Polycyclic compound, pharmaceutical composition thereof and use thereof

Abstract

Disclosed in the present invention are a polycyclic compound, a pharmaceutical composition thereof and the use thereof. Specifically disclosed in the present invention is a compound as represented by formula (II), a pharmaceutically acceptable salt thereof, an isotopically substituted form thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof. The compound of the present invention exhibits a good biological activity and / or pharmacokinetic properties.

Description

Polycyclic compounds, their pharmaceutical compositions and their applications Technical Field

[0001] This invention relates to polycyclic compounds, pharmaceutical compositions thereof, and their applications. Background Technology

[0002] TNF-α is a prototype member of the tumor necrosis factor (TNF) superfamily of proteins that share major functions in regulating cell survival and cell death. A common structural feature of all known members of the TNF superfamily is the formation of a trimer complex that binds to and activates specific TNF superfamily receptors. As an example, TNF-α exists in a soluble and transmembrane form and signals through two receptors called TNFR1 and TNFR2, each with a unique functional endpoint.

[0003] Increased expression of TNF-α occurs in many pathological states, including sepsis, malignant tumors, heart failure, and chronic inflammatory diseases. TNF-α can also be produced by malignant cells and immune cells in the tumor-associated microenvironment, acting as an endogenous tumor promoter to promote the progression of malignant diseases by creating an inflammatory ecological environment. Members of the TNF superfamily, including TNF-α, play pathological and physiological functions in a variety of diseases. For example, TNF-α is cytotoxic to various tumor cells and is an important factor mediating the immune response to bacterial infection. It also plays important roles in septic shock, autoimmune diseases, rheumatoid arthritis, inflammation, and diabetes.

[0004] Several TNF-α inhibitors (monoclonal antibodies, fusion proteins) have been marketed and approved for the treatment of inflammatory and autoimmune disorders such as rheumatoid arthritis, psoriasis, Crohn's disease, ankylosing spondylitis, uveitis, polyarticular juvenile idiopathic arthritis, plaque psoriasis, ulcerative colitis, hidradenitis suppurativa, systemic lupus erythematosus, Wegener's granulomatosis, Behçet's disease, erythema nodosum, folliculitis, and many other indications. Currently, all approved products are large molecules that work by inhibiting the binding of human TNF-α to its receptor; however, small molecule compounds are not yet available. Small molecule compounds offer advantages such as good patient compliance, low production costs, ease of storage and transportation, and high cost-effectiveness. Therefore, the development of small molecule TNF-α inhibitors has significant economic and social value. Summary of the Invention

[0005] The technical problem this invention aims to solve is to address the deficiency in the variety of TNF-α compounds in existing technologies by providing a novel polycyclic compound, its pharmaceutical composition, and its applications. The compound of this invention exhibits good TNF-α inhibitory activity. The compound of this invention has high exposure levels and excellent absolute bioavailability. The compound of this invention exhibits excellent hepatic microsomal metabolic stability and low cardiotoxicity.

[0006] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0007] This invention provides a compound of formula (II-A), a pharmaceutically acceptable salt thereof, an isotopic substituted thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof:

[0008] in,

[0009] Y 1 For N or CR a ;

[0010] Y 2 For N or CR a ;

[0011] Y 3 For N or CR a ;

[0012] Z 1 For N or CR b ;

[0013] Z 2 For N or CR b

[0014] Z 3 For N or CR b ;

[0015] U 1 For bond, O, NR c or CR d R e ;

[0016] U 2 For bond, O, NR c or CR d R e ;

[0017] R a Independently, H, deuterium, halogen, -CN, -NO2, -OH, -OR a1 Optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl, wherein the heteroatom in the heterocycloalkyl and heteroaryl is independently selected from one or more of N, O, S and P, and the number of heteroatoms is independently 1, 2 or 3.

[0018] R a1 Optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic alkyl, optionally substituted C6-C 14The aryl or optionally substituted 5-10-membered heteroaryl groups, wherein the heteroatoms in the 3-7-membered heterocyclic alkyl and 5-10-membered heteroaryl groups are each independently selected from one or more of N, O, S and P, and the number of heteroatoms is independently 1, 2 or 3.

[0019] R b Independently, it is absent, H, deuterium, halogen, -OH, -CN, -OR 2 -S(=O)2C1-C6 alkyl, optionally substituted alkyl or optionally substituted alkoxy;

[0020] R 2 H, deuterium, halogen, -CN, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocycloalkyl, optionally substituted C6-C 14 Aryl, optionally substituted 5-10-membered heteroaryl or optionally substituted C1-C6 alkyl, wherein the 3-7-membered heterocyclic alkyl and 5-10-membered heteroaryl are each independently one or more of N, O, S and P, and the number of heteroatoms is independently one, two or three.

[0021] R c Independently H, deuterium, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, wherein the heteroatom in each of the heterocycloalkyl and heteroaryl groups is independently selected from one or more of N, O, S and P, and the number of heteroatoms is independently 1, 2 or 3.

[0022] R d Independently, it is H, deuterium, or an optionally substituted C1-C6 alkyl group;

[0023] R e Independently, it is H, deuterium, or an optionally substituted C1-C6 alkyl group;

[0024] R 1 The heteroalkyl group is absent, H, deuterium, optionally substituted alkyl group, optionally substituted cycloalkyl group, optionally substituted heterocycloalkyl group, optionally substituted aryl group or optionally substituted heteroaryl group, wherein the heteroatom in the heterocycloalkyl group and heteroaryl group is independently selected from one or more of N, O, S and P, and the number of heteroatoms is independently 1, 2 or 3.

[0025] R 3 and R 4 Each is independently H, deuterium, halogen, or optionally substituted C1-C6 alkyl;

[0026] R 9 It is a C1-C6 alkyl group consisting of H, deuterium, halogen, or optional substitution;

[0027] L is a bond, an optional alkyl group, an optional alkenyl group, an optional alkynyl group, an optional cycloalkyl group, or an optional heterocyclic group;

[0028] Ring A' is optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted heterocyclic alkene, or optionally substituted heteroaryl;

[0029] The ring C is optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkene, optionally substituted aryl or optionally substituted heteroaryl;

[0030] R 10 Independently, it is H, deuterium, halogen, -OH, -NH2, -CN, -NO2, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl or optionally substituted heteroaryl.

[0031] m can be 0, 1, 2, 3, or 4;

[0032] R 12 Independently, it can be H, deuterium, halogen, -OH, -NH2, -CN, -NO2, oxo, or -NHR. 12-1 Optionally substituted alkyl, Optionally substituted alkenyl, Optionally substituted alkynyl, Optionally substituted alkoxy, -SR 12-9 R 12-10 R 12-11 -P = OR 12- 2 R 12-3 -R 12-4 -P=OR 12-2 R 12-3 -R 12-12 -S(=O)2R 12-13 Optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl;

[0033] R 12-1 The substituted C1-C6 alkyl group is optional.

[0034] R 12-2 H, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic alkyl;

[0035] R 12-2 H, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic alkyl; or,

[0036] R 12-2 R 12-3 Together with the P atoms attached to them, they form optionally substituted heterocyclic alkyl groups or optionally substituted 5-10-membered heteroaryl groups;

[0037] R 12-4 It can be an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted 3-7-membered heterocyclic alkyl, or an optionally substituted 5-10-membered heteroaryl;

[0038] R 12-9 R 12-10 and R 12-11 Each can be independently deuterium, halogen, -OH, -NH2, -CN, -NO2, oxo, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy;

[0039] R 12-12 For bond, NH, optional substituted C1-C6 alkylene;

[0040] R 12-13 H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;

[0041] t can be 0, 1, 2, 3, or 4;

[0042] Or, two R atoms on the same carbon atom 12 Together form = O;

[0043] Or, two R atoms on the same carbon atom 12 The ring atoms connected to them together form an optionally substituted cycloalkyl group or an optionally substituted heterocyclic group, wherein the heteroatom or heteroatomic group is selected from one or more of N, O, S, C(=O), S(=O) and S(=O)2, and the number of heteroatoms is 1, 2 or 3.

[0044] In some implementations, U 1 For NR c R c It can be -CD3 or -CH3.

[0045] In some implementations, U 2 For key.

[0046] In some implementations, R a Independently, it can be H, halogen, -CN, -NO2, -OH, or -OR. a1The heteroalkyl, heteroalkyl, heterocyclic, or heteroaryl groups are optionally substituted alkyl, substituted cycloalkyl, heterocyclic, or heteroaryl groups, wherein the heteroatoms are each independently selected from one or more of N, O, S, and P, and the number of heteroatoms is independently 1, 2, or 3.

[0047] In some implementations, R a Independently, H, deuterium, F, Cl, -CN, -NO2, -OH, -OR a1 Methyl, ethyl, deuterated methyl, dideuterated methyl, trideuterated methyl, deuterated ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, or fluoroethyl.

[0048] In some implementations, R a H stands for H independently.

[0049] In some implementations, R a It is independently deuterium.

[0050] In some implementations, R b Independently H, halogen, -OH, -CN, -OR 2 -S(=O)2C1-C6 alkyl, optionally substituted alkyl or optionally substituted alkoxy.

[0051] In some implementations, R b Independently, H, deuterium, halogen, -OH, -CN, -OR 2 -S(=O)2C1-C6 alkyl, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy.

[0052] In some implementations, R b Independently H, deuterium, F, Cl, -OR 2 -S(=O)2CH3, -S(=O)2CH2CH3, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy.

[0053] In some implementations, R b Independently, it can be -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH3, -CH2F, -CHF2, -CH2CH2F, -CH2CHF2, -CH2CF3, -OCH2F, -OCHF2, -OCH2CH2F, -OCH2CHF2, or -OCH2CF3.

[0054] In some implementations, R b It can be H, deuterium, F or -OCHF2 independently.

[0055] In some implementations, R b H stands for H independently.

[0056] In some implementations, R b It is independently deuterium.

[0057] In some implementations, R 1 It is a C1-C6 alkyl group that is absent, H, deuterium, or optionally substituted.

[0058] In some implementations, R 1 It is absent, H, deuterium, C1-C6 alkyl or deuterated C1-C6 alkyl.

[0059] In some implementations, R 1 For the absence of H, deuterium, methyl or -CD3.

[0060] In some implementations, R 3 and R 4 Each can be H, deuterium, or halogen independently.

[0061] In some implementations, R 3 and R 4 Each can be H, deuterium, or F independently.

[0062] In some implementations, R 3 and R 4 For H.

[0063] In some implementations, R 9 It is H, deuterium, or deuterated C1-C6 alkyl.

[0064] In some implementations, R 9 For H.

[0065] In some embodiments, L is a bond, an optionally substituted C1-C6 alkyl group, an optionally substituted C2-C6 alkenyl group, an optionally substituted C2-C6 ynyl group, an optionally substituted C3-C8 cycloalkyl group, or an optionally substituted 3-8 membered heterocyclic group.

[0066] In some embodiments, L is a bond, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, or a 3-8 membered heterocyclic group.

[0067] In some implementations, L is a bond, acetylene, or propyne.

[0068] In some implementations, L is acetylene or propyne.

[0069] In some implementations, L is acetylene.

[0070] In some implementations, L stands for key.

[0071] In some embodiments, ring A' is an optionally substituted C3-C8 cycloalkyl, optionally substituted C5-C8 cycloalkenyl, or optionally substituted C6-C... 10 Aryl, optionally substituted 3-10 membered heterocyclic groups, optionally substituted 4-7 membered heterocyclic alkenes, or optionally substituted 5-10 membered heteroaryl groups.

[0072] In some embodiments, ring A' is an optionally substituted C3-C8 cycloalkyl, optionally substituted C5-C8 cycloalkenyl, or optionally substituted C6-C... 10 Aryl, optionally substituted 3-10 membered heterocyclic groups, optionally substituted 5-8 membered heterocyclic alkenes, or optionally substituted 5-10 membered heteroaryl groups, wherein the C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C6-C 10 Aryl, 3-10-membered heterocyclic, 5-8-membered heterocyclic alkene, or 5-10-membered heteroaryl are optionally selected from deuterium, halogen, -OH, -NH2, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, -P=OR 12-1 R 12-2 -R 12-3 -P=OR 12-1 R 12-2 -SR 12- 9 R 12-10 R 12-11 C3-C8 cycloalkyl, 3-8 membered heterocyclic, C6-C 10 One, two, or three of the following substituents are selected from aryl, 5-10-membered heteroaryl, and 5-8-membered heterocyclic alkenyl groups. In some embodiments, the optionally substituted C3-C8 cycloalkyl, optionally substituted C5-C8 cycloalkenyl, optionally substituted C6-C... 10 The aryl group, optionally substituted 3-10-membered heterocyclic group, optionally substituted 5-8-membered heterocyclic alkene, or optionally substituted 5-10-membered heteroaryl group, optionally selected from -P=O(CH3)2, -P=O(CH2CH3)2, -OCH2-P=O(CH3)2, -COCH3, -CO(OCH3), -CO(NHCH3), -S(=O)2CH3, -NH-S(=O)2CH3, One, two, or three substituents may be used to replace the substituents.

[0073] In some embodiments, ring A' is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cyclooctenyl, cyclooctadienyl, cycloocttrienyl, oxacyclobutyl, azacyclobutyl, tetrahydropyrrole, tetrahydrofuranyl, dioxacyclopentyl, tetrahydropyranyl, dioxacyclohexyl, piperidinyl, Morpholinyl, piperazine, thiacyclohexane, phosphacyclopentyl, oxophosphacyclohexane, oxacycloheptane, thiacycloheptane, azezospiro[3.3]heptyl, azezospiro[3.3]heptyl, azezospiro[3.4]octyl, azezospiro[3.4]octyl, azezospiro[3.5]nonyl, azezospiro[3.5]nonyl, azezospiro[4.5]decyl, azezospiro[4.5]decyl Furan, phenyl, naphthyl, pyrrolyl, pyrazolyl, triazolyl, thiazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, or thiazolyl; Indicates the position where it connects to L.

[0074] In some embodiments, ring A' is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cyclooctenyl, cyclooctadienyl, cycloocttrienyl, oxacyclobutane, azacyclobutane, tetrahydropyrrole, tetrahydrofuranyl, dioxacyclopentane, tetrahydropyranyl, dioxacyclohexane, piperidinyl, morpholinyl, piperazine, thiocyclohexane, phosphacyclopentane, oxophoxacyclohexane, oxacycloheptane, thiocycloheptane. Furan, phenyl, naphthyl, pyrrolyl, pyrazolyl, triazolyl, thiazolyl, thiophene, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, or thiazinyl, wherein the substituent on ring A' is selected from -P=O(CH3)2, -P=O(CH2CH3)2, -OCH2-P=O(CH3)2, -COCH3, -CO(OCH3), -CO(NHCH3). -S(=O)2CH3, -NH-S(=O)2CH3, One, two, or three substituents in it.

[0075] In some embodiments, the ring C is an optionally substituted C3-C8 cycloalkyl group, an optionally substituted 3-8 membered heterocyclic group, or an optionally substituted C6-C... 10 Aryl or optionally substituted 5-10 heteroaryl groups.

[0076] In one embodiment of the present invention, the ring C is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentenyl, cyclohexenyl, oxacyclopentane, oxacyclohexane, dioxacyclohexane, dioxacyclopentane, oxacyclopentenyl, oxacyclohexenyl, dioxacyclopentenyl, dioxacyclohexenyl, phenyl, pyridine, or piperidine.

[0077] In one embodiment of the present invention, the ring C is oxacyclobutane, tetrahydrofuran, dioxacyclopentane, tetrahydropyran, or dioxacyclohexane.

[0078] In one embodiment of the present invention, the ring C is oxacyclobutane, tetrahydrofuran, dioxacyclopentane, tetrahydropyran, dioxacyclohexane, dioxacyclopentyl, or dioxacyclopentenyl.

[0079] In one embodiment of the present invention, the ring C is tetrahydrofuran, dioxacyclopentane, dioxacyclopentyl, or dioxacyclopentenyl.

[0080] In one embodiment of the present invention, the ring C is dioxacyclopentane, dioxacyclopentyl, or dioxacyclopentenyl.

[0081] In one embodiment of the present invention, ring C is dioxacyclopentyl or dioxacyclopentenyl.

[0082] In one embodiment of the present invention, the ring C is tetrahydrofuran or dioxacyclopentane.

[0083] In one embodiment of the present invention, ring C is dioxacyclopentane.

[0084] In one aspect of the present invention, R 10 Independently, it is H, deuterium, -F, -Cl, -OH, -NH2, -CN, -NO2, oxo, or halogenated C1-C6 alkyl, where m is 0, 1, 2, 3, or 4.

[0085] In one aspect of the present invention, R 10 Independently -F, fluorinated C1-C6 alkyl, m is 1 or 2.

[0086] In one aspect of the present invention, R 10 Independently, it is -F, and m is 2.

[0087] In some implementations, R 12 Independently, it can be H, deuterium, halogen, -OH, -NH2, -CN, -NO2, oxo, or -NHR. 12-1 Optionally substituted alkyl, Optionally substituted alkenyl, Optionally substituted alkynyl, Optionally substituted alkoxy, -SR 12- 9 R 12-10 R 12-11 -P = OR 12-2 R12-3 -R 12-4 -P=OR 12-2 R 12-3 Optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl.

[0088] In some implementations, R 12 Independently, it can be H, deuterium, halogen, -OH, -NH2, -CN, -NO2, oxo, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkoxy, optionally substituted C3-C8 cycloalkyl, optionally substituted 3-8 membered heterocyclic group, optionally substituted C6-C 10 aryl, optionally substituted 5-10 heteroaryl, -P=OR 12-1 R 12-2 or -R 12-3 -P=OR 12-1 R 12-2 .

[0089] In some implementations, R 12 Independently, it is C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, 3-8 membered heterocyclic, 4-7 membered heterocyclic, C6-C 10 Aryl or 5-10 heteroaryl compounds.

[0090] In some implementations, R 12 Independently, it can be H, deuterium, halogen, -OH, -NH2, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, or -P=OR. 12-1 R 12-2 -R 12-3 -P=OR 12-1 R 12-2 -SR 12-9 R 12-10 R 12-11 C3-C8 cycloalkyl, 3-8 membered heterocyclic, C6-C 10 Aryl, 5-10 membered heteroaryl, 4-7 membered heterocyclic alkenyl, R 12-9 R 12-10 and R 12-11 Each is independently deuterium, halogen, -OH, -NH2, -CN, -NO2, oxo, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy; in some embodiments, R 12-9 R 12-10 and R 12-11Each is independently deuterated, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy; in some embodiments, R 12-9 R 12-10 and R 12-11 Each of these can be independently deuterium, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, n-propenyl, isopropenyl, n-butenyl, isobutylenyl, sec-butenyl, tert-butenyl, C2-C6 ynylene, or C1-C6 alkoxy; in some embodiments, R 12-9 R 12-10 and R 12-11 Each can be independently oxo, methyl, or ethyl.

