)tert-butyl carbamate

[0168] Step 1: Preparation of tert-butyl ((1S,3S)-3-(furano[2,3-c]pyridin-7-ylamino)cyclopentyl)carbamate

[0169] 7-Chlorofurano[2,3-c]pyridine (6.5 mmol), ((1S,3S)-3-aminocyclopentyl)carbamate tert-butyl ester (7.1 mmol), RuPhos-Pd-G2 (0.65 mmol), sodium tert-butoxide (13.0 mmol), and toluene (20 mL) were added to a reaction flask. The mixture was purged with argon and reacted at 85 °C for 10 h. After cooling to room temperature, the solid was filtered off, and water and ethyl acetate were added. The mixture was separated, and the organic phase was washed once with water and once with saturated brine. The organic phase was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (EA:PE = 1:3, v / v) to give the product (314 mg). ESI-MS (m / z): 318.17 [M+H] + . 1 H NMR (600MHz, CD3Cl): δ7.87(d,J=5.5Hz,1H),7.60(d,J=2.0Hz,1H),6.85(d,J=5.5Hz,1H),6.70(d,J=2.0Hz,1H),4.75(s,1H ),4.68-4.63(m,1H),4.61(s,1H),4.21-4.13(m,1H),2.38-2.18(m,2H),2.04-1.96(m,2H),1.61-1.52(m,2H),1.44(s,9H).

[0170] Step 2: Preparation of tert-butyl ((1S,3S)-3-((4-iodofurano[2,3-c]pyridin-7-yl)amino)cyclopentyl)carbamate

[0171] (1S,3S)-3-(furano[2,3-c]pyridin-7-ylamino)cyclopentyl)tert-butyl carbamate (1.0 mmol) was added to a reaction flask and dissolved in acetonitrile (15 mL). The mixture was cooled to 0 °C in an ice bath, and N-iodosuccinimide (1.2 mmol) was slowly added. After the addition was complete, the mixture was reacted at room temperature for 6 h. Water and ethyl acetate were added, the mixture was stirred, and the layers were separated. The resulting organic phases were washed once with water and once with saturated brine. The organic phases were concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (EA:PE = 1:2, v / v) to give the product (430 mg). ESI-MS (m / z): 444.10 [M+H] + . 1H NMR (600MHz, CDCl3): δ8.05(s,1H),7.66(d,J=2.1Hz,1H),6.64(d,J=2.1Hz,1H),4.91(s,1H),4.6 5-4.51(m,2H),4.16(s,1H),2.38-2.18(m,2H),2.02-1.94(m,2H),1.58-1.49(m,2H),1.44(s,9H).

[0172] Intermediate Preparation Example 5: 6-(7-(((1S,3S)-3-aminocyclopentyl)amino)furano[2,3-c]pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0173] Step 1: Preparation of ((1S,3S)-3-((4-(7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)furano[2,3-c]pyridin-7-yl)amino)cyclopentyl)tert-butyl carbamate

[0174] Add ((1S,3S)-3-((4-iodofurano[2,3-c]pyridin-7-yl)amino)cyclopentyl)tert-butyl carbamate (1.0 mmol), 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (1.2 mmol), cesium carbonate (2.0 mmol), cuprous iodide (1.0 mmol), and (1S,2S)-N 1 N 2 The reaction system was purged with nitrogen using dimethylcyclohexane-1,2-diamine (1.0 mmol) and DMSO (20 mL), and reacted at 120 °C for 8 h. Water and ethyl acetate were added, the mixture was stirred, and the layers were separated. The resulting organic phases were washed once with water and once with saturated brine. The organic phases were concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM:MeOH = 30:1, v / v) to give the product (45 mg). ESI-MS (m / z): 450.20 [M+H] + .

[0175] Step 2: Preparation of 6-(7-(((1S,3S)-3-aminocyclopentyl)amino)furano[2,3-c]pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0176] A solution of ((1S,3S)-3-((4-(7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)furano[2,3-c]pyridin-7-yl)amino)cyclopentyl)carbamate tert-butyl ester (0.1 mmol) and 1,4-dioxane in 4M hydrochloric acid (2 mL) was added to a reaction flask. The reaction solution was reacted at room temperature for 4 h. The reaction solvent was concentrated to dryness under reduced pressure. The concentrate was diluted with methanol, and then Ambersep® 900 resin was added under stirring to adjust the pH of the solution to approximately 8–9. The solution was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the product (30 mg). ESI-MS (m / z): 350.15 [M+H] + .

[0177] Intermediate Preparation Example 6: 2-(7-(((1S,3S)-3-aminocyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridazin-3(2H)-one

[0178] Step 1: Preparation of tert-butyl ((1S,3S)-3-((4-(6-oxopyridazine-1(6H)-yl)furano[2,3-c]pyridin-7-yl)amino)cyclopentyl)carbamate

[0179] Add ((1S,3S)-3-((4-iodofurano[2,3-c]pyridin-7-yl)amino)cyclopentyl)tert-butyl carbamate (1.0 mmol), pyridazine-3(2H)-one (1.2 mmol), cesium carbonate (2.0 mmol), cuprous iodide (1.0 mmol), and (1S,2S)-N to the reaction flask. 1 N 2 The reaction system was purged with nitrogen using dimethylcyclohexane-1,2-diamine (1.0 mmol) and DMSO (20 mL), and reacted at 120 °C for 8 h. Water and ethyl acetate were added, the mixture was stirred, and the layers were separated. The resulting organic phases were washed once with water and once with saturated brine. The organic phases were concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM:MeOH = 60:1, v / v) to give the product (165 mg). ESI-MS (m / z): 412.20 [M+H] + .

[0180] Step 2: Preparation of 2-(7-(((1S,3S)-3-aminocyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridazin-3(2H)-one

[0181] A solution of tert-butyl carbamate ((1S,3S)-3-((4-(6-oxopyridazin-1(6H)-yl)furano[2,3-c]pyridin-7-yl)amino)cyclopentyl)carbamate (0.40 mmol) and 1,4-dioxane in 4M hydrochloric acid (5 mL) was added to a reaction flask. The reaction solution was reacted at room temperature for 4 h. The reaction solvent was concentrated to dryness under reduced pressure. The concentrate was diluted with methanol, and then Ambersep® 900 resin was added under stirring to adjust the pH of the solution to approximately 8–9. The solution was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the product (25 mg). ESI-MS (m / z): 312.15 [M+H] + .

[0182] Intermediate Preparation Example 7: 2-(7-(((1S,3S)-3-aminocyclopentyl)amino)furano[2,3-c]pyridin-4-yl)isoindolin-1-one

[0183] Step 1: Preparation of ((1S,3S)-3-((4-(1-oxoisoindol-2-yl)furano[2,3-c]pyridin-7-yl)amino)cyclopentyl)tert-butyl carbamate

[0184] Add ((1S,3S)-3-((4-iodofurano[2,3-c]pyridin-7-yl)amino)cyclopentyl)tert-butyl carbamate (1.0 mmol), isoindoline-1-one (1.2 mmol), cesium carbonate (2.0 mmol), cuprous iodide (1.0 mmol), and (1S,2S)-N to the reaction flask. 1 N 2 The reaction system was purged with nitrogen using dimethylcyclohexane-1,2-diamine (1.0 mmol) and DMSO (20 mL), and reacted at 120 °C for 8 h. Water and ethyl acetate were added, the mixture was stirred, and the layers were separated. The resulting organic phases were washed once with water and once with saturated brine. The organic phases were concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM:MeOH = 50:1, v / v) to give the product (90 mg). ESI-MS (m / z): 449.20 [M+H] + .

[0185] Step 2: Preparation of 2-(7-(((1S,3S)-3-aminocyclopentyl)amino)furano[2,3-c]pyridin-4-yl)isoindolin-1-one

[0186] A solution of tert-butyl ((1S,3S)-3-((4-(1-oxoisoindol-2-yl)furano[2,3-c]pyridin-7-yl)amino)cyclopentyl)carbamate (0.2 mmol) and 1,4-dioxane in 4 M hydrochloric acid (2 mL) was added to a reaction flask, and the reaction solution was reacted at room temperature for 4 h. The reaction solvent was concentrated to dryness under reduced pressure, the concentrate was diluted with methanol, and then Ambersep® 900 resin was added under stirring to adjust the pH of the solution to approximately 8–9. The solution was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the product (60 mg). ESI-MS (m / z): 349.15 [M+H] + .

[0187] Intermediate Preparation Example 8: 6-Chloro-2-(methanesulfonyl)thiazo[5,4-b]pyridine

[0188]

[0189] Step 1: Synthesis of 6-chlorothiazo[5,4-b]pyridine-2(1H)-thione

[0190] 2-Bromo-5-chloropyridin-3-amine (1.00 g, 4.82 mmol, 1.00 equiv.) and potassium ethyl xanthate (927.2 mg, 5.78 mmol, 1.20 equiv.) were added to dimethyl sulfoxide (100 mL, 100%) and reacted at 130 °C for 16 h. After the reaction was complete, the reaction system was poured into ice water, and a large amount of solid precipitated. The solid was filtered through a Buchner funnel, the filter cake was washed with water, and then dried. After drying, the solid was slurried with MTBE (5 mL), filtered, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative plate (PE:EA = 3:1, v / v) to obtain 6-chlorothiazo[5,4-b]pyridin-2(1H)-thione (1.00 g, 97.2%).

[0191] Step 2: Synthesis of 6-chloro-2-(methylthio)thiazo[5,4-b]pyridine

[0192] 6-Chlorothiazolo[5,4-b]pyridine-2(1H)-thione (0.90 g, 4.40 mmol, 1.00 equiv.), iodomethane (630.3 mg, 4.44 mmol, 1.00 equiv.), and potassium carbonate (1.82 g, 13.20 mmol, 3.00 equiv.) were added to MeOH (20 mL, 100%) and reacted at 25 °C for 12 h. After the reaction was complete, the reaction system was poured into ice water, extracted with ethyl acetate (2 x 10 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative plate (PE:EA = 2:1, v / v) to obtain 6-chloro-2-(methylthio)thiazo[5,4-b]pyridine (450.0 mg, 46.8%). 1 H NMR (400MHz, DMSO-d6): δ8.56(s,1H),8.42(s,1H),2.82(s,3H). ESI-MS(m / z):216.9[M+1] + .

[0193] Step 3: Synthesis of 6-chloro-2-(methanesulfonyl)thiazo[5,4-b]pyridine

[0194] 6-Chloro-2-(methylthio)thiazo[5,4-b]pyridine (100 mg, 0.46 mmol, 1.00 equiv.) was added to DCM (5 mL), followed by slow addition of m-CPBA (235 mg, 1.36 mmol, 3.00 equiv.), and the reaction was carried out at room temperature for 2 h. After the reaction was complete, the reaction solution was washed with saturated sodium bicarbonate solution, and the organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative plate (PE:EA = 2:1, v / v) to obtain 6-chloro-2-(methanesulfonyl)thiazo[5,4-b]pyridine (80 mg, 69.9%).

[0195] Intermediate Preparation Example 9: 6-Methoxy-2-(methanesulfonyl)thiazo[5,4-b]pyridine

[0196] The synthesis method is the same as that in Example 8, except that in step 1, 2-bromo-5-methoxypyridine-3-amine is used instead of 2-bromo-5-chloropyridine-3-amine to obtain 6-methoxy-2-(methanesulfonyl)thiazo[5,4-b]pyridine (85 mg).

[0197] Intermediate Preparation Example 10: 6-(difluoromethoxy)-2-(methanesulfonyl)thiazo[5,4-b]pyridine

[0198] The synthesis method is the same as that in Example 8, except that in step 1, the starting material 2-bromo-5-(difluoromethoxy)pyridine-3-amine is used instead of 2-bromo-5-chloropyridine-3-amine to obtain 6-(difluoromethoxy)-2-(methanesulfonyl)thiazo[5,4-b]pyridine (75 mg).

