Fused heterocyclic derivative and pharmaceutical use thereof

Abstract

A fused heterocyclic derivative and the pharmaceutical use thereof, relating to a compound as represented by general formula (I), or a racemate, a stereoisomer, a tautomer, and a pharmaceutically acceptable salt thereof, and an intermediate thereof, a preparation method therefor, as well as the use thereof in the preparation of a drug for treating autoimmune diseases or inflammatory diseases.

Description

A fused heterocyclic derivative and its pharmaceutical applications 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; its precursor 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 with inhibitory activity against TNFα receptors. These compounds exhibit good inhibitory activity against TNF-α / TNFR1 binding, good pharmacokinetic properties, weak inhibitory effects on various CYP enzyme subtypes CYP1A2, CYP2C9, CYP2D6, CYP2C19, and CYP3A4-M, better stability in human liver microsomes, lower clearance rate, longer half-life, and good permeability.

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

[0005] In some embodiments, the compound represented by formula (I) is selected from the compounds represented by formulas (Ia), (Ib), (Ic), and (Id).

[0006] In some embodiments, the compound represented by formula (I) is selected from the compounds represented by formulas (II) or (III), (IV), and (V).

[0007] In some embodiments, the compound represented by formula (I) is selected from the compounds represented by formulas (Ie) and (If).

[0008] In some implementation schemes, This indicates the presence or absence of a ring; when present, ring B is selected from a 5-membered heteroaryl group, wherein the heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace;

[0009] In some implementations, E is selected from Its left side is connected to an aromatic ring containing Y1;

[0010] In some implementations, E is selected from Or E1;

[0011] In some implementations, E1 is selected from Its left side is connected to a nitrogen-containing heteroaromatic ring;

[0012] In some implementation schemes, Selected from

[0013] In some implementation schemes, Selected from

[0014] In some implementation schemes, Selected from

[0015] In some implementation schemes, Y1 and Y2 are each independently selected from CR y Or N;

[0016] In some implementations, Y1 and Y2 are each independently selected from CH or N; in other implementations, one of Y1 and Y2 is selected from CR. y The other option is selected from N;

[0017] In some implementation schemes, Selected from n2 is selected from 2;

[0018] In some implementation schemes, Selected from

[0019] In some implementations, W is selected from bonds, O, S, C, C (=O), CR 6 NR 6 Or N;

[0020] In some implementations, V is selected from bond, O, S, C, C (=O), CR 8 NR 8 Or N;

[0021] In some implementations, U is selected from bonds, O, S, C, C (=O), CR 5 NR 5 Or N;

[0022] In some implementations, X is selected from bonds, O, S, C, C (=O), CR 7 NR 7 Or N;

[0023] In some implementations, only one of U, W, X, and V is selected from a bond, and ring C is selected from a 5-6 membered heteroaromatic ring or a 6 membered aromatic ring;

[0024] In some implementation schemes, ring C is selected from 5-6 membered heteroaromatic rings;

[0025] In some embodiments, the ring C is selected from phenyl, pyridyl, pyridone, pyrimidinyl, and pyridazinyl, and the ring C is optionally R 5 R 6 R 7 R 8 replace;

[0026] In some embodiments, ring C is selected from ring C1, and ring C1 is selected from thienyl, furanyl, pyrroleyl, thiazolyl, oxazolyl, pyrazolyl, imidazoleyl, pyridinyl, pyridoneyl, pyrimidinyl, and pyridazinyl, wherein ring C1 is optionally R 5 R 6 R 7 R 8 replace;

[0027] In some implementations, ring C is selected from...

[0028] In some embodiments, U and W, W and X, V and X, and their associated skeletons together form a 5-6 membered heteroaryl, a 5-6 membered heterocyclic, or a 5-6 membered carbocyclic, wherein the carbocyclic, heteroaryl, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0029] In some embodiments, U and W, W and X, V and X in ring C1 and their associated skeletons together form a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group, or a 5-6 membered carbocyclic group, wherein the carbocyclic group, heteroaryl, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0030] In some embodiments, U and W, W and X, V and X in ring C1 and their associated skeletons together form an imidazole group, a pyrrole group, a triazole group, a cyclopentyl group, or a pyrrole alkyl group, wherein the imidazole group, pyrrole group, triazole group, cyclopentyl group, or pyrrole alkyl group is optionally surrounded by 1 to 3 R groups. k replace;

[0031] In some implementation schemes, Selected from

[0032] In some implementation schemes, Selected from

[0033] In some implementation schemes, R 5 With R 6 R 7 With R 8 R 6 With R 7 Together with its associated skeleton, it forms a 5-6 membered heteroaryl, 5-6 membered heterocyclic, or 5-6 membered carbocyclic group, wherein the carbocyclic, heteroaryl, or heterocyclic group is optionally surrounded by 1 to 3 R groups. k replace;

[0034] In some implementation schemes, R 5 With R 6 R 7 With R 8 R 6 With R 7 Together with its associated skeleton, it forms a cyclopentyl or pyrrolidinyl group, wherein the cyclopentyl or pyrrolidinyl group is optionally surrounded by 1 to 3 R groups. k replace;

[0035] In some implementations, Z is selected from -(CR z1 R z2 )2- or -CR z1 R z2 -;

[0036] In some implementations, Z is independently selected from -CH2- or Z. 1a ;

[0037] In some implementation schemes, Z 1a Selected from -CH2-CH2-, -CR z1 Rz2 -、-CHR z2 -or can be chosen by 1 to 3 Rs k The following groups are substituted:

[0038] In some implementation schemes, Z 1a Selected from -CH2-CH2-, -CF2-, -C(CH3)2-, -CHCH3-, or optionally by 1 to 3 Rs k The following groups are substituted:

[0039] In some implementations, Q is selected from C, C(=O), C(=S), C(=O)-N(R) q1 ), S(=O)(=N(R) q2 )), S(=O), S(=O)2;

[0040] In some implementations, Q is selected from Q 1a Q 1a Selected from C(=O)-N(R) q1 ), S(=O)(=N(R) q2 ));

[0041] In some implementations, Q is independently selected from C (=O), C (=S), and Q. 1a ;

[0042] In some implementation schemes, Q 1a Selected from C(=O)-NH, S(=O)(=NH);

[0043] In some implementation schemes, Selected from R k One of the following groups is substituted:

[0044] In some implementation schemes, Selected from

[0045] In some implementations, ring A is selected from C. 3-8 Monocycloalkyl, 5-6 membered heteroaryl;

[0046] In some implementations, ring A is selected from C. 3-8 Monocycloalkyl, cycloAl;

[0047] In some implementations, cycloA1 is selected from 5- or 6-membered heteroaryl groups;

[0048] In some embodiments, ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, thiazolyl, and oxazolyl.

[0049] In some implementation schemes, Each independently selected n1 is independently selected from 0, 1, or 2; in some implementations, Each independently selected n4 is independently selected from 1, 2, and 3; in some implementation schemes, Selected from

[0050] In some embodiments, ring A is selected from ring A1, and ring A1 is selected from pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazole, triazolyl, thiadiazolyl, oxadiazolyl, etc.

[0051] In some implementation schemes, Each independently selected n3 is independently selected from 0 and 1;

[0052] In some implementation schemes, Selected from

[0053] In some implementation schemes, R 11 R q1 Each element is independently selected from H, deuterium, and C. 1-6 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0054] In some implementation schemes, R 11 R q1 Each element is independently selected from H, deuterium, and C. 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0055] In some implementation schemes, R 11 R q1 Each element is independently selected from H, deuterium, and methyl, wherein the methyl group is optionally surrounded by 1 to 3 R atoms. k replace;

[0056] In some implementation schemes, R 11 Each is independently selected from H and deuterium;

[0057] In some implementation schemes, R q2 Selected from H, CN, OH, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6Alkoxy, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0058] In some implementation schemes, R q2 Selected from H, CN, OH, NH2, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0059] In some implementation schemes, R q2 Selected from H, CN, OH, NH2, NH-methyl, N(methyl)2, methyl, wherein the methyl group is optionally surrounded by 1 to 3 R groups. k replace;

[0060] In some implementation schemes, R 1 Each element is independently selected from deuterium, halogens, CN, OH, -C(=O)NH2, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -C 1-4 Alkylene-OC 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4 to 7-membered heterocyclic groups, =CR 1a R 1b -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)C 1-6 Alkyl group, -NHC(=O)C 3-6 cycloalkyl, -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, C 5-10aryl, 5- to 6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, cycloalkyl, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace;

[0061] In some implementation schemes, R 1 Each element is independently selected from deuterium, halogens, CN, OH, -C(=O)OH, -C(=O)NH2, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, -C 1-2 Alkylene-OC 1-4 Alkyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-6 cycloalkyl, C 1-2 Alkylene-4 to 7-membered heterocyclic alkyl, =CR 1a R 1b -C(=O)N(C 1-4 Alkyl)2、-NHC(=O)C 1-4 Alkyl group, -NHC(=O)C 3-6 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, C 5-10 aryl, 5- to 6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, cycloalkyl, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace;

[0062] In some implementation schemes, R 1 Each of the following is independently selected from deuterium, F, Cl, Br, CN, OH, -C(=O)OH, -C(=O)NH2, -C(=O)N(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, -CH2CH2O-methyl, -CH2CH2O-ethyl, =CR1a R 1b Cyclopropyl, oxacyclobutyl, tetrahydrofuranyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-oxacyclobutyl, -CH2-azacyclobutyl, -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. Thiophene, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazoleyl, oxadiazolyl, thiazolyl, triazoleyl, isothiazolyl, isoxazolyl, wherein CH2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, azacyclobutyl, thiophene, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazoleyl, oxadiazolyl, thiazolyl, triazoleyl, isothiazolyl, isoxazolyl are optionally surrounded by 1 to 4 R. k replace;

[0063] In some implementation schemes, R 1 Each is independently selected from deuterium, F, Cl, Br, CN, OH, -C(=O)OH, -C(=O)NH2, -C(=O)N(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, CF3, CHF2, CH2F, CH2OH, CD3, -CH2CHF2, -CF2CHF2, -CH2CF3, -C H2CH2OCH3, -CH2CH2OCH2CH2OCH2CH3, cyclopropyl, oxacyclobutyl, tetrahydrofuranyl, -CH2-cyclopropyl, -CH2CH2O-cyclopropyl, -CH2-oxacyclobutyl, -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

[0064] In some implementation schemes, R 1 Selected from R a R a Selected from -CH2F, -C(=O)OH, -C(=O)NH2, C 2-6 alkenyl, C 2-6 alkynyl group, =CR 1a R 1b -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)C1-6 Alkyl group, -NHC(=O)C 3-6 Cycloalkyl, 5- to 6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, cycloalkyl, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace;

[0065] In some implementation schemes, R a Selected from -CH2F, -C(=O)OH, -C(=O)NH2, C 2-4 alkenyl, C 2-4 alkynyl group, =CR 1a R 1b -C(=O)N(C 1-4 Alkyl)2、-NHC(=O)C 1-4 Alkyl group, -NHC(=O)C 3-6 Cycloalkyl, 5- to 6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, cycloalkyl, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace;

[0066] In some implementation schemes, R a Selected from -CH2F, -C(=O)OH, -C(=O)NH2, vinyl, ethynyl, propynyl, propynyl, -NHC(=O)CH3, -NHS(=O)2CH3, =CR 1a R 1b Thiophene, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazoleyl, oxadiazolyl, thiadiazolyl, triazoleyl, isothiazolyl, isoxazolyl, vinyl, ethynyl, propynyl, propargyl, thiophene, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazoleyl, oxadiazolyl, thiadiazolyl, triazoleyl, isothiazolyl, isoxazolyl, optionally with 1 to 4 R k replace;

[0067] In some implementation schemes, R z1 R z2 R 1a R 1b Each element is independently selected from H, deuterium, halogens, and C. 1-6 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0068] In some implementation schemes, R z1 R z2 R 1a R 1b Each element is independently selected from H, deuterium, halogens, and C. 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. kreplace;

[0069] In some implementation schemes, R z1 R z2 R 1a R 1b Each element is independently selected from H, deuterium, F, Cl, Br, and methyl, wherein the methyl group is optionally coated with 1 to 3 R atoms. k replace;

[0070] In some implementation schemes, R z1 R z2 Together with the carbon atoms attached to it, they form C 3-6 A carbocyclic group, wherein the carbocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0071] In some implementation schemes, R z1 R z2 Together with the carbon atoms attached to it, they form C 3-6 cycloalkyl group, wherein the cycloalkyl group is optionally surrounded by 1 to 4 R groups k replace;

[0072] In some implementation schemes, R z1 R z2 Together with the carbon atoms attached thereto, they form cyclopropyl and cyclobutyl groups, wherein the cyclopropyl and cyclobutyl groups are optionally bonded by 1 to 3 R groups. k replace;

[0073] In some implementation schemes, R y R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 Each element is independently selected from H, deuterium, halogens, CN, OH, SF5, NH2, 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 1-4Alkylene-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, 5-6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, heteroaryl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R k replace;

[0074] In some implementation schemes, R y R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, 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)(C1-4 Alkyl) 2, 5-6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R k replace;

[0075] In some implementation schemes, R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 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, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetrahydrofuran The following groups are used: -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, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxacyclobutyl, tetrahydrofuranyl are optionally surrounded by 1 to 4 R groups. k replace;

[0076] In some implementation schemes, R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 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, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetrahydrofuranyl;

[0077] In some implementation schemes, Ry Each of the following is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, thiophene, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazole, oxadiazolyl, thiazolyl, triazolel, -P(=O)(methyl)2, -P(=O)(ethyl)2, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl, thiophene, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazole, oxadiazolyl, thiazolyl, and triazolel groups are optionally selected from 1 to 4 of the following: deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0078] In some implementation schemes, R y Each of the following is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, CF3, CHF2, CH2F, P(=O)(CH3)2, methyl, ethyl, methoxy, ethoxy, cyclopropyl. The methyl, ethyl, methoxy, ethoxy, cyclopropyl groups mentioned above It may be substituted by 1 to 4 elements selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, and methyl.

[0079] In some implementation schemes, R 5 Selected from R 5a R 5a Selected from -SF5, -OCF2Cl, -OC 2-4 Alkyl, -SC 1-4 Alkyl, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -SC 3-7 cycloalkyl, -OC 1-2 Alkylene-C 3-7 cycloalkyl, -SC 1-2 Alkylene-C 3-7 cycloalkyl, -C 1-2 Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k Instead, the -OC 2-4 Alkyl groups are 1 to 4 R k replace;

[0080] In some implementation schemes, R 6 Selected from R 6a R 6a Selected from CN, -SC1-4 Alkyl, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -C 1-2 Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0081] In some implementation schemes, R 7 Selected from R 7a R 7a Selected from F, CN, -SC 1-4 Alkyl, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -C 1-2 Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0082] In some implementation schemes, R 8 Selected from R 8a R 8a Selected from CN, -SC 1-4 Alkyl, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -C 1-2 Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0083] In some implementation schemes, R 2 Selected from R 2a R 2a Selected from CN, OH, SF5, NH2, 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, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -C 1-2 Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, alkenyl, ynyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0084] In some implementation schemes, R 2aSelected from CN, OH, SF5, NH2, cyclopropyl, cyclobutyl, methyl, CF3, CHF2, CH2F, CD3, CHD2, CH2D, wherein the cyclopropyl, cyclobutyl, and methyl groups are optionally coated with 1 to 3 R groups. k replace;

[0085] In some implementation schemes, R 3 R 4 Selected from R 3a R 3a Selected from CN, OH, SF5, NH2, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 2- 4-Alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -C 1-2 Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, alkenyl, ynyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0086] In some implementation schemes, R 3a Selected from CN, OH, SF5, NH2, cyclopropyl, and cyclobutyl, wherein the cyclopropyl and cyclobutyl groups are optionally coated with 1 to 3 R groups. k replace;

[0087] In some implementation schemes, R 5a Selected from -SF5, -OCF2Cl, -OCH2CHF2, -OCH2CF3, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -S-CH2-cyclopropyl, -S-CH2-cyclobutyl, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, wherein the methyl, ethyl, cyclopropyl, and cyclobutyl groups are optionally surrounded by 1 to 4 R groups. k Instead, the -CH2- is optionally replaced by 1 to 2 R k replace;

[0088] In some implementation schemes, R 5aThe molecule is selected from SF5, -OCF2Cl, -OCH2CHF2, -OCF2CHF2, -OCH2CF3, -SCH2CHF2, -SCF2CHF2, -S-methyl, -S-CHF2, -S-CF3, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -S-CH2-cyclopropyl, -S-CH2-cyclobutyl, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, wherein the cyclopropyl and cyclobutyl groups are optionally substituted with 1 to 3 deuterium, F, Cl, Br, CN, OH, methyl, CF3, CHF2, CH2F;

[0089] In some implementation schemes, R 6a R 8a Each of the following is independently selected from CN, -S-methyl, -S-ethyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, cyclopropyl, and cyclobutyl groups are optionally surrounded by 1 to 3 R groups. k replace;

[0090] In some implementation schemes, R 7a Selected from F, CN, -S-methyl, -S-ethyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, cyclopropyl, and cyclobutyl groups are optionally surrounded by 1 to 3 R groups. k replace;

[0091] In some implementation schemes, R 2 With R 3 R 3 With R 9 The atoms or framework attached to it together form a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group, or a 5-6 membered carbocyclic group, wherein the carbocyclic group, heteroaryl group, or heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace;

[0092] In some implementation schemes, R 2 With R 3 R 3 With R 9 The atoms or framework attached to it together form a 5-membered heteroaryl, a 5-membered heterocyclic group, or a 5-membered carbocyclic group, wherein the carbocyclic, heteroaryl, or heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace;

[0093] In some implementation schemes, R 2 With R 3 R 3 With R 9 Together with the atoms or framework attached to it, a cyclopentyl group is formed, wherein the cyclopentyl group is optionally surrounded by 1 to 4 R atoms. k replace;

[0094] In some implementation schemes, R 10 Selected from H, deuterium, and C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4 to 7-membered heterocyclic groups, -C 1-4 Alkylene-OC 3-6 Cycloalkyl, wherein the alkylene, alkyl, alkenyl, ynyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0095] In some implementation schemes, R 10 Selected from H, deuterium, and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-7 Carbocyclic group, -C 1-2 alkylene-4 to 7-membered heterocyclic groups, -C 1-2 Alkylene-OC 3-6 Cycloalkyl, wherein the alkylene, alkyl, alkenyl, ynyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0096] In some implementation schemes, R 10 Each of the following elements is independently selected from H, deuterium, methyl, ethyl, vinyl, ethynyl, propynyl, propynyl, -CH2-propynyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-bicyclo[1,1,1]pentane, -CH2-bicyclo[1,1,0]butane, -CH2-O-cyclopropyl, -CH2CH2-O-cyclopropyl, oxacyclobutyl, and aziridine, wherein CH2, methyl, ethyl, vinyl, ethynyl, propynyl, propynyl, propynyl, cyclopropyl, cyclobutyl, oxacyclobutyl, aziridine, bicyclo[1,1,1]pentane, and bicyclo[1,1,0]butane are optionally surrounded by 1 to 4 R atoms. k replace;

[0097] In some implementation schemes, R 10 Selected from R 10a ;

[0098] In some implementation schemes, R 10a Selected from C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4 to 7-membered heterocyclic groups, -C 1-4 Alkylene-OC3-6 Cycloalkyl, wherein the alkylene, alkenyl, ynyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0099] In some implementation schemes, R 10a Selected from C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-7 Carbocyclic group, -C 1-2 alkylene-4 to 7-membered heterocyclic groups, -C 1-2 Alkylene-OC 3-6 Cycloalkyl, wherein the alkylene, alkyl, alkenyl, ynyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0100] In some implementation schemes, R 10a Selected from -CH2-propynyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-bicyclo[1,1,1]pentane, -CH2-bicyclo[1,1,0]butane, -CH2-O-cyclopropyl, -CH2CH2-O-cyclopropyl, oxacyclobutyl, aziridine, wherein the CH2-propynyl, cyclopropyl, cyclobutyl, oxacyclobutyl, aziridine, bicyclo[1,1,1]pentane, or bicyclo[1,1,0]butane is optionally surrounded by 1 to 4 R-terminals. k replace;

[0101] In some implementation schemes, Selected from

[0102] In some implementations, n1 is independently selected from 0, 1, 2, 3 or 4;

[0103] In some implementation schemes, n2 is independently selected from 0, 1, 2, and 3;

[0104] In some implementations, n2 is independently selected from 0, 1, and 2;

[0105] In some implementation schemes, R k Each element is independently selected from deuterium, ⁵O, halogens, CN, OH, COOH, NH₂, 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 3-6Carbocyclic 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, alkynyl, 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;

[0106] In some implementation schemes, R k Each element is independently selected from deuterium, ⁵O, halogens, CN, OH, COOH, NH₂, 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, alkynyl, 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;

[0107] In some implementation schemes, R kEach group is independently selected from deuterium, =O, F, Cl, Br, I, CN, OH, NH2, 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 methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and pyrrolyl groups are optionally selected from 1 to 4 elements selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0108] In some implementation schemes, R k Each group is independently selected from deuterium, =O, F, Cl, Br, I, CN, OH, NH2, 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 methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and pyrrolyl groups are optionally substituted by 1 to 3 substituents selected from deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, methoxy, and ethoxy;

[0109] In some implementation schemes, R kEach is independently selected from deuterium, F, Cl, Br, I, CN, OH, -CH2OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, 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,

[0110] The condition is that when E is selected from At that time, general formula (I) must satisfy at least one of the following conditions:

[0111] 1) Cycle B is present, wherein cyclic B is selected from 5-membered heteroaryl groups, and the heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace;

[0112] 2)R 2 With R 3 R 3 With R 9 The atoms or framework attached to it together form a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group, or a 5-6 membered carbocyclic group, wherein the carbocyclic group, heteroaryl group, or heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace;

[0113] 3) U and W, W and X, V and X, and their connected skeletons together form a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group, or a 5-6 membered carbocyclic group, wherein the carbocyclic group, heteroaryl group, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0114] 4)R 10 Selected from R 10a R 10a Selected from C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4 to 7-membered heterocyclic groups, -C 1-4 Alkylene-OC 3-6 Cycloalkyl, wherein the alkylene, alkenyl, ynyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0115] 5) Ring C is selected from 5-6 member heteroaryl aromatic rings;

[0116] 6)R 5Unselected from halogens, unsubstituted -OC 1-6 Alkyl, difluoromethoxy, or trifluoromethoxy;

[0117] 7)R 6 R 8 Not selected from H, halogens, or trifluoromethyl;

[0118] 8)R 7 Not selected from H, trifluoromethyl;

[0119] 9)R 2 Not selected from H or halogens;

[0120] 10)R 3 R 4 Not selected from H, halogen, trifluoromethyl or unsubstituted C 1-6 alkyl;

[0121] 11) n1 is not selected from 0, and R 1 At least one of them is selected from R a R a Selected from -CH2F, -C(=O)OH, -C(=O)NH2, C 2-6 alkenyl, C 2-6 alkynyl group, =CR 1a R 1b -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)C 1-6 Alkyl group, -NHC(=O)C 3-6 Cycloalkyl, 5- to 6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, cycloalkyl, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace;

[0122] 12) Q is selected from Q 1a Q 1a Selected from C(=O)-N(R) q1 ), S(=O)(=N(R) q2 ));

[0123] 13) Z is not selected from -CH2-;

[0124] 14) Y1 and Y2 are both selected from CR y ;

[0125] 15) Cycle A is selected from 5-6 membered heteroaryl groups, and when Y1 and Y2 are both selected from CR y Ring A is not selected

[0126] The condition is that the general formula (Ia) satisfies at least one of the following conditions:

[0127] 1)R 2 With R 3 R 3 With R 9 The atoms or framework attached to it together form a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group, or a 5-6 membered carbocyclic group, wherein the carbocyclic group, heteroaryl group, or heterocyclic group is optionally surrounded by 1 to 3 R atoms. k replace;

[0128] 2)R 5 With R 6 R 7 With R 8 R 6 With R 7 Together with its associated skeleton, it forms a 5-6 membered heteroaryl, 5-6 membered heterocyclic, or 5-6 membered carbocyclic group, wherein the carbocyclic, heteroaryl, or heterocyclic group is optionally surrounded by 1 to 3 R groups. k replace;

[0129] 3)R 10 Selected from R 10a ;

[0130] 4)R 5 Selected from R 5a R 5a Selected from -SF5, -OCF2Cl, -OC 2-4 Alkyl, -SC 1-4 Alkyl, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -SC 3-7 cycloalkyl, -OC 1-2 Alkylene-C 3-7 cycloalkyl, -SC 1-2 Alkylene-C 3-7 cycloalkyl, -C 1-2 Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k Instead, the -OC 2-4 Alkyl groups are 1 to 4 R k replace;

[0131] 5)R 6 Selected from R 6a R 6a Selected from CN, -SC 1-4 Alkyl, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -C 1-2 Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0132] 6)R 7 Selected from R 7a R 7a Selected from F, CN, -SC 1-4 Alkyl, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -C 1-2 Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0133] 7)R 8 Selected from R 8a R 8a Selected from CN, -SC 1-4 Alkyl, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -C 1-2 Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0134] 8)R 2 Selected from R 2a R 2a Selected from CN, OH, SF5, NH2, 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, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -C 1-2 Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, alkenyl, ynyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0135] 9)R 3 R 4 Selected from R 3a R 3a Selected from CN, OH, SF5, NH2, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -C 1-2Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, alkenyl, ynyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0136] 10) n1 is not selected from 0, and R 1 At least one of them is selected from R a R a Selected from -CH2F, -C(=O)OH, -C(=O)NH2, C 2-4 base, C 2-4 base, =CR 1a R 1b -C(=O)N(C 1-4 2, -NHC(=O)C 1-4 radical, -NHC(=O)C 3-6 Cycloalkyl, 5- to 6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, cycloalkyl, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace;

[0137] 11) Q is selected from Q 1a Q 1a Selected from C(=O)-N(R) q1 ), S(=O)(=N(R) q2 ));

[0138] 12) Z is not selected from -CH2-;

[0139] 13) Y1 and Y2 are both selected from CR y ;

[0140] 14) Cycle A is selected from 5-6 membered heteroaryl groups, and when Y1 and Y2 are both selected from CR y Ring A is not selected

[0141] 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...

