A class of aromatic heterocyclic compounds, and methods of making and using the same

Abstract

The present application provides a kind of heteroaromatic ring compound shown in formula (A), its stereoisomer, tautomer or pharmaceutically acceptable salt and its preparation method and application.The compound of the present application has the signal transduction of tumor necrosis factor alpha (TNF alpha) Modulatory activity, in treating adverse inflammation and autoimmune diseases, pain and nociceptive sensory disorder, nerve and neurodegenerative diseases, cardiovascular diseases, metabolic diseases, tumor diseases and eye diseases etc.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to a class of aromatic heterocyclic compounds, as well as methods for preparing and using said compounds. Background Technology

[0002] The primary function of the tumor necrosis factor (TNF) superfamily is to regulate cell survival and death. A common structural feature of all known members of the TNF superfamily is the formation of trimeric complexes, which can bind to and activate specific TNF superfamily receptors to emit signals. For example, TNFα, a typical member of the TNF superfamily, exists transmembrane and is soluble, emitting signals through two receptors, TNFR1 and TNFR2, which have different functional endpoints. TNFα is an inflammatory cytokine responsible for a wide range of intracellular signaling events. Abnormal TNFα signaling can induce inflammation and is considered an important component of inflammatory diseases such as rheumatoid arthritis.

[0003] Several products capable of modulating TNFα activity have been approved, such as adalimumab, golimumab, infliximab, etanercept, and sertuzumab, for the prevention and / or treatment of inflammatory and autoimmune diseases such as Crohn's disease and rheumatoid arthritis. All of these products are large-molecule biologics and are injectable. Oral small-molecule drugs have significant advantages over biologics in certain aspects, especially in the treatment of chronic diseases. These advantages include ease of administration, no risk of immunogenicity, and lower production costs. Summary of the Invention

[0004] This invention relates to a class of aromatic heterocyclic compounds and their uses in treatment. These compounds are regulators of tumor necrosis factor α (TNFα) signaling and have potential applications in treating adverse inflammatory and autoimmune diseases, pain and nociceptive disorders, neurological and neurodegenerative diseases, cardiovascular diseases, metabolic diseases, oncological diseases, and eye diseases.

[0005] In a first aspect, the present invention provides compounds of formula (A), their stereoisomers, tautomers, or pharmaceutically acceptable salts:

[0006]

[0007] in,

[0008] for or ;

[0009] X1 and X2 are CR independently. X1 CRX2 Or N; R X1 R X2 The individual groups are H, halogen, cyano, amino, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0010] X3 is NR X3 or CR X31 R X32 ;

[0011] R X3 For H, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0012] R X31 R X32 The individual groups are H, halogen, cyano, amino, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0013] R1 is C 1-6 Alkyl, C 3-6 Monocycloalkyl, C 5-10 Spirocycloalkyl, C 5-10 Bridged cycloalkyl, C 5-10 Polycyclic alkyl, C 4-6 Monocyclic alkyl, 5-10 quinary bridged heterocyclic alkyl or C 3-8 Heterocyclic alkenyl, wherein R1 is optionally substituted with one or more R';

[0014] R' is selected from: deuterium, halogen, cyano, oxo group, hydroxyl group, amino group. , Or, optionally, replaced by one or more Rx: C 1-6 alkyl, C 2-6 alkynyl group, C 1-6 oxane, C 3-6 Monocycloalkyl, C 5-10 Spirocycloalkyl, C 5-10 Bridged cycloalkyl, C 5-10 Polycyclic alkyl, C 4-6 Monocyclic alkyl, 5-10 bridging heterocyclic alkyl, C 3-6 Monocycloalkyl-O-, C 4-6 Monoheterocyclic alkyl-O-, C 3-6 Monocycloalkyl-NH-, C 4-6 Monoheterocyclic alkyl-NH-, hydroxyl C 1-6 Alkyl-C(O)-, C 4-6 Monoheterocyclic alkyl-C(O)-, (C 1-6 alkyl)2-NC 1-6Alkyl-NH-, (C 1-6 alkyl)2-NC 1-6 Alkyl-O-, C 1-6 oxane-N(C) 1-6 alkyl)-, C 1-6 Alkyl-NH-, C 1-6 Alkyl-C(O)-NH-, C 1-6 Thioalkyl, C 2-6 oxaalkyl-C(O)-, phosphate ester-C 1-6 Alkyl, C 2-6 oxaalkyl-C(O)-amino-C 1-6 Alkyl, C 1-6 alkyl-sulfinyl-amino-, C 1-6 alkyl-sulfonyl-amino-C 1-6 Alkyl or -C(O)-C 1-6 Alkyl-C(O)OC 1-6 Alkyl; Ry is selected from: hydrogen, deuterium or C 1-6 alkyl;

[0015] Rx is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thionyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl;

[0016] R2 is hydrogen, deuterium, or optionally substituted: C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, C 3-6 cycloalkyl or C 4-6 Heterocyclic alkyl; wherein optional substitution means unsubstituted or substituted with one or more substituents, each substituent being independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thionyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-6 cycloalkyl, C 4-6 Heterocyclic alkyl, halogenated C 3-6 cycloalkyl or halogenated C 4-6 Heterocyclic alkyl groups;

[0017] R3 is difluoromethoxy, difluoromethylthio, deuterated difluoromethoxy, deuterated difluoromethylthio, or... ;

[0018] Ring D is C 3-6 cycloalkyl or C 4-6 Heterocyclic alkyl groups;

[0019] R d Selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thionyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 Oxyalkyl, deuterated C 1-6 Thioalkyl, halogenated C 1-6 oxane or halogenated C 1-6 Thioalkyl;

[0020] d can be 0, 1, 2, 3, or 4;

[0021] Unless otherwise stated, the heteroatoms in the above heterocyclic alkyl, heterocyclic alkenyl or heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4;

[0022] The prerequisite is that the combination of the definitions of the above variables forms a stable chemical structure.

[0023] The present invention also provides compounds of formula (I), their stereoisomers, tautomers, or pharmaceutically acceptable salts:

[0024]

[0025] in,

[0026] X1 and X2 are CR independently. X1 CR X2 Or N;

[0027] R X1 R X2 The individual groups are H, halogen, cyano, amino, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl;

[0028] R1 is C 1-6 Alkyl, C 3-6 Monocycloalkyl, C 5-10 Spirocycloalkyl, C 5-10 Bridged cycloalkyl, C 5-10 Polycyclic alkyl, C 4-6 Monocyclic alkyl, 5-10 quinary bridged heterocyclic alkyl or C 3-8Heterocyclic alkenyl, wherein R1 is optionally substituted with one or more R';

[0029] R' is selected from: deuterium, halogen, cyano, oxo group, hydroxyl group, amino group. , Or, optionally, replaced by one or more Rx: C 1-6 Alkyl, C 1-6 oxane, C 5-10 Spirocycloalkyl, C 5-10 Bridged cycloalkyl, C 5-10 Polycyclic alkyl, C 4-6 Monocyclic alkyl, 5-10 bridging heterocyclic alkyl, C 3-6 Monocycloalkyl-O-, C 4-6 Monoheterocyclic alkyl-O-, C 3-6 Monocycloalkyl-NH-, C 4-6 Monoheterocyclic alkyl-NH-, hydroxyl C 1-6 Alkyl-C(O)-, C 4-6 Monoheterocyclic alkyl-C(O)-, (C 1-6 alkyl)2-NC 1-6 Alkyl-NH-, (C 1-6 alkyl)2-NC 1-6 Alkyl-O-, C 1-6 oxane-N(C) 1-6 alkyl)-, C 1-6 Alkyl-NH-, C 1-6 Alkyl-C(O)-NH-, C 1-6 Thioalkyl, C 2-6 oxaalkyl-C(O)-, phosphate ester-C 1-6 Alkyl, C 2-6 oxaalkyl-C(O)-amino-C 1-6 Alkyl, C 1-6 alkyl-sulfinyl-amino-, C 1-6 alkyl-sulfonyl-amino-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl-C(O)OC 1-6 alkyl;

[0030] Alternatively, R' can be arbitrarily replaced by one or more Rx: C 2-6 alkynyl or C 3-6 Monocycloalkyl; Ry is selected from: hydrogen, deuterium or C 1-3 alkyl;

[0031] Rx is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6Thionyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl;

[0032] R2 is hydrogen, deuterium, or optionally substituted: C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, C 3-6 cycloalkyl or C 4-6 Heterocyclic alkyl; wherein optional substitution means unsubstituted or substituted with one or more substituents, each substituent being independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thionyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-6 cycloalkyl, C 4-6 Heterocyclic alkyl, halogenated C 3-6 cycloalkyl or halogenated C 4-6 Heterocyclic alkyl groups;

[0033] R3 is difluoromethoxy, difluoromethylthio, deuterated difluoromethoxy, deuterated difluoromethylthio, or... ;

[0034] Ring D is C 3-6 cycloalkyl or C 4-6 Heterocyclic alkyl groups;

[0035] R d Selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thionyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 Oxyalkyl, deuterated C 1-6 Thioalkyl, halogenated C 1-6 oxane or halogenated C 1-6 Thioalkyl;

[0036] d can be 0, 1, 2, 3, or 4;

[0037] Unless otherwise stated, the heteroatoms in the above heterocyclic alkyl, heterocyclic alkenyl or heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4;

[0038] The prerequisite is that the combination of the definitions of the above variables forms a stable chemical structure.

[0039] In some implementations, both X1 and X2 are N.

[0040] In some implementations, both X1 and X2 are CH.

[0041] In some implementations, X1 is N and X2 is CF.

[0042] In some implementations, X1 is N and X2 is CH.

[0043] In some implementations, R1 is C 1-4 Alkyl, C 3-4 Monocycloalkyl, C 5-9 Spirocycloalkyl, C 5-9 Bridged cycloalkyl, C 5-9 Polycyclic alkyl, C 4-6 Monoheteroalkyl or 5-9-membered bridged heteroalkyl, wherein R1 is optionally substituted by one or more R';

[0044] R' is selected from: deuterium, halogen, cyano, oxo group, hydroxyl group, amino group. , Or, optionally, replaced by one or more Rx: C 1-3 Alkyl, C 1-3 oxane, C 5-8 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Polycyclic alkyl, C 4-6 Mono-heterocyclic alkyl, 5-8-membered bridged heterocyclic alkyl, C 3-6 Monocycloalkyl-O-, C 4-6 Monoheterocyclic alkyl-O-, C 3-6 Monocycloalkyl-NH-, C 4-6 Monoheterocyclic alkyl-NH-, hydroxyl C 1-4 Alkyl-C(O)-, C 4-6 Monoheterocyclic alkyl-C(O)-, (C 1-3 alkyl)2-NC 1-3 Alkyl-NH-, (C 1-3 alkyl)2-NC 1-3 Alkyl-O-, C 1-3 oxane-N(C) 1-3 alkyl)-, C 1-3 Alkyl-NH-, C 1-3 Alkyl-C(O)-NH-, C 1-3 Thioalkyl, C 2-4 oxaalkyl-C(O)-, phosphate ester-C 1-3 Alkyl, C 2-4oxaalkyl-C(O)-amino-C 1-3 Alkyl, C 1-3 alkyl-sulfinyl-amino-, C 1-3 alkyl-sulfonyl-amino-C 1-3 Alkyl, -C(O)-C 1-3 Alkyl-C(O)OC 1-3 alkyl;

[0045] Alternatively, R' can be arbitrarily replaced by one or more Rx: Or C 3-6 Monocycloalkyl; Ry is selected from: hydrogen, deuterium or C 1-3 alkyl;

[0046] Rx is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-3 Alkyl, C 1-3 oxane, C 1-3 Thionyl, cyano C 1-3 Alkyl, Halogenated C 1-3 Alkyl or hydroxy C 1-3 alkyl;

[0047] In some implementations, R1 is C 1-4 Alkyl, C 3-4 Monocycloalkyl, C 5-9 Spirocycloalkyl, C 5-9 Bridged cycloalkyl or C 4-6 A monoheterocyclic alkyl group, wherein R1 is optionally substituted with one or more R'; or, R1 is C. 4-6 Monoheteroalkyl, wherein R1 is optionally substituted with one or more R';

[0048] R' is selected from: deuterium, halogen, cyano, oxo group, hydroxyl group, amino group. , Or, optionally, replaced by one or more Rx: C 1-3 Alkyl, C 1-3 oxane, C 5-8 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Polycyclic alkyl, C 4-6 Mono-heterocyclic alkyl, 5-8-membered bridged heterocyclic alkyl, C 3-4 Monocycloalkyl-O-, C 4-6 Monoheterocyclic alkyl-O-, C 3-6 Monocycloalkyl-NH-, C 4-6 Monoheterocyclic alkyl-NH-, hydroxyl C 1-4 Alkyl-C(O)-, C 4-6 Monoheterocyclic alkyl-C(O)-, (C 1-3 alkyl)2-NC 1-3Alkyl-NH-, (C 1-3 alkyl)2-NC 1-3 Alkyl-O-, C 1-3 oxane-N(C) 1-3 alkyl)-, C 1-3 Alkyl-NH-, C 1-3 Alkyl-C(O)-NH- or C 1-3 Thioalkyl;

[0049] Alternatively, R' can be arbitrarily replaced by one or more Rx: Or C 3-5 Monocycloalkyl; Ry is selected from: hydrogen, deuterium, methyl, or ethyl;

[0050] Rx is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-3 Alkyl, C 1-3 oxane, C 1-3 Thioalkyl, halogenated C 1-3 Alkyl or hydroxy C 1-3 alkyl;

[0051] In some implementations, R1 is C 1-3 Alkyl, C 3-4 Monocycloalkyl or C 5-7 Spirocycloalkyl, wherein R1 is optionally substituted with one or more R';

[0052] Alternatively, R1 is C 4-5 Monoheteroalkyl, wherein R1 is optionally substituted with one or more R';

[0053] R' is selected from: deuterium, halogen, cyano, oxo group, hydroxyl group, amino group. , Or, optionally, replaced by one or more Rx: C 1-3 Alkyl, C 1-3 oxane, C 5-7 Spirocycloalkyl, C 5-7 Bridged cycloalkyl, C 4-6 Mono-heterocyclic alkyl, 5-8-membered bridged heterocyclic alkyl, C 3-4 Monocycloalkyl-O-, C 4-6 Monoheterocyclic alkyl-O-, C 3-6 Monocycloalkyl-NH-, C 4-6 Monoheterocyclic alkyl-NH-, hydroxyl C 1-4 Alkyl-C(O)-, C 4-6 Monoheterocyclic alkyl-C(O)-, (C 1-3 alkyl)2-NC 1-3 Alkyl-NH-, (C 1-3 alkyl)2-NC 1-3 Alkyl-O-, C1-3 oxane-N(C) 1-3 alkyl)-, C 1-3 Alkyl-NH- or C 1-3 Alkyl-C(O)-NH-;

[0054] Alternatively, R' can be arbitrarily replaced by one or more Rx: Or C 3-4 Monocycloalkyl; Ry is selected from: hydrogen or deuterium;

[0055] Rx is independently selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-3 Alkyl or C 1-3 oxane;

[0056] Alternatively, Rx is a halogenated C 1-3 alkyl;

[0057] In some embodiments, R1 is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, aziridine, spiro[2.3]hexyl, spiro[2.2]pentyl, spiro[2.4]heptyl or spiro[3.3]heptyl, and R1 may optionally be substituted by one or more R';

