A class of aromatic heterocyclic compounds, their preparation methods and applications

Abstract

This invention provides a fused pentacyclic imidazole compound or its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, as well as its preparation method and applications. These compounds are regulators of tumor necrosis factor α (TNFα) signaling, possess excellent pharmacokinetic properties, and have potential applications in the treatment of adverse inflammatory and autoimmune diseases, pain and nociceptive disorders, neurological and neurodegenerative diseases, cardiovascular diseases, metabolic diseases, tumors, and eye diseases.

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 in a soluble form and 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 fused pentacyclic imidazole derivatives and their uses in treatment. These compounds are regulators of tumor necrosis factor α (TNFα) signaling, possess excellent pharmacokinetic properties, and show potential in the treatment of 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 (I), their stereoisomers, tautomers, or pharmaceutically acceptable salts:

[0006]

[0007] in,

[0008] R1 is hydrogen, deuterium, halogen, or cyano;

[0009] R2 is deuterium, halogen, cyano, or optionally substituted: 3-8 membered heterocyclic alkyl, 3-8 membered heterocyclic alkenyl, C6-10 Aryl, 5-10 heteroaryl, C 3-8 cycloalkyl-C 6-10 Aryl, 3-10 membered heterocyclic alkyl-C 6-10 Aryl, 3-8 membered heterocyclic alkenyl-C 6-10 Aryl, C 3-8 Cycloalkyl-5-10 heteroaryl, 3-10 heterocycloalkyl-5-10 heteroaryl, or 3-8 heterocycloalkenyl-5-10 heteroaryl; wherein optional substitution refers to being unsubstituted or substituted by one or more substituents, wherein the substituent is R'; wherein each R' is independently selected from: deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 oxaalkyl, amino-C 1-6 Alkyl, amino-C 3-6 cycloalkyl, C 1-6 Alkyl-C(O), C 2-6 Oxyalkyl-C(O), Phosphate-C 1-6 Alkyl, C 2-6 oxaalkyl-C(O)-amino-C 1-6 Alkyl, C 1-6 alkyl-sulfinyl-amino-, di-C 1-6 Alkyl-amino-C 1-6 Alkyl, C 2-6 Alkyl-C(O)-amino-C 1-6 Alkyl, diC 1-6 alkenyl-amino-C 1-6 Alkyl, C 2-6 Alkyl-C(O)-amino-C 1-6 Alkyl, C 1-6 alkyl-sulfonyl-amino-C 1-6 Alkyl, tetrahydrofuranyl, sulfate ester-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl-C(O)OC 1-6 alkyl,

[0010] R3 and R4 are independently hydrogen, deuterium, halogen, and carbon, respectively. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl;

[0011] R5 represents hydrogen, deuterium, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl or C 3-6 cycloalkyl;

[0012] R6 is C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 3-6 Cycloalkenyl or 4-6 membered heterocyclic alkenyl;

[0013] R7 is halogen, -OR d -SR e C 1-6 Alkyl, Halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl;

[0014] R8, R9, R 10 Each is independently hydrogen, deuterium, halogen, and carbon. 1-6 Alkyl, Halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl;

[0015] R a R b Each independently represents an optional substitution: C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 3-8 Cycloalkenyl, 4-8 membered heterocyclic alkenyl, 5-10 membered heteroaryl or C 6-10 Aryl; 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 Thioalkyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or -C(O)-C 1-6 alkyl;

[0016] R c1 R c2 Each independently represents an optional substitution: C 1-6 Alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 4-8 membered heterocyclic alkyl, or 4-8 membered heterocyclic alkenyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each substituent being independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl;

[0017] R d R e Each can be independently replaced by C. 1-6 Alkyl; wherein optional substitution means unsubstituted or substituted with one or more substituents, each substituent being independently selected from deuterium, halogen, C 1-6 Alkyl or C 3-6 cycloalkyl;

[0018] The compound of formula (I) is not:

[0019] 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;

[0020] The prerequisite is that the combination of the definitions of the above variables forms a stable chemical structure.

[0021] In some implementations, R1 is hydrogen or deuterium;

[0022] In some implementations, R1 is hydrogen.

[0023] In some embodiments, R2 is deuterium, halogen, cyano, or optionally substituted: 3-8 membered heterocyclic alkyl, 3-8 membered heterocyclic alkenyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 cycloalkyl-C 6-10 Aryl, 3-10 membered heterocyclic alkyl-C 6-10 Aryl, 3-8 membered heterocyclic alkenyl-C 6-10 Aryl, C 3-8 Cycloalkyl-5-10 heteroaryl, 3-10 heterocycloalkyl-5-10 heteroaryl, or 3-8 heterocycloalkenyl-5-10 heteroaryl; wherein optional substitution refers to being unsubstituted or substituted by one or more substituents, wherein the substituent is R'; wherein each R' is independently selected from: deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 oxaalkyl, amino-C 1-6 Alkyl, amino-C 3-6 cycloalkyl, C 1-6 Alkyl-C(O), C 2-6 Oxyalkyl-C(O), Phosphate-C1-6 Alkyl, C 2-6 oxaalkyl-C(O)-amino-C 1-6 Alkyl, C 1-6 alkyl-sulfinyl-amino-, di-C 1-6 Alkyl-amino-C 1-6 Alkyl, C 2-6 Alkyl-C(O)-amino-C 1-6 Alkyl, diC 1-6 alkenyl-amino-C 1-6 Alkyl, C 2-6 Alkyl-C(O)-amino-C 1-6 Alkyl, C 1-6 alkyl-sulfonyl-amino-C 1-6 Alkyl, tetrahydrofuranyl, sulfate ester-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl-C(O)OC 1-6 alkyl,

[0024] R a R b Each independently represents an optional substitution: C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 3-8 Cycloalkenyl, 4-8 membered heterocyclic alkenyl, 5-10 membered heteroaryl or C 6-10 Aryl; 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 Thioalkyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or -C(O)-C 1-6 alkyl;

[0025] In some embodiments, R2 is optionally substituted with: 3-8 membered heterocyclic alkyl, 3-8 membered heterocyclic alkenyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 cycloalkyl-C 6-10 Aryl, 3-10 membered heterocyclic alkyl-C 6-10 Aryl, 3-8 membered heterocyclic alkenyl-C 6-10 Aryl, C 3-8Cycloalkyl-5-10 heteroaryl, 3-10 heterocycloalkyl-5-10 heteroaryl, or 3-8 heterocycloalkenyl-5-10 heteroaryl; wherein optional substitution refers to being unsubstituted or substituted by one or more substituents, wherein the substituent is R'; wherein each R' is independently selected from: deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 oxaalkyl, amino-C 1-6 Alkyl, amino-C 3-6 cycloalkyl, C 1-6 Alkyl-C(O)-, 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-, di-C 1-6 Alkyl-amino-C 1-6 Alkyl, C 2-6 Alkyl-C(O-)amino-C 1-6 Alkyl, diC 1-6 alkenyl-amino-C 1-6 Alkyl, C 2-6 Alkyl-C(O)-amino-C 1-6 Alkyl, C 1-6 alkyl-sulfonyl-amino-C 1-6 Alkyl, tetrahydrofuranyl, sulfate ester-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl-C(O)OC 1-6 alkyl,

[0026] R a R b Each independently represents an optional substitution: C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 3-8 Cycloalkenyl, 4-8 membered heterocyclic alkenyl, 5-6 membered heteroaryl, or phenyl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each of which is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, cyano C1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or -C(O)C 1-6 alkyl;

[0027] In some implementations, R2 is an optional replacement: C 6-10 Aryl, 5-10 heteroaryl, C 3-8 cycloalkyl-C 6-10 Aryl, 3-10 membered heterocyclic alkyl-C 6-10 Aryl, 3-8 membered heterocyclic alkenyl-C 6-10 Aryl, C 3-8 Cycloalkyl-5-10 heteroaryl, 3-10 heterocycloalkyl-5-10 heteroaryl, or 3-8 heterocycloalkenyl-5-10 heteroaryl; wherein optional substitution refers to being unsubstituted or substituted by one or more substituents, wherein the substituent is R'; wherein each R' is independently selected from: deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 oxaalkyl, amino-C 1-6 Alkyl, amino-C 3-6 cycloalkyl, C 1-6 Alkyl-C(O)-, 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-, di-C 1-6 Alkyl-amino-C 1-6 Alkyl, C 2-6 Alkyl-C(O)-amino-C 1-6 Alkyl, diC 1-6 alkenyl-amino-C 1-6 Alkyl, C 2-6 Alkyl-C(O)-amino-C 1-6 Alkyl, C 1-6 alkyl-sulfonyl-amino-C 1-6 Alkyl, tetrahydrofuranyl, sulfate ester-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl-C(O)OC 1-6 alkyl,

[0028] R a R b Each independently represents an optional substitution: C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, 5-6 membered heteroaryl, or phenyl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each of which is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or -C(O)C 1-6 alkyl;