[0142] E is selected from Its left side is connected to an aromatic ring containing Y1;

[0143] Y1 and Y2 are each independently selected from CR y Or N;

[0144] W is selected from bond, O, S, C, C (=O), CR 6 NR 6 Or N;

[0145] V is selected from bond, O, S, C, C (=O), CR 8 NR 8 Or N;

[0146] U is selected from bonds, O, S, C, C (=O), CR 5 NR 5 Or N;

[0147] X is selected from bond, O, S, C, C (=O), CR 7 NR 7 Or N;

[0148] The condition is that only one of U, W, X, and V is selected from the bond, and ring C is selected from a 5-6 member heteroaromatic ring or a 6 member aromatic ring;

[0149] Z is selected from -(CR) z1 R z2 )2- or -CR z1 R z2 -;

[0150] Q is selected from C, C(=O), C(=S), C(=O)-N(R) q1 ), S(=O)(=N(R) q2 )), S(=O), S(=O)2;

[0151] This indicates the presence or absence of a ring; when present, ring B is selected from a 5-membered heteroaryl group, wherein the heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace;

[0152] Alternatively, U and W, W and X, V and X, and their associated skeletons together form a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group, or a 5-6 membered carbocyclic group, wherein the carbocyclic group, heteroaryl, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0153] R 11 R q1 Each element is independently selected from H, deuterium, and C. 1-6 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0154] R q2 Selected from H, CN, OH, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0155] Ring A is selected from C 3-8 Monocycloalkyl, 5-6 membered heteroaryl;

[0156] R 1 Each element is independently selected from deuterium, halogens, CN, OH, -C(=O)OH, -C(=O)NH2, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -C 1-4 Alkylene-OC 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0- 4-alkylene-4 to 7-membered heterocyclic groups, =CR 1a R 1b -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)C 1-6 Alkyl group, -NHC(=O)C 3-6 cycloalkyl, -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, C 5-10 aryl, 5- to 6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, cycloalkyl, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace;

[0157] R z1 R z2 R 1a R 1b Each element is independently selected from H, deuterium, halogens, and C. 1-6 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0158] As an option, R z1 R z2 Together with the carbon atoms attached to it, they form C 3-6 A carbocyclic group, wherein the carbocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0159] R 10 Selected from H, deuterium, and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4 to 7-membered heterocyclic groups, -C 1-4 Alkylene-OC 3-6 Cycloalkyl, wherein the alkylene, alkyl, alkenyl, ynyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0160] R y R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 Each element is independently selected from H, deuterium, halogens, CN, OH, SF5, NH2, 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, ynyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R k replace;

[0161] As an option, R 2 With R 3 R 3 With R 9 The atoms or framework attached to it together form a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group, or a 5-6 membered carbocyclic group, wherein the carbocyclic group, heteroaryl group, or heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace;

[0162] R k Each element is independently selected from deuterium, ⁵O, halogens, CN, OH, COOH, NH₂, 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, alkynyl, 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;

[0163] n1 is independently selected from 0, 1, 2, 3 or 4;

[0164] n2 is independently selected from 0, 1, 2, and 3;

[0165] The condition is that when E is selected from At that time, general formula (I) must satisfy at least one of the following conditions:

[0166] 1) Cycle B is present, wherein cyclic B is selected from 5-membered heteroaryl groups, and the heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace;

[0167] 2)R 2 With R 3 R 3 With R9 The atoms or framework attached to it together form a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group, or a 5-6 membered carbocyclic group, wherein the carbocyclic group, heteroaryl group, or heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace;

[0168] 3) U and W, W and X, V and X, and their connected skeletons together form a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group, or a 5-6 membered carbocyclic group, wherein the carbocyclic group, heteroaryl group, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0169] 4)R 10 Selected from R 10a R 10a Selected from C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4 to 7-membered heterocyclic groups, -C 1-4 Alkylene-OC 3-6 Cycloalkyl, wherein the alkylene, alkenyl, ynyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0170] 5) Ring C is selected from 5-6 member heteroaryl aromatic rings;

[0171] 6)R 5 Unselected from halogens, unsubstituted -OC 1-6 Alkyl, difluoromethoxy, or trifluoromethoxy;

[0172] 7)R 6 R 8 Not selected from H, halogens, or trifluoromethyl;

[0173] 8)R 7 Not selected from H, trifluoromethyl;

[0174] 9)R 2 Not selected from H or halogens;

[0175] 10)R 3 R 4 Not selected from H, halogen, trifluoromethyl or unsubstituted C 1-6 alkyl;

[0176] 11) n1 is not selected from 0, and R 1 At least one of them is selected from R a R a Selected from -CH2F, -C(=O)OH, -C(=O)NH2, C 2-6 alkenyl, C 2-6 alkynyl group, =CR1a R 1b -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)C 1-6 Alkyl group, -NHC(=O)C 3-6 Cycloalkyl, 5- to 6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, cycloalkyl, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace;

[0177] 12) Q is selected from Q 1a Q 1a Selected from C(=O)-N(R) q1 ), S(=O)(=N(R) q2 ));

[0178] 13) Z is not selected from -CH2-;

[0179] 14) Y1 and Y2 are both selected from CR y ;

[0180] 15) Cycle A is selected from 5-6 membered heteroaryl groups, and when Y1 and Y2 are both selected from CR y Ring A is not selected

[0181] 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

[0182] R 11 R q1 Each element is independently selected from H, deuterium, and C. 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0183] R q2 Selected from H, CN, OH, NH2, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0184] R 1 Each element is independently selected from deuterium, halogens, CN, OH, -C(=O)OH, -C(=O)NH2, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C2-4 alkynyl group, C 1-4 Alkoxy, -C 1-2 Alkylene-OC 1-4 Alkyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-6 cycloalkyl, C 1-2 Alkylene-4 to 7-membered heterocyclic alkyl, =CR 1a R 1b -C(=O)N(C 1-4 Alkyl)2、-NHC(=O)C 1-4 Alkyl group, -NHC(=O)C 3-6 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, C 5-10 aryl, 5- to 6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, cycloalkyl, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace;

[0185] R a Selected from -CH2F, -C(=O)NH2, C 2-4 alkenyl, C 2-4 alkynyl group, =CR 1a R 1b -C(=O)N(C 1-4 Alkyl)2、-NHC(=O)C 1-4 Alkyl group, -NHC(=O)C 3-6 Cycloalkyl, 5- to 6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, cycloalkyl, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace;

[0186] R z1 R z2 R 1a R 1b Each element is independently selected from H, deuterium, halogens, and C. 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0187] As an option, R z1 R z2 Together with the carbon atoms attached to it, they form C 3-6 cycloalkyl group, wherein the cycloalkyl group is optionally surrounded by 1 to 4 R groups k replace;

[0188] R 10 Selected from H, deuterium, and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-7 Carbocyclic group, -C 1-2 alkylene-4 to 7-membered heterocyclic groups, -C 1-2 Alkylene-OC 3-6 Cycloalkyl, wherein the alkylene, alkyl, alkenyl, ynyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0189] R 10a Selected from C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-7 Carbocyclic group, -C 1-2 alkylene-4 to 7-membered heterocyclic groups, -C 1-2 Alkylene-OC 3-6 Cycloalkyl, wherein the alkylene, alkyl, alkenyl, ynyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0190] R y R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, 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-C3-7 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, 5-6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, ynyl, cycloalkyl, heteroaryl, heterocycloalkyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R k replace;

[0191] As an option, R 2 With R 3 R 3 With R 9 The atoms or framework attached to it together form a 5-membered heteroaryl, a 5-membered heterocyclic group, or a 5-membered carbocyclic group, wherein the carbocyclic, heteroaryl, or heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace;

[0192] R k Each element is independently selected from deuterium, ⁵O, halogens, CN, OH, COOH, NH₂, 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)-C3-6 Carbocyclic group, -C(=O)-4 to 7-membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, 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;

[0193] The definitions of the remaining functional groups are the same as those in the first embodiment of the present invention.

[0194] As a third embodiment of the present invention, the compounds shown in the above general formulas (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IV), and (V), or their racemic mixtures, stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein,

[0195] E1 is selected from Its left side is connected to a nitrogen-containing heteroaromatic ring;

[0196] Selected from R k One of the following groups is substituted:

[0197] Ring C1 is selected from thienyl, furanyl, pyrroleyl, thiazolyl, oxazolyl, pyrazolyl, imidazoleyl, pyridyl, pyridoneyl, pyrimidinyl, and pyridazinyl, wherein ring C1 is optionally oxidized by R. 5 R 6 R 7 R 8 replace;

[0198] Alternatively, U and W, W and X, V and X in ring C1 and their connected skeletons together form a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group, or a 5-6 membered carbocyclic group, wherein the carbocyclic group, heteroaryl, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0199] The ring C is selected from phenyl, pyridyl, pyridone, pyrimidinyl, and pyridazinyl, wherein the ring C is optionally coated with R. 5 R 6 R 7 R 8 replace;

[0200] n2 is independently selected from 0 or 1;

[0201] As an option, R 2 With R 3 R 3 With R 9The atoms or framework attached to it together form a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group, or a 5-6 membered carbocyclic group, wherein the carbocyclic group, heteroaryl group, or heterocyclic group is optionally surrounded by 1 to 3 R atoms. k replace;

[0202] As an option, R 5 With R 6 R 7 With R 8 R 6 With R 7 Together with its associated skeleton, it forms a 5-6 membered heteroaryl, 5-6 membered heterocyclic, or 5-6 membered carbocyclic group, wherein the carbocyclic, heteroaryl, or heterocyclic group is optionally surrounded by 1 to 3 R groups. k replace;

[0203] The condition is that the general formula (Ia) satisfies at least one of the following conditions:

[0204] 1)R 2 With R 3 R 3 With R 9 The atoms or framework attached to it together form a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group, or a 5-6 membered carbocyclic group, wherein the carbocyclic group, heteroaryl group, or heterocyclic group is optionally surrounded by 1 to 3 R atoms. k replace;

[0205] 2)R 5 With R 6 R 7 With R 8 R 6 With R 7 Together with its associated skeleton, it forms a 5-6 membered heteroaryl, 5-6 membered heterocyclic, or 5-6 membered carbocyclic group, wherein the carbocyclic, heteroaryl, or heterocyclic group is optionally surrounded by 1 to 3 R groups. k replace;

[0206] 3)R 10 Selected from R 10a ;

[0207] 4)R 5 Selected from R 5a R 5a Selected from -SF5, -OCF2Cl, -OC 2-4 Alkyl, -SC 1-4 Alkyl, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -SC 3-7 cycloalkyl, -OC 1-2 Alkylene-C 3-7 cycloalkyl, -SC 1-2 Alkylene-C 3-7 cycloalkyl, -C 1-2Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k Instead, the -OC 2-4 Alkyl groups are 1 to 4 R k replace;

[0208] 5)R 6 Selected from R 6a R 6a Selected from CN, -SC 1-4 Alkyl, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -C 1-2 Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0209] 6)R 7 Selected from R 7a R 7a Selected from F, CN, -SC 1-4 Alkyl, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -C 1-2 Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0210] 7)R 8 Selected from R 8a R 8a Selected from CN, -SC 1-4 Alkyl, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -C 1-2 Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0211] 8)R 2 Selected from R 2a R 2a Selected from CN, OH, SF5, NH2, 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, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -C1-2 Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, alkenyl, ynyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0212] 9)R 3 R 4 Selected from R 3a R 3a Selected from CN, OH, SF5, NH2, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -C 1-2 Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, alkenyl, ynyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0213] 10) n1 is not selected from 0, and R 1 At least one of them is selected from R a R a Selected from -CH2F, -C(=O)NH2, C 2-4 alkenyl, C 2-4 alkynyl group, =CR 1a R 1b -C(=O)N(C 1-4 2, -NHC(=O)C 1-4 radical, -NHC(=O)C 3-6 Cycloalkyl, 5- to 6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, cycloalkyl, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace;

[0214] 11) Q is selected from Q 1a Q 1a Selected from C(=O)-N(R) q1 ), S(=O)(=N(R) q2 ));

[0215] 12) Z is not selected from -CH2-;

[0216] 13) Y1 and Y2 are both selected from CR y ;

[0217] 14) Cycle A is selected from 5-6 membered heteroaryl groups, and when Y1 and Y2 are both selected from CR yRing A is not selected

[0218] The definitions of the remaining functional groups are the same as those in the first or second embodiment of the present invention.

[0219] As a fourth embodiment of the present invention, the compounds shown in general formulas (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IV), and (V), or their racemic mixtures, stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein,

[0220] R 11 R q1 Each element is independently selected from H, deuterium, and methyl, wherein the methyl group is optionally surrounded by 1 to 3 R atoms. k replace;

[0221] R q2 Selected from H, CN, OH, NH2, NH-methyl, N(methyl)2, methyl, wherein the methyl group is optionally surrounded by 1 to 3 R groups. k replace;

[0222] Ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, thiazolyl, and oxazolyl.

[0223] Alternatively, ring A can be selected from ring A1, where ring A1 is selected from pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazole, triazolyl, thiadiazolyl, oxadiazolyl, etc.

[0224] R 1 Each of the following is independently selected from deuterium, F, Cl, Br, CN, OH, -C(=O)OH, -C(=O)NH2, -C(=O)N(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, -CH2CH2O-methyl, -CH2CH2O-ethyl, =CR 1a R 1bCyclopropyl, oxacyclobutyl, tetrahydrofuranyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-oxacyclobutyl, -CH2-azacyclobutyl, -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. Thiophene, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazoleyl, oxadiazolyl, thiazolyl, triazoleyl, isothiazolyl, isoxazolyl, wherein CH2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, azacyclobutyl, thiophene, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazoleyl, oxadiazolyl, thiazolyl, triazoleyl, isothiazolyl, isoxazolyl are optionally surrounded by 1 to 4 R. k replace;

[0225] R a Selected from -CH2F, -C(=O)NH2, vinyl, ethynyl, propynyl, propynyl, -NHC(=O)CH3, -NHS(=O)2CH3, =CR 1a R 1b Thiophene, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazoleyl, oxadiazolyl, thiadiazolyl, triazoleyl, isothiazolyl, isoxazolyl, vinyl, ethynyl, propynyl, propargyl, thiophene, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazoleyl, oxadiazolyl, thiadiazolyl, triazoleyl, isothiazolyl, isoxazolyl, optionally with 1 to 4 R k replace;

[0226] R y Each of the following is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, thiophene, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazole, oxadiazolyl, thiazolyl, triazolel, -P(=O)(methyl)2, -P(=O)(ethyl)2, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl, thiophene, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazole, oxadiazolyl, thiazolyl, and triazolel groups are optionally selected from 1 to 4 of the following: deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0227] R z1 R z2 R 1a R 1bEach element is independently selected from H, deuterium, F, Cl, Br, and methyl, wherein the methyl group is optionally coated with 1 to 3 R atoms. k replace;

[0228] As an option, R z1 R z2 Together with the carbon atoms attached thereto, they form cyclopropyl and cyclobutyl groups, wherein the cyclopropyl and cyclobutyl groups are optionally bonded by 1 to 3 R groups. k replace;

[0229] R 10 Each of the following elements is independently selected from H, deuterium, methyl, ethyl, vinyl, ethynyl, propynyl, propynyl, -CH2-propynyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-bicyclo[1,1,1]pentane, -CH2-bicyclo[1,1,0]butane, -CH2-O-cyclopropyl, -CH2CH2-O-cyclopropyl, oxacyclobutyl, and aziridine, wherein CH2, methyl, ethyl, vinyl, ethynyl, propynyl, propynyl, propynyl, cyclopropyl, cyclobutyl, oxacyclobutyl, aziridine, bicyclo[1,1,1]pentane, and bicyclo[1,1,0]butane are optionally surrounded by 1 to 4 R atoms. k replace;

[0230] R 10a Selected from -CH2-propynyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-bicyclo[1,1,1]pentane, -CH2-bicyclo[1,1,0]butane, -CH2-O-cyclopropyl, -CH2CH2-O-cyclopropyl, oxacyclobutyl, aziridine, wherein the CH2-propynyl, cyclopropyl, cyclobutyl, oxacyclobutyl, aziridine, bicyclo[1,1,1]pentane, or bicyclo[1,1,0]butane is optionally surrounded by 1 to 4 R-terminals. k replace;

[0231] R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9Each 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, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetrahydrofuran The following groups are used: -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, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxacyclobutyl, tetrahydrofuranyl are optionally surrounded by 1 to 4 R groups. k replace;

[0232] R 2a Selected from CN, OH, SF5, NH2, cyclopropyl, cyclobutyl, methyl, CF3, CHF2, CH2F, CD3, CHD2, CH2D, wherein the cyclopropyl, cyclobutyl, and methyl groups are optionally coated with 1 to 3 R groups. k replace;

[0233] R 3a Selected from CN, OH, SF5, NH2, cyclopropyl, and cyclobutyl, wherein the cyclopropyl and cyclobutyl groups are optionally coated with 1 to 3 R groups. k replace;

[0234] R 5a Selected from -SF5, -OCF2Cl, -OCH2CHF2, -OCH2CF3, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -S-CH2-cyclopropyl, -S-CH2-cyclobutyl, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, wherein the methyl, ethyl, cyclopropyl, and cyclobutyl groups are optionally surrounded by 1 to 4 R groups. k Instead, the -CH2- is optionally replaced by 1 to 2 R k replace;

[0235] R 6a R 8a Each of the following is independently selected from CN, -S-methyl, -S-ethyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, cyclopropyl, and cyclobutyl groups are optionally surrounded by 1 to 3 R groups. k replace;

[0236] R 7a Selected from F, CN, -S-methyl, -S-ethyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, cyclopropyl, and cyclobutyl groups are optionally surrounded by 1 to 3 R groups.k replace;

[0237] As an option, R 2 With R 3 R 3 With R 9 Together with the atoms or framework attached to it, a cyclopentyl group is formed, wherein the cyclopentyl group is optionally surrounded by 1 to 4 R atoms. k replace;

[0238] As an option, R 5 With R 6 R 7 With R 8 R 6 With R 7 Together with its associated skeleton, it forms a cyclopentyl or pyrrolidinyl group, wherein the cyclopentyl or pyrrolidinyl group is optionally surrounded by 1 to 3 R groups. k replace;

[0239] Alternatively, in ring C1, U and W, W and X, V and X, and their associated skeletons together form an imidazole group, a pyrrole group, a triazole group, a cyclopentyl group, or a pyrrole alkyl group, wherein the imidazole group, pyrrole group, triazole group, cyclopentyl group, or pyrrole alkyl group is optionally surrounded by 1 to 3 R groups. k replace;

[0240] R k Each group is independently selected from deuterium, =O, F, Cl, Br, I, CN, OH, NH2, 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 methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and pyrrolyl groups are optionally selected from 1 to 4 elements selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0241] The definitions of the remaining functional groups are the same as those in the first, second, or third embodiments of the present invention.

[0242] As a fifth 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 (Ia), (Ib), (Ic), (Id), (Ie), and (If).

[0243] Each independently selected n1 is independently selected from 0, 1, or 2;

[0244] or Each independently selected n4 are each independently selected from 1, 2, and 3;

[0245] Each independently selected

[0246] n3 is independently selected from 0 and 1;

[0247] Q is independently selected from C (=O), C (=S), and Q. 1a ;

[0248] Q 1a Selected from C(=O)-N(R) q1 ), S(=O)(=N(R) q2 ));

[0249] R 11 Each is independently selected from H and deuterium;

[0250] Z is independently selected from -CH2- or Z. 1a ;

[0251] Z 1a Selected from -CH2-CH2-, -CR z1 R z2 -、-CHR z2 -or can be chosen by 1 to 3 Rs k The following groups are substituted:

[0252] R z1 R z2 Each element is independently selected from deuterium, F, Cl, Br, and methyl, wherein the methyl group is optionally coated with 1 to 3 R atoms. k replace;

[0253] Selected from

[0254] Selected from

[0255] Selected from

[0256] n2 is selected from 2;

[0257] As an option, Selected from

[0258] Selected from

[0259] Selected from

[0260] R k Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, -CH2OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, 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,

[0261] The definitions of the remaining functional groups are the same as those in the first, second, third, or fourth embodiments of the present invention.

[0262] As a sixth embodiment of the present invention, the compounds represented by the above general formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), or their racemic mixtures, stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein...

[0263] Q 1a Selected from C(=O)-NH, S(=O)(=NH);

[0264] Z 1a Selected from -CH2-CH2-, -CF2-, -C(CH3)2-, -CHCH3-, or optionally by 1 to 3 Rs k The following groups are substituted:

[0265] Selected from

[0266] R 5a The derivative is selected from -SF5, -OCF2Cl, -OCH2CHF2, -OCF2CHF2, -OCH2CF3, -SCH2CHF2, -SCF2CHF2, -S-methyl, -S-CHF2, -S-CF3, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -S-CH2-cyclopropyl, -S-CH2-cyclobutyl, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, wherein the cyclopropyl and cyclobutyl groups are optionally substituted with 1 to 3 deuterium, F, Cl, Br, CN, OH, methyl, CF3, CHF2, CH2F;

[0267] R 1 Each is independently selected from deuterium, F, Cl, Br, CN, OH, -C(=O)OH, -C(=O)NH2, -C(=O)N(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, CF3, CHF2, CH2F, CH2OH, CD3, -CH2CHF2, -CF2CHF2, -CH2CF3, -C H2CH2OCH3, -CH2CH2OCH2CH2OCH2CH3, cyclopropyl, oxacyclobutyl, tetrahydrofuranyl, -CH2-cyclopropyl, -CH2CH2O-cyclopropyl, -CH2-oxacyclobutyl, -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

[0268] R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9Each 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, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetrahydrofuranyl;

[0269] R y Each of the following is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, CF3, CHF2, CH2F, P(=O)(CH3)2, methyl, ethyl, methoxy, ethoxy, cyclopropyl. The methyl, ethyl, methoxy, ethoxy, cyclopropyl groups mentioned above It may be substituted by 1 to 4 elements selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, and methyl.