[0199] Example 1: 1-(7-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 1)

[0200] Step 1: Preparation of tert-butyl ((1S,3S)-3-(furano[2,3-c]pyridin-7-ylamino)cyclopentyl)carbamate

[0201] 7-Chlorofurano[2,3-c]pyridine (6.5 mmol), ((1S,3S)-3-aminocyclopentyl)carbamate tert-butyl ester (7.1 mmol), RuPhos-Pd-G2 (0.65 mmol), sodium tert-butoxide (13.0 mmol), and toluene (20 mL) were added to a reaction flask. The mixture was purged with argon and reacted at 85 °C for 10 h. After cooling to room temperature, the solid was filtered off, and water and ethyl acetate were added. The mixture was separated, and the organic phase was washed once with water and once with saturated brine. The organic phase was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (EA:PE = 1:3, v / v) to give the product (314 mg). ESI-MS (m / z): 318.17 [M+H] + . 1 H NMR (600MHz, Chloroform-d): δ7.87(d,J=5.5Hz,1H),7.60(d,J=2.0Hz,1H),6.85(d,J=5.5Hz,1H),6.70(d,J=2.0Hz,1H),4.75( s,1H),4.68-4.63(m,1H),4.61(s,1H),4.21-4.13(m,1H),2.38-2.18(m,2H),2.04-1.96(m,2H),1.61-1.52(m,2H),1.44(s,9H).

[0202] Step 2: Preparation of tert-butyl ((1S,3S)-3-((4-iodofurano[2,3-c]pyridin-7-yl)amino)cyclopentyl)carbamate

[0203] (1S,3S)-3-(furano[2,3-c]pyridin-7-ylamino)cyclopentyl)tert-butyl carbamate (1.0 mmol) was added to a reaction flask and dissolved in acetonitrile (15 mL). The mixture was cooled to 0 °C in an ice bath, and N-iodosuccinimide (1.2 mmol) was slowly added. The reaction was allowed to proceed at room temperature for 6 h after the addition was complete. Water and ethyl acetate were added, the mixture was stirred, and the layers were separated. The resulting organic phase was washed once with water and once with saturated brine. The organic phase was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (EA:PE = 1:2, v / v) to give the product (430 mg). ESI-MS (m / z): 444.10 [M+H] + . 1 H NMR (600MHz, Chloroform-d): δ8.05 (s, 1H), 7.66 (d, J = 2.1Hz, 1H), 6.64 (d, J = 2.1Hz, 1H), 4.91 (s, 1H), 4.65-4.51(m,2H),4.16(s,1H),2.38-2.18(m,2H),2.02-1.94(m,2H),1.58-1.49(m,2H),1.44(s,9H).

[0204] Step 3: Preparation of tert-butyl ((1S,3S)-3-((4-(2-oxopyridin-1(2H)-yl)furano[2,3-c]pyridin-7-yl)amino)cyclopentyl)carbamate

[0205] Add ((1S,3S)-3-((4-iodofurano[2,3-c]pyridin-7-yl)amino)cyclopentyl)tert-butyl carbamate (1.0 mmol), pyridin-2(1H)-one (1.2 mmol), cesium carbonate (2.0 mmol), cuprous iodide (1.0 mmol), and (1S,2S)-N to the reaction flask. 1 N 2 The reaction system was purged with nitrogen using dimethylcyclohexane-1,2-diamine (1.0 mmol) and DMSO (20 mL), and reacted at 120 °C for 8 h. Water and ethyl acetate were added, the mixture was stirred, and the layers were separated. The resulting organic phases were washed once with water and once with saturated brine. The organic phases were concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM:MeOH = 30:1, v / v) to give the product (145 mg). ESI-MS (m / z): 411.20 [M+H] + .

[0206] Step 4: Preparation of 1-(7-(((1S,3S)-3-aminocyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one

[0207] Add ((1S,3S)-3-((4-(2-oxopyridin-1(2H)-yl)furano[2,3-c]pyridin-7-yl)amino)cyclopentyl)carbamate tert-butyl ester (0.35 mmol) and 1,4-dioxane solution (5 mL) in 4M hydrochloric acid to a reaction flask, and react the solution at room temperature for 4 h. Concentrate the reaction solvent to dryness under reduced pressure, dilute the concentrate with methanol, and then add Ambersep® 900 resin under stirring to adjust the pH to approximately 8–9. Filter, and concentrate the filtrate to dryness under reduced pressure to obtain the product (110 mg). ESI-MS (m / z): 311.15 [M+H] + .

[0208] Step 5: Preparation of Compound 1

[0209] 1-(7-(((1S,3S)-3-aminocyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (0.35 mmol), DMSO (10 mL), DIPEA (0.70 mmol), and 2-chloro-5-(difluoromethoxy)pyrimidine (0.35 mmol) were added to a reaction flask, and the reaction mixture was heated to 100 °C and reacted for 6 h. Water and ethyl acetate were added, the mixture was stirred, and the layers were separated. The resulting organic phases were washed once with water and once with saturated brine. The organic phases were concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM:MeOH = 20:1, v / v) to give the product (50 mg). ESI-MS (m / z): 455.44 [M+H] + . 1 H NMR (600MHz, CDCl3): δ8.18(s,2H),7.84(s,1H),7.63(s,1H),7.48-7.43(m,1H) ),7.38(d,J=5.9Hz,1H),6.69(d,J=9.0Hz,1H),6.62(s,1H),6.41(t,J=73.2Hz, 1H),6.28(d,J=6.1Hz,1H),5.36(d,J=5.5Hz,1H),5.13(s,1H),4.78-4.71(m,1 H),4.49-4.41(m,1H),2.44-2.34(m,2H),2.19-2.08(m,2H),1.70-1.57(m,2H).

[0210] Example 2: 1-(4-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)furano[3,2-c]pyridin-7-yl)pyridin-2(1H)-one (Compound 2)

[0211]

[0212] The synthesis method was the same as in Example 1, except that 7-chlorofurano[2,3-c]pyridine in step 1 was replaced with 4-chlorofurano[3,2-c]pyridine. ESI-MS (m / z): 455.44 [M+H] + . 1 H NMR (600MHz, CDCl3): δ8.18(s,2H),7.91(s,1H),7.51-7.42(m,2H),7.33(d,J=6.1Hz,1H),6.71(d,J=9.2Hz,2H),6.41(t,J=73.2Hz,1H),6.27( d,J=6.3Hz,1H),5.36-5.29(m,1H),5.05(s,1H),4.69-4.62(m,1H),4.4 7-4.41(m,1H),2.41-2.31(m,2H),2.14-2.06(m,2H),1.62-1.56(m,2H).

[0213] Example 3: 6-(7-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Compound 3)

[0214] The synthesis method was the same as in Example 1, except that in step 3, pyridine-2(1H)-one was replaced with 5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one, and in step 5, 2-chloro-5-(difluoromethoxy)pyrimidine was replaced with 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m / z): 496.16 [M+H] + . 1 H NMR (600MHz, CDCl3): δ8.86(s,1H),8.48(s,2H),8.01-7.87(m,2H),7.63(s,1H),7.52(s,1H),6.81(s,1H),5.84(s,1H), 5.05(s,1H),4.90(s,2H),4.78-4.68(m,1H),4.60-4.50(m,1H),2.46-2.35(m,2H),2.19-2.08(m,2H),1.74-1.58(m,2H).

[0215] Example 4: 4-(7-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)-3,4-dihydrobenzo[f][1,4]thiaza -5(2H)-ketone 1,1-dioxide (compound 4)

[0216] The synthesis method is the same as in Example 1, except that in step 3, pyridine-2(1H)-one is replaced with 3,4-dihydrobenzo[f][1,4]thiazolidinium. -5(2H)-ketone 1,1-dioxide. ESI-MS (m / z): 571.16 [M+H] + . 1 H NMR (600MHz, CDCl3): δ8.18(s,2H),8.10(d,J=7.7Hz,1H),7.97(d,J=7.5Hz,1H),7.92(s,1H),7.83 (t,J=7.6Hz,1H),7.75(t,J=7.7Hz,1H),7.63(d,J=2.1Hz,1H),7.10(s,1H),6.41(t,J=72.9Hz,1H) ,5.39(d,J=7.1Hz,1H),5.09(d,J=7.0Hz,1H),4.72(q,J=6.9Hz,1H),4.45(q,J=6.9Hz,1H),4.16(t ,J=5.9Hz,2H),3.62(t,J=6.0Hz,2H),2.45-2.31(m,2H),2.12(t,J=6.9Hz,2H),1.70-1.57(m,2H).

[0217] Example 12: 1-(7-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)thieno[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 12)

[0218] The synthesis method is the same as in Example 1. ESI-MS (m / z): 471.13 [M+H] + .

[0219] Example 18: 1-(7-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2,3-dihydrofurano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 18)

[0220] Step 1: Preparation of tert-butyl ((1S,3S)-3-(furano[2,3-c]pyridin-7-ylamino)cyclopentyl)carbamate

[0221] 7-Chlorofurano[2,3-c]pyridine (6.5 mmol), ((1S,3S)-3-aminocyclopentyl)carbamate tert-butyl ester (7.1 mmol), RuPhos-Pd-G2 (0.65 mmol), sodium tert-butoxide (13.0 mmol), and toluene (20 mL) were added to a reaction flask. The mixture was purged with argon and reacted at 85 °C for 10 h. After cooling to room temperature, the solid was filtered off, and water and ethyl acetate were added. The mixture was separated, and the organic phase was washed once with water and once with saturated brine. The organic phase was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (EA:PE = 1:3, v / v) to give the product (314 mg). ESI-MS (m / z): 318.17 [M+H] + . 1 H NMR (600MHz, CDCl3): δ7.87(d,J=5.5Hz,1H),7.60(d,J=2.0Hz,1H),6.85(d,J=5.5Hz,1H),6.70(d,J=2.0Hz,1H),4.75(s,1H ),4.68-4.63(m,1H),4.61(s,1H),4.21-4.13(m,1H),2.38-2.18(m,2H),2.04-1.96(m,2H),1.61-1.52(m,2H),1.44(s,9H).

[0222] Step 2: Preparation of tert-butyl ((1S,3S)-3-((2,3-dihydrofurano[2,3-c]pyridin-7-yl)amino)cyclopentyl)carbamate

[0223] 10.0 mmol of ((1S,3S)-3-(furano[2,3-c]pyridin-7-ylamino)cyclopentyl)carbamate tert-butyl ester was added to a reaction flask and dissolved in methanol (25 mL). Pd / C (10.0 mmol) was added, and the mixture was purged three times with hydrogen. The reaction was carried out at 0.4 M pressure and room temperature for 24 h. The mixture was filtered, and the organic phase was concentrated to dryness under reduced pressure. The concentrate was purified by column chromatography to give the product (400 mg). ESI-MS (m / z): 320.18 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ7.52(d,J=5.1Hz,1H),6.89-6.80(m,1H),6.49(d,J=5.0Hz,1H),5.70(d,J=7.4Hz,1H),4.51(t,J=8.9Hz,2H ),4.41-4.28(m,1H),3.95-3.83(m,1H),3.12(t,J=8.9Hz,2H),2.05-1.86(m,2H),1.81-1.67(m,2H),1.37(s,9H),1.50-1.31(m,2H).

[0224] Step 3: Preparation of tert-butyl ((1S,3S)-3-((4-bromo-2,3-dihydrofurano[2,3-c]pyridin-7-yl)amino)cyclopentyl)carbamate

[0225] (1S,3S)-3-((2,3-dihydrofurano[2,3-c]pyridin-7-yl)amino)cyclopentyl)tert-butyl carbamate (1.5 mmol) was added to a reaction flask and dissolved in dichloromethane (15 mL). The mixture was cooled to 0 °C in an ice bath, and N-bromosuccinimide (1.7 mmol) was slowly added. The reaction was allowed to proceed at room temperature for 1 h after the addition was complete. Water and ethyl acetate were added, the mixture was stirred, and the layers were separated. The resulting organic phases were washed once with water and once with saturated brine. The organic phases were concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography to give the product (220 mg). ESI-MS (m / z): 398.18 [M+H] + .

