Cyclobutane derivatives and their use in medicine

Abstract

A cyclobutane derivative and its medical use, relates to a compound described in general formula (I) or its racemate, stereoisomer, tautomer, pharmaceutically acceptable salt, and intermediate and preparation method thereof, and application in preparation of medicine for treating autoimmune diseases or inflammatory diseases.(I).

Description

Technical Field

[0001] This invention relates to a compound of general formula (I) or its racemic, stereoisomer, tautomer, pharmaceutically acceptable salt, intermediates and preparation methods thereof, and its use in the preparation of medicaments for treating autoimmune or inflammatory diseases. Background Technology

[0002] Tumor necrosis factor (TNFα), a member of the tumor necrosis factor superfamily, is a cytokine involved in systemic inflammation. It plays a crucial role in the immune response by regulating multiple signaling pathways, including direct inflammatory responses involving immune cells and subsequent immune cell proliferation, as well as programmed cell death or apoptosis. It is a type II transmembrane protein, the precursor of which consists of 233 amino acids, including a 76-amino acid signal peptide that binds to the cell membrane as a trimer (tmTNFα). Under the action of TNFα convertase (TACE), the membrane-bound TNFα signal peptide is cleaved to form soluble mature TNFα (sTNFα) containing 157 amino acid residues, which is then secreted extracellularly and exerts its biological effects by binding to the tumor necrosis factor receptor (TNFR). TNFα is primarily produced by activated monocytes / macrophages in vivo, but other immune cells such as T cells, B cells, NK cells, and neutrophils also produce TNFα. Its biological functions are diverse. In summary, TNF-α interacts with transmembrane TNFR, controlling cell survival or inducing apoptosis through a unique and complex signaling pathway, thus providing resistance to certain types of infection. Summary of the Invention

[0003] The purpose of this invention is to provide a class of compounds that have inhibitory activity against TNFα receptors, and these compounds have good inhibitory activity and oral bioavailability.

[0004] This invention provides a compound of general formula (I) or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt.

[0005] (I);

[0006] In some embodiments, the compound represented by general formula (I) is selected from the compounds represented by general formulas (II-a) and (II-b).

[0007] (II-a) (II-b), each Each is selected independently, either from the presence or absence of the ring;

[0008] In some embodiments, the compound represented by general formula (I) is selected from the compound represented by general formula (III).

[0009] (III)

[0010] In some implementations, neither C1 nor C2 exists;

[0011] In some implementations, C1 exists, but C2 does not;

[0012] In some implementations, C2 exists, while C1 does not;

[0013] In some implementation schemes, A is selected from or ;

[0014] In some implementation schemes, X1 and X2 are each independently selected from CR x Or N;

[0015] In some implementation schemes, R 2 R 1a R 1b R x R a R b R c Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, SF5, COOH, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-7 Carbocyclic group, -C 0-4 Alkylene-C 3-7 Carbocyclic group, -C 0-4 Alkyl-4 to 7-membered heterocyclic groups, -SC 3-7 carbonyl group, -OC 1-4 Alkylene-C 3-7 carbonyl group, -SC 1-4 Alkylene-C 3-7 Carbocyclic group, -S(=O)C 1-6 Alkyl group, -S(=O)C 3-7 Carbocyclic group, -NHS(=O)C 1-6 Alkyl group, -S(=O)2C 1-6 Alkyl group, -S(=O)2C 3-7 Carbocyclic group, -NHS(=O)2C 1-6 Alkyl group, -S(=O)2NHC 1-6Alkyl, -P(=O)(C 1-6 Alkyl)2, wherein the alkylene, alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R k replace;

[0016] In some implementation schemes, R 2 R 1a R 1b R x R a R b R c Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, SF5, COOH, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 cycloalkyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-7 Carbocyclic group, -C 1-2 Alkyl-4 to 7-membered heterocyclic groups, -SC 3-7 cycloalkyl, -OC 1-2 Alkylene-C 3-7 carbonyl group, -SC 1-2 Alkylene-C 3-7 Cycloalkyl, -S(=O)C 1-4 Alkyl group, -S(=O)C 3-6 cycloalkyl, -NHS(=O)C 1-4 Alkyl group, -S(=O)2C 1-4 Alkyl group, -S(=O)2C 3-6 cycloalkyl, -NHS(=O)2C 1-4 Alkyl group, -S(=O)2NHC 1-4 Alkyl, -P(=O)(C 1-4 Alkyl, 2-phenyl, 5-6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, carbocyclic, phenyl, heteroaryl, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0017] In some implementation schemes, R 2 R 1a R 1b R x R a R b R cEach of these groups is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, SF5, COOH, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetra Hydrofuranyl, -S(=O)CH3, -S(=O)cyclopropyl, -NHS(=O)-CH3, -S(=O)2-CH3, -S(=O)2cyclopropyl, -NHS(=O)2CH3, -S(=O)2NHCH3, -P(=O)(CH3)2, wherein CH2, CH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxacyclobutyl, tetrahydrofuranyl are optionally surrounded by 1 to 4 R k replace;

[0018] In some implementation schemes, R 2 Each of the following is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCF3, OCHF2, OCH2F, OCD3, -OCH2CHF2, -OCF2CHF2, -OCH2CF3, -SCH2CHF2, -SCF2CHF2, SF5, COOH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetrahydrofuranyl;

[0019] In some implementation schemes, R 1a R 1b Each is independently selected from H, deuterium, F, Cl, and Br;

[0020] In some implementation schemes, R x R a R b R cEach of the following is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCF3, OCHF2, OCH2F, OCD3, -OCH2CHF2, -OCF2CHF2, -OCH2CF3, -SCH2CHF2, -SCF2CHF2, SF5, COOH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetrahydrofuranyl;

[0021] In some implementation schemes, R 3 Each is independently selected from H, deuterium, OH, CN, NH2, NO2, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, OC 1-6 Alkyl, -SC 1-6 Alkyl, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 3-7 Carbocyclic groups, 4 to 7 heterocyclic groups, -OC 3-7 Carbocyclic, -O-4 to 7-membered heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0022] In some implementation schemes, R 3 Each is independently selected from H, deuterium, OH, CN, NH2, NO2, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, OC 1-4 Alkyl, -SC 1-4 Alkyl, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 3-6 Carbocyclic groups, 4- to 6-heterocyclic groups, -OC 3-6 Carbocyclic, -O-4 to 6-membered heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0023] In some implementation schemes, R 3Each of the following is independently selected from H, deuterium, OH, CN, NH2, NO2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetrahydrofuranyl, wherein CH2, CH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxacyclobutyl, tetrahydrofuranyl are optionally separated by 1 to 4 R k replace;

[0024] In some implementation schemes, R 3 Each is independently selected from methyl, ethyl, CD3, and cyclopropyl;

[0025] In some implementation schemes, R 4 R 5 or R 6 Each element is independently selected from H, deuterium, halogens, OH, CN, NH2, NO2, SF5, COOH, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, OC 1-6 Alkyl, -SC 1-6 Alkyl, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 3-7 Carbocyclic groups, 4 to 7 heterocyclic groups, -OC 3-7 Carbocyclic, -O-4 to 7-membered heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0026] In some implementation schemes, R 4 R 5 or R 6 Each element is independently selected from H, deuterium, halogens, OH, CN, NH2, NO2, SF5, COOH, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, OC 1-4 Alkyl, -SC 1-4 Alkyl, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 3-6 Carbocyclic groups, 4- to 6-heterocyclic groups, -OC 3-6 Carbocyclic, -O-4 to 6-membered heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0027] In some implementation schemes, R4 R 5 or R 6 Each of the following is independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NO2, SF5, COOH, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetrahydrofuranyl, wherein CH2, CH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxacyclobutyl, tetrahydrofuranyl are optionally separated by 1 to 4 R k replace;

[0028] In some implementation schemes, R 4 R 5 or R 6 Each is independently selected from F, Cl, Br, I, OH, CN, NH2, NO2, SF5, COOH, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCF3, OCHF2, OCH2F, OCD3, -OCH2CHF2, -OCF2CHF2, -OCH2CF3, -SCH2CHF2, -SCF2CHF2, CH2OH, CH2NH2, CH2CN, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetrahydrofuranyl;

[0029] In some implementation schemes, R 5 and R 6 Together replace;

[0030] In some implementation schemes, or R 5 or R 6 Together replace;

[0031] In some implementation schemes, R c With R 4 R c With R 5 R x With R 4 R x With R 5 Together with the atoms or framework attached to it, they form C 4-12 A carbocyclic group or a 4-12 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups.k replace;

[0032] In some implementation schemes, R c With R 4 R c With R 5 R x With R 4 R x With R 5 Together with the atoms or framework attached to it, they form C 4-10 A carbocyclic group or a 4-10 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0033] In some implementation schemes, R x With R 5 Together with the atoms or framework attached thereto, they form a ring C1, which is selected from 4-10 membered heterocyclic groups, and the ring C1 is optionally surrounded by 1 to 4 R atoms. k replace;

[0034] In some implementation schemes, R c With R 4 Together with the atoms or framework attached thereto, they form a ring C2, which is selected from 4-10 membered heterocyclic groups, and the ring C2 is optionally surrounded by 1 to 4 R atoms. k replace;

[0035] In some embodiments, ring C1 or ring C2 is independently selected from 4-9 member heterocyclic groups, which are optionally surrounded by 1 to 4 R groups. k replace;

[0036] In some implementation schemes, Selected from or ;

[0037] In some implementation schemes, R k Each element is independently selected from deuterium, O, halogens, CN, OH, COOH, NH2, SF5, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic groups, -O-4 to 7-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-4 to 7-membered heterocyclic groups, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4alkylene-4 to 7-membered heterocyclic groups, C 3-6 Carbocyclic groups, 4- to 7-membered heterocyclic groups, -C(=O)N(C 1-6 Alkyl)2, -C(=O)NH2, -C(=O)NHC 1-6 Alkyl, -C(=O)-C 3-6 Carbocyclic group, -C(=O)-4 to 7-membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, ynyl, carbocyclic or heterocyclic group is optionally selected from 1 to 4 deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups;

[0038] In some implementation schemes, R k Each element is independently selected from deuterium, O, halogens, CN, OH, COOH, NH2, SF5, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocyclic groups, -O-4 to 7-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-4 to 7-membered heterocyclic groups, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 alkylene-4 to 7-membered heterocyclic groups, C 3-6 Carbocyclic groups, 4- to 7-membered heterocyclic groups, -C(=O)N(C 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NHC 1-4 Alkyl, -C(=O)-C 3-6 Carbocyclic group, -C(=O)-4 to 7-membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, ynyl, carbocyclic or heterocyclic group is optionally selected from 1 to 4 deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups;

[0039] In some implementation schemes, R kEach group is independently selected from deuterium, =O, F, Cl, Br, I, CN, OH, COOH, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, C(=O)NH2, C(=O)NH(CH3), C(=O)NH(CH2CH3), C(=O)N(CH3)2, methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, -CH2-pyrrolyl, C(=O)pyrrolyl, wherein the CH2, CH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and pyrrolyl groups are optionally selected from 1 to 4 of deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0040] In some implementation schemes, R k Each is independently selected from deuterium, =O, F, Cl, Br, I, CN, OH, COOH, NH2, SF5, -CH2OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCF3, OCHF2, OCH2F, OCD3, OCHD2, OCH2D, methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, -CH2CH2OCH2CH3, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C(=O)NH2, C(=O)NH(CH3), C(=O)NH(CH2CH3), C(=O)N(CH3)2, pyrroleyl, , .

[0041] In some implementation schemes, a and c are each independently selected from 0, 1, and 2;

[0042] In some implementation schemes, b is independently selected from 0, 1, 2, and 3;

[0043] In some implementation schemes, R 1a Selected from Cl and H;

[0044] In some implementation schemes, R 1a Selected from H;

[0045] In some implementation schemes, R 2 Selected from H, halogens;

[0046] In some implementation schemes, R 2 Selected from H;

[0047] In some implementation schemes, X1 and X2 are each independently selected from CR x ;

[0048] In some implementation schemes, R x R a R b R c Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, SF5, COOH, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, OC 1-6 Alkyl, C 3-7 The carbocyclic group, wherein the alkyl group or carbocyclic group is optionally composed of 1 to 4 radicals selected from deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl substituents;

[0049] In some implementation schemes, R x R a R b R c Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, and C. 1-6 Alkyl group, wherein the alkyl group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, OH;

[0050] In some implementation schemes, R 3 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Deuterated alkyl group, wherein the alkyl group and the carbocyclic group are optionally replaced by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl substituents;

[0051] In some implementation schemes, R 3 Each is independently selected from C 1-4 Alkyl, C 1-4 Deuterated alkyl group, wherein the alkyl group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, OH, etc.;

[0052] In some implementation schemes, R 4 R 5 or R 6 Each is independently selected from H, deuterium, OH, CN, NH2, and C. 1-6 Alkyl, -C 1-2 Alkylene-OC 1-6Alkyl groups, wherein the alkyl or alkylene groups are optionally composed of one to three elements selected from deuterium, halogens, CN, OH, NH2, C. 1-6 Alkyl substituents;

[0053] In some implementation schemes, R 4 R 5 or R 6 Each is independently selected from deuterium, OH, CN, NH2, and C. 1-6 Alkyl, -C 1-2 Alkylene-OC 1-6 Alkyl groups, wherein the alkyl or alkylene groups are optionally composed of one to three elements selected from deuterium, halogens, CN, OH, NH2, C. 1-6 Alkyl substituents;

[0054] In some implementation schemes, R 4 R 5 or R 6 Each is independently selected from deuterium, OH, CN, NH2, and C. 1-6 Alkyl group, wherein the alkyl group is optionally substituted with one to three substituents selected from deuterium, halogen, CN, and OH;