[0029] In some implementations, R2 is optionally substituted: 5-6 membered heteroaryl, C 3-6 Cycloalkyl-5-6-membered heteroaryl, 3-6-membered heterocycloalkyl-5-6-membered heteroaryl, or 3-6-membered heterocycloalkenyl-5-6-membered heteroaryl; wherein optional substitution refers to being unsubstituted or substituted by one or more substituents, wherein the substituent is R'; wherein each R' is independently selected from: deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-3 Alkyl, C 1-3 oxaalkyl, amino-C 1-3 alkyl,

[0030] R a R b Each independently represents an optional substitution: C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each substituent being independently selected from deuterium, halogen, oxo, hydroxyl, amino, C 1-3 Alkyl or -C(O)C 1-4 alkyl;

[0031] In some implementations, R2 is optionally substituted: 6-membered heteroaryl, C 3-6 Cycloalkyl-6-membered heteroaryl, 3-6-membered heterocycloalkyl-6-membered heteroaryl, or 3-6-membered heterocycloalkenyl-6-membered heteroaryl; wherein optional substitution refers to being unsubstituted or substituted by one or more substituents, wherein the substituent is R'; wherein each R' is independently selected from: deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-3 Alkyl, C 1-3 oxaalkyl, amino-C 1-3 alkyl,

[0032] R a R b Each of the following is independently optionally substituted: methyl, ethyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each of which is independently selected from deuterium, halogen, oxo, hydroxyl, amino, methyl, ethyl, or -C(O)C. 1-4 alkyl;

[0033] In some embodiments, R2 is optionally substituted: a 6-membered nitrogen-containing heteroaryl group, C 3-6 Cycloalkyl-6-membered nitrogen-containing heteroaryl, 3-6-membered heterocycloalkyl-6-membered nitrogen-containing heteroaryl, or 3-6-membered heterocycloalkenyl-6-membered nitrogen-containing heteroaryl; wherein optional substitution refers to being unsubstituted or substituted by one or more substituents, wherein the substituent is R'; wherein each R' is independently selected from: deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-3 Alkyl, C 1-3 oxaalkyl, amino-C 1-3 alkyl,

[0034] R a R b Each of the following is independently optionally substituted: methyl, ethyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each of which is independently selected from deuterium, F, Cl, oxo, hydroxyl, amino, methyl, ethyl, or -C(O)C. 1-3 alkyl;

[0035] In some embodiments, R2 is optionally substituted with: pyrazinyl, pyrimidinyl, tetrahydropyrrolyl-pyrazinyl, imidazolinyl-pyrazinyl, 2,3-dihydro-1H-imidazolinyl-pyrazinyl, piperidinyl-pyrazinyl, morpholinyl-pyrazinyl, azircyclopropane-pyrazinyl, azircyclobutane-pyrazinyl, cyclopropyl-pyrazinyl, cyclobutyl-pyrazinyl, cyclopentyl-pyrazinyl, cyclohexyl-pyrazinyl, ethylene oxide-pyrazinyl, oxacyclobutane-pyrazinyl, tetrahydrofuranyl-pyrazinyl, tetrahydropyranyl-pyrazinyl, tetrahydropyrrolyl-pyrimidinyl, imidazolinyl-pyrimidinyl, 2,3-dihydro-1H-im ... -1H-imidazolyl-pyrimidinyl, piperidinyl-pyrimidinyl, morpholinyl-pyrimidinyl, polyethyleneimine-pyrimidinyl, aziridine-pyrimidinyl, cyclopropyl-pyrimidinyl, cyclobutyl-pyrimidinyl, cyclopentyl-pyrimidinyl, cyclohexyl-pyrimidinyl, ethylene oxide-pyrimidinyl, oxadiazine-pyrimidinyl, tetrahydrofuranyl-pyrimidinyl, or tetrahydropyranyl-pyrimidinyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, the substituent being R'; each R' is independently selected from: deuterium, F, cyano, oxo, hydroxyl, amino, methyl, methoxy, methylamino,

[0036] R a R b Each of the following is independently and optionally substituted: methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolithyl, piperidinyl, piperazinyl, hexahydropyranyl, morpholinyl, furanyl, or thiazolyl; wherein optional substitution means unsubstituted or substituted with one or more substituents, each of which is independently selected from deuterium, F, oxo, hydroxyl, amino, methyl, or -C(O)CH3alkyl;

[0037] In some implementations, R2 is

[0038] In some embodiments, R2 is optionally substituted with: 3-8 membered heterocyclic alkyl, 3-8 membered heterocyclic alkenyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 cycloalkyl-C 6-10 Aryl, 3-10 membered heterocyclic alkyl-C 6-10 Aryl, 3-8 membered heterocyclic alkenyl-C 6-10 Aryl, C 3-8 Cycloalkyl-5-10-membered heteroaryl, 3-10-membered heterocycloalkyl-5-10-membered heteroaryl, or 3-8-membered heterocycloalkenyl-5-10-membered heteroaryl; wherein optional substitution means unsubstituted or substituted by one or more substituents, the substituent being R'; wherein R' is Preferably, R2 is optionally substituted with: 3-8 membered heterocyclic alkyl, 3-8 membered heterocyclic alkenyl, C 6-10 Aryl or 5-10 membered heteroaryl; wherein optional substitution means unsubstituted or substituted by one or more substituents, wherein the substituent is R'; wherein R' is More preferably, R2 is optionally substituted: C 5-6 Aryl or 5-6 membered heteroaryl; wherein optional substitution means unsubstituted or substituted by one or more substituents, wherein the substituent is R'; wherein R' is More preferably, R2 is an optionally substituted 6-membered heteroaryl group; wherein optional substitution means unsubstituted or substituted by one or more substituents, the substituent being R'; wherein R' is

[0039] R c1 R c2 Each independently represents an optional substitution: C 1-4 Alkyl, C 3-6 cycloalkyl, C 4-6 Cycloalkenyl, 4-6 membered heterocyclic alkyl, or 4-6 membered heterocyclic alkenyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each substituent being independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-3 Alkyl, cyano C 1-3 Alkyl, Halogenated C 1-3 Alkyl or hydroxy C 1-3 Alkyl; preferably, R c1 R c2 Each independently represents an optional substitution: C 1-4 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic alkyl; wherein optional substitution means unsubstituted or substituted with one or more substituents, each of which is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, or C. 1-3 Alkyl; preferably, R c1 R c2 Each independently represents an optional substitution: C 1-4 Alkyl or C 3-6 Cycloalkyl; wherein optional substitution means unsubstituted or substituted with one or more substituents, each substituent being independently selected from deuterium, halogen, cyano, oxo, hydroxyl, or amino; more preferably, R c1 R c2 Each of the following is independently and optionally substituted: methyl, ethyl, or cyclopropyl; wherein optional substitution means unsubstituted or substituted with one or more substituents, each substituent being independently selected from deuterium, halogen, cyano, oxo, hydroxyl, or amino; more preferably, R c1 R c2Each methyl group is independently and optionally substituted; wherein optional substitution means unsubstituted or substituted with one or more substituents, each substituent being independently selected from deuterium, halogen, cyano, oxo, hydroxyl, or amino; more preferably, R c1 R c2 Each is independently a methyl group;

[0040] In some implementations, R2 is

[0041] In some implementations, R3 and R4 are independently hydrogen, deuterium, halogen, and C, respectively. 1-3 Alkyl, C 3-6 cycloalkyl, halogenated C 1-3 Alkyl or deuterated C 1-3 alkyl;

[0042] In some implementations, R3 and R4 are independently hydrogen, deuterium, or halogen;

[0043] In some implementations, R3 and R4 are hydrogen, each independently.

[0044] In some implementations, R5 is hydrogen, deuterium, or C. 1-3 Alkyl, deuterated C 1-3 Alkyl or C 3-6 cycloalkyl;

[0045] In some implementations, R5 is hydrogen or deuterium;

[0046] In some implementations, R5 is hydrogen.