[0091] In some implementations, R 12 Independently for -R 12-12 -S(=O)2R 12-13 R 12-12 R is a bond, NH, or optionally substituted C1-C6 alkylene group, wherein the C1-C6 alkylene group is optionally substituted with a C1-C6 alkyl group; 12-13 The C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, 3-7 heterocyclic alkyl, 5-10 aryl, or 5-10 heteroaryl groups are optionally substituted with H, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, 3-7 heterocyclic alkyl, or 5-10 heteroaryl groups, and are optionally substituted with a substituent selected from -OH, -CN, halogen, C1-C6 alkyl, and C1-C6 alkoxy.

[0092] In some implementations, R 12-12 It is a bond, NH, -CH2- or -CH2CH2-.

[0093] In some implementations, R 12-13 The C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, 3-7 heterocyclic alkyl, 5-10 aryl, or 5-10 heteroaryl groups are optionally substituted with H, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, 3-7 heterocyclic alkyl, or 5-10 heteroaryl groups, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, 3-7 heterocyclic alkyl, or 5-10 heteroaryl groups are optionally substituted with one, two, or three substituents selected from -OH, -CN, Cl, Br, I, -CH3, -CH2CH3, -OCH3, and -OCH2CH3.

[0094] In some implementations, R 12-13The derivatives are H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2(CH2)CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH2)CH3, cyclopropane, cyclobutane, cyclopentane, cyclohexane, furan, tetrahydrofuran, tetrahydropyranyl, pyrroleyl, piperidinyl, morpholinyl, phenyl, naphthyl, or pyridinyl, wherein -CH3, -CH2CH3, -CH2CH2CH3, -CH2( CH2)CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH2)CH3, cyclopropane, cyclobutane, cyclopentane, cyclohexane, furan, tetrahydrofuran, tetrahydropyranyl, pyrroleyl, piperidinyl, morpholinyl, phenyl, naphthyl or pyridinyl, optionally substituted with one, two or three substituents selected from -OH, -CN, Cl, Br, I, -CH3, -CH2CH3, -OCH3 and -OCH2CH3.

[0095] In some implementations, R 12 It can be independently H, deuterium, methyl, -C(=O)CH3, -P(=O)CH3CH3, -S(=O)(=O)CH3 or -C(=O)-NHCH3.

[0096] In some implementations, two R 12 Together with the ring atoms to which they are attached, they form optionally substituted C3-C7 cycloalkyl groups, optionally substituted 3-8 membered heterocyclic groups, and optionally substituted C6-C... 10 Aryl or optionally substituted 5-10 heteroaryl groups.

[0097] In some implementations, two R 12 Together with the ring atoms to which they are attached, they form optionally substituted C3-C7 cycloalkyl groups, optionally substituted C5-C8 cycloalkenyl groups, optionally substituted 3-8 membered heterocyclic groups, optionally substituted 4-7 membered heterocyclic alkenyl groups, and optionally substituted C6-C... 10 Aryl or optionally substituted 5-10 heteroaryl groups.

[0098] In some implementations, two R 12 Together with the ring atoms to which they are attached, they form optionally substituted C3-C7 cycloalkyl groups, optionally substituted C5-C8 cycloalkenyl groups, optionally substituted 3-8 membered heterocyclic groups, optionally substituted 4-7 membered heterocyclic alkenyl groups, and optionally substituted C6-C... 10 Aryl or optionally substituted 5-10-membered heteroaryl groups, wherein the optionally substituted C3-C7 cycloalkyl, optionally substituted C5-C8 cycloalkenyl, optionally substituted 3-8-membered heterocyclic group, optionally substituted 4-7-membered heterocyclic alkenyl, optionally substituted C6-C 10The aryl or optionally substituted 5-10-membered heteroaryl group is optionally substituted with one, two, three, four, or five substituents selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, C2-C6 haloynyl, C3-C7 cycloalkyl, 3-7-membered heterocyclic alkyl, 6-14-membered aryl, and 5-10-membered heteroaryl. In some embodiments, the optionally substituted C3-C7 cycloalkyl, optionally substituted C5-C8 cycloalkenyl, optionally substituted 3-8-membered heterocyclic, optionally substituted 4-7-membered heterocyclic alkenyl, optionally substituted C6-C 10 The aryl or optionally substituted 5-10 heteroaryl group is optionally substituted by one, two, three, four or five substituents selected from methyl, ethyl, methoxy, ethoxy, vinyl, propenyl, ethynyl, propynyl, -F, -Cl, -OH, -NH2, -CN and -NO2.

[0099] In one aspect of the present invention, R 12 Independently, -P=O(CH3)2, -P=O(CH2CH3)2, -OCH2-P=O(CH3)2, -COCH3, -CO(OCH3), -CO(NHCH3), -S(=O)2CH3, -NH-S(=O)2CH3,

[0100] In some implementations, two R 12 Together with the ring atoms to which they are attached, they form cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, oxacyclopentyl, pyrrolidinyl, or piperidinyl.

[0101] In some implementation schemes, R b Independently, it is an optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy group, wherein the optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy group is optionally substituted with a substituent selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, 3-7-membered heterocycloalkyl, 6-14-membered aryl, 5-10-membered heteroaryl.

[0102] In some implementations, R 12-4 The derivatives are H, deuterium, -F, -Cl, oxo, methyl, ethyl, fluoromethyl, fluoroethyl, difluoromethyl, methoxy, propenyl, and propynyl.

[0103] In some implementations, R 12-5The derivatives are H, deuterium, -F, -Cl, oxo, methyl, ethyl, fluoromethyl, fluoroethyl, difluoromethyl, methoxy, propenyl, and propynyl.

[0104] In some implementations, R 12-6 The derivatives are H, deuterium, -F, -Cl, oxo, methyl, ethyl, fluoromethyl, fluoroethyl, difluoromethyl, methoxy, propenyl, and propynyl.

[0105] In some implementations, R 12-7 The derivatives are H, deuterium, -F, -Cl, oxo, methyl, ethyl, fluoromethyl, fluoroethyl, difluoromethyl, methoxy, propenyl, and propynyl.

[0106] In some implementations, R 12-8 The derivatives are H, deuterium, -F, -Cl, oxo, methyl, ethyl, fluoromethyl, fluoroethyl, difluoromethyl, methoxy, propenyl, and propynyl.

[0107] This invention provides a compound of formula (II), a pharmaceutically acceptable salt thereof, an isotopic substitute thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof:

[0108] in,

[0109] Y 1 For N or CR a ;

[0110] Y 2 For N or CR a ;

[0111] Y 3 For N or CR a ;

[0112] Z 1 For N or CR b ;

[0113] Z 2 For N or CR b ;

[0114] Z 3 For N or CR b ;

[0115] U 1 For bond, O, NR c or CR d R e ;

[0116] U 2 For bond, O, NR c or CR d R e;

[0117] R a Independently, H, deuterium, halogen, -CN, -NO2, -OH, -OR a1 Optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7-membered heterocycloalkyl or optionally substituted 5-10-membered heteroaryl, wherein the heteroatoms in the 3-7-membered heterocycloalkyl and 5-10-membered heteroaryl are each independently selected from one or more of N, O, S and P, and the number of heteroatoms is each independently 1, 2 or 3;

[0118] R a1 Optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic alkyl, optionally substituted C6-C 14 The aryl or optionally substituted 5-10-membered heteroaryl groups, wherein the heteroatoms in the 3-7-membered heterocyclic alkyl and 5-10-membered heteroaryl groups are each independently selected from one or more of N, O, S and P, and the number of heteroatoms is independently 1, 2 or 3.

[0119] R b Independently, H, deuterium, halogen, -OH, -CN, -OR 2 -S(=O)2C1-C6 alkyl, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy;

[0120] R 2 H, deuterium, halogen, -CN, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocycloalkyl, optionally substituted C6-C 14 Aryl, optionally substituted 5-10-membered heteroaryl or optionally substituted C1-C6 alkyl, wherein the 3-7-membered heterocyclic alkyl and 5-10-membered heteroaryl are each independently one or more of N, O, S and P, and the number of heteroatoms is independently one, two or three.

[0121] R c Independently H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic alkyl, optionally substituted C6-C 14 The aryl or optionally substituted 5-10-membered heteroaryl groups, wherein the heteroatoms in the 3-7-membered heterocyclic alkyl and 5-10-membered heteroaryl groups are each independently selected from one or more of N, O, S and P, and the number of heteroatoms is independently 1, 2 or 3.

[0122] R d Independently, it is H, deuterium, or an optionally substituted C1-C6 alkyl group;

[0123] Re Independently, it is H, deuterium, or an optionally substituted C1-C6 alkyl group;

[0124] R 1 The following are optional substituted C1-C6 alkyl groups, optional C3-C7 cycloalkyl groups, optional substituted 3-7 heterocyclic alkyl groups, and optional substituted C6-C6 alkyl groups: (not present, H, deuterium, optional substituted C1-C6 alkyl groups, optional substituted C3-C7 cycloalkyl groups, optional substituted 3-7 heterocyclic alkyl groups, optional substituted C6-C6 cycloalkyl groups). 14 The aryl or optionally substituted 5-10-membered heteroaryl groups, wherein the heteroatoms in the 3-7-membered heterocyclic alkyl and 5-10-membered heteroaryl groups are each independently selected from one or more of N, O, S and P, and the number of heteroatoms is independently 1, 2 or 3.

[0125] R 3 and R 4 Each is independently H, halogen, or optionally substituted C1-C6 alkyl;

[0126] R 9 It is a C1-C6 alkyl group consisting of H, deuterium, halogen, or optional substitution;

[0127] X represents a bond, O, N, S, or CR. f ;

[0128] R f It is a C1-C6 alkyl group consisting of H, deuterium, halogen, or optional substitution;

[0129] W represents a bond, O, S, N, or CR. 8 ;

[0130] R 8 It is a C1-C6 alkyl group consisting of H, deuterium, halogen, or optional substitution;

[0131] Q 1 For bond, O, S, N or CR q1 ;

[0132] R q1 It is a C1-C6 alkyl group consisting of H, deuterium, halogen, or optional substitution;

[0133] Q 2 For bond, O, S, N or CR q2 ;

[0134] R q2 It is a C1-C6 alkyl group consisting of H, deuterium, halogen, or optional substitution;

[0135] X, W, Q 1 and Q 2 Not both are keys;

[0136] L represents a bond, and can be optionally substituted with C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C3-C8 cycloalkyl, or substituted with a 3-8 membered heterocyclic group.

[0137] Ring A may or may not be present. When present, it is a cycloalkyl, heterocyclic alkene, or heteroaromatic ring. In the heterocyclic alkene and heteroaromatic ring, the heteroatom is independently selected from one or more of N, O, S, and P, and the number of heteroatoms is 1, 2, or 3.

[0138] R 5 Independently, it can be H, deuterium, halogen, -OH, -NH2, or -NHR. 5-1 Optionally substituted C1-C6 alkyl, Optionally substituted C1-C6 alkoxy, Optionally substituted C2-C6 alkenyl, Optionally substituted C2-C6 alkynyl, Optionally substituted C3-C 12 Cycloalkyl, optionally substituted C5-C8 cycloalkenyl, optionally substituted 3-12-membered heterocyclic, optionally substituted 5-8-membered heterocyclic, optionally substituted C6-C 14 aryl, optionally substituted 5-10 heteroaryl, -P=OR 5-2 R 5-3 -R 5-4 -P=OR 5- 2 R 5-3 -SR 5-5 (R 5-6 )2 or -NR 5-7 (R 5-8 );

[0139] R 5-1 The substituted C1-C6 alkyl group is optional.

[0140] R 5-2 H, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic alkyl;

[0141] R 5-2 H, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic alkyl; or,

[0142] R 5-2 R 5-3 Together with the P atoms attached to them, they form optionally substituted heterocyclic alkyl groups or optionally substituted 5-10-membered heteroaryl groups;

[0143] R 5-4It can be an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted 3-7-membered heterocyclic alkyl, or an optionally substituted 5-10-membered heteroaryl;

[0144] R 5-5 Each R 5-6 R 11-7 R 11-8 Each can be independently H, deuterium, halogen, -OH, -NH2, -CN, -NO2, oxo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl;

[0145] n is 0, 1, 2, 3 or 4;

[0146] Or, two R atoms on the same carbon atom 5 Together form = O;

[0147] R 6 and R 7 These are two substituents on the same carbon atom;

[0148] R 6 and R 7 The carbon atoms connected to them together form an optionally substituted C3-C7 saturated carbon ring or an optionally substituted 3-7 membered saturated heterocycle, wherein the heteroatom or heteroatom group in the 3-7 membered saturated heterocycle is selected from one or more of N, O, S, C(=O), S(=O) and S(=O)2, and the number of heteroatoms is 1, 2 or 3.

[0149] The ring C is an optional substituted C3-C7 cycloalkyl, an optional substituted 3-8-membered heterocyclic group, an optional substituted 5-10-membered aryl group, or an optional substituted 5-10-membered heteroaryl group;

[0150] R 10 Independently, it is H, deuterium, halogen, -OH, -NH2, -CN, -NO2, oxo, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkoxy, optionally substituted C3-C8 cycloalkyl, optionally substituted 3-8 membered heterocyclic group, optionally substituted C6-C 10 Aryl, or optionally substituted 5-10 heteroaryl;

[0151] m can be 0, 1, 2, 3, or 4;

[0152] R 11Independently, it is H, deuterium, halogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C5-C8 cycloalkenyl, optionally substituted 3-8 membered heterocyclic group, optionally substituted 4-7 membered heterocyclic alkenyl, optionally substituted C6-C 10 aryl, optionally substituted 5-10 heteroaryl, -P=OR 11-1 R 11-2 -R 11-3 -P=OR 11-1 R 11-2 -SR 11- 4 (R 11-5 (R) 11-6 -NR 11-7 (R 11-8 ) or -R 11-9 -S(=O)2R 11-10 ;

[0153] R 11-1 H, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic alkyl;

[0154] R 11-2 H, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic alkyl; or,

[0155] R 11-1 R 11-2 Together with the P atoms attached to them, they form optionally substituted 3-7-membered heterocyclic alkyl groups or optionally substituted 5-10-membered heteroaryl groups;

[0156] R 11-3 It can be an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted 3-7-membered heterocyclic alkyl, or an optionally substituted 5-10-membered heteroaryl;

[0157] R 11-4 It can be H, deuterium, halogen, -OH, -NH2, -CN, -NO2, oxo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl;

[0158] R 11-5It can be H, deuterium, halogen, -OH, -NH2, -CN, -NO2, oxo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl;

[0159] R 11-6 It can be H, deuterium, halogen, -OH, -NH2, -CN, -NO2, oxo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl;

[0160] R 11-7 It can be H, deuterium, halogen, -OH, -NH2, -CN, -NO2, oxo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl;

[0161] R 11-8 It can be H, deuterium, halogen, -OH, -NH2, -CN, -NO2, oxo, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl;

[0162] R 11-9 It is a C1-C6 alkylene group that is absent, NH, or optionally substituted;

[0163] R 11-10 H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;

[0164] Or, two Rs 11 Together with the ring atoms to which they are attached, they form optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkenyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0165] y can be 0, 1, 2, 3 or 4.

[0166] In some embodiments, the groups in formula (II) are defined as described in any embodiment of the present invention.

[0167] In some implementations, R a Independently, it can be H, halogen, -CN, -NO2, -OH, or -OR. a1The alternatively substituted C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 heterocyclic alkyl, or 5-10 heteroaryl groups, wherein the heteroatoms in the 3-7 heterocyclic alkyl and 5-10 heteroaryl groups are each independently selected from one or more of N, O, S, and P, and the number of heteroatoms is independently 1, 2, or 3.

[0168] In some implementations, R b Independently H, halogen, -OH, -CN, -OR 2 -S(=O)2C1-C6 alkyl, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy.

[0169] In some implementations, R 2 H, halogen, -CN, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic alkyl, optionally substituted C6-C 14 The aryl group, optionally substituted 5-10-membered heteroaryl group, or optionally substituted C1-C6 alkyl group, wherein the heteroatom in the 3-7-membered heterocyclic alkyl group and the 5-10-membered heteroaryl group is independently one or more of N, O, S and P, and the number of heteroatoms is independently one, two or three.

[0170] In some implementations, R 9 It is H, halogen, or optionally substituted C1-C6 alkyl.

[0171] In some implementations, R f It is H, halogen, or optionally substituted C1-C6 alkyl.

[0172] In some implementations, R 8 It is H, halogen, or optionally substituted C1-C6 alkyl.

[0173] In some implementations, Q 1 For bond, N, S or CR q1 R q1 It is a C1-C6 alkyl group consisting of H, deuterium, halogen, or optionally substituted C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted by one, two, or three of deuterium and halogen.

[0174] In some implementations, Q 1 For bond, O, S, N or CR q1 ;R q1 It is H, halogen, or optionally substituted C1-C6 alkyl.

[0175] In some implementations, R q1The substituted compounds are H, deuterium, F, Cl, methyl, ethyl, propyl, or butyl, wherein the methyl, ethyl, propyl, and butyl compounds are optionally substituted by one, two, or three of the substituted compounds selected from deuterium, F, and Cl.

[0176] In some implementations, Q 2 For bond, O, S, N or CR q2 ;R q2 It is H, halogen, or optionally substituted C1-C6 alkyl.

[0177] In some implementations, Q 2 For bond, N, S or CR q2 R q2 It is a C1-C6 alkyl group consisting of H, deuterium, halogen, or optionally substituted C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted by one, two, or three of deuterium and halogen.

[0178] In some implementations, R q2 The substituted compounds are H, deuterium, F, Cl, methyl, ethyl, propyl, or butyl, wherein the methyl, ethyl, propyl, and butyl compounds are optionally substituted by one, two, or three of the substituted compounds selected from deuterium, F, and Cl.

[0179] In some implementations, X is N, S, or CR f .

[0180] In some implementations, W is N or CR 8 .

[0181] In some implementations, Q 1 For bond, N or CR q1 R q1 It is H, a halogen, or an optionally substituted C1-C6 alkyl group. In some embodiments, R q1 It can be H, F, Cl, Br, I, or CH3.

[0182] In some implementations, Q 2 For bond, N or CR q2 CR q2 It is H, a halogen, or an optionally substituted C1-C6 alkyl group. In some embodiments, R q2 It can be H, F, Cl, Br, I, or CH3.