[0058] R' is selected from: deuterium, F, Cl, cyano, oxo, hydroxyl, amino. , Or optionally substituted with one or more Rx: methyl, ethyl, isopropyl, methoxy, ethoxy, spiro[2.3]hexyl, spiro[2.2]pentyl, spiro[2.4]heptyl, spiro[3.3]heptyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, oxacyclobutyl, thiohexanebutyl, azacyclobutyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydrothiazolyl, oxazolyl, 1,3-dioxopentyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,3-oxazinyl, 5-azabicyclo[2.1.1]hexyl, 5-oxabicyclo[2.1.1]hexyl, 3-oxabicyclo[3.1.1]heptyl, cyclopropyl-O-, cyclobutyl-O-, oxacyclo Butyl-O-, Thionyl-Butyl-O-, Azacyclobutyl-O-, Tetrahydrofuranyl-O-, Tetrahydrothiophene-O-, Tetrahydrothiazolyl-O-, Oxazolyl-O-, 1,3-Dioxopentyl-O-, Tetrahydropyranyl-O-, Morpholinyl-O-, Thiomorpholinyl-O-, 1,3-Oxazinyl-O-, Cyclopropyl-NH-, Cyclobutyl-NH-, Oxycyclic Butyl-NH-, Thionyl-Butyl-NH-, Azacyclobutyl-NH-, Tetrahydrofuranyl-NH-, Tetrahydrothiophene-NH-, Tetrahydrothiazolyl-NH-, Oxazolyl-NH-, 1,3-Dioxopentyl-NH-, Tetrahydropyranyl-NH-, Morpholinyl-NH-, Thiomorpholinyl-NH-, 1,3-Oxazinyl-NH-, Hydroxymethyl- C(O)-, hydroxy-ethyl-C(O)-, oxetane-C(O)-, thio-butane-C(O)-, azirane-butane-C(O)-, tetrahydrofuranyl-C(O)-, tetrahydrothiophene-C(O)-, tetrahydrothiazolyl-C(O)-, oxazolyl-C(O)-, 1,3-dioxolane-C(O)-, tetrahydropyranyl-C(O)-, morpholinyl-C(O)-, thiomorpholinyl-C(O)-, 1,3-oxazinyl-C(O)-, (Methyl)2-N-methyl-NH-, (Methyl)2-N-ethyl-NH-, (Ethyl)2-N-ethyl-NH-, (Ethyl)2-N-methyl-NH-, (Methyl)2-N-methyl-O-, (Methyl)2-N-ethyl-O-, (Ethyl)2-N-ethyl-O-, C 1-3 oxane-N(C) 1-3 alkyl)-, C 1-3 Alkyl-NH- or C 1-3 Alkyl-C(O)-NH-;

[0059] Or, R' is Or cyclopropyl;

[0060] Rx is independently selected from deuterium, F, Cl, hydroxyl, amino, methyl, methoxy or ethoxy;

[0061] Alternatively, Rx can be independently selected from cyano, difluoromethyl, or trifluoromethyl;

[0062] In some implementations, R1 is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ;

[0063] Or, R1 is , , , , or ;

[0064] In some implementations, R2 is hydrogen, deuterium, or optionally substituted: C 1-3 Alkyl, C 1-3 oxane, C 1-3 Thioalkyl, C 3-4 cycloalkyl or C 4-5Heterocyclic alkyl; wherein optional substitution means unsubstituted or substituted with one or more substituents, each substituent being independently selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-3 Alkyl, C 1-3 oxane, C 1-3 Thioalkyl, halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 3-4 cycloalkyl, C 4-6 Heterocyclic alkyl, halogenated C 3-4 cycloalkyl or halogenated C 4-6 Heterocyclic alkyl groups;

[0065] In some implementations, R2 is hydrogen, deuterium, or optionally substituted: C 1-3 Alkyl, C 1-3 oxane, C 3-4 cycloalkyl or C 4-5 Heterocyclic alkyl; wherein optional substitution means unsubstituted or substituted with one or more substituents, each substituent being independently selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 3-4 cycloalkyl, C 4-6 Heterocyclic alkyl, halogenated C 3-4 cycloalkyl or halogenated C 4-6 Heterocyclic alkyl groups;

[0066] In some embodiments, R2 is methyl, deuterated methyl, cyclopropyl, cyclobutyl, or... ;

[0067] Alternatively, R2 can be hydrogen. , or .

[0068] In some implementations, ring D is C 3-4 cycloalkyl or C 4-6 Heterocyclic alkyl; preferably, ring D is cyclopropane, cyclobutane, oxetane, thiobutane, azanebutane, tetrahydrofuranyl, tetrahydrothiopheneyl, tetrahydrothiazolyl, oxazolyl, 1,3-dioxopentaneyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl or 1,3-oxazinyl; more preferably, ring D is cyclopropane;

[0069] In some implementation schemes, R d For deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-3 Alkyl, C 1-3 oxane, C 1-3 Thionyl, cyano C 1-3Alkyl, Halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, deuterated C 1-3 Alkyl, deuterated C 1-3 Oxyalkyl, deuterated C 1-3 Thioalkyl, halogenated C 1-3 oxane or halogenated C 1-3 Thionyl alkyl; preferably, R d For deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-3 Alkyl, C 1-3 oxaalkyl, hydroxy C 1-3 Alkyl, deuterated C 1-3 Alkyl, deuterated C 1-3 oxane or halogenated C 1-3 Oxyalkyl; more preferably, R d It is deuterium, halogen, cyano, oxo, hydroxyl, amino, methyl, methoxy, hydroxymethyl, deuterated methyl, deuterated methoxy, or halomethoxy; more preferably, R d For deuterium, F, or Cl; more preferably, R d It is F.

[0070] In some implementations, d is 0, 1, or 2; preferably, d is 0 or 2.

[0071] In some embodiments, the compound represented by formula (I) is a compound represented by formulas (II-a) to (II-i):

[0072]

[0073]

[0074]

[0075]

[0076]

[0077] Wherein, R2, X1, and X2 are as described in compound (I);

[0078] Ra is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, and amino groups. , Or, optionally, replaced by one or more Ra': C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 oxaalkyl, hydroxy C 1-6Alkyl-C(O)-, (C 1-6 alkyl)2-NC 1-6 Alkyl-NH-, (C 1-6 alkyl)2-NC 1-6 Alkyl-O-, C 1-6 oxane-N(C) 1-6 alkyl)-, C 1-6 Alkyl-NH-, C 1-6 Alkyl-C(O)-NH-, C 1-6 Thioalkyl, C 2-6 oxaalkyl-C(O)-, phosphate ester-C 1-6 Alkyl, C 2-6 oxaalkyl-C(O)-amino-C 1-6 Alkyl, C 1-6 alkyl-sulfinyl-amino-, C 1-6 alkyl-sulfonyl-amino-C 1-6 Alkyl or -C(O)-C 1-6 Alkyl-C(O)OC 1-6 alkyl;

[0079] Ra' is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thionyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl;

[0080] a can be 0, 1, 2, 3, 4 or 5.

[0081] In some embodiments, Ra is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, , Or, optionally, replaced by one or more Ra': C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 oxaalkyl, hydroxy C 1-3 Alkyl-C(O)-, (C 1-6 alkyl)2-NC 1-3 Alkyl-NH-, (C 1-3 alkyl)2-NC 1-3 Alkyl-O-, C 1-3 oxane-N(C) 1-3 alkyl)-, C 1-3 Alkyl-NH-, C 1-3 Alkyl-C(O)-NH- or C 1-3 Thioalkyl;

[0082] Ra' is independently selected from deuterium, F, cyano, oxo, hydroxyl, or amino;

[0083] In some embodiments, Ra is independently selected from deuterium, F, oxo group, hydroxyl group, amino group, , , CH3-NH-, CH3-C(O)-NH-, methyl, methoxy or difluoromethoxy.

[0084] In some implementations, a is 1, 2, 3 or 4; preferably, a is 1, 2 or 3; more preferably, a is 1 or 2.

[0085] In some embodiments, the compound represented by formula (I) is a compound represented by formulas (III-a)-(III-c):

[0086]

[0087]

[0088] Wherein, X1 and X2 are as described in compound (I);

[0089] R b C 3-6 Monocycloalkyl, C 5-10 Spirocycloalkyl, C 5-10 Bridged cycloalkyl, C 5-10 Polycyclic alkyl, C 4-6 Monocyclic alkyl, 5-10 quinary bridged heterocyclic alkyl or C 3-8 Heterocyclic alkenyl, the R b Optional by one or more R b 'replace;

[0090] R b Each is independently selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 3-4 cycloalkyl, C 4-6 Heterocyclic alkyl, halogenated C 3-4 cycloalkyl or halogenated C 4-6 Heterocyclic alkyl groups;

[0091] In some implementation schemes, R b C 5-7 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Polycyclic alkyl, C 4-6 Monoheterocyclic alkyl groups or 5-8 membered bridged heterocyclic alkyl groups;

[0092] R b Each is independently selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-3 Alkyl, Halogenated C 1-3 Alkyl or hydroxy C 1-3 alkyl;

[0093] Or, R b C 5-7 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Polycyclic alkyl groups or 5-8 membered bridged heterocyclic alkyl groups;

[0094] R b Each is independently selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-3 Alkyl, Halogenated C 1-3 Alkyl or hydroxy C 1-3 alkyl;

[0095] In some implementation schemes, R b It is spiro[2.3]hexyl, spiro[2.2]pentyl, spiro[2.4]heptyl, spiro[3.3]heptyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, oxacyclobutyl, thiohexacyclobutyl, azacyclobutyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiazolyl, oxazolyl, 1,3-dioxolanecycloyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,3-oxazinyl, 5-azabicyclo[2.1.1]hexyl, 5-oxabicyclo[2.1.1]hexyl or 3-oxabicyclo[3.1.1]heptyl;

[0096] R b Each is independently selected from deuterium, halogen, cyano, C 1-3 Alkyl or halogenated C 1-3 alkyl;

[0097] Or, R b It is spiro[2.3]hexyl, spiro[2.2]pentyl, spiro[2.4]heptyl, spiro[3.3]heptyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, 5-azabicyclo[2.1.1]hexyl, 5-oxabicyclo[2.1.1]hexyl or 3-oxabicyclo[3.1.1]heptyl;

[0098] R b Each is independently selected from deuterium, halogen, cyano, C 1-3 Alkyl or halogenated C 1-3 alkyl;

[0099] In some implementation schemes, R b for , , , , , , , , or ;

[0100] Or, R b for , , , , , , , or ;

[0101] Or, R b for .

[0102] In some embodiments, the compound represented by formula (I) is a compound represented by formula (IV):

[0103]

[0104] R1, R2, X1, and X2 are as described in compound (I).

[0105] In some embodiments, the compound represented by formula (I) is a compound represented by formulas (V-a)-(V-c):

[0106]

[0107]

[0108] Wherein, X1 and X2 are as described in compound (I);

[0109] R c for Or optionally by one or more R c 'Replaced by: C' 3-6 Monocycloalkyl-O-, C 4-6 Monoheterocyclic alkyl-O-, C 3-6 Monocycloalkyl-NH-, C 4-6 Monoheterocyclic alkyl-NH-, hydroxyl C 1-6 Alkyl-C(O)-, C 4-6 Monoheterocyclic alkyl-C(O)-, C 1-6 Aza-alkyl NH-, C 1-6 Aza-alkyl-O-, C1-6 oxane-N(C) 1-6 alkyl)-, C 1-6 Alkyl-NH- or C 1-6 Alkyl-C(O)-NH-;

[0110] Or, R c For optional use by one or more R c 'Replaced by: C' 3-6 Alkyl, C 3-6 oxane or Ry is selected from: hydrogen, deuterium, or C. 1-3 alkyl;

[0111] R c Each is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thionyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl;

[0112] In some implementation schemes, R c for Or optionally by one or more R c 'Replaced by: C' 3-4 Monocycloalkyl-O-, C 4-6 Monoheterocyclic alkyl-O-, C 3-4 Monocycloalkyl-NH-, C 4-6 Monoheterocyclic alkyl-NH-, hydroxyl C 1-4 Alkyl-C(O)-, C 4-6 Monoheterocyclic alkyl-C(O)-, C 1-4 Aza-alkyl-NH-, C 1-6 Aza-alkyl-O- or C 1-4 oxane-N(C) 1-4 alkyl)-;

[0113] Or, R c For optional use by one or more R c 'Replaced by: C' 3-4 Alkyl, C 3-4 oxane or Ry is selected from: hydrogen, deuterium, methyl, or ethyl.

[0114] R c Each is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, or C. 1-3 alkyl;

[0115] In some implementation schemes, R c for Or optionally by one or more R c Substituted: cyclopropane-O-, cyclobutane-O-, oxacyclobutane-O-, thiohexacyclobutane-O-, aziranebutane-O-, tetrahydrofuranyl-O-, tetrahydrothiophene-O-, tetrahydrothiazolyl-O-, oxazolyl-O-, 1,3-dioxolanecycloyl-O-, tetrahydropyranyl-O-, morpholinyl-O-, thiomorpholinyl-O-, 1,3-oxazinyl-O-, cyclopropane-N H-, cyclobutyl-NH-, oxetyl-NH-, thiobutyl-NH-, aziryl-NH-, tetrahydrofuranyl-NH-, tetrahydrothiophene-NH-, tetrahydrothiazolyl-NH-, oxazolyl-NH-, 1,3-dioxopentyl-NH-, tetrahydropyranyl-NH-, morpholinyl-NH-, thiomorpholinyl-NH-, 1,3-oxazinyl-NH-, hydroxyl C 1-3 Alkyl-C(O)-, oxetane-butyl-C(O)-, thio-butyl-C(O)-, azirane-butyl-C(O)-, tetrahydrofuranyl-C(O)-, tetrahydrothiophene-C(O)-, tetrahydrothiazolyl-C(O)-, oxazolyl-C(O)-, 1,3-dioxolanecycloyl-C(O)-, tetrahydropyranyl-C(O)-, morpholinyl-C(O)-, thiomorpholinyl-C(O)-, 1,3-oxazinyl-C(O)-, (C 1-3 alkyl)2-NC 1-3 Alkyl-NH-, (C 1-3 alkyl)2-NC 1-4 Alkyl-O- or C 1-3 oxane-N(C) 1-3 alkyl)-;

[0116] Or, R c For optional use by one or more R c Substituted with: tert-butyl, methoxy, or ;

[0117] R c Each is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, or methyl;

[0118] In some implementation schemes, R c for , , , , , , , , , , or ;

[0119] Or, R c for , or .

[0120] In some embodiments, the compound represented by formula (I) is a compound represented by formula (VI):

[0121]

[0122] Among them, R1, R2, X1, X2, ring D, R d And d as described in compound (I).

[0123] In some embodiments, the compound represented by formula (I) is a compound represented by formula (VII-a) or formula (VII-b):

[0124]

[0125] Wherein, X1 and X2 are as described in compound (I);

[0126] R e For optional use by one or more R e 'Replaced by: C' 3-6 Monocyclic alkyl or 4-6 membered heterocyclic alkyl;

[0127] R e Each is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thionyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl;

[0128] m can be 1, 2, or 3.

[0129] In some implementation schemes, R e For optional use by one or more R e 'Replaced by: C' 3-4 Monocyclic alkyl or 4-5 membered heterocyclic alkyl;

[0130] R e Each is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, or C. 1-3 alkyl;

[0131] In some implementation schemes, R e For optional use by one or more R eSubstituted with: cyclopropane, cyclobutane, oxetane, thiobutane, azirane, tetrahydrofuranyl, tetrahydrothiopheneyl, tetrahydrothiazolyl, oxazolyl, 1,3-dioxolanecycloyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl or 1,3-oxazinyl;

[0132] R e Each is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, or methyl;

[0133] In some implementation schemes, R e for .

[0134] In some implementations, m is 1 or 2; further, m is 1.

[0135] In the above embodiments of the present invention, except for the defined groups, the definitions of other groups are as described in the present invention, and will not be described one by one to save space.

[0136] The above embodiments of the present invention can be combined arbitrarily, and the resulting embodiments are all embodiments of the present invention.

[0137] In a second aspect, the present invention provides the following compounds, or their stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein the compounds are selected from:

[0138]

[0139]

[0140]

[0141]

[0142]

[0143] Thirdly, the present invention provides a method for preparing the compound represented by formula (I), including but not limited to the following methods:

[0144]

[0145] Where X is Cl, Br, I, OSO2Me, etc.; M1 is: -B(OH)2, -BF3K, Etc.; X1, X2, R1, R2, R3 are defined as described in the compound of the first aspect (I) of the present invention.

[0146] Fourthly, the present invention provides a pharmaceutical composition comprising a compound described in the first or second aspect of the present invention, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, optionally further comprising a pharmaceutically acceptable carrier.

[0147] Fifthly, the present invention provides the use of the compounds described in the first or second aspect of the present invention, or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described in the fourth aspect, as a medicament or in the preparation of a medicament; preferably, the medicament is a medicament for regulating TNFα activity; more preferably, the medicament is a medicament for preventing and / or treating diseases regulated by TNFα; more preferably, the medicament is a medicament for treating and / or preventing diseases or conditions caused by abnormal TNFα; more preferably, the medicament is a medicament for treating and / or preventing diseases or conditions such as inflammatory diseases and autoimmune disorders; more preferably, the medicament is a medicament for treating and / or preventing diseases or conditions such as autoimmune and inflammatory disorders, pain and nociceptive disorders, neurological disorders and neurodegenerative disorders, metabolic disorders, cardiovascular disorders, tumor disorders, and ocular disorders.