[0047] In some implementations, R6 is C 3-6 cycloalkyl or 4-6 membered heterocyclic alkyl;

[0048] In some implementations, R6 is C 3-6 cycloalkyl;

[0049] In some implementations, R6 is cyclopropane, cyclobutane, cyclopentane, or cyclohexane;

[0050] In some implementations, R6 is

[0051] In some implementations, R7 is halogen, -OR d -SR e C 1-3 Alkyl, Halogenated C 1-3 Alkyl or deuterated C 1-3 alkyl;

[0052] R d R e C, each independently, is an optional substitution.1-4 Alkyl; wherein optional substitution means unsubstituted or substituted with one or more substituents, each substituent being independently selected from deuterium, halogen, C 1-4 Alkyl or C 3-6 cycloalkyl;

[0053] In some implementations, R7 is -OR d or -SR e ;

[0054] R d R e C, each independently, is an optional substitution. 1-3 Alkyl; wherein optional substitution means unsubstituted or substituted with one or more substituents, each of which is independently selected from deuterium, halogen, or C. 1-3 alkyl;

[0055] In some implementations, R7 is -OR d or -SR e ;

[0056] R d R e C, each independently, is an optional substitution. 1-3 Alkyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each of which is independently selected from deuterium or halogen;

[0057] In some implementations, R7 is

[0058] In some implementation schemes, R8, R9, R 10 Each is independently hydrogen, deuterium, halogen, and carbon. 1-4 Alkyl, Halogenated C 1-4 Alkyl or deuterated C 1-4 alkyl;

[0059] In some implementation schemes, R8, R9, R 10 Each can be independently hydrogen, deuterium, halogen, or C. 1-4 alkyl;

[0060] In some implementation schemes, R8, R9, R 10 Each can be independently hydrogen, deuterium, or halogen;

[0061] In some implementation schemes, R8, R9, R 10 Each is hydrogen, independently.

[0062] In some embodiments, the compound represented by formula (I) is a compound represented by formula (II):

[0063]

[0064] X1, X2, X3, and X4 are each independently selected from N or CR. x And not all of them are N;

[0065] R x It is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl or halogenated C 1-6 oxane;

[0066] R 11 For LR 12 ,

[0067] L stands for bond, C 3-8 Cycloalkyl, 3-10 membered heterocyclic alkyl or 3-8 membered heterocyclic alkenyl;

[0068] R 12 It is hydrogen or R';

[0069] Among them, R1, R3, R4, R5, R6, R7, R8, R9, R 10 R' is as described in compound (I).

[0070] In some implementations, X1 and X4 are both N, and X2 and X3 are both CR. x ;

[0071] R x It is hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, Halogenated C 1-3 Alkyl or halogenated C 1-3 Oxyalkyl; further preferably hydrogen, deuterium, halogen or halogenated C 1-3 Alkyl; more preferably hydrogen;

[0072] In some implementations, X1 and X3 are both N, and X2 and X4 are both CR. x ;

[0073] R x It is hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, Halogenated C 1-3 Alkyl or halogenated C 1-3 Oxyalkyl; further preferably hydrogen, deuterium, halogen or halogenated C 1-3 Alkyl; more preferably hydrogen;

[0074] In some implementations, X2 and X4 are both N, and X1 and X3 are both CR. x ;

[0075] R x It is hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, Halogenated C1-3 Alkyl or halogenated C 1-3 Oxyalkyl; further preferably hydrogen, deuterium, halogen or halogenated C 1-3 Alkyl; more preferably hydrogen;

[0076] In some implementations, X2 and X3 are both N, and X1 and X4 are both CR. x ;

[0077] R x It is hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, Halogenated C 1-3 Alkyl or halogenated C 1-3 Oxyalkyl; further preferably hydrogen, deuterium, halogen or halogenated C 1-3 Alkyl; more preferably hydrogen;

[0078] In some implementations, X1 and X4 are both N, and X2 and X3 are both CH.

[0079] In some implementations, L stands for key and C stands for key. 3-6 Cycloalkyl, 3-9 membered heterocyclic alkyl or 3-6 membered heterocyclic alkenyl;

[0080] In some implementations, L stands for key and C stands for key. 3-6 cycloalkyl, 3-6 membered heterocycloalkyl or 3-6 membered heterocycloalkenyl;

[0081] In some embodiments, L is a bond, tetrahydropyrrole, imidazolinyl, 2,3-dihydro-1H-imidazolinyl, piperidinyl, morpholinyl, polyethyleneimine, aziridine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, oxadiazine, tetrahydrofuranyl, or tetrahydropyranyl.

[0082] In some implementation schemes, R 11 for

[0083] In some implementation schemes, R 11 for

[0084] In some embodiments, the compound represented by formula (I) is a compound represented by formula (III):

[0085]

[0086] Among them, R6, R7, R 11 X1, X2, X3, and X4 are as described in compounds of formula (I) or (II).

[0087] In some embodiments, the compound represented by formula (I) is a compound represented by formula (IV), formula (V), formula (VI) or formula (VII):

[0088]

[0089] Among them, R6, R7, R 11 As described in compounds of formula (I) or (II).

[0090] 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.

[0091] The above embodiments of the present invention can be combined arbitrarily, and the resulting embodiments are all embodiments of the present invention.

[0092] 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:

[0093]

[0094]

[0095]

[0096]

[0097]

[0098] Thirdly, the present invention provides a method for preparing the compound represented by formula (III).

[0099] Including but not limited to the following methods:

[0100] General preparation method one:

[0101]

[0102] Where Y1 is Cl, Br, I, OSO2, Me, etc.; X8 is Cl, Br, I, OT. f ,OTs,OMs, -B(OH)2, -BF3K, etc.; X is: Cl,Br,I,OT f ,OTs,OMs, etc.; R6, R7, R 11 The definition is as described in the compound of the first aspect (III) of this invention.

[0103] Fourthly, the present invention provides a pharmaceutical composition comprising a compound of the first aspect of the present invention (a compound represented by formula (I), (II), (III), (IV), (V), (VI), or (VII)) or a compound of the second aspect of the present invention, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, optionally, the pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[0104] Fifthly, the present invention provides the use of the compounds described in the first aspect of the present invention (compounds represented by formula (I), (II), (III), (IV), (V), (VI), or (VII)) or the compounds described in the second aspect of the present invention, or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions 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.

[0105] 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.

[0106] definition

[0107] 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.

[0108] C in this article m-n This refers to the part having an integer number of carbon atoms within a given range. For example, "C 1-6 "" 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.

[0109] 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 ... 1-6Alkyl 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.

[0110] 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.

[0111] Unless otherwise specified, the terms "halogen" or "halogenated" refer to F, Cl, Br, I; preferably F, Cl, Br; more preferably F, Cl.

[0112] 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.

[0113] 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.

[0114] 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., C64-C64). 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).

[0115] Unless otherwise specified, the term "oxaalkyl" refers to an alkyl residue in which one or more carbon atoms (and associated hydrogens) 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.

[0116] "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.

[0117] Unless otherwise specified, the terms "thioalkyl" and "azialkyl" refer to the replacement of oxygen with sulfur or nitrogen in the term "oxaalkyl".

[0118] 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.

[0119] 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.

[0120] 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 part, each heterocyclic alkyl group or other cyclic group may be optionally substituted.

[0121] 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.

[0122] 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, anthraceneyl, phenanthrene, or pyreneyl. "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 for each individual section, each aryl or other cyclic group may be optionally substituted.

[0123] 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, thiazolyl, pyrrole, pyrazolyl, imidazole, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purine, indoleyl, isoindoleyl, indazoleyl, benzofuranyl, benzothiophene, benzopyridyl, benzopyrimidinyl, and benzene. Pyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, etc. "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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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 6-14 The 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, C1-4 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.

[0129] The terms “optional” or “optional” mean that the event or situation described below may, but does not have to, occur, and the description includes the circumstances under which the event or situation may or may not occur.

[0130] 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”.

[0131] 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.

[0132] "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.

[0133] 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.

[0134] 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.

[0135] 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

[0136] 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.

[0137] 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 400MHz and / or Varian 400MHz 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 DAICEL chiral column. OD; Column volume: 20×250mm (10μm particle size packing).

[0138] 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.

[0139] This invention provides a method for preparing the compound. The compound can be prepared by the following steps.

[0140] Preparation Example

[0141] Preparation Example 1: Preparation of (7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-methanebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazozin-5(14H)-one (intermediate b-11)

[0142]

[0143] Step 1: Synthesis of 2-bromo-6-(difluoromethoxy)benzaldehyde (intermediate b-1)

[0144] Under ice bath conditions, an acetonitrile (800 mL) solution of 2-bromo-6-hydroxybenzaldehyde (SM1, 50 g) was added to an aqueous (800 mL) solution of potassium hydroxide (139.56 g). Then, diethyl bromodifluoromethylphosphonate (99.62 g) was added dropwise to the reaction solution. The mixture was stirred at 0 °C for 4 hours. The reaction was confirmed by TLC. Water (1000 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (500 mL × 3). The organic phases were combined. The organic phase was washed with saturated brine (1000 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by rapid chromatography (silica gel, petroleum ether: ethyl acetate = 20:1) to obtain the target compound (40 g). LCMS (ESI) [M+H] + =250.94; 1 H NMR (400MHz, CDCl3) δ10.34(s,1H),7.57(dd,J=8.1,0.9Hz,1H),7.41(t,J=8.2Hz,1H),7.26(t,J=5.8Hz,1H),6.61(t,J=73.4Hz,1H).