[0183] In some implementations, R 5 Independently, it can be H, deuterium, halogen, -OH, -NH2, or -NHR. 5-1 Optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy, -P=OR 5-2 R 5-3 or -R 5-4 -P=OR 5-2 R5-3 .

[0184] In some implementations, R 5 Independently, it can be H, deuterium, halogen, -OH, -NH2, or -NHR. 5-1 Optionally substituted C1-C6 alkyl, Optionally substituted C1-C6 alkoxy, Optionally substituted C2-C6 alkenyl, Optionally substituted C2-C6 alkynyl, Optionally substituted C3-C 12 Cycloalkyl, optionally substituted C5-C8 cycloalkenyl, optionally substituted 3-12-membered heterocyclic, optionally substituted 5-8-membered heterocyclic, optionally substituted C6-C 14 aryl, optionally substituted 5-10 heteroaryl, -P=OR 5- 2 R 5-3 -R 5-4 -P=OR 5-2 R 5-3 -SR 5-5 (R 5-6 )2 or -NR 5-7 (R 5-8 ), wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 12 Cycloalkyl, C5-C8 cycloalkenyl, 3-12 membered heterocyclic, 5-8 membered heterocyclic, C6-C 14 Aryl and 5-10-membered heteroaryl groups are optionally selected from deuterium, halogen, -OH, -NH2, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8-membered heterocyclic, C6-C 14 One, two, or three of the following are substituted: aryl, 5-10-membered heteroaryl, or 5-8-membered heterocyclic alkenyl. In some embodiments, the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C... 12 Cycloalkyl, C5-C8 cycloalkenyl, 3-12 membered heterocyclic, 5-8 membered heterocyclic, C6-C 14 Aryl and 5-10 heteroaryl groups are optionally selected from deuterium, oxo, halogen, -OH, -NH2, -N(R) -9 )2、-CN、C1-C6 alkyl、halogenated C1-C6 alkyl、C1-C6 alkoxy、C2-C6 alkenyl、C2-C6 alkynyl、C3-C8 cycloalkyl、3-8 membered heterocyclic group、C6-C 14 One, two, three, or four substitutions are made in aryl, 5-10-membered heteroaryl, and 5-8-membered heterocyclic alkenyl groups, wherein R 5-9Each can be independently H, deuterium, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, -C(=O)C1-C6 alkyl, -C(=O)C1-C6 alkenyl or -C(=O)C1-C6 alkynyl.

[0185] In some implementations, R 5-5 Each R 5-6 R 11-7 R 11-8 Each can be independently H, deuterium, -F, -Cl, oxo, methyl, ethyl, fluoromethyl, fluoroethyl, difluoromethyl, methoxy, propenyl, or propynyl.

[0186] In some implementation schemes, R 5 They are -SH(=O)2, SCH3(=O)2, -SF(=O)2, -S(CH=CH2)(=O)2, -S(CH≡CH)(=O)2.

[0187] In some implementations, R 5 Independently, -P=O(CH3)2, -P=O(CH2CH3)2, -OCH2-P=O(CH3)2, -COCH3, -CO(OCH3), -CO(NHCH3), -S(=O)2CH3, -NH-S(=O)2CH3,

[0188] In some embodiments, ring A may be absent or present. When present, it is a 4-7 membered heterocyclic alkene or a 5-10 membered heteroaromatic ring, wherein the heteroatom in the 4-7 membered heterocyclic alkene and the 5-10 membered heteroaromatic ring is independently selected from one or more of N, O, S and P, and the number of heteroatoms is 1, 2 or 3.

[0189] In some embodiments, ring A may be absent or present, and when present, it may be a C3-C8 cycloalkyl group, a 3-8 membered heterocyclic alkene, or a 5-10 membered heteroaromatic ring, wherein the heterocyclic alkene and heteroaromatic ring are present.

[0190] In some embodiments, the ring C is an optionally substituted C3-C7 cycloalkyl, an optionally substituted C3-C7 heterocyclic, an optionally substituted 5-10 aryl, or an optionally substituted 5-10 heteroaryl.

[0191] In some implementations, R 11 Independently, it is H, deuterium, halogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, -P=OR 11-1 R 11-2 or -R11-3 -P=OR 11-1 R 11-2 .

[0192] In some implementations, R 11 Independently, it is H, deuterium, halogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C5-C8 cycloalkenyl, optionally substituted 3-8 membered heterocyclic group, optionally substituted 4-7 membered heterocyclic alkenyl, optionally substituted C6-C 10 aryl, optionally substituted 5-10 heteroaryl, -P=OR 11-1 R 11-2 -R 11- 3 -P=OR 11-1 R 11-2 -SR 11-4 (R 11-5 (R) 11-6 ) or -NR 11-7 (R 11-8 ).

[0193] In some implementations, R 11 Independently, it is H, deuterium, halogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C5-C8 cycloalkenyl, optionally substituted 3-8 membered heterocyclic group, optionally substituted 4-7 membered heterocyclic alkenyl, optionally substituted C6-C 10 Aryl, optionally substituted 5-10-membered heteroaryl, wherein optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C5-C8 cycloalkenyl, optionally substituted 3-8-membered heterocyclic, optionally substituted 4-7-membered heterocyclic alkenyl, optionally substituted C6-C 10 aryl, optionally substituted 5-10-membered heteroaryl, optionally selected from deuterium, halogen, -OH, -NH2, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8-membered heterocyclic, C6-C 10 Aryl, 5-10 membered heteroaryl, 4-7 membered heterocyclic alkenyl.

[0194] In some implementations, two R 11Together with the ring atoms to which they are attached, they form optionally substituted C3-C7 cycloalkyl groups, optionally substituted 3-8 membered heterocyclic groups, and optionally substituted C6-C... 10 Aryl or optionally substituted 5-10 heteroaryl groups.

[0195] In some implementations, two R 11 Together with the ring atoms to which they are attached, they form optionally substituted C3-C7 cycloalkyl groups, optionally substituted C5-C8 cycloalkenyl groups, optionally substituted 3-8 membered heterocyclic groups, optionally substituted 4-7 membered heterocyclic alkenyl groups, and optionally substituted C6-C... 10 Aryl or optionally substituted 5-10 heteroaryl groups.

[0196] In some implementations, two R 11 Together with the ring atoms to which they are attached, they form optionally substituted C3-C7 cycloalkyl groups, optionally substituted C5-C8 cycloalkenyl groups, optionally substituted 3-8 membered heterocyclic groups, optionally substituted 4-7 membered heterocyclic alkenyl groups, and optionally substituted C6-C... 10 Aryl or optionally substituted 5-10-membered heteroaryl groups, wherein the optionally substituted C3-C7 cycloalkyl, optionally substituted C5-C8 cycloalkenyl, optionally substituted 3-8-membered heterocyclic group, optionally substituted 4-7-membered heterocyclic alkenyl, optionally substituted C6-C 10 The aryl or optionally substituted 5-10-membered heteroaryl group is optionally substituted with one, two, three, four, or five substituents selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, C2-C6 haloynyl, C3-C7 cycloalkyl, 3-7-membered heterocyclic alkyl, 6-14-membered aryl, and 5-10-membered heteroaryl. In some embodiments, the optionally substituted C3-C7 cycloalkyl, optionally substituted C5-C8 cycloalkenyl, optionally substituted 3-8-membered heterocyclic, optionally substituted 4-7-membered heterocyclic alkenyl, optionally substituted C6-C 10 The aryl or optionally substituted 5-10 heteroaryl group is optionally substituted by one, two, three, four or five substituents selected from methyl, ethyl, methoxy, ethoxy, vinyl, propenyl, ethynyl, propynyl, -F, -Cl, -OH, -NH2, -CN and -NO2.

[0197] In some implementations, two R 11Together with the ring atoms to which they are attached, they form cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, oxacyclopentyl, pyrrolidinyl, or piperidinyl groups; in some embodiments, the cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, oxacyclopentyl, pyrrolidinyl, or piperidinyl groups are optionally substituted with one, two, three, four, or five substituents selected from methyl, ethyl, methoxy, ethoxy, vinyl, propynyl, ethynyl, propynyl, -F, -Cl, -OH, -NH2, -CN, and -NO2.

[0198] In some implementations, R 11 Independently, -P=O(CH3)2, -P=O(CH2CH3)2, -OCH2-P=O(CH3)2, -COCH3, -CO(OCH3), -CO(NHCH3), -S(=O)2CH3, -NH-S(=O)2CH3,

[0199] In some implementation schemes, R b Independently, it is an optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy group, wherein the optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy group is optionally substituted with a substituent selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, 3-7-membered heterocycloalkyl, 6-14-membered aryl, 5-10-membered heteroaryl.

[0200] In some implementations, R 11-4 R 11-5 R 11-6 R 11-7 and R 11-8 Each can be independently H, deuterium, -F, -Cl, oxo, methyl, ethyl, fluoromethyl, fluoroethyl, difluoromethyl, methoxy, propenyl, or propynyl.

[0201] In some implementations, R 11-9 For non-existent, NH, -CH2- or -CH2CH2-.

[0202] In some implementations, R 11-10The C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, 3-7 heterocyclic alkyl, 5-10 aryl, or 5-10 heteroaryl groups are optionally substituted with H, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, 3-7 heterocyclic alkyl, or 5-10 heteroaryl groups, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, 3-7 heterocyclic alkyl, or 5-10 heteroaryl groups are optionally substituted with one, two, or three substituents selected from -OH, -CN, Cl, Br, I, -CH3, -CH2CH3, -OCH3, and -OCH2CH3.

[0203] In some implementations, R 11-10 The derivatives are H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2(CH2)CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH2)CH3, cyclopropane, cyclobutane, cyclopentane, cyclohexane, furan, tetrahydrofuran, tetrahydropyranyl, pyrroleyl, piperidinyl, morpholinyl, phenyl, naphthyl, or pyridinyl, wherein -CH3, -CH2CH3, -CH2CH2CH3, -CH2( CH2)CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH2)CH3, cyclopropane, cyclobutane, cyclopentane, cyclohexane, furan, tetrahydrofuran, tetrahydropyranyl, pyrroleyl, piperidinyl, morpholinyl, phenyl, naphthyl or pyridinyl, optionally substituted with one, two or three substituents selected from -OH, -CN, Cl, Br, I, -CH3, -CH2CH3, -OCH3 and -OCH2CH3.

[0204] In certain embodiments of the present invention, certain groups in the compounds represented by formula (II) or formula (II-A), their pharmaceutically acceptable salts, isotopic substitutes, their solvates or solvates of their pharmaceutically acceptable salts are defined as follows, and groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in one embodiment of the present invention" or "in some embodiments").

[0205] In one embodiment of the present invention, each “C1-C6 alkyl” is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0206] In one embodiment of the present invention, each “C1-C6 alkyl” is independently methyl.

[0207] In one embodiment of the present invention, each “C3-C7 cycloalkyl group” is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0208] In one embodiment of the present invention, each “C3-C7 cycloalkyl” or “cycloalkyl” is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0209] In one embodiment of the present invention, each “C3-C7 cycloalkyl” is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0210] In one embodiment of the present invention, each “C3-C7 cycloalkyl” or “cycloalkyl” is independently cyclopropyl.

[0211] In one embodiment of the present invention, each “C3-C7 cycloalkyl group” is independently cyclopropyl.

[0212] In one embodiment of the present invention, each "3-7 membered heterocyclic alkyl", "3-8 membered heterocyclic alkyl" or "heterocyclic alkyl" is independently an oxacyclobutane, an azacyclobutane, a tetrahydropyrrole, a tetrahydrofuran, a dioxacyclopentane, a tetrahydropyran, a dioxacyclohexane, a piperidinyl, a tetrahydrothiaranyl, a morpholinyl, a piperazine, a phosphacene, an oxacyclohexane, or an oxaazabicycloheptane.

[0213] In one embodiment of the present invention, each “3-7 membered heterocyclic alkyl”, “3-8 membered heterocyclic alkyl” or “heterocyclic alkyl” is independently an oxocyclic butyl, an azocyclic butyl, a tetrahydropyrrole, a tetrahydrofuranyl, a tetrahydropyranyl, a piperidinyl, a morpholinyl, or a piperazine.

[0214] In one embodiment of the present invention, each "3-7 membered heterocyclic alkyl group" is independently an oxocyclic butyl group, an azacyclic butyl group, a tetrahydropyrroleyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a piperidinyl group, a morpholinyl group, or a piperazineyl group.

[0215] In one embodiment of the present invention, each “3-7 membered heterocyclic alkyl”, “3-8 membered heterocyclic alkyl” or “heterocyclic alkyl” is independently an oxocyclic butyl, an azacyclic butyl, a tetrahydropyrrole, a tetrahydrofuranyl, a tetrahydropyranyl, a piperidinyl, a morpholinyl, a piperazine, a tetrahydrothiaranyl, a phosphacene, or an oxophosphacene.

[0216] In one embodiment of the present invention, each "3-7 membered heterocyclic alkyl group" is independently oxocyclic butyl, azacyclic butyl, tetrahydropyrrole, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazine, tetrahydrothiaranyl, phosphacene or oxophosphacene.

[0217] In one embodiment of the present invention, each “3-7 membered heterocyclic alkyl”, “3-8 membered heterocyclic alkyl” or “heterocyclic alkyl” is independently a phosphacene or oxyphosphacene.

[0218] In one embodiment of the present invention, each "3-7 membered heterocyclic alkyl group" is independently either phosphacyclopentane or oxyphosphacyclohexane.

[0219] In one embodiment of the present invention, each "5-10 heteroaryl group" is independently furanyl, thiophene, pyrazolyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl.

[0220] In one embodiment of the present invention, each “5-10 heteroaryl” or “heteroaryl” is independently furanyl, thiophene, pyrazolyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl.

[0221] In one embodiment of the present invention, each "aryl" is independently phenyl, naphthyl, anthraceneyl, or phenanthrene.

[0222] In one embodiment of the present invention, each "C6-C" 14 Each aryl group can be either phenyl or naphthyl.

[0223] In one embodiment of the present invention, each "halogen" is independently F, Cl, Br or I.

[0224] In one embodiment of the invention, each "halogen" is independently F.

[0225] In one embodiment of the present invention, each "alkoxy group" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, methylbutoxy, dimethylpropoxy, ethylpropoxy, n-hexoxy, methylpentoxy, ethylbutoxy, ethylmethylpropoxy, dimethylbutoxy, or trimethylpropoxy.

[0226] In one embodiment of the present invention, each “C1-C6 alkoxy” is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0227] In one embodiment of the present invention, each "heterocyclic alkene" is independently a 4-12 member heterocyclic alkene with O, S and / or N heteroatoms, and the number of heteroatoms is 1, 2 or 3.

[0228] In one embodiment of the present invention, each “4-7 membered heterocyclic alkene” is independently a 4-7 membered heterocyclic alkene with heteroatoms of O, S and / or N, and the number of heteroatoms is 1, 2 or 3.

[0229] In one embodiment of the present invention, each "heterocyclic alkene" is independently a 5-6 membered heterocyclic alkene with one or two heteroatoms, consisting of O and / or N heteroatoms.

[0230] In one embodiment of the present invention, each “4-7 membered heterocyclic alkene” is independently a 5-6 membered heterocyclic alkene with O and / or N heteroatoms, and the number of heteroatoms is 1 or 2.

[0231] In one embodiment of the present invention, each "4-7 membered heterocyclic alkene" is independently a dihydrofuran ring, a dihydropyran ring, or a dihydropyrrole ring.

[0232] In one embodiment of the present invention, each "4-7 membered heterocyclic ene" is independently...

[0233] In one embodiment of the present invention, each “3-10 member heterocyclic group” or “3-8 member heterocyclic group” is independently tetrahydropyrrole or piperidinyl.

[0234] In one embodiment of the invention, each "3-10 membered heterocyclic group" is independently tetrahydropyrrole, piperidinyl, dihydropyrazolothiazine, dihydropyrazoloxazine, or dihydrothienopiperidine. In another embodiment of the invention, each "5-10 membered heteroaromatic ring" is independently a 5-6 membered heteroaromatic ring, such as a furan ring, thiophene ring, pyrazole ring, thiazole ring, imidazole ring, pyrazole ring, oxazole ring, isoxazole ring, pyridine ring, pyrimidine ring, pyrazine ring, or pyridazine ring.

[0235] In one embodiment of the present invention, each “C3-C7 saturated carbon ring” is independently cyclopropane, cyclobutane, cyclopentane or cyclohexane.

[0236] In one embodiment of the present invention, each “C3-C7 saturated carbon ring” is independently cyclopropane, cyclobutane, cyclopentane, cyclohexane or cycloheptane.

[0237] In one embodiment of the present invention, each “C3-C7 saturated carbon ring” is independently cyclopropane.

[0238] In one embodiment of the present invention, each “3-7 member saturated heterocycle” is independently an oxacyclopropane, an azacyclopropane, an oxacyclobutane, an azacyclobutane, a tetrahydropyrrole ring, a tetrahydrofuran ring, a tetrahydropyran ring, a piperidine ring, a morpholine ring, a piperazine ring, or a tetrahydrothiaran ring.

[0239] In one embodiment of the present invention, each “C5-C8 cycloalkenyl” is independently cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cycloheptadienyl, cyclooctenyl, cyclooctadienyl or cycloocttrienyl.

[0240] In one embodiment of the present invention, each "3-10 membered heterocyclic alkyl" or "heterocyclic alkyl" is independently oxetane, azirne, tetrahydropyrrole, tetrahydrofuran, dioxetane, tetrahydropyran, dioxetane, piperidinyl, morpholinyl, piperazine, thiohexane, phosphonone, oxophoxetane, oxetane, thiohexane, azispiro[3.3]heptane, azispiro[3.3]heptane, azispiro[3.4]octane, azispiro[3.4]octane, azispiro[3.5]nonane, azispiro[3.5]nonane, azispiro[4.5]decane, azispiro[4.5]decane,

[0241] In one embodiment of the present invention, each “5-8 membered heterocyclic alkenyl” or “heterocyclic alkenyl” is independently dihydrofuranyl, dihydropyrroleyl, dihydropyranyl, azircyclohexenyl, dihydropyridyl, pyranyl, dihydropyranyl, thiaran, dihydrothiaranyl, azircycloheptenyl or azircycloheptendienyl.

[0242] In one embodiment of the present invention, each of the “4-7 membered heterocyclic alkene”, “5-8 membered heterocyclic alkenyl” or “heterocyclic alkenyl” is independently dihydrofuranyl, dihydropyrroleyl, dihydropyranyl, azircyclohexenyl, dihydropyridyl, pyranyl, dihydropyranyl, thiaran, dihydrothiaranyl, azircycloheptenyl or azircycloheptenadienyl.