[0148] In some embodiments, the use of the compound described in the first or second aspect, or its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in the fourth aspect, in the preparation of a medicament for treating and / or preventing diseases or conditions caused by abnormal TNFα; preferably, the medicament is for treating and / or preventing diseases or conditions such as inflammatory diseases and autoimmune disorders; more preferably, the medicament is for treating and / or preventing diseases or conditions such as autoimmune and inflammatory disorders, pain and nociceptive disorders, neurological disorders and neurodegenerative disorders, metabolic disorders, cardiovascular disorders, tumor disorders, and ocular disorders.

[0149] In a sixth aspect, the present invention provides synthetic intermediates for the compounds of the present invention or their tautomers, stereoisomers or pharmaceutically acceptable salts thereof, such as synthetic intermediates in general preparation methods or synthetic intermediates in specific embodiments.

[0150] definition

[0151] Unless otherwise stated, the following terms as used in this invention have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0152] C in this article m-n This refers to the part having an integer number of carbon atoms within a given range. For example, "C1-6 "" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

[0153] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight-chain or branched group containing 1-20 carbon atoms, preferably containing 1-10 carbon atoms (i.e., C10). 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 groups, more preferably containing 1-4 carbon atoms (i.e., C464-C ... 1-4 Alkyl groups, more preferably containing 1-3 carbon atoms (i.e., C464-C ... 1-3 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.

[0154] Unless otherwise specified, the term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. Alkenyl groups may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C2H2O). 2-10 Alkenyl), further preferably containing 2-8 carbon atoms (C 2-8 Alkenyl), more preferably containing 2-6 carbon atoms (i.e., C14-C2 ... 2-6 alkenyl), 2-5 carbon atoms (i.e., C) 2-5 alkenyl), 2-4 carbon atoms (i.e., C) 2-4 alkenyl), 2-3 carbon atoms (i.e., C) 2-3 Alkenyl), 2 carbon atoms (i.e., C2 alkenyl), for example "C 2-6 "Alkenyl" refers to a group that is alkenyl and has 2 to 6 carbon atoms in its carbon chain (specifically, 2, 3, 4, 5, or 6). Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl.

[0155] Unless otherwise specified, the terms "halogen" or "halogenated" refer to F, Cl, Br, I; preferably F, Cl, Br; more preferably F, Cl.

[0156] The term "halogenated alkyl" refers to an alkyl group as defined above in which one, two, or more hydrogen atoms (e.g., 3, 4, 5, 6, 7, 8) or all of the hydrogen atoms are replaced by a halogen, such as C. 1-6 Alkyl substitution by halogens refers to C 1-6 Haloalkyl groups, such as CCl3, CH2F, CHF2, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, CF2CF3, etc.

[0157] Unless otherwise specified, the term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, 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, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Examples of bicyclic cycloalkyl groups include those having 5 to 12, more such as 7 to 12 or 5 to 10 ring atoms arranged in a fused bicyclic arrangement selected from the [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems, or arranged in a bridging bicyclic arrangement selected from bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane and bicyclic [3.2.2]nonane. Other examples of bicyclic cycloalkyl groups include rings arranged in a bicyclic arrangement selected from the [5,6] and [6,6] ring systems.

[0158] Unless otherwise specified, "cycloalkenyl" refers to a system composed of monocyclic, bicyclic, and spirocyclic hydrocarbon rings as daughter groups; however, the system is unsaturated, meaning it contains at least one C-C double bond but no aromatic system. Preferably, it contains 3-12 carbon atoms (i.e., C12-C22). 3-12 Cycloalkenyl), more preferably containing 3-10 carbon atoms (C 3-10 Cycloalkenyl), further preferably 3-6 carbon atoms (C 3-6 Cycloalkenyl), 4-6 carbon atoms (C 4-6 Cycloalkenyl), 5-6 carbon atoms (C 5-6 (Cycloalkenyl).

[0159] Unless otherwise specified, the term "oxaalkyl" refers to an alkyl residue in which one or more carbon atoms (and associated hydrogen atoms) are replaced by oxygen, such as "alkoxy" or "alkoxyalkyl". Examples include methoxy, ethoxy, propoxy, methoxypropyl, etc. The term oxaalkyl means as understood in the art [see Nomenclature and Index of Chemical Substances for Chemical Extraction, published by the American Chemical Society, 196, but not limited to 127(a)], that is, it refers to a compound in which oxygen is bonded to its adjacent atoms by a single bond (forming an ether bond); it does not refer to the double oxygen bond found in the carbonyl group.

[0160] "Alkoxy" refers to -O-alkyl, and 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.

[0161] Unless otherwise specified, the terms "thioalkyl" and "nitroalkyl" refer to the replacement of oxygen with sulfur or nitrogen in the term "oxaalkyl".

[0162] Unless otherwise specified, the term "aminoalkyl" refers to -NH-alkyl, -N-dialkyl, -alkyl-NH2, -alkyl-NH-alkyl, -alkyl-N-dialkyl, and -dialkyl-N-alkyl, wherein the alkyl group is defined as above, i.e., containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, and even more preferably 1 to 6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, -NH-methyl, -NH-ethyl, -NH-isopropyl, -methylamino, -ethylamino, -isopropylamino, -dimethylamino, and -N-methylethylamino.

[0163] Unless otherwise specified, the term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon substituent, having a non-aromatic structure, containing 3-20 ring atoms, wherein one, two, three, or more (e.g., four, five, six, seven, or eight) ring atoms are selected from N, O, or S, and the remaining ring atoms are C. Preferably, it contains 3-14 ring atoms, 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 (or fused) and bridged heterocyclic groups. The heterocyclic group may be attached (e.g., bridged, spiro-attached, or fused (or fused)) to other cyclic groups (including cycloalkyl, cycloalkenyl, heterocyclic alkenyl, aryl, or heteroaryl), but the attachment point must be on a carbon atom or heteroatom of the heterocyclic group. Each heterocyclic group or other cyclic group may be optionally substituted, as defined herein with respect to each individual section.

[0164] The term "heterocyclic alkyl" refers to a saturated "heterocyclic group" as defined above, comprising 3-20 ring atoms, wherein one, two, three, or more (e.g., four, five, six, seven, or eight) ring atoms are selected from N, O, or S, and the remaining ring atoms are C. Preferably, it comprises 3-14 ring atoms, 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). Bicyclic or polycyclic heterocyclic alkyl groups include spirocyclic, fused (or fused) ring, and bridged ring heterocyclic alkyl groups. The heterocyclic alkyl group may be attached (e.g., bridged, screwed, or fused (or paralleled)) to other cyclic groups (including cycloalkyl, cycloalkenyl, heterocyclic alkenyl, aryl, or heteroaryl), but the attachment point to the parent group must be on a carbon atom or heteroatom of the heterocyclic alkyl group. As defined herein with respect to each individual section, each heterocyclic alkyl group or other cyclic group may be optionally substituted.

[0165] The term "heterocyclic alkenyl" refers to an unsaturated "heterocyclic group" as defined above, comprising 3-20 ring atoms, wherein one, two, three, or more (e.g., four, five, six, seven, or eight) ring atoms are selected from N, O, or S, and the remaining ring atoms are C. Preferably, it comprises 3-14 ring atoms, 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). Bicyclic or polycyclic heterocyclic alkenyl groups include spirocyclic, fused (or fused) ring, and bridged ring heterocyclic alkenyl groups. The heterocyclic alkenyl group may be attached (e.g., bridged, helicaled, or fused (or paralleled)) to other cyclic groups (including cycloalkyl, cycloalkenyl, heterocyclic alkenyl, aryl, or heteroaryl), but the attachment point to the parent group must be on a carbon atom or heteroatom of the heterocyclic alkenyl group. As defined herein with respect to each individual section, each heterocyclic alkenyl or other cyclic group may be optionally substituted.

[0166] Unless otherwise specified, the term "aryl" refers to an aromatic carbocyclic system containing 6-16 carbon atoms (6-16 membered aryl), 6-14 carbon atoms, 6-12 carbon atoms, or 6-10 carbon atoms, preferably 6-10 carbon atoms. 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, anthracene, phenanthrene, or pyrene. "Aryl" also includes ring systems in which the aryl group as defined above is fused or fused with one or more cycloalkyl, heterocyclic, or heteroaryl groups, but the point of attachment to the parent group must be on a carbon atom of the aryl group. As defined herein with respect to each individual section, each aryl or other cyclic group may be optionally substituted.

[0167] Unless otherwise specified, the term "heteroaryl" refers to an aromatic monocyclic, bicyclic, or polycyclic cyclic system containing 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, wherein one, two, three, or more (e.g., four, five, six, seven, or eight) ring atoms are heteroatoms and the remaining atoms are carbon atoms, the heteroatoms being independently selected from O, N, or S, and the number of heteroatoms is preferably one, two, three, or four; more preferably one, two, or three. Examples of heteroaryl groups may include, but are not limited to, furanyl, thiophene, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrroloyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purine, indoleyl, isoindoleyl, indazoleyl, benzofuranyl, benzothiophene, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzoimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, and 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]pyridinyl, etc. "Heteroaryl" also includes ring systems in which the heteroaryl groups as defined above are fused or fused with one or more cycloalkyl, heterocyclic, or aryl groups, but the point of attachment to the parent group must be on an atom of the heteroaryl group. As defined herein for each individual part, each aryl or other cyclic group may be optionally substituted.

[0168] Unless otherwise specified, the terms "pharmaceutically acceptable salt" or "medicinal salt" refer to a salt that, within reasonable medical judgment, is suitable for contact with mammalian, particularly human, tissues without excessive toxicity, irritation, allergic reactions, etc., and is proportionate to 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 of this invention, or solely by reacting a free base or free acid with a suitable reagent.

[0169] Unless otherwise specified, the term "stereoisomer" refers to compounds that have the same chemical structure but differ in the spatial arrangement of their atoms or groups. Stereoisomers include optical isomers, enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (or cis / trans isomers), and trans-reactive isomers. Any mixture of stereoisomers can be separated into pure or substantially pure optical isomers, geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0170] 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.

[0171] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or its enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers), is within the scope of this invention.

[0172] Unless otherwise specified, the term "optional substitution" means that the hydrogen at the substituted site of the group is not substituted, or is substituted by one or more substituents, preferably selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, nitro, amino, azide, oxo (=O), 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 membered heteroaryl rings, 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 alkyl, C 6-14The aryl or 5-10 membered heteroaryl group may optionally be selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6 The alkoxy group is substituted by one or more substituents, wherein the oxo group refers to a double bond formed by replacing two H atoms at the same substitution position with the same O atom group. Preferably, the substituents are selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, nitro, amino, azide, oxo (=O), carboxyl, C. 2-4 Alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-7 cycloalkyl, C 3-7 Cycloalkylsulfonyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl rings, wherein the C 2-4 Alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-7 cycloalkyl, C 3-7 Cycloalkylsulfonyl, 3-7 membered heterocyclic group, C 6-10 The aryl or 5-10 membered heteroaryl group may optionally be selected from halogen, hydroxyl, amino, cyano, C 1-4 Alkyl or C 1-4 The alkoxy group is substituted by one or more substituents. Preferably, the substituents are selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, nitro, amino, azide, oxo (=O), carboxyl, C 2-4 Alkenyl, C 2-4 alkynyl group, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkylsulfonyl, 4-6 membered heterocyclic, phenyl, or 5-6 membered heteroaromatic, wherein the C 2-4 Alkenyl, C 2-4 alkynyl group, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkylsulfonyl, 4-6 membered heterocyclic, phenyl, or 5-6 membered heteroaromatic rings may optionally be selected from halogen, hydroxyl, amino, cyano, C 1-3 Alkyl or C 1-3 It is replaced by one or more substituents in the alkoxy group.

[0173] The terms “optional” or “optional” mean that the event or situation described below may but does not have to happen, and the description includes the circumstances under which the event or situation may or may not occur.

[0174] The word “comprise” or “include” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0175] The term “subject” can also be referred to as “individual” or “subject”, referring to a cell or animal, including but not limited to mammals such as laboratory animals or humans.

[0176] "Effective amount" means an amount of the compound or pharmaceutical composition described herein sufficient to achieve the intended application, including but not limited to the treatment of a disease or the relief of its symptoms. In some embodiments, for example, the amount may be a dose that can induce a specific response in cells, or a dose that exerts a therapeutic effect on a disease in a model animal. The specific amount will vary depending on, for example, the specific compound selected, the type of subject and their age / pre-existing health condition, the dosing regimen followed, the severity of the disease, whether it is administered in combination with other agents, the timing of administration, the tissue of administration, and the physical delivery system carrying it.

[0177] Some of the compounds in this invention are optically active. The compounds in this application can be racemic, optical isomers or mixtures thereof. The optical isomers in the compounds of this invention can be synthesized either by using the starting materials of the optical isomers or by separating the racemic mixtures.

[0178] Unless otherwise specified, the term "pharmaceuticalally acceptable carrier," also known as "pharmaceuticalally acceptable excipient" or "pharmaceuticalally acceptable excipient," refers to a generally recognized medium in the field of delivering bioactive agents to animals (specifically, mammals). Pharmaceutically acceptable carriers are formulated based on a number of factors well understood by those skilled in the art. These include (but are not limited to) the type and nature of the formulated active agent, the subject to whom the composition containing the pharmaceutical agent is to be administered, the intended route of administration of the composition, and the targeted therapeutic indication. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. The preparation of pharmaceutical compositions described herein includes, but is not limited to, mixing, for example, the compounds described in the first or second aspect, or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, with a pharmaceutically acceptable carrier.

[0179] The above embodiments represent exemplary embodiments of the present invention, but the present invention is not limited to the above embodiments. Furthermore, the various technical features in the above embodiments of the present invention can be combined with each other to constitute one or more new technical solutions, and these new technical solutions also fall within the scope of the present invention, as long as such new technical solutions are technically feasible. Detailed Implementation

[0180] The present invention will be 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 invention. 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 are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of the present invention. The preferred embodiments and materials shown herein are for illustrative purposes only.

[0181] The structures of the compounds in this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or high-performance liquid chromatography (HPLC). The NMR measurements were performed using a Bruker 400 MHz and / or Varian 400 MHz instrument; the LC-MS instrument used was an Agilent 1260 Infinity II-6120 / 6125MSD; and the HPLC instrument used was a Waters Acquity UPLC_2 and / or Shimadzu LC2030 and / or Agilent 1260 Infinity II. Chiral compound separation was performed using an SFC-150 (Waters) instrument and a DAICL CHIRALCEL column. ® OD; Column volume: 20×250mm (10 μm particle size packing).

[0182] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0183] This invention provides a method for preparing the compound. The compound can be prepared by the following steps.

[0184] Preparation Example

[0185] Preparation Example 1: Preparation of Intermediate 11-3

[0186]

[0187] Starting material a (synthetic method referred to WO2025038927A1 intermediate 9, 300 mg) and pinacol diboronate (390.9 mg) were dissolved in 1,4-dioxane (10 mL). Potassium acetate (226.6 mg), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (56.32 mg), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (60.48 mg) were added. The reaction solution was heated to 90 °C and stirred for 16 hours under nitrogen protection. The reaction solution was filtered, and the filtrate was concentrated to obtain the target compound (500 mg). LCMS (ESI) [M+H] + =482.2.

[0188] Example

[0189] Example 1: Preparation of Compound 11

[0190]

[0191] Step 1: Synthesis of Intermediate 11-1

[0192] Spiro[2.3]hexane-5-one (900 mg) was dissolved in tetrahydrofuran (15 mL), and tert-butylsulfinamide (1.13 g) and tetraethyl titanate (3.2 g) were added. The reaction mixture was stirred at room temperature for 16 hours. Water (30 mL) and ethyl acetate (50 mL) were added to the reaction mixture, and the mixture was filtered. The filtrate was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by rapid chromatography (silica gel, petroleum ether: ethyl acetate = 3:1) to give the target compound (1.1 g). LCMS (ESI) [M+H] + =200.1.

[0193] Step 2: Synthesis of intermediate 11-2

[0194] Under nitrogen protection, 5-bromo-2-iodopyrimidine (715.05 mg) was dissolved in dichloromethane (10 mL). Butyllithium (1 mL, 2.5 M) was slowly added dropwise at -78 °C, and the reaction mixture was stirred at -78 °C for 30 minutes. Then, a dichloromethane (3 mL) solution of intermediate 11-1 (500 mg) was slowly added dropwise to the above reaction mixture, and the mixture was stirred at -78 °C for 2 hours. The reaction was quenched with saturated ammonium chloride solution (5 mL), and water (30 mL) was added to the reaction mixture. Extraction was performed with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by rapid chromatography (silica gel, petroleum ether: ethyl acetate = 2:1) to give the target compound (180 mg). LCMS (ESI) [M+H] + =358.0.