[0226] Step 4: Preparation of tert-butyl ((1S,3S)-3-((4-(2-oxopyridin-1(2H)-yl)-2,3-dihydrofurano[2,3-c]pyridin-7-yl)amino)cyclopentyl)carbamate

[0227] Add ((1S,3S)-3-((4-bromo-2,3-dihydrofurano[2,3-c]pyridin-7-yl)amino)cyclopentyl)tert-butyl carbamate (0.5 mmol), pyridin-2(1H)-one (0.6 mmol), cesium carbonate (1.0 mmol), cuprous iodide (0.5 mmol), and (1S,2S)-N to the reaction flask. 1 N 2The reaction system was purged with nitrogen using dimethylcyclohexane-1,2-diamine (0.5 mmol) and DMSO (10 mL), and reacted at 120 °C for 8 h. Water and ethyl acetate were added, the mixture was stirred, and the layers were separated. The resulting organic phases were washed once with water and once with saturated brine. The organic phases were concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM:MeOH = 30:1, v / v) to give the product (50 mg). ESI-MS (m / z): 413.20 [M+H] + .

[0228] Step 5: Preparation of 1-(7-(((1S,3S)-3-aminocyclopentyl)amino)-2,3-dihydrofurano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one

[0229] A solution of ((1S,3S)-3-((4-(2-oxopyridin-1(2H)-yl)-2,3-dihydrofurano[2,3-c]pyridin-7-yl)amino)cyclopentyl)carbamate tert-butyl ester (0.12 mmol) and 1,4-dioxane in 4M hydrochloric acid (2 mL) was added to a reaction flask. The reaction solution was reacted at room temperature for 4 h. The reaction solvent was concentrated to dryness under reduced pressure. The concentrate was diluted with methanol, and then Ambersep® 900 resin was added under stirring to adjust the pH of the solution to approximately 8–9. The solution was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the product (38 mg). ESI-MS (m / z): 313.15 [M+H] + .

[0230] Step 6: Preparation of 1-(7-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-2,3-dihydrofurano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one

[0231] 1-(7-(((1S,3S)-3-aminocyclopentyl)amino)-2,3-dihydrofurano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (0.1 mmol), DMSO (5 mL), DIPEA (0.20 mmol), and 2-chloro-5-(difluoromethoxy)pyrimidine (0.15 mmol) were added to a reaction flask, and the reaction mixture was heated to 100 °C and reacted for 6 h. Water and ethyl acetate were added, the mixture was stirred, and the layers were separated. The resulting organic phases were washed once with water and once with saturated brine. The organic phases were concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM:MeOH = 20:1, v / v) to give the product (25 mg). ESI-MS (m / z): 457.17 [M+H] + . 1H NMR (600MHz, CDCl3): δ8.17(s,2H),7.60(s,1H),7.44-7.38(m,1H),7.31(d,J =6.6Hz,1H),6.64(d,J=9.0Hz,1H),6.40(t,J=73.2Hz,1H),6.23(t,J=6.9Hz, 1H),5.37-5.27(m,1H),4.65(t,J=6.4Hz,2H),4.60-4.48(m,2H),4.46-4.36( m,1H),3.18(s,2H),2.41-2.28(m,2H),2.12-2.00(m,2H),1.63-1.52(m,2H).

[0232] Example 38: 2-(7-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridazin-3(2H)-one (Compound 38)

[0233] The synthesis method was the same as in Example 1, except that in step 3, pyridine-2(1H)-one was replaced with pyridazine-3(2H)-one. ESI-MS (m / z): 456.15 [M+H] + . 1 H NMR (600MHz, DMSO-d6): δ8.23(s,2H),8.09(d,J=2.0Hz,1H),8.06(dd,J=3.8,1.6Hz,1 H),7.88(s,1H),7.52(dd,J=9.5,3.8Hz,1H),7.48(d,J=7.2Hz,1H),7.21(d,J=7.3Hz,1 H),7.09(dd,J=9.5,1.5Hz,1H),7.03(t,J=78.0Hz,1H),6.70(d,J=2.0Hz,1H),4.70-4. 60(m,1H),4.39-4.32(m,1H),2.22-2.11(m,2H),2.05-1.92(m,2H),1.71-1.52(m,2H).

[0234] Example 43: 1-(7-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)-3-methylpyridin-2(1H)-one (Compound 43)

[0235] The synthesis method was the same as in Example 1, except that in step 3, pyridine-2(1H)-one was replaced with 3-methylpyridine-2(1H)-one. ESI-MS (m / z): 469.17 [M+H] + . 1 H NMR (600MHz, DMSO-d6): δ8.23(s,2H),8.07(s,1H),7.73(s,1H),7.51(s,1H),7.48(d,J=6.0Hz 1H),7.41(s,1H),7.18(s,1H),7.03(t,J=12.0Hz 1H),6.59(s,1H),6.26-6.21(m,1H),4.65(s,1H),4.36(s,1H),2.21-2.11(m,2H),2.06(s,3H),2.03-1.92(m,2H),1.70-1.52(m,2H).

[0236] Example 46: 1-(7-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)-3-methoxypyridin-2(1H)-one (Compound 46)

[0237] The synthesis method was the same as in Example 1, except that in step 3, pyridine-2(1H)-one was replaced with 3-methoxypyridine-2(1H)-one. ESI-MS (m / z): 485.16 [M+H] + . 1 H NMR (600MHz, DMSO-d6): δ8.23(s,2H),8.08(s,1H),7.73(s,1H),7.48(d,J= 6.6Hz,1H),7.22(dd,J=15.6,6.4Hz,2H),7.02(t,J=72.0Hz,1H),6.95-6.8 7(m,1H),6.60(s,1H),6.27-6.22(m,1H),4.69-4.60(m,1H),4.39-4.33(m, 1H),3.74(s,3H),2.21-2.10(m,2H),2.05-1.91(m,2H),1.72-1.51(m,2H).

[0238] Example 48: 3-Chloro-1-(7-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 48)

[0239] The synthesis method was the same as in Example 1, except that in step 3, pyridine-2(1H)-one was replaced with 3-chloropyridine-2(1H)-one. ESI-MS (m / z): 489.11 [M+H] + . 1 H NMR (600MHz, DMSO-d6): δ8.23(s,2H),8.11(d,J=2.0Hz,1H),7.87(dd,J=7.3,1.8Hz, 1H),7.78(s,1H),7.73(dd,J=6.8,1.8Hz,1H),7.48(d,J=7.2Hz,1H),7.28(d,J=7.1Hz ,1H),7.03(t,J=78.0Hz,1H),6.69(d,J=2.0Hz,1H),6.35(t,J=7.0Hz,1H),4.69-4.6 2(m,1H),4.40-4.33(m,1H),2.21-2.10(m,2H),2.05-1.92(m,2H),1.70-1.53(m,2H).

[0240] Example 55: 2-(7-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)isoindoline-1-one (Compound 55)

[0241] The synthesis method was the same as in Example 1, except that in step 3, pyridine-2(1H)-one was replaced with isoindolin-1-one. ESI-MS (m / z): 493.17 [M+H] + . 1 H NMR (600MHz, CDCl3): δ8.18(s,2H),7.99-7.93(m,2H),7.65-7.60(m,2H),7.56-7.52(m,2H),6.79(s,1H),6.41(t,J=72.9Hz,1H),5.32(d .

[0242] Example 56: 6-(7-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Compound 56)

[0243] The synthesis method was the same as in Example 1, except that in step 3, pyridine-2(1H)-one was replaced with 5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one. ESI-MS (m / z): 494.17 [M+H] + . 1 H NMR (600MHz, CDCl3): δ8.86(s,1H),8.18(s,2H),7.96-7.89(m,2H),7.63(s,1H),7.51(s,1H),6.81(s,1H),6.42(t,J=72.9Hz,1H),5.44(d,J= 4.9Hz,1H),5.00(d,J=5.0Hz,1H),4.90(s,2H),4.76-4.67(m,1H),4.51 -4.41(m,1H),2.44-2.30(m,2H),2.18-2.06(m,2H),1.68-1.56(m,2H).

[0244] Example 57: 2-(7-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Compound 57)

[0245] The synthesis method was the same as in Example 1, except that in step 3, pyridine-2(1H)-one was replaced with 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-1-one. ESI-MS (m / z): 494.17 [M+H] + . 1 H NMR (600MHz, CDCl3): δ8.93(s,1H),8.85(s,1H),8.18(s,2H),7.96(s,1H),7 .85(d,J=5.0Hz,1H),7.64(s,1H),6.74(s,1H),6.42(t,J=72.9Hz,1H),5.48 (d,J=7.1Hz,1H),5.04(d,J=7.1Hz,1H),4.97(s,2H),4.77-4.69(m,1H),4.5 0-4.42(m,1H),2.46-2.33(m,2H),2.13(t,J=6.9Hz,2H),1.73-1.55(m,2H).

[0246] Example 62: 6-(7-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Compound 62)

[0247] The synthesis method is the same as in Example 82. ESI-MS (m / z): 443.19 [M+H] + . 1 H NMR (600MHz, CD3OD): δ8.78(s,1H),8.19(s,1H),8.14(d,J=7.8Hz,1H),7.94(s,1H),7.88(s,1H),7.72-7.63(m,1H),6.86(s,1H) ),5.02(s,2H),4.70-4.62(m,1H),4.51-4.44(m,1H),2.44(s,3H),2.38-2.29(m,2H),2.12(t,J=6.8Hz,2H),1.78-1.65(m,2H).

[0248] Example 66: 6-(7-(((1S,3S)-3-(oxazolo[5,4-b]pyridin-2-ylamino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Compound 66)

[0249] The synthesis method is the same as in Example 1. ESI-MS (m / z): 468.17 [M+H] + . 1 H NMR (600MHz, CDCl3): δ8.86 (d, J = 3.6Hz, 1H), 7.97-7.89 (m, 2H), 7.62 (s, 1H), 7 .58(d,J=7.4Hz,1H),7.53-7.49(m,1H),7.15-7.08(m,1H),6.81(s,1H),6.24( s,1H),5.30(s,1H),5.06(d,J=6.2Hz,1H),4.92-4.85(m,2H),4.79-4.71(m,1H ),4.53-4.44(m,1H),2.50-2.40(m,2H),2.36-2.28(m,2H),1.85-1.63(m,2H).

[0250] Example 67: 6-(7-(((1S,3S)-3-(thiazo[5,4-b]pyridin-2-ylamino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Compound 67)

[0251] The synthesis method is the same as in Example 1. ESI-MS (m / z): 484.15 [M+H] + . 1 H NMR (600MHz, DMSO-d6): δ8.79(s,1H),8.47(s,1H),8.20-7.92(m,3H),7.66(s,2H),7.24(s,1H),7.12(s,1H), 6.95(s,1H),4.99(s,2H),4.68(s,1H),4.45(s,1H),2.34-2.15(m,2H),2.15-2.00(m,2H),1.75-1.55(m,2H).

[0252] Example 68: 6-(7-(((1S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Compound 68)

[0253] The synthesis method is the same as in Example 91. ESI-MS (m / z): 442.19 [M+H] + . 1 H NMR (600MHz, CD3OD): δ8.77(d,J=5.0Hz,1H),8.13(d,J=7.7Hz,1H),7.95-7.91(m,1H),7.87(s,1H),7.81(d,J=9.8Hz,2H),7.69-7.63(m,1H ), 6.88-6.84(t,J=2.2Hz,1H),5.02(s,2H),4.69-4.60(m,1H),4.38-4.31(m,1H),2.39-2.25(m,5H),2.15-2.00(m,3H),1.76-1.64(m,2H).

[0254] Example 73: 1-(7-(((1S,3S)-3-(oxazolo[5,4-b]pyridin-2-ylamino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 73)

[0255] The synthesis method is the same as in Example 1. ESI-MS (m / z): 429.16 [M+H] + . 1 H NMR (600MHz, DMSO-d6): δ8.42(d,J=7.0Hz,1H),8.10(d,J=2.0Hz,1H),7.84(dd,J=5.0,1.2Hz,1H),7 .76(s,1H),7.68(dd,J=6.7,1.7Hz,1H),7.58(dd,J=7.6,1.2Hz,1H),7.56-7.51(m,1H),7.28(d,J=7. 2Hz,1H),7.16(dd,J=7.6,5.1Hz,1H),6.64(d,J=2.0Hz,1H),6.51(d,J=9.2Hz,1H),6.32(t,J=6.6Hz ,1H),4.74-4.65(m,1H),4.38-4.29(m,1H),2.27-2.17(m,2H),2.14-2.05(m,2H),1.74-1.63(m,2H).