[0055] Optionally, the compound represented by general formula (I) satisfies one of the following conditions:

[0056] 1) When R 1a When selected from H, R 2 Selected from halogens, and the compound is not halogenated. ;

[0057] 2) When R 1a When selected from Cl, R 5 and R 6 Not selected from H;

[0058] 3) When A is selected from At that time, X1 and X2 are selected from CR x ;

[0059] 4) When R 1a When X1 and X2 are selected from C1, X1 and X2 are selected from CR. x ;

[0060] 5) When X1 and X2 are selected from CR x At that time, R 5 and R 6 Not selected from H;

[0061] Optionally, the compound represented by general formula (III) satisfies one of the following conditions:

[0062] 1) R 1a Selected from H, R 2 Selected from halogens;

[0063] 2) R 1a Selected from Cl;

[0064] 3) X1 and X2 are selected from CR x Optionally, the compound represented by general formula (I) satisfies at least one of the following conditions:

[0065] 1) When R 1a When selected from H, R 2 Not selected from H or CF3, and the compound does not have the following structure:

[0066] , , ;

[0067] 2) When R 2 When selected from H, R 1a Selected from Cl and R 5 and R 6 Not selected from H;

[0068] 3) When R 1b When selected from H, R 5 and R 6 Not selected from H, and the compound is not H. ;

[0069] 4) When R 1a Selected from H, R 2 When selected from H and CF3, R c With R 4 R c With R 5 R x With R 4 R x With R 5 Together with the atoms or framework attached to it, they form C 4-12 A carbocyclic group or a 4-12 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replace, or R 5 and R 6 Together Substitution, and the compound is not , , ;

[0070] 5) When R 1b Selected from H, and R 5 and R 6 When selected from H, Not selected ;

[0071] 6) When R 2 Selected from H, R 1aSelected from Cl and R 5 and R 6 When selected from H, Not selected ;

[0072] 7) X1 and X2 are selected from CR x ;

[0073] Optionally, the compounds represented by general formula (II-a) or general formula (II-b) satisfy at least one of the following conditions:

[0074] 1) When R 1a When selected from H, R 2 Not selected from H or CF3, and the compound does not have the following structure:

[0075] , , ;

[0076] 2) When R 2 When selected from H, R 1a Selected from Cl and R 5 and R 6 Not selected from H;

[0077] 3) When R 1b When selected from H, R 5 and R 6 Not selected from H, and the compound is not H. ;

[0078] 4) When R 1a Selected from H, R 2 When H and CF3 are selected, at least one of rings C1 and C2 exists, or R... 5 and R 6 Together Substitution, and the compound is not , , ;

[0079] 5) When R 1b Selected from H, and R 5 and R 6 When selected from H, Not selected ;

[0080] 6) When R 2 Selected from H, R 1a Selected from Cl and R 5 and R 6 When selected from H, Not selected ;

[0081] 7) X1 and X2 are selected from CR x .

[0082] As a first embodiment of the present invention, the compound represented by the following general formula (I) or its racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof

[0083] A is selected from or ;

[0084] X1 and X2 are each independently selected from CR x Or N;

[0085] R 2 R 1a R 1b R x R a R b R c Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, SF5, COOH, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-7 Carbocyclic group, -C 0-4 Alkylene-C 3-7 Carbocyclic group, -C 0-4 Alkyl-4 to 7-membered heterocyclic groups, -SC 3-7 carbonyl group, -OC 1-4 Alkylene-C 3-7 carbonyl group, -SC 1-4 Alkylene-C 3-7 Carbocyclic group, -S(=O)C 1-6 Alkyl group, -S(=O)C 3-7 Carbocyclic group, -NHS(=O)C 1-6 Alkyl group, -S(=O)2C 1-6 Alkyl group, -S(=O)2C 3-7 Carbocyclic group, -NHS(=O)2C 1-6 Alkyl group, -S(=O)2NHC 1-6 Alkyl, -P(=O)(C 1-6 Alkyl)2, wherein the alkylene, alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R k replace;

[0086] R 3Each is independently selected from H, deuterium, OH, CN, NH2, NO2, and C. 1-6 Alkyl, C 2-6 Alkyl, C 2-6 alkynyl group, OC 1-6 Alkyl, -SC 1-6 Alkyl, NHC 1-6 Alkyl, N(C) 1-6 Alkane)2, C 3-7 Carbocyclic groups, 4 to 7 heterocyclic groups, -OC 3-7 Carbocyclic, -O-4 to 7-membered heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0087] R 4 R 5 or R 6 Each element is independently selected from H, deuterium, halogens, OH, CN, NH2, NO2, SF5, COOH, and C. 1-6 Alkyl, C 2-6 Alkyl, C 2-6 alkynyl group, OC 1-6 Alkyl, -SC 1-6 Alkyl, NHC 1-6 Alkyl, N(C) 1-6 Alkane)2, C 3-7 Carbocyclic groups, 4 to 7 heterocyclic groups, -OC 3-7 Carbocyclic, -O-4 to 7-membered heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0088] Or R 5 and R 6 Together replace;

[0089] Or R c With R 4 R c With R 5 R x With R 4 R x With R 5 Together with the atoms or framework attached to it, they form C 4-12 A carbocyclic group or a 4-12 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0090] R k Each element is independently selected from deuterium, O, halogens, CN, OH, COOH, NH2, SF5, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic groups, -O-4 to 7-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-4 to 7-membered heterocyclic groups, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 alkylene-4 to 7-membered heterocyclic groups, C 3-6 Carbocyclic groups, 4- to 7-membered heterocyclic groups, -C(=O)N(C 1-6 Alkyl)2, -C(=O)NH2, -C(=O)NHC 1-6 Alkyl, -C(=O)-C 3-6 Carbocyclic group, -C(=O)-4 to 7-membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, ynyl, carbocyclic or heterocyclic group is optionally selected from 1 to 4 deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups;

[0091] a and c are each independently selected from 0, 1, and 2;

[0092] b is independently selected from 0, 1, 2, and 3;

[0093] The condition is that the compound represented by general formula (I) satisfies at least one of the following conditions:

[0094] 1) When R 1a When selected from H, R 2 Not selected from H or CF3, and the compound does not have the following structure:

[0095] , , ;

[0096] 2) When R 2 When selected from H, R 1a Selected from Cl and R 5 and R 6 Not selected from H;

[0097] 3) When R 1b When selected from H, R 5 and R 6 Not selected from H, and the compound is not H. ;

[0098] 4) When R 1a Selected from H, R 2 When selected from H and CF3, Rc With R 4 R c With R 5 R x With R 4 R x With R 5 Together with the atoms or framework attached to it, they form C 4-12 A carbocyclic group or a 4-12 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replace, or R 5 and R 6 Together Substitution, and the compound is not , , ;

[0099] 5) When R 1b Selected from H, and R 5 and R 6 When selected from H, Not selected ;

[0100] 6) When R 2 Selected from H, R 1a Selected from Cl and R 5 and R 6 When selected from H, Not selected ;

[0101] 7) X1 and X2 are selected from CR x .

[0102] As a second embodiment of the present invention, the compound represented by the above general formula (I) or its racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof

[0103] R 2 R 1a R 1b R x R a R b R c Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, SF5, COOH, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 cycloalkyl, C 3-6Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-7 Carbocyclic group, -C 1-2 Alkyl-4 to 7-membered heterocyclic groups, -SC 3-7 cycloalkyl, -OC 1-2 Alkylene-C 3-7 carbonyl group, -SC 1-2 Alkylene-C 3-7 Cycloalkyl, -S(=O)C 1-4 Alkyl group, -S(=O)C 3-6 cycloalkyl, -NHS(=O)C 1-4 Alkyl group, -S(=O)2C 1-4 Alkyl group, -S(=O)2C 3-6 cycloalkyl, -NHS(=O)2C 1-4 Alkyl group, -S(=O)2NHC 1-4 Alkyl, -P(=O)(C 1-4 Alkyl, 2-phenyl, 5-6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, carbocyclic, phenyl, heteroaryl, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0104] R 3 Each is independently selected from H, deuterium, OH, CN, NH2, NO2, and C. 1-4 Alkyl, C 2-4 Alkyl, C 2-4 alkynyl group, OC 1-4 Alkyl, -SC 1-4 Alkyl, NHC 1-4 Alkyl, N(C) 1-4 Alkane)2, C 3-6 Carbocyclic groups, 4- to 6-heterocyclic groups, -OC 3-6 Carbocyclic, -O-4 to 6-membered heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0105] R 4 R 5 or R 6 Each element is independently selected from H, deuterium, halogens, OH, CN, NH2, NO2, SF5, COOH, and C. 1-4 Alkyl, C 2-4 Alkyl, C 2-4 alkynyl group, OC 1-4 Alkyl, -SC 1-4 Alkyl, NHC 1-4 Alkyl, N(C) 1-4 Alkane)2, C 3-6 Carbocyclic groups, 4- to 6-heterocyclic groups, -OC3-6 Carbocyclic, -O-4 to 6-membered heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0106] Or R 5 or R 6 Together replace;

[0107] Or R c With R 4 R c With R 5 R x With R 4 R x With R 5 Together with the atoms or framework attached to it, they form C 4-10 A carbocyclic group or a 4-10 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0108] R k Each element is independently selected from deuterium, O, halogens, CN, OH, COOH, NH2, SF5, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocyclic groups, -O-4 to 7-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-4 to 7-membered heterocyclic groups, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 alkylene-4 to 7-membered heterocyclic groups, C 3-6 Carbocyclic groups, 4- to 7-membered heterocyclic groups, -C(=O)N(C 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NHC 1-4 Alkyl, -C(=O)-C 3-6 Carbocyclic group, -C(=O)-4 to 7-membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, ynyl, carbocyclic or heterocyclic group is optionally selected from 1 to 4 deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups;

[0109] The definitions of the remaining functional groups are the same as those in the first embodiment of the present invention.

[0110] As a third embodiment of the present invention, the compound represented by general formula (I) or its racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I) is selected from the compounds represented by general formulas (II-a) and (II-b).

[0111] (II-a) (II-b);

[0112] Each Each is selected independently, either from the presence or absence of the ring;

[0113] When present, ring C1 or ring C2 is independently selected from 4-10 member heterocyclic groups, wherein the heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0114] The condition is that the compound represented by general formula (II-a) or general formula (II-b) satisfies at least one of the following conditions:

[0115] 1) When R 1a When selected from H, R 2 Not selected from H or CF3, and the compound does not have the following structure:

[0116] , , ;

[0117] 2) When R 2 When selected from H, R 1a Selected from Cl and R 5 and R 6 Not selected from H;

[0118] 3) When R 1b When selected from H, R 5 and R 6 Not selected from H, and the compound is not H. ;

[0119] 4) When R 1a Selected from H, R 2 When H and CF3 are selected, at least one of rings C1 and C2 exists, or R... 5 and R 6 Together Substitution, and the compound is not , , ;

[0120] 5) When R 1b Selected from H, and R 5 and R 6 When selected from H, Not selected ;

[0121] 6) When R 2 Selected from H, R 1a Selected from Cl and R 5 and R 6 When selected from H, Not selected ;

[0122] 7) X1 and X2 are selected from CR x .

[0123] The definitions of the remaining functional groups are the same as those in the first or second embodiment of the present invention.

[0124] As a fourth embodiment of the present invention, the compounds represented by the above general formulas (I), (II-a), and (II-b), or their racemic mixtures, stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein...

[0125] R 2 R 1a R 1b R x R a R b R c Each of these groups is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, SF5, COOH, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetra Hydrofuranyl, -S(=O)CH3, -S(=O)cyclopropyl, -NHS(=O)-CH3, -S(=O)2-CH3, -S(=O)2cyclopropyl, -NHS(=O)2CH3, -S(=O)2NHCH3, -P(=O)(CH3)2, wherein CH2, CH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxacyclobutyl, tetrahydrofuranyl are optionally surrounded by 1 to 4 R k replace;

[0126] R 3Each of the following is independently selected from H, deuterium, OH, CN, NH2, NO2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetrahydrofuranyl, wherein CH2, CH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxacyclobutyl, tetrahydrofuranyl are optionally separated by 1 to 4 R k replace;

[0127] R 4 R 5 or R 6 Each of the following is independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NO2, SF5, COOH, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetrahydrofuranyl, wherein CH2, CH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxacyclobutyl, tetrahydrofuranyl are optionally separated by 1 to 4 R k replace;

[0128] Or R 5 or R 6 Together replace;

[0129] Ring C1 or ring C2 are each independently selected from 4-9 member heterocyclic groups, wherein the heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0130] R kEach group is independently selected from deuterium, =O, F, Cl, Br, I, CN, OH, COOH, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, C(=O)NH2, C(=O)NH(CH3), C(=O)NH(CH2CH3), C(=O)N(CH3)2, methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, -CH2-pyrrolyl, C(=O)pyrrolyl, wherein the CH2, CH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and pyrrolyl groups are optionally selected from 1 to 4 of deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0131] The definitions of the remaining functional groups are the same as those in the first, second, or third embodiments of the present invention.

[0132] As a fifth embodiment of the present invention, the compounds represented by the above general formulas (I), (II-a), and (II-b), or their racemic mixtures, stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, are used.

[0133] R k Each is independently selected from deuterium, =O, F, Cl, Br, I, CN, OH, COOH, NH2, SF5, -CH2OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCF3, OCHF2, OCH2F, OCD3, OCHD2, OCH2D, methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, -CH2CH2OCH2CH3, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C(=O)NH2, C(=O)NH(CH3), C(=O)NH(CH2CH3), C(=O)N(CH3)2, pyrroleyl, , ;

[0134] The definitions of the remaining functional groups are the same as those in the first, second, third, or fourth embodiments of the present invention.