[0243] In one embodiment of the present invention, the isotope substitute is a deuterium-substituted product.

[0244] In one aspect of this invention, Y 1 For CR a , where R a It is H, halogen, C1-C6 alkoxy, halo-C1-C6 alkyl, or C1-C6 alkyl substituted with one or more 5-10 heteroaryl groups, wherein the heteroatom in the 5-10 heteroaryl group is independently selected from one or more of N, O, S, and P, and the number of heteroatoms is independently 1, 2, or 3.

[0245] In one aspect of this invention, Y 1 For CF or CH.

[0246] In one aspect of this invention, Y 2 For CR a , where R a It can be H, halogen, C1-C6 alkoxy or halogenated C1-C6 alkyl.

[0247] In one aspect of this invention, Y 2 For CH.

[0248] In one aspect of this invention, Y 3 For CR a , where R a It can be H, halogen, C1-C6 alkoxy or halogenated C1-C6 alkyl.

[0249] In one aspect of this invention, Y 3 For CH.

[0250] In one aspect of this invention, Z 1 For CH.

[0251] In one aspect of this invention, Z 2 For CH.

[0252] In one aspect of this invention, Z 3 For CH.

[0253] In one aspect of the present invention, U 1 For bond, O or NR c .

[0254] In one aspect of the present invention, U 1 For key.

[0255] In one aspect of the present invention, U 1 It is O.

[0256] In one aspect of the present invention, U 2 For key or NR c .

[0257] In one aspect of the present invention, U 2 It is a bond or NH or N(CH3).

[0258] In one aspect of the present invention, U 1 for O,U 2 For NR c .

[0259] In one aspect of the present invention, U 1 For NR c U 2 For key.

[0260] In one aspect of the present invention, R c It is a C1-C6 alkyl, a C1-C6 alkyl substituted with one or more deuterium, a halo-C1-C6 alkyl, or a C3-C6 saturated cycloalkyl.

[0261] In one aspect of the present invention, R c It is a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one, two or three deuterium atoms.

[0262] In one aspect of the present invention, Rc It is a methyl group, a methyl group substituted with one, two or three deuterium groups, a fluoromethyl group or a cyclopropyl group.

[0263] In one aspect of the present invention, R c It is a methyl group or a methyl group substituted with one, two or three deuterium groups.

[0264] In one aspect of the present invention, R c Methyl, Fluoromethyl or cyclopropyl.

[0265] In one aspect of the present invention, R c Methyl or

[0266] In one aspect of the present invention, R 2 It is a C1-C6 alkyl group substituted with one or more halogens.

[0267] In one aspect of the present invention, R 2 A methyl group that is substituted with one, two, or three F atoms.

[0268] In one aspect of the present invention, R 2 for

[0269] In one aspect of the present invention, R 3 It is H or halogen.

[0270] In one aspect of the present invention, R 3 It can be H or F.

[0271] In one aspect of the present invention, R 4 It is H or halogen.

[0272] In one aspect of the present invention, R 4 It can be H or F.

[0273] In one aspect of the present invention, R 3 and R 4 All are H.

[0274] In one aspect of the present invention, R 3 and R 4 All are F.

[0275] In one aspect of the present invention, R 9 It is H or C1-C6 alkyl.

[0276] In one aspect of the present invention, R 9 It is H or methyl.

[0277] In one aspect of the present invention, each R... 5 None of them contain P atoms.

[0278] In one aspect of the present invention, each R... 5 It can be independently H, deuterium, fluorine, -OH, -NH2, -NH-C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy or halo-C1-C6 alkyl.

[0279] In one aspect of the present invention, each R... 5 It can be -NH2, methyl, difluoromethyl or methoxy.

[0280] In one aspect of the present invention, each R... 5 Independently -NH2.

[0281] In one aspect of the present invention, R 6 and R 7 The carbon atoms connected to them together form a group consisting of one, two, or three R atoms. s1 Substituted 3-6 saturated heterocycles, R s1 Independently deuterium, halogen, oxo, -OH, -NH2, -NHR 5-1 Or optionally substituted C1-C6 alkyl groups.

[0282] In one aspect of the present invention, R 6 and R 7 The carbon atoms connected to them together form a group consisting of one, two, or three R atoms. s1 Substituted 3-6 saturated heterocycles, R s1 Independently deuterium, halogen, oxo, -OH, -NH2, -NHR 5-1 C1-C6 alkyl or halogenated C1-C6 alkyl.

[0283] In one aspect of the present invention, R 6 and R 7 The carbon atoms bonded to them together form a C3-C6 saturated carbon ring or a 3-6 membered saturated heterocycle; the C3-C6 saturated carbon ring or the 3-6 membered saturated heterocycle may optionally be substituted by 1-3 substituents, which are independently selected from deuterium, halogen, -OH, oxo, -NH2, and -NHR. 5-1 Or halogenated C1-C6 alkyl groups.

[0284] In one aspect of the present invention, R 6 and R 7 The carbon atoms connected to them together form a group consisting of one, two, or three R atoms. s1 Substituted 3-6 saturated heterocycles, R s1 Independently deuterium, halogen, -OH, -NH2, -NHR 5-1 Or optionally substituted C1-C6 alkyl groups.

[0285] In one aspect of the present invention, R 6 and R 7 The carbon atoms connected to them together form a group consisting of one, two, or three R atoms. s2 Replaced C3-C6 saturated carbon rings, R s2 Independently deuterium, halogen, oxo, -OH, -NH2, -NHR 5-1 Or optionally substituted C1-C6 alkyl groups.

[0286] In one aspect of the present invention, R 6 and R 7 The carbon atoms connected to them together form a group consisting of one, two, or three R atoms. s2 Replaced C3-C6 saturated carbon rings, R s2 Independently deuterium, halogen, -OH, oxo, -NH2, -NHR 5-1 Or halogenated C1-C6 alkyl groups.

[0287] In one aspect of the present invention, R 6 and R 7 The carbon atoms connected to them together form a group consisting of one, two, or three R atoms. s1 Substituted 3-6 saturated heterocycles, R s1 Independently deuterium, halogen, -OH, -NH2, -NHR 5-1 Or halogenated C1-C6 alkyl groups.

[0288] In one aspect of the present invention, R 6 and R 7 The carbon atoms connected to them together form a group consisting of one, two, or three R atoms. s2 Replaced C3-C6 saturated carbon rings, R s2 Independently deuterium, halogen, -OH, -NH2, -NHR 5-1 Or optionally substituted C1-C6 alkyl groups.

[0289] In one aspect of the present invention, R 6 and R 7 The carbon atoms connected to them together form a group consisting of one, two, or three R atoms. s2 Replaced C3-C6 saturated carbon rings, R s2 Independently deuterium, halogen, -OH, -NH2, -NHR 5-1 Or halogenated C1-C6 alkyl groups.

[0290] In one aspect of the present invention, R 6 and R 7 The carbon atoms connected to them together form C3-C6 saturated carbon rings.

[0291] In one aspect of the present invention, R 6 and R7 The carbon atoms connected to them together form cyclopropane, cyclobutane, oxocyclobutane, cyclopentane, cyclohexane, piperidine, epoxide, or tetrahydrothiaran, wherein the cyclopropane, cyclobutane, oxocyclobutane, cyclopentane, cyclohexane, piperidine, epoxide, or tetrahydrothiaran may optionally be substituted by one, two, or three substituents, wherein the substituents are independently selected from deuterium, fluorine, -OH, oxo, -NH2, -NHCH3, -N(CH3)2, trifluoromethyl, trifluoroethyl, or trifluoropropyl.

[0292] In one aspect of the present invention, R 6 and R 7 The carbon atoms bonded to them together form cyclopropane, cyclobutane, cyclopentane, cyclohexane, or tetrahydrothiaran, which may be substituted by one or two substituents, the substituents being independently selected from deuterium, fluorine, or oxo.

[0293] In one aspect of the present invention, R 6 and R 7 The carbon atoms bonded to them together form cyclopropane or cyclobutane.

[0294] In one aspect of the present invention, R 6 and R 7 The carbon atoms bonded to them together form cyclopropane.

[0295] In one embodiment of the present invention, X is N.

[0296] In one embodiment of the present invention, W is CH.

[0297] In one embodiment of the present invention, ring A is a 4-7 membered heterocyclic alkene, wherein the heteroatom is N and / or O, and the number of heteroatoms is 1 or 2.

[0298] In one embodiment of the present invention, ring A is a 5-6 membered heteroaromatic ring, wherein the heteroatom is N and / or O, and the number of heteroatoms is 1, 2 or 3.

[0299] In one embodiment of the present invention, ring A is a C3-C8 cycloalkyl group, and the C3-C7 cycloalkyl group is optionally -P=OR. 11- 1 R 11-2 or -R 11-3 -P=OR 11-1 R 11-2 replace.

[0300] In one embodiment of the present invention, ring A is a 3-8 member heterocyclic group, wherein the 3-8 member heterocyclic group is optionally converted to -P = OR 11- 1 R 11-2 or -R11-3 -P=OR 11-1 R 11-2 Substitution. In one embodiment, the 3-8 membered heterocyclic group is optionally substituted with -P=OCH3CH3.

[0301] In one embodiment of the invention, ring A is tetrahydropyrrolyl, piperidinyl, dihydropyrazolothiazine, dihydropyrazoloxazine, or dihydrothiophenepiperidine, wherein the tetrahydropyrrolyl, piperidinyl, dihydropyrazolothiazine, dihydropyrazoloxazine, or dihydrothiophenepiperidine is optionally converted to -P = OR 11-1 R 11-2 or -R 11-3 -P=OR 11-1 R 11-2 Replacement; in a given scheme, it is optionally replaced by -P=OCH3CH3.

[0302] In one embodiment of the present invention, rings A and R 6 and R 7 The carbon atoms connected to them together form optional substituted C3-C7 saturated carbon rings or optional substituted 3-7 membered saturated heterocycles with a total number of 7 ring atoms.

[0303] In one embodiment of the present invention, rings A and R 6 and R 7 The carbon atoms connected to them together form optional substituted C3-C7 saturated carbon rings or optional substituted 3-7 membered saturated heterocycles with a total number of ring atoms of 9-14.

[0304] In one embodiment of the present invention, rings A and R 6 and R 7 The carbon atoms bonded to them together form optional substituted C3-C7 saturated carbon rings or optional substituted 3-7 membered saturated heterocycles with a total number of ring atoms of 9-10. In one embodiment of the invention, R 10 Optionally selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic, C6-C 10 One or more substituted aryl and 5-10 membered heteroaryl groups, -NH2, -CN, -NO2, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic, C6-C 10 Aryl, or 5-10 heteroaryl.

[0305] In one embodiment of the present invention, each R 11 None of them contain P atoms.

[0306] In one aspect of the present invention, R 11 Independently and optionally selected from deuterium, halogen, -OH, -NH2, -CN, -NO2, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic, C6-C 10 One or more substituted aryl and 5-10 heteroaryl groups, -NH2, C1-C6 alkyl, C1-C6 alkoxy.

[0307] In one aspect of the present invention, for The carbon atoms marked with "*" have the configuration of R, S, or a mixture thereof.

[0308] In one aspect of the present invention, for The carbon atoms marked with "*" have the configuration of R, S, or a mixture thereof.

[0309] In one aspect of the present invention, for

[0310] In one aspect of the present invention, for

[0311] In one aspect of the present invention, for

[0312] In one aspect of the present invention, the compound represented by formula (II-A) is a compound represented by formula (II-B), a pharmaceutically acceptable salt thereof, an isotopically substituted derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof:

[0313] In the formula,

[0314] Q 3 For bond, O, S, N or CR q3 ;

[0315] CR q3 It is a C1-C6 alkyl group consisting of H, deuterium, halogen, or optional substitution;

[0316] Q 1 Q 2 Q 3 Three or more of W and X are not simultaneously used as keys.

[0317] The definitions of the remaining groups are as described in any embodiment of the present invention.

[0318] In some implementations, CR q3 It is H, halogen, or optionally substituted C1-C6 alkyl.

[0319] In some implementations, Q 3 For bond, N, S or CR q3 R q3 It is a C1-C6 alkyl group consisting of H, deuterium, halogen, or optionally substituted C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted by one, two, or three of deuterium and halogen.

[0320] In some implementations, R q3 The substituted compounds are H, deuterium, F, Cl, methyl, ethyl, propyl, or butyl, wherein the methyl, ethyl, propyl, and butyl compounds are optionally substituted by one, two, or three of the substituted compounds selected from deuterium, F, and Cl.

[0321] In one aspect of the present invention, the compound represented by formula (II) or (II-A) is a compound represented by formula (II-1):

[0322] Among them, R 5 Independently, it can be H, deuterium, halogen, -OH, -NH2, or -NHR. 5-1 Optionally substituted C1-C6 alkyl groups, Optionally substituted C1-C6 alkoxy groups;

[0323] R 5-1 The substituted C1-C6 alkyl group is optional.

[0324] n is 0, 1, 2, 3 or 4;

[0325] R 11 Independently, it is H, deuterium, halogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy;

[0326] y is 0, 1, 2, 3 or 4;

[0327] The definitions of the remaining groups are as described in any embodiment of the present invention.

[0328] In one aspect of the present invention, the compound represented by formula (II) is a compound represented by formula (II-2) or (II-3):

[0329] The definitions of each group are as described in any embodiment of the present invention.

[0330] In one aspect of the invention, the compounds represented as in formula (II-2) or (II-3),

[0331] R c It is a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one, two or three deuterium atoms;

[0332] R 3 and R 4 Each can be H or F independently;

[0333] R 9 It is H or methyl;

[0334] Y 1 For CF or CH;

[0335] for

[0336] for

[0337] The carbon atoms marked with "*" have the configuration of R, S, or a mixture thereof;

[0338] X is N;

[0339] W stands for CH;

[0340] The definitions of the remaining groups are as described in any embodiment of the present invention.

[0341] In one aspect of the present invention, the compound represented by formula (II) is a compound represented by formula (II-4) or (II-5):

[0342] The definitions of each group are as described in any embodiment of the present invention.

[0343] In some embodiments, such as the compounds of formula (II-5), W is CH or N, and Q is... 1 For CH or N, X is a bond, Q 2 Let it be S.

[0344] In one aspect of the present invention, the compound represented by formula (II) is a compound represented by formula (II-6), (II-7), (II-8), or (II-9):

[0345] The definitions of each group are as described in any embodiment of the present invention.

[0346] In one embodiment, in the compounds represented by formulas (II-6), (II-7), (II-8), or (II-9), Q 1 For bonds, O, N, or CH2. In one embodiment, in the compounds represented as shown in formulas (II-6), (II-7), (II-8), or (II-9), Q 2 For bonds, O, N or CH2.

[0347] In one embodiment, in the compound represented by formula (II-8) or (II-9), Q 3 It can be N or CH2.

[0348] In one embodiment, in the compounds represented by formulas (II-6), (II-7), (II-8), or (II-9), X is a bond, O, N, or CH2.

[0349] In one embodiment, in the compounds represented by formulas (II-6), (II-7), (II-8), or (II-9), W is a bond, S, N, or CH2.

[0350] In one aspect of the present invention, in the compound represented by formula (II-7), R 11-1 It is a C1-C6 alkyl group.

[0351] In one embodiment, in the compound represented by formula (II-7), R 11-2 It is a C1-C6 alkyl group.

[0352] In one embodiment, the compound represented by formula (II-7), for

[0353] In one embodiment, in the compound represented by formula (II-8), R 12-9 R 12-10 and R 12-11 Each can be either oxo or methyl.

[0354] In one embodiment, in the compound represented by formula (II-9), R 12-12 It is a bond or NH.

[0355] In one embodiment, in the compound represented by formula (II-9), R 12-13 It can be CH3, cyclopropane, furanyl, tetrahydropyranyl, pyridyl, methylpyridyl, methoxypyridyl, pyrimidinyl, methylpyrimidinyl, or morpholinylpyridyl.

[0356] In one aspect of the present invention, the compound represented by formula (II) is any one of the following compounds:

[0357] The present invention also provides a pharmaceutical composition comprising a compound of formula (II) as described in any of the above embodiments, a pharmaceutically acceptable salt thereof, an isotopic substitute thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0358] The present invention also provides the use of a compound of formula (II) as described in any of the above embodiments, a pharmaceutically acceptable salt thereof, an isotope substitute thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a TNF-α inhibitor.

[0359] The present invention also provides the use of any of the above-described compounds of formula (II), pharmaceutically acceptable salts thereof, isotopic substitutes thereof, solvates thereof, solvates of pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for the prevention and / or treatment of TNF-α-related diseases, wherein the TNF-α-related diseases are inflammatory or autoimmune disorders, neurological or neurodegenerative disorders, pain or nociceptive disorders, cardiovascular disorders, metabolic disorders, ocular disorders, or oncological disorders.

[0360] In one embodiment of the present invention, the TNF-α-related disease is an inflammatory disorder or an autoimmune disorder.

[0361] In one embodiment of the present invention, the TNF-α-related diseases are juvenile idiopathic arthritis, septic shock, and autoimmune hepatitis.

[0362] In one embodiment of the present invention, the TNF-α-related diseases are rheumatoid arthritis, ankylosing spondylitis, uveitis, polyarticular juvenile idiopathic arthritis, irritable bowel syndrome, ulcerative colitis, hidradenitis suppurativa, Wegener's granulomatosis, Behçet's disease, erythema nodosum, folliculitis, Crohn's disease, nonradioactive axial spondyloarthritis, psoriatic arthritis, Blau syndrome, polyarticular juvenile idiopathic arthritis, chronic granulomatous disease, psoriasis (including but not limited to plaque psoriasis, erythrodermic psoriasis, psoriasis vulgaris, pustular psoriasis, plaque psoriasis, chronic macropsoriasis) or systemic lupus erythematosus.

[0363] In one embodiment of the present invention, the TNF-α-related disease is fibroblastoma.

[0364] The present invention also provides the use of a compound of formula (II) as described in any of the above embodiments, a pharmaceutically acceptable salt thereof, an isotope substitute thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of inflammatory disorders or autoimmune disorders, neurological disorders or neurodegenerative disorders, pain or nociceptive disorders, cardiovascular disorders, metabolic disorders, ocular disorders, or oncological disorders.

[0365] The present invention also provides the use of the compound of formula (II) as described in any of the above embodiments, its pharmaceutically acceptable salt, isotope-substituted product, its solvate, its pharmaceutically acceptable salt solvate, or the above pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of inflammatory disorders or autoimmune disorders.