[0256] Example 74: 1-(7-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 74)

[0257] The synthesis method is the same as in Example 82. ESI-MS (m / z): 430.19 [M+H] + . 1 H NMR (600MHz, CDCl3): δ8.03 (s, 1H), 7.83 (s, 1H), 7.64 (d, J = 2.0Hz, 1H), 7.48-7.42 (m, 1H), 7. 38(dd,J=6.8,1.6Hz,1H),6.69(d,J=9.2Hz,1H),6.62(d,J=2.0Hz,1H),6.27(td,J=6.7,1.1H z,1H),5.32(s,1H),5.19(s,1H),4.79-4.73(m,1H),4.58-4.52(m,1H),2.46-2.37(m,2H),2. 21-2.13(m,2H),1.99-1.94(m,1H),1.71-1.63(m,2H),1.11-1.07(m,2H),1.05-0.99(m,2H).

[0258] Example 75: 1-(7-(((1S,3S)-3-(thiazo[5,4-b]pyridin-2-ylamino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 75)

[0259] The synthesis method is the same as in Example 1. ESI-MS (m / z): 445.14 [M+H] + . 1 H NMR (600MHz, DMSO-d6): δ8.47(d,J=6.8Hz,1H),8.10(d,J=2.0Hz,1H),8.08(dd,J=4.8,1.4H z,1H),7.76(s,1H),7.69-7.65(m,2H),7.56-7.51(m,1H),7.29(d,J=7.3Hz,1H),7.23(dd,J= 8.0,4.8Hz,1H),6.63(d,J=2.1Hz,1H),6.50(d,J=9.2Hz,1H),6.31(td,J=6.7,1.1Hz,1H),4. 74-4.67(m,1H),4.48-4.41(m,1H),2.27-2.16(m,2H),2.13-2.02(m,2H),1.77-1.58(m,2H).

[0260] Example 76: 1-(7-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)furanzo[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 76)

[0261] Step 1: Preparation of 1-(7-(((1S,3S)-3-((3-(4-methoxybenzyl)-3H-imidazol[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one

[0262] 1-(7-(((1S,3S)-3-aminocyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (0.1 mmol), DMSO (5 mL), DIEA (0.20 mmol), and 3-(4-methoxybenzyl)-2-(methanesulfonyl)-3H-imidazo[4,5-b]pyridine (0.15 mmol) were added to a reaction flask, and the reaction solution was heated to 100 °C and reacted for 6 h. Water and ethyl acetate were added, the mixture was stirred, and the liquid was separated. The resulting organic phase was washed once with water and once with saturated brine. The organic phase was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM:MeOH = 20:1, v / v) to give the product (25 mg).

[0263] Step 2: Preparation of 1-(7-(((1S,3S)-3-((3H-imidazo[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)furanzo[2,3-c]pyridin-4-yl)pyridin-2(1H)-one

[0264] 1-(7-(((1S,3S)-3-(((3-(4-methoxybenzyl)-3H-imidazol[4,5-b]pyridin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (25 mg) was dissolved in trifluoroacetic acid (3 mL) and stirred at room temperature for 6 h. After the reaction was complete, the pH was adjusted with sodium carbonate, and the solution was concentrated to dryness under reduced pressure. The concentrate was purified by column chromatography (DCM:MeOH = 20:1, v / v) to give the product (10 mg). ESI-MS (m / z): 428.18 [M+H] + . 1 H NMR (600MHz, DMSO-d6): δ11.37 (s, 0.5H), 10.76 (s, 0.5H), 8.09 (d, J = 2.0Hz, 1H), 7.97-7.80 ( m,1H),7.75(s,1H),7.67(dd,J=6.7,1.6Hz,1H),7.56-7.51(m,1H),7.37(s,1H),7.23(d,J=6. 2Hz,1H),7.11-6.75(m,2H),6.63(d,J=2.0Hz,1H),6.50(d,J=9.2Hz,1H),6.34-6.29(m,1H),4 .74-4.64(m,1H),4.37-4.30(m,1H),2.27-2.16(m,2H),2.10-2.00(m,2H),1.73-1.58(m,2H).

[0265] Example 77: 2-(7-(((1S,3S)-3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridazin-3(2H)-one (Compound 77)

[0266] The synthesis method is the same as in Example 1. ESI-MS (m / z): 458.15 [M+H] + . 1 H NMR (600MHz, DMSO-d6): δ8.62(d,J=27.5Hz,2H),8.21(d,J=7.0Hz,1H),8.10(d ,J=1.8Hz,1H),8.08-8.05(m,1H),7.91-7.88(m,1H),7.55-7.49(m,1H),7.25( d,J=7.0Hz,1H),7.09(d,J=9.5Hz,1H),6.70(d,J=1.8Hz,1H),4.75-4.61(m,1H ),4.53-4.42(m,1H),2.24-2.12(m,2H),2.08-1.96(m,2H),1.75-1.54(m,2H).

[0267] Example 78: 2-(7-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridazin-3(2H)-one (Compound 78)

[0268] The synthesis method is the same as in Example 82. ESI-MS (m / z): 431.19 [M+H] + . 1 H NMR (600MHz, CDCl3): δ8.09(s,1H),8.03(s,1H),7.93(dd,J=3.8,1.6Hz,1H),7.63(d,J=2 .0Hz,1H),7.29(dd,J=9.5,3.8Hz,1H),7.09(dd,J=9.5,1.6Hz,1H),6.64(d,J=2.0Hz,1H) ,5.37(s,1H),5.11(s,1H),4.82-4.73(m,1H),4.60-4.50(m,1H),2.47-2.37(m,2H),2.20 -2.14(m,2H),2.00-1.93(m,1H),1.71-1.60(m,2H),1.12-1.06(m,2H),1.05-1.00(m,2H).

[0269] Example 80: 1-(7-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)-5-methoxypyridin-2(1H)-one (Compound 80)

[0270] The synthesis method is the same as in Example 1. ESI-MS (m / z): 485.17 [M+H] + . 1 H NMR (600MHz, DMSO-d6): δ8.23(s,2H),8.08(d,J=2.0Hz,1H),7.79(s,1H),7.48(d,J=7. 2Hz,1H),7.41(dd,J=9.9,3.3Hz,1H),7.24(d,J=3.2Hz,1H),7.17(d,J=7.2Hz,1H),7.0 3(t,J=78.0Hz,1H),6.65(d,J=2.0Hz,1H),6.48(d,J=9.9Hz,1H),4.70-4.59(m,1H),4. 40-4.30(m,1H),3.64(s,3H),2.21-2.10(m,2H),2.05-1.92(m,2H),1.70-1.51(m,2H).

[0271] Example 81: 2-(7-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridazin-3(2H)-one (Compound 81)

[0272] The synthesis method is the same as in Example 82. ESI-MS (m / z): 405.17 [M+H] + . 1 H NMR (600MHz, CDCl3): δ8.09(s,1H),8.03(s,1H),7.93(d,J=2.3Hz,1H),7.65(s,1H),7.29(dd,J=9.5,3.7Hz,1H),7.09(d,J=9.4H z,1H),6.65(s,1H),4.81-4.76(m,1H),4.59-4.53(m,1H),2.51(s,3H),2.47-2.38(m,2H),2.22-2.12(m,2H),1.72-1.61(m,2H).

[0273] Example 82: 1-(7-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 82)

[0274] Step 1: Synthesis of 3-(methanesulfonyl)-1,2,4-triazine

[0275] 3-(methylthio)-1,2,4-triazine (157.3 mmol), m-chloroperoxybenzoic acid (191.2 mmol), and DCM (300 mL) were added to a reaction flask. The mixture was stirred at room temperature for 2 h, and the reaction was confirmed to be complete by LC-MS. The solution was concentrated to dryness under reduced pressure to obtain the target product 3-(methanesulfonyl)-1,2,4-triazine, which was used directly in the next reaction without purification. ESI-MS (m / z): 160.01 [M+H] + .

[0276] Step 2: Synthesis of tert-butyl ((1S,3S)-3-((1,2,4-triazine-3-yl)amino)cyclopentyl)carbamate

[0277] The product from step one above, tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (174.8 mmol), and n-butanol (200 mL) were added to a reaction flask. The reaction was carried out at 120 °C for 5 h, and LC-MS showed that the reaction was complete. After cooling to room temperature, water and ethyl acetate were added, and the mixture was separated. The organic phase was washed once with water and once with saturated brine. The organic phase was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (PE:EA = 2:1, v / v) to give the product (21.8 g). ESI-MS (m / z): 280.17 [M+H] + .

[0278] Step 3: Synthesis of tert-butyl ((1S,3S)-3-((6-bromo-1,2,4-triazine-3-yl)amino)cyclopentyl)carbamate

[0279] (1S,3S)-3-((1,2,4-triazine-3-yl)amino)cyclopentyl)carbamate tert-butyl ester (71.7 mmol) was added to a reaction flask and dissolved in DMF (200 mL). The mixture was cooled to 0°C in an ice bath, and N-bromosuccinimide (87.1 mmol) was slowly added. The reaction was allowed to proceed at room temperature for 6 h after the addition was complete. Water and ethyl acetate were added, the mixture was stirred, and the layers were separated. The resulting organic phase was washed once with water and once with saturated brine. The organic phase was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (PE:EA = 2:1, v / v) to give the product (11.5 g). ESI-MS (m / z): 358.08 / 360.08 [M+H] + .

[0280] Step 4: Synthesis of tert-butyl ((1S,3S)-3-((6-methyl-1,2,4-triazine-3-yl)amino)cyclopentyl)carbamate

[0281] In a reaction flask, tert-butyl ((1S,3S)-3-((6-bromo-1,2,4-triazine-3-yl)amino)cyclopentyl)carbamate (32.1 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-boronoxane (50% dioxane solution) (95.6 mmol), Na₂CO₃ (96.2 mmol), Pd(dppf)Cl₂ (4.78 mmol), 1,4-dioxane (150 mL), and water (30 mL) were added. The mixture was replaced with N₂ and reacted at 100 °C for 8 h. LC-MS showed that the reaction was complete. After cooling to room temperature, the solid was filtered off, and water and ethyl acetate were added. The mixture was separated, and the organic phase was washed once with water and once with saturated brine. The organic phase was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM:MeOH = 50:1, v / v) to give the product (1.4 g). ESI-MS (m / z): 294.20 [M+H] + .

[0282] Step 5: (1S,3S)-N 1 Synthesis of 1,3-(6-methyl-1,2,4-triazine-3-yl)cyclopentane-1,3-diamine

[0283] A solution of tert-butyl ((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)carbamate (4.78 mmol) and 1,4-dioxane in 4M hydrochloric acid (30 mL) was added to a reaction flask, and the reaction mixture was reacted at room temperature for 3 h. The reaction solvent was concentrated to dryness under reduced pressure, and the concentrate was diluted with methanol. Then, Ambersep® 900 resin was added under stirring to adjust the pH of the solution to approximately 8–9. The solution was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the product (0.92 g). ESI-MS (m / z): 194.13 [M+H] + .

[0284] Step Six: (1S, 3S) - N 1 -(furano[2,3-c]pyridin-7-yl)-N 3 Synthesis of 1,3-(6-methyl-1,2,4-triazine-3-yl)cyclopentane-1,3-diamine

[0285] (1S,3S)-N was added to the reaction flask 1-(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine (4.66 mmol), 7-chlorofurano[2,3-c]pyridine (6.19 mmol), Ruphos-pd-G2 (1.03 mmol), sodium tert-butoxide (10.4 mmol), and DMF (20 mL) were added, purged with argon, and reacted at 85 °C for 10 h. After cooling to room temperature, the solid was filtered off, and water and ethyl acetate were added. The mixture was separated, and the organic phase was washed once with water and once with saturated brine. The organic phase was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM:MeOH = 50:1, v / v) to give the product (950 mg). ESI-MS (m / z): 311.15 [M+H] + .