[0135] As a sixth embodiment of the present invention, the compound represented by the above general formulas (I), (II-a), and (II-b), or its racemic mixture, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein...

[0136] R 2 Each of the following is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCF3, OCHF2, OCH2F, OCD3, -OCH2CHF2, -OCF2CHF2, -OCH2CF3, -SCH2CHF2, -SCF2CHF2, SF5, COOH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetrahydrofuranyl;

[0137] R 3 Each is independently selected from methyl, ethyl, CD3, and cyclopropyl;

[0138] R 4 R 5 or R 6 Each is independently selected from F, Cl, Br, I, OH, CN, NH2, NO2, SF5, COOH, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCF3, OCHF2, OCH2F, OCD3, -OCH2CHF2, -OCF2CHF2, -OCH2CF3, -SCH2CHF2, -SCF2CHF2, CH2OH, CH2NH2, CH2CN, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetrahydrofuranyl;

[0139] Or R 5 or R 6 Together replace;

[0140] R 1a R 1b Each is independently selected from H, deuterium, F, Cl, and Br;

[0141] R x R a R b R cEach of the following is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCF3, OCHF2, OCH2F, OCD3, -OCH2CHF2, -OCF2CHF2, -OCH2CF3, -SCH2CHF2, -SCF2CHF2, SF5, COOH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetrahydrofuranyl;

[0142] or Selected from or ;

[0143] The definitions of the remaining functional groups are the same as those in the first, second, third, fourth, or fifth embodiments of the present invention.

[0144] As a sixth embodiment of the present invention, the compound represented by the above general formula (I) or its racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof

[0145] A is selected from or ;

[0146] X1 and X2 are each independently selected from CR x Or N;

[0147] R 1a Selected from Cl and H;

[0148] R 2 Selected from H, halogens;

[0149] X1 and X2 are each independently selected from CR x Or N;

[0150] R x R a R b R c Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, SF5, COOH, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, OC 1-6 Alkyl, C 3-7 The carbocyclic group, wherein the alkyl group or carbocyclic group is optionally composed of 1 to 4 radicals selected from deuterium, halogen, CN, OH, NH2, C 1-6Alkyl substituents;

[0151] R 3 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Deuterated alkyl group, wherein the alkyl group and the carbocyclic group are optionally replaced by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl substituents;

[0152] R 4 R 5 or R 6 Each is independently selected from H, deuterium, OH, CN, NH2, and C. 1-6 Alkyl, -C 1-2 Alkylene-OC 1-6 Alkyl groups, wherein the alkyl or alkylene groups are optionally composed of one to three elements selected from deuterium, halogens, CN, OH, NH2, C. 1-6 Alkyl substituents;

[0153] a and c are each independently selected from 0, 1, and 2;

[0154] b is independently selected from 0, 1, 2, and 3;

[0155] The condition is that the compound represented by general formula (I) satisfies one of the following conditions:

[0156] 1) When R 1a When selected from H, R 2 Selected from halogens, and the compound is not halogenated. ;

[0157] 2) When R 1a When selected from Cl, R 5 and R 6 Not selected from H;

[0158] 3) When A is selected from At that time, X1 and X2 are selected from CR x ;

[0159] 4) When R 1a When X1 and X2 are selected from C1, X1 and X2 are selected from CR. x ;

[0160] 5) When X1 and X2 are selected from CR x At that time, R 5 and R 6 Not selected from H.

[0161] As a seventh embodiment of the present invention, the compound represented by general formula (I) or its racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I) is selected from the compound represented by general formula (III).

[0162] (III)

[0163] R 1a Selected from Cl and H;

[0164] R 2 Selected from H, halogens;

[0165] X1 and X2 are each independently selected from CR x Or N;

[0166] R x R a R b R c Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, SF5, COOH, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, OC 1-6 Alkyl, C 3-7 The carbocyclic group, wherein the alkyl group or carbocyclic group is optionally composed of 1 to 4 radicals selected from deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl substituents;

[0167] R 3 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Deuterated alkyl group, wherein the alkyl group is optionally replaced by one to four atoms selected from deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl substituents;

[0168] R 4 R 5 or R 6 Each is independently selected from deuterium, OH, CN, NH2, and C. 1-6 Alkyl, -C 1-2 Alkylene-OC 1-6 Alkyl groups, wherein the alkyl or alkylene groups are optionally composed of one to three elements selected from deuterium, halogens, CN, OH, NH2, C. 1-6 Alkyl substituents;

[0169] a and c are each independently selected from 0, 1, and 2;

[0170] b is independently selected from 0, 1, 2, and 3;

[0171] The condition is that the compound represented by general formula (III) satisfies one of the following conditions:

[0172] 1) R 1a Selected from H, R 2 Selected from halogens;

[0173] 2) R 1a Selected from Cl;

[0174] 3) X1 and X2 are selected from CR x .

[0175] As an eighth embodiment of the present invention, the compound represented by the above general formula (III) or its racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein...

[0176] R 1a Selected from H;

[0177] R 2 Selected from H;

[0178] X1 and X2 are each independently selected from CR x ;

[0179] R x R a R b R c Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, and C. 1-6 Alkyl group, wherein the alkyl group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, OH;

[0180] R 3 Each is independently selected from C 1-4 Alkyl, C 1-4 Deuterated alkyl group, wherein the alkyl group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, CN, OH, etc.;

[0181] R 4 R 5 or R 6 Each is independently selected from deuterium, OH, CN, NH2, and C. 1-6 Alkyl group, wherein the alkyl group is optionally substituted with one to three substituents selected from deuterium, halogen, CN, and OH;

[0182] a and c are each independently selected from 0, 1, and 2;

[0183] b is independently selected from 0, 1, 2, and 3.

[0184] The present invention relates to a compound or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the structures shown in Table E below.

[0185] This invention relates to a pharmaceutical composition comprising any of the above-described compounds, their racemic, stereoisomer, tautomer, pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0186] This invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the racemic, stereoisomer, tautomer, pharmaceutically acceptable salt of the above-described compound of this invention, and a pharmaceutically acceptable carrier.

[0187] In some embodiments, the pharmaceutical composition of the present invention may be in unit dosage form (the amount of the active pharmaceutical ingredient in a unit dosage form is also referred to as a "dosage strength").

[0188] The term "effective amount" or "therapeutic effective amount" as used in this application means that administering a sufficient amount of the compound disclosed in this application will alleviate, to some extent, one or more symptoms of the treated disease or condition (e.g., autoimmune diseases or inflammatory diseases (preferably psoriasis or rheumatoid arthritis, ulcerative colitis, Crohn's disease)). In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of the compound disclosed in this application required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective doses include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, and 1-500 mg. 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg , 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-40 0mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250- 400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg , 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1000mg, 80-800mg.

[0189] In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, etc. The compounds of the present invention, or their stereoisomers, pharmaceutically acceptable salts, or eutectics, in mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, and 840 mg.

[0190] A method for treating a disease in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound of the present invention or its stereoisomers, pharmaceutically acceptable salts or cocrystals, preferably 1-1500 mg, wherein the disease is preferably an autoimmune disease or an inflammatory disease (preferably psoriasis or rheumatoid arthritis, ulcerative colitis, Crohn's disease).

[0191] A method for treating or alleviating a disease in a mammal. The method comprises administering a medicament, a compound of the present invention or its stereoisomers, pharmaceutically acceptable salts, or cocrystals, to a subject at a daily dose of 1-1000 mg / day. The daily dose may be a single dose or multiple doses. In some embodiments, the daily dose includes, but is not limited to, 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, and 25-400 mg / day. The daily dose may be 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 160 mg / day, 200 mg / day, 300 mg / day, 320 mg / day, 400 mg / day, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, or 1000 mg / day.

[0192] This invention relates to a kit that may include a single-dose or multi-dose composition comprising a compound of the present invention or its stereoisomers, a pharmaceutically acceptable salt or a cocrystal, wherein the amount of the compound of the present invention or its racemic, stereoisomer, tautomer or pharmaceutically acceptable salt is the same as that in the above-described pharmaceutical composition.

[0193] This invention relates to the use of any of the above-described compounds or their racemates, stereoisomers, tautomers, or pharmaceutically acceptable salts in the preparation of medicaments for treating autoimmune diseases or inflammatory diseases (preferably psoriasis or rheumatoid arthritis, ulcerative colitis, Crohn's disease).

[0194] This invention relates to the use of the above-described pharmaceutical composition in the preparation of a medicament for treating autoimmune diseases or inflammatory diseases (preferably psoriasis or rheumatoid arthritis).

[0195] The amounts of racemic, stereoisomer, tautomer, and pharmaceutically acceptable salts of the compounds of this invention are converted in each case as free bases.

[0196] The compounds of this invention include their racemic, stereoisomer, tautomer, isotopic compounds, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals.

[0197] The carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds described in this invention include their isotopic forms. That is, the carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds described in this invention may be optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 11 C 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 15 O、 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S, 35 S and 36 S, nitrogen isotopes include 13 N、 14 N and 15 N, isotopes of fluorine include 17 F, 18 F and 19 F, isotopes of chlorine include 35 Cl、36 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br, an isotope of iodine, includes 123 I, 125 I, phosphorus isotopes include 31 P, 32 P.

[0198] “CN” refers to cyano.

[0199] "Halogen" refers to F, Cl, Br or I.

[0200] "Halogen-substituted" refers to substitution with F, Cl, Br, or I, including but not limited to 1 to 10 substituents selected from F, Cl, Br, or I, 1 to 6 substituents selected from F, Cl, Br, or I, and 1 to 4 substituents selected from F, Cl, Br, or I. "Halogen-substituted" is abbreviated as "halogenated".

[0201] "alkyl" refers to a substituted or unsubstituted straight-chain or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups with 1 to 20 carbon atoms, alkyl groups with 1 to 8 carbon atoms, alkyl groups with 1 to 6 carbon atoms, and alkyl groups with 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and their various branched isomers; the alkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0202] "Alkylene" refers to substituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups, including ‒(CH2). v (v is an integer from 1 to 10), alkylene examples include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0203] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 12 carbon atoms. Cycloalkyl groups can be monocyclic, fused, bridged, or spirocyclic. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirobutyl, adamantane, etc. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0204] "Heterocyclic alkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 12 atoms or 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O, S, or Se. The C, N, and S atoms on the ring of the heterocyclic alkyl group can be oxidized to various oxidation states. Heterocyclic alkyl groups can be monocyclic, fused, bridged, or spirocyclic. Heterocyclic alkyl groups can be attached to heteroatoms or carbon atoms. Non-limiting examples include epoxyethyl, aziridinepropyl, oxacyclobutyl, aziridinebutyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxopentyl, dioxohexyl, pyrrolylalkyl, piperidinyl, imidazoalkyl, oxazolidinyl, oxazinylalkyl, morpholinyl, hexahydropyrimidinyl, piperazineyl, etc. , , , , , , , Heterocyclic alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0205] "Alkenyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon double bonds. The main chain has, but is not limited to, 2 to 10, 2 to 6, or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-... The alkenyl group can be monovalent, divalent, trivalent, or tetravalent, including methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene.

[0206] "Alynyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon triple bonds. The main chain comprises 2 to 10 carbon atoms, including but not limited to having 2 to 6 carbon atoms on the main chain, or 2 to 4 carbon atoms on the main chain. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, and 4-pentynyl. The alkynyl group can be monovalent, divalent, trivalent, or tetravalent. Examples of alkynyl groups include: 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-hepynyl, 2-hepynyl, 3-hepynyl, 4-hepynyl, 1-octyynyl, 3-octyynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.

[0207] "Alkoxy" refers to a substituted or unsubstituted ‒O‒alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy.

[0208] "Carbocyclic group" or "carbocyclic ring" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered quaternary system. The carbocyclic group can be attached to an aromatic or non-aromatic ring, and the ring can be optionally a monocyclic, fused, bridged, or spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, etc. , , or "Carbocyclic group" or "carbon ring" can be monovalent, divalent, trivalent or tetravalent.

[0209] "Heterocyclic group" or "heterocyclic" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered quaternary system, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The C, N, S or Se selectively substituted in the ring of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused, or spirocyclic ring. Non-limiting examples include epoxyethyl, azirropropyl, oxacyclobutyl, azirrobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxahexacycloyl, azirroheptyl, pyridinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithioyl, dihydrofuranyl, dihydropyranyl, dithiapentylcycloyl. Tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophene, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl, , , , , , , , , , , , , , , , , , , , , , "Heterocyclic group" or "heterocyclic ring" can be monovalent, divalent, trivalent or tetravalent.

[0210] "Spirocyclic" or "spirocyclic group" refers to a polycyclic group in which substituted or unsubstituted rings share a single atom (called a spiro atom). The number of ring atoms in a spirocyclic system includes, but is not limited to, 5 to 20, 6 to 14, 6 to 12, or 6 to 10. One or more rings may contain 0 or more (including but not limited to 1, 2, 3, or 4) double bonds, and optionally may contain 0 to 5 double bonds selected from N, O, or S (=O). n Heteroatoms (n is 0, 1, or 2). Non-limiting embodiments include:

[0211] "Spirocyclic" or "spirocyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0212] "Burying" or "burying group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with the other rings in the system. One or more rings may contain zero or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted. Each ring in the burying system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to those selected from N, S (=O)). n Or O, where n is 0, 1, or 2). The number of ring atoms in a cyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include:

[0213] A "cyclic compound" or "cyclic base" can be monovalent, divalent, trivalent, or tetravalent.

[0214] A “bridged ring” or “bridged ring group” refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain zero or more double bonds. Any ring in a bridged ring system may contain 0 to 5 groups selected from heteroatoms or containing heteroatoms (including but not limited to N, S(=O)n, or O, where n is 0, 1, or 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include: Cubicane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0215] "Carbon spirocyclic", "spirocyclic carbon cyclic", "spirocarbon cyclic", or "carbon spirocyclic" refers to a spirocyclic system composed only of carbon atoms.