[0145] Step 2: Synthesis of (S,Z)-N-(2-bromo-6-(difluoromethoxy)benzylmethyl)-2-methylpropane-2-sulfinamide (intermediate b-2)

[0146] At room temperature, cesium carbonate (46.73 g) was added to a dichloromethane (200 mL) solution of intermediate b-1 (18 g) and (S)-2-methylpropane-2-sulfinamide (8.69 g). The mixture was stirred at room temperature for 18 hours. The reaction system was filtered, the filtrate was diluted with water (1 L), and extracted with ethyl acetate (500 mL × 3). The combined organic phases were washed with brine (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by rapid chromatography (silica gel, petroleum ether: ethyl acetate = 10:1) to give the target product (20 g). LCMS (ESI) [M+H] + =353.99; 1 H NMR (400MHz, CDCl3) δ8.84(s,1H),7.58(dd,J=8.0,1.1Hz,1H),7.33(t,J=8.2Hz,1H),7.25(dd,J=8.3,0.8Hz,1H),6.57(t,J=73.8Hz,1H),1.30(s,9H).

[0147] Step 3: Synthesis of (R)-3-(2-bromo-6-(difluoromethoxy)phenyl)-3-(((S)-tert-butylsulfinyl)amino)propionate ethyl ester (intermediate b-3)

[0148] At room temperature, zinc powder (36.92 g) and cuprous chloride (5.59 g) were added to tetrahydrofuran (200 mL). The reaction mixture was stirred at 70 °C for 0.5 h. After cooling to room temperature, a tetrahydrofuran solution of ethyl bromoacetate (15.72 mL) (200 mL) was added to the reaction mixture. The reaction mixture was heated to 50 °C and stirred for 0.5 h. After cooling to 0 °C, a tetrahydrofuran solution of intermediate b-2 (20 g) (20 mL) was added. The mixture was stirred at room temperature for 2 h, and LCMS showed that the reaction was complete. The reaction mixture was diluted with water (500 mL), extracted with ethyl acetate (500 mL × 3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by rapid chromatography (silica gel, petroleum ether: ethyl acetate = 3:1) to obtain the target compound (20 g). LCMS (ESI) [M+H] + =442.0.

[0149] Step 4: Synthesis of (R)-3-amino-3-(2-bromo-6-(difluoromethoxy)phenyl)propionate ethyl hydrochloride (intermediate b-4):

[0150] At room temperature, a 40 mL, 4.0 M solution of dioxane chloride was added to a 40 mL solution of intermediate b-3 (17 g) containing dioxane. The mixture was stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated to give the target product (17 g). LC-MS (ESI) [M+H] + =338.0.

[0151] Step 5: Synthesis of (R)-3-(2-bromo-6-(difluoromethoxy)phenyl)-3-((5-chloro-2-nitrophenyl)amino)propionate (intermediate b-5)

[0152] At room temperature, intermediate b-4 (14 g) and potassium carbonate (15.5 g) were added to a solution of 4-chloro-2-fluoro-1-nitrobenzene (7.87 g) in acetonitrile (200 mL). The reaction mixture was stirred at 80 °C for 18 hours, and LCMS showed that the reaction was complete. The reaction mixture was filtered, concentrated, and the crude product was purified by rapid chromatography (silica gel, petroleum ether: ethyl acetate = 10:1) to obtain the target product (7 g). LCMS (ESI) [M+H] + =493.0.

[0153] Step 6: Synthesis of (R)-3-(2-bromo-6-(difluoromethoxy)phenyl)-3-((5-chloro-2-nitrophenyl)amino)propionaldehyde (intermediate b-6)

[0154] At -78°C, diisobutylaluminum hydride (40.51 mL, 1.0 M n-hexane solution) was added to a dichloromethane (100 mL) solution of intermediate b-5 (10 g). The mixture was stirred at -78°C for 1 hour, and LC-MS showed the reaction was complete. Saturated ammonium chloride (30 mL) was added to the reaction mixture, and the mixture was filtered. The filtrate was extracted with dichloromethane (50 mL × 3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The solution was purified by rapid chromatography (silica gel, petroleum ether: ethyl acetate = 5:1) to give the target compound (7 g). LC-MS (ESI) [M+H] + =449.1.

[0155] Step 7: Synthesis of (4R)-4-(2-bromo-6-(difluoromethoxy)phenyl)-4-((5-chloro-2-nitrophenyl)amino)-2-((trimethylsilyl)oxy)butyronitrile (intermediate b-7)

[0156] At room temperature, trimethylsilyl cyanide (3.09 g), triethylamine (157.54 mg), and zinc iodide (496.93 mg) were added to dichloromethane (100 mL) containing intermediate b-6 (7 g). The mixture was stirred at room temperature for 4 hours, and LC-MS showed complete reaction. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined. The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude target compound (8 g). LC-MS (ESI) [M+H] + =548.0.

[0157] Step 8: Synthesis of (1R)-1-(2-bromo-6-(difluoromethoxy)phenyl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol (intermediate b-8)

[0158] Stannous chloride dihydrate (14.39 g) was added to ethanol (100 mL) of intermediate b-7 (7 g) at room temperature. The reaction mixture was stirred at 80 °C for 18 hours. Water (100 mL) was added to the reaction mixture, the pH was adjusted to 8 with potassium hydroxide aqueous solution (1 M), and the mixture was extracted with ethyl acetate (130 mL × 3). The organic phases were combined. The organic phase was washed with saturated sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by rapid chromatography (silica gel, petroleum ether:tetrahydrofuran = 4:1) to give the target compound (3.8 g). LCMS (ESI) [M+H] + =428.9.

[0159] Step 9: Synthesis of (1R)-3-azido-1-(2-bromo-6-(difluoromethoxy)phenyl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazolium (intermediate b-9)

[0160] At room temperature, diphenyl azidophosphate (5.9 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (6.37 mL) were added to tetrahydrofuran (50 mL) containing intermediate b-8 (4.5 g). The reaction mixture was stirred at 45 °C for 18 hours, and LC-MS showed product formation. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined. The organic phase was washed with saturated sodium chloride solution (50 mL), dried, filtered, and concentrated. The mixture was purified by rapid chromatography (silica gel, petroleum ether: ethyl acetate = 3:1) to give the target compound (3.4 g). LC-MS (ESI) [M+H] + =454.1.

[0161] Step 10: Synthesis of (1R)-1-(2-bromo-6-(difluoromethoxy)phenyl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-amine (intermediate b-10)

[0162] At room temperature, triphenylphosphine (2.94 g) was added to a solution of intermediate b-9 (3.4 g) in tetrahydrofuran (30 mL) and water (3 mL). The reaction mixture was stirred at 50 °C for 18 hours, and LC-MS showed product formation. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution (20 mL), dried, filtered, concentrated, and purified by rapid chromatography (silica gel, dichloromethane:methanol = 10:1) to give the target compound (2.5 g). LC-MS (ESI) [M+H] + =428.0.

[0163] Step 11: Synthesis of (7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-methanebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazozin-5(14H)-one (intermediate b-11)

[0164] At room temperature, palladium acetate (0.13 g), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (0.34 g), and potassium carbonate (8.06 g) were added to dioxane (250 mL) of intermediate b-10 (5 g). The mixture was heated to 100 °C under carbon monoxide (balloon pressure) and stirred for 18 hours. LC-MS showed the reaction was complete. The reaction solution was filtered, concentrated, and the crude product was purified by rapid chromatography (silica gel, dichloromethane:tetrahydrofuran = 3:2). The obtained product was further slurried in methyl tert-butyl ether (10 mL), filtered, and dried to obtain the target product (1.6 g). LC-MS (ESI) [M+H] + =376.1; 1 ¹H NMR (400MHz, CDCl₃) δ 8.42 (dd, J = 8.0, 1.3Hz, 1H), 7.63 (d, J = 8.7Hz, 1H), 7.47–7.39 (m, 3H), 7.33–7.28 (m, 1H), 7.21 (dd, J = 8.7, 2.0Hz, 1H), 7.03–6.65 (m, 1H), 6.29 (d, J = 7.3Hz, 1H), 4.95 (t, J = 6.6Hz, 1H), 3.51–3.41 (m, 1H), 2.85 (d, J = 13.3Hz, 1H). Preparation Example 2: Preparation of (1-(5-bromopyrimidin-2-yl)cyclopropyl)(imino)(methyl)-16-sulfoxide (intermediate d)

[0165]

[0166] Step 1: Synthesis of (5-bromopyrimidin-2-yl)methylmethanesulfonate (intermediate d-1)

[0167] At room temperature, (5-bromopyrimidin-2-yl)methanol (3.3 g) and triethylamine (3.53 g) were dissolved in dichloromethane (50 mL). Methanesulfonic anhydride (4.56 g) was added at 0 °C, and the reaction mixture was stirred at 25 °C for 1 hour. LC-MS showed the reaction was complete. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid chromatography (silica gel, petroleum ether: ethyl acetate = 2:1) to give the target compound (3.82 g). LC-MS (ESI) [M+H] + =267.1; 1 HNMR (400MHz, CDCl3) δ8.84(s,2H),5.39(s,2H),3.21(s,3H).