[0286] Step 7: (1S, 3S) - N 1 -(4-Iodofurano[2,3-c]pyridin-7-yl)-N 3 Synthesis of 1,3-(6-methyl-1,2,4-triazine-3-yl)cyclopentane-1,3-diamine

[0287] (1S,3S)-N was added to the reaction flask 1 -(furano[2,3-c]pyridin-7-yl)-N 3 -(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine (2.90 mmol) was dissolved in acetonitrile (15 mL), cooled to 0 °C in an ice bath, and N-iodosuccinimide (3.56 mmol) was slowly added. The reaction was carried out at room temperature for 6 h after the addition was complete. Water and ethyl acetate were added, the mixture was stirred, and the liquid was separated. The resulting organic phase was washed once with water and once with saturated brine. The organic phase was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM:MeOH = 60:1, v / v) to give the product (1.25 g). ESI-MS (m / z): 437.05 [M+H] + .

[0288] Step 8: Synthesis of 1-(7-(((1S,3S)-3-((6-methyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one

[0289] (1S,3S)-N was added to the reaction flask 1 -(4-Iodofurano[2,3-c]pyridin-7-yl)-N 3 -(6-methyl-1,2,4-triazin-3-yl)cyclopentane-1,3-diamine (0.344 mmol), pyridin-2(1H)-one (0.42 mmol), potassium carbonate (0.72 mmol), cuprous iodide (0.34 mmol), (1S,2S)-N 1 N2 The reaction system was purged with nitrogen using 0.35 mmol of dimethylcyclohexane-1,2-diamine and 50 mL of DMSO, and reacted at 120 °C for 8 h. Water and ethyl acetate were added, the mixture was stirred, and the layers were separated. The resulting organic phases were washed once with water and once with saturated brine. The organic phases were concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM:MeOH = 30:1, v / v) to give the product (40 mg). ESI-MS (m / z): 404.18 [M+H] + . 1 H NMR (600MHz, CDCl3): δ8.03(s,1H),7.84(s,1H),7.63(s,1H),7.50-7.42( m,1H),7.38(d,J=5.8Hz,1H),6.69(d,J=9.0Hz,1H),6.61(s,1H),6.27(t, J=5.9Hz,1H),5.46(s,1H),5.08(s,1H),4.80-4.71(m,1H),4.62-4.51(m, 1H),2.51(s,3H),2.46-2.36(m,2H),2.22-2.11(m,2H),1.73-1.60(m,2H).

[0290] Example 83: 1-(7-(((1S,3S)-3-((5-chloropyrazin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)-3-methylpyridin-2(1H)-one (Compound 83)

[0291] The synthesis method is the same as in Example 1. ESI-MS (m / z): 437.14 [M+H] + . 1 H NMR (600MHz, DMSO-d6): δ8.08(d,J=1.9Hz,1H),8.03(s,1H),7.73(s,2H),7.51(d,J=6.0Hz,1H),7.44-7.40(m,2H),7.23(d,J=6.7Hz,1H),6.60(d ,J=1.9Hz,1H),6.23(t,J=6.7Hz,1H),4.73-4.63(m,1H),4.32-4.24(m,1 H),2.22-2.15(m,2H),2.05(s,3H),2.09-1.90(m,2H),1.70-1.50(m,2H).

[0292] Example 84: 6-(7-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 84)

[0293] The synthesis method is the same as in Example 1. ESI-MS (m / z): 494.17 [M+H] + . 1 H NMR (600MHz, DMSO-d6): δ8.84(s,1H),8.23(s,2H),8.20(d,J=7.3Hz,1H),8.11(s,1H),7.98(s,1H),7.63-7.57(m,1H),7.48(d,J=6.3Hz,1H),7 .03(t,J=78.0Hz,1H),6.99(s,2H),5.03(s,2H),4.65-4.58(m,1H),4.4 0-4.31(m,1H),2.22-2.09(m,2H),2.06-1.94(m,2H),1.70-1.50(m,2H).

[0294] Example 85: 6-(7-(((1S,3S)-3-(((5-chloropyrazin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 85)

[0295] The synthesis method is the same as in Example 1. ESI-MS (m / z): 462.14 [M+H] + . 1 H NMR (600MHz, CD3OD): δ8.83-8.81(m,1H),8.27(dd,J=7.7,1.5Hz,1H),7.95(d,J=1.6Hz,2H),7.90(d,J=2.1Hz,1H),7.69-7.67(m,1H),7.64-7 .61(m,1H),6.88(d,J=2.1Hz,1H),5.04(s,2H),4.67-4.61(m,1H),4.39 -4.31(m,1H),2.38-2.25(m,2H),2.12-2.05(m,2H),1.79-1.57(m,2H).

[0296] Example 87: 1-(7-(((1S,3S)-3-((5-chloropyrazin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 87)

[0297] The synthesis method is the same as in Example 1. ESI-MS (m / z): 423.13 [M+H] + . 1 H NMR (600MHz, CD3OD): δ7.95(s,1H),7.88(s,1H),7.78-7.61(m,4H),6.72-6.57(m,2H),6.51 (s,1H),4.67(s,1H),4.36(s,1H),2.41-2.27(m,2H),2.15-2.02(m,2H),1.77-1.56(m,2H).

[0298] Example 88: 2-(7-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (Compound 88)

[0299] The synthesis method is the same as in Example 1. ESI-MS (m / z): 494.17 [M+H] + . 1 H NMR (600MHz, CDCl3): δ9.22(s,1H),8.86(d,J=5.1Hz,1H),8.18(s,2H),7.86(s,1H),7.77(s,1H),7.54(d,J=5.1Hz,1H),6.85(s,1H),6.41(s,J=7 2.0Hz,1H),5.39(s,1H),4.92(s,2H),4.86-4.78(m,1H),4.69(s,1H),4. 51-4.44(m,1H),2.48-2.39(m,2H),2.23-2.16(m,2H),1.78-1.70(m,2H).

[0300] Example 91: 1-(7-(((1S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 91)

[0301] 1-(7-(((1S,3S)-3-aminocyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (0.1 mmol), 2-bromo-5-methylpyrazine (0.12 mmol), Pd-PEPPSI-IPentCl (0.05 mmol), cesium carbonate (0.2 mmol), and dioxane (5 mL) were added to a reaction flask, purged with argon, and reacted at 85 °C for 10 h. After cooling to room temperature, the solid was filtered off, and water and ethyl acetate were added. The mixture was separated, and the organic phase was washed once with water and once with saturated brine. The organic phase was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography to give the product (15 mg). ESI-MS (m / z): 403.18 [M+H] + . 1 H NMR (600MHz, CD3OD): δ7.95-7.60(m,6H),6.74-6.54(m,2H),6.53-6.46(m,1H),4.72-4 .60(m,1H),4.39-4.27(m,1H),2.40-2.22(m,5H),2.15-1.98(m,2H),1.75-1.55(m,2H).

[0302] Example 92: 1-(7-(((1S,3S)-3-((5-cyclopropylpyrazin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 92)

[0303] The synthesis method is the same as in Example 91. ESI-MS (m / z): 429.19 [M+H] + , 1 H NMR (600MHz, CD3OD): δ8.22 (d, J = 3.6Hz, 1H), 7.91-7.79 (m, 3H), 7.75-7. 66(m,2H),6.88-6.81(m,1H),6.74-6.66(m,1H),6.57-6.52(m,1H),4.59- 4.50(m,1H),4.41-4.33(m,1H),2.49-2.23(m,3H),2.16-2.07(m,1H),1. 97-1.83(m,2H),1.76-1.67(m,1H),1.24-1.19(m,2H),0.83-0.74(m,2H).

[0304] Example 93: 2-(7-(((1S,3S)-3-((5-chloropyrazin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)isoindoline-1-one (Compound 93)

[0305] The synthesis method is the same as in Example 1. ESI-MS (m / z): 461.14 [M+H] + , 1 H NMR (600MHz, CDCl3): δ8.01-7.98(m,1H),7.96(d,J=7.5Hz,1H),7.93(s,1H),7.68( d,J=1.2Hz,1H),7.64(d,J=1.8Hz,1H),7.63-7.61(m,1H),7.55-7.52(m,2H),6.81(d ,J=2.0Hz,1H),5.10(s,1H),5.02(s,1H),4.88(s,2H),4.82-4.71(m,1H),4.35-4.28 (m,1H),2.45-2.34(m,2H),2.21-2.15(m,1H),2.13-2.06(m,1H),1.72-1.59(m,2H).

[0306] Example 94: 6-(7-(((1S,3S)-3-((5-cyclopropylpyrazin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Compound 94)

[0307] The synthesis method is the same as in Example 91. ESI-MS (m / z): 468.20 [M+H] + . 1 H NMR (600MHz, CD3OD): δ8.77(s,1H),8.12(d,J=7.9Hz,1H),7.99-7.73(m,4H),7.66(s,1H),6.86(s,1H),5.01(s,2H),4.69-4. 56(m,1H),4.38-4.25(m,1H),2.39-2.20(m,2H),2.14-1.96(m,2H),1.96-1.85(m,1H),1.67-1.46(m,2H),0.90-0.76(m,4H).

[0308] Example 95: 3-Chloro-1-(7-(((1S,3S)-3-((5-chloropyrazin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 95)

[0309] The synthesis method is the same as in Example 1. ESI-MS (m / z): 457.20 [M+H]+ .

[0310] Example 96: 2-(7-(((1S,3S)-3-((5-chloropyrazin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Compound 96)

[0311] The synthesis method is the same as in Example 1. ESI-MS (m / z): 462.13 [M+H] + .

[0312] Example 97: 2-(7-(((1S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)isoindoline-1-one (Compound 97)

[0313] The synthesis method is the same as in Example 1. ESI-MS (m / z): 441.09 [M+H] + . 1 H NMR (600MHz, CDCl3): δ7.98-7.93(m,2H),7.86(s,1H),7.82(s,1H),7.61(s,2H),7.53(t,J=7.2Hz,2H),6.78(s,1H),4.96( d,J=6.2Hz,1H),4.87(s,2H),4.75-4.65(m,2H),4.38-4.29(m,1H),2.37(s,5H),2.11(t,J=6.4Hz,2H),1.70-1.55(m,2H).

[0314] Example 98: 2-(7-(((1S,3S)-3-((5-cyclopropylpyrazin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)isoindoline-1-one (Compound 98)

[0315] The synthesis method is the same as in Example 1. ESI-MS (m / z): 467.20 [M+H] + . 1H NMR (600MHz, CDCl3): δ7.94(s,2H),7.90(s,1H),7.76(s,1H),7.60(s,2H),7.53(s,2H),6.87-6.68(m,1H),4.97(s,1H),4. 86(s,2H),4.71(s,2H),4.31(s,1H),2.36(d,J=4.2Hz,2H),2.10(s,2H),1.91(s,1H),1.61(d,J=33.2Hz,2H),0.86(s,4H).

[0316] Example 99: 6-(7-(((1S,3S)-3-((5,6-dimethylpyrazin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Compound 99)

[0317] The synthesis method is the same as in Example 1. ESI-MS (m / z): 456.20 [M+H] + .

[0318] Example 100: 1-(7-(((1S,3S)-3-((5,6-dimethylpyrazin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 100)

[0319] The synthesis method is the same as in Example 1. ESI-MS (m / z): 417.20 [M+H] + . 1 H NMR (600MHz, CDCl3): δ7.84 (s, 1H), 7.63 (d, J = 2.3Hz, 2H), 7.44 (ddd, J = 8.9, 6.6, 2.0Hz, 1H), 7.38 (dd, J=6.8,1.7Hz,1H),6.69(d,J=9.2Hz,1H),6.62(d,J=2.0Hz,1H),6.27(td,J=6.7,0.9Hz,1H),4.98(d,J= 7.0Hz,1H),4.73(dt,J=14.1,7.0Hz,1H),4.45(d,J=6.6Hz,1H),4.27(dt,J=12.9,6.5Hz,1H),2.38(s, 3H), 2.36 (s, 3H), 2.12 (dd, J=12.7, 6.0Hz, 2H), 1.70-1.65 (m, 2H), 1.60 (ddd, J=19.2, 13.5, 6.4Hz, 2H).