[0366] The present invention also provides the use of the compound of formula (II) as described in any of the above embodiments, its pharmaceutically acceptable salt, isotope-substituted product, its solvate, a solvate of its pharmaceutically acceptable salt, or the above pharmaceutical composition in the preparation of a drug for the prevention and / or treatment of rheumatoid arthritis, ankylosing spondylitis, uveitis, polyarticular juvenile idiopathic arthritis, irritable bowel syndrome, ulcerative colitis, hidradenitis suppurativa, Wegener's granulomatosis, Behçet's disease, erythema nodosum, folliculitis, Crohn's disease, nonradioactive axial spondyloarthritis, psoriatic arthritis, Blau syndrome, polyarticular juvenile idiopathic arthritis, chronic granulomatous disease, psoriasis (including but not limited to plaque psoriasis, erythrodermic psoriasis, psoriasis vulgaris, pustular psoriasis, plaque psoriasis, chronic macropsoriasis) or systemic lupus erythematosus.

[0367] The present invention also provides the use of a compound of formula (II) as described in any of the above embodiments, a pharmaceutically acceptable salt thereof, an isotope substitute thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of fibroblastoma.

[0368] Terminology Explanation

[0369] Linking substituents are described in various places in this application. If the structure clearly requires a linking group, the Markush variations listed for that group should be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for that group lists "alkyl", then "alkyl" should be understood to represent a linked alkylene group.

[0370] When the bond attached to a substituent is shown to cross the bond connecting two atoms in the ring, the substituent may be bonded to any atom in the ring. When a substituent is listed but not specified by which atomic bond it is attached to the remainder of the given formula, the substituent may be attached by any atomic bond in the formula. Combinations of substituents and / or groups are permitted, provided that the combination yields a stable compound.

[0371] wavy lines on the group This indicates the position where the group is attached to other groups in the compound.

[0372] “Cyano” refers to the -CN group.

[0373] "Hydroxy" refers to the -OH group.

[0374] "Oxytochemical" means =O.

[0375] "-CO-" refers to -C (=O)-.

[0376] In this application, the term "C" i -C j "C1-C6" represents a range of carbon atoms, where i and j are integers, and the range includes the endpoints (i.e., i and j) and every integer point in between, where j is greater than i. For example, C1-C6 represents a range of 1 to 6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. In some implementations, the term "C1-C6" is used to indicate the number of carbon atoms. 12 "Indicates 1 to 12, especially 1 to 10, especially 1 to 8, especially 1 to 6, especially 1 to 5, especially 1 to 4, especially 1 to 3 or especially 1 to 2 carbon atoms.

[0377] The term "alkyl" refers to a straight-chain or branched alkyl group having a specified number of carbon atoms (e.g., C1-C6). The term "C i -C j"Alkyl" refers to an alkyl group having i to j carbon atoms. In some embodiments, the alkyl group contains 1 to 12 carbon atoms. In some embodiments, the alkyl group contains 1 to 11 carbon atoms. In some embodiments, the alkyl group contains 1 to 10 carbon atoms, 1 to 9 carbon atoms, 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and similar alkyl groups. In some embodiments, non-limiting examples of alkyl groups also include sec-propyl, tert-pentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless otherwise specifically specified in this specification, the alkyl group may optionally be substituted.

[0378] As a group or part of other groups, "alkenyl" refers to a straight-chain or branched hydrocarbon chain group having one or more carbon-carbon double bonds (-C=C-). In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms. In some embodiments, the alkenyl group contains 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkenyl group contains 2 carbon atoms. Non-limiting examples of alkenyl groups include vinyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7 -Nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, 11-dodecenyl. Unless otherwise specifically specified in this specification, the alkenyl group may optionally be substituted.

[0379] As a group or part of other groups, the term "alkynyl" refers to a straight-chain or branched hydrocarbon chain group having one or more carbon-carbon triple bonds (-C≡C-). In some embodiments, the alkynyl group contains 2 to 12 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms. In some embodiments, the alkynyl group contains 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkynyl group contains 2 carbon atoms. Non-limiting examples of alkynyl include ethynyl, propynyl, butynyl, pentyynyl, etc. Unless otherwise specifically specified in this specification, the alkynyl group may optionally be substituted.

[0380] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic (two or more) cyclic group having a specified number of carbon atoms in the ring (e.g., C3-C6) and consisting solely of carbon atoms; it also includes partially unsaturated monocyclic or polycyclic (two or more) cyclic groups. In certain embodiments, the cycloalkyl group comprises 3 to 14 (C3-C6) carbon atoms in the ring. 14 Carbon atoms. Unless otherwise specifically indicated in this specification, carbon atoms in cycloalkyl groups may optionally be oxidized, and cycloalkyl groups may optionally be substituted.

[0381] In certain embodiments, the cycloalkyl group may contain 3 to 12 cyclic carbon atoms, 3 to 10 cyclic carbon atoms, 3 to 9 cyclic carbon atoms, 3 to 8 cyclic carbon atoms, 3 to 7 cyclic carbon atoms, 3 to 6 cyclic carbon atoms, 3 to 5 cyclic carbon atoms, 4 to 12 cyclic carbon atoms, 4 to 10 cyclic carbon atoms, 4 to 9 cyclic carbon atoms, 4 to 8 cyclic carbon atoms, 4 to 7 cyclic carbon atoms, 4 to 6 cyclic carbon atoms, or 4 to 5 cyclic carbon atoms.

[0382] In certain embodiments, the cycloalkyl group can be a saturated or partially unsaturated monocyclic hydrocarbon group, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl.

[0383] In certain embodiments, monocycloalkyl or monocycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0384] In certain embodiments, the cycloalkyl group may be a saturated or partially unsaturated polycyclic (e.g., bicyclic and tricyclic) hydrocarbon group, which may be a fused ring system, a spirocyclic system, or a bridged ring system. The term "fused ring" refers to a ring system having two rings sharing two adjacent atoms, the term "spirocyclic" refers to a ring system having two rings connected by a single common atom, and the term "bridged ring" refers to a ring system having two rings sharing three or more atoms. Examples of fused cycloalkyl groups include, but are not limited to, H-indenyl, 2,3-dihydroindenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo[2.2.1]heptyl, Examples of spirocyclic compounds include, but are not limited to, spiro[2.2.1]heptyl, spiro[2.2.1]heptyl, spiro[2.2.2]octyl, spiro[3.1.1]heptyl, spiro[3.2.1]octyl, spiro[2.2.2]octenyl, spiro[3.2.1]octenyl, adamantyl, octahydro-4,7-methylene-1H-indenyl, and octahydro-2,5-methylene-cyclopentadienyl. Examples of spirocyclic compounds include, but are not limited to, spiro[5.5]undecyl, spiro-pentadienyl, and spiro[3.6]decyl. Examples of bridged cyclic groups include, but are not limited to, bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.3]undecane, etc.

[0385] The terms "heterocyclic alkyl" and "heterocyclic group" refer to a saturated or partially unsaturated cyclic group having a specified number of ring atoms (e.g., 4-7, 4-20, and in some embodiments, examples may be 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20), a specified number of heteroatoms (e.g., 1, 2 or 3, 4, 5 or 6), and a specified type of heteroatom (one or more of N, O, S and P, and in some embodiments, the heteroatom may also include P). In some embodiments, the heterocyclic group may contain 4 to 20 cyclic atoms, 3 to 19 cyclic atoms, 3 to 18 cyclic atoms, 3 to 17 cyclic atoms, 3 to 16 cyclic atoms, 3 to 15 cyclic atoms, 4 to 12 cyclic atoms, 4 to 10 cyclic carbon atoms, 4 to 9 cyclic atoms, 4 to 8 cyclic atoms, 4 to 7 cyclic atoms, 4 to 6 cyclic atoms, or 4 to 5 cyclic atoms. Unless otherwise specifically indicated in this specification, the heterocyclic group may be a monocyclic, bicyclic, tricyclic, or more cyclic system, which may include fused ring systems, bridged ring systems, or spirocyclic systems. The nitrogen, carbon, or sulfur atoms in the heterocyclic group may optionally be oxidized, and the nitrogen atom may optionally be quaternized. The heterocyclic group may be connected to the rest of the molecule via a carbon atom or a heteroatom and by a single bond. In some cases, the heterocyclic group may be carbon-linked, nitrogen-linked, or sulfur-linked. In some embodiments, the heterocyclic group is carbon-linked. In some embodiments, the heterocyclic group is nitrogen-linked. In some embodiments, the heterocyclic group is sulfur-linked.

[0386] Heterocyclic groups also include groups in which the heterocyclic group is fused with a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring. In heterocyclic groups containing fused rings, one or more rings may be aryl or heteroaryl as defined below. Examples of fused heterocyclic groups include, but are not limited to, phenyl fused rings or pyridyl fused rings, such as quinolinyl, isoquinolinyl, quinoxalinyl, quinazinyl, quinazolinyl, azidoindolazinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolazinyl, indazoleyl, purineyl, benzofuranyl, isobenzofuranyl, benzoimidazolyl, benzothiopheneyl, benzothiazolyl, carbazolyl, phenazinyl, phenthiazolyl, phenanthidyl, imidazo[1,2-a]pyridyl, [1,2,4]triazo[4,3-a]pyridyl, [1,2,3]triazo[4,3-a]pyridyl, etc.

[0387] In some embodiments, the heterocyclic group is a stable 4- to 12-membered (i.e., 4, 5, 6, 7, 8, 9, 10, 11, or 12), 5- to 12-membered (i.e., 5, 6, 7, 8, 9, 10, 11, or 12), or 4- to 10-membered (i.e., 4, 5, 6, 7, 8, 9, or 10) non-aromatic monocyclic, bicyclic, bridged, or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. For example, a stable 5- to 10-membered (i.e., 5, 6, 7, 8, 9, or 10) non-aromatic monocyclic, bicyclic, bridged, or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonane-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptane-2-yl, azacyclic butyl, oxacyclic butyl, thiocyclic butyl, thiocyclic pentyl, pyrrolidinyl Plønyl, tetrahydropyranyl, thiaranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, imidazolinyl, imidazoalkyl, quinazinyl, thiazoalkyl, isothiazylalkyl, isoxazylalkyl, pyrazolyl, phthalimide, dioxothiomorpholinyl, dioxothiocyclopentyl, dioxothiocyclobutyl, thiocyclohexyl, dioxothiocyclohexyl, thiomorpholinyl, 1,4-oxothiocyclohexyl, etc.

[0388] The term "halogen" refers to F, Cl, Br, and I.

[0389] The term "heterocyclic alkene" refers to an unsaturated ring having a specified number of ring atoms (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20), a specified number of heteroatoms (e.g., 1, 2, 3, 4, 5, or 6), and a specified heteroatom type (N, O, S, C(=O), S(=O), and S(=O)2; in some embodiments, the heteroatom may also include P), which is non-aromatic and satisfies any of the following conditions: 1. It is connected to the rest of the molecule by two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

[0390] The term "saturated carbon ring" refers to a saturated ring having a specified number of carbon atoms (e.g., C3, C4, C5, C6, or C7) that satisfies any of the following conditions: 1. It is connected to the rest of the molecule by two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

[0391] The term "saturated heterocycle" refers to a saturated ring having a specified number of ring atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14-membered rings), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, S, and P). It satisfies any of the following conditions: 1. It is connected to the rest of the molecule by two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

[0392] The term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C6-C). 18 Furthermore, for example, C6, C7, C8, C9, C 10 C 11 C 12 C 13 C 14 C 15 C 16 C 17 C 18 The aryl group is a group in a conjugated hydrocarbon ring system. The aryl group can be a monocyclic, bicyclic, tricyclic, or multicyclic system, and can be fused with cycloalkyl or heterocyclic groups as defined above. In the case of polycyclic systems, all rings may be aromatic, or only one ring may be aromatic. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, phenanthrene, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, or 2H-1,4-benzoxazine-3(4H)-one-7-yl. Unless otherwise specifically specified in this specification, the aryl group may optionally be substituted.

[0393] The term "aromatic ring" is defined as follows, with the rest being the same as the term "aryl": 1. It is connected to the rest of the molecule by two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

[0394] The term "heteroaryl" refers to a hydrocarbon group having a specified number of ring atoms (e.g., 5-20, further, 5-10, and even further, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20), a specified type of heteroatom (one or more of N, O, S, and P), and a specified number of heteroatoms (e.g., 1, 2, or 3). Unless otherwise specifically indicated in this specification, heteroaryl groups can be monocyclic, bicyclic, tricyclic, or more cyclic systems, and can be fused with cycloalkyl, aryl, or heterocyclic alkyl groups as defined above. In the case of polycyclic systems, all rings may be aromatic, or only one ring may be aromatic. Unless otherwise specifically indicated in this specification, heteroaryl groups may optionally be substituted. For the purposes of this invention, the heteroaryl group comprises 1 to 5 stable 5- to 12-membered (i.e., 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered) aromatic groups selected from nitrogen, oxygen, and sulfur, or comprises 1 to 4 (i.e., 1, 2, 3, or 4) stable 5- to 10-membered (i.e., 5-, 6-, 7-, 8-, 9-, or 10-membered) aromatic groups selected from nitrogen, oxygen, and sulfur, or comprises 1 to 3 (i.e., 1, 2, or 3) 5- to 6-membered aromatic groups selected from nitrogen, oxygen, and sulfur.

[0395] Examples of "heteroaryl" groups include, but are not limited to, thiophene, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrazinyl, pyrazinyl, benzimidazolyl, benzimorpholinyl, benziisodiazolyl, benzotriazolyl, benzopyrazolyl, imidazopyridyl, pyridomorpholinyl, pyrazolopyridyl, indole, furanyl, pyrroleyl, triazolyl, tetrazolyl, triazinyl, pyridinoneyl, pyrimidinoneyl, pyrazinoneyl, inazinyl, isoindoleyl, indazole, and iso Indazole, purine, quinolinyl, isoquinolinyl, diazonyl, naphridyl, quinoxolinyl, pteridinyl, carbazoyl, carolinyl, phenanthridine, phenanthroxolinyl, acridineyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothiophene, oxatriazolyl, cinolinyl, quinazolinyl, indene, o-diazaphenanthyl, phenoxazinyl, phenthiazolyl, tetrahydrobenzothiapheneyl, naphridyl, triazolopyridinyl, triazolopyridinyl, triazolopyrimidinyl, imidazopyridinyl, imidazopyridinyl, and imidazopyridinyl, etc.

[0396] The term “heteroaryl ring” meets any of the following conditions, and the rest of the definition is the same as that of the term “heteroaryl group”: 1. It is connected to the rest of the molecule by two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

[0397] The terms “optional” or “optionally” indicate that the event or condition described below may or may not occur, and the description includes both the possibility that the event or condition will occur and the possibility that it will not occur.

[0398] The term “substitution,” whether preceded by the term “optionally,” means that one or more hydrogen atoms of a specified moiety are substituted by a suitable substituent. It will be understood that “substitution” or “replaced by…” includes the implicit condition that such substitution occurs according to the permissible valence of the substituted atom and that the substitution yields a stable or chemically viable compound, such as a compound that does not spontaneously transform, for example, through rearrangement, cyclization, elimination, etc. Unless otherwise stated, an “optionally substituted” group may have a suitable substituent at each substituted position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from the specified group, the substituent may be the same or different at each position. Those skilled in the art will understand that the substituent itself can be substituted, if appropriate. Unless specifically indicated as “unsubstituted,” references to the chemical moiety herein should be understood to include substituted variants. For example, references to an “aryl” group or moiety implicitly include both substituted and unsubstituted variants.

[0399] The "optional" substituents described in this application include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, cyano, hydroxyl, amino, monoalkylamino, dialkylamino, nitro, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclic, etc., as described herein. These substituents include alkyl, alkenyl, alkynyl, alkyl of haloalkyl, alkenyl of haloalkenyl, alkynyl of haloalkynyl, alkoxy, alkyl of monoalkylamino, alkyl of dialkylamino, aryl, heteroaryl, cycloalkyl, and heterocyclic groups, and may optionally be substituted by one or more groups selected from alkyl, halogen, haloalkyl, alkoxy, hydroxyl, amino, monoalkylamino, dialkylamino, nitro, aryl, heteroaryl, cycloalkyl, and heterocyclic groups. The number of substituents may be one or more, i.e., 1, 2, 3, 4, 5, or 6 or more, depending on the substituted group and the nature of the substituent. For example, when the substituent is halogen, depending on the structure of the substituted group, the group can be replaced by 1 to 6 substituents, such as trifluoromethyl, pentafluoroethyl, etc.

[0400] The terms "part," "structural part," "chemical part," "group," and "chemical group" refer to specific segments or functional groups within a molecule. A chemical part is generally considered a chemical entity embedded in or attached to a molecule.

[0401] Those skilled in the art will also understand that, in the methods described below, the functional groups of the intermediate compounds may require protection by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto, and carboxylic acids. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable amino, amidine, and guanidine protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable mercapto protecting groups include -C(O)-R" (where R is alkyl, aryl, or aralkyl), p-methoxybenzyl, triphenylmethyl, etc. Suitable carboxyl protecting groups include alkyl esters, aryl esters, or aralkyl esters.

[0402] Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is detailed in Greene, TW & PGMUTS, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley. Protecting groups can also be polymer resins.

[0403] The term "pharmaceuticalally acceptable salt" refers to a salt prepared from the compounds of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compounds of the present invention contain relatively acidic functional groups, a base addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, an acid addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. See Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0404] In this invention, the term "isotope-substituted compound" refers to a compound whose structure differs only in the presence of one or more isotope-enriched atoms. For example, a compound having the structure of this invention, except that hydrogen is replaced by "deuterium" or "tritium," or by using... 18 F-fluorine labeling (18 F isotopes) can be used instead of fluorine, or... 11 C-, 13 C-, or 14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14 Compounds in which carbon atoms are replaced by C-isotopes are within the scope of this invention. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamic, pharmacokinetic, or receptor studies. Deuterated compounds typically retain activity comparable to their undeuterated counterparts, and deuteration at certain sites can result in better metabolic stability, thereby providing certain therapeutic advantages (such as increased in vivo half-life or reduced dose requirements). Therefore, in this invention, the isotope-substituted compounds are preferably deuterated compounds.

[0405] The term "solvate" refers to a substance formed by the combination of the compound of this invention with a stoichiometric or non-stoichiometric solvent. Solvent molecules in a solvate can exist in an ordered or disordered arrangement.

[0406] The terms “pharmaceutical-acceptable salt” and “solvent” in the term “pharmaceutical-acceptable salt solvate” as described above refer to substances formed by the compounds of the present invention in combination with (1) a relatively non-toxic, pharmaceutically acceptable acid or base and (2) a stoichiometric or non-stoichiometric solvent.

[0407] The term "pharmaceuticalally acceptable excipients" refers to excipients and additives used in the manufacture and dispensing of pharmaceutical products. These are all substances included in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2020 Edition), Volume IV, or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition).