[0195] Step 3: Synthesis of intermediate 11-4

[0196] Under nitrogen protection, potassium phosphate (118.87 mg) and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (20.49 mg) were added sequentially to a mixed solvent of dioxane (4 mL) and water (2 mL) of intermediates 11-2 (100 mg) and 11-3 (147.76 mg). The reaction mixture was heated to 90 °C and stirred for 3 hours. The reaction mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by rapid chromatography (silica gel, petroleum ether: tetrahydrofuran = 1: 2) to give the target compound (65 mg). LCMS (ESI) [M+H] + =633.2.

[0197] Step 4: Synthesis of Compound 11

[0198] Intermediate 11-4 (65 mg) was dissolved in dioxane (2 mL), and dioxane hydrochloride solution (2 mL, 2.0 M) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the pH was adjusted to neutral with 10% sodium hydroxide aqueous solution. The resulting reaction mixture was directly purified by reverse-phase preparative separation (C18, 0.1% formic acid aqueous solution / acetonitrile) to obtain the target compound (16 mg). LCMS (ESI) [M+H] + =529.2; ¹H NMR (400 MHz, DMSO-d 6 ) δ 9.19(s, 2H), 8.85 (d, J = 7.2 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.73 (s, 1H), 7.61 (s,1H), 7.47 - 7.25 (m, 3H), 5.07 (d, J = 6.8 Hz, 1H), 5.02 (d, J = 6.4 Hz, 1H),3.35-3.20 (m, 4H), 2.95 – 2.74 (m,3H), 2.36 – 2.16 (m, 2H), 0.60 – 0.48 (m,2H), 0.46 – 0.35 (m, 2H).

[0199] Example 2: Preparation of compound 29

[0200]

[0201] Step 1: Synthesis of intermediate 29-3

[0202] Under nitrogen protection, potassium acetate (142 mg), tris(bis(benzylacetone)bispalladium) (43 mg), and tricyclohexylphosphine fluoroborate (17 mg) were added sequentially to a 1,4-dioxane (20 mL) solution of intermediate 11-2 (170 mg) and pinacol diborate (241 mg). The reaction mixture was heated to 100 °C and stirred for 48 hours. After cooling to room temperature, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography (silica gel, petroleum ether: ethyl acetate = 1:1) to obtain the target compound (115 mg). LCMS (ESI) [M+H] + =406.4.

[0203] Step 2: Synthesis of intermediate 29-5

[0204] Potassium hydroxide (5.6 g) was dissolved in heavy water (60 mL) at room temperature, cooled to 0 °C, and an ultra-dry acetonitrile solution (60 mL) of intermediate 29-4 (3.39 g) was added dropwise. The mixture was stirred at 0 °C for 15 minutes, followed by the addition of diethyl bromofluoromethylphosphonate (4.0 g). The reaction mixture was stirred at 25 °C for 4 hours. The reaction mixture was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by rapid chromatography (silica gel, dichloromethane:methanol = 20:1) to give the target compound (860 mg). LCMS (ESI) [M+H] + =391.3.

[0205] Step 3: Preparation of Compound 29

[0206] Referring to Example 1, intermediate 11-3 was replaced with intermediate 29-3, and intermediate 11-2 was replaced with intermediate 29-5 to obtain the target compound (20 mg). LCMS (ESI) [M+H] + =530.2; ¹H NMR (400 MHz, DMSO- d 6 ) δ9.18(s, 2H), 8.86 (d, J = 7.2 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.72 (s,1H), 7.60 (s, 1H), 7.49 - 7.23 (m, 2H), 5.07 (d, J = 6.8 Hz, 1H), 5.02 (d, J = 6.4 Hz, 1H), 3.35-3.20 (m, 4H), 2.95 – 2.74 (m, 3H), 2.35 – 2.16 (m, 2H), 0.61 – 0.49 (m, 2H), 0.47 – 0.35 (m, 2H).

[0207] Example 3: Preparation of compound 45

[0208]

[0209] Step 1: Synthesis of Intermediate 45-1

[0210] 1-(5-bromopyrimidin-2-yl)cyclobutane-1,3-diol (synthetic method referred to Example 7, Step 2, WO2025218735A1, 2 g) was dissolved in vinyl n-butyl ether (40 mL), and 4,7-diphenyl-1,10-phenanthroline (271.27 mg), palladium acetate (183.22 mg), and triethylamine (412.9 mg) were added. The reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 4 hours. The reaction mixture was concentrated, and the residue was purified by rapid chromatography (silica gel, petroleum ether: tetrahydrofuran = 3:1) to give the target compound (1.8 g). LCMS (ESI) [M+H] + =271.0.

[0211] Step 2: Synthesis of intermediate 45-2

[0212] Under nitrogen protection and an ice-water bath, diiodomethane (7.41 g) was slowly added dropwise to a solution of diethylzinc (6.83 mL, 2 M n-hexane) in anhydrous dichloromethane (6.8 mL). The reaction mixture was stirred in an ice-water bath for 10 minutes, and then a solution of intermediate 45-1 (1.5 g) in anhydrous dichloromethane (2 mL) was added. The reaction mixture was stirred at 25 °C for 3 hours. Saturated ammonium chloride (10 mL) was added dropwise to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the reaction mixture was concentrated to obtain a crude product. The crude product was purified by rapid chromatography (silica gel, petroleum ether: ethyl acetate = 5:1) to obtain the target compound (825 mg). LCMS (ESI) [M+H] + =285.1.

[0213] Step 3: Synthesis of intermediate 45-3

[0214] In 0 At 0 °C, 168 mg of 60% pure sodium hydroxide solution was added to an anhydrous tetrahydrofuran (10.5 mL) solution of intermediate 45-2 (600 mg). After stirring at 0 °C for 10 minutes, p-toluenesulfonyl chloride (602 mg) was added. The mixture was stirred at 25 °C for 2 hours. Saturated ammonium chloride (10 mL) was added dropwise to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to obtain the crude product. The crude product was then purified by rapid chromatography (silica gel, petroleum ether: ethyl acetate = 1:1) to obtain the target compound (829 mg). LCMS (ESI) [M+H] + =439.1.

[0215] Step 4: Synthesis of intermediate 45-4

[0216] To a xylene (9 mL) solution of intermediate 45-3 (0.80 g), diphenyl azidophosphate (1.00 g) and 1,8-diazobisspirocyclic [5.4.0]undecyl-7-ene (0.55 g) were added sequentially. The reaction mixture was stirred at 25 °C for 1 hour, then stirred at 60 °C for 16 hours. The reaction was monitored by LCMS, and the target product was observed. The reaction mixture was concentrated to obtain a crude product, which was purified by rapid chromatography (silica gel, petroleum ether: ethyl acetate = 10:1) to obtain the target compound (0.45 g). LCMS (ESI) [M+H] + =310.2.

[0217] Step 5: Synthesis of intermediate 45-5

[0218] Triphenylphosphine (0.57 g) and water (3.5 mL) were added to a 7 mL solution of intermediate 45-4 (0.45 g) in ethyl acetate. The reaction mixture was stirred at 70 °C for 4 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to obtain the crude product. The crude product was purified by rapid chromatography (silica gel, dichloromethane:methanol = 20:1) to obtain the target compound (0.34 g). LCMS (ESI) [M+H] + = 284.1.

[0219] Step 6: Synthesis of intermediate 45-6

[0220] Triethylamine (0.32 g) and di-tert-butyl dicarbonate (0.46 g) were added to a solution of intermediate 45-5 (0.30 g) in anhydrous dichloromethane (5 mL). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated to obtain a crude product, which was purified by rapid chromatography (silica gel, petroleum ether: ethyl acetate = 5:1) to obtain the target compound (328 mg). LCMS (ESI) [M+H-56] + = 328.1.

[0221] Step 7: Synthesis of intermediate 45-7

[0222] Under nitrogen protection, 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (38 mg), potassium acetate (102 mg), and pinacol diborate (198 mg) were added sequentially to an anhydrous dioxane (2 mL) solution of intermediate 45-6 (200 mg). The reaction mixture was heated to 100 °C and stirred for 1 hour. The reaction mixture was filtered through a silica gel short column, washed with ethyl acetate (50 mL), and the filtrate was concentrated to obtain the crude product. The crude product was purified by rapid chromatography (silica gel, dichloromethane:methanol = 20:1) to obtain the target compound (145 mg). LCMS (ESI) [M+H] + = 350.3.

[0223] Step 8: Synthesis of Compound 45

[0224] Referring to Example 1, intermediate 11-3 was replaced with intermediate 45-7, and intermediate 11-2 was replaced with intermediate a, yielding the target compound (4 mg). LCMS (ESI) [M+H] + = 559.3; 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.14(s, 2H), 8.83 (d, J = 7.4 Hz, 1H), 8.22 (dd, J = 7.9, 1.6 Hz, 1H), 7.81 –7.57 (m, 2H), 7.42 – 7.27 (m, 3H), 5.08 (d, J = 6.9 Hz, 1H), 5.02 (d, J = 6.6Hz, 1H), 4.42 (p, J = 7.2 Hz, 1H), 3.28 (s, 3H), 3.25-3.22 (m, 1H), 2.39 –2.32 (m, 3H), 2.06 – 1.91 (m, 1H), 1.27-1.18 (m, 2H), 0.51-0.44 (m, 2H),0.44-0.37 (m, 2H).

[0225] Example 4: Preparation of Compound 46

[0226]

[0227] Step 1: Synthesis of intermediate 46-1

[0228] The crude product, prepared from 3-(benzyloxy)-1-cyclobutanone and tert-butylsulfinamide using a synthetic method similar to the first step of Example 1, was purified by rapid chromatography (silica gel, petroleum ether:tetrahydrofuran = 10:1) to obtain the target compound (12 g). LCMS (ESI) [M+H] + =280.1.

[0229] Step 2: Synthesis of intermediate 46-2

[0230] At -78 °C under a nitrogen atmosphere, 7.37 mL of 2.5 M n-butyllithium was slowly added dropwise to 100 mL of dichloromethane containing 5 g of 5-bromo-2-iodopyrimidine. After stirring for 30 minutes, 10 mL of dichloromethane containing 4.9 g of intermediate 46-1 was slowly added. The mixture was then heated to room temperature and stirred for 16 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by rapid chromatography (silica gel, petroleum ether:tetrahydrofuran = 3:1) to give the target compound (1.4 g). LCMS (ESI) [M+H] + =438.0.

[0231] Step 3: Synthesis of intermediate 46-3

[0232] Under a nitrogen atmosphere and in an ice bath, 2 M boron tribromide (5.49 mL) was added to 20 mL of dichloromethane containing intermediate 46-2 (1.2 g), and the mixture was heated to room temperature and stirred for 2 hours. Ethanol (5 mL) was added to the reaction solution, which was then concentrated. The pH was adjusted to 7-8 with 1 M sodium hydroxide. The residue was then subjected to reverse-phase preparation (C18, 0.1% formic acid aqueous solution / acetonitrile) to obtain the target compound (550 mg). LCMS (ESI) [M+H] + =244.0.

[0233] Step 4: Synthesis of intermediate 46-4

[0234] Di-tert-butyl dicarbonate (670.6 mg) was added to intermediate 46-3 (500 mg) and triethylamine (621.84 mg) in 10 mL of 2-methyltetrahydrofuran under ice bath conditions. The reaction mixture was heated to room temperature and stirred for 16 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by rapid chromatography (silica gel, petroleum ether:tetrahydrofuran = 3:1) to give the target compound (240 mg). LCMS (ESI) [M+H] + =344.0.

[0235] Step 5: Synthesis of intermediate 46-5

[0236] Under ice bath conditions, the Dys-Martin oxidant (443.61 mg) was added to intermediate 46-4 (240 mg) in 10 mL of dichloromethane. The reaction mixture was heated to room temperature and stirred for 2 hours. Water (10 mL) was added to the reaction mixture, followed by extraction with 3 x 10 mL dichloromethane solutions. The organic phases were combined, washed with 3 x 10 mL saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by rapid chromatography (silica gel, petroleum ether:tetrahydrofuran = 3:1) to give the target compound (170 mg). LCMS (ESI) [M+H] + =342.0. 1 H NMR (400 MHz, DMSO- d 6) δ 8.99 (s, 2H), 8.03 (s, 1H), 3.70 – 3.61 (m, 2H), 3.48 – 3.39 (m, 2H), 1.38 (s, 9H).

[0237] Step 6: Synthesis of intermediate 46-6

[0238] Tetraisopropyl titanate (98.91 mg) was added to intermediate 46-5 (100 mg) and cyclopropylamine (24.83 mg) in tetrahydrofuran (10 mL), and the reaction mixture was stirred at room temperature for 16 hours. Sodium borohydride (16.46 mg) was added under ice bath conditions, and the mixture was stirred at room temperature for 2 hours. Water (10 mL) was added, the mixture was filtered, and the filtrate was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by rapid chromatography (silica gel, petroleum ether:tetrahydrofuran = 2:1) to give the target compound (50 mg). LCMS (ESI) [M+H] + =383.0.

[0239] Step 7: Synthesis of Compound 46

[0240] Referring to Example 1, intermediate 11-2 was replaced with intermediate 46-6 to obtain the target compound (7.25 mg). LCMS (ESI) [M+H] + =558.3; 1 H NMR (400 MHz, MeOD- d 4) δ 9.18 (d, J = 3.8 Hz, 2H), 8.64 (d, J = 7.4 Hz, 1H), 8.45 (s, 1H), 8.29 (d, J = 8.0 Hz, 1H), 7.82(s, 1H), 7.41 – 7.20 (m, 4H), 5.16 (d, J = 6.6 Hz, 1H), 5.07 (d, J = 6.9 Hz,1H), 4.01 – 3.86 (m, 1H), 3.40 (s, 3H), 3.37 – 3.33 (m, 1H), 3.11 – 3.01 (m,1H), 2.92 – 2.79 (m, 2H), 2.57 – 2.46 (m, 1H), 2.36 – 2.29 (m, 1H), 2.18 (t, J = 7.5 Hz, 1H), 0.64 – 0.56 (m, 2H), 0.56 – 0.41 (m, 2H).

[0241] Example 5: Preparation of Compound 75

[0242]

[0243] Step 1: Synthesis of Intermediate 75-1

[0244] The crude product, prepared from 3-oxocyclobutylneovalerate using the synthetic method in step 2 of Example 1, was purified by rapid chromatography (silica gel, petroleum ether: ethyl acetate = 4:1) to obtain the target compound (560 mg). LCMS (ESI) [M+H] + =329.1.

[0245] Step 2: Synthesis of intermediate 75-2

[0246] Potassium carbonate (1.41 g) was added to a methanol (15 mL) solution of intermediate 75-1 (560 mg), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with water (15 mL), then extracted with dichloromethane (15 mL × 3). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was dried under vacuum to give the target compound (360 mg). LCMS (ESI) [M+H] + =245.1; 1 H NMR (400 MHz, DMSO- d 6) δ 8.98 (s, 2H), 5.65 (s, 1H), 5.10 (s, 1H), 4.06 – 3.93 (m, 1H), 2.88 – 2.78 (m, 2H), 2.26 – 2.17 (m, 2H).

[0247] Step 3: Synthesis of intermediate 75-3

[0248] Cuprous iodide (77.71 mg) was added to a solution of intermediate 75-2 (500 mg) in acetonitrile (12 mL). The reaction mixture was heated to 50 °C, and then 2,2-difluoro-2-(fluorosulfonyl)acetic acid (436.01 mg) was slowly added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was stirred at 50 °C for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (15 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography (silica gel, petroleum ether: ethyl acetate = 2:1) to give the target compound (240 mg). LCMS (ESI) [M+H] + =295.0.1 HNMR (400 MHz, DMSO- d 6) δ 9.07 – 8.98 (m, 2H), 6.70 – 6.48 (m, 1H), 6.00 (s,1H), 4.61 – 4.51 (m, 1H), 3.00 – 2.90 (m, 2H), 2.48 – 2.41 (m, 2H).