[0320] Example 101: 2-(7-(((1S,3S)-3-((5,6-dimethylpyrazin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)isoindoline-1-one (Compound 101)

[0321] The synthesis method is the same as in Example 1. ESI-MS (m / z): 455.17 [M+H] + .

[0322] Example 102: 1-(7-(((1S,3S)-3-((5,6-dimethylpyrazin-2-yl)amino)cyclopentyl)amino)-2,3-dihydrofurano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 102)

[0323] The synthesis method is the same as in Example 18. ESI-MS (m / z): 419.20 [M+H] + . 1 H NMR (600MHz, CD3OD): δ7.67-7.60(m,2H),7.58(s,1H),7.53(s,1H),6.64(d,J=9.1Hz,1H),6.49(t,J=6.7Hz,1H),4.69(t,J=9.0Hz,2H),4.5 6-4.48(m,1H),4.39-4.32(m,1H),3.12(t,J=8.9Hz,2H),2.36(s,3H), 2.34(s,3H),2.32-2.25(m,2H),2.06-1.99(m,2H),1.67-1.55(m,2H).

[0324] Example 103: 1-(7-(((1S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)amino)-2,3-dihydrofurano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 103)

[0325] The synthesis method is the same as in Example 18. ESI-MS (m / z): 405.12 [M+H] + . 1H NMR (600MHz, CDCl3): δ7.79(s,1H),7.73(s,1H),7.53(s,1H),7.33(s,1H),7.24(s,1H),6.56(d,J=8.8Hz,1H),6.16(d,J=5.7Hz,1H),4.58(s,2H) ,4.50(s,1H),4.41(d,J=19.7Hz,2H),4.21(s,1H),3.10(s,2H),2.30(d, J=4.2Hz, 3H), 2.27 (d, J=4.6Hz, 2H), 1.97 (d, J=5.8Hz, 2H), 1.50 (s, 2H).

[0326] Example 104: 1-(7-(((1S,3S)-3-((5-cyclopropylpyrazin-2-yl)amino)cyclopentyl)amino)-2,3-dihydrofurano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 104)

[0327] The synthesis method is the same as in Example 18. ESI-MS (m / z): 431.10 [M+H] + . 1 H NMR (600MHz, CDCl3): δ7.90(s,1H),7.74(s,1H),7.59(s,1H),7.40(d,J=6.9Hz,1H),7.31(d,J=5.6Hz,1H),6.63(d,J=8.9Hz,1H),6.23(s,1H) ,4.64(s,2H),4.56(d,J=6.0Hz,1H),4.46(s,2H),4.26(s,1H),3.17(s ,2H),2.33(s,2H),2.04(s,2H),1.91(s,1H),1.56(s,2H),1.04(s,4H).

[0328] Example 105: 3-Methoxy-1-(7-(((1S,3S)-3-((5-methylpyrazin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 105)

[0329] The synthesis method is the same as in Example 1. ESI-MS (m / z): 433.06 [M+H] + . 1H NMR (600MHz, CD3OD): δ7.89(d,J=1.8Hz,1H),7.84(s,1H),7.82(s,1H),7.77(s,1H),7.24(d,J=6.0Hz,1H),7.06(d,J=7.3Hz,1H),6.60(d,J=1 .8Hz,1H),6.45(t,J=7.2Hz,1H),4.72-4.64(m,1H),4.39-4.31(m,1H) ,3.89(s,3H),2.39-2.26(m,5H),2.16-2.02(m,2H),1.79-1.59(m,2H).

[0330] Example 106: 1-(7-(((1S,3S)-3-((3-(methylthio)-1,2,4-triazin-6-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 106)

[0331] The synthesis method is the same as in Example 1. ESI-MS (m / z): 436.20 [M+H] + . 1 H NMR (600MHz, CD3OD): δ8.05(s,1H),7.90(s,1H),7.77(s,1H),7.72-7.64(m,2H),6.69(d,J=9.0Hz,1H),6.62(s,1H),6.52(t ,J=6.7Hz,1H),4.75-4.63(m,1H),4.45-4.35(m,1H),2.56(s,3H),2.42-2.29(m,2H),2.19-2.06(m,2H),1.79-1.64(m,2H).

[0332] Example 107: 1-(7-(((1S,3S)-3-([1,2,4]triazolo[4,3-b]pyridazin-6-ylamino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 107)

[0333] The synthesis method is the same as in Example 1. ESI-MS (m / z): 429.14 [M+H] + .

[0334] Example 108: 1-(7-(((1S,3S)-3-(imidazo[1,2-b]pyridazin-6-ylamino)cyclopentyl)amino)furanzo[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 108)

[0335] The synthesis method is the same as in Example 1. ESI-MS (m / z): 428.25 [M+H] + . 1 H NMR (600MHz, CD3OD): δ7.90(s,1H),7.78(s,1H),7.72-7.65(m,3H),7.57(d,J=9.7Hz,1H),7.38(s,1H),6.68(t,J=9.0Hz,2H),6. 63(s,1H),6.52(t,J=6.7Hz,1H),4.74-4.63(m,1H),4.41-4.31(m,1H),2.44-2.29(m,2H),2.22-2.10(m,2H),1.76-1.66(m,2H).

[0336] Example 109: 1-(7-(((1S,3S)-3-(imidazo[1,2-c]pyrimidin-7-ylamino)cyclopentyl)amino)furanzo[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 109)

[0337] The synthesis method is the same as in Example 1. ESI-MS (m / z): 428.17 [M+H] + . 1 H NMR (600MHz, CD3OD): δ8.90(s,1H),7.91(d,J=2.0Hz,1H),7.78(s,1H),7.72-7.65(m,2H),7.61(s,1H),7.33(s,1H),6.69(d,J=9.0Hz,1H),6.63(d ,J=2.0Hz,1H),6.53(t,J=6.3Hz,1H),6.22(s,1H),4.76-4.67(m,1H),4. 26-4.15(m,1H),2.43-2.30(m,2H),2.26-2.12(m,2H),1.83-1.70(m,2H).

[0338] Example 110: 1-(7-(((1S,3S)-3-((6-chlorothiazo[5,4-b]pyridin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 110)

[0339] The synthesis method was the same as in Example 1, except that in step 5, 2-chloro-5-(difluoromethoxy)pyrimidine was replaced with an intermediate to prepare compound 8. ESI-MS (m / z): 479.20 [M+H]+ . 1 H NMR (600MHz, CD3OD): δ8.08(d,J=2.1Hz,1H),7.89(d,J=2.0Hz,1H),7.77(s,1H),7.68-7.63(m,3H),6.67(d,J=8.9Hz,1H),6.61(d,J=2 .0Hz,1H),6.51(td,J=6.7,1.0Hz,1H),4.73-4.63(m,1H),4.55-4.42(m,1H),2.41-2.28(m,2H),2.23-2.09(m,2H),1.81-1.69(m,2H).

[0340] Example 111: 1-(7-(((1S,3S)-3-((6-methoxythiazo[5,4-b]pyridin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 111)

[0341] The synthesis method was the same as in Example 1, except that in step 5, 2-chloro-5-(difluoromethoxy)pyrimidine was replaced with an intermediate to prepare compound 9. ESI-MS (m / z): 475.13 [M+H] + . 1 H NMR (600MHz, DMSO-d6): δ8.47(d,J=6.7Hz,1H),8.10(d,J=1.5Hz,1H),7.85(d,J=2.3Hz,1H) ,7.77(s,1H),7.68(d,J=5.7Hz,1H),7.59-7.48(m,1H),7.37(d,J=2.2Hz,1H),7.28(d,J=7.1 Hz,1H),6.64(d,J=1.5Hz,1H),6.51(d,J=9.2Hz,1H),6.32(t,J=6.6Hz,1H),4.75-4.64(m,1 H),4.49-4.36(m,1H),3.82(s,3H),2.31-2.16(m,2H),2.15-2.01(m,2H),1.75-1.58(m,2H).

[0342] Example 112: 1-(7-(((1S,3S)-3-((6-(difluoromethoxy)thiazo[5,4-b]pyridin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 112)

[0343] The synthesis method was the same as in Example 1, except that in step 5, 2-chloro-5-(difluoromethoxy)pyrimidine was replaced with an intermediate to prepare compound 10. ESI-MS (m / z): 511.17 [M+H] + . 1 H NMR (600MHz, DMSO-d6): δ8.69(d,J=6.8Hz,1H),8.11(d,J=2.0Hz,1H),8.02(d,J=2.4Hz,1H),7. 76(s,1H),7.68(dd,J=6.8,1.4Hz,1H),7.59-7.52(m,2H),7.40(s,0.25H),7.30(s,1H),7.27(s, 0.5H),7.15(s,0.25H),6.64(d,J=2.0Hz,1H),6.51(d,J=9.1Hz,1H),6.32(td,J=6.7,1.2Hz,1H) ,4.78-4.64(m,1H),4.51-4.36(m,1H),2.31-2.17(m,2H),2.14-2.02(m,2H),1.74-1.58(m,2H).

[0344] Example 113: 1-(7-(((1S,3S)-3-((5-(difluoromethoxy)pyrazin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 113)

[0345] The synthesis method is the same as in Example 1. ESI-MS (m / z): 455.20 [M+H] + . 1 H NMR (600MHz, DMSO-d6): δ8.10(s,1H),7.91(s,1H),7.75(s,1H),7.67(d,J=5.7Hz,1H),7.62(s,1H),7 .58-7.51(m,1H),7.45(s,0.25H),7.33(s,0.5H),7.24(d,J=7.0Hz,1H),7.20(s,0.25H),7.16(d,J=6 .5Hz,1H),6.63(s,1H),6.50(d,J=9.1Hz,1H),6.32(t,J=6.4Hz,1H),4.74-4.62(m,1H),4.35-4.23(m ,1H),2.27-2.13(m,2H),2.11-2.00(m,1H),1.99-1.88(m,1H),1.73-1.62(m,1H),1.59-1.48(m,1H).

[0346] Example 114: 1-(7-(((1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazine-4-ylamino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 114)

[0347] The synthesis method was the same as in Example 1, except that in step 5, 2-chloro-5-(difluoromethoxy)pyrimidine was replaced with 4-chloropyrrolo[2,1-f][1,2,4]triazine. ESI-MS (m / z): 428.21 [M+H] + . 1 H NMR (600MHz, DMSO-d6): δ8.13(d,J=7.3Hz,1H),8.10(d,J=1.6Hz,1H),7.86(s,1H),7.76(s,1H),7. 68(dd,J=6.7,1.8Hz,1H),7.58(s,1H),7.54(ddd,J=8.7,6.7,1.7Hz,1H),7.30(d,J=7.2Hz,1H),6. 96(dd,J=4.1,1.0Hz,1H),6.64(d,J=1.6Hz,1H),6.60(dd,J=3.8,2.7Hz,1H),6.51(d,J=9.2Hz,1H) ,6.32(t,J=6.6Hz,1H),4.86-4.68(m,2H),2.33-2.18(m,2H),2.18-2.04(m,2H),1.77-1.62(m,2H).

[0348] Example 115: 1-(7-(((1S,3S)-3-((6-(cyclopropylamino)pyrazin-2-yl)amino)cyclopentyl)amino)furano[2,3-c]pyridin-4-yl)pyridin-2(1H)-one (Compound 115)

[0349] The synthesis method is the same as in Example 1. ESI-MS (m / z): 444.20 [M+H] + . 1H NMR (600MHz, DMSO-d6): δ8.09(s,1H),7.75(s,1H),7.69-7.64(m,1H),7.57-7.50(m,1H),7.17(d,J=7. 2Hz,1H),7.15(s,1H),7.13(s,1H),6.63(d,J=1.8Hz,1H),6.56(d,J=6.8Hz,1H),6.50(d,J=9.2Hz,1H), 6.46(s,1H),6.32(t,J=6.7Hz,1H),4.74-4.59(m,1H),4.32-4.21(m,1H),2.49-2.42(m,1H),2.22-2.12 (m,2H),2.04-1.92(m,2H),1.68-1.59(m,1H),1.56-1.45(m,1H),0.68-0.59(m,2H),0.45-0.36(m,2H).