[0408] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0409] The term “treatment” refers to a therapeutic approach. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment; or (4) slowing the development of the condition or one or more biological manifestations of the condition.

[0410] In the described applications, the "inhibitor" can be used in mammalian organisms or in vitro, primarily for experimental purposes, such as providing a standard or control sample for comparison, or preparing a kit according to conventional methods in the art to provide rapid detection of TNF-α inhibitory effects.

[0411] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0412] The reagents and raw materials used in this invention are all commercially available.

[0413] The positive and progressive effects of this invention are as follows: the compound of this invention has a novel structure and has one or more of the following effects:

[0414] (1) The compounds of the present invention have good inhibitory activity against TNF-α;

[0415] (2) The compounds of the present invention have good killing and inhibitory effects on TNFα-mediated tumor cells (e.g., fibroblastoma cells);

[0416] (3) The compounds of the present invention have good pharmacokinetic properties. Detailed Implementation

[0417] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0418] Example 1: Preparation of intermediates

[0419] 1.1 Synthesis of intermediate A1

[0420] Step 1: Dissolve A1-1 (10 g, 42.194 mmol) in anhydrous tetrahydrofuran (100 mL), add diisopropylaminolithium (31.646 mL, 63.291 mmol) at -78 °C, and react the solution at this temperature for 30 minutes. Then add N,N-dimethylformamide (4.895 mL, 63.291 mmol), and continue the reaction at -78 °C for 1 hour. After the reaction is complete, quench the reaction solution with water and extract with ethyl acetate. Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain A1-2 (11 g, yield: 98.37%).

[0421] Step 2: Dissolve A1-2 (5.49 g, 37.73 mmol) in tetrahydrofuran (300 mL), and add (S)-tert-butylsulfinamide (18.556 mL, 45.281 mmol) and cesium carbonate (24.59 g, 75.469 mmol) at room temperature. React the mixture at room temperature for 16 hours. Then filter the reaction mixture through a Buchner funnel, and wash the filter cake with ethyl acetate. Combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography (0-10% ethyl acetate / petroleum ether) to give A1-3 (13 g, yield: 93.57%).

[0422] LC-MS (ESI) m / z: 368.1 [M+H] + .

[0423] Step 3: Zinc powder (5.5 g, 84.696 mmol) and cuprous chloride (4.4 g, 42.348 mmol) were mixed in tetrahydrofuran (40 mL), and the solution was heated to 50 °C. A solution of A1-3 (10 g, 28.232 mmol) and allyl bromide (9.392 mL, 84.696 mmol) in tetrahydrofuran (10 mL) was then slowly added dropwise to the above solution. The reaction mixture was reacted at 50 °C for 3 hours. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to give a yellow oily substance A1-4 (8.6 g, yield: 68.87%).

[0424] LC-MS (ESI) m / z: 410.1 [M+H] + .

[0425] Step 4: Dissolve A1-4 (13.00 g, 29.390 mmol) in ethyl acetate (15 mL), add dioxane hydrochloride (7.3 mL, 4 N) at room temperature, and react the solution at room temperature for 2 hours. Then concentrate the reaction solution under reduced pressure to obtain a yellow oily substance A1-5 (9 g, yield: 90%).

[0426] LC-MS (ESI) m / z: 306.1 [M+H] + .

[0427] Step 5: Dissolve A1-5 (9 g, 26.615 mmol) in acetonitrile (90 mL), add 4-chloro-2-fluoro-1-nitrobenzene (4.67 g, 26.615 mmol) and potassium carbonate (7.6 g, 60 mmol) at room temperature, and react the solution at 80 °C for 16 hours. Then filter the reaction solution through a Buchner funnel, and wash the filter cake with ethyl acetate. Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue obtained is purified by silica gel chromatography (0-8% ethyl acetate / petroleum ether) to give a yellow oily substance A1-6 (10.6 g, yield: 80.66%).

[0428] LC-MS (ESI) m / z: 461.1 [M+H] + .

[0429] Step Six: Dissolve A1-6 (10.6 g, 21 mmol) in ultra-dry tetrahydrofuran (100 mL), add potassium osmium tetroxide dihydrate (350 mg, 1 mmol) at 0 °C, and react the solution at 0 °C for 3 hours. Then add sodium periodate (14 g, 66 mmol), and stir the solution overnight at room temperature. Dilute the reaction solution with water and extract with ethyl acetate. Combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue obtained is purified by silica gel chromatography to give A1-7 (9 g, yield: 88%).

[0430] LC-MS (ESI) m / z: 463.1 [M+H] + .

[0431] Step 7: Dissolve A1-7 (8 g, 17.79 mmol) in dichloromethane (80 mL), add zinc iodide (570 mg, 1.779 mmol), trimethylcyanosilane (5.30 g, 53.378 mmol), and triethylamine (0.25 mL, 1.779 mmol) at room temperature. React at room temperature for 12 hours. Dilute the reaction solution with water and extract with ethyl acetate. Combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography (0-17% ethyl acetate / petroleum ether) to give a yellow oily substance A1-8 (9 g, yield: 90%).

[0432] LC-MS (ESI) m / z: 562.1 [M+H] + .

[0433] Step 8: Dissolve A1-8 (6 g, 10.067 mmol) in ethanol (70 mL), add stannous chloride dihydrate (9.5 g, 50.333 mmol) at room temperature, and react the solution at 80 °C for 12 hours. Adjust the pH of the reaction solution to 8 with potassium hydroxide aqueous solution, then filter the reaction solution through a Buchner funnel, and wash the filter cake with dichloromethane. Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a yellow solid A1-9 (2.7 g, yield: 62%).

[0434] LC-MS (ESI) m / z: 443.1 [M+H] + .

[0435] Step 9: Dissolve A1-9 (1 g, 2.327 mmol) in tetrahydrofuran (80 mL), add diphenyl azidophosphate (1.308 mL, 6.051 mmol) and 1,8-diazobisspirocyclic [5.4.0]undec-7-ene (0.974 mL, 6.517 mmol) at room temperature, and react the solution at 50 °C for 18 hours. Add 10 mL of water to the reaction solution, then add a tetrahydrofuran solution of trimethylphosphine, and continue the reaction at room temperature for 1 hour. Extract the reaction solution with ethyl acetate. Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography (0-6% methanol / dichloromethane) to give a white solid A1-10 (0.9 g, yield: 90%).

[0436] LC-MS (ESI) m / z: 442.1 [M+H] + .

[0437] Step 10: Dissolve A1-10 (400 mg, 0.969 mmol) in N,N-dimethylformamide (5 mL), add potassium carbonate (400.00 mg, 2.866 mmol), tris(dibenzylacetone)dipalladium (20.95 mg, 0.093 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (53.99 mg, 0.093 mmol) at room temperature. Under carbon monoxide protection, react the solution at 100 °C for 12 hours. Quench the reaction solution with water and extract with ethyl acetate. Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to give A1-11 (0.2 g, yield: 51.62%).

[0438] LC-MS (ESI) m / z: 390.1 [M+H] + .

[0439] Step 11: Dissolve A1-11 (200 mg, 0.532 mmol) in N,N-dimethylformamide (1 mL), add sodium hydride (32 mg, 0.798 mmol, 60%) under ice bath conditions, react for half an hour, then add iodomethane (226.64 mg, 1.594 mmol), and react the solution at room temperature for 2 hours. Quench the reaction solution with water and extract with ethyl acetate. Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography (0-5% methanol / dichloromethane) to give A1-12 (0.14 g, yield: 59%).

[0440] LC-MS (ESI) m / z: 404.1 [M+H] + .

[0441] Step 12: Dissolve A1-12 (140 mg, 0.359 mmol) in anhydrous 1,4-dioxane (3 mL), add pinacol diboronate (137 mg, 0.539 mmol), tris(dibenzylacetone)dipalladium (32.89 mg, 0.036 mmol), and tricyclohexylphosphine (20.15 mg, 0.072 mmol) at room temperature. Under nitrogen protection, react the solution at 100 °C for 18 hours. Quench the reaction solution with water and extract with ethyl acetate. Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to give A1 (0.14 g, yield: 89%).

[0442] LC-MS (ESI) m / z: 496.2 [M+H] + .

[0443] Using the above method and the corresponding raw materials, the following intermediates were synthesized:

[0444] 1.2 Preparation of intermediate II-B1

[0445] 4-Bromoiodobenzene (10 g, 30.348 mmol) was dissolved in anhydrous 1,4-dioxane (200 mL). Under nitrogen protection, dimethylphosphine oxide (2.76 g, 35.347 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (2.045 g, 3.534 mmol), triethylamine (4.29 g, 42.417 mmol), and tris(dibenzylacetone)dipalladium (1.62 g, 1.768 mmol) were added. The reaction mixture was then reacted at 100 °C for 4 hours. The reaction solution was directly concentrated, and the crude product was purified by column chromatography (dichloromethane / methanol = 10:1) to give a pale yellow solid II-B1 (6.22 g, 26.7 mmol, 88%).

[0446] LC-MS (ESI) m / z: 233.0 [M+H] + .

[0447] Using the above method and the corresponding raw materials, the following intermediates were synthesized:

[0448] 1.3 Preparation of intermediate II-B9

[0449] 5-Bromo-2-chloropyrimidine (3.5 g, 18.094 mmol) was dissolved in N,N-dimethylformamide (40 mL), and (dimethylphosphono)methanol (2.35 g, 21.713 mmol) and potassium carbonate (7.5 g, 54.282 mmol) were added at room temperature. The reaction mixture was then incubated at 80 °C for 16 hours. After the reaction was complete, the mixture was extracted with dichloromethane, washed with saturated sodium chloride water, concentrated, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (dichloromethane / methanol = 10:1) to give a white solid II-B9 (3.89 g, 14.734 mmol, 81%).

[0450] LC-MS (ESI) m / z: 265.0 [M+H] + .

[0451] 1.4 Preparation of intermediate II-B10

[0452] 5-Bromopyrimidine-2-amine (1.86 g, 10.66 mmol) was dissolved in N,N-dimethylformamide (20 mL), and NaH (426 mg, 10.66 mmol, 60%) was added at room temperature. The mixture was then heated to 50 °C and reacted for 1 hour. Next, under nitrogen protection, dimethylphosphorus chloride (300 mg, 2.667 mmol) was added in an ice bath, and the reaction was continued at room temperature for 2 hours. After the reaction was complete, the mixture was quenched with ice water, extracted with ethyl acetate, and the organic phase was concentrated to give a yellow solid II-B10 (320 mg, 1.279 mmol, 12%).

[0453] LC-MS (ESI) m / z: 250.0 [M+H] + .

[0454] 1.5 Preparation of intermediate II-B11

[0455] Step 1: Dissolve II-B11-1 (114 mg, 0.5 mmol) in anhydrous methanol (1.5 mL), and slowly add sodium borohydride (22.8 mg, 0.6 mmol) under ice bath conditions. Then, react at room temperature overnight. Quench the reaction solution with ice water under ice bath conditions, extract with dichloromethane, and concentrate the reaction solution to obtain crude II-B11-2 (103 mg, yield: 90%).

[0456] Step 2: Dissolve II-B11-2 (103 mg, 0.45 mmol) in dichloromethane (3 mL), and slowly add phosphorus tribromide (121.5 mg, 0.45 mmol) dropwise at 0 °C. Then, react at room temperature for 1 hour. Quench the reaction solution in ice water, extract with dichloromethane, and concentrate the reaction solution to obtain crude II-B11-3 (65 mg, yield: 80%).

[0457] Step 3: Dissolve dimethylphosphine oxide (28 mg, 0.36 mmol) in anhydrous tetrahydrofuran (0.5 mL). Under nitrogen protection, slowly add NaHMDS (0.18 mL, 0.36 mmol, 2N) dropwise in an ice bath. After reacting for 1 hour, add II-B11-3 (65 mg, 0.36 mmol) in tetrahydrofuran (0.5 mL) dropwise, and then stir overnight at room temperature. After the reaction is complete, quench with ice water dropwise in an ice bath, extract with dichloromethane, and purify the crude product by silica gel chromatography (dichloromethane / methanol = 10:1) to obtain the yellow liquid compound II-B11 (16 mg, yield: 15%).

[0458] LC-MS (ESI) m / z: 290.0 [M+H] + .

[0459] Using the above method and the corresponding raw materials, the following intermediates were synthesized:

[0460] 1.6 Preparation of intermediate II-B31

[0461] 2-Amino-5-bromothiazole (300 mg, 1.68 mmol) was dissolved in dichloromethane (5 mL), cooled to 0 °C, and then triethylamine (0.47 mL, 3.35 mmol) and chloroacetyl isocyanate (0.16 mL, 1.84 mmol) were added sequentially. The mixture was then heated to room temperature and stirred for 1 hour. DBU (0.50 mL, 3.35 mmol) was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was extracted with dichloromethane and water. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentration of the filtrate was separated by column chromatography (0-20% methanol / dichloromethane) to give a yellow solid II-B31 (360 mg, 1.374 mmol, 81.97%).

[0462] LC-MS (ESI) m / z: 260.0 [MH] -

[0463] Example 2: Compound Synthesis

[0464] 2.1 Synthesis of Compound II-2

[0465] Step 1: Dissolve A1 (99 mg, 0.2 mmol) in 1,4-dioxane (4 mL) and water (0.4 mL), and add II-B2 (47 mg, 0.2 mmol), 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (15 mg, 0.02 mmol), and potassium phosphate (127 mg, 0.6 mmol) under nitrogen protection. The reaction system is then reacted at 100 °C for 2 hours. The reaction solution is directly concentrated, and the crude product is purified by column chromatography (dichloromethane / methanol = 10:1) to obtain a white solid II-2 (52 mg, 50%).

[0466] LC-MS (ESI) m / z: 524.1 [M+H] + .

[0467] Using the above method and the corresponding intermediates, the following compounds were synthesized:

[0468] 2.2 Synthesis of Compound II-15

[0469] Step 1: Dissolve A1-12 (201 mg, 0.5 mmol) in anhydrous acetonitrile (5 mL). Under nitrogen protection, add tert-butyl 3-ethynylpiperidin-1-carboxylate (522.5 mg, 2.5 mmol), methanesulfonic acid (2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-3-yl)palladium(II) (78 mg, 0.1 mmol), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (41 mg, 0.1 mmol), and potassium carbonate (345 mg, 2.5 mmol). Then, seal the tube and react for 1 hour at 100 °C. The reaction solution was directly concentrated, and the crude product was purified by silica gel chromatography (dichloromethane / methanol = 10:1) to obtain a yellow solid compound II-15-1 (245 mg, yield: 85%).

[0470] LC-MS (ESI) m / z: 577.2 [M+H] + .

[0471] Step 2: Dissolve II-15-1 (245 mg, 0.425 mmol) in dichloromethane (5 mL), then add trifluoroacetic acid (1 mL) dropwise at room temperature, and react at room temperature for 2 hours. Concentrate the reaction solution under reduced pressure, and the residue obtained is purified by high performance liquid chromatography (alkaline conditions) to obtain a white solid compound II-15 (101 mg, yield: 50%).

[0472] LC-MS (ESI) m / z: 477.1 [M+H] + .

[0473] Using the above method and the corresponding intermediates, the following compounds were synthesized:

[0474] 2.3 Synthesis of Compound II-16

[0475] Step 1: Dissolve A1-12 (680 mg, 1.684 mmol) and triisopropylsilylacetylene (614 mg, 3.368 mmol) in DMF (7 mL). Add Sphos (138 mg, 0.337 mmol), Sphos Pd G3 (263 mg, 0.337 mmol), and potassium carbonate (698 mg, 5.052 mmol) at room temperature. Under nitrogen protection, react the solution at 120 °C for 2 hours. Quench the reaction solution with water and extract with ethyl acetate. Combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography (0-20% methanol / dichloromethane) to give II-16-1 (880 mg, yield: 95%).

[0476] LC-MS (ESI) m / z: 550.2 [M+H] + .

[0477] Step 2: Dissolve II-16-1 (880 mg, 1.601 mmol) in THF (8 mL), add TBAF solution (4 mL, 1 mol / L) at room temperature, and react the solution at room temperature for 2 hours. Quench the reaction solution with water and extract with ethyl acetate. Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography (0-15% methanol / dichloromethane) to give II-16-2 (550 mg, yield: 87%).

[0478] LC-MS (ESI) m / z: 394.2 [M+H] + .

[0479] Step 3: Dissolve II-16-2 (25 mg, 0.064 mmol) and II-B8 (18 mg, 0.076 mmol) in DMSO (0.8 mL). Add CuI (0.24 mg, 0.001 mmol), Pd(dppf)Cl2.CH2Cl2 (0.52 mg, 0.001 mmol), and triethylamine (19.3 mg, 0.191 mmol) at room temperature under nitrogen protection. React at 80°C for 2 hours. Quench the reaction solution with water and extract with ethyl acetate. Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue obtained is analyzed by pre-HPLC to give II-16 (7.64 mg, yield: 21.8%).

[0480] LC-MS (ESI) m / z: 552.2 [M+H] + .

[0481] 1 H NMR (600MHz, DMSO-d6) δ8.27(d,J=8.9Hz,1H),7.68(d,J=8.4Hz,1H),7.60–7.54(m,2H),7.47(dd,J=19.8,5.5Hz,2H),7.38(d,J=7.8H z,1H),6.14(d,J=6.7Hz,1H),5.33(d,J=7.2Hz,1H),3.50–3.45(m,1H),3.33(s,3H),2.94(d,J=13.7Hz,1H),1.77(s,3H),1.75(s,3H).

[0482] Using the above method and the corresponding intermediates, the following compounds were synthesized:

[0483] 2.4 Synthesis of Compound II-67

[0484] Step 1: Dissolve II-16-2 (150 mg, 0.381 mmol) and II-67-1 (151 mg, 0.61 mmol) in DMF (3 mL). Add X-PHOS (18.2 mg, 0.038 mmol), XPhos Pd G3 (32.3 mg, 0.038 mmol), and DIEA (246 mg, 1.907 mmol) at room temperature. Under nitrogen protection, react the solution at 90 °C for 6 hours. Quench the reaction solution with water and extract with ethyl acetate. Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to obtain II-67-2 (150 mg, yield: 70%).

[0485] LC-MS (ESI) m / z: 560.2 [M+H] + .

[0486] Step 2: Dissolve II-67-2 (150 mg, 0.267 mmol) in DCM (5 mL), add TFA (1 mL) at room temperature, and react the solution at room temperature for 1 hour. Quench the reaction solution with saturated sodium bicarbonate aqueous solution and adjust the pH to weakly alkaline, then extract with DCM. Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to obtain II-67-3 (100 mg, yield: 81.3%).