[0168] Step 2: Synthesis of 5-bromo-2-(methylthio)methyl pyrimidine (intermediate d-2)

[0169] At room temperature, intermediate d-1 (4.5 g) was dissolved in DMF (40 mL), and sodium methanethiol (2.36 g) was added at 25 °C. The reaction solution was stirred at 25 °C for 1 hour under argon protection. TLC analysis (petroleum ether:ethyl acetate = 5:1) confirmed the reaction was complete. The reaction solution was quenched with water (50 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride aqueous solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to obtain the target compound (2.32 g). LCMS (ESI) [M+H] + =218.9; 1 HNMR (400MHz, CDCl3) δ8.76(s,2H),3.86(s,2H),2.16(s,3H).

[0170] Step 3: Synthesis of 5-bromo-2-((methylsulfinyl)methyl)pyrimidine (intermediate d-3)

[0171] At room temperature, intermediate d-2 (2.6 g) was dissolved in DCM (25 mL), and m-chloroperoxybenzoic acid (2.41 g) was added. The reaction mixture was stirred at 25 °C for 0.5 hours, and LC-MS showed that the reaction was complete. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated. The residue was purified by rapid chromatography (silica gel, dichloromethane:methanol = 20:1) to give the target compound (2.24 g). LC-MS (ESI) [M+H] + =235.1; 1 H NMR (400MHz, CDCl3) δ8.82(s,2H),4.32(s,2H),2.73(s,3H).

[0172] Step 4: Synthesis of N-(((5-bromopyrimidin-2-yl)methyl)(methyl)(oxo)-16-thionyl)-2,2,2-trifluoroacetamide (intermediate d-4)

[0173] At room temperature, intermediate d-3 (200 mg) and trifluoroacetamide (192.33 mg) were dissolved in 1,2-dichloroethane (10 mL), followed by the addition of rhodium dimeracetate (3.76 mg), iodophenylacetic acid (548.02 mg), and magnesium oxide (171.42 mg). The reaction mixture was stirred at 60 °C for 16 hours under argon protection, and the reaction was confirmed to be complete by LCMS. 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 aqueous solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid chromatography (silica gel, petroleum ether: ethyl acetate = 2:1) to obtain the target compound (110 mg). LCMS (ESI) [M+H] + =346.0; 1 H NMR (400MHz, CDCl3) δ8.86 (s, 2H), 5.19 (d, J = 13.9Hz, 1H), 5.01 (d, J = 13.9Hz, 1H), 3.48 (s, 3H).

[0174] Step 5: Synthesis of (1-(5-bromopyrimidin-2-yl)cyclopropyl)(imino)(methyl)-16-sulfoxide (intermediate d)

[0175] At room temperature, intermediate d-4 (140 mg) and potassium carbonate (167.71 mg) were dissolved in acetonitrile (10 mL), and 1,2-dibromoethane (379.93 mg) was added. The reaction mixture was stirred at 80 °C for 2 hours under argon protection, and LCMS analysis showed that the reaction was complete. Methanol (5 mL) was added to the reaction mixture, and stirring was continued at 80 °C for 0.5 hours. LCMS analysis showed that the reaction was complete. The reaction mixture was cooled to room temperature. 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 aqueous solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid chromatography (silica gel, ethyl acetate: methanol = 20:1) to obtain the target compound (40 mg). LCMS (ESI) [M+H] + =276.1; 1 HNMR (400MHz, CDCl3) δ8.76(s,2H),3.40(s,3H),2.96(s,2H),2.89(s,2H).

[0176] Example

[0177] Example 1: Preparation of (7R,14R)-6-cyclopropyl-1-(difluoromethoxy)-11-(2-(1-(S-methylsulfonylimino)cyclopropyl)pyrimidin-5-yl)-6,7-dihydro-7,14-methanebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazozin-5(14H)-one (compound 2)

[0178]

[0179] Step 1: Synthesis of (7R,14R)-11-chloro-6-cyclopropyl-1-(difluoromethoxy)-6,7-dihydro-7,14-methanebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazozin-5(14H)-one (intermediate 2-1)

[0180] At 0°C, cyclopropylboronic acid (342.91 mg), copper acetate (290.02 mg), and sodium bis(trimethylsilyl)amino (1.98 mL) were sequentially added to a tetrahydrofuran (15 mL) solution of intermediate b-11 (300 mg). The reaction mixture was stirred at 50°C for 4 hours under an oxygen atmosphere (oxygen bulb). LCMS showed the reaction was complete. A saturated ammonium chloride aqueous solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined. The organic phase was washed with a saturated sodium chloride solution (20 mL), separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by rapid chromatography (silica gel, petroleum ether: ethyl acetate = 1:5) to give the target compound (150 mg). LCMS (ESI) [M+H] + =416.2.

[0181] Step 2: Synthesis of (7R,14R)-6-cyclopropyl-1-(difluoromethoxy)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-6,7-dihydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazozin-5(14H)-one (intermediate 2-2)

[0182] Intermediate 2-1 (1.6 g) and pinacol diborate (6.84 g) were dissolved in 1,4-dioxane (80 mL) solution, followed by the addition of potassium acetate (2.64 g), tris(bis(benzylacetone)bispalladium) (704.7 mg), and tricyclohexylphosphine tetrafluoroborate (565.21 mg). The reaction mixture was heated to 140 °C under a nitrogen atmosphere and stirred for 48 hours. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:2) to obtain the target compound (1.2 g). LCMS (ESI) [M+H]+ =508.2; 1 HNMR (400MHz, DMSO-d6) δ8.13(dd,J=6.7,2.7Hz,1H),7.93(s,1H),7.90–7.89(m,1H),7.61–7.57(m,1H),7.48–7.44(m,3H),6.25(d,J=7.0H z,1H),5.27(d,J=7.4Hz,1H),3.63–3.57(m,1H),3.54–3.45(m,1H),3.16–3.09(m,1H),1.29(s,12H),1.25–1.20(m,2H),0.97–0.91(m,2H).

[0183] Step 3: Synthesis of Compound 2

[0184] At room temperature, intermediate d (70 mg) and intermediate 2-2 (128.6 mg) were dissolved in dioxane (4 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (8.05 mg), sodium bicarbonate (63.89 mg), and water (1 mL) were added. The reaction mixture was stirred at 90 °C for 2 hours under argon protection, and LCMS analysis showed that the reaction was complete. The reaction mixture was cooled to room temperature, and water (10 mL) was added. Extraction was performed with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase preparative separation (C). 18 The target compound (11.79 mg) was obtained by reacting acetonitrile in an aqueous solution of 0.03% formic acid. LCMS (ESI) [M+H] + =577.3; 1 H NMR (400MHz, MeOD-d4): δ9.01(s,2H),8.29–8.15(m,1H),7.86(s,1H),7.77(d,J=8.5H z,1H),7.64–7.54(m,1H),7.49–7.42(m,2H),7.42–7.05(m,1H),6.43(d,J=7.1Hz,1H), 5.38(d,J=7.4Hz,1H),3.64–3.51(m,1H),3.42(s,3H),3.26–3.15(m,1H),2.88(d,J=13 .8Hz,1H),1.97–1.73(m,4H),1.39–1.28(m,1H),1.18–0.96(m,2H),0.83–0.61(m,1H).

[0185] Example 2: Preparation of (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-6-cyclopropyl-1-(difluoromethoxy)-6,7-dihydro-7,14-methanebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazozin-5(14H)-one (compound 6)

[0186]

[0187] Step 1: Synthesis of (7R,14R)-11-chloro-6-cyclopropyl-1-(difluoromethoxy)-6,7-dihydro-7,14-methanebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazozin-5(14H)-one (intermediate 6-1)

[0188] At 0°C, cyclopropylboronic acid (342.91 mg), copper acetate (290.02 mg), and sodium bis(trimethylsilyl)amino (1.98 mL, 1.0 M) were sequentially added to a tetrahydrofuran (15 mL) of intermediate b-11 (300 mg). The reaction mixture was stirred at 50°C for 4 hours under an oxygen atmosphere (oxygen bulb). LCMS showed the reaction was complete. A saturated ammonium chloride aqueous solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined. The organic phase was washed with a saturated sodium chloride solution (20 mL), separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by rapid chromatography (silica gel, petroleum ether: ethyl acetate = 1:5) to give the target compound (150 mg). LCMS (ESI) [M+H] + =416.2.