[0249] Step 4: Synthesis of intermediate 75-4

[0250] At 0 °C, 60% sodium hydroxide (86.76 mg) was slowly added to a tetrahydrofuran (15 mL) solution of intermediate 75-3 (320 mg). The reaction mixture was stirred at 0 °C for 30 minutes, followed by the addition of p-toluenesulfonyl chloride (310.13 mg). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was quenched with saturated ammonium chloride solution (15.0 mL), then extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried, and concentrated. The residue was purified by rapid chromatography (silica gel, petroleum ether: ethyl acetate = 4:1) to give the target compound (380 mg). LCMS (ESI) [M+H] + =449.0.

[0251] Step 5: Synthesis of intermediate 75-5

[0252] To intermediate 75-4 (380 mg) N,N Sodium azide (164.96 mg) was added to a 10 mL solution of dimethylformamide. The reaction mixture was heated to 80 °C and stirred for 3 hours. After cooling to room temperature, the mixture was diluted with 15 mL of water and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with water (30 mL × 2) and saturated sodium chloride solution (30 mL × 2), respectively. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound (270 mg). LCMS (ESI) [M+H] + =320.1.

[0253] Step 6: Synthesis of intermediate 75-6

[0254] Triphenylphosphine (330.48 mg) was added to a mixed solution of intermediate 75-5 (270 mg) in ethyl acetate (5 mL) and water (5 mL). The reaction mixture was heated to 70 °C and stirred for 4 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by reverse-phase preparative separation (C18, 0.1% formic acid aqueous solution / acetonitrile) to give the target compound (120 mg). LCMS (ESI) [M+H] + =294.1; 1 H NMR (400 MHz, DMSO- d 6) δ 9.01 (s, 2H), 6.68 (t, J = 75.8 Hz, 1H), 4.98 – 4.89 (m, 1H), 2.71 – 2.61 (m, 2H), 2.48 – 2.40 (m, 2H).

[0255] Step 7: Synthesis of Compound 75

[0256] Referring to Example 1, intermediate 11-2 was replaced with intermediate 75-6 to obtain the crude product, which was then purified by reverse-phase preparative separation (C-18, 0.1% NH2HCO3 in H2O / acetonitrile) to obtain the target compound (5.5 mg). LCMS (ESI) [M+H] + =569.1; 1 H NMR (400 MHz, DMSO- d 6) δ 9.15 (s, 2H), 8.84 (d, J = 7.4 Hz, 1H), 8.22 (dd, J = 7.9, 1.4 Hz, 1H), 7.80 – 7.53 (m, 2H), 7.41 – 7.33 (m, 2H), 7.32 – 7.29 (m, 1H), 6.69 (t, J = 76.0 Hz, 1H), 5.08 (d, J = 6.9 Hz, 1H), 5.02 (d, J = 6.6 Hz, 1H), 5.00 – 4.91 (m, 1H), 3.31 – 3.29 (m, 1H), 3.28 (s,3H), 2.73 – 2.67 (m, 2H), 2.54 – 2.53 (m, 1H), 2.47 – 2.40 (m, 2H).

[0257] Example 6: Preparation of Compound 76

[0258]

[0259] Step 1: Synthesis of intermediate 76-1

[0260] The target compound (1.5 g) was prepared from 3-(tert-butyl)cyclobutane-1-one using a synthetic method similar to the first step of Example 1. LCMS (ESI) [M+H] + =230.3; 1 H NMR (400 MHz, CDCl3) δ 3.48 –2.80 (m, 4H), 2.42 – 2.30 (m, 1H), 1.24 (s, 9H), 0.90 (d, J = 2.3 Hz, 9H).

[0261] Step 2: Synthesis of intermediate 76-2

[0262] The target compound (500 mg) was prepared from intermediate 76-1 using a synthetic method similar to step two of Example 1. LCMS (ESI) [M+H] + =388.1.

[0263] Step 3: Synthesis of intermediate 76-3

[0264] Intermediate 76-2 (500 mg) was dissolved in ethyl acetate (8 mL), and 4 M dioxane hydrochloride solution (4 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to give the crude product (500 mg). LCMS (ESI) [M+H] + =283.9.

[0265] Step 4: Synthesis of intermediate 76-4

[0266] Intermediate 76-3 (400 mg) was dissolved in 2-methyltetrahydrofuran (5 mL), and triethylamine (0.26 mL) and di-tert-butyl dicarbonate (0.21 mL) were added at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated, and the crude product was purified by rapid column chromatography (silica gel, petroleum ether: ethyl acetate = 5:1) to give the target compound (200 mg). LCMS (ESI) [M+H] + =384.0; 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 2H), 5.35 (s,1H), 2.66 – 2.56 (m, 2H), 2.37 – 2.25 (m, 1H), 2.22 – 2.10 (m, 2H), 1.36 (s,9H), 0.86 (s, 9H).

[0267] Step 5: Synthesis of intermediate 76-5

[0268] Intermediate 76-4 (100 mg) and pinacol diboronate (132.05 mg) were dissolved in dioxane (4 mL), followed by the addition of potassium acetate (76.55 mg) and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (19.02 mg). The reaction mixture was heated to 90 °C and stirred for 16 hours under nitrogen protection. The reaction mixture was filtered, and the filtrate was concentrated and purified by reverse-phase separation (C18, acetonitrile / 0.1% formic acid aqueous solution = 70%) to obtain the target compound (60 mg). LCMS (ESI) [M+H] + =350.2.

[0269] Step 6: Synthesis of Compound 76

[0270] Referring to Example 1, intermediate 11-3 was replaced with intermediate 76-5, and intermediate 11-2 was replaced with intermediate a, yielding the target compound (27.29 mg). LCMS (ESI) [M+H] + =559.2; 1 H NMR (400 MHz, MeOD- d 4 ) δ9.18 (s, 2H), 8.65 (d, J = 7.4 Hz, 1H), 8.30 (dd, J = 8.1, 1.3 Hz, 1H), 7.84(d, J = 1.2 Hz, 1H), 7.42 – 7.02 (m, 4H), 5.17 (d, J = 6.6 Hz, 1H), 5.07 (d,J = 6.9 Hz, 1H), 3.40 (s, 3H), 3.39 – 3.33 (m, 1H), 2.77 – 2.68 (m, 1H), 2.66– 2.55 (m, 3H), 2.44 – 2.26 (m, 2H), 0.94 (s, 9H).

[0271] Example 7: Preparation of Compound 77

[0272]

[0273] Step 1: Synthesis of Intermediate 77-1

[0274] At room temperature, bicyclo[1.1.1]pentane-1-carboxylic acid (3.36 g) and dimethylhydroxylamine hydrochloride (4.38 g) were dissolved in... N,N - Dimethylformamide (30 mL), followed by 2-(7-azobenzotriazole)- N,N,N',N' -Tetramethylurea hexafluorophosphate (22.79 g) and N,N - Diisopropylethylamine (11.62 g); the reaction mixture was stirred at 25 °C for 3 hours. Water (200 mL) and ethyl acetate (200 mL) were added to the reaction mixture, and the mixture was extracted and separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to obtain the target compound (2.2 g). LCMS (ESI) [M+H] + =156.11.

[0275] Step 2: Synthesis of intermediate 77-2

[0276] 4.04 g of 5-bromo-2-iodopyrimidine was dissolved in 50 mL of dichloromethane. Under nitrogen protection, 9.3 mL of n-butyllithium (in 1.6 M n-hexane) was added, and the mixture was stirred at -78 °C for 1 hour. 2.2 g of intermediate 77-1 was added to the reaction mixture, and the mixture was slowly brought to room temperature with continued stirring for 16 hours. 2 mL of saturated ammonium chloride solution, 100 mL of water, and 100 mL of dichloromethane were added sequentially to the reaction mixture. The mixture was extracted and separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then separated by rapid chromatography (silica gel, petroleum ether: ethyl acetate = 10:1) to obtain the target compound (0.75 g). LCMS (ESI) [M+H] + =253.03.

[0277] Step 3: Synthesis of intermediate 77-3

[0278] Intermediate 77-2 (300 mg) was dissolved in ethanol (10 mL). Ammonium chloride (126.8 mg), tetraisopropyl titanate (673.77 mg), and triethylamine (239.88 mg) were added sequentially to the reaction solution. The reaction solution was stirred at 25 °C for 6 hours. Sodium borohydride (67.26 mg) was added to the reaction solution, and stirring continued for 16 hours. A saturated sodium chloride solution (2 mL), water (60 mL), and dichloromethane (60 mL) were added sequentially to the reaction solution. The mixture was extracted and separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by rapid chromatography (silica gel, dichloromethane:methanol = 20:1) to obtain the target compound (90 mg). LCMS (ESI) [M+H] + =254.07.

[0279] Step 4: Synthesis of intermediate 77-4

[0280] Intermediate 77-3 (240 mg) was dissolved in dichloromethane (5 mL), and triethylamine (286.69 mg), di-tert-butyl dicarbonate (247.34 mg), and 4-dimethylaminopyridine (11.54 mg) were added under ice bath conditions. The reaction mixture was heated to room temperature and stirred for 2 hours. Water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by rapid chromatography (silica gel, petroleum:tetrahydrofuran = 10:1) to give the target compound (130 mg). LCMS (ESI) [M+H] + =354.1.

[0281] Step 5: Synthesis of intermediate 77-5

[0282] Under a nitrogen atmosphere, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (20.66 mg) was added to intermediate 77-4 (100 mg), pinacol diboronate (107.53 mg), and potassium acetate (83.11 mg) in 1,4-dioxane (5 mL). The reaction mixture was heated to 90 °C and stirred for 16 hours. The mixture was filtered, the filtrate was concentrated, and the residue was purified by reverse preparative separation (C18, 0.1% NH3·H2O in H2O / acetonitrile) to give the target compound (50 mg). LCMS (ESI) [M+H] + =320.1.

[0283] Step 6: Synthesis of Compound 77

[0284] Referring to Example 1, intermediate 11-3 was replaced with intermediate 77-5, and intermediate 11-2 was replaced with intermediate a, yielding the target compound (42.19 mg). LCMS (ESI) [M+H] + =529.2. 1 H NMR (400 MHz, MeOD- d 4) δ 9.13 (s, 2H), 8.63 (d, J = 7.4 Hz, 1H), 8.29 (dd, J = 8.1, 1.3 Hz, 1H), 7.82(s, 1H), 7.42 – 7.05 (m, 4H), 5.16 (d, J = 6.6 Hz, 1H), 5.07 (d, J = 6.9 Hz,1H), 4.44 (s, 1H), 3.40 (s, 3H), 3.39 – 3.33 (m, 1H), 2.62 (d, J = 13.5 Hz,1H), 2.54 (s, 1H), 1.81 (s, 6H).

[0285] Example 8: Preparation of Compound 78

[0286]

[0287] Step 1: Synthesis of intermediate 78-1

[0288] In a sealed container, 600 mg of 33-(5-bromopyrimidin-2-yl)azacyclobutane-3-ol, 727.37 mg of 1-ethoxy-1-trimethoxycyclopropane, 0.75 mL of acetic acid, and 300 mg of 4A molecular sieve were dissolved in 10 mL of methanol. The reaction mixture was heated to 80 °C and stirred for 2 hours under nitrogen protection, then cooled to room temperature. Sodium cyanoborohydride (429.41 mg) was added, and the mixture was then heated to 40 °C and stirred for 3 hours. The reaction mixture was concentrated, diluted with 35 mL of saturated sodium bicarbonate aqueous solution, and extracted with dichloromethane (16 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was purified by reverse-phase chromatography (0.1% ammonia aqueous solution / acetonitrile) to obtain the target compound (180 mg). LCMS (ESI) [M+H] + =270.0.

[0289] Step 2: Synthesis of intermediate 78-2

[0290] Intermediate 78-1 (300 mg) was dissolved in tetrahydrofuran (5 mL). Under nitrogen protection and in an ice bath, 60% sodium hydride (88.85 mg) was added. After stirring for 10 minutes, methanesulfonyl chloride (0.26 mL) was added, and stirring was continued at 0 °C for 1 hour. The reaction solution was concentrated to give the target compound (380 mg). LCMS (ESI) [M+H] + =348.0

[0291] Step 3: Synthesis of intermediate 78-3

[0292] Intermediate 78-2 (380 mg) was dissolved in N,N-dimethylformamide (5 mL), and sodium azide (354.72 mg) was added. The mixture was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (12 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by rapid chromatography (silica gel, petroleum ether:ethyl acetate = 4:1) to obtain the target compound (180 mg). LCMS (ESI) [M+H] + =295.0.

[0293] Step 4: Synthesis of intermediate 78-4

[0294] Intermediate 78-3 (180 mg) was dissolved in ethyl acetate (2 mL) and water (1 mL), and triphenylphosphine (239.95 mg) was added. The mixture was stirred at 70 °C for 2 hours. The reaction solution was concentrated and purified by reverse-phase chromatography (0.1% ammonia aqueous solution / acetonitrile) to obtain the target compound (150 mg). LCMS (ESI) [M+H] + =269.1

[0295] Step 5: Synthesis of Compound 78

[0296] Referring to Example 1, intermediate 11-2 was replaced with intermediate 78-4 to obtain the target compound (9.73 mg). LCMS (ESI) [M+H] + =544.2; 1 H NMR (400 MHz, DMSO- d 6) δ 9.14 (s, 2H), 8.84 (d, J = 7.5 Hz, 1H), 8.21 (dd, J= 7.9, 1.5 Hz, 1H), 7.78 – 7.57 (m, 2H), 7.40 –7.33 (m, 2H), 7.32 – 7.29 (m, 1H), 5.08 (d, J = 6.9 Hz, 1H), 5.02 (d, J = 6.6Hz, 1H), 3.87 (d, J = 7.3 Hz, 2H), 3.30 – 3.27 (m, 7H), 1.99 – 1.94 (m, 1H), 0.35 – 0.30 (m, 2H), 0.23 – 0.19 (m, 2H).

[0297] Example 9: Preparation of compound 79:

[0298]

[0299] Step 1: Synthesis of intermediate 79-1

[0300] 5-Bromo-2-chloro-4-methoxypyrimidine (10 g) was dissolved in hydroiodic acid (100 mL, 47% inH2O) at room temperature, and the reaction mixture was stirred at 40 °C for 40 hours. An aqueous solution (30 mL) was added, the pH was adjusted to 9 with sodium bicarbonate, and the mixture was extracted three times with ethyl acetate (80 mL). The combined organic phases were backwashed with an aqueous sodium thiosulfate solution and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product was purified by rapid column chromatography (silica gel, petroleum ether:tetrahydrofuran = 10:1) to give the target compound (2 g). LCMS (ESI) [M+H] + =314.8.

[0301] Step 2: Synthesis of intermediate 79-2

[0302] At room temperature, intermediate 79-1 (9 g) was dissolved in diethyl ether (150 mL), and n-butyllithium (11.44 mL) (2.5 min n-hexane) was added under nitrogen protection at -78 °C. The mixture was stirred at -78 °C for 0.5 hours. N5.94 g of cyclobutylmethylene-2-propane-2-sulfinamide was dissolved in tetrahydrofuran and added at -78 °C. The reaction mixture was stirred at -78 °C under nitrogen protection for 2 hours. 100 mL of ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted three times with 100 mL of ethyl acetate. The combined organic phases were backwashed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product was purified by rapid column chromatography (silica gel, petroleum ether:tetrahydrofuran = 1:1) to give the target compound (5 g). LCMS (ESI) [M+H] + =362.1.

[0303] Step 3: Synthesis of intermediate 79-3

[0304] Intermediate 79-2 (2.5 g) was dissolved in hydrobromic acid (40 mL, 33% in acetic acid) at room temperature, and the reaction was stirred at 90 °C for 2 hours. The solution was directly concentrated, and triethylamine was added to adjust the pH to 8 to give the target compound (1.6 g). LCMS (ESI) [M+H] + =244.0.

[0305] Step 4: Synthesis of intermediate 79-4

[0306] Intermediate 79-3 was dissolved in tetrahydrofuran (10 mL) at room temperature. Triethylamine was added to adjust the pH to 8, followed by the addition of triethylamine (6.63 g) and di-tert-butyl dicarbonate (2.15 g) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was then added to an aqueous solution (20 mL) and extracted three times with ethyl acetate (20 mL). The combined organic phases were backwashed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product was purified by rapid column chromatography (silica gel, petroleum ether:tetrahydrofuran = 1:1) to give the target compound (1.8 g). LCMS (ESI) [M+H] + =344.1.