[0350] Examples 5-11, 13-17, 19-37, 39-42, 44-45, 47, 49-54, 58-61, 63-65, 69-72, 137-172

[0351] Referring to the synthesis method of the foregoing embodiments, the compounds of the following embodiments were synthesized.

[0352] Comparative Example 1: (Compound 458B in CN113574055B, namely AZD0780, is synthesized using the method in this patent);

[0353] Comparative Example 2: (Compound 134 in WO2024078620A1 was synthesized according to the method of Example 134).

[0354] Experimental Example 1: In vitro LDL uptake assay of HepG2 cells

[0355] Table 1. Reagents and consumables used in in vitro LDL uptake experiments

[0356] Experimental steps:

[0357] 1. HepG2 cells were cultured in MEM medium with 10% FBS and a penicillin-streptomycin mixture of 100 units per milliliter, and cultured at 37°C under 5% CO2 conditions.

[0358] 2. Add 100 μL of cells to a 96-well poly-D-lysine-coated culture plate at a density of 20,000 cells per well. Incubate the cell culture plates overnight at 37°C and 5% CO2.

[0359] 3. Starve HepG2 cells using FBS-free MEM medium. Incubate the cell plates overnight at 37°C and 5% CO2.

[0360] 4. Starting from 40 mM, the test compound was diluted 3-fold in DMSO to obtain 7 dose concentrations.

[0361] 5. The diluted compound was diluted 100 times with MEM medium and then co-incubated with an equal volume of PCSK9 protein for 1 hour.

[0362] 6. Remove the supernatant from the cell plate and add 50 μL of the compound and protein mixture. Incubate the cell plate at 37°C and 5% CO2 for 23 h.

[0363] 7. Remove the cell plate supernatant and add 50 μL of BODIPY LDL dye. Incubate the cell plate at 37°C and 5% CO2 for 4 h.

[0364] 8. Remove the cell plate cleanser and wash 3 times with 100 μL PBS.

[0365] 9. High content system detects fluorescence intensity at 480nm / 530nm and calculates uptake.

[0366] Table 2. Effects of the compounds of this disclosure on restoring cellular LDL uptake activity A: EC 50 <20μM, B: 20μM≤EC 50 <60μM, C:EC 50 ≥60μM

[0367] Experimental results show that the compound disclosed herein can significantly enhance the LDL uptake capacity of HepG2 cells.

[0368] Experimental Example 2: PCSK9 In Vitro Binding Assay

[0369] The ability of different compounds to bind to the PCSK9 protein was detected using the conventional surface plasmon resonance (SPR) method.

[0370] 1. Test parameters:

[0371] 1) Proteins: PCSK9, Acro

[0372] 2) Chip: SA chip

[0373] 3) Experimental temperature: 25℃

[0374] 4) Experimental flow rate: 30 μL / min

[0375] 5) Fixing method: Tag capture method

[0376] 6) Combined measurement mode: multi-cycle dynamics

[0377] 7) Buffer solution:

[0378] a) Protein fixation: HBSP + 0.1 mM CaCl2, pH 7.4

[0379] b) Compound analysis: HBSP + 0.1 mM CaCl2, pH 7.4, 4% DMSO

[0380] 2. Protein fixation:

[0381] 1) The PCSK9 (Acro) protein is immobilized onto the SA chip via biotin-SA tag capture, and the channel is closed after immobilization.

[0382] 2) The reference channel is closed.

[0383] 3. Analysis and Testing:

[0384] 1) Prepare compound analysis buffer (HBSP + 0.1mM CaCl2, pH 7.4, 4% DMSO) and filter it through a 0.22μm filter membrane.

[0385] 2) Prepare a series of compounds with different concentration gradients, a total of 8 concentrations, and perform multiple cycles of detection.

[0386] 4. Data Analysis:

[0387] The final binding and dissociation curves were obtained by subtracting the reference channel and buffer blank control from the experimental channel signal values. Affinity data were obtained by fitting the curves using a 1:1 binding mode kinetic method. Binding and dissociation curves were fitted for all concentrations, and Ka (binding rate constant), Kd (dissociation rate constant), and K were calculated. D (Affinity constant, K) D =Kd / Ka), K D The value reflects the affinity between the protein and the compound.

[0388] Table 3. Binding activity of the compounds of this disclosure to PCSK9 protein.

[0389] Experimental results show that the compound disclosed herein has a high affinity for PCSK9 protein.

[0390] Experimental Example 3: Mouse PK Test

[0391] ICR mice (Beijing Vitonda Biotechnology Co., Ltd.) were administered different compounds by gavage (5 mg / kg) or intravenously (1 mg / kg). At different time points after administration (gavage group: 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h; intravenous group: 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h), 100 μL of blood was collected from the orbital sinus of the mice and placed in a heparin sodium anticoagulant tube. Plasma samples were obtained by centrifugation at 3000 rpm for 10 min within 2 h. Methanol protein precipitation was used, and the drug concentration in the mouse plasma after administration was determined by HPLC-MS / MS. Drug-time curves were plotted, and pharmacokinetic parameters were calculated. The pharmacokinetic behavior of the compounds in mice after administration was described by statistical moment parameters of a non-compartmental model.

[0392] Table 4. Pharmacokinetic parameters of mice after gavage administration of 5 mg / kg

[0393] The experimental results show that the disclosed compound has good in vivo pharmacokinetics and has the potential to become a drug.

[0394] Experimental Example 4: In vivo efficacy test of B6-hPCSK9-CDS mouse model

[0395] B6-hPCSK9-CDS transgenic C57 mice (5-6 weeks old, male, purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.) were introduced to the barrier system and allowed to acclimatize for 3-5 days before being fed Western Diets (Changzhou Shuyi Shuer Biotechnology Co., Ltd., catalog number 12079B). After 5-6 weeks of feeding, blood was collected from the orbital sinus of the mice into EP tubes. After standing at room temperature for 30 minutes, the samples were centrifuged at 5000 rpm for 10 minutes to collect serum samples. The serum LDL-c level was measured using a fully automated blood biochemistry analyzer. The serum LDL-c level was measured again after 1 week. Once the level stabilized, mice were randomly assigned to different groups based on their LDL-c levels and given appropriate drug treatments. The indicators monitored during the experiment were body weight and serum LDL-c level.

[0396] The experimental results show that the disclosed compound can effectively reduce serum LDL-c levels and has the potential to become a drug.

[0397] Experiment Example 5: In vivo PK experiment in cynomolgus monkeys

[0398] The pharmacokinetic (PK) behavior of different compounds was studied by single-dose gavage administration to cynomolgus monkeys (Guangxi Guidong Primate Development and Experiment Co., Ltd.). The compound was administered at a dose of 1.5 mg / kg. At different time points after administration (0 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h, and 48 h), 0.5 mL of whole blood was collected from the forelimb vein and placed in EP tubes containing EDTA-K2. Plasma samples were obtained by centrifugation at 2000 rpm for 10 min within 30 min. Methanol protein precipitation was used, and the drug concentration in the cynomolgus monkey plasma was determined by HPLC-MS / MS. Drug-time curves were plotted, and pharmacokinetic parameters were calculated. The pharmacokinetic behavior of the compounds in cynomolgus monkeys after administration was described using non-compartmental model statistical moment parameters.

[0399] Table 5. Pharmacokinetic parameters of cynomolgus monkeys administered via gavage at 1.5 mg / kg

[0400] The experimental results show that the disclosed compound has good in vivo pharmacokinetics and has the potential to become a drug.

[0401] Experimental Example 6: In vitro inhibition of human potassium ion channels (hERG)

[0402] 1. Experimental equipment:

[0403] Electrophysiological assays were performed using a fully automated patch-clamp QPatch 48 X (Sophion) device.

[0404] 2. Experimental Procedure:

[0405] Prepared cells were placed on a centrifuge in the Qpatch workbench and washed using multiple centrifugation / resuspension methods to replace the cell culture medium with extracellular fluid. An MTP-96 plate was removed and placed in the MTP source position. The QPlate chip was removed and then placed in the Qplate source position. A robotic arm scanned the barcodes on the MTP-96 plate and the QPlate chip and picked them up to the measurement station. Intracellular and extracellular fluids were aspirated from the liquid pool and added to the intracellular fluid pool and cell and test substance pool of the QPlate chip, respectively. At the measurement station, all measurement sites on the QPlate underwent initial quality control. The quality control process included aspirating the cell suspension from the centrifuge's cell container and positioning the cells onto the chip wells using a pressure controller to establish a high-resistance seal and form a whole-cell recording mode. Once a stable control current baseline was obtained, the test substance was aspirated from the MTP-96 plate according to the concentration gradient and applied to the cells. The current detected in the compound-free extracellular fluid for each cell served as its control group, and two cells were independently tested repeatedly. All Qpatch electrophysiological experiments were performed at 24°C.

[0406] 3. Compound treatment:

[0407] The compound was diluted in dilution gradients of 0.3, 1, 3, 10, and 30 μM.

[0408] 4. Data Processing:

[0409] Calculate IC using GraphPad Prism software 50 value.

[0410] Table 6. Results of in vitro hERG inhibition experiments

[0411] The experimental results show that the compound disclosed herein does not have a significant inhibitory effect on the hERG channel within the detection concentration range of this experiment, indicating that the compound disclosed herein has a low risk of cardiotoxicity.

Claims

1. A compound of formula (IA), its stereoisomers, tautomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof: in, Ring A is a 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups; R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C respectively. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, -N(C) 1-6 Alkyl)2, -N(C 3-6 2-cycloalkyl-NHC 1-6 Alkyl and -NHC 3-6 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, -N(C) 1-6 Alkyl)2, -N(C 3-6 2-cycloalkyl-NHC 1-6 Alkyl or -NHC 3-6 The cycloalkyl group may be optionally substituted by one, two or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl and cyano groups; Ring B is a 5-12 membered heterocyclic group, C 6-10 Aryl or 5-12 heteroaryl groups; R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C, respectively. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 5-6 membered heterocyclic, aryl, and 5-6 membered heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 The cycloalkyl, 5-6 membered heterocyclic, aryl, or 5-6 membered heteroaryl groups are optionally substituted by one, two, or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, and cyano groups; or two R groups attached to the same atom. b The linkage forms a 3-6 membered cycloalkyl group or a 4-6 membered heterocyclic group, wherein the 3-6 membered cycloalkyl group or the 4-6 membered heterocyclic group is optionally composed of 1, 2 or 3 groups selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy and halogenated C 1-4 The substituents of the alkylthio group are replaced; Ring C is C 5-6 Cycloalkyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; the C 5-6 Cycloalkyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl groups are optionally surrounded by 1, 2, or 3 groups selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy and halogenated C 1-4 The substituents of the alkylthio group are replaced; R c Selected from hydrogen, deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, and C, respectively. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy and halogenated C 1-4 Alkylthio; x is 0, 1, 2, 3 or 4; y is 0, 1, 2, 3 or 4; p can be 0, 1, 2, 3, or 4.

2. A compound of formula (I), its stereoisomers, tautomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof: in, Ring A is a 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 heteroaryl groups; R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C respectively. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 alkylthio and C 3-6 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 alkylthio or C 3-6 The cycloalkyl group may be optionally substituted by one, two or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl and cyano groups; Ring B is a 5-12 membered heterocyclic group, C 6-10 Aryl or 5-12 heteroaryl groups; R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C, respectively. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 5-6 membered heterocyclic, aryl, and 5-6 membered heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 The cycloalkyl, 5-6 membered heterocyclic, aryl, or 5-6 membered heteroaryl groups are optionally substituted by one, two, or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, and cyano groups; or two R groups attached to the same atom. b The linkage forms a 3-6 membered cycloalkyl group or a 4-6 membered heterocyclic group, wherein the 3-6 membered cycloalkyl group or the 4-6 membered heterocyclic group is optionally composed of 1, 2 or 3 groups selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy and halogenated C 1-4 The substituents of the alkylthio group are replaced; Ring C is C 5-6 Cycloalkyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl; the C 5-6 Cycloalkyl, 5-6 membered heterocyclic, phenyl, or 5-6 membered heteroaryl groups are optionally surrounded by 1, 2, or 3 groups selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy and halogenated C 1-4 The substituents of the alkylthio group are replaced; R c Selected from hydrogen, deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, and C, respectively. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy and halogenated C 1-4 Alkylthio; x is 0, 1, 2, 3 or 4; y is 0, 1, 2, 3 or 4; p can be 0, 1, 2, 3, or 4.