[0216] "Carbon fused ring", "fused cyclic carbon cyclic group", "fused carbon cyclic group" or "carbon fused cyclic group" refers to a ring system composed only of carbon atoms.

[0217] "Carbon bridged ring", "bridged ring carbon cyclo group", "bridged carbon cyclo group" or "carbon bridged ring group" refers to a ring system composed only of carbon atoms.

[0218] "Hybrid monocyclic", "monocyclic heterocyclic group" or "hybrid monocyclic group" refers to the "heterocyclic group" or "heterocyclic" in a monocyclic system.

[0219] "Hydrocyclic ring", "hydrocyclic cyclic group", "fused cyclic heterocyclic group" or "fused heterocyclic group" refers to a "fused ring" containing heteroatoms.

[0220] "Heterospirocyclic", "heterospirocyclic group", "spirocyclic heterocyclic group" or "spiroheterocyclic group" refers to a "spirocycle" containing heteroatoms.

[0221] "Hybrid-bridged ring", "hybrid-bridged ring group", "bridged ring heterocyclic group" or "bridged heterocyclic group" refers to a "bridged ring" containing heteroatoms.

[0222] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring. Non-limiting embodiments include benzene rings, naphthalene rings, etc. The "aryl" or "aryl ring" can be monovalent, divalent, trivalent, or tetravalent. When it is divalent, trivalent, or tetravalent, the linker site is located on the aryl ring.

[0223] "Heteroaryl" or "heteroary ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or a group containing heteroatoms (including but not limited to N, O, S(=O)n or Se(=O)n, where n is 0, 1, or 2). The number of ring atoms in the heteroaryl ring includes, but is not limited to, 5 to 15, 5 to 10, or 5 to 6. The atoms C, N, and S on the ring may be optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, where n is 1 or 2). Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furanyl, thiophenyl, selenyl, pyridyl, pyranyl, N-alkylpyrrolithyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazoleyl, benzopyrazolyl, benzimidazoleyl, benzopyridyl, pyrrolopyridyl, pyridinoneyl, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbon ring or heterocycle, wherein the ring connected to the parent structure is an aryl ring. Non-limiting embodiments include: , , The definition of heteroaryl groups used in this paper is consistent with that in this paper. Heteroaryl groups can be monovalent, divalent, trivalent, or tetravalent. When they are divalent, trivalent, or tetravalent, the linking site is located on an aromatic ring.

[0224] "Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4, or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged cyclic, spirocyclic, fused cyclic, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, and ‒(CH2). m ‒C(=O)‒R a 、‒O‒(CH2) m ‒C(=O)‒R a 、‒(CH2) m ‒C(=O)‒NR b R c 、‒(CH2) m S(=O) n R a 、‒(CH2) m ‒Alkenyl‒R a OR d Or (CH2) m ‒Alkyne‒R a (where m and n are 0, 1, or 2), arylthio, thiocarbonyl, silyl, or ‒NR b R c Groups, wherein R b With R c Independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, R b With R c It can form five- or six-membered cycloalkyl or heterocyclic groups, R a With R d Each group is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic, carbonyl, ester, bridged cyclic, spirocyclic, or fused cyclic groups.

[0225] "1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents selected from..., where X is any integer between 1 and 10. For example, "1 to 4 R..." k "Replace" refers to being replaced by 1, 2, 3, or 4 Rs. k Substitution. For example, "1 to 5 substituents selected from ..." means that the ring is substituted by 1, 2, 3, 4 or 5 substituents selected from ... . For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F.

[0226] X-Y member rings (where X and Y are integers, and 3 ≤ X < Y, X < Y ≤ 20, selected from any integer between 4 and 20) include rings of the X, X+1, X+2, X+3, X+4…Y member categories. These rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterofused rings, heterospirocyclic rings, or heterobridged rings. For example, “4-7 member heteromonocyclic rings” refers to heteromonocyclic rings of 4, 5, 6, or 7 members, and “5-10 member heterofused rings” refers to heterofused rings of 5, 6, 7, 8, 9, or 10 members.

[0227] C x-y Carbocyclic rings (including aryl, cycloalkyl, monocyclic, spirocyclic, fused, or bridged carbocyclic rings) include C x C x+1 C x+2 C x+3 C x+4 …. C y A ring of elements (x is an integer, and 3 ≤ x < y, where y is any integer between 4 and 20), for example, C. 3‒6 "Cycloalkyl" refers to C3, C4, C5, or C6 cycloalkyl groups.

[0228] When a functional group has one or more connectable sites, any one or more of these sites can be linked to other functional groups via chemical bonds. When the chemical bond connection is non-directional and a hydrogen atom is present at the connectable site, the number of hydrogen atoms at that site decreases accordingly with the number of bonds being formed, resulting in a functional group with a corresponding valence. For example... This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... These four connection methods, even if an H atom is drawn on -N-, This also includes .For example This indicates that the R group on the piperidinyl group can be located on C or N, and at least includes [missing information]. For example, the general formula fragment is: When X is selected from CH2 or NH, it means that the R group on the general formula fragment can be located on C or X. When X is selected from CH2, the general formula fragment can be... , When X is selected from NH, the general formula fragment can be... .

[0229] When the listed linking groups do not specify their linking direction, the linking direction includes the direction of the reading order from left to right and from right to left. For example, when ALB is selected from -MW-, it includes AMWB and AWMB.

[0230] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or possibility that the event or environment may or may not occur. For example, "optionally substituted F alkyl" means that the alkyl group may but does not have to be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

[0231] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means that the compound of the present invention retains the bioavailability and properties of a free acid or a free base, and that the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0232] "Pharmaceutical composition" refers to a mixture of one or more compounds described in this invention, or stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0233] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0234] "Carrier" refers to a material that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the compound given.

[0235] "Prodrug" refers to a compound of the present invention that can be metabolized in vivo and converted into a biologically active compound. The prodrug of the present invention is prepared by modifying the amino or carboxyl groups in the compound of the present invention. This modification can be performed through conventional procedures or removed in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free amino or carboxyl groups.

[0236] "Co-crystal" refers to a crystal formed by the bonding of an active pharmaceutical ingredient (API) and a co-crystal form (CCF) through hydrogen bonds or other non-covalent bonds. Both API and CCF are solids at room temperature in their pure states, and a fixed stoichiometric ratio exists between the components. Co-crystal is a multi-component crystal, encompassing both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.

[0237] "Animals" refers to mammals, such as humans, companion animals, zoo animals, and livestock, with humans, horses, or dogs being preferred.

[0238] "Stereoisomers" refer to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0239] "Tautomers" refer to functional group isomers that are produced by the rapid movement of an atom in two positions within a molecule, such as keto-enol isomers and amide-imine alcohol isomers. Detailed Implementation

[0240] The following embodiments illustrate the technical solution of the present invention in detail, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0241] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were measured in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0242] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0243] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM).

[0244] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used for TLC have a diameter of 0.15 mm to 0.20 mm, and the diameter of the plates used for TLC separation and purification is 0.4 mm to 0.5 mm.

[0245] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0246] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0247] THF: Tetrahydrofuran; DMF: N,N-Dimethylformamide; DIPEA: N,N-Diisopropylethylamine; HATU: CAS148893-10-1

[0248] Retention time: Unless otherwise specified in the embodiments, this represents the retention time corresponding to the analysis method.

[0249] Example 1: Preparation of Compound 1

[0250]

[0251] Step 1: Synthesis of compound 1b

[0252] Compound 1a (60 g, 151.9 mmol) was dissolved in 300 mL of dichloromethane. Under ice bath conditions, a 20% aqueous solution of potassium hydroxide (255.2 g, 911.4 mmol) was added dropwise, followed by the addition of a dichloromethane solution of TMSCF2Br (61.6 g, 303.8 mmol). After the addition was complete, the reaction was continued under ice bath conditions for another 30 minutes. After concentration, ethyl acetate and water were added. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography to obtain compound 1b (28.5 g, 42%).

[0253] LCMS m / z = 446.1 [M+H] +

[0254] Step 2: Synthesis of compound 1c

[0255] Dissolve 1b (25 g, 56.2 mmol) in 112 mL of dichloromethane. Add a solution of DBU (25.6 g, 168.6 mmol) in dichloromethane dropwise to the solution under ice bath conditions. Continue the reaction for half an hour. Concentrate and precipitate by silica gel column chromatography to obtain 1c (6.1 g, 49%).

[0256] LCMS m / z = 224.0 [M+H] +

[0257] Step 3: Synthesis of compound 1d

[0258] 1c (10.5 g, 47.1 mmol), cuprous bromide (10.2 g, 70.7 mmol), and 95 mL of acetonitrile were added sequentially to a reaction flask. A solution of tert-butyl nitrite (5.82 g, 56.5 mmol) in acetonitrile was then added dropwise under ice bath conditions. After the addition was complete, the reaction was brought to room temperature and allowed to proceed overnight. The solution was concentrated and purified by silica gel column chromatography to obtain 1d (3.7 g, 27%).

[0259] Step 4: Synthesis of compound 1e

[0260] 1d (3.7 g, 12.9 mmol) was dissolved in 40 mL of dichloromethane, cooled to -78 °C, and a toluene solution of DIBAL-H (1.5 M, 17.2 mL, 25.8 mmol) was added dropwise. After reacting for 1 hour, a saturated ammonium chloride solution was slowly added to quench the reaction. The mixture was filtered, the filter cake was washed with dichloromethane, and the organic phase was dried, concentrated, and subjected to silica gel column chromatography to obtain compound 1e (3.1 g, 93%).

[0261] Step 5: Synthesis of compound 1f

[0262] 1e (3.1 g, 12.0 mmol) was dissolved in 36 mL of dichloromethane, and Dys-Martin oxidant (10.18 g, 24.0 mmol) was added under ice bath conditions. The reaction mixture was then brought to room temperature and reacted for 2 hours. The reaction solution was filtered, washed, concentrated, and subjected to silica gel column chromatography to obtain 1f (2.7 g, 86%).

[0263] Step 6: Synthesis of 1g of compound

[0264] 1f (2.7 g, 10.5 mmol), (S)-tert-butylsulfinamide (1.4 g, 11.6 mmol), cesium carbonate (3.4 g, 10.5 mmol), and 30 mL of dichloromethane were added sequentially to a reaction flask and reacted at room temperature for 4 hours. After adding appropriate amounts of water and dichloromethane, the organic phase was dried, concentrated, and subjected to silica gel column chromatography to obtain 1 g (3.6 g, 95%) of compound.

[0265] Step 7: Synthesis of compound 1h

[0266] Zinc powder (13 g, 200 mmol), cuprous chloride (2.97 g, 30 mmol), and 40 mL of tetrahydrofuran were added sequentially to a reaction flask and reacted at 70 °C for 2 hours. The mixture was then cooled to room temperature, and ethyl bromoacetate (15.0 g, 90 mmol) was slowly added, with the reaction continuing at 50 °C for 1 hour. The reaction mixture was then filtered at room temperature, and the filtrate was slowly added to a tetrahydrofuran solution containing 1 g (3.6 g, 10 mmol) of the substrate. The reaction was continued at room temperature for 1 hour, and the reaction was quenched with saturated ammonium chloride solution. An appropriate amount of ethyl acetate was added, and the mixture was filtered. The organic phase was dried, concentrated, and subjected to silica gel column chromatography to obtain 1 h (3.7 g, 83%).

[0267] Step 8: Synthesis of Compound 1i

[0268] Substrate 1i (3.7 g, 8.3 mmol) was dissolved in 30 mL of dichloromethane, and a dioxane solution of HCl (4 M, 30 mL, 120 mmol) was added. The reaction was carried out at room temperature for 4 hours. The reaction solution was then concentrated directly to obtain crude 1i.

[0269] LCMS m / z = 343.9, 346.0 [M+H] +

[0270] Step 9: Synthesis of Compound 1j

[0271] The crude product 1i obtained in the previous step was dissolved in 30 mL of acetonitrile, and 4-chloro-2-fluoronitrobenzene (2.9 g, 16.6 mmol) and potassium carbonate (3.4 g, 24.9 mmol) were added. The reaction was carried out overnight at 80 °C. The reaction solution was directly concentrated and subjected to silica gel column chromatography to obtain 1j (3.2 g, 78% yield in two steps).

[0272] LCMS m / z = 500.8 [M+H] +

[0273] Step 10: Synthesis of compound 1k

[0274] 1 J (3.2 g, 6.4 mmol) was dissolved in 25 mL of dichloromethane, and a toluene solution of DIBAL-H (1.5 M, 4.3 mL, 6.4 mmol) was added dropwise at -78 °C. The reaction was continued at this temperature for 40 minutes. The reaction was quenched by adding saturated ammonium chloride solution, and an appropriate amount of dichloromethane was added. After filtration and washing, the organic phase was dried and concentrated to obtain crude product 1 K.

[0275] Step 11: Synthesis of Compound 1l

[0276] The crude product obtained in the previous step was dissolved in 20 mL of dichloromethane, and (R)-tert-butylsulfinamide (847 mg, 7.0 mmol) and cesium carbonate (2.1 g, 6.4 mmol) were added. The mixture was reacted at room temperature for 4 hours, concentrated, and purified by silica gel column chromatography to obtain 1 L (2.5 g, 70% yield in two steps).

[0277] Step 12: Synthesis of compound 1m

[0278] 1 L (2.5 g, 4.5 mmol), cesium fluoride (1.4 g, 9.0 mmol), and 20 mL tetrahydrofuran were added to a reaction flask, followed by the slow addition of TMSCN (891 mg, 9.0 mmol). The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated and purified by silica gel column chromatography to obtain 1 mL (2.5 g, 94% yield).