[0307] Step 5: Synthesis of intermediate 79-5

[0308] Intermediate 79-4 (2 g) was dissolved in methanol (30 mL) at room temperature. Potassium carbonate (1.61 g) and iodomethane (8.25 g) were added at room temperature, and the reaction mixture was stirred at 70 °C for 16 hours. After concentration, an aqueous solution (30 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were backwashed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by rapid column chromatography (silica gel, petroleum ether:tetrahydrofuran = 2:1) to give the target compound (380 mg). LCMS (ESI) [M+H] + =358.0.

[0309] Step 6: Synthesis of Compound 79

[0310] Referring to Example 1, intermediate 11-2 was replaced with intermediate 79-5 to obtain the target compound (5 mg). LCMS (ESI) [M+H] + =533.2; 1 H NMR (400 MHz, MeOD- d 4) δ 8.47 (d, J = 7.4 Hz, 1H), 8.28 (d, J = 7.2 Hz, 1H), 8.18 (s, 1H), 7.93 (s, 1H), 7.36 – 7.33 (m, 1H),7.28 (t, J = 8.1 Hz, 1H), 7.17 – 6.93 (m, 2H), 5.12 (d, J = 6.7 Hz, 1H), 5.02(d, J = 6.9 Hz, 1H), 3.61 (s, 3H), 3.39 (s, 3H), 3.35 – 3.31 (m, 1H), 2.95 –2.82 (m, 2H), 2.58 (d, J = 13.4 Hz, 1H), 2.24 – 2.11 (m, 3H), 1.82 – 1.72 (m,1H).

[0311] Example 10: Preparation of compound 80:

[0312]

[0313] Referring to Example 1, intermediate 11-2 was replaced with starting material 80-1 (synthetic method referred to WO2023146512A1, compound 28D), yielding the target compound (14.75 mg). LCMS (ESI) [M+H] + =499.1; 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.11 (s, 2H), 8.84 (d, J = 7.4 Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H),7.77 – 7.27 (m, 5H), 5.08 (d, J = 6.9 Hz, 1H), 5.02 (d, J = 6.6 Hz, 1H), 3.30– 3.25 (m, 4H), 2.54 – 2.52 (m, 1H), 2.00 – 1.91 (m, 2H), 1.87 – 1.79 (m, 2H).

[0314] Example 11: Preparation of Compound 81

[0315]

[0316] Step 1: Synthesis of Compound 81

[0317] Referring to Example 1, only intermediate 11-2 was replaced with tert-butyl (1-(5-bromopyrimidin-2-yl)-3-methylenecyclobutyl)carbamate (synthesis reference WO2025247401A1, intermediate 14 g), to prepare the target compound (11 mg). LCMS (ESI) [M+H] + = 515.3; 1 H NMR (400 MHz, DMSO- d 6) δ = 9.14 (s, 2H), 8.83 (d,J = 7.4 Hz, 1H), 8.22 (dd, J = 8.0, 1.5 Hz, 1H), 7.81 – 7.25 (m, 5H), 5.08(d, J = 6.9 Hz, 1H), 5.02 (d, J = 6.6 Hz, 1H), 4.88 (t, J = 2.4 Hz, 2H), 3.29-3.23 (m, 4H), 2.85-2.74 (m, 2H), 2.69-2.56 (m, 2H), 2.55-2.51 (m, 1H).

[0318] Referring to the above examples, the following compounds were prepared:

[0319]

[0320]

[0321]

[0322]

[0323] Control compound 1 (WO2018197503A1, compound of Example 6):

[0324]

[0325] Control compound 2 (WO2025038927A1·Ex.15 compound):

[0326] .

[0327] Biological test cases

[0328] Test Example 1: Detection of TNF Prevalence in Human Whole Blood by Compounds

[0329] I. Experimental Objective

[0330] The effect of the compound on the binding of TNFα protein in induced human whole blood was detected.

[0331] II. Reagents, Materials and Instruments

[0332]

[0333]

[0334] III. Procedure for Whole Blood Stimulation Test

[0335] 1. In a 96-well plate, add serially diluted compounds (5 μL per well, duplicates) to wells in columns 1-10. The maximum concentration is 200 μM (20X), serially diluted 3-fold with PBS to achieve a final concentration of 0.5 nM–10 μM. Add 5 μL of DMSO to wells in column 11 as a control.

[0336] 2. Take freshly collected heparin sodium anticoagulated whole blood from healthy individuals and add 90 μL to each well of the 96-well plate.

[0337] 3. Incubate whole blood and the compound in a 37°C incubator for 1 hour.

[0338] 4. Then add 5 μL of 3 EU / mL LPS to each well (final reaction concentration is 0.15 EU / mL) and incubate at 37°C for 4 hours.

[0339] 5. After incubation, add 200 μL of pre-chilled PBS (on ice) to each well to terminate the reaction.

[0340] Collect plasma by centrifugation at 6.2250g for 5 minutes.

[0341] 7. Divide the plasma sample into two parts. One part is used for the detection of TNF binding compounds. The other part is incubated with 10 μMUCB-9260 at 37℃ for 1 hour to obtain the total TNF sample. Store the sample at -80℃.

[0342] IV. CA1974 Test Procedure

[0343] 1. Following the instructions, label the CA1974 antibody with biotin using the Biotin Conjugation Kit (Thermo, 21435). Following the instructions, label the ab9348 antibody with SULFO-TAG using the SULFO-TAG Conjugation Kit (MSD, R91AO-1).

[0344] 2. Antibody coating: Dilute the biotin-labeled CA1974 antibody to 1 μg / ml with 1% BSA / PBS, add 25 μL to each well of an MSD GOLD 96-well streptavidin plate, and incubate with shaking at room temperature for 1 hour.

[0345] 3. Preparation of standards: Recombinant human TNF pre-incubated with an excess of inhibitor was prepared using IgM Reducing Assay Diluent (BUF038) and 5% blank matrix (plasma from 10 healthy donors) as a standard curve sample.

[0346] 4. Sample preparation: Dilute the compound-bound sample and the total TNF sample at least 2-fold using IgM Reducing Assay Diluent.

[0347] 5. Wash the plate three times with PBS + 0.05% Tween 20.

[0348] 6. Load the standards and samples into the MSD plate, 50 μL per well, and incubate with shaking at room temperature for 1 hour.

[0349] 7. Wash the plate three times with PBS + 0.05% Tween 20.

[0350] 8. Incubation: Dilute the detection antibody (Sulfo-TAG labeled ab9348) to 0.3 μg / ml with BD OptEIA Assay Diluent, add 25 μL to each well, and incubate with shaking at room temperature for 1 hour.

[0351] 9. Wash the plate three times with PBS + 0.05% Tween 20.

[0352] 10. Dilute MSD Read Buffer T (4X) twice to 2X with ultrapure water, 150 μL of MSD Read Buffer T per well, and immediately read the results using MESO® QuickPlex SQ120.

[0353] V. Results Processing

[0354] 1. Construction of standard curve: Plot the standard curve with the logarithm of the concentration of each standard as the horizontal axis and the logarithm of the reading (after subtracting the zero-point sample background value) as the vertical axis. Perform linear regression analysis to fit the standard curve and equation.

[0355] 2. Calculation of results for unknown samples: Interpolate the detection readings of unknown samples according to the standard curve equation to calculate the concentration. Multiply by the dilution factor to obtain the TNFα concentration bound to the compound in the unknown sample.

[0356] 3. Calculate the TNFα occupancy rate in each sample using the following formula:

[0357] Occupancy % = Inhibitor-bound TNFα concentration / (TNFα concentration in the saturated sample of the compound (total TNFα concentration)) × 100.

[0358] 4. Use software to generate compound concentration-occupancy curves to determine the factors leading to a 50% occupancy rate (OCC). 50 The concentration of the compound.

[0359] The compounds of the present invention have good activity in regulating TNF, and the activity data of exemplary compounds are shown in the table below.

[0360] Table 1. Results of the assay for TNF occupancy of the compounds in human whole blood.

[0361]

[0362] Note: +: OCC 50 (nM)<500nM.

[0363] Test Example 2: TNF L929 Cytotoxicity Assay

[0364] I. Experimental Objective

[0365] The inhibitory effect of the compound on TNFα-induced L929 cell cytotoxicity was investigated.

[0366] II. Reagents

[0367]

[0368] III. Experimental Procedure

[0369] 1. L929 cell preparation:

[0370] Cells were cultured in DMEM medium containing 10% fetal bovine serum at 37°C with 5% CO2 until 80% confluence, and then set aside for use.

[0371] 2. Cell inoculation:

[0372] Cells were digested with trypsin, centrifuged at 1000 rpm for 4 min, the supernatant was removed, and the cells were resuspended in DMEM medium containing 10% fetal bovine serum to adjust the cell density to 12.5 × 10⁶ cells / min. 4 Cells / mL: 80 μL of the cell suspension was seeded into 96-well plates to obtain a final cell density of 10,000 cells / well. An additional 10 μL of DMEM medium containing 10% fetal bovine serum was added, and the cells were incubated overnight in a 5% CO2 incubator at 37°C.

[0373] 3. Add the test sample:

[0374] 1) Preparation of test solution:

[0375] The test sample was dissolved in DMSO to prepare a 10 mM stock solution (the concentration of control compound 1 was 1 mM). The stock solution was then serially diluted three times with DMSO to obtain a series of solutions of different concentrations for later use.

[0376] Add 10% fetal bovine serum, 500 pg / mL recombinant human TNF, 10 μg / mL Actinomycin D, and 1% of the volume of the above-prepared test solutions of different concentrations to DMEM medium, mix well to prepare a 10X working solution.

[0377] Add 10 μL of the above 10X working solution to each well of the cells incubated overnight, resulting in the following final concentrations of the compounds: 10,000 nM, 3333.33 nM, 1111.11 nM, 370.37 nM, 123.46 nM, 41.15 nM, 13.72 nM, 4.57 nM, and 1.52 nM. The final concentration of control compound 1 was 0.15 nM–1,000 nM.

[0378] 2) Setting of reference holes:

[0379] Positive control: Cells were inoculated only in a medium containing 10% fetal bovine serum and 10 μg / mL Actinomycin D, without the addition of the compound.

[0380] Negative control: Cells were seeded only in a medium containing 10% fetal bovine serum, 500 pg / mL recombinant human TNF and 10 μg / mL Actinomycin D, without the addition of any compounds.

[0381] 3) Incubate this 96-well plate in an incubator with 5% CO2 and 37°C for 18 hours.

[0382] 4. CTG detection method:

[0383] 1) Add an equal volume (100 μL) of CellTiter-Glo® reagent to each well of cell culture medium, and shake in the dark for 2 minutes to induce cell lysis.

[0384] 2) Incubate the plate at room temperature for 10 minutes to stabilize the luminescence signal.

[0385] 3) Read the results using the ELISA reader in Luminescence mode.

[0386] 5. Results Processing

[0387] IC 50 Calculate: TNF killing inhibition rate (%) = (OD compound - OD minimum) / (OD maximum - OD minimum) × 100. Perform curve fitting to obtain IC50. 50 value.

[0388] Maximum OD value: positive control; Minimum OD value: negative control.

[0389] The inhibitory effects of the compounds of the present invention on TNFα-induced L929 cytotoxicity are shown in the table below, with activity data of exemplary compounds.

[0390] Table 2 Results of TNF L929 Cytotoxicity Assay

[0391]

[0392] Note: A + IC 50 (nM)≤1nM;A:1nM <IC 50 (nM) ≤5nM; B: 5nM <IC 50 (nM) <100nM.

[0393] Test Example 3: Testing the expression of CD11b in human whole blood after compound treatment

[0394] I. In vitro potency test:

[0395] The in vitro potency of the compound was determined by detecting the expression of CD11b on zymosan-activated granulocytes in human whole blood.

[0396] II. Experimental Materials:

[0397] 2.1 Reagents

[0398]

[0399] 2.2 Compound Preparation

[0400]

[0401] III. Experimental Procedure:

[0402] 3.1 Human Whole Blood (HWB) Preparation

[0403] Venous blood is drawn directly from the donor into test tubes containing EDTA anticoagulant. The tubes are placed in a 4°C freezer, with the temperature monitored throughout the process. The blood is then transported from the hospital to Pharmaron via a dedicated vehicle. Upon receipt, it is temporarily stored at 4°C.

[0404] 3.2 Compound Preparation

[0405] Add 8 µL of DMSO to columns 2 through 8 of the new 384-LDV plate.

[0406] Transfer 12 µL of 10 mM stock solution to column 1 of a 384-LDV plate.

[0407] Compound stock solutions were prepared by 3-fold dilution in 384-LDV plates to achieve 8 concentration gradients.

[0408] Briefly centrifuge the LDV source plate.

[0409] The compound was transferred from the source plate to a 96-well cell culture plate (Corning, 3799) using an Echo 655, with DMSO as a positive control and DMSO without the irritant as a negative control.

[0410] 3.3 Whole blood sample preparation

[0411] Invert the test tube gently 7-8 times to mix the fresh whole blood thoroughly. Then add 90 µL of fresh whole blood to the 96-well plate, mix gently, and incubate at 37°C and 5% CO2 for 1 hour.

[0412] Add 10 µL of 10 µg / mL Zymosan (final concentration 1 µg / mL) to each well, mix gently, and incubate at 37°C and 5% CO2 for 3 hours. The final concentration of the compound will be diluted 1000-fold.

[0413] Add 10 µL of antibody to each well and incubate the stained whole blood at 4°C for 30 minutes.

[0414] Dilute BD Phosflow™ lysis / fixation buffer (5×) with distilled water at a ratio of 1:5 (at room temperature), and then preheat the solution to 37°C. Prepare a fresh working solution for each experiment.

[0415] Add 1 mL of 1×BD Phosflow™ lysis / fixation buffer to each well of the deep well plate using a 1200 µL pipette. Transfer the blood to the preheated solution, mix well, and incubate in a 37°C water bath for 15 minutes.

[0416] Centrifuge at 1200g / min for 5 minutes and discard the supernatant.

[0417] Add 1 mL of PBS to each well, centrifuge at 1200 g / min for 5 minutes, and discard the supernatant.

[0418] Resuspend the cells in 100 µL of cell staining buffer and store the plate at 4°C overnight.

[0419] Data were acquired on a CytoFLEX S flow cytometer.

[0420] IV. Data Processing:

[0421] 4.1 Data Quality Control (QC): Calculate the Z' value to assess the quality of experimental data.

[0422] .

[0423] STDEV Positive / Negative Control: Standard deviation of the means of the positive and negative controls

[0424] AVG positive / negative control: Mean values ​​of positive and negative controls

[0425] 4.2 Calculation Description: IC 50 or EC 50

[0426] x 100

[0427] 4.3 Curve Fitting: Four-parameter logistic curve fitting was used.

[0428]

[0429] The compounds of the present invention have an inhibitory effect on the expression of CD11b on granulocytes in human whole blood. The activity data of exemplary compounds are shown in the table below.

[0430] Table 3. Expression of CD11b in whole blood of test subjects after compound treatment

[0431]

[0432] Note: A: IC 50 (nM) <100nM.

[0433] Test Example 4: Determination of the effect of the compound of the present invention on TNF-induced NF-κB phosphorylation in HEK293 cells

[0434] I. Experimental Principle:

[0435] HEK-Blue™ TNFα cells are reporter cell lines that stably integrate the TNF-α receptor (TNFR1 / TNFR2 complex gene) and the NF-κB / AP-1 signaling pathway into the human embryonic kidney HEK293 cell line, regulating secretory embryonic alkaline phosphatase (SEAP). This enables dynamic monitoring of the TNF-α signaling pathway. When TNF-α binds to its receptor, it activates the downstream NF-κB / AP-1 transcriptional pathway and induces SEAP expression. The activation level of the TNF-α pathway can be accurately reflected by rapidly quantifying SEAP activity in the culture supernatant using QUANTI-Blue™ chromogenic reagent.

[0436] II. Experimental Materials:

[0437] 2.1 Reagents

[0438]

[0439] 2.2 Compound Preparation

[0440]

[0441] III. Experimental Procedure:

[0442] 3.1 HEK-Blue TM TNF-α cell preparation:

[0443] Resuscitate the cells and resuspend them in growth medium: (DMEM, 10% FBS, 100 U / mL Pen-Strep, 100 µg / mL Normocin). Incubate the cells at 37°C in a 5% CO2 incubator until they reach 70-80% confluence.

[0444] Wash cells twice with preheated PBS, centrifuge at 150 xg for 10 minutes, and collect cells.

[0445] Cells were resuspended in assay medium (DMEM, 10% FBS, 100 U / mL Pen-Strep).

[0446] Add 90 μL of HEK-Blue™ TNFα cell suspension to each well of a 96-well plate, at a cell density of 20,000 cells / well. Incubate overnight at 37°C in a 5% CO2 incubator.