[0270] 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.

[0271] As a seventh embodiment of the present invention, the compound represented by the above general formulas (Ie) and (If) or its racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein...

[0272] Selected from

[0273] R 1 Each of the following is independently selected from deuterium, F, Cl, Br, CN, OH, -C(=O)OH, -C(=O)NH2, -C(=O)N(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, -CH2CH2O-methyl, -CH2CH2O-ethyl, =CR 1a R 1bCyclopropyl, oxacyclobutyl, tetrahydrofuranyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-oxacyclobutyl, -CH2-azacyclobutyl, -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. Thiophene, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazoleyl, oxadiazolyl, thiazolyl, triazoleyl, isothiazolyl, isoxazolyl, wherein CH2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, azacyclobutyl, thiophene, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazoleyl, oxadiazolyl, thiazolyl, triazoleyl, isothiazolyl, isoxazolyl are optionally surrounded by 1 to 4 R. k replace;

[0274] R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, 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 1-4Alkyl, -P(=O)(C 1-4 Alkyl) 2, 5-6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R k Replacement; preferably, R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 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, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetrahydrofuran The following groups are used: -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, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxacyclobutyl, tetrahydrofuranyl are optionally surrounded by 1 to 4 R groups. k replace;

[0275] R y Each of the following groups is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, thiophene, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazole, oxadiazolyl, thiazolyl, triazolel, -P(=O)(methyl)2, -P(=O)(ethyl)2, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl, thiophene, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazole, oxadiazolyl, thiazolyl, and triazolel groups are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, and methoxy groups;

[0276] R 7a Selected from F, CN, -S-methyl, -S-ethyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, cyclopropyl, and cyclobutyl groups are optionally surrounded by 1 to 3 R groups. k replace;

[0277] R 10Each of the following elements is independently selected from H, deuterium, methyl, ethyl, vinyl, ethynyl, propynyl, propynyl, -CH2-propynyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-bicyclo[1,1,1]pentane, -CH2-bicyclo[1,1,0]butane, -CH2-O-cyclopropyl, -CH2CH2-O-cyclopropyl, oxacyclobutyl, and aziridine, wherein CH2, methyl, ethyl, vinyl, ethynyl, propynyl, propynyl, propynyl, cyclopropyl, cyclobutyl, oxacyclobutyl, aziridine, bicyclo[1,1,1]pentane, and bicyclo[1,1,0]butane are optionally surrounded by 1 to 4 R atoms. k replace;

[0278] Selected from

[0279] Selected from

[0280] The definitions of the remaining functional groups are the same as those in the first, second, third, fourth, fifth, or sixth embodiments of the present invention.

[0281] This invention relates to compounds as shown below, or their racemates, stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein the compound is selected from one of the structures shown in Table E below.

[0282] Table E

[0283] 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.

[0284] 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.

[0285] 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").

[0286] 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.

[0287] 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.

[0288] 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).

[0289] 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.

[0290] 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.

[0291] 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).

[0292] 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).

[0293] The amounts of racemic, stereoisomer, tautomer, and pharmaceutically acceptable salts of the compounds of this invention are converted in each case as free bases.

[0294] Synthesis Method 1:

[0295] General formula (Z1) reacts with diphenyl azidophosphate under alkaline conditions and is then reduced with triphenylphosphine to give the corresponding general formula (Z2). General formula (Z2) reacts with carbon monoxide under palladium catalysis to give the corresponding general formula (Z3). General formula (Z3) reacts with general formula (Z3) under alkaline conditions to give the corresponding general formula (Z5). General formula (Z5) reacts with pinacol diboronate under palladium catalysis to give the corresponding general formula (Z6). General formula (Z6) and general formula (Z7) are coupled under palladium catalysis to give the corresponding general formula (Ia').

[0296] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0297] The compounds of this invention include their racemic, stereoisomer, tautomer, deuterated, solvated, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal.

[0298] 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 14C, 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.

[0299] “CN” refers to cyano.

[0300] "Halogen" refers to F, Cl, Br or I.

[0301] "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".

[0302] "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.

[0303] "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.

[0304] "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.

[0305] "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.

[0306] "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... -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, etc.; the alkenyl group can be monovalent, divalent, trivalent, or tetravalent.

[0307] "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.

[0308] "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.

[0309] "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. "Carbocyclic group" or "carbon ring" can be monovalent, divalent, trivalent or tetravalent.

[0310] "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, aziridinepropyl, oxacyclobutyl, aziridinebutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxahexane, aziridineheptyl, 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" can be monovalent, divalent, trivalent or tetravalent.

[0311] A "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 zero 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:

[0312] "Spirocyclic" or "spirocyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0313] "Circular fused" or "circular fused group" refers to a polycyclic group in which each ring in a system shares a pair of adjacent atoms with 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 a circular fused 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:

[0314] "Cyclone" or "cyclone base" can be monovalent, divalent, trivalent, or tetravalent.

[0315] 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:

[0316] Cubicane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0317] "Carbon spirocyclic", "spirocyclic carbon cyclic", "spirocarbon cyclic", or "carbon spirocyclic" refers to a spirocyclic system composed only of carbon atoms.

[0318] "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.

[0319] "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.

[0320] "Hybrid monocyclic", "monocyclic heterocyclic group" or "hybrid monocyclic group" refers to the "heterocyclic group" or "heterocyclic" in a monocyclic system.

[0321] "Hydrocyclic ring", "hydrocyclic cyclic group", "fused cyclic heterocyclic group" or "fused heterocyclic group" refers to a "fused ring" containing heteroatoms.

[0322] "Heterospirocyclic", "heterospirocyclic group", "spirocyclic heterocyclic group" or "spiroheterocyclic group" refers to a "spirocycle" containing heteroatoms.

[0323] "Hybrid-bridged ring", "hybrid-bridged ring group", "bridged ring heterocyclic group" or "bridged heterocyclic group" refers to a "bridged ring" containing heteroatoms.

[0324] "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 linking site is located on the aryl ring.

[0325] "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 heteroaryl groups mentioned in this article are defined in accordance with this definition. Heteroaryl groups can be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the linkage site is located on an aromatic ring.

[0326] "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 -alkynyl-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.

[0327] "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.

[0328] The XY-membered 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-membered elements. 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-membered heteromonocyclic rings" refers to heteromonocyclic rings of 4, 5, 6, or 7 members, and "5-10-membered heterofused rings" refers to heterofused rings of 5, 6, 7, 8, 9, or 10 members.

[0329] 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 yA 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.

[0330] 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 segment 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:

[0331] 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.

[0332] "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.

[0333] "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.

[0334] "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.

[0335] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0336] "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.

[0337] "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.

[0338] "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.

[0339] "Animals" refers to mammals, such as humans, companion animals, zoo animals, and livestock, with humans, horses, or dogs being preferred.

[0340] "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.

[0341] "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

[0342] 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.

[0343] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6The 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).

[0344] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0345] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM).

[0346] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) are 0.15mm-0.20mm in diameter, and the silica gel plates used for thin-layer chromatography separation and purification are 0.4mm-0.5mm in diameter.

[0347] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0348] 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.

[0349] THF: Tetrahydrofuran; DMF: N,N-Dimethylformamide; DIPEA: N,N-Diisopropylethylamine; HATU: CAS148893-10-1

[0350] Retention time: Unless otherwise specified in the embodiments, this represents the retention time corresponding to the analysis method.

[0351] Example 1: Preparation of Compound 1

[0352] Step 1: Preparation of compound 1c

[0353] Dissolve 1a (200 mg, 0.53 mmol) in tetrahydrofuran (8 mL) and purge three times with nitrogen. Cool the mixture to -78 °C, and slowly add bis(trimethylsilyl)amino potassium (1 M in THF, 1 mL). Stir for 2 minutes, then add 1b (107 mg, 0.80 mmol). Heat to 70 °C and stir for 8 hours. Quench with saturated ammonium chloride solution (5 mL), extract with ethyl acetate (10 mL × 3), and dry the separated organic layer with anhydrous sodium sulfate. Filter the solution, concentrate the filtrate, and separate by silica gel column chromatography to obtain 1c (110 mg, yield 48.1%).

[0354] LCMS m / z = 430.1 [M+H] + ;

[0355] Step 2: Preparation of compound 1e

[0356] 1c (110 mg, 0.26 mmol) was dissolved in 1,4-dioxane (2 mL). 1d (99 mg, 0.39 mmol), tricyclohexylphosphine tetrafluoroborate (3 mg, 0.008 mmol), tris(dibenzylacetone)dipalladium (12 mg, 0.013 mmol), and potassium carbonate (77 mg, 0.78 mmol) were added to the system. The mixture was stirred in a microwave at 140 °C for 3 hours under a nitrogen atmosphere. The solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the concentrated filtrate was purified by silica gel column chromatography to obtain 1e (100 mg, 75.0% yield).

[0357] LCMS m / z = 522.3 [M+H] + ;

[0358] Step 3: Preparation of 1g of compound

[0359] 1e (100 mg, 0.19 mmol) and 1f (62 mg, 0.19 mmol) were added to a mixed solution of 1,4-dioxane and water (5:1, 3.6 mL), followed by the addition of Pd(dppf)Cl2 dichloromethane complex (8 mg, 0.01 mmol) and potassium carbonate (66 mg, 0.47 mmol). The mixture was stirred at 90 °C for 12 hours under a nitrogen atmosphere. The reaction solution was diluted with water, extracted with ethyl acetate (10 mL × 3), and the organic phase was washed with saturated brine (10 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by silica gel column chromatography to obtain 1 g (95 mg, yield 77.1%).

[0360] LCMS m / z = 643.4 [M+H] + ;

[0361] Step 4: Preparation of Compound 1

[0362] 1 g (95 mg, 0.15 mmol) was dissolved in 1,4-dioxane (1 mL), and then hydrochloric acid (4 N in 1,4-dioxane, 1 mL) was added. The mixture was stirred at room temperature for 1 hour. The solution was concentrated, then diluted with water, and the aqueous phase was washed with ethyl acetate. The combined aqueous phases were adjusted to pH 9 with 1 N sodium hydroxide solution. The precipitated solid was extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and then subjected to pre-HPLC to prepare compound 1 (13 mg, yield 16.1%). HPLC preparation conditions: Instrument: Waters 2767 preparative HPLC; Column: XSelect CSH C18 (19 mm × 250 mm). The sample was dissolved in DMF and filtered through a 0.45 μM filter to prepare the sample solution. Preparative chromatographic conditions: a. Mobile phase A: acetonitrile; b. Water (50 mM ammonium bicarbonate); elution gradient of mobile phase A from 15% to 60%; c. Flow rate 12 mL / min; d. Elution time 15 min.

[0363] 1 H NMR(400MHz,DMSO-d6)δ9.05(s,2H),8.34–8.27(m,1H),7.79–7.74(m,2H),7.69(t ,1H),7.63–7.58(m,1H),7.52–7.46(m,2H),6.33(d,1H),5.40(d,1H),3.89(dd,1H) ,3.61–3.45(m,2H),2.82(d,1H),2.69–2.58(m,2H),2.46–2.35(m,2H),2.16–2.06( m,2H),2.05–1.93(m,1H),1.88–1.75(m,1H),1.48–1.35(m,1H),0.62–0.40(m,4H).

[0364] LCMS m / z = 543.2 [M+H] + ;

[0365] Example 2: Preparation of Compound 2

[0366] Step 1: Preparation of compound 2c

[0367] Dissolve 1a (150 mg, 0.40 mmol) in toluene (4.5 mL), add 2b (69 mg, 0.80 mmol), cuprous acetate (74 mg, 0.60 mmol), and sodium carbonate (64 mg, 0.60 mmol), purge three times with nitrogen, then purge three times with oxygen, and stir at 80 °C for 48 hours. Filter and wash the filter cake with ethyl acetate. Dry the organic layer with anhydrous sodium sulfate and filter again. Concentrate the filtrate and separate by silica gel column chromatography to obtain 2c (140 mg, yield 84.3%).

[0368] LCMS m / z = 416.2[M+H] + ;

[0369] Steps 2 to 4: Preparation of Compound 2

[0370] Compound 2 (6 mg) was obtained by following the synthetic method and HPLC preparation and purification of compound 1. HPLC preparation conditions: Instrument: Waters 2767 preparative HPLC; Column: XSelect CSH C18 (19 mm × 250 mm). The sample was dissolved in DMF and filtered through a 0.45 μM filter to prepare the sample solution. Preparative chromatographic conditions: a. Mobile phase A: acetonitrile; b. Water (50 mM ammonium bicarbonate); gradient elution of mobile phase A from 15% to 60%; c. Flow rate: 12 mL / min; d. Elution time: 15 min.

[0371] 1 H NMR(400MHz,DMSO-d6)δ9.05(s,2H),8.19–8.12(m,1H),7.81–7.75(m,2H),7.67(t,1H) ,7.61(dd,1H),7.51–7.44(m,2H),6.29(d,1H),5.30(d,1H),3.58–3.46(m,1H),3.20–3. 11(m,1H),2.83(d,1H),2.69–2.58(m,2H),2.44–2.35(m,2H),2.16–2.06(m,2H),2.05–1 .92(m,1H),1.88–1.75(m,1H),1.51–1.41(m,1H),1.01–0.89(m,2H),0.59–0.48(m,1H).

[0372] LCMS m / z = 529.2 [M+H] + ;

[0373] Example 3: Preparation of Compound 3

[0374] Compound 3 (3 mg) was obtained by following the synthetic method and HPLC preparation and purification of compound 1. HPLC preparation conditions: Instrument: Waters 2767 preparative HPLC; Column: XSelect CSH C18 (19 mm × 250 mm). The sample was dissolved in DMF and filtered through a 0.45 μM filter to prepare the sample solution. Preparative chromatographic conditions: a. Mobile phase A: acetonitrile; b. Water (50 mM ammonium bicarbonate); gradient elution of mobile phase A from 15% to 60%; c. Flow rate: 12 mL / min; d. Elution time: 15 min.

[0375] 1 H NMR(400MHz,DMSO-d6)δ9.05(s,2H),8.34–8.27(m,1H),7.81–7.74(m,2H),7.68(t,1H) ,7.61(dd,1H),7.53–7.46(m,2H),6.31(d,1H),5.32(d,1H),4.12–3.99(m,1H),3.93–3. 78(m,3H),3.60–3.49(m,1H),3.47–3.39(m,1H),2.80(d,1H),2.70–2.58(m,2H),2.44–2 .35(m,2H),2.18–2.06(m,2H),2.05–1.93(m,1H),1.89–1.73(m,1H),0.61–0.41(m,4H).

[0376] LCMS m / z = 573.3 [M+H] + ;

[0377] Example 4: Preparation of Compound 4

[0378] Step 1: Preparation of compound 4b

[0379] A DMA (10 mL) solution containing substrate 4a (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 4b (2.02 g, 80%).

[0380] Step 2: Preparation of compound 4c

[0381] 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 4b (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 4c (2.04 g, 96%).

[0382] LCMS m / z = 274.1 [M+H] +

[0383] Step 3: Preparation of compound 4d

[0384] 4c (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 reacted 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 the crude product 4d (1.77 g).

[0385] LCMS m / z = 275.1 [M+H] +

[0386] Step 4: Preparation of compound 4e

[0387] Triethylamine (852 mg, 8.42 mmol) and diphenyl azidophosphate (2.32 g, 8.42 mmol) were added sequentially to a 22 mL solution of crude product 4d (1.77 g, 6.48 mmol) obtained in the previous step in dioxane, 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, and the mixture 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 the crude product 4e (1.64 g).

[0388] Step 5: Preparation of compound 4f

[0389] DIPEA (867 mg, 6.72 mmol) and di-tert-butyl dicarbonate (2.9 g, 13.44 mmol) were added sequentially to a THF (20 mL) solution of 4e (1.64 g, 6.72 mmol), and the reaction was carried out overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give intermediate 4f (1.7 g, 68% yield in three steps).

[0390] LCMS m / z = 344.1 [M+H]+

[0391] Step 6: Preparation of compound 4h

[0392] 4f (14 mg, 0.04 mmol), 4 g (20 mg, 0.04 mmol), Pd(dppf)Cl2 (3 mg, 0.004 mmol), potassium carbonate (12 mg, 0.08 mmol), and 3 mL of dioxane were added to a reaction flask and reacted overnight at 100 °C. The mixture was concentrated, and the residue was purified by preparative TLC to give intermediate 4h (20 mg, 78%).

[0393] LCMS m / z = 619.2 [M+H] +

[0394] Step 7: Preparation of Compound 4

[0395] 1 mL of dichloromethane and 1 mL of trifluoroacetic acid were added to 4 h (20 mg, 0.03 mmol), and the mixture was stirred at room temperature for 3 hours. After concentration, the mixture was dissolved again in 10 mL of dichloromethane. The mixture was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC to obtain compound 4 (10 mg, 65%).

[0396] 1 H NMR (400MHz, CD3OD) δ8.40–8.33(m,1H),7.78–7.75(m,1H),7.69(d,1H),7.52–7.41(m,4H),7.37–7.27(m,2H),7.19(t,1H),6.41(d,1H) ,5.20(d,1H),3.62–3.52(m,1H),3.48(s,3H),2.90(d,1H),2.66–2.57(m,2H),2.38–2.27(m,2H),2.22–2.07(m,2H),1.89–1.77(m,1H).

[0397] LCMS m / z = 519.2 [M+H] +

[0398] Example 5: Preparation of Compound 5

[0399] Step 1: Preparation of compound 5B

[0400] 5A (450 mg, 1.83 mmol) and sodium carbonate (580 mg, 5.49 mmol) were dissolved in tetrahydrofuran (30 mL) and water (6 mL). Di-tert-butyl dicarbonate (600 mg, 2.75 mmol) was slowly added at 0 °C, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue purified by silica gel column chromatography to obtain 5B (510 mg, yield 80.37%).

[0401] LCMS m / z = 344.1 [M+H] + ;

[0402] Step 2: Preparation of compound 5D

[0403] 5B (14 mg, 0.04 mmol) and 4 g (15 mg, 0.031 mmol) were added to a mixed solution of 1,4-dioxane and water (5:1, 3.6 mL). Pd(dppf)Cl₂ dichloromethane complex (3 mg, 0.0031 mmol) and potassium carbonate (12.85 mg, 0.093 mmol) were added. The mixture was stirred at 90 °C for 12 hours under a nitrogen atmosphere. The solution was diluted with water, extracted with ethyl acetate (10 mL × 3), and the organic phase was washed with saturated brine (10 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to give 5D (15 mg, 77.8% yield).

[0404] LCMS m / z = 619.2 [M+H] + ;

[0405] Step 3: Preparation of Compound 5

[0406] 5D (15 mg, 0.024 mmol) was dissolved in DCM (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hour. After concentration, the residue was subjected to pre-HPLC to prepare trifluoroacetate of compound 5 (3 mg, yield 23.86%). Preparation method: (Instrument: Waters 2767 preparative HPLC; Column: SUNFIRE@Prep C18 (19 mm × 250 mm)) 2. The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% TFA) b. Gradient elution: Mobile phase A content from 5% to 40% c. Flow rate 15 mL / min d. Elution time 15 min).

[0407] 1H NMR (400MHz, CD3OD) δ8.41–8.34(m,1H),7.87–7.81(m,1H),7.72(d,1H),7.60–7.53(m,3H),7.52–7.44(m,3H),7.29(t,1H),6.43 (d,1H),5.22(d,1H),3.64–3.53(m,1H),3.48(s,3H),2.96–2.85(m,3H),2.71–2.60(m,2H),2.42–2.27(m,1H),2.12–1.99(m,1H).

[0408] LCMS m / z = 519.2 [M+H] +

[0409] Example 6: Preparation of Compound 6

[0410] Step 1: Preparation of compound 6c

[0411] 6a (10 g, 105.15 mmol) was dissolved in toluene (150 mL), and 6b (9.79 g, 157.73 mmol) and p-toluenesulfonic acid (910 mg, 5.26 mmol) were added. The mixture was heated to 110 °C and reacted for 12 hours to remove water. After cooling to room temperature, the mixture was diluted with saturated sodium bicarbonate (100 mL), extracted with ethyl acetate (200 mL × 3), and the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain 6c (12.2 g, yield 83.4%).

[0412] LCMS m / z = 140.1 [M+H] + ;

[0413] Step 2: Preparation of compound 6e

[0414] 6c (14.3 g, 102.77 mmol) was dissolved in ethanol (150 mL), 6d (8.14 g, 123.32 mmol) was added, the mixture was heated to 80 °C and stirred for 12 hours, and then concentrated and dried to obtain 6e (17.6 g, yield 99.5%).

[0415] Step 3: Preparation of 6g of compound

[0416] A mixture of 6e (10 g, 58.08 mmol) and 6f (118.59 g, 1161.6 mmol) was heated to 120 °C and stirred for 30 minutes. After cooling to room temperature, the mixture was diluted with water (200 mL), extracted with ethyl acetate (150 mL × 3), and the organic phase was washed with saturated brine (150 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography to give 6 g (6.7 g, yield 58.8%).

[0417] LCMS m / z = 197.1 [M+H] + ;

[0418] Step 4: Preparation of compound 6h

[0419] 6 g (6.7 g, 34.15 mmol) was dissolved in tetrahydrofuran (70 mL), and 2N hydrochloric acid (25 mL) was added. The mixture was stirred at 65 °C for 5 hours. The solution was diluted with water (150 mL), extracted with ethyl acetate (150 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain 6 h (3.2 g, 61.6% yield).

[0420] LCMS m / z = 153.1 [M+H] + ;

[0421] Step 5: Preparation of compound 6j

[0422] 6h (3.2 g, 21.03 mmol) was dissolved in tetrahydrofuran (40 mL). 6i (2.55 g, 21.03 mmol) and tetraisopropyl titanate (11.95 g, 42.06 mmol) were added to the system, and the mixture was stirred at 60 °C for 12 hours. After cooling to room temperature, water (100 mL) was added to precipitate the solid. The solid was filtered, and the filter cake was washed with ethyl acetate. The organic layer was washed with water (150 mL) and saturated brine (150 mL), respectively. After drying with anhydrous sodium sulfate, the solid was filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain 6j (4.2 g, 78.2% yield).

[0423] LCMS m / z = 256.1 [M+H] + ;

[0424] Step 6: Preparation of compound 6l

[0425] 6J (3.7 g, 14.49 mmol) was dissolved in dichloromethane (100 mL), cooled to -78 °C, and n-butyllithium (2.5 M in hexane, 7.5 mL) was added dropwise. The mixture was stirred at -78 °C for 2 hours. A solution of 6K (5.78 g, 20.29 mmol) in dichloromethane (50 mL) was slowly added to the reaction mixture. After stirring at -78 °C for 2 hours, the mixture was heated to room temperature and stirred for 12 hours. The reaction mixture was quenched dropwise in a saturated ammonium chloride solution (200 mL), and extracted with dichloromethane (150 mL × 3). The organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the concentrated filtrate was purified by silica gel column chromatography to obtain 6L (1.9 g, yield 31.7%).

[0426] Step 7: Preparation of compound 6m

[0427] 6 L (1.9 g, 4.59 mmol) was dissolved in methanol (10 mL), and hydrochloric acid (4 N in MeOH, 10 mL) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and diethyl ether:methanol (10:1, 2 mL) was added. After stirring, the mixture was filtered, and the filter cake was washed with diethyl ether. The filter cake was dried to obtain 6 M (2 g, crude product).