[0189] Step 2: Synthesis of (1-(5-((7R,14R)-6-cyclopropyl-1-(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-toluidine[f]benzo[4,5]imidazo[1,2-a][1,4]diazozin-11-yl)pyrimidin-2-yl)cyclobutyl)tert-butyl carbamate (intermediate 6-2)

[0190] Under a nitrogen atmosphere, N-{1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrimidin-2-yl]cyclobutyl}carbamate (162.45 mg), potassium carbonate (119.66 mg), dicyclohexyl({2',6'-dimethoxy-[1,1'-biphenyl]-2-yl})phosphine (23.69 mg), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (22.52 mg) were added to intermediate 6-1 (120 mg) in 4 mL of dioxane and 1 mL of water. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined. The organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by rapid chromatography (silica gel, petroleum ether:ethyl acetate = 1:3) to give the target compound (80 mg). LCMS (ESI) [M+H] + =629.2.

[0191] Step 3: Synthesis of (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-6-cyclopropyl-1-(difluoromethoxy)-6,7-dihydro-7,14-methanebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazozin-5(14H)-one

[0192] Under a nitrogen atmosphere, trifluoroacetic acid (1 mL) was added to 2 mL of dichloromethane (80 mg) of intermediate 6-2, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated and purified by reversed-phase liquid chromatography (0.1% FA in water / acetonitrile) to obtain the target compound (26.31 mg). LCMS (ESI) [M+H] + =529.3; 1 H NMR (400MHz, DMSO-d6) δ9.12 (s, 2H), 8.16 (dd, J = 6.6, 2.8Hz, 1H), 7.86–7.46 (m,6H),6.29(d,J=7.0Hz,1H),5.31(d,J=7.4Hz,1H),3.57–3.49(m,1H),3.1 9–3.13(m,1H),2.84(d,J=13.8Hz,1H),2.74–2.61(m,2H),2.33–2.25(m,2H) ,2.15–1.91(m,2H),1.50–1.41(m,1H),1.02–0.90(m,2H),0.57–0.49(m,1H).

[0193] Example 3: Preparation of (7R,14R)-6-cyclopropyl-1-(difluoromethoxy)-11-(2-(dimethylphospho)pyrimidin-5-yl)-6,7-dihydro-7,14-methanebenzo[f]benzo[4,5]imidazol[1,2-a][1,4]diazozosin-5(14H)-one (compound 67):

[0194]

[0195] Step 1: Synthesis of (5-bromopyrimidin-2-yl)dimethylphosphine oxide (intermediate 67-1)

[0196] Triethylamine (1420.81 mg) was added to a solution of 5-bromo-2-iodopyrimidine (SM4, 2 g), dimethylphosphine oxide (821.93 mg), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (406.22 mg), and tris(dibenzylacetone)dipalladium (642.88 mg) in dioxane (20 mL). The reaction mixture was heated to 100 °C and stirred for 3 hours under nitrogen protection. The reaction was detected by LCMS to indicate completion. The reaction solution was concentrated, and the residue was purified by rapid chromatography (silica gel, dichloromethane:methanol = 20:1) to obtain the target compound (1 g). LCMS (ESI) [M+H] + =234.9.

[0197] Step 2: Synthesis of Compound 67

[0198] Potassium phosphate (144.51 mg) and 1,1-bis(diphenylphosphine)diferropalladium dichloride (24.91 mg) were added sequentially to a mixed solution of dioxane (5 mL) and water (1 mL) of intermediates 67-1 (80 mg) and 2-2 (103.62 mg). The reaction mixture was heated to 90 °C and stirred for 16 hours under a nitrogen atmosphere. LC-MS showed the reaction was complete. The reaction mixture was cooled to room temperature, water (10 mL) was added, and then extracted with ethyl acetate (15 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase preparative separation (C18, 0.1% NH3·H2O in H2O / ACN) to give the target compound (7.27 mg). LC-MS (ESI) [M+H] + =536.1; 1HNMR(400MHz,DMSO-d6)δ9.24(d,J=3.2Hz,2H),8.22–8.07(m,1H),7.89–7.65(m,4H),7.50–7.46(m,2H),6.30(d,J=7.0Hz,1H),5.32(d,J=7.4Hz,1H ),3.58–3.48(m,1H),3.19–3.11(m,1H),2.85(d,J=13.8Hz,1H),1.83(s,3 H),1.80(s,3H),1.52–1.41(m,1H),1.01–0.89(m,2H),0.60–0.47(m,1H).

[0199] Referring to Examples 1-3, the following compounds were prepared:

[0200]

[0201]

[0202]

[0203]

[0204] Control compound (WO2018197503A1, compound of Example 6):

[0205]

[0206] Biological test cases

[0207] Test Example 1: Detection of TNF Prevalence in Human Whole Blood by Compounds

[0208] 1. Experimental Methods

[0209] (1) Procedure of whole blood stimulation test

[0210] In a 96-well plate, serially diluted compounds were added to wells in columns 1-10, 5 μL per well, in duplicate. The maximum concentration was 200 μM (20X), serially diluted 3-fold with PBS to achieve a final concentration of 0.5 nM–10 μM. 5 μL of DMSO was added to well 11 as a control. Freshly collected heparin-anticoagulated whole blood from healthy individuals was added to each well (90 μL). The whole blood and compound were incubated at 37°C for 1 hour. Then, 5 μL of 3 EU / mL PBS (final concentration 0.15 EU / mL) was added to each well, and the plate was incubated at 37°C for 4 hours. After incubation, 200 μL of pre-chilled PBS was added to each well to terminate the reaction. Plasma was collected by centrifugation at 2250g for 5 minutes. The plasma sample was aliquoted into two portions; one portion was used for TNF binding assay. Another portion was incubated with 10 μMUCB-9260 at 37°C for 1 hour to obtain the total TNF sample, which was then stored at -80°C.

[0211] (2) CA1974 Experimental Procedure

[0212] According to the instructions, the CA1974 antibody was labeled with biotin using a biotin-conjugation kit (Thermo, 21435). The ab9348 antibody was labeled with SULFO-TAG using a SULFO-TAG conjugation kit (MSD, R91AO-1) according to the instructions.

[0213] Antibody coating: Dilute the biotin-labeled CA1974 antibody to 1 μg / mL with 1% BSA / PBS, add 25 μL to each well of an MSDGOLD 96-well streptavidin plate, and incubate with shaking at room temperature for 1 hour.

[0214] 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.

[0215] Sample preparation: Dilute the compound-bound sample and the total TNF sample at least 2-fold using IgM Reducing Assay Diluent.

[0216] The plate was washed three times with PBS + 0.05% Tween 20.

[0217] Standards and samples were loaded onto MSD plates, 50 μL per well, and incubated with shaking at room temperature for 1 hour.

[0218] The plate was washed three times with PBS + 0.05% Tween 20.

[0219] 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.

[0220] The plate was washed three times with PBS + 0.05% Tween 20.

[0221] Dilute MSD Read Buffer T (4X) twice to 2X with ultrapure water, 150 μL per well, use immediately. QuickPlex SQ120 reads the results.

[0222] 2. Result Processing

[0223] Standard curve construction: Plot the standard curve with the logarithm of the concentration of each standard as the horizontal axis and the logarithm of the readings (after subtracting the zero-point sample background value) as the vertical axis. Perform linear regression analysis to fit the standard curve and equation.

[0224] Calculation of results for unknown samples: The detection readings of unknown samples are interpolated according to the standard curve equation to calculate the concentration. This concentration is then multiplied by a dilution factor to obtain the TNFα concentration bound to the compound in the unknown sample.

[0225] Calculate the TNFα occupancy rate in each sample using the following formula:

[0226] Occupancy rate % = TNFα concentration bound by inhibitor / (TNFα concentration in the saturated sample of the compound (total TNFα concentration)) × 100

[0227] Perform curve fitting and calculate the OCC of the compound. 50 value.

[0228] 3. Experimental Results

[0229] 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.

[0230] Table 1. Results of the assay for TNF occupancy of the compounds in human whole blood.

[0231] compound <![CDATA[OCC 50 (nM)]]> Compound 6 +

[0232] Note: +: OCC 50 (nM)<500nM.

[0233] Test Example 2: TNF L929 Cytotoxicity Assay

[0234] 1. Experimental Methods

[0235] (1) L929 cell preparation

[0236] 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.

[0237] (2) Inoculation of cells

[0238] 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.

[0239] (3) Add the test sample

[0240] 1) Preparation of test solution:

[0241] The test sample was dissolved in DMSO to prepare a 10 mM stock solution (the concentration of compound SAR441566 was 1 mM). The stock solution was then serially diluted with DMSO three times to obtain a series of solutions of different concentrations for later use.

[0242] 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.

[0243] Add 10 μL of the above 10X working solution to each well of the cells after overnight incubation. The final concentrations of the compounds were: 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 concentrations of the control drug SAR441566 were 0.15 nM-1,000 nM.

[0244] 2) Setting of reference holes:

[0245] 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.

[0246] 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 any added compounds.

[0247] 3) Incubate this 96-well plate in an incubator with 5% CO2 and 37°C for 18 hours.