[0447] 3.2 Preparation of compound solutions:

[0448] Add 20 µL of DMSO to columns 2 through 10 of the 96-well plate.

[0449] Transfer 50 µL of 1 mM stock solution to column 1 of a 96-well plate.

[0450] Take 10 μL from the first column and add it to the second column. Then, perform 3-fold serial dilutions downwards in a 96-well plate to prepare compound stock solutions with nine concentration gradients. The tenth column, which does not contain DMSO, serves as a 0-concentration positive control.

[0451] Take a new 96-well plate and add 147 μL of DMEM to columns 1 to 10. Transfer 3 μL of the above compound stock solution to the corresponding wells of the plate and mix well. Obtain a 50-fold diluted compound stock solution.

[0452] 3.3 Sample addition process:

[0453] Take 50 μL of the diluted compound stock solution and incubate it with 50 μL of 1,000 pg / mL TNF-α at 37°C for 1 hour.

[0454] 50 μL of 400 ng / mL Adalimumab and 50 μL of 1,000 pg / mL TNF-α were co-incubated at 37℃ for 1 hour as a negative control.

[0455] Add 10 µL of co-incubated TNF-α solution (final concentration 50 pg / mL) to each well of HEK-Blue™ TNFα cells, mix, and incubate at 37°C and 5% CO2 for 18 hours.

[0456] 3.4 SEAP activity assay:

[0457] Transfer 20 µL / well of cell culture supernatant to a new 96-well plate.

[0458] Add 180 µL of QUANTI-Blue™ solution to each well and incubate at 37°C for 1 hour.

[0459] SEAP levels were detected by reading the OD value at 620 nM using an ELISA reader.

[0460] IV. Data Processing:

[0461] 4.1 Data Quality Control (QC): Calculate the Z' value to assess the quality of experimental data.

[0462] .

[0463] STDEV PC / NC Standard deviation of the means of positive control (PC) and negative control (NC)

[0464] AVG PC / NC Mean values ​​of positive control (PC) and negative control (NC)

[0465] 4.2 Calculation Description: IC 50 or EC 50 :

[0466]

[0467] 4.3 Curve Fitting: Curve fitting was performed using software (Model 205):

[0468]

[0469] The compounds of this invention showed strong inhibitory effects on TNF-induced NF-κB phosphorylation levels in HEK293 cells in experiments. Activity data for exemplary compounds are shown in the table below.

[0470] Table 4. Determination of the effect of compounds on TNF-induced NF-κB phosphorylation in HEK293 cells.

[0471]

[0472] Note: A: IC 50 (nM)<100nM.

[0473] Test Example 5: Measurement of Cardiac Cell Inhibition Using a Multi-Electrode Array (MEA)

[0474] I. Experimental Principle

[0475] The MEA study was designed to evaluate the in vitro inhibitory effect of compounds on extracellular field potential (EFP) in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) using the Maestro Pro multielectrode array system. Concentration-response relationships (double replicates) of each test substance at two concentrations were determined, the potential risk of early afterdepolarization (EAD) was assessed, and the percentage change in EFP signal parameters (amplitude / field potential duration / beating cycle, etc.) was calculated.

[0476] II. Experimental Procedure

[0477] HiPSC-CM cells (purchased from Cauliscell™) were seeded at 10,000-20,000 cells / well in fibronectin-coated CytoView MEA 96-White plates. On the second day, two-thirds of the plate-forming medium volume was removed and replaced with maintenance medium. Half of the maintenance medium was removed and replaced every two days. Field potential monitoring was performed starting on day 6 post-coating. Once uniform and coordinated cell beating was confirmed, the medium was completely replaced. On this day, the cells were treated with a compound for 1 hour, and MEA monitoring (37℃ / 5% CO2 environment) was performed. Raw data were recorded using the Cardiac Beat Detector / Field Potential module, and mean field potential waveforms were generated by recording 30-second stable EFP.

[0478] The following criteria are used to determine data acceptability:

[0479] 1) The stable initial peak amplitude should be >300uV;

[0480] 2) hiPSC-CM should have a stable rhythm within an initial sampling interval of 20 s, with a beat frequency of 40-90 BPM.

[0481] Data that meets the EFP record quality standards outlined above will be further analyzed as follows:

[0482] Three parameters were selected upwards to describe the effect of the drug on the field potential of cardiomyocytes in different dimensions:

[0483] SA: Peak amplitude.

[0484] BP: Pulse cycle

[0485] FPD: Duration of Field Potential

[0486] FPDc = FPD ÷ 3√BP

[0487] III. Results Processing

[0488] Extract the peak current from the raw data. Calculate the percentage change in amplitude relative to the baseline using the following equation.

[0489] Change in %EFP parameter = (baseline - compound) × 100 / baseline

[0490] %Standardized treatment = 100% × [1 - (%Change in blank control / %Change in treatment group)]

[0491] Use two key readings from the MEA assay to assess the risk of QT prolongation.

[0492] Early afterpolarization (EAD) is known to cause arrhythmias, including torsades de pointes and tachycardia. EAD can be triggered by drugs that prolong the QT interval. Field potential duration is another commonly used parameter in MEA cardiotoxicity assays, with 20% FPDc being the threshold for QT prolongation.

[0493] The test results for the exemplary compounds are as follows:

[0494] Table 5. Results of the MEA compound's cardiomyocyte inhibition assay

[0495]

[0496] Test Example 6: CYP Inhibition Test

[0497] I. Experimental Objective

[0498] The aim of this study was to determine the inhibitory effect of the test compounds on the activity of human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A (with midazolam as a substrate)).

[0499] II. Experimental Procedure

[0500] 1.1) Prepare working solutions for the test compound and positive control (test compound: 1:1 DMSO: MeOH, positive control sample: 1:9 DMSO: MeOH). Remove human liver microsomes from the refrigerator and thaw on ice.

[0501] 1.2) Transfer 20 µL of substrate working solution to the corresponding wells, and transfer 20 µL of potassium phosphate buffer to the blank wells of the culture plate. Transfer 158 µL of human liver microsome working solution to all wells of the culture plate. Transfer 2 µL of the test compound or positive control working solution to the wells, and transfer 2 µL of the blank control working solution to the inhibitor-free control wells. Preheat the prepared incubation plate at 37.0 °C for 10 min, then add 20 µL of NADPH working solution to initiate the reaction, and incubate the plate at 37.0 °C for 10 min.

[0502] 1.3) After incubation, add 400 µL of stop solution containing internal standard to terminate the reaction, shake for 10 minutes, and centrifuge at 3220 ×g for 20 minutes. Take 200 µL of the supernatant and mix it with 100 µL of ultrapure water. After shaking for 10 minutes, inject into LC-MS / MS to analyze the substrate metabolites.

[0503] III. Data Analysis

[0504] XL fitting was used to plot the percentages of negative control, positive control, and test compound concentrations, and for nonlinear regression analysis of the data. IC50 was determined using three-parameter or four-parameter logistic equations. 50 Value. When the % inhibition rate is less than 50% at the highest test concentration (50.0 µM), IC50 value is... 50 The value is ">50.0µM".

[0505] 2.1) Equation of the three-parameter Logistic S-curve

[0506]

[0507] 2.2) Equation of a four-parameter Logistic S-curve

[0508]

[0509] IV. Test Results

[0510] The compounds of this invention have no significant inhibitory effect on various cytochrome P450 isoenzymes. The test results of exemplary compounds are as follows:

[0511] Table 6 Results of CYP Inhibition Tests for Compounds

[0512]

[0513] The full names and Chinese names of the English abbreviations used in this invention are as follows:

[0514]

Claims

1. The compound represented by formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts: in, X1 and X2 are CR independently. X1 CR X2 Or N; R X1 R X2 The individual groups are H, halogen, cyano, amino, and C, respectively. 1-6 Alkyl or halogenated C 1-6 alkyl; R1 is C 1-6 Alkyl, C 3-6 Monocycloalkyl, C 5-10 Spirocycloalkyl, C 5-10 Bridged cycloalkyl, C 5-10 Polycyclic alkyl, C 4-6 Monocyclic alkyl, 5-10 quinary bridged heterocyclic alkyl or C 3-8 Heterocyclic alkenyl, wherein R1 is optionally substituted with one or more R'; R' is selected from: deuterium, halogen, cyano, oxo group, hydroxyl group, amino group. , Or, optionally, replaced by one or more Rx: C 1-6 Alkyl, C 1-6 oxane, C 5-10 Spirocycloalkyl, C 5-10 Bridged cycloalkyl, C 5-10 Polycyclic alkyl, C 4-6 Monocyclic alkyl, 5-10 bridging heterocyclic alkyl, C 3-6 Monocycloalkyl-O-, C 4-6 Monoheterocyclic alkyl-O-, C 3-6 Monocycloalkyl-NH-, C 4-6 Monoheterocyclic alkyl-NH-, hydroxyl C 1-6 Alkyl-C(O)-, C 4-6 Monoheterocyclic alkyl-C(O)-, (C 1-6 alkyl)2-NC 1-6 Alkyl-NH-, (C 1-6 alkyl)2-NC 1-6 Alkyl-O-, C 1-6 oxane-N(C) 1-6 alkyl)-, C 1-6 Alkyl-NH-, C 1-6 Alkyl-C(O)-NH-, C 1-6 Thioalkyl, C 2-6 oxaalkyl-C(O)-, phosphate ester-C 1-6 Alkyl, C 2-6 oxaalkyl-C(O)-amino-C 1-6 Alkyl, C 1-6 alkyl-sulfinyl-amino-, C 1-6 alkyl-sulfonyl-amino-C 1-6 Alkyl, or -C(O)-C 1-6 Alkyl-C(O)OC 1-6 Alkyl; or, R' is optionally substituted with one or more Rx: C 2-6 alkynyl or C 3-6 Monocycloalkyl; Ry is selected from: hydrogen, deuterium or C 1-3 alkyl; Rx is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thionyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl; R2 is hydrogen, deuterium, or optionally substituted: C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, C 3-6 cycloalkyl or C 4-6 Heterocyclic alkyl; wherein optional substitution means unsubstituted or substituted with one or more substituents, each substituent being independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thionyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 3-6 cycloalkyl, C 4-6 Heterocyclic alkyl, halogenated C 3-6 cycloalkyl or halogenated C 4-6 Heterocyclic alkyl groups; R3 is difluoromethoxy, difluoromethylthio, deuterated difluoromethoxy, deuterated difluoromethylthio, or... ; Ring D is C 3-6 cycloalkyl or C 4-6 Heterocyclic alkyl groups; R d Selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thionyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 Oxyalkyl, deuterated C 1-6 Thioalkyl, halogenated C 1-6 oxane or halogenated C 1-6 Thioalkyl; d can be 0, 1, 2, 3, or 4; Unless otherwise stated, the heteroatoms in the above heterocyclic alkyl, heterocyclic alkenyl or heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4; The prerequisite is that the combination of the definitions of the above variables forms a stable chemical structure.

2. The compound of claim 1, its stereoisomers, tautomers, or pharmaceutically acceptable salts, characterized in that: X1 and X2 are both N; or X1 and X2 are both CH; or X1 is N and X2 is CF; or X1 is N and X2 is CH.

3. The compound, its stereoisomer, tautomer, or pharmaceutically acceptable salt as described in any one of claims 1-2, characterized in that: R1 is selected from: C 1-4 Alkyl, C 3-4 Monocycloalkyl, C 5-9 Spirocycloalkyl, C 5-9 Bridged cycloalkyl, C 5-9 Polycyclic alkyl, C 4-6 Monoheteroalkyl or 5-9-membered bridged heteroalkyl, wherein R1 is optionally substituted by one or more R'; R' is selected from: deuterium, halogen, cyano, oxo group, hydroxyl group, amino group. , Or, optionally, replaced by one or more Rx: C 1-3 Alkyl, C 1-3 oxane, C 5-8 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Polycyclic alkyl, C 4-6 Mono-heterocyclic alkyl, 5-8-membered bridged heterocyclic alkyl, C 3-6 Monocycloalkyl-O-, C 4-6 Monoheterocyclic alkyl-O-, C 3-6 Monocycloalkyl-NH-, C 4-6 Monoheterocyclic alkyl-NH-, hydroxyl C 1-4 Alkyl-C(O)-, C 4-6 Monoheterocyclic alkyl-C(O)-, (C 1-3 alkyl)2-NC 1-3 Alkyl-NH-, (C 1-3 alkyl)2-NC 1-3 Alkyl-O-, C 1-3 oxane-N(C) 1-3 alkyl)-, C 1-3 Alkyl-NH-, C 1-3 Alkyl-C(O)-NH-, C 1-3 Thioalkyl, C 2-4 oxaalkyl-C(O)-, phosphate ester-C 1-3 Alkyl, C 2-4 oxaalkyl-C(O)-amino-C 1-3 Alkyl, C 1-3 alkyl-sulfinyl-amino-, C 1-3 alkyl-sulfonyl-amino-C 1-3 Alkyl, or -C(O)-C 1-3 Alkyl-C(O)OC 1-3 Alkyl; or, R' is optionally substituted with one or more Rx: Or C 3-6 Monocycloalkyl; Ry is selected from: hydrogen, deuterium or C 1-3 Alkyl groups; Rx are each independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-3 Alkyl, C 1-3 oxane, C 1-3 Thionyl, cyano C 1-3 Alkyl, Halogenated C 1-3 Alkyl or hydroxy C 1-3 alkyl; or, R1 is selected from: C 1-4 Alkyl, C 3-4 Monocycloalkyl, C 5-9 Spirocycloalkyl, C 5-9 Bridged cycloalkyl or C 4-6 Monoheteroalkyl, wherein R1 is optionally substituted with one or more R'; R' is selected from: deuterium, halogen, cyano, oxo group, hydroxyl group, amino group. , Or, optionally, replaced by one or more Rx: C 1-3 Alkyl, C 1-3 oxane, C 5-8 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Polycyclic alkyl, C 4-6 Mono-heterocyclic alkyl, 5-8-membered bridged heterocyclic alkyl, C 3-4 Monocycloalkyl-O-, C 4-6 Monoheterocyclic alkyl-O-, C 3-6 Monocycloalkyl-NH-, C 4-6 Monoheterocyclic alkyl-NH-, hydroxyl C 1-4 Alkyl-C(O)-, C 4-6 Monoheterocyclic alkyl-C(O)-, (C 1-3 alkyl)2-NC 1-3 Alkyl-NH-, (C 1-3 alkyl)2-NC 1-3 Alkyl-O-, C 1-3 oxane-N(C) 1-3 alkyl)-, C 1-3 Alkyl-NH-, C 1-3 Alkyl-C(O)-NH- or C 1-3 Thiazane; or, R' is optionally substituted with one or more Rx: Or C 3-5 Monocycloalkyl; Ry is selected from: hydrogen, deuterium, methyl, or ethyl; Rx is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-3 Alkyl, C 1-3 oxane, C 1-3 Thioalkyl, halogenated C 1-3 Alkyl or hydroxy C 1-3 alkyl; or, R1 is selected from: C 1-3 Alkyl, C 3-4 Monocycloalkyl or C 5-7 Spirocycloalkyl, wherein R1 is optionally substituted with one or more R'; or, R1 is C 4-5 Monoheteroalkyl, wherein R1 is optionally substituted with one or more R'; R' is selected from: deuterium, halogen, oxo group, hydroxyl group, amino group, , Or, optionally, replaced by one or more Rx: C 1-3 Alkyl, C 1-3 oxane, C 5-7 Spirocycloalkyl, C 5-7 Bridged cycloalkyl, C 4-6 Mono-heterocyclic alkyl, 5-8-membered bridged heterocyclic alkyl, C 3-4 Monocycloalkyl-O-, C 4-6 Monoheterocyclic alkyl-O-, C 3-6 Monocycloalkyl-NH-, C 4-6 Monoheterocyclic alkyl-NH-, hydroxyl C 1-4 Alkyl-C(O)-, C 4-6 Monoheterocyclic alkyl-C(O)-, (C 1-3 alkyl)2-NC 1-3 Alkyl-NH-, (C 1-3 alkyl)2-NC 1-3 Alkyl-O-, C 1-3 oxane-N(C) 1-3 alkyl)-, C 1-3 Alkyl-NH- or C 1-3 Alkyl-C(O)-NH-; or, R' is optionally substituted with one or more Rx: Or C 3-4 Monocycloalkyl; Ry is selected from: hydrogen or deuterium; Rx is independently selected from deuterium, halogen, hydroxyl, amino, and C. 1-3 Alkyl or C 1-3 Oxaalkyl; or, Rx is a haloalkyl C 1-3 alkyl; or, R1 is selected from: methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, spiro[2.3]hexyl, spiro[2.2]pentyl, spiro[2.4]heptyl or spiro[3.3]heptyl, wherein R1 is optionally substituted by one or more R'; R' is selected from: deuterium, F, Cl, oxo group, hydroxyl group, amino group. , Or optionally substituted with one or more Rx: methyl, ethyl, isopropyl, methoxy, ethoxy, spiro[2.3]hexyl, spiro[2.2]pentyl, spiro[2.4]heptyl, spiro[3.3]heptyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, oxacyclobutyl, thiohexanebutyl, azacyclobutyl, tetrahydrofuranyl, tetrahydrothiopheneyl, tetrahydrothiazolyl, oxazolyl, 1,3-dioxopentyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,3-oxazinyl, 5-azabicyclo[2.1.1]hexyl, 5-oxabicyclo[ 2.1.1] Hexyl, 3-oxabicyclo[3.1.1] heptyl, cyclopropyl-O-, cyclobutyl-O-, oxacyclobutyl-O-, thiohexacyclobutyl-O-, aziroxybutyl-O-, tetrahydrofuranyl-O-, tetrahydrothiophene-O-, tetrahydrothiazolyl-O-, oxazolyl-O-, 1,3-dioxolanecycloyl-O-, tetrahydropyranyl-O-, morpholinyl-O-, thiomorpholinyl-O-, 1,3-oxazinyl -O-, cyclopropyl-NH-, cyclobutyl-NH-, oxacyclobutyl-NH-, thiocyclobutyl-NH-, aziroxybutyl-NH-, tetrahydrofuranyl-NH-, tetrahydrothiophene-NH-, tetrahydrothiazolyl-NH-, oxazolyl-NH-, 1,3-dioxolanecycloyl-NH-, tetrahydropyranyl-NH-, morpholinyl-NH-, thiomorpholinyl-NH-, 1,3-oxazinyl-NH-, hydroxy-methyl- C(O)-, hydroxy-ethyl-C(O)-, oxetane-C(O)-, thio-butane-C(O)-, azirane-butane-C(O)-, tetrahydrofuranyl-C(O)-, tetrahydrothiophene-C(O)-, tetrahydrothiazolyl-C(O)-, oxazolyl-C(O)-, 1,3-dioxolane-C(O)-, tetrahydropyranyl-C(O)-, morpholinyl-C(O)-, thiomorpholinyl-C(O)-, 1,3-oxazinyl-C(O)-, (Methyl)2-N-methyl-NH-, (Methyl)2-N-ethyl-NH-, (Ethyl)2-N-ethyl-NH-, (Ethyl)2-N-methyl-NH-, (Methyl)2-N-methyl-O-, (Methyl)2-N-ethyl-O-, (Ethyl)2-N-ethyl-O-, C 1-3 oxane-N(C) 1-3 alkyl)-, C 1-3 Alkyl-NH- or C 1-3 Alkyl-C(O)-NH-; or, R' is Or cyclopropyl; Rx is independently selected from deuterium, F, Cl, hydroxyl, amino, methyl, methoxy or ethoxy; or, Rx is independently selected from cyano, difluoromethyl or trifluoromethyl. or, R1 is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or Or, R1 is , , , , or .