[0279] LCMS m / z = 587.0 [M+H] +

[0280] Step 13: Synthesis of Compound 1n

[0281] The crude product 1m obtained in the previous step, 25 mL of ethanol and a hydrochloric acid solution of titanium trichloride (15%, 28.6 g, 36 mmol) were added to a reaction flask and reacted at 80 °C for 5 hours. After the reaction solution was concentrated, an appropriate amount of saturated sodium bicarbonate solution and ethyl acetate were added. After filtration and washing, the organic phase was dried, concentrated and subjected to silica gel column chromatography to obtain 1n (950 mg, two-step yield 49%).

[0282] LCMS m / z = 436.0 [M+H] +

[0283] Step 14: Synthesis of Compound 1o

[0284] In (950 mg, 2.2 mmol), palladium acetate (49 mg, 0.22 mmol), XantPhos (127 mg, 0.22 mmol), potassium carbonate (1.5 g, 11.0 mmol), and 10 mL of dioxane were added to a reaction flask, and the reaction was carried out overnight at 100 °C under a carbon monoxide atmosphere. The reaction solution was concentrated and purified by silica gel column chromatography to obtain 1O (220 mg, 27%).

[0285] LCMS m / z = 382.0 [M+H] +

[0286] Step 15: Synthesis of compound 1p

[0287] 1o (220 mg, 0.58 mmol) was dissolved in 10 mL of tetrahydrofuran. After cooling to -78 °C, a tetrahydrofuran solution of KHMDS (1.0 M, 1.16 mL, 1.16 mmol) was added dropwise. The reaction was allowed to proceed at this temperature for half an hour. Iodomethane (165 mg, 1.16 mmol) was then added, and the mixture was allowed to rise to room temperature and reacted overnight. The reaction was quenched with saturated ammonium chloride solution. The mixture was extracted twice with ethyl acetate. The organic phase was dried, concentrated, and purified by silica gel column chromatography to obtain 1p (210 mg, 92%).

[0288] Step 16: Synthesis of compound 1q

[0289] 1p (210 mg, 0.53 mmol), pinacol diboronate (202 mg, 0.80 mmol), Pd2dba3 (25 mg, 0.027 mmol), PCy3.HBF4 (20 mg, 0.054 mmol), potassium acetate (156 mg, 1.59 mmol), and 5 mL of dioxane were added to a 30 mL microwave-safe tube and reacted at 140 °C for 4 hours under a nitrogen atmosphere. The reaction solution was concentrated and purified by silica gel column chromatography to obtain 1q (220 mg, 86%).

[0290] LCMS m / z = 488.1 [M+H] +

[0291] Step 17: Preparation of compound 1s-2

[0292] A DMA (10 mL) solution containing substrate 1s⁻¹ (2.14 g, 10 mmol) and 1,3-dibromopropane (2.22 g, 11 mmol) was added dropwise at 0 °C to a DMA (20 mL) suspension containing sodium hydride (528 mg, 22 mmol). After the addition was complete, the reaction was heated to room temperature and continued for 1 hour. The reaction was quenched by adding saturated ammonium chloride solution at 0 °C. The mixture was extracted twice with ethyl acetate. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1s⁻² (2.02 g, 80%).

[0293] Step 18: Preparation of compound 1s-3

[0294] Potassium carbonate (217 mg, 1.57 mmol) and 30% hydrogen peroxide solution (1.78 g, 15.74 mmol) were added sequentially to a DMSO (40 mL) solution of 1s⁻³ (2.0 g, 7.87 mmol), and the mixture was reacted at room temperature for 16 hours. The mixture was extracted twice with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography to obtain 1s⁻³ (2.04 g, 96%).

[0295] LCMS m / z = 274.1 [M+H] +

[0296] Step 19: Preparation of compound 1s-4

[0297] 1s⁻³ (2.0 g, 7.35 mmol) was dissolved in 15 mL of dioxane, followed by the addition of 15 mL of 3N hydrochloric acid, and the reaction was carried out at 100 °C for 16 hours. After cooling to room temperature, the product was extracted twice with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 1s⁻⁴ (1.77 g).

[0298] LCMS m / z = 275.1 [M+H] +

[0299] Step 20: Preparation of compound 1s-5

[0300] Triethylamine (852 mg, 8.42 mmol) and diphenyl azidophosphate (2.32 g, 8.42 mmol) were added sequentially to a 22 mL solution of dioxane (1.77 g, 6.48 mmol) of the crude 1s⁻⁴ obtained in the previous step, and the mixture was reacted at room temperature for 2 hours. The mixture was extracted twice with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was added to dilute hydrochloric acid (2N, 30 mL), and the mixture was reacted at 60 °C for 16 hours. After cooling to room temperature, the pH was adjusted to near neutral by adding saturated sodium bicarbonate solution. The mixture was extracted twice with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 1s⁻⁵ (1.64 g).

[0301] Step 21: Preparation of Compound 1s

[0302] DIPEA (867 mg, 6.72 mmol) and di-tert-butyl dicarbonate (2.9 g, 13.44 mmol) were added sequentially to a 20 mL solution of 1s⁻⁵ (1.64 g, 6.72 mmol) of THF, and the reaction was allowed to proceed overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give intermediate 1s (1.7 g, 68% yield in three steps).

[0303] LCMS m / z = 344.1 [M+H] +

[0304] Example 2: Preparation of Compound 2

[0305]

[0306] Step 1: Synthesis of compound 2b

[0307] 2a (19.4 g, 100 mmol) was dissolved in 200 mL of acetonitrile. NBS (17.8 g, 100 mmol) was added in portions under ice bath conditions. The reaction was continued for one hour, concentrated, and an appropriate amount of ethyl acetate was added. After washing twice with water, the organic phase was concentrated and subjected to silica gel column chromatography to obtain the target compound 2b (26.8 g, 98.3%).

[0308] Step 2: Synthesis of compound 2c

[0309] Compound 2b (5.45 g, 20 mmol) and hydrochloric acid (6N, 16.7 mL, 100 mmol) were added to a reaction flask. Under ice-salt bath conditions, 10 mL of sodium nitrite (2.76 g, 40 mmol) aqueous solution was added dropwise. After the addition was complete, the reaction was continued for one hour. Then, hypophosphite aqueous solution (50 wt.%, 5.12 g, 40 mmol) was added dropwise, and the reaction was continued for another 2 hours. The reaction mixture was extracted twice with ethyl acetate. The organic phase was dried, concentrated, and subjected to silica gel column chromatography to give compound 2c (3.45 g, 67%).

[0310] Step 3: Synthesis of compound 2d

[0311] 2c (3.45 g, 13.4 mmol) was dissolved in 40 mL of tetrahydrofuran. LDA (2 M, 7.4 mL, 14.7 mmol) was added dropwise to the solution under dry ice and ethanol bath conditions, and the reaction was continued for 2 hours. An appropriate amount of dry ice that had been thoroughly rinsed with tetrahydrofuran was added to the reaction solution, and the reaction was continued for 2 hours. The reaction solution was then concentrated, and dilute hydrochloric acid was slowly added to adjust the pH to about 3. The solution was then extracted twice with ethyl acetate. The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product of the target compound 2d.

[0312] Step 4: Synthesis of compound 2e

[0313] The crude product of compound 2d was dissolved in 30 mL of tetrahydrofuran. Borane dimethyl sulfide solution (10.0 M, 2.7 mL, 26.8 mmol) was slowly added dropwise under ice bath conditions. After the addition was complete, the reaction was carried out overnight at 50 °C. The reaction was quenched by adding an appropriate amount of methanol under ice bath conditions. The reaction solution was concentrated and an appropriate amount of water was added. The organic phase obtained by extraction with ethyl acetate twice was concentrated and subjected to silica gel column chromatography to obtain the target product 2e (3.0 g, two-step yield 78%).

[0314] 1H NMR (400 MHz, CDCl3) δ 7.56 (dd, 1H), 7.33 – 7.28 (m, 1H), 7.24 (t,1H), 4.87 (s, 2H).

[0315] Steps 5 to 16: Synthesis of compound 2q

[0316] Following the synthetic route from steps five to sixteen in Example 1, intermediate 2q (1.2 g) was obtained using 2e as a substrate.

[0317] Step 17: Preparation of Compound 2

[0318] Compound 2q (52 mg, 0.1 mmol), compound 2r (27 mg, 0.1 mmol), Pd(dppf)Cl2 (8 mg, 0.01 mmol), potassium carbonate (23 mg, 0.2 mmol), 2 mL of dioxane, and 0.2 mL of water were added to a reaction flask and reacted overnight at 100 °C. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give compound 2 (12 mg, 21%).

[0319] LCMS m / z = 577.2 [M+H] +

[0320] 1 H NMR (400 MHz, CD3OD) δ 9.07 (s, 2H), 8.53 – 8.48 (m, 1H), 7.83 –7.75 (m, 2H), 7.70 – 7.59 (m, 2H), 7.53 (t, 1H), 6.38 (d, 1H), 5.25 (d, 1H), 3.68 – 3.58 (m, 1H), 3.49 (s, 3H), 3.46 – 3.38 (m, 2H), 2.97 (d, 1H), 2.52 –2.45 (m, 2H), 1.76 (s, 3H).

[0321] Following the synthetic method of compound 2, the following compounds can be obtained:

[0322] 4 577.2 <![CDATA[ 1 H NMR (400 MHz, CD3OD) δ 9.04 (s,2H), 8.51 (dd, 1H), 7.80 (d, 1H),7.75 (d, 1H), 7.69 – 7.64 (m,1H), 7.61 (dd, 1H), 7.53 (t, 1H),6.38 (d, 1H), 5.25 (d, 1H), 3.68– 3.59 (m, 1H), 3.49 (s, 3H),3.04 – 2.94 (m, 3H), 2.90 – 2.84(m, 2H), 1.61 (s, 3H).]]> 5 568.2 6 568.2 7 567.2 8 567.2 9 577.2 10 577.2 11 581.2 12 581.2 13 582.2 14 582.2 15 576.2 16 576.2 17 553.2 18 571.2 19 571.2 20 570.2 21 570.2 22 580.2 <![CDATA[ 1 H NMR (400 MHz, CD3OD) δ 9.07 (s,2H), 8.51 (dd, 1H), 7.80 (d, 1H),7.77 (d, 1H), 7.70 – 7.65 (m,1H), 7.63 (dd, 1H), 7.53 (t, 1H),6.39 (d, 1H), 5.25 (d, 1H), 3.68– 3.59 (m, 1H), 3.14 – 3.08 (m,2H), 2.97 (d, 1H), 2.91 (d, 2H),1.35 (s, 3H).]]> 23 580.2 <![CDATA[ 1 H NMR (400 MHz, CD3OD) δ 9.06 (s,2H), 8.51 (dd, 1H), 7.80 (d, 1H),7.77 (d, 1H), 7.70 – 7.65 (m,1H), 7.63 (dd, 1H), 7.53 (t, 1H),6.38 (d, 1H), 5.25 (d, 1H), 3.68– 3.59 (m, 1H), 3.12 (d, 2H),2.97 (d, 1H), 2.91 – 2.84 (m,2H), 1.69 (s, 3H).]]> 24 584.2 <![CDATA[ 1 H NMR (400 MHz, CD3OD) δ 9.01 (s,2H), 8.51 (dd, 1H), 7.79 (d, 1H),7.74 (d, 1H), 7.70 – 7.65 (m,1H), 7.60 (dd, 1H), 7.54 (t, 1H),6.38 (d, 1H), 5.25 (d, 1H), 3.68– 3.58 (m, 1H), 3.51 (s, 2H),2.97 (d, 1H), 2.87 (d, 2H), 2.01(d, 2H), 1.37 (s, 3H).]]> 25 584.2 <![CDATA[ 1 H NMR (400 MHz, CD3OD) δ 9.04 (s,2H), 8.52 (dd, 1H), 7.80 (d, 1H),7.76 (d, 1H), 7.70 – 7.65 (m,1H), 7.62 (dd, 1H), 7.54 (t, 1H),6.38 (d, 1H), 5.25 (d, 1H), 3.67– 3.59 (m, 1H), 3.53 (s, 2H),2.97 (d, 1H), 2.70 (d, 2H), 2.35(d, 2H), 1.20 (s, 3H). <!-- 27 -->]]> 26 585.2 <![CDATA[ 1 H NMR (400 MHz, CD3OD) δ 9.03 (s,2H), 8.51 (dd, 1H), 7.80 (d, 1H),7.76 (d, 1H), 7.70 – 7.65 (m,1H), 7.62 (dd, 1H), 7.53 (t, 1H),6.38 (d, 1H), 5.25 (d, 1H), 3.67(s, 2H), 3.66 – 3.59 (m, 1H),2.97 (d, 1H), 2.63 (d, 2H), 2.30(d, 2H), 1.21 (s, 3H).]]> 27 585.2 28 579.2 <![CDATA[ 1 H NMR (400 MHz, CD3OD) δ 9.04 (s,2H), 8.51 (dd, 1H), 7.80 (d, 1H),7.75 (d, 1H), 7.70 – 7.65 (m,1H), 7.61 (dd, 1H), 7.53 (t, 1H),6.37 (d, 1H), 5.25 (d, 1H), 3.68– 3.58 (m, 1H), 3.04 (d, 2H),2.97 (d, 1H), 2.80 (d, 2H), 1.57(s, 3H).]]> 29 579.2 <![CDATA[ 1 H NMR (400 MHz, CD3OD) δ 9.07 (s,2H), 8.51 (dd, 1H), 7.80 (d, 1H),7.77 (d, 1H), 7.70 – 7.65 (m,1H), 7.63 (dd, 1H), 7.53 (t, 1H),6.38 (d, 1H), 5.25 (d, 1H), 3.68– 3.59 (m, 1H), 3.45 – 3.39 (m,2H), 2.97 (d, 1H), 2.44 (d, 2H),1.71 (s, 3H).]]> 30 556.2 31 580.2 32 580.2

[0323] Example 3: Preparation of Compound 3

[0324]

[0325] Step 1: Synthesis of 3b

[0326] 3a (7 g, 31.96 mmol) was dissolved in 70 mL of acetonitrile, and potassium hydroxide aqueous solution (8.97 g, 159.8 mmol) was added dropwise at -20 °C, followed by TMSCF2Br (12.9 g, 63.92 mmol). After the addition was complete, the reaction was continued for 0.5 hours. Ethyl acetate and water were added, and the resulting organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography to obtain 3b (28.5 g, 42%).