[0248] (4) CTG detection method:

[0249] 1) Add an equal volume (100 μL) of cell culture medium per well. The reagents were mixed by shaking in the dark for 2 minutes to induce cell lysis.

[0250] 2) Incubate the plate at room temperature for 10 minutes to stabilize the luminescence signal.

[0251] 3) Read the results using the ELISA reader in Luminescence mode.

[0252] 2. Result Processing

[0253] IC 50 Calculate: TNF killing inhibition rate (%) = (OD compound - minimum OD value) / (maximum OD value - minimum OD value) × 100, perform curve fitting, and obtain IC50. 50 value.

[0254] Maximum OD value: positive control; Minimum OD value: negative control.

[0255] 3. Experimental Results

[0256] Table 2 Results of the TNF L929 cytotoxicity assay

[0257] Compound numbering <![CDATA[IC 50 (nM)]]> Compound 2 A Compound 6 A control compound A

[0258] Note: A: IC 50 (nM)<100nM.

[0259] Test Example 3: Determination of the effect of the compound of the present invention on TNF-induced NF-κB phosphorylation in HEK293 cells

[0260] 1. Experimental Methods

[0261] (1) HEK-Blue TM TNF-α cell preparation:

[0262] • Resuscitate cells and resuspend them in growth medium: (DMEM, 10% FBS, 100 U / mL Pen-Strep, 100 μg / mL Normocin). Incubate cells at 37°C in a 5% CO2 incubator until confluence reaches 70-80%.

[0263] • Rinse the cells twice with preheated PBS, and collect the cells by centrifugation at 150x g for 10 minutes.

[0264] • Resuspend cells in assay medium (DMEM, 10% FBS, 100 U / mL Pen-Strep).

[0265] Add 90 μL of HEK-Blue to each well of the 96-well plate. TM TNFα cell suspension, with a cell density of 20,000 cells / well. Incubated overnight at 37°C in a 5% CO2 incubator.

[0266] (2) Prepare the compound solution:

[0267] • Add 20 μL of DMSO to columns 2 through 10 of a 96-well plate.

[0268] Transfer 50 μL of 1 mM stock solution to column 1 of a 96-well plate.

[0269] • 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 does not contain DMSO and serves as a 0-concentration positive control.

[0270] • 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 this plate and mix well. Obtain a 50-fold diluted compound stock solution.

[0271] (3) Sample addition treatment:

[0272] • Take 50 μL of diluted compound stock solution and incubate it with 50 μL of 1,000 pg / mL TNF-α at 37 °C for 1 hour.

[0273] • Take 50 μL of 400 ng / mL Adalimumab and 50 μL of 1,000 pg / mL TNF-α and incubate them together at 37℃ for 1 hour as a negative control.

[0274] To HEK-Blue TM Add 10 μL of co-incubated TNF-α solution (final concentration 50 pg / mL) to each well of TNFα cells, mix, and incubate at 37°C and 5% CO2 for 18 hours.

[0275] (4) SEAP activity detection:

[0276] • Transfer 20 μL / well of cell culture supernatant to a new 96-well plate.

[0277] Add 180 μL of QUANTI-Blue to each well. TM Incubate the solution at 37°C for 1 hour.

[0278] • SEAP levels were detected by reading the OD value at 620 nM using an ELISA reader.

[0279] 2. Result Processing

[0280] Calculation description: IC 50 or EC 50 Curve fitting was performed (Model 205):

[0281]

[0282] 3. Experimental Results

[0283] Experiments show that the compounds of the present invention exhibit a strong inhibitory effect on TNF-induced NF-κB phosphorylation levels in HEK293 cells. The measurement data of exemplary compounds are shown in the table below.

[0284] Table 3. Determination of the effect of compounds on TNF-induced NF-κB phosphorylation in HEK293 cells.

[0285] Compound numbering <![CDATA[abs,IC 50 (nM)]]> Compound 6 A Compound 67 A control compound A

[0286] Note: A: IC 50 (nM)<100nM.

[0287] Test Example 4: Pharmacokinetic Experiment in Mice

[0288] 1. Experimental Methods

[0289] (1) Drug preparation

[0290] Prepare the compound using the following preparation method.

[0291] The dosage was 2 mg / kg, the administration volume was 5 mL / kg, and the concentration was 0.4 mg / mL; the solvent was 5% DMSO + 10% Solutol + 85% physiological saline.

[0292] (2) Dosing regimen

[0293] Healthy 6-8 week old CD1 mice (n=3 per group) were administered the drug via tail vein injection (2 mg / kg IV). In the IV group, 0.03 mL of blood was collected from the dorsal metatarsal vein at 5 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h post-administration in EDTA-K2 anticoagulant tubes. After collection, the blood samples were centrifuged at 4000 g for 5 min at 4℃ to separate the plasma, which was then stored at -80℃ for analysis. The plasma drug concentration was determined by LC / MS / MS, and plasma concentration-time curves were plotted to calculate the main pharmacokinetic parameters.

[0294] 2. Experimental Results

[0295] The compounds of this application exhibit excellent PK properties. The PK parameters of exemplary compounds are shown in the table below.

[0296] Table 4 Effects of compounds on pharmacokinetics in mice

[0297]

Claims

1. A compound of formula (III), its tautomer, stereoisomer, or pharmaceutically acceptable salt: in, X1, X2, X3, and X4 are each independently selected from N or CR. x And not all of them are N; R x It is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl or halogenated C 1-6 oxane; R6 is C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 3-6 Cycloalkenyl or 4-6 membered heterocyclic alkenyl; R7 is halogen, -OR d -SR e C 1-6 Alkyl, Halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl; R 11 For LR 12 , L stands for bond, C 3-8 Cycloalkyl, 3-10 membered heterocyclic alkyl or 3-8 membered heterocyclic alkenyl; R 12 It is hydrogen or R'; R' is independently selected from: deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 oxaalkyl, amino-C 1-6 Alkyl, amino-C 3-6 cycloalkyl, C 1-6 Alkyl-C(O), C 2-6 Oxyalkyl-C(O), Phosphate-C 1-6 Alkyl, C 2-6 oxaalkyl-C(O)-amino-C 1-6 Alkyl, C 1-6 alkyl-sulfinyl-amino-, di-C 1-6 Alkyl-amino-C 1-6 Alkyl, C 2-6 Alkyl-C(O)-amino-C 1-6 Alkyl, diC 1-6 alkenyl-amino-C 1-6 Alkyl, C 2-6 Alkyl-C(O)-amino-C 1-6 Alkyl, C 1-6 alkyl-sulfonyl-amino-C 1-6 Alkyl, tetrahydrofuranyl, sulfate ester-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl-C(O)OC 1-6 alkyl, R a R b Each independently represents an optional substitution: C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 3-8 Cycloalkenyl, 4-8 membered heterocyclic alkenyl, 5-10 membered heteroaryl or C 6-10 Aryl; 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 Thioalkyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or -C(O)-C 1-6 alkyl; R c1 R c2 Each independently represents an optional substitution: C 1-6 Alkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 4-8 membered heterocyclic alkyl, or 4-8 membered heterocyclic alkenyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each substituent being independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl or hydroxyl C 1-6 alkyl; R d R e Each can be independently replaced by C. 1-6 Alkyl; wherein optional substitution means unsubstituted or substituted with one or more substituents, each substituent being independently selected from deuterium, halogen, C 1-6 Alkyl or C 3-6 cycloalkyl; The compound of formula (Ⅲ) is not: Unless otherwise stated, the heteroatoms of the aforementioned heterocyclic alkyl or heterocyclic alkenyl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

2. The compound of claim 1, its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, X1 and X4 are both N, X2 and X3 are both CR x ;R x It is hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, Halogenated C 1-3 Alkyl or halogenated C 1-3 Oxyalkyl; further preferably hydrogen, deuterium, halogen or halogenated C 1-3 Alkyl; more preferably hydrogen; or, X1 and X3 are both N, X2 and X4 are both CR x ;R x It is hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, Halogenated C 1-3 Alkyl or halogenated C 1-3 Alkoxy; further preferably hydrogen, deuterium, halogen or halogenated C 1-3 Alkyl; more preferably hydrogen; or, X2 and X4 are both N, X1 and X3 are both CR x ;R x It is hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, Halogenated C 1-3 Alkyl or halogenated C 1-3 Oxyalkyl; further preferably hydrogen, deuterium, halogen or halogenated C 1-3 Alkyl; more preferably hydrogen; or, X2 and X3 are both N, X1 and X4 are both CR x ;R x It is hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, Halogenated C 1-3 Alkyl or halogenated C 1-3 Oxyalkyl; further preferably hydrogen, deuterium, halogen or halogenated C 1-3 Alkyl; more preferably hydrogen; or, X1 and X4 are both N, and X2 and X3 are both CH.