4. The compound, its stereoisomer, tautomer, or pharmaceutically acceptable salt as described in any one of claims 1-3, characterized in that: R2 is selected from: hydrogen, deuterium, or optionally substituted C. 1-3 Alkyl, C 1-3 oxane, C 1-3 Thioalkyl, C 3-4 cycloalkyl or C 4-5 Heterocyclic alkyl; wherein optional substitution means unsubstituted or substituted with one or more substituents, each substituent being independently selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-3 Alkyl, C 1-3 oxane, C 1-3 Thioalkyl, halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 3-4 cycloalkyl, C 4-6 Heterocyclic alkyl, halogenated C 3-4 cycloalkyl or halogenated C 4-6 Heterocyclic alkyl groups; Alternatively, R2 can be selected from: hydrogen, deuterium, or optionally substituted C. 1-3 Alkyl, C 1-3 oxane, C 3-4 cycloalkyl or C 4-5 Heterocyclic alkyl; wherein optional substitution means unsubstituted or substituted with one or more substituents, each substituent being independently selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 3-4 cycloalkyl, C 4-6 Heterocyclic alkyl, halogenated C 3-4 cycloalkyl or halogenated C 4-6 Heterocyclic alkyl groups; Alternatively, R2 is selected from: methyl, deuterated methyl, cyclopropyl, cyclobutyl, or... ; Alternatively, R2 can be hydrogen. , or .

5. The compound, its stereoisomer, tautomer, or pharmaceutically acceptable salt as described in any one of claims 1-4, characterized in that: Ring D is selected from: C 3-4 cycloalkyl or C 4-6 Heterocyclic alkyl groups; Preferably, ring D is selected from: cyclopropane, cyclobutane, oxetane, thiobutane, azirane, tetrahydrofuranyl, tetrahydrothiopheneyl, tetrahydrothiazolyl, oxazolyl, 1,3-dioxolanecycloyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl or 1,3-oxazinyl. More preferably, ring D is cyclopropane.

6. The compound, its stereoisomer, tautomer, or pharmaceutically acceptable salt as described in any one of claims 1-5, characterized in that: R d For deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-3 Alkyl, C 1-3 oxane, C 1-3 Thionyl, cyano C 1-3 Alkyl, Halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, deuterated C 1-3 Alkyl, deuterated C 1-3 Oxyalkyl, deuterated C 1-3 Thioalkyl, halogenated C 1-3 oxane or halogenated C 1-3 Thioalkyl; Preferably, R d For deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-3 Alkyl, C 1-3 oxaalkyl, hydroxy C 1-3 Alkyl, deuterated C 1-3 Alkyl, deuterated C 1-3 oxane or halogenated C 1-3 oxane; More preferably, R d It can be deuterium, halogen, cyano, oxo, hydroxy, amino, methyl, methoxy, hydroxymethyl, deuterated methyl, deuterated methoxy, or halomethoxy; More preferably, R d It is deuterium, F, or Cl; Further optimization, R d It is F.

7. The compound, its stereoisomer, tautomer, or pharmaceutically acceptable salt as described in any one of claims 1-6, characterized in that: d is 0, 1 or 2; preferably, d is 0 or 2.

8. The compound, its stereoisomer, tautomer, or pharmaceutically acceptable salt as described in any one of claims 1-7, characterized in that: The compound represented by formula (I) is a compound represented by formula (II-a), formula (II-b), formula (II-c), formula (II-d), formula (II-e), or formula (II-f): Wherein, R2, X1, and X2 are as described in compound (I); Ra is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, and amino groups. , Or, optionally, replaced by one or more Ra': C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 oxaalkyl, hydroxy C 1-6 Alkyl-C(O)-, (C 1-6 alkyl)2-NC 1-6 Alkyl-NH-, (C 1-6 alkyl)2-NC 1-6 Alkyl-O-, C 1-6 oxane-N(C) 1-6 alkyl)-, C 1-6 Alkyl-NH-, C 1-6 Alkyl-C(O)-NH-, C 1-6 Thioalkyl, C 2-6 oxaalkyl-C(O)-, phosphate ester-C 1-6 Alkyl, C 2-6 oxaalkyl-C(O)-amino-C 1-6 Alkyl, C 1-6 alkyl-sulfinyl-amino-, C 1-6 alkyl-sulfonyl-amino-C 1-6 Alkyl or -C(O)-C 1-6 Alkyl-C(O)OC 1-6 alkyl; or, Ra is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, and amino groups. , Or, optionally, replaced by one or more Ra': C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 oxaalkyl, hydroxy C 1-3 Alkyl-C(O)-, (C 1-6 alkyl)2-NC 1-3 Alkyl-NH-, (C 1-3 alkyl)2-NC 1-3 Alkyl-O-, C 1-3 oxane-N(C) 1-3 alkyl)-, C 1-3 Alkyl-NH-, C 1-3 Alkyl-C(O)-NH- or C 1-3 Thioalkyl; Preferably, Ra' is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thionyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl; Alternatively, Ra' can be independently selected from deuterium, F, cyano, oxo, hydroxyl, or amino. or, Ra is independently selected from deuterium, F, oxo group, hydroxyl group, amino group, etc. , , CH3-NH-, CH3-C(O)-NH-, methyl, methoxy or difluoromethoxy; Preferably, a is 0, 1, 2, 3, 4 or 5; or a is 1, 2, 3 or 4; or a is 1, 2 or 3; or a is 1 or 2.

9. The compound, its stereoisomer, tautomer, or pharmaceutically acceptable salt as described in any one of claims 1-7, characterized in that: The compound represented by formula (I) is either a compound represented by formula (III-a) or formula (III-b): Wherein, X1 and X2 are as described in compound (I); R b C 3-6 Monocycloalkyl, C 5-10 Spirocycloalkyl, C 5-10 Bridged cycloalkyl, C 5-10 Polycyclic alkyl, C 4-6 Monocyclic alkyl, 5-10 quinary bridged heterocyclic alkyl or C 3-8 Heterocyclic alkenyl, the R b Optional by one or more R b 'replace; or, R b C 5-7 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Polycyclic alkyl, C 4-6 Monoheterocyclic alkyl groups or 5-8 membered bridged heterocyclic alkyl groups; or, R b C 5-7 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Polycyclic alkyl groups or 5-8 membered bridged heterocyclic alkyl groups; or, R b It is spiro[2.3]hexyl, spiro[2.2]pentyl, spiro[2.4]heptyl, spiro[3.3]heptyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, oxacyclobutyl, thiohexacyclobutyl, azacyclobutyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiazolyl, oxazolyl, 1,3-dioxolanecycloyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,3-oxazinyl, 5-azabicyclo[2.1.1]hexyl, 5-oxabicyclo[2.1.1]hexyl or 3-oxabicyclo[3.1.1]heptyl; or, R b It is spiro[2.3]hexyl, spiro[2.2]pentyl, spiro[2.4]heptyl, spiro[3.3]heptyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, 5-azabicyclo[2.1.1]hexyl, 5-oxabicyclo[2.1.1]hexyl or 3-oxabicyclo[3.1.1]heptyl; Preferably, R b Each is independently selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 3-4 cycloalkyl, C 4-6 Heterocyclic alkyl, halogenated C 3-4 cycloalkyl or halogenated C 4-6 Heterocyclic alkyl groups; Or, R b Each is independently selected from deuterium, halogen, cyano, hydroxyl, amino, C 1-3 Alkyl, Halogenated C 1-3 Alkyl or hydroxy C 1-3 alkyl; Or, R b Each is independently selected from deuterium, halogen, cyano, C 1-3 Alkyl or halogenated C 1-3 alkyl; or, R b for , , , , , , , , or ; or, R b for , , , , , , , , or ; or, R b for .

10. The compound, its stereoisomer, tautomer, or pharmaceutically acceptable salt as described in any one of claims 1-7, characterized in that: The compound represented by formula (I) is either a compound represented by formula (V-a) or formula (V-b): Wherein, X1 and X2 are as described in compound (I); R c for Or optionally by one or more R c 'Replaced by: C' 3-6 Monocycloalkyl-O-, C 4-6 Monoheterocyclic alkyl-O-, C 3-6 Monocycloalkyl-NH-, C 4-6 Monoheterocyclic alkyl-NH-, hydroxyl C 1-6 Alkyl-C(O)-, C 4-6 Monoheterocyclic alkyl-C(O)-, C 1-6 Aza-alkyl NH-, C 1-6 Aza-alkyl-O-, C 1-6 oxane-N(C) 1-6 alkyl)-, C 1-6 Alkyl-NH- or C 1-6 Alkyl-C(O)-NH-; or, R c For optional use by one or more R c 'Replaced by: C' 3-6 Alkyl, C 3-6 oxane or Ry is selected from: hydrogen, deuterium, or C. 1-3 alkyl; or, R c for Or optionally by one or more R c 'Replaced by: C' 3-4 Monocycloalkyl-O-, C 4-6 Monoheterocyclic alkyl-O-, C 3-4 Monocycloalkyl-NH-, C 4-6 Monoheterocyclic alkyl-NH-, hydroxyl C 1-4 Alkyl-C(O)-, C 4-6 Monoheterocyclic alkyl-C(O)-, C 1-4 Aza-alkyl-NH-, C 1-6 Aza-alkyl-O- or C 1-4 oxane-N(C) 1-4 alkyl)-; or, R c For optional use by one or more R c 'Replaced by: C' 3-4 Alkyl, C 3-4 oxane or Ry is selected from: hydrogen, deuterium, methyl, or ethyl. or, R c for Or optionally by one or more R c Substituted: cyclopropane-O-, cyclobutane-O-, oxetane-O-, thiobutane-O-, azirane-O-, tetrahydrofuranyl-O-, tetrahydrothiophene-O-, tetrahydrothiazolyl-O-, oxazolyl-O-, 1,3-dioxopentane-O-, tetrahydropyranyl-O-, morpholinyl-O-, thiomorpholinyl-O-, 1,3-oxazinyl-O-, cyclopropane-N H-, cyclobutyl-NH-, oxetyl-NH-, thiobutyl-NH-, aziryl-NH-, tetrahydrofuranyl-NH-, tetrahydrothiophene-NH-, tetrahydrothiazolyl-NH-, oxazolyl-NH-, 1,3-dioxopentyl-NH-, tetrahydropyranyl-NH-, morpholinyl-NH-, thiomorpholinyl-NH-, 1,3-oxazinyl-NH-, hydroxyl C 1-3 Alkyl-C(O)-, oxetane-butyl-C(O)-, thio-butyl-C(O)-, azirane-butyl-C(O)-, tetrahydrofuranyl-C(O)-, tetrahydrothiophene-C(O)-, tetrahydrothiazolyl-C(O)-, oxazolyl-C(O)-, 1,3-dioxolanecycloyl-C(O)-, tetrahydropyranyl-C(O)-, morpholinyl-C(O)-, thiomorpholinyl-C(O)-, 1,3-oxazinyl-C(O)-, (C 1-3 alkyl)2-NC 1-3 Alkyl-NH-, (C 1-3 alkyl)2-NC 1-4 Alkyl-O-, C 1-3 oxane-N(C) 1-3 alkyl)-; or, R c For optional use by one or more R c Substituted with: tert-butyl, methoxy, or ; Preferably, R c Each is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thionyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl; Or, R c Each is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-3 alkyl; Or, R c Each is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, and methyl. or, R c for , , , , , , , , , , or ; or, R c for , or .

11. The compound, its stereoisomer, tautomer, or pharmaceutically acceptable salt as claimed in any one of claims 1-7, characterized in that: The compound represented by formula (I) is a compound represented by formula (VII-a) or formula (VII-b): Wherein, X1 and X2 are as described in compound (I); R e For optional use by one or more R e 'Replaced by: C' 3-6 Monocyclic alkyl or 4-6 membered heterocyclic alkyl; or, R e For optional use by one or more R e 'Replaced by: C' 3-4 Monocyclic alkyl or 4-5 membered heterocyclic alkyl; or, R e For optional use by one or more R e Substituted with: cyclopropane, cyclobutane, oxetane, thiobutane, azirane, tetrahydrofuranyl, tetrahydrothiopheneyl, tetrahydrothiazolyl, oxazolyl, 1,3-dioxolanecycloyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl or 1,3-oxazinyl; Preferably, R e Each is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thionyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl; Or, R e Each is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, or C. 1-3 alkyl; Or, R e Each is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, or methyl; or, R e for ; Preferably, m is 1, 2, or 3; or m is 1 or 2; or m is 1.

12. The following compounds, or their stereoisomers, tautomers, or pharmaceutically acceptable salts, are selected from: 。 13. A pharmaceutical composition comprising the compound of claims 1-12, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, optionally further comprising a pharmaceutically acceptable carrier.

14. Use of the compounds of claims 1-12, or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 13, in the preparation of a medicament for treating and / or preventing diseases or conditions caused by abnormal TNFα; preferably, the medicament is for treating and / or preventing diseases or conditions such as inflammatory diseases and autoimmune disorders; more preferably, the medicament is for treating and / or preventing diseases or conditions such as autoimmune and inflammatory disorders, pain and nociceptive disorders, neurological disorders and neurodegenerative disorders, metabolic disorders, cardiovascular disorders, tumor disorders, and ocular disorders.

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