[0428] LCMS m / z = 311.0 / 312.0 [M+H] + ;

[0429] Step 8: Preparation of compound 6n

[0430] 1 M (2 g, crude product) was dissolved in tetrahydrofuran (20 mL) and cooled to 0 °C. Then, di-tert-butyl dicarbonate (1.41 g, 6.45 mmol) and triethylamine (2.69 mL, 19.35 mmol) were added. The mixture was stirred at 0 °C for 30 minutes, then heated to room temperature and stirred for 1 hour. The mixture was diluted with water, extracted with ethyl acetate (50 mL × 3), and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain 6N (1.3 g, 49.1% yield).

[0431] Step 9: Preparation of compounds 6n-P1 and 6n-P2

[0432] Fragment 6n was prepared and separated by SFC to obtain 6n-P1 (367.3 mg, chiral analysis retention time: 1.593 min) and 6n-P2 (849.8 mg, chiral analysis retention time: 1.945 min).

[0433] Chiral preparation method: Instrument: Waters 150 Prep-SFC; Preparative column: Chiral IG column; Mobile phase: A is CO2; B is 0.1% ammonia-methanol solution; Elution conditions: B for 30%; Flow rate: 110 mL / min; Pressure: 100 bar; Column temperature: room temperature; Detection wavelength: 220 nm;

[0434] Chiral analysis method: Instrument: SHIMADZU LC-30AD SFC; Preparative column: Chiral IG column; Mobile phase: A for CO2; B for 0.05% DEA in methanol; Elution conditions: B for 5-40%; Flow rate: 3 mL / min; Pressure: 100 bar; Column temperature: 35℃; Detection wavelength: 220 nm;

[0435] Step 10: Preparation of compound 6o-P1

[0436] 4 g (15 mg, 0.031 mmol) was dissolved in 2 mL of 1,4-dioxane and 0.2 mL of water. 6n-P1 (25 mg, 0.062 mmol), potassium carbonate (21 mg, 0.15 mmol), and Pd(dppf)Cl2 dichloromethane complex (5 mg, 0.0062 mmol) were added. The reaction was carried out at 100 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with 10 mL of ethyl acetate and washed once with 10 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography to give 6o-P1 (12 mg, yield: 56.24%).

[0437] LCMS m / z = 685.3 [M+H] +

[0438] Step 11: Preparation of Compound 6

[0439] Compound 6 (12 mg, 0.018 mmol) was dissolved in 4 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 4 h. The reaction solvent was removed by concentration under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain target compound 6 (4 mg, yield: 39.04%).

[0440] 1H NMR (400MHz, CD3OD) δ9.18–8.89(m,2H),8.37(dd,1H),7.86(d,1H),7.78(d,1H),7.60(dd,1H),7.52–7.43(m,2H),7.31(t,1H), 6.46(d,1H),5.23(d,1H),4.07–3.94(m,1H),3.64–3.54(m,1H),3.49(s,3H),3.25–3.11(m,2H),2.92(d,1H),2.64–2.51(m,5H).

[0441] LCMS m / z = 585.2 [M+H] +

[0442] Example 7: Synthesis of Compound 7

[0443] Step 1: Preparation of compound 7b

[0444] 4 g (15 mg, 0.031 mmol) was dissolved in 2 mL of 1,4-dioxane and 0.2 mL of water. 6n-P2 (25 mg, 0.062 mmol), potassium carbonate (21 mg, 0.15 mmol), and Pd(dppf)Cl2 dichloromethane complex (5 mg, 0.0062 mmol) were added. The reaction was carried out at 100 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with 10 mL of ethyl acetate and washed once with 10 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography to give compound 7b (14 mg, yield: 65.61%).

[0445] LCMS m / z = 685.3 [M+H] +

[0446] Step 2: Preparation of Compound 7

[0447] 7b (14 mg, 0.020 mmol) was dissolved in 4 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 4 h. The solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain target compound 7 (8 mg, yield: 66.93%).

[0448] LCMS m / z = 585.2 [M+H] +

[0449] 1H NMR(400MHz,CD3OD)δ9.09(s,2H),8.37(dd,1H),7.89(d,1H),7.79(d,1H),7.63(dd,1H),7.53–7.45(m,2H),7.32(t,1H),6.47(d,1 H),5.23(d,1H),3.85–3.74(m,1H),3.65–3.54(m,1H),3.49(s,3H),3.18–3.09(m,2H),2.92(d,1H),2.72–2.63(m,2H),2.61(s,3H).

[0450] Example 8: Preparation of Compound 8

[0451] Step 1: Preparation of 8B

[0452] Methyl 3-carbonyl-cyclobutanecarboxylate 8A (10 g, 78.05 mmol) and tert-butylsulfinamide (10.41 g, 85.86 mmol) were dissolved in 150 mL of tetrahydrofuran. Tetraethyl titanate (35.6 g, 156.10 mmol) was slowly added dropwise at 0 °C, and the reaction was carried out at 60 °C for 16 h after the addition was complete. The reaction mixture was cooled to room temperature, and 200 mL of water and 250 mL of ethyl acetate were added. The mixture was filtered, and the filter cake was washed with 250 mL of ethyl acetate. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain the target compound 8B (7.2 g, yield 37.60%).

[0453] LCMS m / z = 246.2[M+H] +

[0454] Step 2: Preparation of 8C

[0455] 5-Bromo-2-iodopyrimidine (9.75 g, 34.24 mmol) was dissolved in 120 mL of dichloromethane. Under a nitrogen atmosphere, n-butyllithium (13.7 mL, 2.5 N n-hexane solution) was slowly added dropwise at -78 °C. After the addition was complete, the reaction was carried out at -78 °C for 2 h. Then, 15 mL of a dichloromethane solution of 8B (7 g, 28.53 mmol) was slowly added dropwise. After the addition was complete, the reaction was allowed to return to room temperature and the reaction was allowed to proceed for 16 h. 150 mL of a saturated aqueous solution of NH4Cl was added to the reaction mixture. The mixture was separated, and the aqueous phase was extracted with 100 mL of dichloromethane. The combined organic phases were washed once with 140 mL of a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography to obtain the target compound 8C (3.1 g, yield 26.87%).

[0456] LCMS m / z = 404.0 [M+H] +

[0457] Step 3: Preparation of 8D

[0458] 8C (3.1 g, 7.67 mmol) was dissolved in 15 mL of dichloromethane solution, and 5 mL of 4N HCl dioxane solution was added. The reaction was carried out at room temperature for 3 h. After concentration under reduced pressure, the hydrochloride salt of the target compound 8D (2.0 g, yield 86.91%) was obtained. No further purification was performed, and the reaction proceeded directly to the next step.

[0459] LCMS m / z = 300.1[M+H] +

[0460] Step 4: Preparation of 8E

[0461] The hydrochloride salt of 8D (2.00 g, 6.66 mmol) was dissolved in 20 mL of tetrahydrofuran solution, and triethylamine (2.02 g, 19.98 mmol) and di-tert-butyl dicarbonate (2.18 g, 9.99 mmol) were added. The reaction was carried out at room temperature for 16 h. After concentration under reduced pressure, the residue was chromatographically analyzed by silica gel column chromatography to obtain the target compound 8E (0.63 g, yield 23.62%).

[0462] LCMS m / z = 400.1[M+H] +

[0463] Step 5: Preparation of 8F

[0464] 8E (0.63 g, 1.57 mmol) was dissolved in a mixed solvent of 15 mL ethanol and 2 mL water, and reacted at 45 °C for 3 h. After cooling to room temperature, the reaction solvent was removed by concentration under reduced pressure. The residue was adjusted to pH 3 with 3N hydrochloric acid and extracted twice with dichloromethane (20 mL × 2). The organic phases were combined and washed once with 20 mL of saturated NaCl aqueous solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound 8F (0.546 g, yield 93.20%).

[0465] LCMS m / z = 372.7 [M+H] +

[0466] Step 6: Preparation of 8G

[0467] 8F (0.546 g, 1.47 mmol) was dissolved in 15 mL of DMF, and HATU (0.84 g, 2.21 mmol), diisopropylethylamine (0.38 g, 2.94 mmol), and ammonium chloride (0.79 g, 14.7 mmol) were added sequentially. The reaction was carried out at room temperature for 16 h. 25 mL of water was added, and the mixture was extracted twice with ethyl acetate (25 mL × 2). The organic phases were combined and washed twice with water (25 mL × 2) and once with 25 mL of saturated NaCl aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography to obtain the target compound 8G (0.35 g, yield 64.27%).

[0468] LCMS m / z = 371.1 [M+H] +

[0469] Step 7: Preparation of 8G-P1 and 8G-P2.

[0470] Compound 8G was prepared and resolved by SFC to obtain 8G-P1 (155.2 mg, chiral analysis retention time: 1.199 min) and 8G-P2 (78.9 mg, chiral analysis retention time: 1.279 min).

[0471] Chiral preparation method: Instrument: Waters 150Prep-SFC; Preparative column: Chiral OD column; Mobile phase: A is CO2; B is ethanol solution; Elution conditions: B for 20%; Flow rate: 120 mL / min; Pressure: 100 bar; Column temperature: room temperature; Detection wavelength: 220 nm;

[0472] Chiral analysis method: Instrument: SHIMADZU LC-30AD SFC; Preparative column: Chiral OD column; Mobile phase: A is CO2; B is 0.05% DEA methanol solution; Elution conditions: B for 5-40%; Flow rate: 3 mL / min; Pressure: 100 bar; Column temperature: 35℃; Detection wavelength: 220 nm;

[0473] 8G-P1: 1 H NMR (400MHz, DMSO-d6) δ8.97(s,2H),7.78–7.58(m,1H),7.24(s,1H),6.75(s,1H),3.07–2.92(m,1H),2.72–2.56(m,2H),2.54–2.39(m,2H).

[0474] 8G-P2: 1H NMR (400MHz, DMSO-d6) δ8.93(s,2H),7.77–7.42(m,1H),7.22(s,1H),6.75(s,1H),3.18–3.05(m,1H),2.84–2.68(m,2H),2.45–2.33(m,2H).

[0475] Step 8: Preparation of 8H

[0476] 4 g (20 mg, 0.042 mmol) of the intermediate was dissolved in 2 mL of 1,4-dioxane and 0.2 mL of water. 8G-P1 (20 mg, 0.055 mmol), potassium carbonate (17 mg, 0.13 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (7 mg, 0.0084 mmol) were added. The reaction was carried out at 100 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with 10 mL of ethyl acetate and washed once with 10 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography to give 8H (15 mg, yield: 55.91%).

[0477] LCMS m / z = 646.3 [M+H] +

[0478] Step 9: Preparation of Compound 8

[0479] 8H (15 mg, 0.023 mmol) was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 3 h. The reaction solvent was removed by concentration under reduced pressure, and the residue was purified to obtain the target compound 8 (4 mg, yield: 31.56%).

[0480] Preparation conditions: Instrument: Waters automated purification system; Column: SunFire (19mm × 250mm);

[0481] Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, mobile phase B: water (0.1% ammonium acetate); gradient elution; flow rate 15 ml / min.

[0482] LCMS m / z = 546.3 [M+H] +

[0483] 1 H NMR(400MHz,CD3OD)δ9.11(s,2H),8.40–8.33(m,1H),7.91–7.87(m,1H),7.79(d,1H),7.65–

[0484] 7.56(m,1H),7.51–7.44(m,2H),7.37(t,1H),6.45(d,1H),5.23(d,1H),3.64–3.54(m,1 H),3.49(s,3H),3.45–3.36(m,1H),3.12–3.01(m,2H),2.92(d,1H),2.74–2.61(m,2H).

[0485] Example 9: Preparation of Compound 9

[0486] Step 8: Preparation of 9B

[0487] 4 g (20 mg, 0.042 mmol) was dissolved in 2 mL of 1,4-dioxane and 0.2 mL of water. 8 G-P2 (20 mg, 0.055 mmol), potassium carbonate (17 mg, 0.13 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (7 mg, 0.0084 mmol) were added. The reaction was carried out at 100 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with 10 mL of ethyl acetate and washed once with 10 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography to give 9B (18 mg, yield: 67.09%).

[0488] LCMS m / z = 646.3 [M+H] +

[0489] Step 9: Preparation of Compound 9

[0490] 9B (18 mg, 0.028 mmol) was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 3 h. The reaction solvent was removed by concentration under reduced pressure, and the residue was purified to obtain target compound 9 (4.5 mg, yield: 29.59%).

[0491] Preparation conditions: Instrument: Waters automated purification system; Column: SunFire (19mm×250mm); Preparative chromatographic conditions: Mobile phase A: acetonitrile, Mobile phase B: water (0.1% ammonium acetate), gradient elution; Flow rate: 15ml / min.

[0492] LCMS m / z = 546.3 [M+H] +

[0493] 1H NMR(400MHz,CD3OD)δ9.06(s,2H),8.40–8.32(m,1H),7.89–7.84(m,1H),7.78(d,1H),7.59(dd,1H),7.51–7.42(m,2H),7.30 (t,1H),6.45(d,1H),5.22(d,1H),3.64–3.53(m,1H),3.53–3.45(m,4H),3.23–3.11(m,2H),2.91(d,1H),2.64–2.51(m,2H).

[0494] Example 10: Synthesis of Compound 10

[0495] Steps 1-5: Synthesis of compound 10f

[0496] Compound 10f was prepared using compound 10a as the starting material, following the synthetic route of compound 4f in Example 4.

[0497] Step 6: Synthesis of 10g of compound

[0498] 10 g (37 mg, 0.1 mmol) of compound, 4 g (50 mg, 0.1 mmol) of compound, Pd2dba3 (5 mg, 0.005 mmol), PCy3·HBF4 (4 mg, 0.012 mmol), potassium phosphate (53 mg, 0.25 mmol), 3 mL of dioxane, and 0.15 mL of water were added to a reaction flask and reacted overnight at 100 °C. The reaction solution was concentrated and subjected to silica gel column chromatography to obtain 10 g (50 mg, 80%) of intermediate.

[0499] LCMS m / z = 637.0 [M+H] +

[0500] Step 7: Synthesis of Compound 10

[0501] 2 mL of dichloromethane and 2 mL of trifluoroacetic acid were added to compound 10h (50 mg, 0.079 mmol), and the mixture was stirred at room temperature for 3 hours. After concentration, the residue was dissolved again in 10 mL of dichloromethane. The crude product of compound 10 was obtained by washing with saturated sodium bicarbonate solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was purified by preparative TLC to obtain compound 10 (25 mg, 60%).

[0502] 1H NMR (400MHz, CD3OD) δ8.41–8.34(m,1H),7.72–7.64(m,2H),7.50–7.49–7.42(m,2H),7.36–6.94(m,4H),6.40(d,1H),5.21(d, 1H),3.63–3.52(m,1H),3.49(s,3H),2.89(d,1H),2.61–2.51(m,2H),2.33–2.23(m,2H),2.22–2.06(m,1H),1.90–1.76(m,1H).

[0503] LCMS m / z = 537.0 [M+H] +

[0504] Example 11: Synthesis of Compound 11

[0505] Step 1: Synthesis of 11b

[0506] 11a (0.5 g, 1.28 mmol) was dissolved in 10 mL of THF, and KHMDS (6.4 mL, 6.4 mmol) was added dropwise at 0 °C. After the addition was complete, the reaction was carried out at room temperature for 2 h. The reaction was quenched with an aqueous solution of ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography was performed to obtain 11b (0.35 g, 80% yield).

[0507] LCMS m / z = 340.1 [M+H] +

[0508] Step 2: Synthesis of compound 11c

[0509] 11b (0.35 g, 1.03 mmol) was dissolved in 10 mL of LMF, and 1,1-difluoro-2-iodoethane (0.3 g, 1.54 mmol) and cesium carbonate (0.67 g, 2.06 mmol) were added. The mixture was heated to 80 °C and reacted for 2 h. The reaction was quenched with 30 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 11c (0.35 g, 84% yield).

[0510] LCMS m / z = 404.1 [M+H] +

[0511] Step 3: Synthesis of compound 11d

[0512] 11c (0.35 g, 0.87 mmol) was dissolved in 1 mL of 1,4-dioxane, and pinacol diboronate (0.44 g, 1.74 mmol), potassium acetate (0.26 g, 2.61 mmol), tricyclohexylphosphine tetrafluoroborate (32 mg, 0.087 mmol), and tris(dibenzylacetone)palladium (80 mg, 0.087 mmol) were added sequentially. The reaction was carried out under a nitrogen atmosphere and microwaved at 140 °C for 3 h. After cooling to room temperature, the residue was concentrated under reduced pressure and then chromatographically analyzed by silica gel column chromatography to obtain the target compound 11d (0.32 g, 74.%).

[0513] LCMS m / z = 496.2[M+H] +

[0514] Step 4: Synthesis of compound 11e

[0515] 11d (80 mg, 0.16 mmol) was dissolved in 4 mL of 1,4-dioxane and 0.4 mL of water. 1f (63 mg, 0.19 mmol), potassium carbonate (44 mg, 0.32 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (13 mg, 0.016 mmol) were added. The reaction was carried out at 100 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with 10 mL of ethyl acetate and washed once with 10 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography to give 11e (70 mg, yield: 70%).

[0516] LCMS m / z = 617.2 [M+H] +

[0517] Step 5: Preparation of Compound 11

[0518] 11e (70 mg, 0.11 mmol) was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 3 h. The reaction solvent was removed by concentration under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain the target compound 11 (35 mg, yield: 60%).

[0519] 1H NMR(400MHz,CD3OD)δ9.05–9.00(m,2H),8.20–8.13(m,1H),7.96–7.89(m,1H),7 .80–7.73(m,1H),7.62–7.55(m,1H),7.44–7.31(m,2H),6.68–6.35(m,2H),5.24 –5.16(m,1H),4.72–4.59(m,1H),4.57–4.44(m,1H),3.61–3.51(m,1H),3.48(s, 3H),2.91–2.83(m,1H),2.83–2.73(m,2H),2.35–2.24(m,2H),2.16–1.99(m,2H).

[0520] LCMS m / z = 517.2 [M+H] +

[0521] Example 12: Synthesis of Compound 12

[0522] Step 1: Synthesis of compound 12b

[0523] 4f (172 mg, 0.5 mmol), 12a (200 mg, 0.041 mmol), Pd(dppf)Cl2 (30 mg, 0.04 mmol), potassium carbonate (114 mg, 0.083 mmol), 4 mL of dioxane, and 0.8 mL of water were added to a reaction flask and reacted overnight at 100 °C. The reaction solution was concentrated and subjected to silica gel column chromatography to obtain 12b (20 mg, 9%).

[0524] LCMS m / z = 622.5[M+H] +

[0525] Step 2: Synthesis of Compound 12

[0526] 2 mL of dichloromethane and 2 mL of trifluoroacetic acid were added to compound 12b (20 mg, 0.032 mmol), and the mixture was stirred at room temperature for 3 hours. The resulting reaction solution was concentrated and then dissolved again in 10 mL of dichloromethane. The solution was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound 12. The crude product was purified by preparative TLC to obtain compound 12 (10 mg, 59%).

[0527] 1H NMR (400MHz, CD3OD) δ8.40–8.34(m,1H),7.77(s,1H),7.68(d,1H),7.51–7.41(m,4H),7.37–7.26(m,1H),7.19(t,1H),6.41(d,1H ),5.20(d,1H),3.62–3.52(m,1H),2.91–2.88(m,1H),2.64–2.54(m,2H),2.35–2.25(m,2H),2.20–2.05(m,1H),1.88–1.76(m,1H).

[0528] LCMS m / z = 522.2[M+H] +

[0529] Example 13: Synthesis of Compound 13

[0530] Step 1: Synthesis of compound 13b

[0531] 4f (21 mg, 0.06 mmol), 13a (20 mg, 0.04 mmol), Pd2dba3 (2 mg, 0.002 mmol), PCy3·HBF4 (2 mg, 0.004 mmol), potassium phosphate (22 mg, 0.1 mmol), 2 mL of dioxane, and 0.1 mL of water were added to a reaction flask and reacted overnight at 100 °C. The reaction solution was concentrated and subjected to silica gel column chromatography to obtain intermediate 13b (22 mg, 57%).

[0532] LCMS m / z = 645.2 [M+H] +

[0533] Step 2: Synthesis of Compound 13

[0534] 2 mL of dichloromethane and 2 mL of trifluoroacetic acid were added to 13b (21 mg, 0.034 mmol), and the mixture was stirred at room temperature for 3 hours. After concentration, the residue was dissolved again in 10 mL of dichloromethane. The mixture was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound 13. The crude compound 13 (14 mg, 76%) was purified by preparative TLC.

[0535] 1H NMR(400MHz,CD3OD)δ8.26–8.19(m,1H),7.76(s,1H),7.68(d,1H),7.52–7.39(m, 4H),7.38–7.26(m,2H),7.17(t,1H),6.38(d,1H),5.36(d,1H),3.66–3.51(m,1H) ,3.23–3.17(m,1H),2.85(d,1H),2.60(ddd,2H),2.36–2.25(m,2H),2.18–2.06(m ,1H),1.85–1.78(m,1H),1.10–1.04(m,2H),0.94–0.82(m,1H),0.77–0.70(m,1H).

[0536] LCMS m / z = 545.3 [M+H] +

[0537] Example 14: Synthesis of Compound 14

[0538] Step 1: Preparation of 14b

[0539] 14a (5 g, 28.38 mmol) and tert-butylsulfinamide (3.44 g, 28.38 mmol) were dissolved in 50 mL of tetrahydrofuran. Tetraisopropyl titanate (16.13 g, 56.76 mmol) was slowly added dropwise at 0 °C, and the reaction was carried out at 60 °C for 16 h after the addition was complete. The reaction mixture was cooled to room temperature, and 100 mL of water and 100 mL of ethyl acetate were added. The mixture was filtered, and the filter cake was washed twice with ethyl acetate (100 mL × 2). The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain the target compound 14b (6 g, 75% yield).

[0540] LCMS m / z = 280.1 [M+H] +

[0541] Step 2: Preparation of 14c

[0542] 5-Bromo-2-iodopyrimidine (7.95 g, 27.91 mmol) was dissolved in 100 mL of dichloromethane. Under a nitrogen atmosphere, n-butyllithium (11 mL, 2.5 M n-hexane solution) was slowly added dropwise at -78 °C for 2 h after the addition was complete. Then, 30 mL of a dichloromethane solution containing 14b (6 g, 21.47 mmol) was slowly added dropwise, and the reaction was allowed to return to room temperature for 16 h. 100 mL of a saturated NH4Cl aqueous solution was added, and the mixture was separated. The aqueous phase was extracted with 100 mL of dichloromethane, and the organic phases were combined. The organic phase was washed once with 100 mL of a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography to obtain the target compound 14c (3.2 g, 34% yield).

[0543] LCMS m / z = 438.1 [M+H] +

[0544] Step 3: Preparation at 14 days

[0545] 14c (3 g, 6.84 mmol) was dissolved in 30 mL of dichloromethane, and boron tribromide (34 mL, 1 mol / L in DCM) was added. The reaction was carried out at room temperature for 16 h. The solution was concentrated to give crude compound 14d (1.5 g).

[0546] LCMS m / z = 244[M+H] +

[0547] Step 4: Preparation of 14e

[0548] 14d (1.5 g, 6.15 mmol) was dissolved in 30 mL of tetrahydrofuran solution, and triethylamine (3.11 g, 30.75 mmol) and di-tert-butyl dicarbonate (2.68 g, 12.3 mmol) were added. The reaction was carried out at room temperature for 16 h. The residue was concentrated under reduced pressure and then chromatographically analyzed by silica gel column chromatography to obtain the target compound 14e (1.65 g, 78% yield).