[0327] LCMS m / z = 250.9 [M+H] +

[0328] Step 2: Synthesis of 3C

[0329] 3b (6.3 g, 25.1 mmol), (S)-tert-butylsulfinamide (3.35 g, 27.61 mmol), and cesium carbonate (12.27 g, 37.65 mmol) were added to 100 mL of dichloromethane and reacted at room temperature for 4 hours. After adding appropriate amounts of water and dichloromethane, the resulting organic phase was dried, concentrated, and subjected to silica gel column chromatography to obtain 3c (7.3 g, 78%).

[0330] Step 3: 3D compositing

[0331] Zinc powder (12.89 g, 197.1 mmol) and cuprous chloride (5.85 g, 59.13 mmol) were added to 150 mL of tetrahydrofuran and reacted at 70 °C for 2 hours. Ethyl bromoacetate (9.87 g, 59.13 mmol) was slowly added at room temperature, and the reaction was continued at 50 °C for 1 hour. The reaction solution was cooled to room temperature, and 30 mL of tetrahydrofuran solution containing 3c (7.3 g, 19.71 mmol) was added dropwise. After reacting at room temperature for 1 hour, a saturated ammonium chloride solution was added to quench the reaction, and an appropriate amount of ethyl acetate was added. The resulting organic phase was filtered, washed, dried, concentrated, and subjected to silica gel column chromatography to obtain 3d (7.3 g, 80%).

[0332] Step 4: Synthesis of 3e

[0333] 3d (7.3 g, 15.86 mmol) was dissolved in 30 mL of dichloromethane, and a dioxane solution of HCl (4 M, 30 mL, 120 mmol) was added. The reaction was carried out at room temperature for 4 hours. The reaction solution was directly concentrated to obtain crude 3e hydrochloride.

[0334] LCMS m / z = 356[M+H] +

[0335] Step 5: Synthesis of 3f

[0336] Add 4-chloro-2-fluoronitrobenzene (3.33 g, 18.97 mmol), potassium carbonate (10.93 g, 79.05 mmol), and 80 mL of acetonitrile to the crude 3e hydrochloride (5.6 g, 15.81 mmol) from the previous step, and react overnight at 80 °C. The reaction solution was directly concentrated and subjected to silica gel column chromatography to give 3f (3.5 g, two-step yield 43.4%).

[0337] LCMS m / z = 510.8 [M+H] +

[0338] Step 6: Synthesis of 3g

[0339] 3f (3.5 g, 6.84 mmol) was dissolved in 25 mL of dichloromethane, and a toluene solution of DIBAL-H (1.5 M, 9.1 mL, 13.68 mmol) was added at -78 °C. The reaction was carried out at -78 °C for 40 minutes. The reaction was quenched by adding saturated ammonium chloride solution, and an appropriate amount of dichloromethane was added. The organic phase obtained after filtration and washing of the reaction solution was dried and concentrated to obtain 3 g of crude product.

[0340] Steps 7-12: Synthesis of compound 3m:

[0341] Compound 3m (200 mg) was prepared according to steps 11 to 16 of Example 1.

[0342] LCMS m / z = 500.2 [M+H] +

[0343] Steps 13 and 14: Preparation of Compound 3

[0344] Following step seventeen of the synthesis of compound 2, crude compound 3n was obtained. The Boc protecting group of crude compound 3n was removed by trifluoroacetic acid to obtain target compound 3 (15 mg).

[0345] LCMS m / z = 537.2[M+H]+

[0346] Reference compound 1-3 The following compounds can be prepared by the synthetic method:

[0347] 33 <![CDATA[562.2 [M+H] + ]]> <![CDATA[ 1 H NMR (400 MHz, CD3OD) δ8.40 – 8.34 (m, 1H), 7.78 –7.75 (m, 1H), 7.69 (d, 1H),7.52 (t, 1H), 7.48 – 7.00(m, 6H), 6.41 (d, 1H), 5.20(d, 1H), 3.62 – 3.52 (m,1H), 3.14 (d, 2H), 2.90 (d,1H), 2.54 (d, 2H), 1.75 (s,3H).]]> 34 <![CDATA[562.2 [M+H] + ]]> <![CDATA[ 1 H NMR (400 MHz, CD3OD) δ8.40 – 8.34 (m, 1H), 7.78 –7.75 (m, 1H), 7.69 (d, 1H),7.53 – 7.41 (m, 4H), 7.39 –6.99 (m, 3H), 6.41 (d, 1H),5.20 (d, 1H), 3.62 – 3.53(m, 1H), 2.93 – 2.82 (m,3H), 2.77 – 2.70 (m, 2H),1.53 (s, 3H). <!-- 30 -->]]> 35 <![CDATA[564.2 [M+H] + ]]> <![CDATA[ 1 1H NMR (400 MHz, CD3OD) δ9.10 (s, 2H), 8.12 (dd, 1H), 7.90 (d, 1H), 7.83 (d, 1H), 7.69 (dd, 1H), 7.57–7.16 (m, 2H), 6.46 (d, 1H), 5.29 (d, 1H), 3.66–3.56 (m, 1H), 3.42 (d, 2H), 2.95 (d, 1H), 2.49 (d, 2H), 1.76 (s, 3H). 36 <![CDATA[563.2 [M+H] + ]]> <![CDATA[ 1 1H NMR (400 MHz, CD3OD) δ9.08 (s, 2H), 8.11 (dd, 1H), 7.86 (d, 1H), 7.80 (d, 1H), 7.63 (dd, 1H), 7.56–7.15 (m, 2H), 6.41 (d, 1H), 5.22 (d, 1H), 3.64–3.54 (m, 1H), 3.42 (d, 2H), 2.92 (d, 1H), 2.43 (d, 2H), 1.71 (s, 3H). 37 <![CDATA[564.2 [M+H] + ]]> <![CDATA[ 1 1H NMR (400 MHz, CD3OD) δ9.08 (s, 2H), 8.11 (dd, 1H), 7.86 (d, 1H), 7.80 (d, 1H), 7.63 (dd, 1H), 7.57–7.15 (m, 2H), 6.41 (d, 1H), 5.22 (d, 1H), 3.64–3.54 (m, 1H), 3.12 (d, 2H), 2.95–2.84 (m, 3H), 1.69 (s, 3H). 38 <![CDATA[553.2 [M+H] + ]]> <![CDATA[ 1 H NMR (400 MHz, CD3OD) δ8.42 – 8.36 (m, 1H), 7.85(s, 1H), 7.74 (d, 1H), 7.58– 7.45 (m, 4H), 7.41 – 7.03(m, 3H), 6.50 (d, 1H), 5.31(d, 1H), 3.66 – 3.57 (m,1H), 2.96 (d, 1H), 2.84 –2.78 (m, 2H), 2.59 – 2.51(m, 2H), 1.21 (s, 3H). <!-- 31 -->]]> 39 <![CDATA[564.0 [M+H] + ]]> <![CDATA[ 1 1H NMR (400 MHz, CD3OD) δ9.08 (s, 2H), 8.12 (dd, 1H), 7.89 (d, 1H), 7.82 (d, 1H), 7.68 (dd, 1H), 7.57–7.17 (m, 2H), 6.46 (d, 1H), 5.29 (d, 1H), 3.66–3.56 (m, 1H), 3.06–2.84 (m, 5H), 1.61 (s, 3H). 40 <![CDATA[564.0 [M+H] + ]]> <![CDATA[ 1 1H NMR (400 MHz, CD3OD) δ9.09 (s, 2H), 8.11 (dd, 1H), 7.87 (d, 1H), 7.80 (d, 1H), 7.64 (dd, 1H), 7.57–7.18 (m, 2H), 6.42 (d, 1H), 5.23 (d, 1H), 3.64–3.54 (m, 1H), 3.14–3.07 (m, 2H), 2.96–2.88 (m, 3H), 1.35 (s, 3H). 41 <![CDATA[563.3 [M+H] + ]]> <![CDATA[ 1 1H NMR (400 MHz, CD3OD) δ9.06 (s, 2H), 8.11 (dd, 1H), 7.85 (d, 1H), 7.79 (d, 1H), 7.62 (dd, 1H), 7.57–7.16 (m, 2H), 6.41 (d, 1H), 5.22 (d, 1H), 3.64–3.53 (m, 1H), 3.04 (d, 2H), 2.92 (d, 1H), 2.80 (d, 2H), 1.57 (s, 3H). 42 <![CDATA[553.3 [M+H] + ]]> <![CDATA[ 1 H NMR (400 MHz, CD3OD) δ8.40 – 8.34 (m, 1H), 7.77(s, 1H), 7.68 (d, 1H), 7.49– 7.42 (m, 4H), 7.41 – 7.00(m, 3H), 6.41 (d, 1H), 5.20(d, 1H), 3.62 – 3.53 (m,1H), 2.89 (d, 1H), 2.64 –2.57 (m, 2H), 2.49 – 2.42(m, 2H), 1.61 (s, 3H). <!-- 32 -->]]> 43 <![CDATA[561.2 [M+H] + ]]> <![CDATA[ 1 H NMR (400 MHz, DMSO-d6) δ8.28 (dd, 1H), 7.75 – 7.53(m, 3H), 7.52 – 7.42 (m,3H), 7.39 – 7.24 (m, 3H),6.26 (d, 1H), 5.23 (d, 1H),3.58 – 3.47 (m, 1H), 2.81(d, 1H), 2.59 (dd, 4H),2.41 (s, 2H), 1.43 (s, 3H).]]> 44 <![CDATA[567.3 [M+H] + ]]> <![CDATA[ 1 H NMR (400 MHz, DMSO-d6) δ8.31 – 8.24 (m, 1H), 7.76 –7.63 (m, 2H), 7.58 – 7.30(m, 7H), 6.26 (d, 1H), 5.47(s, 1H), 5.23 (d, 1H), 4.74(t, 1H), 3.58 – 3.47 (m,1H), 3.21 (d, 2H), 2.82 (d,1H), 2.52 (d, 2H), 1.90 (d,2H), 1.29 (s, 3H).]]> 45 <![CDATA[566.3 [M+H] + ]]> <![CDATA[ 1 H NMR (400 MHz, DMSO-d6) δ8.31 – 8.24 (m, 1H), 7.74 –7.63 (m, 2H), 7.56 – 7.27(m, 7H), 6.26 (d, 1H), 5.23(d, 1H), 3.57 – 3.48 (m,1H), 3.40 (s, 2H), 2.82 (d,1H), 2.20 (s, 4H), 1.03 (s,3H).]]>

[0348] Biological test cases

[0349] 1. TNF-α / TNFR1 binding assay

[0350] The inhibition of TNF-α / TNFR1 binding by the compound was tested using the TR-FRET method. Solutions of proteins TNF-α (ACRO, Cat #TNA-H82E3) and TNFR1 (ACRO, Cat #TN1-H5251) were prepared in reaction buffer PPI (Revvity, Cat #61DB10RDF). The final concentrations of TNF-α / TNFR1 in the reaction mixture were both 0.15 nM. The positive reference, adalimumab, was initially diluted 3-fold at a concentration of 1 μM, 10 doses. 0.1 μL of the diluted positive reference in reaction buffer was transferred to a 384-well plate (Grenier, Cat #784075) using acoustic liquid delivery technology (Echo655) and centrifuged at 1000 rpm for 1 min. 2.5 μL of TNF-α solution was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 min, then incubated at 25°C for 15 min. 2.5 μL of TNFR1 solution was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 min. Transfer 5 μL of the streptavidin-Tb cryptate and PAb Anti-Human IgG-XL665 detection mixture to a 384 reaction plate and centrifuge at 1000 rpm for 1 minute. Incubate at 25°C for 60 minutes. Finally, read the HTRF signal (Ratio 665 / 620 nm) using a BMG high-throughput drug screening multi-mode microplate reader. Obtain the IC50 using GraphPad Prism software. 50 Fitting values ​​and nonlinear regression curves.

[0351] The experimental results are as follows

[0352] Compound 4 A Compound 22 A Compound 26 A Compound 28 A Compound 33 A Compound 34 A Compound 35 A Compound 37 A Compound 38 A Compound 39 A Compound 40 A Compound 41 A Compound 42 A Compound 43 A Compound 44 A

[0353] A: < 50 nM.

[0354] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity against TNF-α / TNFR1 binding.

[0355] 2. Detection experiment of Membrane TNFα and H_TNFR1 / H_TNFR2 reporter cells:

[0356] Cell line GM-C33297: Membrane Bound H_TNFα (cleavage-resistant) CHO-K1 Cell Line;

[0357] GM-C27615:H_TNFR2 Null Reporter Cell Line

[0358] GM-C25776: H_TNFR2 Reporter V2 Cell Line

[0359] Experimental methods:

[0360] 16-24 hours before the experiment, Membrane Bound H_TNFα CHO-K1 Cell Line cell pellets were collected by digestion and centrifugation. Cells were resuspended in complete culture medium, and cell density and viability were calculated. The appropriate cell density was adjusted by adding more complete culture medium. 100 μL cells / well were added to the center well using a multipipeline, and 100 μL PBS was added to the surrounding wells. The plates were then capped and incubated overnight. 1-2 hours before the experiment, effector cells (H_TNFR1 / H_TNFR2 reporter cell lines) were collected by centrifugation and resuspended in Assay Buffer. Cell density and viability were calculated, and the effector cell density was adjusted to an appropriate level by adding more Assay Buffer. Anti-TNFα drugs were serially diluted in Assay Buffer in sterile 96-well V plates. The overnight Membrane Bound H_TNFα CHO-K1 Cell Line plates were removed, the supernatant was discarded, and serially diluted drugs were added at 50 μL / well. The plates were incubated for 1 hour. One hour later, effector cells (H_TNFR1 / H_TNFR2 reporter cell line) were added at 50 μL per well, the plate was capped, and incubation continued for another 6 hours. Samples were then collected for Luciferase detection.