3. The compound according to claim 1 or 2, its stereoisomers, tautomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is C 6-10 Aryl or 5-10 heteroaryl groups; Preferably, ring A is phenyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, 5-membered 6-membered bicyclic heteroaryl, 6-membered 5-membered bicyclic heteroaryl, 5-membered 5-membered bicyclic heteroaryl or 6-membered 6-membered bicyclic heteroaryl; More preferably, ring A is a 5-membered monocyclic heteroaryl, a 6-membered monocyclic heteroaryl, a 5-membered 6-membered bicyclic heteroaryl, or a 6-membered 5-membered bicyclic heteroaryl; More preferably, ring A is a 6-membered monocyclic heteroaryl, a 5-membered 6-membered bicyclic heteroaryl, or a 6-membered 5-membered bicyclic heteroaryl; or, More preferably, ring A is More preferably, ring A is 4. The compound according to claim 1 or 2, its stereoisomers, tautomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is Preferably, ring A is More preferably, ring A is 5. The compound according to claim 1 or 2, its stereoisomers, tautomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is 6. The compound according to any one of claims 1-5, its stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, R a Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, and C respectively. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 alkylthio and C 3-6 cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 alkylthio or C 3-6 The cycloalkyl group may be optionally substituted by one, two or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl and cyano groups; Preferably, R a The groups are selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, and cyclopropyl, wherein the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, or cyclopropyl groups are optionally substituted by one, two, or three substituents selected from deuterium and halogen; More preferably, R a The groups are selected from hydrogen, deuterium, halogen, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, and cyclopropyl, respectively, wherein the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, or cyclopropyl groups are optionally substituted by one, two, or three substituents selected from deuterium and halogen. More preferably, R a The groups are selected from hydrogen, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, and cyclopropyl, respectively, wherein the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, or cyclopropyl groups are optionally substituted by one, two, or three substituents selected from halogens. More preferably, R a The groups are selected from hydrogen, F, Cl, Br, methyl, ethyl, methoxy, -OCHF2, -CF3 and cyclopropyl, respectively. More preferably, R a They are selected from Cl, methyl, methoxy, -OCHF2, -CF3 and cyclopropyl, respectively.

7. The compound according to any one of claims 1-5, its stereoisomers, tautomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein, R a Selected from methylthio, -OCF3, and -N(C) respectively 1-3 Alkyl)2, -N(C 3-6 2-cycloalkyl-NHC 1-3 Alkyl and -NHC 3-6 cycloalkyl; Preferably, R a They are selected from methylthio, -OCF3 and -NH-cyclopropyl, respectively.

8. The compound according to any one of claims 1-5, its stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, When ring A is hour, R a Selected from amino, hydroxyl, cyano, nitro, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkylthio, -N(C) 1-6 Alkyl)2, -N(C 3-6 2-cycloalkyl-NHC 1-6 Alkyl and -NHC 3-6 cycloalkyl, the C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkylthio, -N(C) 1-6 Alkyl)2, -N(C 3-6 2-cycloalkyl-NHC 1-6 Alkyl or -NHC 3-6 The cycloalkyl group may be optionally substituted by one, two or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl and cyano groups; Preferably, R a Selected from C respectively 2-6 alkenyl and C 2-6 alkynyl group, the C 2-6 alkenyl or C 2-6 The alkynyl group may optionally be substituted with one, two, or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, and cyano, preferably vinyl or acetyl, said vinyl or acetyl group may optionally be substituted with one, two, or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, and cyano; or, Preferably, R a C respectively 1-6 Alkylthio, the C 1-6 The alkylthio group may be optionally replaced by one, two or three substituents selected from deuterium and halogens, preferably methylthio and -SCHF2.

9. The compound according to claim 1 or 2, its stereoisomers, tautomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein, for 10. The compound according to claim 1 or 2, its stereoisomers, tautomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein, for 11. The compound according to any one of claims 1-10, its stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring B is a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group, a 7-membered monocyclic heterocyclic group, a 5-membered 6-membered bicyclic heterocyclic group, a 6-membered 5-membered bicyclic heterocyclic group, a 5-membered 5-membered bicyclic heterocyclic group, a 6-membered 6-membered bicyclic heterocyclic group, a 5-membered 7-membered bicyclic heterocyclic group, a 7-membered 5-membered bicyclic heterocyclic group, a 7-membered 6-membered bicyclic heterocyclic group, a 6-membered 7-membered bicyclic heterocyclic group, a phenyl group, a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group, a 5-membered 6-membered bicyclic heterocyclic group, a 6-membered 5-membered bicyclic heterocyclic group, a 5-membered 5-membered bicyclic heterocyclic group, a 6-membered 6-membered bicyclic heterocyclic group, a 5-membered 7-membered bicyclic heterocyclic group, a 7-membered 5-membered bicyclic heterocyclic group, a 7-membered 6-membered bicyclic heterocyclic group, or a 6-membered 7-membered bicyclic heterocyclic group. Preferably, ring B is a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group, a 5-membered 6-membered bicyclic heterocyclic group, a 6-membered 5-membered bicyclic heterocyclic group, a 5-membered 5-membered bicyclic heterocyclic group, a 6-membered 6-membered bicyclic heterocyclic group, a 7-membered 6-membered bicyclic heterocyclic group, a 6-membered 7-membered bicyclic heterocyclic group, a phenyl group, a 5-membered monocyclic heterocyclic group, a 6-membered monocyclic heterocyclic group, a 5-membered 6-membered bicyclic heterocyclic group, a 6-membered 5-membered bicyclic heterocyclic group, a 5-membered 5-membered bicyclic heterocyclic group, a 6-membered 6-membered bicyclic heterocyclic group, a 7-membered 6-membered bicyclic heterocyclic group, or a 6-membered 7-membered bicyclic heterocyclic group. More preferably, ring B is a 6-membered monocyclic heterocyclic group, a 6-membered 5-membered bicyclic heterocyclic group, or a 6-membered 7-membered bicyclic heterocyclic group; or, More preferably, ring B is More preferably, ring B is 12. The compound according to any one of claims 1-11, its stereoisomers, tautomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein, R b Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C, respectively. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 3-6 Cycloalkyl, phenyl, and 5-6-membered heteroaryl groups, wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 3-6 The cycloalkyl, phenyl, or 5-6-membered heteroaryl group is optionally substituted by one, two, or three substituents selected from deuterium, halogen, and cyano; or two R groups attached to the same atom. b Linkage forms a 3-6 membered cycloalkyl group, wherein the 3-6 membered cycloalkyl group is optionally surrounded by 1, 2, or 3 groups selected from deuterium, halogen, cyano, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl thiols, halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy and halogenated C 1-3 The substituents of the alkylthio group are replaced; Preferably, R b The radicals are selected from hydrogen, deuterium, halogen, cyano, oxo, thio, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, cyclopropyl, phenyl, and 6-membered heteroaryl, wherein the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, cyclopropyl, phenyl, or 6-membered heteroaryl radicals are optionally substituted by 1, 2, or 3 substituents selected from halogens; or two R radicals attached to the same atom. b The links form 3-4 membered cycloalkyl groups, wherein the 3-4 membered cycloalkyl groups are optionally substituted by 1, 2 or 3 substituents selected from deuterium, halogen, cyano, methyl and methoxy; More preferably, R b The radicals are selected from hydrogen, F, Cl, Br, cyano, oxo, methyl, ethyl, methoxy, ethoxy, cyclopropyl, and pyrimidinyl, respectively, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl, or pyrimidinyl radicals are optionally substituted by one, two, or three substituents selected from halogens; or two R radicals attached to the same atom. b The linker forms a cyclopropane, which is optionally substituted with one, two, or three substituents selected from halogens, methyl groups, and methoxy groups; More preferably, R b The radicals are selected from hydrogen, F, Cl, Br, cyano, oxo, methyl, ethyl, methoxy, ethoxy, cyclopropyl, pyrimidinyl, -OCF3, and -CF3, or two R radicals attached to the same atom. b Linkage forms cyclopropane; More preferably, R b They are selected from Cl, methyl, and methoxy, respectively.

13. The compound according to any one of claims 1-10, its stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, for Preferably, for 14. The compound according to any one of claims 1-10, its stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, for 15. The compound according to any one of claims 1-14, its stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, The ring C is a 5-6 membered heterocyclic group, phenyl, or 5-6 membered heteroaryl; wherein the 5-6 membered heterocyclic group, phenyl, or 5-6 membered heteroaryl group is optionally composed of 1, 2, or 3 selected from deuterium, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl thiols, halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy and halogenated C 1-3 The substituents of the alkylthio group are replaced; Preferably, ring C is a 5-membered heterocyclic group or a 5-membered heteroaryl group; the 5-membered heterocyclic group or 5-membered heteroaryl group may be optionally substituted by 1, 2 or 3 substituents selected from deuterium, halogen, cyano, methyl and methoxy. More preferably, for in This represents the bond connected to NH in formula (IA) or formula (I). This represents the bond connected to ring B; More preferably, for in This represents the bond connected to NH in formula (IA) or formula (I). This represents the bond connected to ring B; More preferably, for in This represents the bond connected to NH in formula (IA) or formula (I). This represents the bond connected to ring B.

16. The compound according to any one of claims 1-15, its stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, R c Selected from hydrogen, deuterium, halogen, cyano, and C respectively 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkyl thiols, halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy and halogenated C 1-3 Alkylthio; Preferably, R c They are selected from hydrogen, deuterium, halogen, cyano, methyl, and methoxy, respectively; More preferably, R c It is hydrogen.

17. The compound according to any one of claims 1-14, its stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, for in This represents the bond connected to NH in formula (IA), formula (I), or formula (II). This represents the bond connected to ring B.

18. The compound according to any one of claims 1-17, its stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, x is 0, 1, 2, or 3, preferably 0 or 1, more preferably 1; and / or, y is 0, 1, 2, or 3, preferably 0 or 1, more preferably 0; and / or, p can be 0 or 1, preferably 0.

19. A compound of formula (II), its stereoisomers, tautomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof: in, Each substituent in formula (II) is as described in formula (IA) or formula (I).

20. A compound having the following structure, its stereoisomers, tautomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof:

21. A compound having the following structure, its stereoisomers, tautomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof:

22. A pharmaceutical composition comprising the compound according to any one of claims 1-21, its stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof; Furthermore, the pharmaceutical composition also contains pharmaceutically acceptable excipients.

23. The use of the compound according to any one of claims 1-21, its stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 22, in the preparation of a medicament for treating and / or preventing diseases mediated by PCSK9; Preferably, the PCSK9-mediated diseases are selected from cardiovascular diseases, liver diseases, infectious and autoimmune diseases, neurocognitive disorders, and cancer.

24. The use of the compound according to any one of claims 1-21, its stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 22, in the preparation of a medicament for lowering LDL.

25. A method of preventing and / or treating a disease mediated by PCSK9, comprising administering to an individual (e.g., a patient) a preventive and / or therapeutically effective dose of a compound according to any one of claims 1-21, its stereoisomers, tautomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22. Preferably, the PCSK9-mediated diseases are selected from cardiovascular diseases, liver diseases, infectious and autoimmune diseases, neurocognitive disorders, and cancer.

26. A method for lowering LDL, comprising administering to an individual (e.g., a patient) a preventive and / or therapeutically effective dose of a compound according to any one of claims 1-21, its stereoisomers, tautomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22.

27. The use of the compound according to any one of claims 1-21, its stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 22, in a medicament for the treatment and / or prevention of diseases mediated by PCSK9; Preferably, the PCSK9-mediated diseases are selected from cardiovascular diseases, liver diseases, infectious and autoimmune diseases, neurocognitive disorders, and cancer.

28. The compound according to any one of claims 1-21, its stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 22, for lowering LDL.

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