[0549] LCMS m / z = 344.1 [M+H] +

[0550] Step 5: Preparation of 14f

[0551] 14e (1.5 g, 4.36 mmol) was dissolved in 30 mL of dichloromethane solution, and Dysmartin oxidant (3.7 g, 8.72 mmol) was added. The reaction was carried out at room temperature for 2 h. The residue was concentrated under reduced pressure and then subjected to silica gel column chromatography to obtain the target compound 14f (1.1 g, 73% yield).

[0552] LCMS m / z = 342.1 [M+H] +

[0553] Step 6: Preparation of 14g

[0554] Methyltriphenylphosphine bromide (0.31 g, 0.87 mmol) was dissolved in 10 mL of tetrahydrofuran solution. LiHMDS (0.87 mL, 0.87 mmol) was added at 0 °C, and the mixture was stirred for 30 min. Then, 2 mL of 14f (0.2 g, 0.58 mmol) tetrahydrofuran solution was added, and the reaction was allowed to proceed at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride solution, extracted once with 40 mL of ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography to obtain 14 g (90 mg, 45%) of the target compound.

[0555] LCMS m / z = 340.1 [M+H] +

[0556] Step 5: Preparation over 14 hours

[0557] 14 g (21 mg, 0.063 mmol) and 4 g (20 mg, 0.042 mmol) were added to a mixed solution of 1,4-dioxane and water (5:1, 1.8 mL), followed by the addition of Pd(dppf)Cl2 dichloromethane complex (3.4 mg, 0.0042 mmol) and potassium carbonate (17 mg, 0.13 mmol). The mixture was stirred at 90 °C for 12 hours under a nitrogen atmosphere. The reaction solution was diluted with water, extracted with ethyl acetate (10 mL × 3), and the organic phase was washed with saturated brine (10 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by silica gel column chromatography to obtain 14 h (15 mg, 58%).

[0558] LCMS m / z = 615.2[M+H] + ;

[0559] Step 6: Preparation of Compound 14

[0560] 14h (15 mg, 0.024 mmol) was dissolved in 3 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 1 hour. After concentration, the trifluoroacetate of compound 14 (2.6 mg, 20.7%) was prepared by pre-HPLC. HPLC preparation conditions: Instrument: Waters 2767 preparative HPLC; Column: XSelect CSH C18 (19 mm × 250 mm). The sample was dissolved in DMF and filtered through a 0.45 μM filter to prepare the sample solution. Preparative chromatographic conditions: a. Mobile phase A: acetonitrile; b. Water (50 mM trifluoroacetic acid); gradient elution of mobile phase A from 15% to 60%; c. Flow rate: 12 mL / min; d. Elution time: 15 min.

[0561] 1H NMR(400MHz,CD3OD)δ9.13(s,2H),8.40–8.34(m,1H),7.89(d,1H),7.80(d,1H),7.63(dd,1H),7.50–7.43(m,2H),7.30(t,1H),7.12(s,1H),6.4 6(d,1H),5.24(d,1H),5.19–5.12(m,2H),3.70–3.65(m,1H),3.65–3.61 (m,1H),3.61–3.55(m,1H),3.49(s,3H),3.30–3.20(m,2H),2.93(d,1H).

[0562] LCMS m / z = 515.2 [M+H] + .

[0563] Example 15: Preparation of Compound 15

[0564] Step 1: Preparation of compound 15b

[0565] 15a (50 g, 196.51 mmol) was dissolved in a mixture of 450 mL toluene and 150 mL water. Potassium cyclopropyltrifluoroborate (34.90 g, 235.81 mmol), tricyclohexylphosphine (16.53 g, 58.95 mmol), cesium carbonate (384.16 g, 1179.06 mmol), and palladium acetate (8.82 g, 39.30 mmol) were added sequentially. The reaction mixture was heated to 120 °C and reacted for 16 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (300 mL), and the organic phase was washed once with water (400 mL) and once with a saturated aqueous solution of NaCl (250 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography to obtain 15b (28 g, 66.09% yield).

[0566] 1 H NMR (400MHz, CDCl3) δ7.68(d,1H),7.32(d,1H),2.18–2.10(m,1H),1.14–1.08(m,2H),0.77–0.71(m,2H).

[0567] Step 2: Preparation of compound 15c

[0568] 15b (25 g, 115.95 mmol) was dissolved in 250 mL of acetonitrile, and 15b-1 (39.21 g, 115.95 mmol) and potassium carbonate (48.08 g, 347.85 mmol) were added. The mixture was heated to 80 °C and reacted for 16 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (250 mL), and the organic phase was washed once with water (300 mL) and once with a saturated NaCl aqueous solution (250 mL). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography to obtain 15c (22 g, 35.55% yield).

[0569] 1 H NMR(400MHz, CDCl3)δ8.74(d,1H),7.79(s,1H),7.45(dd,1H),7.19–7.10(m,3H),6.83–6.43(t,1H),5.85–5.77(m,1H) ,4.14(q,2H),3.27–3.15(m,1H),2.91(dd,1H),1.98–1.90(m,1H),1.22(t,3H),0.98–0.85(m,2H),0.65–0.55(m,2H).

[0570] Step 3: Preparation of compound 15d

[0571] 15c (22 g, 41.22 mmol) was dissolved in 300 mL of dichloromethane. Under a nitrogen atmosphere, diisobutylaluminum hydride (55 mL, 1.5 mol / L in toluene, 82.70 mmol) was slowly added dropwise at -78 °C. After the addition was complete, the reaction was carried out at -78 °C for 2 hours. Then, 200 mL of saturated NH4Cl aqueous solution was slowly added dropwise at -78 °C, and the mixture was slowly brought back to room temperature with stirring for 20 min. The mixture was then filtered. The filter cake was washed twice with dichloromethane (150 mL × 2), and the filtrate was washed once with saturated NaCl aqueous solution (250 mL). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 19.5 g of the crude 15c product.

[0572] Step 4: Preparation of compound 15e

[0573] Crude product 15d (19.5 g, 41.22 mmol) was dissolved in 150 mL of dichloromethane, and R-tert-butylsulfinamide (5.79 g, 47.78 mmol) and cesium carbonate (6.49 g, 19.91 mmol) were added sequentially. The reaction was carried out at room temperature for 16 hours. 150 mL of water was added, and the aqueous phase was extracted with (150 mL × 2) dichloromethane. The organic phases were combined, washed once with 250 mL of saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography to obtain 15e (14.5 g, yield 61.42%).

[0574] LCMS m / z = 592.1 [M+H] +

[0575] Step 5: Preparation of compound 15f

[0576] 15e (14.5 g, 24.46 mmol) was dissolved in 100 mL of tetrahydrofuran, and cesium fluoride (7.43 g, 48.92 mmol) and trimethylsilyl cyanide (4.85 g, 48.92 mmol) were added sequentially. The mixture was reacted at room temperature for 30 minutes. 150 mL of saturated NaHCO3 aqueous solution was added, and the mixture was extracted twice with ethyl acetate (200 mL × 2). The organic layers were combined, washed once with saturated NaCl aqueous solution (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude 15f, which was used directly for the next step without purification.

[0577] LCMS m / z = 619.1 [M+H] +

[0578] Step 6: Preparation of 15g of compound

[0579] 15f (15g, 24.20mmol) was dissolved in 100mL of anhydrous ethanol, and 60mL of titanium trichloride solution was slowly added. The reaction was carried out at 80℃ for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was adjusted to pH 8 with 300mL of saturated NaHCO3 aqueous solution and diluted with 300mL of ethyl acetate. The mixture was filtered, and the filter cake was washed twice with ethyl acetate (150mL × 2). The organic phases were combined and washed once with saturated NaCl aqueous solution (250mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography to obtain 15g (4.6g, yield 45.72%).

[0580] LCMS m / z = 468.1 [M+H] +

[0581] Step 7: Preparation of compound 15h

[0582] 15 g (4.6 g, 9.81 mmol) was dissolved in 40 mL of 1,4-dioxane, and Xant-PHOS (0.28 g, 0.49 mmol), potassium carbonate (6.78 g, 49.05 mmol), and palladium acetate (0.44 g, 1.96 mmol) were added sequentially. The reaction was carried out at 100 °C for 16 hours under a carbon monoxide atmosphere. After cooling to room temperature, the solution was diluted with 30 mL of ethyl acetate. The organic phase was washed once with water (30 mL) and once with a saturated NaCl aqueous solution (25 mL). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography to obtain 15 h (0.88 g, yield 21.56%).

[0583] LCMS m / z = 416.1 [M+H] +

[0584] Step 8: Preparation of Compound 15i

[0585] 15h (0.4 g, 0.96 mmol) was dissolved in 15 mL of tetrahydrofuran. Under a nitrogen atmosphere, KHMDS (1.92 mL, 1.0 mol / L in THF, 1.92 mmol) was slowly added dropwise at -78 °C for 30 min. Iodomethane (0.2 g, 1.44 mmol) was then slowly added dropwise while maintaining the temperature at -78 °C. After the addition was complete, the temperature was slowly restored to room temperature for 2 h. 25 mL of saturated NH4Cl aqueous solution was added, and the mixture was extracted twice with ethyl acetate (25 mL × 2). The organic phases were combined, washed once with saturated NaCl aqueous solution (25 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography to obtain 15i (0.25 g, yield 60.46%).

[0586] LCMS m / z = 430.1 [M+H] +

[0587] Step 9: Preparation of compound 15j

[0588] 15i (0.15 g, 0.35 mmol) was dissolved in 2 mL of 1,4-dioxane, and then pinacol diboronate (0.13 g, 0.52 mmol), potassium acetate (0.10 g, 1.05 mmol), tricyclohexylphosphine fluoroborate (4 mg, 0.01 mmol), and tris(dibenzylacetone)palladium (32 mg, 0.035 mmol) were added sequentially. The mixture was reacted in a microwave oven at 140 °C for 3.5 h under a nitrogen atmosphere. After cooling to room temperature, the reaction solvent was removed by concentration under reduced pressure. The residue was separated by silica gel column chromatography to give 15j (0.12 g, yield 65.96%).

[0589] LCMS m / z = 522.2.[M+H] +

[0590] Step 10: Preparation of 15k

[0591] 15kJ (50 mg, 0.083 mmol) was dissolved in 2 mL of 1,4-dioxane and 0.2 mL of water. 1f (54 mg, 0.17 mmol), potassium carbonate (23 mg, 0.17 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (14 mg, 0.017 mmol) were added. The reaction was carried out at 100 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with 10 mL of ethyl acetate, washed once with 10 mL of water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography to give 15kJ (44 mg, yield: 82.08%).

[0592] LCMS m / z = 643.3 [M+H] +

[0593] Step 11: Preparation of Compound 15

[0594] 15kJ (44mg, 0.068mmol) was dissolved in 5mL of dichloromethane, and 1mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (preparative conditions: instrument: Waters automated purification system; column: SunFire (19mm × 250mm); sample was dissolved in DMF and filtered through a 0.45μm filter to prepare sample solution; preparative chromatographic conditions: a. mobile phase A, B composition: mobile phase A: acetonitrile; mobile phase B: water (0.1% trifluoroacetic acid); b. gradient elution; c. flow rate 15mL / min). This yielded the trifluoroacetate salt of compound 15 (15mg, yield: 40.38%).

[0595] LCMS m / z = 543.2 [M+H] +

[0596] 1 H NMR(400MHz,CD3OD)δ8.98(s,2H),8.37(dd,1H),7.51–7.40(m,4H),7.37–6.98(m,1H),6.38(d,1H),5.22(d,1H),3.62–3.51(m,1H ),3.46(s,3H),2.99–2.86(m,3H),2.68–2.56(m,2H),2.48–2.23(m,2H),1.90–1.81(m,1H),0.90–0.76(m,2H),0.72–0.60(m,2H).

[0597] Example 16: Preparation of Compound 16

[0598] Step 1: Synthesis of Compound 16b

[0599] Compound 16a (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 a solution of TMSCF2Br (61.6 g, 303.8 mmol) in dichloromethane. 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 16b (28.5 g, 42%).

[0600] LCMS m / z = 446.1 [M+H] +

[0601] Step 4: Synthesis of compound 16c

[0602] 16b (25 g, 56.2 mmol) was dissolved in 112 mL of dichloromethane. A dichloromethane solution of DBU (25.6 g, 168.6 mmol) was added dropwise to the solution under ice bath conditions. The reaction was continued for half an hour. The solution was concentrated and purified by silica gel column chromatography to obtain 16c (6.1 g, 49%).

[0603] LCMS m / z = 224.0 [M+H] +

[0604] Step 5: Synthesis of compound 16d

[0605] 16c (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 mixture was brought to room temperature and allowed to react overnight. The solution was concentrated and purified by silica gel column chromatography to obtain 16d (3.7 g, 27%).

[0606] Step 6: Synthesis of compound 16e

[0607] 16d (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 16e (3.1 g, 93%).

[0608] Step 7: Synthesis of compound 16f

[0609] 16e (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 16f (2.7 g, 86%).

[0610] Step 8: Synthesis of 16g ​​of compound

[0611] 16f (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 16 g (3.6 g, 95%) of compound.

[0612] Step 9: Synthesis of compound 16h

[0613] 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, while the reaction continued at 50 °C for 1 hour. The reaction solution was filtered after cooling to room temperature, and the filtrate was slowly added to a tetrahydrofuran solution containing 16 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 16 h (3.7 g, 83%).

[0614] Step 10: Synthesis of Compound 16i

[0615] Substrate 16i (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 to obtain crude 16i.

[0616] LCMS m / z = 343.9, 346.0 [M+H] +

[0617] Step 11: Synthesis of Compound 16j

[0618] The crude product 16i 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 16j (3.2 g, two-step yield 78%).

[0619] LCMS m / z = 500.8 [M+H] +

[0620] Step 12: Synthesis of compound 16k

[0621] 16kJ (3.2g, 6.4mmol) was dissolved in 25mL of dichloromethane, and a toluene solution of DIBAL-H (1.5M, 4.3mL, 6.4mmol) was added dropwise at -78℃. 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 resulting organic phase was dried and concentrated to obtain the crude product of 16kJ.

[0622] Step 13: Synthesis of Compound 16l

[0623] 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 16 l (2.5 g, 70% yield in two steps).

[0624] Step 14: Synthesis of compound 16m

[0625] 16 μL (2.5 g, 4.5 mmol), cesium fluoride (1.4 g, 9.0 mmol), and 20 mL of 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 16 μL (2.5 g, 94% yield).

[0626] LCMS m / z = 587.0 [M+H] +

[0627] Step 15: Synthesis of Compound 16n

[0628] The crude product 16m 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 resulting organic phase was dried, concentrated, and subjected to silica gel column chromatography to obtain 16n (950 mg, two-step yield 49%).

[0629] LCMS m / z = 436.0 [M+H] +

[0630] Step 16: Synthesis of Compound 16o

[0631] 16n (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 16O (220 mg, 27%).

[0632] LCMS m / z = 382.0 [M+H] +

[0633] Step 17: Synthesis of compound 16p

[0634] 16O (220 mg, 0.58 mmol) was dissolved in 10 mL of tetrahydrofuran. The solution was cooled to -78 °C, and 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. Iodimethane (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, and the organic phase was dried, concentrated, and purified by silica gel column chromatography to obtain 16p (210 mg, 92%).

[0635] Step 18: Synthesis of compound 16q

[0636] 16p (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 16q (220 mg, 86%).

[0637] LCMS m / z = 488.1 [M+H] +

[0638] Step 19: Synthesis of compound 16s

[0639] 16q (20 mg, 0.04 mmol), 1f (22 mg, 0.06 mmol), Pd(dppf)Cl2 (5 mg, 0.006 mmol), potassium carbonate (11 mg, 0.08 mmol), 1 mL dioxane and 0.2 mL water were added to a reaction flask and reacted overnight at 100 °C under a nitrogen atmosphere. The reaction solution was concentrated and purified by silica gel column chromatography to obtain crude compound 16s.

[0640] LCMS m / z = 609.3 [M+H] +

[0641] Step 20: Synthesis of Compound 16

[0642] The crude compound 16 was dissolved in 2 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 1 hour. After concentration, an appropriate amount of ethyl acetate and saturated sodium bicarbonate solution were added and stirred for 2 minutes. After concentration of the organic phase, the crude compound was purified by preparative HPLC to obtain trifluoroacetate salt of compound 16 (3 mg). Preparative HPLC purification was performed (preparative conditions: instrument: Waters automated purification system; column: SunFire (19 mm × 250 mm); 2. The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution; 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: mobile phase A: acetonitrile; mobile phase B: water (0.1% trifluoroacetic acid); b. gradient elution; c. flow rate 15 mL / min).

[0643] LCMS m / z = 509.1 [M+H] +

[0644] 1 H NMR(400MHz,CD3OD)δ9.16(s,2H),7.85(d,1H),7.81(d,1H),7.65(dd,1H),7.29(s,1H),7.14(t,1H),5.94(d,1H), 5.33(d,1H),3.62–3.53(m,1H),3.48(s,3H),2.98(d,1H),2.95–2.86(m,2H),2.65–2.56(m,2H),2.46–2.24(m,2H).

[0645] Example 17: Synthesis of Compound 17

[0646] Step 1: Synthesis of Compound 17B

[0647] 17A (1 g, 4.81 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxapentoboran-2-yl)-1H-pyrazole (2.05 g, 7.22 mmol) were added to a mixed solution of 1,4-dioxane and water (2.5:1, 70 mL), followed by the addition of tetraphenylphosphine palladium (556 mg, 0.481 mmol) and potassium phosphate (3.06 g, 14.43 mmol). The reaction was carried out at 80 °C for 12 hours under a nitrogen atmosphere. The mixture was diluted with water, extracted with ethyl acetate (100 mL × 3), and washed with saturated brine (100 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. After concentration, the residue was separated by silica gel column chromatography to give 17B (1.1 g, yield: 99%).

[0648] LCMS m / z(ESI): 239.0 [M+H] +

[0649] Step 2: Synthesis of Compound 17

[0650] 17B (58 mg, 0.243 mmol) and 4 g (34 mg, 0.081 mmol) were added to a mixed solution of 1,4-dioxane and water (5:1, 3.6 mL). Pd(dppf)Cl2 dichloromethane complex (6.6 mg, 0.0081 mmol) and potassium carbonate (33.5 mg, 0.243 mmol) were added. The mixture was stirred at 100 °C for 12 hours under a nitrogen atmosphere. The mixture was diluted with water, extracted with ethyl acetate (10 mL × 3), and washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by silica gel column chromatography to obtain 17B (25 mg, 69% yield).

[0651] LCMS m / z(ESI): 514.2 [M+H] +

[0652] 1 H NMR(400MHz,CD3OD)δ8.96(s,2H),8.41–8.34(m,1H),8.30(s,1H),8.17(s,1H),7.88–7.82(m,1H),7.77(d,1H),7.60(d, 1H),7.53–7.44(m,2H),7.32(t,1H),6.45(d,1H),5.22(d,1H),3.98(s,3H),3.64–3.54(m,1H),3.48(s,3H),2.91(d,1H).

[0653] Example 18: Synthesis of Compound 18

[0654] Compound 18 (16 mg) was prepared by referring to the synthesis method of compound 17.

[0655] LCMS m / z(ESI): 530.2 [M+H] +

[0656] 1 H NMR (400MHz, CD3OD) δ8.40–8.33(m,1H),8.02(s,1H),7.87(s,1H),7.80–7.75(m,1H),7.68(d,1H),7.49–7. 36(m,6H),7.20(t,1H),6.40(d,1H),5.20(d,1H),3.94(s,3H),3.62–3.52(m,1H),3.48(s,3H),2.89(d,1H).

[0657] Example 19: Synthesis of Compound 19

[0658] Compound 19 (19 mg) was prepared by referring to the synthesis method of compound 17.

[0659] LCMS m / z(ESI): 532.2 [M+H] +

[0660] Example 20: Synthesis of Compound 20

[0661] Compound 20 (23 mg) was prepared by referring to the synthesis method of compound 17.

[0662] LCMS m / z(ESI): 548.2 [M+H] +

[0663] 1 H NMR (400MHz, CD3OD): δ8.41–8.34(s,1H),8.04(s,1H),7.88(s,1H),7.57(d,1H),7.49–7.35(m,6H) ,7.18(t,1H),6.39(d,1H),5.20(d,1H),3.94(s,3H),3.62–3.52(m,1H),3.48(s,3H),2.89(d,1H).

[0664] Example 21: Synthesis of Compound 21

[0665] Compound 21 (25 mg) was prepared by referring to the synthesis method of compound 17.

[0666] LCMS m / z(ESI): 514.2 [M+H] +

[0667] 1 H NMR (400MHz, CD3OD) δ9.04(s,2H),8.41–8.34(m,1H),7.89(s,1H),7.79(d,1H),7.73–7.67(m,1H),7.66–7.60(m,1H),7.54–7. 44(m,2H),7.34(t,1H),7.07–7.00(m,1H),6.47(d,1H),5.22(d,1H),4.01(s,3H),3.66–3.54(m,1H),3.48(s,3H),2.92(d,1H).

[0668] Example 22: Synthesis of Compound 21

[0669] Compound 22 (20 mg) was prepared by referring to the synthesis method of compound 17.

[0670] LCMS m / z(ESI): 554.2 [M+H] +

[0671] 1 H NMR(400MHz,CD3OD)δ8.94(s,2H),8.44–8.34(m,2H),8.17(s,1H),7.87– 7.81(m,1H),7.76(d,1H),7.63–7.56(m,1H),7.53–7.44(m,2H),7.33(t, 1H),6.44(d,1H),5.21(d,1H),4.07(d,2H),3.63–3.53(m,1H),3.48(s,3 H),2.91(d,1H),1.40–1.31(m,1H),0.71–0.63(m,2H),0.49–0.41(m,2H).

[0672] Example 23: Synthesis of Compound 23

[0673] Step 1: Synthesis of 23B

[0674] 23A (0.6 g, 2.88 mmol) and 4-bromo-2-fluorophenol (0.83 g, 4.32 mmol) were added to a mixed solution of 1,4-dioxane and water (5:1, 20 mL). Pd(dppf)Cl2 (0.33 g, 0.29 mmol) and potassium carbonate (1.2 g, 8.64 mmol) were added. The mixture was stirred at 100 °C for 12 hours under a nitrogen atmosphere. The reaction solution was diluted with water, extracted with ethyl acetate (100 mL × 3), and the organic phase was washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. After concentration, the residue was separated by silica gel column chromatography to obtain 23B (0.4 g, yield: 72%).

[0675] Ms m / z(ESI):193.1[M+H] +

[0676] Step 2: Synthesis of compound 23C

[0677] 23B (0.4 g, 2.08 mmol), DMAP (51 mg, 0.42 mmol), and triethylamine (0.42 g, 4.16 mmol) were dissolved in 10 mL of ultra-dry dichloromethane, and the system was stirred in an ice bath for 5 min. PhN(Tf)₂ (1.11 g, 3.12 mmol) was added, and the mixture was slowly heated to room temperature. The reaction was quenched with saturated sodium bicarbonate, extracted with dichloromethane (50 mL × 3), and the organic phase was washed with saturated brine (100 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by silica gel column chromatography to obtain 23C (0.46 g, yield: 68%).

[0678] Ms m / z(ESI): 325.1 [M+H] +

[0679] Step 3: Synthesis of Compound 23

[0680] Compound 23 (65 mg, 0.20 mmol) and 4 g (50 mg, 0.10 mmol) were added to a mixed solution of 1,4-dioxane and water (5:1, 3.6 mL). Pd(dppf)Cl2 dichloromethane complex (8.2 mg, 0.01 mmol) and potassium carbonate (28 mg, 0.2 mmol) were added, and the mixture was stirred at 100 °C for 12 hours under a nitrogen atmosphere. The reaction solution was diluted with water, extracted with ethyl acetate (10 mL × 3), and the organic phase was washed with saturated brine (10 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by silica gel column chromatography to give compound 23 (26 mg, 47% yield).