[0361] 3. HT-29 cell apoptosis experiment

[0362] HT-29 (ATCC) cells were seeded at 12,000 cells / 100 μL / well in 96-well plates (corning, 3599) and allowed to adhere overnight. TNF-α (R&D, 210-TA-020) was diluted to a final concentration of 20 pg / mL using culture medium, and different concentrations of the compound were added (starting at 10 μM, serially diluted 3 times, setting 9 concentration points), and pre-incubated at 37°C for 1 hour. Transfer 100 μL of the pre-incubated mixture of TNF-α and the compound into 100 μL of cells. Add Z-VAD (MCE, HY-16658B) to a final concentration of 20 μM and AT406 (MCE, HY-15454) to 25 μM. Incubate at 37°C with 5% CO2 for 24 hours. Add CellCounting-Lite (vazyme, DD1102), shake for 2 minutes in the dark, and incubate at room temperature in the dark for 30 minutes. Read the luminescence signal value using a microplate reader.

[0363] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity against HT-29 cells.

[0364] 4. Pharmacokinetic assays in mice

[0365] Experimental animals: Male C57 mice, 20-25 g, 6 mice / compound. Purchased from Sichuan Vital River Laboratory Animal Technology Co., Ltd.

[0366] Experimental design: On the day of the experiment, 6 C57 mice were randomly divided into groups according to their body weight. They were fasted for 12-14 hours before administration but allowed free access to water, and were fed 4 hours after administration.

[0367] Dosage information

[0368] Note: Intravenous administration solvent: 10% DMA + 10% Solutol + 80% Saline; Gavage administration solvent: 0.5% MC

[0369] DMA: Dimethylacetamide; Solutol: Polyethylene glycol-15-hydroxystearate; Saline: Physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose

[0370] Blood samples of 0.06 mL were collected via the orbital cavity before and after isoflurane anesthesia, placed in EDTAK2 centrifuge tubes, and centrifuged at 5000 rpm for 10 min at 4 °C to collect plasma. Blood collection time points for both the intravenous and gavage groups were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, and 24 h. All samples were stored at -80 °C before analysis and quantitative analysis was performed using LC-MS / MS.

[0371] Mouse PK Results

[0372]

[0373] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties.

[0374] 5. CYP450 enzyme inhibition test

[0375] The aim of this study was to evaluate the effects of test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro assay system. Specific probe substrates for CYP450 isoenzymes were co-incubated with human liver microsomes and different concentrations of the test substances. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS) after sample processing. Changes in CYP enzyme activity were measured, IC50 values ​​were calculated, and the inhibitory potential of the test substances on each CYP enzyme isoform (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4-M with midazolam as a substrate) was evaluated.

[0376] Test results:

[0377] Compound 34 >30uM

[0378] Conclusion: The compounds of the present invention, such as those in the examples, have no significant inhibitory effect on any of the CYP enzyme subtypes.

[0379] 6. hERG potassium ion channel function test

[0380] Experimental platform: Electrophysiological manual patch-clamp system

[0381] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channels

[0382] Experimental Methods: CHO (Chinese Hamster Ovary) cells stably expressing the hERG potassium channel were used to record hERG potassium channel currents at room temperature using whole-cell patch-clamp technique. Glass microelectrodes were fabricated from glass electrode blanks (BF150-86-10, Sutter) using a stretching device. The tip resistance after perfusion with electrode fluid was approximately 2-5 MΩ. The glass microelectrodes were inserted into the amplifier probe to connect to the patch-clamp amplifier. Clamping voltage and data recording were controlled and recorded using pClamp 10 software via computer, with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After obtaining whole-cell recordings, the cells were clamped at -80 mV. The step voltage to induce hERG potassium current (IhERG) was applied from -80 mV with a 2-second depolarization voltage to +20 mV, followed by repolarization to -50 mV, held for 1 second, and then returned to -80 mV. This voltage stimulation is applied every 10 seconds. Once the hERG potassium current has stabilized (at least 1 minute), the dosing process begins. Each test concentration of the compound is administered for at least 1 minute, and at least 2 cells are tested for each concentration (n≥2).

[0383] Data processing: Data analysis and processing were performed using pClamp 10, GraphPad Prism 5, and Excel software. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula:

[0384] Inhibition % = [1 – (I / Io)]×100%

[0385] Where Inhibition % represents the percentage of inhibition of hERG potassium current by the compound, and I and Io represent the amplitude of hERG potassium current before and after drug administration, respectively.

[0386] Compound IC 50 The following equations were fitted and calculated using GraphPad Prism 5 software:

[0387] Y=Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope))

[0388] Where X is the Log value of the detected concentration of the test sample, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0389] Compound 34 >10

[0390] Conclusion: The compounds of the present invention, such as the compounds in the examples, do not exhibit significant hERG inhibitory activity.

[0391] 7. Caco2 Permeability Test

[0392] The experiment used monolayers of Caco-2 cells, incubated in triple parallel in 96-well Transwell plates. A transport buffer solution (HBSS, 10 mM HEPES, pH 7.4±0.05) containing either the compound of the present invention (2 μM) or the control compounds digoxin (10 μM), naldolol (2 μM), and metoprolol (2 μM) was added to the dosing well on the apical or basal side. A transport buffer solution containing DMSO was added to the corresponding receiving well. After incubation at 37±1°C for 2 hours, the cell plate was removed, and appropriate amounts of sample were transferred from both the apical and basal sides to new 96-well plates. Acetonitrile containing an internal standard was then added to precipitate the protein. The samples were analyzed using LC MS / MS to determine the concentrations of the compound of the present invention and the control compounds. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical to the basal side of the monolayer cells, and from the basal side to the apical side, thereby calculating the efflux rate. Leakage of fluorescein was used to evaluate the integrity of the monolayer cells after 2 hours of incubation.

[0393] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good permeability.

[0394] 8. Experiment on recombinant human TNFα inducing apoptosis in L929 cells:

[0395] First, human recombinant TNFα was dissolved in PBS containing 0.1% BSA to prepare a stock solution of 100 μg / mL, aliquoted, and stored at -80°C. 100 mg of actinomycin D was dissolved in 1 mL of DMSO (Sigma, D2650) to prepare a stock solution of 100 mg / mL, aliquoted, and stored at -20°C. Next, L929 cells were cultured in 225 cm² flasks until confluence reached 70%–80%. After gently washing the cells twice with pre-chilled PBS, 5 mL of pre-warmed trypsin-EDTA solution (Solarbio, T1300) was added and incubated at 37°C for approximately 1 minute. Then, 10 mL of culture medium (DMEM + 10% FBS, DMEM provided by Hyclone, SH3002201) was added to neutralize the trypsin. The cell suspension was transferred to 50 mL centrifuge tubes (Biofil, CFT011500), centrifuged at 300–400 x g for 5 minutes, and the supernatant was removed. The cells were resuspended in 10 mL of pre-warmed culture medium (DMEM + 2% FBS). 20 μL of the cell suspension was mixed with 20 μL of 0.2% trypan blue solution (Invitrogen, T10282) for cell counting, and the cells were diluted to 2 × 10⁶ cells / mL. 5Cells / mL were added to each well of a 384-well culture plate (Corning, 3570). Then, 100 mg / mL actinomycin D was diluted to 32 μg / mL in culture medium (DMEM + 2% FBS), and 5 μL of the 32 μg / mL actinomycin D was added to each well of the cell culture plate. The culture plates were incubated at 37°C for 1 hour in a 5% CO2 incubator. Next, the test compound was dissolved in DMSO to prepare a 10 mM stock solution, which was then transferred to a 384-LDV plate at the highest concentration of 10 mM. 4 μL of the solution was transferred to the next well containing 8 μL of DMSO for a 3-fold dilution. The dilution steps were repeated for 10 concentration points from 10 mM to 0.5 mM. Using an Echo 655 (Labcyte), the diluted test compound was transferred to a 384-well plate (Corning, 3764) at a volume of 160 nL per well. DMSO was added to the control wells without the compound. This plate served as the experimental preparation plate. Next, 2.5 μL of recombinant human TNFα was thawed and 2 μL was transferred to a 1.5 mL centrifuge tube (Axygen, MCT-150-C) containing 198 μL of culture medium (DMEM + 2% FBS) to obtain a 1 μg / mL TNFα solution. Then, 60 μL of the 1 μg / mL TNFα solution was added to 15 mL of culture medium (DMEM + 2% FBS) to obtain a 4 ng / mL TNFα working solution (4 times the final concentration). Add 40 μL of 4 ng / mL TNFα working solution to each well of the experimental preparation plate, which contains 160 nL of the test compound solution or DMSO. Briefly centrifuge at 1000 rpm for 1 minute, and then incubate at 37°C for 1 hour. After 1 hour, use the Apricot Designs Pipetting System to transfer 10 μL of TNFα complex solution to a cell culture plate containing L929 cells. The culture medium is 30 μL, including the control group without the compound and TNFα. The final detection medium per well is 40 μL, containing 1 ng / mL TNFα, 4 μg / mL actinomycin D, and 0.1% DMSO. The cell plate is incubated at 37°C in a 5% CO2 humidified incubator for 24 hours. Finally, the cell culture plates were removed from the incubator and equilibrated to room temperature for 15 minutes. Before use, the CellTiter-Glo® 2.0 reagent was equilibrated to room temperature. 30 μL of CellTiter-Glo® 2.0 reagent was added to each well of the cell culture plate. After incubation at room temperature in the dark for 30 minutes, the plates were analyzed using an Envision instrument (PerkinElmer, New York, US). Data quality was assessed by calculating the Z' value and IC50. 50 The value is calculated by fitting a four-parameter logic curve.

[0396] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity against human recombinant TNFα-induced L929 cells.

[0397] 9. Zymosan-induced human whole blood CD11b expression experiment:

[0398] First, venous blood was drawn directly from the donor into test tubes containing EDTA anticoagulant and stored at 4°C. Next, the test compounds were prepared. 8 μL of DMSO was added to columns 2 through 8 of a 384-LDV plate (Labcyte, LP-0200-BC), and 12 μL of 10 mM stock solution was transferred to column 1 for a 3-fold dilution, creating eight concentration gradients of the test compound stock solutions. The compounds were then transferred to 96-well cell culture plates (Corning, 3799) using an Echo 655 (Labcyte) plate. DMSO was used as a positive control, and DMSO without irritants was used as a negative control. Then, gently invert the test tube 7-8 times to mix the fresh whole blood thoroughly. Add 90 μL of fresh whole blood to a 96-well plate, mix gently, and incubate at 37°C and 5% CO2 for 1 hour. Add 10 μL of 10 μg / mL Zymosan (Invivogen, Z2849, final concentration 1 μg / mL) to each well, mix gently, and incubate at 37°C and 5% CO2 for 3 hours. The final concentration of the test compound is diluted 1000-fold. Next, add 10 μL of antibody (FITC anti-human CD11b (activated) Antibody, Biolegend, 301404; APC anti-human CD45 Antibody, Biolegend, 304037; PE anti-mouse / human CD11b, Biolegend, 101208) to each well and incubate the stained whole blood at 4°C for 30 minutes. Dilute BD Phosflow™ lysis / fixation buffer (5×, BD Phosflow, 558049) with distilled water at a ratio of 1:5 and preheat to 37°C. Add 1 mL of 1× BD Phosflow™ lysis / fixation buffer to each well of the deep-well plate. Transfer blood to the preheated solution, mix well, and incubate in a 37°C water bath for 15 minutes. Centrifuge at 1200 g / min for 5 minutes and discard the supernatant. Add 1 mL of PBS (Solarbio, P1020) to each well and centrifuge at 1200 g / min for 5 minutes. Discard the supernatant. Resuspend the cells in 100 μL of cell staining buffer (Biolegend, 420201) and store the plate at 4°C overnight. Finally, data were acquired on a CytoFLEX S flow cytometer, and analyzed using FlowJo to obtain the MFI (mean fluorescence intensity) for each sample. After removing noise and adherent cells, gated detection of the MFI of CD11b-activated cells in CD45⁺CD11b⁺ cells was performed. Data quality was assessed by calculating the Z' value and IC50. 50 The value is calculated by fitting a four-parameter logic curve.

[0399] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity against Zymosan-induced CD11b in human whole blood.

[0400] 10. Human microparticle stability test

[0401] At 37°C, 1 µM of the analyte compound was incubated with human liver microsomes (0.5 mg / mL) in a NADPH regeneration system for 5, 10, 20, 30, and 60 minutes. The concentration of the analyte compound in the resulting samples was then determined by LC-MS / MS. The half-life (T5) of the compound in the human liver microsome solution was calculated by relating it to the remaining percentage of the compound at each time point. 1 / 2 ), inherent clearance rate (CL) int(mic) ) and the remaining percentage of the compound after 60 minutes.

[0402] Conclusion: The compounds of the present invention, such as the compounds in the examples, have lower clearance rates and longer half-lives in human liver microsomes, and exhibit superior stability in human liver microsomes.