[0487] LC-MS (ESI) m / z: 460.2 [M+H] + .

[0488] Step 3: Dissolve II-67-3 (70 mg, 0.152 mmol) in DCE (5 mL), add TEA (46.25 mg, 0.457 mmol) and cyclopropanesulfonyl chloride (32.1 mg, 0.229 mmol) at room temperature, and react under nitrogen protection at 30 °C for 12 hours. Quench the reaction solution with water and extract with DCM. Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue obtained is analyzed by pre-HPLC to give II-67 (17.21 mg, yield: 20.04%).

[0489] LC-MS (ESI) m / z: 564.2 [M+H] + .

[0490] 1 HNMR (600MHz, DMSO-d6) δ8.69(s,1H),8.28(d,J=8.9Hz,1H),8.19(s,1H),7.67(d,J=8. 4Hz,1H),7.51(d,J=0.9Hz,1H),7.46(d,J=8.9Hz,1H),7.35(dd,J=8.4,1.5Hz,1H),6.1 3(d,J=6.7Hz,1H),5.32(d,J=7.2Hz,1H),3.51–3.44(m,1H),3.36(s,3H),3.23–3.17(m ,1H),2.93(d,J=13.8Hz,1H),1.32(dd,J=7.5,3.9Hz,2H),1.24(dd,J=7.7,2.4Hz,2H).

[0491] Using the above method and the corresponding intermediates, the following compounds were synthesized:

[0492] Example 3: Analysis of the binding ability of compounds to TNFα using fluorescence polarization (FP)

[0493] The binding affinity of the compound to TNFα was assessed using fluorescence polarization (FP) assay.

[0494] The experimental method is as follows: The test compound was dissolved in DMSO to prepare a 10 mM stock solution, which was then serially diluted 3-fold with DMSO to a total of 12 concentration points. The tracer was prepared into a 10 mM stock solution with DMSO. Human TNFα protein (ACROBiosystems, GMP-TNAH23), the test compound, and the tracer were added to 384-well plates (PerkinElmer, Proxiplate). The final concentrations of human TNFα protein and tracer were 6.67 nM and 50 nM, respectively. The initial concentration of the test compound was 10 μM, and the final concentration of DMSO was 1%. After shaking and mixing, the microplate was incubated at 37°C for 4 hours. The plate was read using Envision, the fluorescence polarization detection program was selected, and the excitation wavelength was set to 480 nm and the emission wavelength to 535 nm. The experimental data were analyzed using GraphPad Prsim. The tracer is compound 53 from the literature Journal of Medicinal Chemistry 2021 64(1), 417-429, as detailed below:

[0495] The binding activities of the compounds of this invention to TNFα are shown in Table 1.

[0496] Table 1: Binding activity of some compounds of the present invention on TNFα

[0497] Where A represents IC 50 Less than 100 nM; B indicates IC 50 The range is between 100nM and 1000nM; C represents IC. 50 The range is between 1000nM and 10000nM; D represents IC. 50 It is greater than 10000nM.

[0498] Example 4: Inhibitory effect of the compound on TNFα-mediated killing of L929 cells

[0499] The following method was used to determine the inhibitory activity of the compounds of this invention against TNFα-mediated, actinomycin D-treated mouse fibroblast cell line L929. L929 cells were cultured in RPMI-1640 medium (Gibco, catalog number A1049101) supplemented with 10% fetal bovine serum (FBS, Gibco, catalog number 10099-141C) at 37°C and 5% CO2. The activity of the compounds was determined by detecting cellular ATP levels using the Promega CellTiter-GloR Luminescent Cell Viability Assay kit (catalog number G7573).

[0500] The experimental method is as follows: L929 cells in the logarithmic growth phase were collected by centrifugation and diluted with RPMI-1640 medium (containing 10% FBS) to prepare a cell suspension with a concentration of 1.67E5 / ml. 30 μl of the cell suspension was added to each well of a sterile white 384-well cell culture plate. The test compound was dissolved in DMSO to prepare a 10 mM stock solution, which was then serially diluted 3-fold with DMSO to a total of 12 concentration points, with a final starting concentration of 2.5 μM. hTNFα (ACROBiosystems, catalog number GMP-TNAH23) was prepared as a 100 μg / ml stock solution with ultrapure water. Actinomycin D (MCE, catalog number HY-17559) was prepared as a 10 mg / ml stock solution with DMSO. hTNFα, Actinomycin D, and the test compound were mixed in RPMI-1640 medium (containing 10% FBS) and incubated at 37°C for 2 hours. Then, 10 μl / well was added to each well of a 384-well plate containing cells. The final concentrations of hTNFα and Actinomycin D were 0.1 ng / ml and 4 μg / ml, respectively. After vortexing, the cell culture plate was incubated at 37°C in a 5% CO2 incubator for 24 hours. After 24 hours, the plate was removed and allowed to equilibrate to room temperature for 30 minutes. Then, 15 μL of pre-equilibrated CellTiter-Glo Reagent (at room temperature) was added to each well, and the mixture was vortexed. After incubation in the dark for 15 minutes, the luminescence readings of each well were measured using a microplate reader. Finally, the IC50 of the compound was calculated using GraphPad Prsim. 50 value.

[0501] Table 2: Inhibitory effects of some compounds of the present invention on TNFα-mediated killing of L929 cells

[0502] Where A represents IC 50 Less than 200 nM; B indicates IC 50 The range is between 200nM and 2000nM; C represents IC. 50 The range is between 2000nM and 20000nM; D represents IC. 50 It is greater than 20000nM.

[0503] Example 5: Pharmacokinetics of the compound in mice

[0504] Pharmacokinetic determinations were performed on the compounds of the present invention. Specifically, the pharmacokinetic parameters of the compounds disclosed herein were determined using the following methods.

[0505] This study used healthy male adult mice, with each group receiving a single intravenous injection or gavage. Animals in the gavage group were fasted from 2 hours before administration to 2 hours after administration. Blood samples were collected at different time points after administration, and plasma concentrations of the compound were determined using LC-MS / MS. The plasma concentration-time relationship was analyzed using specialized software (WinNonlin), and the pharmacokinetic parameters of the compound were calculated. The compound disclosed in this study exhibits excellent pharmacokinetic properties.

[0506] Table 3: Pharmacokinetic parameters of some compounds of the present invention in mice

[0507] The compounds of this invention have high exposure levels and excellent absolute bioavailability.

[0508] Example 6: Rat pharmacokinetic experiment of the compound

[0509] The pharmacokinetic parameters of the compounds of this invention were determined in rats using the following methods.

[0510] This study used healthy adult male rats, with each group receiving a single intravenous injection or gavage. Animals in the gavage group were fasted overnight (≥12 hours) and fed uniformly 4 hours after administration. Blood samples were collected at different time points after administration, and plasma concentrations of the compound were determined using LC-MS / MS. The plasma concentration-time relationship was analyzed using specialized software (WinNonlin), and the pharmacokinetic parameters of the compound were calculated. The compound disclosed in this study exhibits excellent pharmacokinetic properties.

[0511] Table 4: Rat pharmacokinetic parameters of some compounds of the present invention

[0512] The compounds of this invention have high exposure levels and excellent absolute bioavailability.

[0513] Example 7: Canine pharmacokinetics of the compound

[0514] The pharmacokinetic parameters of the compounds of this invention were determined in dogs using the following methods.

[0515] This study used healthy male beagle dogs, with each group receiving a single intravenous injection or gavage. Animals in the gavage group were fasted overnight (≥12 hours) and fed uniformly 4 hours after administration. Blood samples were collected at different time points after administration, and plasma concentrations of the compound were determined using LC-MS / MS. The plasma concentration-time relationship was analyzed using specialized software (WinNonlin), and the pharmacokinetic parameters of the compound were calculated. The compound disclosed in this study exhibits excellent pharmacokinetic properties.

[0516] Table 5: Pharmacokinetic parameters of compound II-19 of the present invention in dogs

[0517] The compounds of this invention have high exposure levels and excellent absolute bioavailability.

[0518] Example 8: Liver microsomal stability experiment of the compound

[0519] The in vitro metabolic stability of the compounds of this invention was determined. Specifically, the liver microsomal stability parameters of the compounds of this disclosure were determined using the following methods.

[0520] In this study, various preclinical liver microsomes were co-incubated with the test compound for 60 minutes. The reaction was terminated at time points of 0 min, 5 min, 15 min, 30 min, 45 min, and 60 min. The concentration of the compound in the sample at each time point was determined by LC-MS / MS. The natural logarithm of the remaining percentage of the compound was linearly fitted to the incubation time to determine the elimination rate constant (k). The half-life was further calculated using the following formula:

[0521] Half-life (t) 1 / 2 ) Calculated by eliminating the rate constant: t 1 / 2 =0.693 / k

[0522] Table 6: Liver microsomal metabolic stability data of some compounds of the present invention

[0523] The compounds disclosed herein exhibit excellent stability in liver microsomal metabolism.

[0524] Example 9: In vitro toxicity test of the compound

[0525] The compounds of this invention were subjected to in vitro drug interaction (DDI) and effect on the cardiac QT interval. Specifically, the CYP IC50 of the disclosed compounds was determined using the following methods. 50 and hERG IC 50 Numerical value.

[0526] 1. CYP IC 50 Measurement

[0527] The inhibitory potential of compounds against cytochrome P450 enzymes was evaluated using a phosphate-buffered saline (100 mM, pH 7.4) system containing 0.2 mg / mL human liver microsomes. The test concentrations of the compounds were 0.05, 0.15, 0.5, 1.5, 5, 15, and 50 μM. Specific substrates in the incubation system included phenacetin (CYP1A2), diclofenac (CYP2C9), (S)-methionine (CYP2C19), dextromethorphan (CYP2D6), and testosterone (CYP3A). The reaction was terminated after incubation, and the amount of metabolites of the specific substrates produced was detected by LC-MS / MS to calculate the IC50 inhibitory effect of the compounds on CYP enzymes. 50 value.

[0528] The disclosed compounds have a low risk of drug-drug interaction (DDI).

[0529] 2.hERG IC 50 Measurement

[0530] The inhibitory effect of compounds on hERG currents in human embryonic kidney cells (hERG-HEK293 cells) stably expressing hERG channels was detected using a manual patch-clamp system. Compound concentrations were set at 0.37, 1.11, 3.33, 10.0, and 30.0 μM, and hERG channel tail currents were recorded to obtain the peak tail current values ​​at each concentration. The peak tail current value recorded in the negative control was taken as 100%, and the inhibition rate of different concentrations of the compound on hERG currents was calculated. Concentration-response curve fitting and IC50 calculation were performed using the standard Hill equation.

[0531] The compounds disclosed herein have a low risk of QT interval prolongation and low cardiotoxicity.

[0532] Table 7: CYP IC of some compounds of the present invention 50 and hERG IC 50 data

Claims

1. A compound of formula (II-A), a pharmaceutically acceptable salt thereof, an isotopically substituted derivative thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: in, Y 1 For N or CR a ; Y 2 For N or CR a ; Y 3 For N or CR a ; Z 1 For N or CR b ; Z 2 For N or CR b ; Z 3 For N or CR b ; U 1 For bond, O, NR c or CR d R e ; U 2 For bond, O, NR c or CR d R e ; R a Independently, H, deuterium, halogen, -CN, -NO2, -OH, -OR a1 Optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl, wherein the heteroatom in the heterocycloalkyl and heteroaryl is independently selected from one or more of N, O, S and P, and the number of heteroatoms is independently 1, 2 or 3. R a1 Optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic alkyl, optionally substituted C6-C 14 The aryl or optionally substituted 5-10-membered heteroaryl groups, wherein the heteroatoms in the 3-7-membered heterocyclic alkyl and 5-10-membered heteroaryl groups are each independently selected from one or more of N, O, S and P, and the number of heteroatoms is independently 1, 2 or 3. R b Independently, H, deuterium, halogen, -OH, -CN, -OR 2 -S(=O)2C1-C6 alkyl, optionally substituted alkyl or optionally substituted alkoxy; R 2 H, halogen, -CN, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic alkyl, optionally substituted C6-C 14 Aryl, optionally substituted 5-10-membered heteroaryl or optionally substituted C1-C6 alkyl, wherein the 3-7-membered heterocyclic alkyl and 5-10-membered heteroaryl are each independently one or more of N, O, S and P, and the number of heteroatoms is independently one, two or three. R c Independently H, deuterium, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, wherein the heteroatom in each of the heterocycloalkyl and heteroaryl groups is independently selected from one or more of N, O, S and P, and the number of heteroatoms is independently 1, 2 or 3. R d Independently, it is H, deuterium, or an optionally substituted C1-C6 alkyl group; R e Independently, it is H, deuterium, or an optionally substituted C1-C6 alkyl group; R 1 The heteroalkyl group is absent, H, deuterium, optionally substituted alkyl group, optionally substituted cycloalkyl group, optionally substituted heterocycloalkyl group, optionally substituted aryl group or optionally substituted heteroaryl group, wherein the heteroatom in the heterocycloalkyl group and heteroaryl group is independently selected from one or more of N, O, S and P, and the number of heteroatoms is independently 1, 2 or 3. R 3 and R 4 Each is independently H, deuterium, halogen, or optionally substituted C1-C6 alkyl; R 9 It is a C1-C6 alkyl group consisting of H, deuterium, halogen, or optional substitution; L is a bond, an optional alkyl group, an optional alkenyl group, an optional alkynyl group, an optional cycloalkyl group, or an optional heterocyclic group; Ring A' is optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted heterocyclic alkene, or optionally substituted heteroaryl; The ring C is optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkenyl, optionally substituted aryl or optionally substituted heteroaryl; R 10 Independently, it is H, deuterium, halogen, -OH, -NH2, -CN, -NO2, oxo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl or optionally substituted heteroaryl. m can be 0, 1, 2, 3, or 4; R 12 Independently, it can be H, deuterium, halogen, -OH, -NH2, -CN, -NO2, oxo, or -NHR. 12-1 Optionally substituted alkyl, Optionally substituted alkenyl, Optionally substituted alkynyl, Optionally substituted alkoxy, -SR 12-9 R 12-10 R 12-11 -P = OR 12- 2 R 12-3 -R 12-4 -P=OR 12-2 R 12-3 -R 12-12 -S(=O)2R 12-13 Optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl; R 12-1 The substituted C1-C6 alkyl group is optional. R 12-2 H, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic alkyl; R 12-2 H, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic alkyl; or, R 12-2 R 12-3 Together with the P atoms attached to them, they form optionally substituted heterocyclic alkyl groups or optionally substituted 5-10-membered heteroaryl groups; R 12-4 It can be an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted 3-7-membered heterocyclic alkyl, or an optionally substituted 5-10-membered heteroaryl; R 12-9 R 12-10 and R 12-11 Each can be independently deuterium, halogen, -OH, -NH2, -CN, -NO2, oxo, -NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkoxy; R 12-12 For bond, NH, optional substituted C1-C6 alkylene; R 12-13 H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl; t can be 0, 1, 2, 3, or 4; Or, two R atoms on the same carbon atom 12 Together form = O; Or, two R atoms on the same carbon atom 12 The ring atoms connected to them together form an optionally substituted cycloalkyl group or an optionally substituted heterocyclic group, wherein the heteroatom or heteroatomic group is selected from one or more of N, O, S, C(=O), S(=O) and S(=O)2, and the number of heteroatoms is 1, 2 or 3.