[0681] Ms m / z(ESI): 530.3 [M+H] +

[0682] 1 H NMR (400MHz, CD3OD) δ8.41–8.34(m,1H),7.82–7.78(m,1H),7.72–7.67(m,1H),7.67–7.57(m,3H),7.53–7.41(m,4 H),7.21(t,1H),6.68(d,1H),6.42(d,1H),5.20(d,1H),3.95(s,3H),3.62–3.53(m,1H),3.49(s,3H),2.89(d,1H).

[0683] Example 24: Synthesis of Compound 24

[0684] Compound 24 (28 mg, 47% yield) was prepared by referring to the synthesis method of compound 23.

[0685] LCMS m / z(ESI): 570.2 [M+H] +

[0686] 1 H NMR (400MHz, CD3OD) δ8.41–8.34(m,1H),8.12(s,1H),7.89(s,1H),7.80–7.76(m,1H),7.68(d,1H),7.49–7.40(m,6H),7.21(t,1H),6.41 (d,1H),5.20(d,1H),4.04(d,2H),3.62–3.53(m,1H),3.48(s,3H),2.89(d,1H),1.41–1.26(m,1H),0.69–0.61(m,2H),0.47–0.40(m,2H).

[0687] Example 25: Synthesis of Compound 25

[0688] Compound 25 (14 mg) was prepared using the same synthetic method as compound 17.

[0689] LCMS m / z(ESI): 570.2 [M+H] +

[0690] 1H NMR(400MHz,DMSO-d6)δ9.02(s,2H),8.49(s,1H),8.31–8.23(m,1H),8.14(s,1H),7.90–7.61(m,4H),7.54–7.46(m,2H),6.32(d,1H), 5.25(d,1H),5.17–5.08(m,1H),4.07–3.93(m,3H),3.90–3.81(m,1H),3.58–3.47(m,1H),3.36(s,3H),2.84(d,1H),2.47–2.30(m,2H).

[0691] Example 26: Synthesis of Compound 26

[0692] Compound 26 (19 mg) was prepared by referring to the synthetic method of compound 17.

[0693] LCMS m / z(ESI): 558.2 [M+H] +

[0694] 1 H NMR(400MHz,DMSO-d6)δ9.01(s,2H),8.42(s,1H),8.31–8.24(m,1H),8.10(s,1H),7.90–7.60(m,4H),7.54–7.46(m,2H),6 .32(d,1H),5.25(d,1H),4.39–4.31(m,2H),3.79–3.71(m,2H),3.57–3.48(m,1H),3.36(s,3H),3.27(s,3H),2.84(d,1H).

[0695] Example 27: Synthesis of Compound 27

[0696] Step 1: Synthesis of Compound 27B

[0697] 27A (912 mg, 3.45 mmol) and 4-bromo-2-fluorophenol (600 mg, 3.14 mmol) were added to a mixed solution of 1,4-dioxane and water (2.5:1, 40 mL). Pd(dppf)Cl2 (256 mg, 0.314 mmol) and potassium carbonate (1.3 g, 9.42 mmol) were added, and the mixture was stirred at 100 °C for 12 hours under a nitrogen atmosphere. The reaction solution was diluted with water, extracted with ethyl acetate (100 mL × 3), and the organic phase was washed with saturated brine (100 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by silica gel column chromatography to obtain 27B (0.5 g, yield: 64%).

[0698] LCMS m / z(ESI): 249.1 [M+H] +

[0699] Step 2: Synthesis of compound 27C

[0700] 27B (500 mg, 2.0 mmol), DMAP (49 mg, 0.4 mmol), and triethylamine (0.6 mL, 4.0 mmol) were dissolved in 10 mL of dry dichloromethane, and the mixture was stirred in an ice bath for 5 min. PhN(Tf)₂ (1.1 g, 3.0 mmol) was added, and the mixture was slowly heated to room temperature. The reaction was quenched with saturated sodium bicarbonate, extracted with ethyl acetate (100 mL × 3), and the organic phase was washed with saturated brine (100 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by silica gel column chromatography to obtain 27C (681 mg, yield: 89%).

[0701] LCMS m / z(ESI): 381.1 [M+H] +

[0702] Step 3: Synthesis of Compound 27

[0703] 27C (114 mg, 0.3 mmol) and 4 g (34 mg, 0.081 mmol) were added to a mixed solution of 1,4-dioxane and water (5:1, 3.6 mL). Pd(dppf)Cl₂ dichloromethane complex (6.6 mg, 0.0081 mmol) and potassium carbonate (33.5 mg, 0.243 mmol) were added, and the mixture was stirred at 100 °C for 12 hours under a nitrogen atmosphere. The reaction solution was diluted with water, extracted with ethyl acetate (10 mL × 3), and the organic phase was washed with saturated brine (10 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by silica gel column chromatography to obtain 27C (23 mg, 55% yield).

[0704] LCMS m / z(ESI): 586.2 [M+H] +

[0705] 1H NMR(400MHz,DMSO-d6)δ8.38(s,1H),8.31–8.25(m,1H),8.03(s,1H),7.76–7. 65(m,2H),7.64–7.55(m,2H),7.53–7.44(m,4H),7.43–7.36(m,1H),6.27(d,1H ),5.24(d,1H),5.07–4.99(m,1H),4.06–3.98(m,2H),3.98–3.91(m,1H),3.89 –3.81(m,1H),3.58–3.47(m,1H),3.36(s,3H),2.82(d,1H),2.47–2.30(m,2H).

[0706] Example 28: Synthesis of Compound 28

[0707] Compound 28 (20 mg) was prepared by referring to the synthetic method of compound 27.

[0708] LCMS m / z(ESI): 574.2 [M+H] +

[0709] 1 H NMR (400MHz, DMSO-d6) δ8.32–8.25(m,2H),8.01(s,1H),7.77–7.65(m,2H),7.60–7.44(m,6H),7.42–7.36(m,1H) ,6.27(d,1H),5.24(d,1H),4.28(t,2H),3.73(t,2H),3.58–3.48(m,1H),3.36(s,3H),3.26(s,3H),2.82(d,1H).

[0710] Example 29: Synthesis of Compound 29

[0711] Step 1: Preparation of Compound 29

[0712] 15 J (65 mg, 0.12 mmol) was dissolved in 2 mL of 1,4-dioxane and 0.2 mL of water. 17B (43 mg, 0.18 mmol), potassium carbonate (50 mg, 0.36 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (20 mg, 0.024 mmol) were added. The reaction was carried out at 100 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with 10 mL of ethyl acetate and washed once with 10 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to give compound 29 (15 mg, yield: 21.73%). (Preparation method: 1. Instrument: Waters 2767 preparative liquid chromatograph; column: SUNFIRE@Prep C18 (19mm×250mm). 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 50mM ammonium bicarbonate); b. Gradient elution, with mobile phase A content ranging from 25% to 70%; c. Flow rate: 12mL / min; d. Elution time: 15min.)

[0713] LCMS m / z = 554.3 [M+H] +

[0714] 1 H NMR(400MHz,CD3OD)δ8.80(s,2H),8.39–8.33(m,1H),8.32(s,1H),8.18(s,1H),7.50–7.42(m,4H),7.20(t,1H),6.38(d,1H),5 .20(d,1H),3.99(s,3H),3.60–3.51(m,1H),3.47(s,3H),2.88(d,1H),1.95–1.85(m,1H),0.93–0.80(m,2H),0.72–0.60(m,2H).

[0715] Example 30: Preparation of compound 30

[0716] Step 1: Synthesis of compound 30b

[0717] Compound 30a (11 g, 44 mmol), EDCI (8.4 g, 44 mmol), HOBt (6.0 g, 44 mmol), ethanol (4.0 g, 88 mmol), and 60 mL of dichloromethane were added to an anti-reverse flask, and NMI (7.2 g, 88 mmol) was added. The reaction was carried out at room temperature for 4 hours, and the reaction was quenched with water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and subjected to silica gel column chromatography to obtain compound 30b (11.8 g, 97%).

[0718] Step 2: Synthesis of compound 30c

[0719] Sodium hydride (60% w / w, 3.7 g, 93.3 mmol) and 80 mL of DMA were added sequentially to the reaction flask. After the temperature dropped to 0 °C, a DMA solution containing substrate 30b (11.8 g, 42.4 mmol) and 1,3-dibromopropane (9.4 g, 46.7 mmol) was added dropwise. The reaction was allowed to return to room temperature and continue for 1 hour. The reaction was quenched with saturated ammonium chloride solution. The mixture was extracted twice with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography to obtain compound 30c (5.6 g, 42%).

[0720] Step 3: Synthesis of compound 30d

[0721] Compound 30d (8 g, 25.2 mmol) was dissolved in 50 mL of methanol, and lithium hydroxide (3.0 g, 125.8 mmol) and 10 mL of water were added. The mixture was reacted at 60 °C for 1 hour. 2N hydrochloric acid was slowly added until the pH reached approximately 3. After concentration, an appropriate amount of water was added, and the mixture was extracted twice with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product of compound 30d.

[0722] Step 4: Synthesis of compound 30e

[0723] The crude compound 30e was dissolved in 50 mL of dioxane, and diphenyl azidophosphate (9 g, 32.8 mmol) and triethylamine (3.3 g, 32.8 mmol) were added. The mixture was reacted at room temperature for three hours. The reaction solution was concentrated, and an appropriate amount of water was added. The mixture was extracted twice with dichloromethane, and the organic phase was concentrated. Hydrochloric acid (2N, 25 mL) and an appropriate amount of water were added to the residue, and the mixture was reacted overnight at 60 °C. Saturated sodium bicarbonate solution was added until the pH was weakly alkaline, and the mixture was extracted twice with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude compound 30e.

[0724] Step 5: Synthesis of compound 30f

[0725] The crude product of 30e was dissolved in 50 mL of tetrahydrofuran, and di-tert-butyl dicarbonate (11 g, 50.4 mmol) and DIPEA (3.3 g, 25.2 mmol) were added. The reaction was carried out at room temperature for four hours. The reaction solution was directly concentrated and subjected to silica gel column chromatography to give compound 30f (6.0 g, 66% yield in three steps).

[0726] Step 6: Synthesis of 30g of compound

[0727] 30f (270 mg, 0.75 mmol), Pd(PPh3)4 (87 mg, 0.075 mmol), ZnCN2 (44 mg, 0.375 mmol) and 2 mL DMF were added to a microwave tube and the reaction was carried out at 120 °C for half an hour. The reaction solution was concentrated and silica gel column chromatography was used to obtain 30 g (195 mg, 85%) of the compound.

[0728] LCMS m / z = 307.1 [M+H] +

[0729] Step 7: Synthesis of Compound 30i

[0730] 30 g (31 mg, 0.1 mmol), 4 g (48 mg, 0.1 mmol), Pd2dba3 (4.6 mg, 0.005 mmol), PCy3.HBF4 (3.7 mg, 0.012 mmol), potassium phosphate (53 mg, 0.25 mmol), 2 mL dioxane, and 0.2 mL water were added to a reaction flask and reacted overnight at 100 °C under a nitrogen atmosphere. The reaction solution was concentrated and purified by silica gel column chromatography to obtain compound 30i (46 mg, 74%).

[0731] LCMS m / z = 626.3 [M+H] +

[0732] Step 8: Synthesis of Compound 30

[0733] Compound 30 (46 mg, 0.073 mmol) was dissolved in 2 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 1 hour. After concentration, an appropriate amount of ethyl acetate and saturated sodium bicarbonate solution was added and stirred for 2 minutes. The organic phase was concentrated and subjected to silica gel column chromatography to obtain compound 30 (22 mg, 58%).

[0734] LCMS m / z = 526.2 [M+H] +

[0735] 1 H NMR (400MHz, CD3OD) δ8.41–8.34(m,1H),7.93–7.89(m,1H),7.85–7.79(m,2H),7.75(d,1H),7.59(d,1H),7.48–7.41(m,3H),7.24(t,1H),6.44 (d,1H),5.22(d,1H),3.63–3.54(m,1H),3.49(s,3H),2.90(d,1H),2.66 –2.55(m,2H),2.38–2.27(m,2H),2.22–2.08(m,1H),1.89–1.76(m,1H).

[0736] Example 31: Preparation of compound 31

[0737] Step 1: Synthesis of compound 31b

[0738] Compound 30f (542 mg, 1.5 mmol), 31a (468 mg, 2.25 mmol), Pd(dppf)Cl2 (110 mg, 0.15 mmol), potassium carbonate (414 mg, 3 mmol), 5 mL of dioxane, and 1 mL of water were added to a reaction flask and reacted overnight at 100 °C under a nitrogen atmosphere. The reaction solution was directly concentrated and purified by silica gel column chromatography to give compound 31b (420 mg, 78%).

[0739] Step 2: Synthesis of compound 31c

[0740] Compound 31b (73 mg, 0.2 mmol), pinacol diboronate (77 mg, 0.3 mmol), Pd2dba3 (10 mg, 0.01 mmol), PCy3.HBF4 (6.2 mg, 0.02 mmol), potassium acetate (59 mg, 0.6 mmol), and 2 mL of dioxane were added to a 10 mL microwave-safe tube and reacted at 140 °C for 4 hours under a nitrogen atmosphere. The reaction solution was directly concentrated and purified by silica gel column chromatography to obtain crude compound 31c.

[0741] LCMS m / z = 454.3 [M+H] +

[0742] Step 3: Synthesis of compound 31e

[0743] The crude product 31c, 4 g (47 mg, 0.12 mmol), Pd2dba3 (5.5 mg, 0.006 mmol), PCy3.HBF4 (3.7 mg, 0.012 mmol), potassium phosphate (64 mg, 0.3 mmol), 2 mL of dioxane, and 0.2 mL of water were added to a reaction flask and reacted overnight at 100 °C under a nitrogen atmosphere. The reaction solution was directly concentrated and purified by silica gel column chromatography to obtain compound 31e (20 mg, 15% yield in two steps).

[0744] LCMS m / z = 681.2[M+H] +

[0745] Step 4: Synthesis of Compound 31

[0746] Compound 31e (20 mg, 0.030 mmol) was dissolved in 2 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 1 hour. After concentration, an appropriate amount of ethyl acetate and saturated sodium bicarbonate solution were added and stirred for 2 minutes. The organic phase was concentrated and subjected to silica gel column chromatography to obtain compound 31 (10 mg, 57%).

[0747] LCMS m / z = 581.3 [M+H] +

[0748] 1 H NMR(400MHz,CD3OD)δ8.38(d,1H),7.61(d,1H),7.56–7.52(m,1H),7.48(t,1 H),7.44–7.35(m,3H),7.30(d,1H),7.18–7.13(m,1H),7.08(s,1H),7.01(t, 1H),6.97(s,1H),6.27(d,1H),5.18(d,1H),3.58–3.44(m,7H),2.85(d,1H), 2.72–2.60(m,2H),2.37–2.25(m,2H),2.19–2.05(m,1H),1.88–1.76(m,1H).

[0749] Example 32: Preparation of compound 32

[0750] 17B (24 mg, 0.1 mmol), 16q (49 mg, 0.1 mmol), Pd(dppf)Cl2 (7.4 mg, 0.01 mmol), potassium carbonate (27 mg, 0.2 mmol), 2 mL dioxane, and 0.2 mL water were added to a reaction flask and reacted overnight at 100 °C under a nitrogen atmosphere. The reaction solution was directly concentrated, purified by silica gel column chromatography, and preparative HPLC to obtain trifluoroacetate of compound 32 (10 mg, 14%). (Preparation method: 1. Instrument: Waters 2767 preparative liquid chromatograph; column: SUNFIRE@Prep C18 (19mm×250mm). 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% trifluoroacetic acid). b. Gradient elution, with mobile phase A content ranging from 25% to 50%. c. Flow rate: 12mL / min. d. Elution time: 15min.)

[0751] LCMS m / z = 520.1 [M+H] +

[0752] 1H NMR (400MHz, CD3OD) δ8.99(s,2H),8.32(s,1H),8.17(s,1H),7.85–7.81(m,1H),7.79(d,1H),7.60(s,1H),7. 31(s,1H),7.17(t,1H),5.95(d,1H),5.32(d,1H),3.98(s,3H),3.62–3.53(m,1H),3.48(m,3H),2.97(d,1H).

[0753] Example 33: Preparation of compound 33

[0754] Step 1: Synthesis of compound 33c

[0755] Compound 33a (955 mg, 5 mmol), 33b (1.04 g, 5 mmol), Pd(dppf)Cl2 (366 mg, 0.5 mmol), potassium carbonate (1.38 g, 10 mmol), 10 mL of dioxane, and 1 mL of water were added to a reaction flask and reacted overnight at 100 °C under a nitrogen atmosphere. The reaction solution was directly concentrated and subjected to silica gel column chromatography to give compound 33c (210 mg, 22%).

[0756] Step 2: Synthesis of compound 33d

[0757] Compound 33c (210 mg, 1.1 mmol), DMAP (27 mg, 0.22 mmol), and triethylamine (224 mg, 2.2 mmol) were dissolved in 5 mL of dichloromethane. Trifluoromethanesulfonic anhydride (621 mg, 2.2 mmol) was slowly added at 0 °C, and the reaction was allowed to proceed overnight at room temperature. The reaction solution was directly concentrated and subjected to silica gel column chromatography to give compound 33d (320 mg, 90%).

[0758] Step 3: Synthesis of Compound 33

[0759] Compound 33 (33 mg, 0.1 mmol), 16q (48 mg, 0.1 mmol), Pd(dppf)Cl2 (8 mg, 0.01 mmol), potassium carbonate (27 g, 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 under a nitrogen atmosphere. The reaction solution was directly concentrated and purified by silica gel column chromatography to obtain compound 33 (15 mg, 28%).

[0760] LCMS m / z = 536.1 [M+H] +

[0761] 1H NMR(400MHz,CD3OD)δ8.03(s,1H),7.88(s,1H),7.73–7.66(m,2H),7.52–7.37(m,4H),7.28(s,1H) ,7.06(s,1H),5.88(d,1H),5.29(d,1H),3.94(s,3H),3.61–3.50(m,1H),3.48(s,3H),2.95(d,1H).

[0762] Example 34: Preparation of compound 34

[0763] Step 1: Synthesis of compound 34c

[0764] Compounds 34a (570 mg, 2 mmol), 34b (488 mg, 2 mmol), Pd(dppf)Cl2 (146 mg, 0.2 mmol), potassium carbonate (552 mg, 4 mmol), 6 mL of dioxane, and 0.6 mL of water were added to a reaction flask and reacted overnight at 80 °C under a nitrogen atmosphere. The reaction solution was directly concentrated and subjected to silica gel column chromatography to obtain compound 34c (380 mg, 70%).

[0765] LCMS m / z = 275.0 277.0 [M+H] +

[0766] Step 2: Synthesis of Compound 34

[0767] Compound 34 (42 mg, 0.15 mmol), 4 g (48 mg, 0.1 mmol), Pd(dppf)Cl2 (8 mg, 0.01 mmol), potassium carbonate (27 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 under a nitrogen atmosphere. The reaction solution was directly concentrated and subjected to silica gel column chromatography to give compound 34 (22 mg, 40%).

[0768] LCMS m / z = 550.3 [M+H] +

[0769] 1H NMR(400MHz,CD3OD)δ9.02(s,2H),8.74(s,1H),8.41–8.34(m,2H),7.90–7.86(m,1H),7.78(d,1H),7.65–7.60(m,1H) ,7.58(t,1H),7.51–7.44(m,2H),7.33(t,1H),6.46(d,1H),5.22(d,1H),3.63–3.54(m,1H),3.49(s,3H),2.92(d,1H).

[0770] Example 35: Preparation of compound 35

[0771] Step 1: Synthesis of compound 35b

[0772] Compounds 34a (570 mg, 2 mmol), 35a (468 mg, 2 mmol), Pd(dppf)Cl2 (146 mg, 0.2 mmol), potassium carbonate (552 mg, 4 mmol), 6 mL of dioxane, and 0.6 mL of water were added to a reaction flask and reacted overnight at 80 °C under a nitrogen atmosphere. The reaction solution was directly concentrated and subjected to silica gel column chromatography to give compound 35b (270 mg, 51%).

[0773] Step 2: Synthesis of Compound 35

[0774] Compound 35b (40 mg, 0.15 mmol), 4 g (48 mg, 0.1 mmol), Pd(dppf)Cl2 (8 mg, 0.01 mmol), potassium carbonate (27 mg, 0.2 mmol), 2 mL dioxane, and 0.2 mL water were added to a reaction flask and reacted overnight at 100 °C under a nitrogen atmosphere. The reaction solution was directly concentrated and subjected to silica gel column chromatography to give compound 35 (18 mg, 33%).

[0775] LCMS m / z = 540.2 [M+H] +

[0776] 1 H NMR(400MHz,CD3OD)δ8.95(s,2H),8.40–8.35(m,2H),8.15(s,1H),7.86–7.83(m,1H),7.77(d,1H),7.59(dd,1H),7.52–7.45(m, 2H),7.32(t,1H),6.45(d,1H),5.21(d,1H),3.79–3.71(m,1H),3.63–3.53(m,1H),3.48(s,3H),2.91(d,1H),1.20–1.06(m,4H).

[0777] Example 36: Preparation of compound 36

[0778] Step 1: Synthesis of compound 36b

[0779] Compound 34a (570 mg, 2 mmol), 36a (552 mg, 2 mmol), Pd(dppf)Cl2 (146 mg, 0.2 mmol), potassium carbonate (552 mg, 4 mmol), 6 mL of dioxane, and 0.6 mL of water were added to a reaction flask and reacted overnight at 80 °C under a nitrogen atmosphere. The reaction solution was directly concentrated and subjected to silica gel column chromatography to obtain compound 36b (390 mg, 64%).

[0780] LCMS m / z = 307.0 308.9 [M+H] +

[0781] Step 2: Synthesis of Compound 36

[0782] Compound 36 (47 mg, 0.15 mmol), 30 h (48 mg, 0.1 mmol), Pd(dppf)Cl2 (8 mg, 0.01 mmol), potassium carbonate (27 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 under a nitrogen atmosphere. The reaction solution was directly concentrated and subjected to silica gel column chromatography to give compound 36 (25 mg, 43%).

[0783] LCMS m / z = 582.1 [M+H] +

[0784] 1 H NMR(400MHz,CD3OD)δ8.99(s,2H),8.48(s,1H),8.37(dd,1H),8.27(s,1H),7.87(d,1H),7.78(d,1H),7.62(dd,1H), 7.52–7.45(m,2H),7.33(t,1H),6.46(d,1H),5.22(d,1H),5.05(q,2H),3.64–3.54(m,1H),3.48(s,3H),2.92(d,1H).

[0785] Example 37: Preparation of compound 37

[0786] Step 1: Synthesis of compound 37b

[0787] Compound 37a (500 mg, 5.55 mmol) and triethylamine (1.40 g, 13.88 mmol) were dissolved in 5 mL of dichloromethane. Methylsulfonyl chloride (759.2 mg, 6.66 mmol) was slowly added at 0 °C, and the reaction was allowed to proceed overnight at room temperature. The reaction solution was directly concentrated and subjected to silica gel column chromatography to give compound 37b (800 mg, 85.71%).

[0788] Step 2: Synthesis of compound 37c

[0789] Compound 37b (600 mg, 4.69 mmol), 4-bromopyrazole (689 mg, 4.69 mmol), and potassium carbonate (1.30 g, 9.38 mmol) were dissolved in acetonitrile and reacted overnight at 80 °C. The reaction solution was directly concentrated and subjected to silica gel column chromatography to give compound 37c (600 mg, 77.42%).

[0790] LCMS m / z = 219.0 [M+H] +

[0791] Step 3: Synthesis of compound 37d

[0792] Compound 37c (300 mg, 1.37 mmol), pinacol diboronate (522 mg, 2.05 mmol), Pd(dppf)Cl2 (102 mg, 0.14 mmol), potassium acetate (403 mg, 4.11 mmol), and 10 mL of dioxane were added to a reaction flask and reacted overnight at 90 °C under a nitrogen atmosphere. The reaction solution was directly concentrated and subjected to silica gel column chromatography to obtain compound 37d (160 mg, 43.90%).