[0403] 11. Rat Pharmacokinetic Tests

[0404] Experimental animals: Male SD rats, approximately 220 g in size, 6-8 weeks old, 6 rats per compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0405] Experimental design: On the day of the experiment, SD rats (6 rats / compound) were randomly divided into groups according to body weight. They were fasted for 12-14 hours before administration but allowed free access to water, and were fed 4 hours after administration.

[0406] Dosage information

[0407] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Gavage administration solvent: 0.5% MC.

[0408] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose)

[0409] Before and after administration of isoflurane anesthesia, 0.15 ml of blood was drawn through the orbit and placed in an EDTAK2 centrifuge tube. The centrifuge was then incubated at 5000 rpm for 4 hours. o Plasma was collected after centrifugation at C for 10 min. Blood samples were collected at the following time points for both the intravenous and gavage groups: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, and 24 h. All samples were stored at -80°C before analysis.o C. Quantitative analysis of the sample was performed using LC-MS / MS.

[0410] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption in rats.

[0411] 12. Pharmacokinetics of Beagle Dogs

[0412] Experimental animals: Male beagle dogs, approximately 8-11 kg, 3 dogs per compound, purchased from Beijing Mars Biotechnology Co., Ltd.

[0413] Experimental method: On the day of the experiment, beagle dogs (3 dogs / compound) were randomly divided into groups according to body weight. They were fasted for 12-14 hours before administration but allowed free water. They were fed 4 hours after administration.

[0414] Dosage information

[0415] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Gavage administration solvent: 0.5% MC.

[0416] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose)

[0417] Blood samples (1 ml) were collected via jugular or limb veins before and after drug administration and placed in EDTAK2 centrifuge tubes. Plasma was collected by centrifugation at 5000 rpm and 4 °C for 10 min. Blood collection time points for both the intravenous and gavage groups were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 h. All samples were stored at -80 °C before analysis and quantitative analysis was performed using LC-MS / MS.

[0418] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption in beagle dogs.

[0419] 13. Pharmacokinetics in monkeys

[0420] Experimental animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 6 animals / compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0421] Experimental method: On the day of the experiment, monkeys (6 per compound) were randomly divided into groups according to their body weight. They were fasted for 14-18 hours before administration but allowed free access to water, and were fed 4 hours after administration.

[0422] Dosage information

[0423] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Gavage administration solvent: 0.5% MC.

[0424] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose) *Dosage is based on free base.

[0425] Blood samples of 1.0 mL were collected via venous sampling from each limb before and after administration and placed in EDTAK2 centrifuge tubes. The centrifuge volume was 5000 rpm, 4 mL. o Plasma was collected after centrifugation at C for 10 min. Blood samples were collected at the following time points for both the intravenous and gavage groups: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, and 24 h. All samples were stored at -80°C before analysis. o C. Quantitative analysis of the sample was performed using LC-MS / MS.

[0426] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption in monkeys.

Claims

1. A compound or its racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is selected from compounds represented by general formula (I). (I)； A is selected from or ; X1 and X2 are each independently selected from CR x Or N; R 2 R 1a R 1b R x R a R b R c Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, SF5, COOH, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-7 Carbocyclic group, -C 0-4 Alkylene-C 3-7 Carbocyclic group, -C 0-4 Alkyl-4 to 7-membered heterocyclic groups, -SC 3-7 carbonyl group, -OC 1-4 Alkylene-C 3-7 carbonyl group, -SC 1-4 Alkylene-C 3-7 Carbocyclic group, -S(=O)C 1-6 Alkyl group, -S(=O)C 3-7 Carbocyclic group, -NHS(=O)C 1-6 Alkyl group, -S(=O)2C 1-6 Alkyl group, -S(=O)2C 3-7 Carbocyclic group, -NHS(=O)2C 1-6 Alkyl group, -S(=O)2NHC 1-6 Alkyl, -P(=O)(C 1-6 Alkyl)2, wherein the alkylene, alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R k replace; R 3 Each is independently selected from H, deuterium, OH, CN, NH2, NO2, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, OC 1-6 Alkyl, -SC 1-6 Alkyl, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 3-7 Carbocyclic groups, 4 to 7 heterocyclic groups, -OC 3-7 Carbocyclic, -O-4 to 7-membered heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R 4 R 5 or R 6 Each element is independently selected from H, deuterium, halogens, OH, CN, NH2, NO2, SF5, COOH, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, OC 1-6 Alkyl, -SC 1-6 Alkyl, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 3-7 Carbocyclic groups, 4 to 7 heterocyclic groups, -OC 3-7 Carbocyclic, -O-4 to 7-membered heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; Or R 5 and R 6 Together replace; Or R c With R 4 R c With R 5 R x With R 4 R x With R 5 Together with the atoms or framework attached to it, they form C 4-12 A carbocyclic group or a 4-12 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R k Each element is independently selected from deuterium, O, halogens, CN, OH, COOH, NH2, SF5, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic groups, -O-4 to 7-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-4 to 7-membered heterocyclic groups, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 alkylene-4 to 7-membered heterocyclic groups, C 3-6 Carbocyclic groups, 4- to 7-membered heterocyclic groups, -C(=O)N(C 1-6 Alkyl)2, -C(=O)NH2, -C(=O)NHC 1-6 Alkyl, -C(=O)-C 3-6 Carbocyclic group, -C(=O)-4 to 7-membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, ynyl, carbocyclic or heterocyclic group is optionally selected from 1 to 4 deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups; a and c are each independently selected from 0, 1, and 2; b is independently selected from 0, 1, 2, and 3; The condition is that the compound represented by general formula (I) satisfies at least one of the following conditions: 1) When R 1a When selected from H, R 2 Not selected from H or CF3, and the compound does not have the following structure: 、 、 ； 2) When R 2 When selected from H, R 1a Selected from Cl and R 5 and R 6 Not selected from H; 3) When R 1b When selected from H, R 5 and R 6 Not selected from H, and the compound is not H. ; 4) When R 1a Selected from H, R 2 When selected from H and CF3, R c With R 4 R c With R 5 R x With R 4 R x With R 5 Together with the atoms or framework attached to it, they form C 4-12 A carbocyclic group or a 4-12 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k Replace, or R 5 and R 6 Together Substitution, and the compound is not , , ; 5) When R 1b Selected from H, and R 5 and R 6 When selected from H, Not selected ; 6) When R 2 Selected from H, R 1a Selected from Cl and R 5 and R 6 When selected from H, Not selected ; 7) X1 and X2 are selected from CR x .

2. The compound according to claim 1, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. R 2 R 1a R 1b R x R a R b R c Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, SF5, COOH, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 cycloalkyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-7 Carbocyclic group, -C 1-2 Alkyl-4 to 7-membered heterocyclic groups, -SC 3-7 cycloalkyl, -OC 1-2 Alkylene-C 3-7 carbonyl group, -SC 1-2 Alkylene-C 3-7 Cycloalkyl, -S(=O)C 1-4 Alkyl group, -S(=O)C 3-6 cycloalkyl, -NHS(=O)C 1-4 Alkyl group, -S(=O)2C 1-4 Alkyl group, -S(=O)2C 3-6 cycloalkyl, -NHS(=O)2C 1-4 Alkyl group, -S(=O)2NHC 1-4 Alkyl, -P(=O)(C 1-4 Alkyl, 2-phenyl, 5-6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, carbocyclic, phenyl, heteroaryl, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R 3 Each is independently selected from H, deuterium, OH, CN, NH2, NO2, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, OC 1-4 Alkyl, -SC 1-4 Alkyl, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 3-6 Carbocyclic groups, 4- to 6-heterocyclic groups, -OC 3-6 Carbocyclic, -O-4 to 6-membered heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R 4 R 5 or R 6 Each element is independently selected from H, deuterium, halogens, OH, CN, NH2, NO2, SF5, COOH, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, OC 1-4 Alkyl, -SC 1-4 Alkyl, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 3-6 Carbocyclic groups, 4- to 6-heterocyclic groups, -OC 3-6 Carbocyclic, -O-4 to 6-membered heterocyclic groups, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; Or R 5 or R 6 Together replace; Or R c With R 4 R c With R 5 R x With R 4 R x With R 5 Together with the atoms or framework attached to it, they form C 4-10 A carbocyclic group or a 4-10 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R k Each element is independently selected from deuterium, O, halogens, CN, OH, COOH, NH2, SF5, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocyclic groups, -O-4 to 7-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-4 to 7-membered heterocyclic groups, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 alkylene-4 to 7-membered heterocyclic groups, C 3-6 Carbocyclic groups, 4- to 7-membered heterocyclic groups, -C(=O)N(C 1-4 Alkyl)2, -C(=O)NH2, -C(=O)NHC 1-4 Alkyl, -C(=O)-C 3-6 Carbocyclic group, -C(=O)-4 to 7-membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, ynyl, carbocyclic or heterocyclic group is optionally selected from 1 to 4 deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 The alkoxy group is replaced by a substituent.

3. The compound according to claim 2, or its racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I) is selected from the compounds represented by general formulas (II-a) and (II-b). (II-a)、 (II-b)? Each Each is selected independently, either from the presence or absence of the ring; When present, ring C1 or ring C2 is independently selected from 4-10 member heterocyclic groups, wherein the heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; The condition is that the compound represented by general formula (II-a) or general formula (II-b) satisfies at least one of the following conditions: 1) When R 1a When selected from H, R 2 Not selected from H or CF3, and the compound does not have the following structure: 、 、 ； 2) When R 2 When selected from H, R 1a Selected from Cl and R 5 and R 6 Not selected from H; 3) When R 1b When selected from H, R 5 and R 6 Not selected from H, and the compound is not H. ; 4) When R 1a Selected from H, R 2 When H and CF3 are selected, at least one of rings C1 and C2 exists, or R... 5 and R 6 Together Substitution, and the compound is not , , ; 5) When R 1b Selected from H, and R 5 and R 6 When selected from H, Not selected ; 6) When R 2 Selected from H, R 1a Selected from Cl and R 5 and R 6 When selected from H, Not selected ; 7) X1 and X2 are selected from CR x .

4. The compound according to claim 3, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, R 2 R 1a R 1b R x R a R b R c Each of these groups is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, SF5, COOH, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetra Hydrofuranyl, -S(=O)CH3, -S(=O)cyclopropyl, -NHS(=O)-CH3, -S(=O)2-CH3, -S(=O)2cyclopropyl, -NHS(=O)2CH3, -S(=O)2NHCH3, -P(=O)(CH3)2, wherein CH2, CH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxacyclobutyl, tetrahydrofuranyl are optionally surrounded by 1 to 4 R k replace; R 3 Each of the following is independently selected from H, deuterium, OH, CN, NH2, NO2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetrahydrofuranyl, wherein CH2, CH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxacyclobutyl, tetrahydrofuranyl are optionally separated by 1 to 4 R k replace; R 4 R 5 or R 6 Each of the following is independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NO2, SF5, COOH, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetrahydrofuranyl, wherein CH2, CH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxacyclobutyl, tetrahydrofuranyl are optionally separated by 1 to 4 R k replace; Or R 5 or R 6 Together replace; Ring C1 or ring C2 are each independently selected from 4-9 member heterocyclic groups, wherein the heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R k Each group is independently selected from deuterium, =O, F, Cl, Br, I, CN, OH, COOH, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, C(=O)NH2, C(=O)NH(CH3), C(=O)NH(CH2CH3), C(=O)N(CH3)2, methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, -CH2-pyrrolyl, C(=O)pyrrolyl, wherein the CH2, CH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and pyrrolyl groups are optionally selected from 1 to 4 of deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 The alkoxy group is replaced by a substituent.

5. The compound according to claim 4, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, R k Each is independently selected from deuterium, =O, F, Cl, Br, I, CN, OH, COOH, NH2, SF5, -CH2OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCF3, OCHF2, OCH2F, OCD3, OCHD2, OCH2D, methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, -CH2CH2OCH2CH3, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C(=O)NH2, C(=O)NH(CH3), C(=O)NH(CH2CH3), C(=O)N(CH3)2, pyrroleyl, , .

6. The compound according to claim 5, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, R 2 Each of the following is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCF3, OCHF2, OCH2F, OCD3, -OCH2CHF2, -OCF2CHF2, -OCH2CF3, -SCH2CHF2, -SCF2CHF2, SF5, COOH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetrahydrofuranyl; R 3 Each is independently selected from methyl, ethyl, CD3, and cyclopropyl; R 4 R 5 or R 6 Each is independently selected from F, Cl, Br, I, OH, CN, NH2, NO2, SF5, COOH, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCF3, OCHF2, OCH2F, OCD3, -OCH2CHF2, -OCF2CHF2, -OCH2CF3, -SCH2CHF2, -SCF2CHF2, CH2OH, CH2NH2, CH2CN, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetrahydrofuranyl; Or R 5 or R 6 Together replace; R 1a R 1b Each is independently selected from H, deuterium, F, Cl, and Br; R x R a R b R c Each of the following is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCF3, OCHF2, OCH2F, OCD3, -OCH2CHF2, -OCF2CHF2, -OCH2CF3, -SCH2CHF2, -SCF2CHF2, SF5, COOH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetrahydrofuranyl; or Selected from or .

7. The compound according to claim 1 or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the structures shown in Table E. Table E 8. A pharmaceutical composition comprising the compound of any one of claims 1-7 or a racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, preferably comprising 1-1500 mg of the compound of any one of claims 1-7 or a racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

9. The use of the compound according to any one of claims 1-7, or its racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating autoimmune diseases or inflammatory diseases (preferably psoriasis or rheumatoid arthritis, ulcerative colitis, Crohn's disease).

10. A method for treating or alleviating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound of any one of claims 1-7 or a racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, preferably 1-1500 mg, wherein the disease is preferably an autoimmune disease or an inflammatory disease (preferably psoriasis or rheumatoid arthritis, ulcerative colitis, Crohn's disease)).

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