3. The compound, its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, as described in any one of claims 1-2, characterized in that, R6 is C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl; or, R6 is C 3-6 Cycloalkyl; or, R6 is cyclopropane, cyclobutane, cyclopentane, or cyclohexane; or, R6 is 4. The compound, its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, as described in any one of claims 1-3, characterized in that, R7 is halogen, -OR d -SR e C 1-3 Alkyl, Halogenated C 1-3 Alkyl or deuterated C 1-3 alkyl; R d R e C, each independently, is an optional substitution. 1-4 Alkyl; wherein optional substitution means unsubstituted or substituted with one or more substituents, each substituent being independently selected from deuterium, halogen, C 1-4 Alkyl or C 3-6 cycloalkyl; Alternatively, R7 is -OR d or -SR e ; R d R e C, each independently, is an optional substitution. 1-3 Alkyl; wherein optional substitution means unsubstituted or substituted with one or more substituents, each of which is independently selected from deuterium, halogen, or C. 1-3 alkyl; Alternatively, R7 is -OR d or -SR e ; R d R e C, each independently, is an optional substitution. 1-3 Alkyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each of which is independently selected from deuterium or halogen; Or, R7 is 5. The compound, its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, as described in any one of claims 1-4, characterized in that, R' is independently selected from: deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 oxaalkyl, amino-C 1-6 Alkyl, amino-C 3-6 cycloalkyl, C 1-6 Alkyl-C(O), C 2-6 Oxyalkyl-C(O), Phosphate-C 1-6 Alkyl, C 2-6 oxaalkyl-C(O)-amino-C 1-6 Alkyl, C 1-6 alkyl-sulfinyl-amino-, di-C 1-6 Alkyl-amino-C 1-6 Alkyl, C 2-6 Alkyl-C(O)-amino-C 1-6 Alkyl, diC 1-6 alkenyl-amino-C 1-6 Alkyl, C 2-6 Alkyl-C(O)-amino-C 1-6 Alkyl, C 1-6 alkyl-sulfonyl-amino-C 1-6 Alkyl, tetrahydrofuranyl, sulfate ester-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl-C(O)OC 1-6 alkyl, R a R b Each independently represents an optional substitution: C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 3-8 Cycloalkenyl, 4-8 membered heterocyclic alkenyl, 5-10 membered heteroaryl or C 6-10 Aryl; 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 Thioalkyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or -C(O)-C 1-6 alkyl; Alternatively, R' can be independently selected from: deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 oxaalkyl, amino-C 1-6 Alkyl, amino-C 3-6 cycloalkyl, C 1-6 Alkyl-C(O)-, 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-, di-C 1-6 Alkyl-amino-C 1-6 Alkyl, C 2-6 Alkyl-C(O-)amino-C 1-6 Alkyl, diC 1-6 alkenyl-amino-C 1-6 Alkyl, C 2-6 Alkyl-C(O)-amino-C 1-6 Alkyl, C 1-6 alkyl-sulfonyl-amino-C 1-6 Alkyl, tetrahydrofuranyl, sulfate ester-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl-C(O)OC 1-6 alkyl, R a R b Each independently represents an optional substitution: C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 3-8 Cycloalkenyl, 4-8 membered heterocyclic alkenyl, 5-6 membered heteroaryl, or phenyl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each of which is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or -C(O)C 1-6 alkyl; Alternatively, R' can be independently selected from: deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 oxaalkyl, amino-C 1-6 Alkyl, amino-C 3-6 cycloalkyl, C 1-6 Alkyl-C(O)-, 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-, di-C 1-6 Alkyl-amino-C 1-6 Alkyl, C 2-6 Alkyl-C(O)-amino-C 1-6 Alkyl, diC 1-6 alkenyl-amino-C 1-6 Alkyl, C 2-6 Alkyl-C(O)-amino-C 1-6 Alkyl, C 1-6 alkyl-sulfonyl-amino-C 1-6 Alkyl, tetrahydrofuranyl, sulfate ester-C 1-6 Alkyl, -C(O)-C 1-6 Alkyl-C(O)OC 1-6 alkyl, R a R b Each independently represents an optional substitution: C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, 5-6 membered heteroaryl, or phenyl; wherein optional substitution refers to unsubstituted or substituted by one or more substituents, each of which is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-6 Alkyl, C 1-6 oxane, C 1-6 Thioalkyl, cyano C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl or -C(O)C 1-6 alkyl; Alternatively, R' can be independently selected from: deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-3 Alkyl, C 1-3 oxaalkyl, amino-C 1-3 alkyl, R a R b Each independently represents an optional substitution: C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each substituent being independently selected from deuterium, halogen, oxo, hydroxyl, amino, C 1-3 Alkyl or -C(O)C 1-4 alkyl; Alternatively, R' can be independently selected from: deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-3 Alkyl, C 1-3 oxaalkyl, amino-C 1-3 alkyl, R a R b Each of the following is independently optionally substituted: methyl, ethyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each of which is independently selected from deuterium, halogen, oxo, hydroxyl, amino, methyl, ethyl, or -C(O)C. 1-4 alkyl; Alternatively, R' can be independently selected from: deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-3 Alkyl, C 1-3 oxaalkyl, amino-C 1-3 alkyl, R a R b Each of the following is independently optionally substituted: methyl, ethyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; wherein optional substitution means unsubstituted or substituted with one or more substituents, each of which is independently selected from deuterium, F, Cl, oxo, hydroxyl, amino, methyl, ethyl, or -C(O)C. 1-3 alkyl; Alternatively, R' can be independently selected from: deuterium, F, cyano, oxo, hydroxyl, amino, methyl, methoxy, methylamino. R a R b The substituents are, independently and optionally, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolithyl, piperidinyl, piperazinyl, hexahydropyranyl, morpholinyl, furanyl, or thiazolyl; wherein optional substitution means unsubstituted or substituted with one or more substituents, each substituent being independently selected from deuterium, F, oxo, hydroxyl, amino, methyl, or -C(O)CH3alkyl.

6. The compound, its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, as described in any one of claims 1-4, characterized in that, R' is R c1 R c2 Each independently represents an optional substitution: C 1-4 Alkyl, C 3-6 cycloalkyl, C 4-6 Cycloalkenyl, 4-6 membered heterocyclic alkyl, or 4-6 membered heterocyclic alkenyl; wherein optional substitution means unsubstituted or substituted by one or more substituents, each substituent being independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, C 1-3 Alkyl, cyano C 1-3 Alkyl, Halogenated C 1-3 Alkyl or hydroxyl C 1-3 Alkyl; or, R c1 R c2 Each independently represents an optional substitution: C 1-4 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic alkyl; wherein optional substitution means unsubstituted or substituted with one or more substituents, each of which is independently selected from deuterium, halogen, cyano, oxo, hydroxyl, amino, or C. 1-3 Alkyl; or, R c1 R c2 Each independently represents an optional substitution: C 1-4 Alkyl or C 3-6 Cycloalkyl; wherein optional substitution means unsubstituted or substituted with one or more substituents, each substituent being independently selected from deuterium, halogen, cyano, oxo, hydroxyl, or amino; or, R c1 R c2 Each of the following is independently and optionally substituted: methyl, ethyl, or cyclopropyl; wherein optional substitution means unsubstituted or substituted with one or more substituents, each substituent being independently selected from deuterium, halogen, cyano, oxo, hydroxyl, or amino; or, R c1 R c2 Each methyl group is independently and optionally substituted; wherein optional substitution means unsubstituted or substituted with one or more substituents, each substituent being independently selected from deuterium, halogen, cyano, oxo, hydroxyl, or amino; or, R c1 R c2 Each is independently a methyl group.

7. The compound, its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, as described in any one of claims 1-6, characterized in that, L stands for bond, C 3-6 Cycloalkyl, 3-9 membered heterocyclic alkyl, or 3-6 membered heterocyclic alkenyl; or, L is a bond, C is a bond. 3-6 Cycloalkyl, 3-6-membered heterocyclic alkyl or 3-6-membered heterocyclic alkenyl; or, L is a bond, tetrahydropyrroleyl, imidazolinyl, 2,3-dihydro-1H-imidazolinyl, piperidinyl, morpholinyl, polyethyleneimine, aziridine, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, oxadienoyl, tetrahydrofuranyl or tetrahydropyranyl.

8. The compound, its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, as described in any one of claims 1-7, characterized in that, R 11 for 9. The compound, its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, as described in any one of claims 1-7, characterized in that, R 11 for 10. The compound, its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, as described in any one of claims 1-9, characterized in that, The compound represented by formula (Ⅲ) is a compound represented by formula (Ⅳ), formula (V), formula (Ⅵ) or formula (Ⅶ): Among them, R6, R7, R 11 As described in compound (Ⅲ).

11. The following compounds represented by structural formulas, their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof:

12. A pharmaceutical composition comprising a compound as claimed in any one of claims 1-11, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, optionally further comprising a pharmaceutically acceptable carrier.

13. Use of the compound, its tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 12, 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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