[0793] LCMS m / z = 267.1 [M+H] +

[0794] Step 4: Synthesis of compound 37e

[0795] Compound 34a (171 mg, 0.60 mmol), 37d (160 mg, 0.60 mmol), Pd(dppf)Cl2 (44 mg, 0.06 mmol), potassium carbonate (207 mg, 1.50 mmol), 6 mL of dioxane, and 0.6 mL of water were added to a reaction flask and reacted overnight at 100 °C under a nitrogen atmosphere. The reaction solution was directly concentrated and subjected to silica gel column chromatography to give compound 37e (160 mg, 89.56%).

[0796] LCMS m / z = 297.0 [M+H] +

[0797] Step 5: Synthesis of Compound 37

[0798] Compound 37e (45 mg, 0.15 mmol), 4 g (48 mg, 0.1 mmol), Pd(dppf)Cl2 (8 mg, 0.01 mmol), potassium carbonate (27 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 under a nitrogen atmosphere. The reaction solution was directly concentrated and subjected to silica gel column chromatography to give compound 37 (10 mg, 17.58%).

[0799] LCMS m / z = 572.2 [M+H] +

[0800] Example 38: Preparation of compound 38

[0801] Compound 38 (10 mg) was prepared by referring to steps four and five of the synthesis of compound 37.

[0802] LCMS m / z = 588.2 [M+H] + .

[0803] Example 39: Preparation of compound 39

[0804] Step 1: Synthesis of compound 39b

[0805] 39a (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 39b (26.8 g, 98.3%).

[0806] Step 2: Synthesis of compound 39c

[0807] Substrate 39b (5.45 g, 20 mmol) and hydrochloric acid (6 N, 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 obtain compound 39c (3.45 g, 67%).

[0808] Step 3: Synthesis of compound 39d

[0809] Substrate 39c (3.45 g, 13.4 mmol) was dissolved in 40 mL of tetrahydrofuran. Under dry ice and ethanol bath conditions, LDA (2 M, 7.4 mL, 14.7 mmol) was added dropwise 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 over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product of the target compound 39d.

[0810] Step 4: Synthesis of compound 39e

[0811] The crude product of compound 39d 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 39e (3.0 g, two-step yield 78%).

[0812] 1 H NMR (400MHz, CDCl3) δ7.56(dd,1H),7.33–7.28(m,1H),7.24(t,1H),4.87(s,2H).

[0813] Steps 5 to 16: Synthesis of compound 39q

[0814] Following the synthetic route from steps five to sixteen in Example 16, intermediate 39q (1.2g) was obtained using 39e as a substrate.

[0815] Step 17: Preparation of Compound 39r

[0816] Compound 39q (52 mg, 0.1 mmol), compound 1f (33 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 39r (42 mg, 66%).

[0817] LCMS m / z = 637.3 [M+H] +

[0818] Step 18: Preparation of Compound 39

[0819] 2 mL of dichloromethane and 2 mL of trifluoroacetic acid were added to compound 39r (40 mg, 0.062 mmol), and the mixture was stirred at room temperature for 3 hours. The resulting reaction solution was concentrated and then dissolved again in 10 mL of dichloromethane. The solution was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was purified by preparative HPLC to obtain compound 39 (12 mg, 37%). (Preparation method: 1. Instrument: Waters 2767 preparative HPLC; Column: SUNFIRE@Prep C18 (19 mm × 250 mm). 2. The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 50 mM ammonium bicarbonate); b. Gradient elution, with mobile phase A content ranging from 25% to 70%; c. Flow rate: 12 mL / min; d. Elution time: 15 min.)

[0820] 1 H NMR(400MHz,CD3OD)δ9.02(s,2H),8.51(d,1H),7.79(d,1H),7.75(d,1H),7.70–7.65(m,1H),7.61(dd,1H),7.53(dd,1H),6.3 8(d,1H),5.26(d,1H),3.68–3.58(m,1H),3.49(s,3H),2.97(d,1H),2.84–2.73(m,2H),2.34–2.23(m,2H),2.18–1.97(m,2H).

[0821] LCMS m / z = 537.2 [M+H] +

[0822] Example 40: Preparation of Compound 40

[0823] Step 1: Preparation of compound 40c

[0824] 40a (1.76 g, 5 mmol) was dissolved in 50 mL of dichloromethane. Under dry ice-ethanol bath conditions, n-butyllithium (2.5 M, 2 mL, 5 mmol) was added dropwise. After reacting for 1 hour, a dichloromethane solution of 40b (545 mg, 5 mmol) was added dropwise. Once the addition was complete, the reaction was allowed to proceed overnight at room temperature. The reaction was quenched with a suitable amount of saturated ammonium chloride solution. The reaction mixture was diluted with dichloromethane, washed with saturated brine, concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain crude 40c. This crude product was purified by SFC to separate compounds 40c-P1 (235 mg, yield: 14.02%; analytical retention time: Rt = 0.774 min) and 40c-P2 (796 mg, yield: 47.49%; analytical retention time: Rt = 1.037 min).

[0825] Chiral analysis method: 1. Instrument: CAS-05-ANA-SFC-D; Column: IG column; 3. Preparative chromatographic conditions: a. Composition of mobile phase A and B: Mobile phase A: CO2; Mobile phase B: Isopropanol containing 0.05% M NH3 b. Flow rate: 3 mL / min, Column temperature: 35℃; Detection wavelength: 220 nm.

[0826] Preparation method: 1. Instrument: CAS-05-Prep-SFC-E; Column: IG column; 2. The sample was dissolved in acetonitrile and methanol to a concentration of 40 mg / mL, and filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: CO2; Mobile phase B: Isopropanol containing 0.1% ammonia; b. Flow rate: 100 mL / min

[0827] 40c-P1: 1 H NMR (400MHz, DMSO-d6) δ7.91(d,1H),7.87(d,1H),7.71(dd,1H),6.15(s,1H),3.08–3.00(m,2H),2.49–2.43(m,2H),1.67(s,3H).

[0828] 40c-P2: 1 H NMR (400MHz, DMSO-d6) δ7.87(d,1H),7.79(d,1H),7.65(dd,1H),6.14(s,1H),2.75–2.68(m,2H),2.65–2.59(m,2H),1.48(s,3H).

[0829] Step 2: Preparation of Compound 40

[0830] Compound 40c-P1 (51 mg, 0.15 mmol), compound 40d (73 mg, 0.15 mmol), Pd(dppf)Cl2 (11 mg, 0.015 mmol), potassium carbonate (42 mg, 0.3 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 obtain a crude product, which was then lyophilized to obtain compound 40 (39 mg, 43%).

[0831] Preparation method: 1. Instrument: Waters AutoP; Column: SunFire@Prep C18 (19mm×250mm); 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (5mM ammonium acetate); b. Gradient elution, with mobile phase A content ranging from 10-70%; c. Flow rate: 15ml / min; d. Elution time: 20min.

[0832] LCMS m / z = 612.2[M+H] +

[0833] 1 H NMR(400MHz,CD3OD)δ8.38(dd,1H),7.93(d,1H),7.79(dd,1H),7.66(d,1H),7.54(s,1H),7.49–7.38(m,3H),7.29–6.8 9(m,2H),6.38(d,1H),5.20(d,1H),3.62–3.53(m,1H),3.20–3.12(m,2H),2.89(d,1H),2.61–2.53(m,2H),1.76(s,3H).

[0834] Example 41: Preparation of compound 41

[0835] Compound 40c-P2 (51 mg, 0.15 mmol), compound 40d (73 mg, 0.15 mmol), Pd(dppf)Cl2 (11 mg, 0.015 mmol), potassium carbonate (42 mg, 0.3 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 obtain a crude product, which was then lyophilized to obtain compound 41 (45 mg, 50%).

[0836] Preparation method: 1. Instrument: Waters AutoP; Column: SunFire@Prep C18 (19mm×250mm); 2. Dissolve the sample in DMF and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (5mM ammonium acetate); b. Gradient elution, with mobile phase A content ranging from 10-70%; c. Flow rate: 15ml / min; d. Elution time: 20min.

[0837] LCMS m / z = 612.2[M+H] +

[0838] 1 H NMR(400MHz,CD3OD)δ8.38(dd,1H),7.84(d,1H),7.69(dd,1H),7.65(d,1H),7.52(s,1H),7.49–7.41(m,2H),7.38(d,1 H),7.28–6.88(m,2H),6.37(d,1H),5.20(d,1H),3.62–3.53(m,1H),2.94–2.85(m,3H),2.80–2.72(m,2H),1.55(s,3H).

[0839] Example 42: Preparation of compound 42

[0840] Compound 42 (17 mg) was obtained by referring to steps 15 to 18 of the synthesis of compound 39.

[0841] LCMS m / z = 540.1 [M+H] +

[0842] 1 H NMR(400MHz,CD3OD)δ9.12(s,2H),8.52(d,1H),7.82(d,1H),7.78(d,1H),7.69–7.61(m,2H),7.54(t,1H),6.39 (d,1H),5.27(d,1H),3.70–3.59(m,1H),2.98(d,1H),2.96–2.86(m,2H),2.67–2.55(m,2H),2.46–2.23(m,2H).

[0843] Example 43: Synthesis of Compound 43

[0844] Step 1: Synthesis of 43b

[0845] 43a (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 43b (28.5 g, 42%).

[0846] LCMS m / z = 250.9[M+H] +

[0847] Step 2: Synthesis of 43c

[0848] 43b (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 43c (7.3 g, 78%).

[0849] Step 3: 43D Synthesis

[0850] 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 a tetrahydrofuran solution containing 43c (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 43d (7.3 g, 80%).

[0851] Step 4: Synthesis of 43e

[0852] 43d (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 43e hydrochloride.

[0853] LCMS m / z = 356[M+H] +

[0854] Step 5: Synthesis of 43f

[0855] In the previous step, crude 43e hydrochloride (5.6 g, 15.81 mmol) was reacted with 4-chloro-2-fluoronitrobenzene (3.33 g, 18.97 mmol), potassium carbonate (10.93 g, 79.05 mmol), and 80 mL of acetonitrile, and reacted overnight at 80 °C. The reaction solution was directly concentrated and subjected to silica gel column chromatography to give 43f (3.5 g, two-step yield 43.4%).

[0856] LCMS m / z = 510.8 [M+H] +

[0857] Step 6: Synthesis of 43g

[0858] 43f (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. After filtration and washing, the organic phase obtained from the reaction solution was dried and concentrated to obtain 43 g of crude product.

[0859] Steps 7-14: Synthesis of compound 43:

[0860] Following the synthesis steps four through eleven of Example 15, 21 mg of trifluoroacetate of compound 43 was obtained.

[0861] (Preparation conditions: Instrument: Waters automated purification system; Column: SunFire (19mm×250mm); 2. Dissolve the sample in DMF and filter with a 0.45μm filter to prepare the sample solution; 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (0.1% trifluoroacetic acid); b. Gradient elution; c. Flow rate 15mL / min.)

[0862] LCMS m / z = 521.3 [M+H] +

[0863] 1 H NMR(400MHz,CD3OD)δ9.14(s,2H),8.12(dd,1H),7.88(d,1H),7.82(d,1H),7.65(dd,1H),7.56–7.15(m,2H),6.4 1(d,1H),5.25(d,1H),3.66–3.54(m,1H),3.50(s,3H),2.97–2.85(m,3H),2.67–2.54(m,2H),2.46–2.23(m,2H).

[0864] Example 44: Synthesis of Compound 44

[0865] Step 1: Preparation of 44a-1 and 44a-2

[0866] Compound 8E (1.4 g) was prepared (Preparation method: Instrument: CAS-05-Semi-prep J; Preparative column: C18 reversed-phase column; Mobile phase: A is 10 mmol / L NH4HCO3 aqueous solution; B is acetonitrile; Flow rate: 25 mL / min; Column temperature: room temperature; Detection wavelength: 210 & 254 nm) to obtain compounds 44a-P1 (212 mg, preparative retention time: 2.405 min) and 44a-P2 (358 mg, preparative retention time: 2.482 min).

[0867] 44a-P1: 1 H NMR (400MHz, DMSO-d6) δ8.97(s,2H),7.81–7.43(m,1H),4.09(q,2H),3.22–3.08(m,1H),2.82–2.70(m,2H),2.62–2.52(m,2H),1.41–0.99(m,12H).

[0868] 44a-P2: 1 H NMR (400MHz, DMSO-d6) δ8.95(s,2H),7.82–7.41(m,1H),4.07(q,2H),3.29–3.19(m,1H),2.91–2.76(m,2H),2.60–2.50(m,2H),1.44–0.96(m,12H).

[0869] Step 2: Preparation of compound 44b

[0870] 40d (50 mg, 0.096 mmol) was dissolved in 2 mL of 1,4-dioxane and 0.2 mL of water. 44e-P1 (58 mg, 0.14 mmol), potassium carbonate (27 mg, 0.19 mmol), and Pd(dppf)Cl2 dichloromethane complex (8 mg, 0.0096 mmol) were added. The reaction was carried out at 100 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with 10 mL of ethyl acetate and washed once with 10 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography to give 44b (50 mg, yield: 72.8%).

[0871] LCMS m / z = 678.3 [M+H] +

[0872] Step 3: Preparation of compound 44c

[0873] 44b (50 mg, 0.074 mmol) was dissolved in 2 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 4 h. The reaction solvent was removed by concentration under reduced pressure to obtain crude trifluoroacetate of compound 44c.

[0874] Step 7: Preparation of Compound 44

[0875] The crude trifluoroacetate of 44c from the previous step was dissolved in 5 ml of ethanol, and 1 ml of an aqueous solution of lithium hydroxide (30 mg, 0.69 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed, the solvent was removed under reduced pressure to prepare and isolate compound 44 (15 mg).

[0876] Preparation conditions: Instrument: Waters automated purification system; Column: SunFire (19mm × 250mm);

[0877] Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, mobile phase B: water (0.1% ammonium acetate); gradient elution; flow rate 15 ml / min.

[0878] LCMS m / z = 550.1 [M+H] +

[0879] 1 H NMR(400MHz,CD3OD)δ9.15(s,2H),8.41–8.35(m,1H),7.90(d,1H),7.80(d,1H),7.60(dd,1H),7.50–7.44 (m,2H),7.30(t,1H),6.46(d,1H),5.24(d,1H),3.71–3.54(m,2H),3.07–2.97(m,2H),2.96–2.82(m,3H).

[0880] Example 45: Synthesis of Compound 45

[0881] Using 44a-2 as a starting material, and referring to the synthesis of compound 44, compound 45 (16 mg) was prepared.

[0882] Preparation conditions: Instrument: Waters automated purification system; chromatographic column: SunFire (19mm×250mm); Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, mobile phase B: water (0.1% ammonium acetate); gradient elution; flow rate 15ml / min.

[0883] LCMS m / z = 550.1 [M+H] +

[0884] 1 H NMR(400MHz,CD3OD)δ9.08(s,2H),8.40–8.34(m,1H),7.89–7.87(m,1H),7.81–7.76(m,1H),7.60(dd,1H),7.50–7.45(m,2H),7 .30(t,1H),6.45(d,1H),5.22(d,1H),3.63–3.54(m,1H),3.42–3.34(m,1H),3.28–3.19(m,2H),2.91(d,1H),2.65–2.55(m,2H).

[0885] Example 46: Synthesis of Compound 46

[0886] Step 1: Preparation of compound 46b

[0887] 1-Bromo-2-fluoro-4-iodobenzene (0.68 g, 2.24 mmol) was dissolved in dichloromethane (10 mL), cooled to -78 °C, and n-butyllithium (2.5 M in hexane, 0.9 mL) was added dropwise. The mixture was stirred at -78 °C for 2 hours. A solution of 46a (0.4 g, 1.87 mmol) in dichloromethane (2 mL) was slowly added to the reaction system. After stirring at -78 °C for 2 hours, the mixture was heated to room temperature and stirred for 12 hours. The reaction solution was quenched dropwise in a saturated ammonium chloride solution (20 mL), and extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 46b-P1 (0.15 g) and 46b-P2 (0.05 g).

[0888] 46-P1:

[0889] 1 H NMR(400MHz,DMSO-d6)δ7.65(dd,1H),7.37(dd,1H),7.21(dd,1H),5.61(s,1H) ,2.77–2.68(m,2H),2.49–2.42(m,2H),1.07(s,3H),0.87(s,9H),0.08(s,6H).

[0890] 46-P2:

[0891] 1H NMR (400MHz, DMSO-d6) δ7.67(dd,1H),7.32(dd,1H),7.19(dd,1H),5.61(s,1H),2.48–2.34(m,4H),1.58(s,3H),0.84(s,9H),0.05(s,6H).

[0892] Step 2: Preparation of compound 46c

[0893] Intermediate 40d (50 mg, 0.10 mmol) was dissolved in 2 mL of 1,4-dioxane and 0.2 mL of water. 46b-P1 (43 mg, 0.11 mmol), potassium carbonate (41 mg, 0.30 mmol), and Pd(dppf)Cl2 dichloromethane complex (8 mg, 0.01 mmol) were added. The reaction was carried out at 100 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with 10 mL of ethyl acetate and washed once with 10 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography to give 46c (50 mg, yield: 72.6%).

[0894] LCMS m / z = 667.3 [M+H] +

[0895] Step 3: Preparation of Compound 46

[0896] 46c (50 mg, 0.075 mmol) was dissolved in 2 mL of tetrahydrofuran, and tetrabutylammonium fluoride (0.38 mL, 0.38 mmol) was added. The mixture was reacted at room temperature for 2 h, concentrated under reduced pressure, and the residue was prepared and separated. The residue was lyophilized to give compound 46 (15 mg, yield: 36%). (Preparation method: 1. Instruments: Waters 2767 preparative liquid chromatograph; column: SUNFIRE@Prep C18 (19 mm × 250 mm). 2. The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (0.1% trifluoroacetic acid); b. Gradient elution, with mobile phase A content ranging from 10% to 70%; c. Flow rate: 15 mL / min; d. Elution time: 15 min.)

[0897] LCMS m / z = 553.2 [M+H] +

[0898] 1H NMR (400MHz, CD3OD) δ8.41–8.34(m,1H),7.85–7.82(m,1H),7.73(d,1H),7.56–7.44(m,4H),7.40–7.01(m,3H) ,6.49(d,1H),5.30(d,1H),3.66–3.56(m,1H),2.95(d,1H),2.83–2.76(m,2H),2.58–2.49(m,2H),1.20(s,3H).

[0899] Example 47: Preparation of Compound 47

[0900] Step 1: Preparation of 47B

[0901] 1-Bromo-2-fluoro-4-iodobenzene (6.13 g, 20.37 mmol) was dissolved in 120 mL of dichloromethane. Under a nitrogen atmosphere, n-butyllithium (8.15 mL, 2.5 N n-hexane solution) was slowly added dropwise at -78 °C. After the addition was complete, the reaction was carried out at -78 °C for 2 h. Then, 15 mL of a dichloromethane solution of 47A (3.6 g, 16.98 mmol) was slowly added dropwise. After the addition was complete, the reaction was allowed to return to room temperature and the reaction was allowed to proceed for 16 h. 150 mL of a saturated aqueous solution of NH4Cl was added to the reaction mixture. The mixture was separated, and the aqueous phase was extracted with 100 mL of dichloromethane. The combined organic phases were washed once with 140 mL of a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain the target compound 47B (0.98 g, 15% yield).

[0902] LCMS m / z = 387.0 [M+H] +

[0903] Step 2: Preparation of 47C

[0904] 47B (0.98 g, 2.53 mmol) was dissolved in 10 mL of dichloromethane solution, and 5 mL of 4N HCl dioxane solution was added. The reaction was carried out at room temperature for 3 h. The solution was concentrated under reduced pressure to give the hydrochloride salt of the target compound 47C (0.69 g, 95% yield).

[0905] Analytical methods: 1. Instrument: CAS-05-LCMS-P; Column: C18; 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: water (containing 0.0375% trifluoroacetic acid); Mobile phase B: acetonitrile (containing 0.0187% trifluoroacetic acid); Mobile phase B 5%-95%, 10 min; b. Flow rate: 1 mL / min, Column temperature: 45℃; Detection wavelength: 210 & 254 nm.

[0906] Preparation method: 1. Instrument: CAS-05-Semi-prep S; Column: C18; 2. Preparative chromatographic conditions: a. Composition of mobile phase A and B: Mobile phase A: water; Mobile phase B: acetonitrile b. Flow rate: 90 mL / min, Column temperature: room temperature; Detection wavelength: 210 & 254 nm.

[0907] LCMS m / z = 283.0 [M+H] +

[0908] 1 H NMR (400MHz, DMSO-d6) δ9.71(d,2H),7.81(t,1H),7.49(d,1H),7.22(d,1H),2.94–2.87(m,2H),2.81–2.75(m,2H),1.41(s,3H).

[0909] Step 3: Preparation of 47D

[0910] 47C (56 mg, 0.2 mmol) was dissolved in 5 mL of tetrahydrofuran solution, and triethylamine (40 mg, 0.4 mmol) and di-tert-butyl dicarbonate (87 mg, 0.4 mmol) were added. The mixture was reacted at room temperature for 16 h. The solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give the target compound 47D (75 mg, 98% yield).

[0911] LCMS m / z = 383.1 [M+H] +

[0912] Step 4: Preparation of 47E

[0913] Intermediate 40D (83 mg, 0.2 mmol) was dissolved in 2 mL of 1,4-dioxane and 0.2 mL of water. 47D (75 mg, 0.2 mmol), potassium carbonate (83 mg, 0.6 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (16 mg, 0.02 mmol) were added. The reaction was carried out at 100 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with 10 mL of ethyl acetate, washed once with 10 mL of water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography to give 47E (83 mg, yield: 64%).

[0914] LCMS m / z = 660.3 [M+H] +

[0915] Step 5: Preparation of Compound 47

[0916] 47E (83 mg, 0.13 mmol) was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 3 h. The mixture was concentrated under reduced pressure, and the residue was purified and lyophilized to give the target compound 47 (10 mg, yield: 14%).

[0917] Preparation conditions: Instrument: Waters 2767 preparative HPLC; Column: XSelect CSH C18 (19mm × 250mm). The sample was dissolved in DMF and filtered through a 0.45 μM filter to prepare the sample solution. Preparative chromatographic conditions: a. Mobile phase A: acetonitrile; b. Water (50 mM ammonium bicarbonate); gradient elution of mobile phase A from 15% to 70%; c. Flow rate: 15 mL / min; d. Elution time: 15 min.

[0918] LCMS m / z = 561.2 [M+H] +

[0919] 1 H NMR(400MHz,DMSO-d6)δ8.28(dd,1H),7.75–7.52(m,3H),7.51–7.42(m,3H),7.38–7.24(m,3H),6.26(d ,1H),5.23(d,1H),3.58–3.47(m,1H),2.81(d,1H),2.68–2.53(m,4H),2.46–2.33(m,2H),1.42(s,3H).

[0920] Example 48: Preparation of Compound 48

[0921] Following the synthetic route and preparation method of compound 46, crude compound 48 was obtained. The crude product was purified by prep-HPLC and lyophilized to obtain compound 48-P1 (12 mg, analytical retention time: R). t =2.015 min) and compound 48-P2 (3 mg, retention time: R t =2.273min).

[0922] Chiral analysis method: 1. Instrument: CAS-05-ANA-SFC-D; Column: OX column; 2. Preparative chromatographic conditions: a. Composition of mobile phase A and B: Mobile phase A: CO2; Mobile phase B: Ethanol containing 0.05% M NH3 b. Flow rate: 3 mL / min, Column temperature: 35℃; Detection wavelength: 220 nm.

[0923] Preparation method: 1. Instrument: CAS-05-Prep-HPLC-O; Column: C18; 2. The sample was dissolved in acetonitrile to a concentration of 20 mg / ml, filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: water (containing 10 mmol / L NH4HCO3); Mobile phase B: acetonitrile; b. Flow rate: 25 mL / min; Column temperature: room temperature; Detection wavelength: 220 nm.