2. The compound of formula (II) as claimed in claim 1, its pharmaceutically acceptable salt, its isotopic substitution, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compound shown in formula (II-A) is the same as the compound shown in formula (II): in, Y 1 For N or CR a ; Y 2 For N or CR a ; Y 3 For N or CR a ; Z 1 For N or CR b ; Z 2 For N or CR b ; Z 3 For N or CR b ; U 1 For bond, O, NR c or CR d R e ; U 2 For bond, O, NR c or CR d R e ; R a Independently, H, deuterium, halogen, -CN, -NO2, -OH, -OR a1 Optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7-membered heterocyclic alkyl or optionally substituted 5-10-membered heteroaryl, wherein the heteroatoms in the 3-7-membered heterocyclic alkyl and 5-10-membered heteroaryl are each independently selected from one or more of N, O, S and P, and the number of heteroatoms is each independently 1, 2 or 3; R a1 Optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic alkyl, optionally substituted C6-C 14 The aryl or optionally substituted 5-10-membered heteroaryl groups, wherein the heteroatoms in the 3-7-membered heterocyclic alkyl and 5-10-membered heteroaryl groups are each independently selected from one or more of N, O, S and P, and the number of heteroatoms is independently 1, 2 or 3. R b Independently, H, deuterium, halogen, -OH, -CN, -OR 2 -S(=O)2C1-C6 alkyl, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy; R 2 H, deuterium, halogen, -CN, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocycloalkyl, optionally substituted C6-C 14 Aryl, optionally substituted 5-10-membered heteroaryl or optionally substituted C1-C6 alkyl, wherein the 3-7-membered heterocyclic alkyl and 5-10-membered heteroaryl are each independently one or more of N, O, S and P, and the number of heteroatoms is independently one, two or three. R c Independently H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic alkyl, optionally substituted C6-C 14 The aryl or optionally substituted 5-10-membered heteroaryl groups, wherein the heteroatoms in the 3-7-membered heterocyclic alkyl and 5-10-membered heteroaryl groups are each independently selected from one or more of N, O, S and P, and the number of heteroatoms is independently 1, 2 or 3. R 1 The following are optional substituted C1-C6 alkyl groups, optional C3-C7 cycloalkyl groups, optional substituted 3-7 heterocyclic alkyl groups, and optional substituted C6-C6 alkyl groups: (not present, H, deuterium, optional substituted C1-C6 alkyl groups, optional substituted C3-C7 cycloalkyl groups, optional substituted 3-7 heterocyclic alkyl groups, optional substituted C6-C6 cycloalkyl groups). 14 The aryl or optionally substituted 5-10-membered heteroaryl groups, wherein the heteroatoms in the 3-7-membered heterocyclic alkyl and 5-10-membered heteroaryl groups are each independently selected from one or more of N, O, S and P, and the number of heteroatoms is independently 1, 2 or 3. R d Independently, it is H, deuterium, or an optionally substituted C1-C6 alkyl group; R e Independently, it is H, deuterium, or an optionally substituted C1-C6 alkyl group; R 3 and R 4 Each is independently H, deuterium, halogen, or optionally substituted C1-C6 alkyl; R 9 It is H, halogen, or optionally substituted C1-C6 alkyl; X represents a bond, O, N, S, or CR. f ; R f It is a C1-C6 alkyl group consisting of H, deuterium, halogen, or optional substitution; W represents a bond, O, S, N, or CR. 8 ; R 8 It is H, halogen, or optionally substituted C1-C6 alkyl; Q 1 For bond, O, S, N or CR q1 ; R q1 It is a C1-C6 alkyl group consisting of H, deuterium, halogen, or optional substitution; Q 2 For bond, O, S, N or CR q2 ; CR q2 It is a C1-C6 alkyl group consisting of H, deuterium, halogen, or optional substitution; X, W, Q 1 and Q 2 Not both are keys; L represents a bond, and can be optionally substituted with C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C3-C8 cycloalkyl, or substituted with a 3-8 membered heterocyclic group. Ring A may or may not be present. When present, it is a cycloalkyl group, a 4-7 membered heterocyclic alkene, or a heteroaromatic ring. In the 4-7 membered heterocyclic alkene and the 5-10 membered heteroaromatic ring, the heteroatom is independently selected from one or more of N, O, S, and P, and the number of heteroatoms is 1, 2, or 3. R 5 Independently H, deuterium, oxo, halogen, -OH, -NH2, -NHR 5-1 Optionally substituted C1-C6 alkyl groups, Optionally substituted C1-C6 alkoxy groups, -P=OR 5-2 R 5-3 or -R 5-4 -P=OR 5-2 R 5-3 、; R 5-1 The substituted C1-C6 alkyl group is optional. R 5-2 H, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic alkyl; R 5-2 H, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic alkyl; or, R 5-2 R 5-3 Together with the P atoms attached to them, they form optionally substituted heterocyclic alkyl groups or optionally substituted 5-10-membered heteroaryl groups; R 5-4 It can be an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted 3-7-membered heterocyclic alkyl, or an optionally substituted 5-10-membered heteroaryl; n is 0, 1, 2, 3 or 4; Or, two R atoms on the same carbon atom 5 Together form = O; R 6 and R 7 These are two substituents on the same carbon atom; R 6 and R 7 The carbon atoms connected to them together form an optionally substituted C3-C7 saturated carbon ring or an optionally substituted 3-7 membered saturated heterocycle, wherein the heteroatom or heteroatom group in the 3-7 membered saturated heterocycle is selected from one or more of N, O, S, C(=O), S(=O) and S(=O)2, and the number of heteroatoms is 1, 2 or 3. The ring C is optionally substituted C3-C7 cycloalkyl, optionally substituted C5-C8 cycloalkenyl, optionally substituted 3-8-membered heterocyclic group, optionally substituted 5-8-membered heterocyclic alkenyl, optionally substituted 5-10-membered aryl or optionally substituted 5-10-membered heteroaryl. R 10 Independently, it is H, deuterium, halogen, -OH, -NH2, -CN, -NO2, oxo, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkoxy, optionally substituted C3-C8 cycloalkyl, optionally substituted 3-8 membered heterocyclic group, optionally substituted C6-C 10 Aryl, or optionally substituted 5-10 heteroaryl; m can be 0, 1, 2, 3, or 4; R 11 Independently, it is H, deuterium, halogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, -P=OR 11-1 R 11-2 -R 11-3 -P=OR 11-1 R 11-2 or -R 11-9 -S(=O)2R 11-10 ; R 11-1 H, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic alkyl; R 11-2 H, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C7 cycloalkyl, optionally substituted 3-7 membered heterocyclic alkyl; or, R 11-1 R 11-2 Together with the P atoms attached to them, they form optionally substituted 3-7-membered heterocyclic alkyl groups or optionally substituted 5-10-membered heteroaryl groups; R 11-3 It can be an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C3-C7 cycloalkyl, an optionally substituted 3-7-membered heterocyclic alkyl, or an optionally substituted 5-10-membered heteroaryl; R 11-9 It is a C1-C6 alkylene group that is absent, NH, or optionally substituted; R 11-10 H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl; y can be 0, 1, 2, 3 or 4.

3. The compound of formula (II-A) or (II) as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its isotopic substitution, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) Each "C1-C6 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (2) Each "C3-C7 cycloalkyl group" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (3) Each "3-7 membered heterocyclic alkyl" is independently oxocyclic butyl, azacyclic butyl, tetrahydropyrrole, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazine, phosphotene or oxophosphotene; (4) Each "5-10 heteroaryl group" is independently furanyl, thiophene, pyrazolyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; (5) Each "C6-C" 14 Each aryl group can be either phenyl or naphthyl. (6) Each "halogen" is independently F, Cl, Br or I; (7) Each "C1-C6 alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; (8) Each "4-7 membered heterocyclic alkene" is independently a 5-6 membered heterocyclic alkene with O and / or N heteroatoms, and the number of heteroatoms is 1 or 2. (9) Each "5-10 member heteroaromatic ring" is independently a 5-6 member heteroaromatic ring, such as furan ring, thiophene ring, pyrazole ring, thiazole ring, imidazole ring, pyrazole ring, oxazole ring, isoxazole ring, pyridine ring, pyrimidine ring, pyrazine ring or pyridazine ring. (10) Each "C3-C7 saturated carbon ring" is independently cyclopropane, cyclobutane, cyclopentane, cyclohexane, or cycloheptyl; (11) Each of the "3-7 member saturated heterocycles" is independently an oxacyclopropane, an azacyclopropane, an oxacyclobutane, an azacyclobutane, a tetrahydropyrrole ring, a tetrahydrofuran ring, a tetrahydropyran ring, a piperidine ring, a morpholine ring, a tetrahydrothiaranyl ring, or a piperazine ring. (12) Each "alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, methylbutoxy, dimethylpropoxy, ethylpropoxy, n-hexoxy, methylpentoxy, ethylbutoxy, ethylmethylpropoxy, dimethylbutoxy or trimethylpropoxy. (13) Each “3-10 membered heterocyclic group” or “3-8 membered heterocyclic group” is independently tetrahydropyrrole or piperidinyl. (14) Each “3-10 member heterocyclic group” is independently tetrahydropyrrole, piperidinyl, dihydropyrazolothiazine, dihydropyrazoloxazine or dihydrothiophenepiperidine. (15) Each "3-10 membered heterocyclic group" or "heterocyclic group" is independently oxetane, azirane, tetrahydropyrrole, tetrahydrofuran, dioxetane, tetrahydropyran, dioxetane, piperidinyl, morpholinyl, piperazine, thiohexane, phosphonone, oxophoxetane, oxetane, thiohexane, azispiro[3.3]heptane, azispiro[3.3]heptane, azispiro[3.4]octane, azispiro[3.4]octane, azispiro[3.5]nonane, azispiro[3.5]nonane, azispiro[4.5]decane, azispiro[4.5]decane, (16) Each “4-7 membered heterocyclic alkene” or “5-8 membered heterocyclic alkene” is independently dihydrofuranyl, dihydropyrroleyl, dihydropyranyl, azircyclohexenyl, dihydropyridyl, pyranyl, dihydropyranyl, thiaran, dihydrothiaranyl, azircycloheptenyl or azircycloheptenyl. (17) Each “C5-C8 cycloalkenyl” or “cycloalkenyl” is independently cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cycloheptadienyl, cyclooctenyl, cyclooctadienyl or cycloocttrienyl.

4. The compound of formula (II-A) or (II) as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its isotopic substitution, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) Each "C1-C6 alkyl group" is independently methyl; (2) Each "C3-C7 cycloalkyl group" is independently cyclopropyl; (3) Each "halogen" is independently F; (4) Each "4-7 membered heterocyclic alkene" is independently a dihydrofuran ring, a dihydropyran ring, or a dihydropyrrole ring, for example (5) Each "C3-C7 saturated carbon ring" is independently cyclopropane, cyclobutyl, cyclopentyl or cyclohexyl; (6) Each “3-7 membered heterocyclic alkyl” is independently an oxocyclic butyl, an azacyclic butyl, a tetrahydropyrrole, a tetrahydrofuran, a tetrahydropyran, a piperidinyl or a tetrahydrothiaran.

5. The compound of formula (II-A) or (II) as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its isotopic substitution, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) The isotope-substituted product is a deuterium-substituted product; (2)Y 1 For CR a , where R a It is H, halogen, C1-C6 alkoxy, halo-C1-C6 alkyl or C1-C6 alkyl substituted with one or more 5-10-membered heteroaryl groups, wherein the heteroatom in the 5-10-membered heteroaryl group is independently selected from one or more of N, O, S and P, and the number of heteroatoms is independently 1, 2 or 3. (3)Y 2 For CH; (4)Y 3 For CR a , where R a It can be H, halogen, C1-C6 alkoxy or halo-C1-C6 alkyl; (5)Z 1 For CH; (6)Z 2 For CH; (7)Z 3 For CH; (8)U 1 For bond, O or NR c ; (9)U 2 For key or NR c ; (10)R c It is a C1-C6 alkyl, a C1-C6 alkyl substituted with one or more deuterium, a halo-C1-C6 alkyl, or a C3-C6 saturated cycloalkyl; (11)R 2 It is a C1-C6 alkyl group substituted with one or more halogens; (12)R 3 It is H or halogen; (13)R 4 It is H or halogen; (14)R 9 It is H or C1-C6 alkyl; (15) Each R 5 Independently, it is H, deuterium, fluorine, -OH, -NH2, -NH-C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy or halo-C1-C6 alkyl; (16)R 6 and R 7 The carbon atoms connected to them together form a group consisting of one, two, or three R atoms. s1 Substituted 3-6 saturated heterocycles, R s1 Independently deuterium, halogen, oxo, -OH, -NH2, -NHR 5-1 Or optionally substituted C1-C6 alkyl groups; Or, R 6 and R 7 The carbon atoms connected to them together form a group consisting of one, two, or three R atoms. s2 Replaced C3-C6 saturated carbon rings, R s2 Independently deuterium, halogen, oxo, -OH, -NH2, -NHR 5-1 Or optionally substituted C1-C6 alkyl groups; (17) X is N; (18) W is CH; (19) Ring A is a 4-7 membered heterocyclic alkene, wherein the heteroatom is N and / or O, and the number of heteroatoms is 1 or 2; Alternatively, ring A is a 5-6 membered heteroaromatic ring, wherein the heteroatom is N and / or O, and the number of heteroatoms is 1, 2 or 3.

6. The compound of formula (II-A) or (II) as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its isotopic substitution, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)Y 1 For CF or CH; (2)Y 2 For CH; (3)Y 3 For CH; (4)U 1 for O,U 2 For NR c Or, U 1 For NR c U 2 For key; (5)R c It is a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one, two or three deuterium atoms; (6)R 2 A methyl group substituted with one, two, or three F atoms; (7)R 3 For H or F; (8)R 4 For H or F; (9)R 9 It is H or methyl; (10) Each R 5 Independently -NH2, methyl, difluoromethyl or methoxy; (11)R 6 and R 7 The carbon atoms connected to them together form a group consisting of one, two, or three R atoms. s1 Substituted 3-6 saturated heterocycles, R s1 Independently deuterium, oxo, halogen, -OH, -NH2, -NHR 5-1 C1-C6 alkyl or halogenated C1-C6 alkyl; Or, R 6 and R 7 The carbon atoms connected to them together form a group consisting of one, two, or three R atoms. s2 Replaced C3-C6 saturated carbon rings, R s2 Independently deuterium, halogen, -OH, oxo, -NH2, -NHR 5-1 Or halogenated C1-C6 alkyl; (12) for The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof; (13) for 7. The compound of formula (II-A) or (II) as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its isotopic substitution, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)U 1 For key; or U 1 It is O; (2)U 2 For bonds, either NH or N(CH3); (3)R c It is a methyl group, a methyl group substituted with one, two or three deuterium groups, a fluoromethyl group or a cyclopropyl group; (4)R 2 for (5)R 3 and R 4 Both are H; or, R 3 and R 4 All are F; (6) Each R 5 Independently -NH2; (7)R 6 and R 7 The carbon atoms bonded to them together form a C3-C6 saturated carbon ring or a 3-6 membered saturated heterocycle; the C3-C6 saturated carbon ring or the 3-6 membered saturated heterocycle may optionally be substituted by 1-3 substituents, which are independently selected from deuterium, halogen, -OH, oxo, -NH2, and -NHR. 5-1 Or halogenated C1-C6 alkyl; (8) for 8. The compound of formula (II-A) or (II) as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its isotopic substitution, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)R c Methyl, Fluoromethyl or cyclopropyl; (2)R 6 and R 7 The carbon atoms bonded to them together form cyclopropane, cyclobutane, oxocyclobutane, cyclopentane, piperidine, hexylene oxide, or tetrahydrothiaran; the cyclopropane, cyclobutane, oxocyclobutane, cyclopentane, cyclohexane, piperidine, hexylene oxide, or tetrahydrothiaran may optionally be substituted by one, two, or three substituents, the substituents being independently selected from deuterium, fluorine, -OH, oxo, -NH2, -NHCH3, -N(CH3)2, trifluoromethyl, trifluoroethyl, or trifluoropropyl.

9. The compound of formula (II-A) as claimed in claim 1, its pharmaceutically acceptable salt, its isotopic substitution, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compound shown in formula (II-A) is the same as the compound shown in formula (II-B): In the formula, Q 3 For bond, O, S, N or CR q3 ; CR q3 It is H, halogen, or optionally substituted C1-C6 alkyl; Q 1 Q 2 Q 3 Three or more of W and X are not simultaneously used as keys. The definitions of the remaining groups are as described in any one of claims 1-8.

10. The compound of formula (II-A) or (II) as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its isotopic substitution, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compounds represented by formula (II-A) or (II) are compounds represented by formula (II-1): Among them, R 5 Independently, it can be H, deuterium, halogen, -OH, -NH2, or -NHR. 5-1 Optionally substituted C1-C6 alkyl groups, Optionally substituted C1-C6 alkoxy groups; R 5-1 The substituted C1-C6 alkyl group is optional. n is 0, 1, 2, 3 or 4; R 11 Independently, it is H, deuterium, halogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy; y is 0, 1, 2, 3 or 4; The definitions of the remaining groups are as described in any one of claims 1-8.

11. The compound of formula (II-A) or (II) as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its isotopic substitution, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compounds represented by formula (II-A) or (II) are compounds represented by formula (II-2) or (II-3): The definitions of each group are as described in any one of claims 1-8.

12. The compound of formula (II-A) or (II) as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its isotopic substitution, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compounds represented by formula (II-A) or (II) are compounds represented by formula (II-4) or (II-5): The definitions of each group are as described in any one of claims 1-7.

13. The compound of formula (II-A) as claimed in claim 1, its pharmaceutically acceptable salt, its isotopic substitution, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compounds represented by formula (II-A) or (II) are compounds represented by formula (II-6), (II-7), (II-8), or (II-9): The definitions of each group are as described in any one of claims 1-8.

14. The compound of formula (II) as claimed in claim 11 or 12, its pharmaceutically acceptable salt, its isotopic substitution, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, In compounds such as those shown in formula (II-2) or (II-3): R c It is a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one, two or three deuterium atoms; R 3 and R 4 Each can be H or F independently; R 9 It is H or methyl; Y 1 For CF or CH; for for The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof; X is N; W stands for CH; The definitions of each group are as described in any one of claims 1-9.

15. The compound of formula (II-A) or (II) as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its isotopic substitution, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula (II-A) or (II) is any one of the following compounds:

16. A pharmaceutical composition comprising a compound of formula (II) as claimed in any one of claims 1-15, a pharmaceutically acceptable salt thereof, an isotopic substitute thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

17. The use of the compound of formula (II) as claimed in any one of claims 1-15, its pharmaceutically acceptable salt, its isotopic substitute, its solvate, a solvate of its pharmaceutically acceptable salt, or the pharmaceutical composition as claimed in claim 16 in the preparation of a TNF-α inhibitor.

18. The use of the compound of formula (II) as claimed in any one of claims 1-15, its pharmaceutically acceptable salt, its isotopic substitute, its solvate, a solvate of its pharmaceutically acceptable salt, or the pharmaceutical composition as claimed in claim 16 in the preparation of a medicament for the prevention and / or treatment of TNF-α-related diseases, wherein the TNF-α-related diseases are inflammatory or autoimmune disorders, neurological or neurodegenerative disorders, pain or nociceptive disorders, cardiovascular disorders, metabolic disorders, ocular disorders, or oncological disorders; Preferably, the TNF-α-related diseases are inflammatory disorders or autoimmune disorders; More preferably, the TNF-α-related diseases include rheumatoid arthritis, ankylosing spondylitis, uveitis, non-infectious uveitis, juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, psoriatic arthritis, Crohn's disease, irritable bowel syndrome, ulcerative colitis, hidradenitis suppurativa, multiple sclerosis-related neuroinflammation, Wegener's granulomatosis, Behçet's disease, erythema nodosum, folliculitis, Crohn's disease, non-radioactive axial spondyloarthritis, axial spondyloarthritis, psoriatic arthritis, Blau syndrome, chronic granulomatous disease, psoriasis, atopic dermatitis, systemic lupus erythematosus, multiple sclerosis, Behçet's disease, Alzheimer's disease, or cachexia; the psoriasis includes, for example, plaque psoriasis, erythrodermic psoriasis, vulgaris psoriasis, pustular psoriasis, plaque psoriasis, and chronic macropsoriasis. The diseases associated with TNF-α include, for example, fibroblastoma, multiple myeloma, or bone metastases.

19. The use of the compound of formula (II) as claimed in any one of claims 1-15, its pharmaceutically acceptable salt, its isotopic substitute, its solvate, a solvate of its pharmaceutically acceptable salt, or the pharmaceutical composition as claimed in claim 16 in the preparation of a medicament for the prevention and / or treatment of a disease, wherein the disease is an inflammatory disorder or autoimmune disorder, a neurological disorder or neurodegenerative disorder, a pain or nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder; Preferably, the disease is an inflammatory disorder or an autoimmune disorder; More preferably, the diseases mentioned are rheumatoid arthritis, ankylosing spondylitis, uveitis, non-infectious uveitis, juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, psoriatic arthritis, Crohn's disease, irritable bowel syndrome, ulcerative colitis, hidradenitis suppurativa, multiple sclerosis-associated neuroinflammatory disease, Wegener's granulomatosis, Behçet's disease, erythema nodosum, folliculitis, Crohn's disease, non-radioactive axial spondyloarthritis, axial spondyloarthritis, psoriatic arthritis, Blau syndrome, chronic granulomatous disease, psoriasis, atopic dermatitis, systemic lupus erythematosus, multiple sclerosis, Behçet's disease, Alzheimer's disease, or cachexia; the psoriasis mentioned includes, for example, plaque psoriasis, erythrodermic psoriasis, vulgaris psoriasis, pustular psoriasis, plaque psoriasis, and chronic macropsoriasis. The diseases mentioned include, for example, fibroblastoma, multiple myeloma, or bone metastases.

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