[0924] Chiral separation method: 1. Instrument: CAS-05-Prep-SFC-A; Column: OX column; 2. The sample was dissolved in acetonitrile and ethanol to a concentration of 1 mg / mL, filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phases A and B: Mobile phase A: CO2; Mobile phase B: Ethanol containing 0.1% NH3; b. Flow rate: 120 mL / min; Column temperature: room temperature; Detection wavelength: 220 nm.

[0925] Compound 48-P1: LCMS m / z = 567.3 [M+H] +

[0926] 1 H NMR(400MHz,DMSO-d6)δ8.27(dd,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),3.19(dd,2H),2.82(d,1H),2.51–2.44(m,2H),1.93–1.86(m,2H),1.29(s,3H).

[0927] Compound 48-P2: LCMS m / z = 567.3 [M+H] +

[0928] Example 49: Preparation of Compound 49

[0929] Following the synthetic route and preparation method of compound 47, compound 49 (5 mg) was obtained.

[0930] LCMS m / z = 566.2 [M+H] +

[0931] Example 50: Synthesis of Compound 50

[0932] Following the synthesis of compound 46, 46-P2 was used instead of 46-P1 to synthesize compound 50 (10 mg).

[0933] LCMS m / z = 553.3 [M+H] +

[0934] 1 H NMR (400MHz, CD3OD) δ8.40–8.34(m,1H),7.77(s,1H),7.68(d,1H),7.50–7.42(m,4H),7.41–7.00(m,3H),6.41 (d,1H),5.20(d,1H),3.62–3.52(m,1H),3.28–3.19(m,6H),2.89(d,1H),2.65–2.57(m,2H),2.50–2.42(m,2H).

[0935] Biological test cases

[0936] 1. TNF-α / TNFR1 binding assay

[0937] 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 to 10 doses at a concentration of 1 μM. 0.1 μL of the diluted positive reference in the 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 minute. 2.5 μL of TNF-α solution was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute, then incubated at 25°C for 15 minutes. 2.5 μL of TNFR1 solution was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 minute. 5 μL of adalimumab was then transferred to the plate. The Streptavidin-Tb cryptate and PAb Anti-Human IgG-XL665 assay mixture was transferred to a 384 reaction plate and centrifuged at 1000 rpm for 1 minute, then incubated at 25°C for 60 minutes. Finally, the HTRF signal (Ratio 665 / 620 nm) was read using a BMG high-throughput drug screening multi-mode microplate reader. The IC50 was obtained using GraphPad Prism software. 50 Fitting values ​​and nonlinear regression curves.

[0938] The experimental results are shown in Table 1:

[0939] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity against TNF-α / TNFR1 binding.

[0940] 2. Detection experiment of Membrane TNFα and H_TNFR1 / H_TNFR2 reporter cells:

[0941] Cell line GM-C33297: Membrane Bound H_TNFα (cleavage-resistant) CHO-K1 Cell Line;

[0942] GM-C27615:H_TNFR2 Null Reporter Cell Line

[0943] GM-C25776: H_TNFR2 Reporter V2 Cell Line

[0944] Experimental methods:

[0945] 16-24 hours before the experiment, Membrane Bound H_TNFαCHO-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 of cells / well was added to the center well using a multipipeline, and 100 μL of 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_TNFαCHO-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 collected and Luciferase was detected.

[0946] 3. HT-29 cell apoptosis experiment

[0947] 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. 100 μL of pre-incubated TNF-α and the compound mixture was transferred to 100 μL of cells. Z-VAD (MCE, HY-16658B) and AT406 (MCE, HY-15454) were added to a final concentration of 20 μM and incubated at 37°C with 5% CO2 for 24 hours. CellCounting-Lite (vazyme, DD1102) was added, and the mixture was shaken for 2 minutes in the dark and incubated at room temperature in the dark for 30 minutes. The luminescence signal value was read using a microplate reader.

[0948] The experimental results are shown in Table 2:

[0949] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity against HT-29 cells.

[0950] 4. Pharmacokinetic assays in mice

[0951] Test animals: Male C57 mice, 20–25 g, 6 mice / compound. Purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0952] 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.

[0953] Dosage information

[0954] Note: Intravenous administration solvent: 10% DMA + 10% Solutol + 80% Saline; Gavage administration solvent: 0.5% MC

[0955] DMA: Dimethylacetamide; Solutol: Polyethylene glycol-15-hydroxystearate; Saline: Physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose

[0956] 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.

[0957] The pharmacokinetic results of the test compounds in mice are shown in Table 3:

[0958] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties.

[0959] 5. CYP450 enzyme inhibition test

[0960] 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, and the changes in CYP enzyme activity were measured. The IC50 values ​​were calculated. 50 The value was used to evaluate the inhibitory potential of the test substance against each CYP enzyme subtype CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4-M (with midazolam as a substrate).

[0961] The test results are shown in Table 4:

[0962] 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.

[0963] 6. hERG potassium ion channel function test

[0964] Experimental platform: Electrophysiological manual patch-clamp system

[0965] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channels

[0966] 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, then repolarized to -50 mV, held for 1 second, and then returned to -80 mV. This voltage stimulation was applied every 10 seconds. After confirming that the hERG potassium current was stable (at least 1 minute), the drug delivery process began. Each compound was administered for at least 1 minute at each test concentration, and at least 2 cells were tested for each concentration (n≥2).

[0967] 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 (the peak hERG tail current induced at -50mV) by different compound concentrations was calculated using the following formula:

[0968] Inhibition%=[1–(I / Io)]×100%

[0969] 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.

[0970] Compound IC 50 The following equations were fitted and calculated using GraphPad Prism 5 software:

[0971] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope))

[0972] 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.

[0973] Conclusion: The compounds of the present invention, such as the compounds in the examples, do not exhibit significant hERG inhibitory activity.

[0974] 7. Caco2 Permeability Test

[0975] 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.

[0976] The CaCO2 test results of the compounds of this invention are shown in Table 5:

[0977] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good permeability.

[0978] 8. Experiment on recombinant human TNFα-induced apoptosis in L929 cells:

[0979] First, recombinant human 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 incubated at 225 cm⁻¹. 2 After culturing in culture flasks until confluence reaches 70%–80%, gently wash the cells twice with pre-chilled PBS. Add 5 mL of pre-warmed trypsin-EDTA solution (Solarbio, T1300) and incubate at 37°C for approximately 1 minute. Then, add 10 mL of culture medium (DMEM + 10% FBS, DMEM provided by Hyclone, SH3002201) to neutralize the trypsin. Transfer the cell suspension to a 50 mL centrifuge tube (Biofil, CFT011500), centrifuge at 300–400 x g for 5 minutes, remove the supernatant, and resuspend the cells in 10 mL of pre-warmed culture medium (DMEM + 2% FBS). Mix 20 μL of the cell suspension with 20 μL of 0.2% trypan blue solution (Invitrogen, T10282) for cell counting. Dilute the cells 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 this 32 μg / mL actinomycin D was added to each well of the cell culture plate. The culture plate was 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, and 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, thaw 2.5 μL of recombinant human TNFα and transfer 2 μL 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, take 60 μL of the 1 μg / mL TNFα solution and add it 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 nmL of the test compound solution or DMSO. Briefly centrifuge at 1000 rpm for 1 minute, then incubate at 37°C for 1 hour. After 1 hour, use the Apricot Designs Pipetting System to transfer 10 μL of the TNFα complex solution to a cell culture plate containing L929 cells. The culture medium is 30 μL, including a 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. Incubate the cell culture plates at 37°C in a 5% CO2 humidified incubator for 24 hours. Finally, remove the cell culture plates from the incubator and allow them to equilibrate to room temperature for 15 minutes before use. Equilibrate the reagents to room temperature and add 30 μL to each well of the cell plate. The reagents were incubated at room temperature in the dark for 30 minutes before being 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.

[0980] 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.

[0981] 9. Zymosan-induced human whole blood CD11b expression experiment:

[0982] 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% CO3 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. Use distilled water to rinse the BD Phosflow... TM Dilute lysis / fixation buffer (5×, BD Phosflow, 558049) 1:5 and preheat to 37°C. Add 1 mL of 1× BD Phosflow buffer to each well of the deep well plate. TMFor lysis / fixation buffer, transfer blood to a preheated solution, mix well, and incubate at 37°C for 15 minutes. Centrifuge at 1200g / min for 5 minutes, discard the supernatant, add 1mL of PBS (Solarbio, P1020) to each well, centrifuge at 1200g / min for 5 minutes, discard the supernatant, resuspend cells in 100μL of cell staining buffer (Biolegend, 420201), and store the plates at 4°C overnight. Finally, acquire data on a CytoFLEX S flow cytometer, analyze the data using FlowJo to obtain the MFI (mean fluorescence intensity) for each sample, remove noise and adherent cells, and perform gated detection of CD45. + CD11b + MFI of CD11b activated cells in cells. Data quality was assessed by calculating the Z' value and IC50. 50 The value is calculated by fitting a four-parameter logic curve.

[0983] The experimental results are shown in Table 6:

[0984] 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.

[0985] 10. Human microparticle stability test

[0986] 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.

[0987] The test results are shown in Table 7:

[0988] Conclusion: The compounds of the present invention, such as those in the examples, exhibit lower clearance rates and longer half-lives in human liver microsomes, and also demonstrate superior stability in human liver microsomes.

[0989] 11. Rat Pharmacokinetic Tests

[0990] Experimental animals: Male SD rats, approximately 220g, 6-8 weeks old, 6 rats / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0991] 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.

[0992] Dosage information

[0993] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Gavage administration solvent: 0.5% MC.

[0994] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose)

[0995] Blood samples of 0.15 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.

[0996] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption in rats.

[0997] 12. Pharmacokinetics of Beagle Dogs

[0998] Experimental animals: Male beagles, weighing approximately 8–11 kg, 6 per compound, purchased from Beijing Mars Biotechnology Co., Ltd.

[0999] Experimental method: On the day of the experiment, beagles (6 dogs / 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. They were fed 4 hours after administration.

[1000] Dosage information

[1001] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Gavage administration solvent: 0.5% MC.

[1002] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose)

[1003] 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.

[1004] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption in beagle dogs.

[1005] 13. Pharmacokinetics in monkeys

[1006] Experimental animals: Male cynomolgus monkeys, 3–5 kg, 3–6 years old, 6 animals / compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[1007] 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.

[1008] Dosage information

[1009] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Gavage administration solvent: 0.5% MC.

[1010] (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.

[1011] Blood samples of 1.0 mL were collected from venous sites in the extremities 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 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, and 24 h. All samples were stored at -80°C before analysis and quantitative analysis was performed using LC-MS / MS.

[1012] 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). E is selected from Its left side is connected to an aromatic ring containing Y1; Y1 and Y2 are each independently selected from CR y Or N; W is selected from bond, O, S, C, C (=O), CR 6 NR 6 Or N; V is selected from bond, O, S, C, C (=O), CR 8 NR 8 Or N; U is selected from bonds, O, S, C, C (=O), CR 5 NR 5 Or N; X is selected from bond, O, S, C, C (=O), CR 7 NR 7 Or N; The condition is that only one of U, W, X, and V is selected from the bond, and ring C is selected from a 5-6 member heteroaromatic ring or a 6 member aromatic ring; Z is selected from -(CR) z1 R z2 )2- or -CR z1 R z2 -; Q is selected from C, C(=O), C(=S), C(=O)-N(R) q1 ), S(=O)(=N(R) q2 )), S(=O), S(=O)2; This indicates the presence or absence of a ring; when present, ring B is selected from a 5-membered heteroaryl group, wherein the heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace; Alternatively, U and W, W and X, V and X, and their associated skeletons together form a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group, or a 5-6 membered carbocyclic group, wherein the carbocyclic group, heteroaryl, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R 11 R q1 Each element is independently selected from H, deuterium, and C. 1-6 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace; R q2 Selected from H, CN, OH, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace; Ring A is selected from C 3-8 Monocycloalkyl, 5-6 membered heteroaryl; R 1 Each element is independently selected from deuterium, halogens, CN, OH, -C(=O)OH, -C(=O)NH2, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -C 1-4 Alkylene-OC 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4 to 7-membered heterocyclic groups, =CR 1a R 1b -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)C 1-6 Alkyl group, -NHC(=O)C 3-6 cycloalkyl, -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, C 5-10 aryl, 5- to 6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, cycloalkyl, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace; R z1 R z2 R 1a R 1b Each element is independently selected from H, deuterium, halogens, and C. 1-6 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R z1 R z2 Together with the carbon atoms attached to it, they form C 3-6 A carbocyclic group, wherein the carbocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R 10 Selected from H, deuterium, and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4 to 7-membered heterocyclic groups, -C 1-4 Alkylene-OC 3-6 Cycloalkyl, wherein the alkylene, alkyl, alkenyl, ynyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R y R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 Each element is independently selected from H, deuterium, halogens, CN, OH, SF5, NH2, 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 carbonyl group, -C 0-4 Alkylene-C 3-7 carbonyl 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, ynyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R k replace; As an option, R 2 With R 3 R 3 With R 9 The atoms or framework attached to it together form a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group, or a 5-6 membered carbocyclic group, wherein the carbocyclic group, heteroaryl group, or heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace; R k Each element is independently selected from deuterium, ⁵O, halogens, CN, OH, COOH, NH₂, 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 carbonyl 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, alkynyl, 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; n1 is independently selected from 0, 1, 2, 3 or 4; n2 is independently selected from 0, 1, 2, and 3; The condition is that when E is selected from At that time, general formula (I) must satisfy at least one of the following conditions: 1) Cycle B is present, wherein cyclic B is selected from 5-membered heteroaryl groups, and the heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace; 2)R 2 With R 3 R 3 With R 9 The atoms or framework attached to it together form a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group, or a 5-6 membered carbocyclic group, wherein the carbocyclic group, heteroaryl group, or heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace; 3) U and W, W and X, V and X, and their connected skeletons together form a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group, or a 5-6 membered carbocyclic group, wherein the carbocyclic group, heteroaryl group, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; 4)R 10 Selected from R 10a R 10a Selected from C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4 to 7-membered heterocyclic groups, -C 1-4 Alkylene-OC 3-6 Cycloalkyl, wherein the alkylene, alkenyl, ynyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; 5) Ring C is selected from 5-6 member heteroaryl aromatic rings; 6)R 5 Unselected from halogens, unsubstituted -OC 1-6 Alkyl, difluoromethoxy, or trifluoromethoxy; 7)R 6 R 8 Not selected from H, halogens, or trifluoromethyl; 8)R 7 Not selected from H, trifluoromethyl; 9)R 2 Not selected from H or halogens; 10)R 3 R 4 Not selected from H, halogen, trifluoromethyl or unsubstituted C 1-6 alkyl; 11) n1 is not selected from 0, and R 1 At least one of them is selected from R a R a Selected from -CH2F, -C(=O)OH, -C(=O)NH2, C 2-6 alkenyl, C 2-6 alkynyl group, =CR 1a R 1b -C(=O)N(C 1-6 Alkyl)2、-NHC(=O)C 1-6 Alkyl group, -NHC(=O)C 3-6 Cycloalkyl, 5- to 6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, cycloalkyl, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace; 12) Q is selected from Q 1a Q 1a Selected from C(=O)-N(R) q1 ), S(=O)(=N(R) q2 )); 13) Z is not selected from -CH2-; 14) Y1 and Y2 are both selected from CR y ; 15) Cycle A is selected from 5-6 membered heteroaryl groups, and when Y1 and Y2 are both selected from CR y Ring A is not selected 2. The compound according to claim 1, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. R 11 R q1 Each element is independently selected from H, deuterium, and C. 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace; R q2 Selected from H, CN, OH, NH2, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace; R 1 Each element is independently selected from deuterium, halogens, CN, OH, -C(=O)OH, -C(=O)NH2, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, -C 1-2 Alkylene-OC 1-4 Alkyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-6 cycloalkyl, C 1-2 Alkylene-4 to 7-membered heterocyclic alkyl, =CR 1a R 1b -C(=O)N(C 1-4 Alkyl)2、-NHC(=O)C 1-4 Alkyl group, -NHC(=O)C 3-6 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, C 5-10 aryl, 5- to 6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, cycloalkyl, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace; R a Selected from -CH2F, -C(=O)OH, -C(=O)NH2, C 2-4 alkenyl, C 2-4 alkynyl group, =CR 1a R 1b -C(=O)N(C 1-4 Alkyl)2、-NHC(=O)C 1-4 Alkyl group, -NHC(=O)C 3-6 Cycloalkyl, 5- to 6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, cycloalkyl, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace; R z1 R z2 R 1a R 1b Each element is independently selected from H, deuterium, halogens, and C. 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R z1 R z2 Together with the carbon atoms attached to it, they form C 3-6 cycloalkyl group, wherein the cycloalkyl group is optionally surrounded by 1 to 4 R groups k replace; R 10 Selected from H, deuterium, and C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-7 carbonyl group, -C 1-2 alkylene-4 to 7-membered heterocyclic groups, -C 1-2 Alkylene-OC 3-6 Cycloalkyl, wherein the alkylene, alkyl, alkenyl, ynyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R 10a Selected from C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-7 carbonyl group, -C 1-2 alkylene-4 to 7-membered heterocyclic groups, -C 1-2 Alkylene-OC 3-6 Cycloalkyl, wherein the alkylene, alkyl, alkenyl, ynyl, cycloalkyl or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R y R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, 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 carbonyl 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, 5-6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, carbocyclic, heteroaryl or heterocyclic group is optionally surrounded by 1 to 4 R k replace; As an option, R 2 With R 3 R 3 With R 9 The atoms or framework attached to it together form a 5-membered heteroaryl, a 5-membered heterocyclic group, or a 5-membered carbocyclic group, wherein the carbocyclic, heteroaryl, or heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace; R k Each element is independently selected from deuterium, ⁵O, halogens, CN, OH, COOH, NH₂, 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 carbonyl 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, alkynyl, 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 racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I) is selected from the compounds represented by general formulas (Ia), (Ib), (Ic), and (Id). E1 is selected from Its left side is connected to a nitrogen-containing heteroaromatic ring; Selected from R k One of the following groups is substituted: Ring C1 is selected from thienyl, furanyl, pyrroleyl, thiazolyl, oxazolyl, pyrazolyl, imidazoleyl, pyridyl, pyridoneyl, pyrimidinyl, and pyridazinyl, wherein ring C1 is optionally oxidized by R. 5 R 6 R 7 R 8 replace; Alternatively, U and W, W and X, V and X in ring C1 and their connected skeletons together form a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group, or a 5-6 membered carbocyclic group, wherein the carbocyclic group, heteroaryl, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; The ring C is selected from phenyl, pyridyl, pyridone, pyrimidinyl, and pyridazinyl, wherein the ring C is optionally coated with R. 5 R 6 R 7 R 8 replace; n2 is independently selected from 0, 1, or 2; As an option, R 2 With R 3 R 3 With R 9 The atoms or framework attached to it together form a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group, or a 5-6 membered carbocyclic group, wherein the carbocyclic group, heteroaryl group, or heterocyclic group is optionally surrounded by 1 to 3 R atoms. k replace; As an option, R 5 With R 6 R 7 With R 8 R 6 With R 7 Together with its associated skeleton, it forms a 5-6 membered heteroaryl, 5-6 membered heterocyclic, or 5-6 membered carbocyclic group, wherein the carbocyclic, heteroaryl, or heterocyclic group is optionally surrounded by 1 to 3 R groups. k replace; The condition is that the general formula (Ia) satisfies at least one of the following conditions: 1)R 2 With R 3 R 3 With R 9 The atoms or framework attached to it together form a 5-6 membered heteroaryl, a 5-6 membered heterocyclic group, or a 5-6 membered carbocyclic group, wherein the carbocyclic group, heteroaryl group, or heterocyclic group is optionally surrounded by 1 to 3 R atoms. k replace; 2)R 5 With R 6 R 7 With R 8 R 6 With R 7 Together with its associated skeleton, it forms a 5-6 membered heteroaryl, 5-6 membered heterocyclic, or 5-6 membered carbocyclic group, wherein the carbocyclic, heteroaryl, or heterocyclic group is optionally surrounded by 1 to 3 R groups. k replace; 3)R 10 Selected from R 10a ; 4)R 5 Selected from R 5a R 5a Selected from -SF5, -OCF2Cl, -OC 2-4 Alkyl, -SC 1-4 Alkyl, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -SC 3-7 cycloalkyl, -OC 1-2 Alkylene-C 3-7 cycloalkyl, -SC 1-2 Alkylene-C 3-7 cycloalkyl, -C 1-2 Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k Instead, the -OC 2-4 Alkyl groups are 1 to 4 R k replace; 5)R 6 Selected from R 6a R 6a Selected from CN, -SC 1-4 Alkyl, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -C 1-2 Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace; 6)R 7 Selected from R 7a R 7a Selected from F, CN, -SC 1-4 Alkyl, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -C 1-2 Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace; 7)R 8 Selected from R 8a R 8a Selected from CN, -SC 1-4 Alkyl, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -C 1-2 Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace; 8)R 2 Selected from R 2a R 2a Selected from CN, OH, SF5, NH2, 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, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -C 1-2 Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, alkenyl, ynyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace; 9)R 3 R 4 Selected from R 3a R 3a Selected from CN, OH, SF5, NH2, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 3-7 cycloalkyl, -OC 3-7 cycloalkyl, -C 1-2 Alkylene-C 3-7 Cycloalkyl, wherein the alkylene, alkyl, alkenyl, ynyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace; 10) n1 is not selected from 0, and R 1 At least one of them is selected from R a R a Selected from -CH2F, -C(=O)OH, -C(=O)NH2, C 2-4 alkenyl, C 2-4 alkynyl group, =CR 1a R 1b -C(=O)N(C 1-4 2, -NHC(=O)C 1-4 radical, -NHC(=O)C 3-6 Cycloalkyl, 5- to 6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, cycloalkyl, aryl, or heteroaryl group is optionally surrounded by 1 to 4 R groups. k replace; 11) Q is selected from Q 1a Q 1a Selected from C(=O)-N(R) q1 ), S(=O)(=N(R) q2 )); 12) Z is not selected from -CH2-; 13) Y1 and Y2 are both selected from CR y ; 14) Cycle A is selected from 5-6 membered heteroaryl groups, and when Y1 and Y2 are both selected from CR y Ring A is not selected 4. The compound according to claim 3, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, R 11 R q1 Each element is independently selected from H, deuterium, and methyl, wherein the methyl group is optionally surrounded by 1 to 3 R atoms. k replace; R q2 Selected from H, CN, OH, NH2, NH-methyl, N(methyl)2, methyl, wherein the methyl group is optionally surrounded by 1 to 3 R groups. k replace; Ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, thiazolyl, and oxazolyl. Alternatively, ring A can be selected from ring A1, where ring A1 is selected from pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazole, triazolyl, thiadiazolyl, oxadiazolyl, etc. R 1 Each of the following is independently selected from deuterium, F, Cl, Br, CN, OH, -C(=O)OH, -C(=O)NH2, -C(=O)N(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, -CH2CH2O-methyl, -CH2CH2O-ethyl, =CR 1a R 1b Cyclopropyl, oxacyclobutyl, tetrahydrofuranyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-oxacyclobutyl, -CH2-azacyclobutyl, -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. Thiophene, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazoleyl, oxadiazolyl, thiazolyl, triazoleyl, isothiazolyl, isoxazolyl, wherein CH2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, azacyclobutyl, thiophene, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazoleyl, oxadiazolyl, thiazolyl, triazoleyl, isothiazolyl, isoxazolyl are optionally surrounded by 1 to 4 R. k replace; R a Selected from -CH2F, -C(=O)OH, -C(=O)NH2, vinyl, ethynyl, propynyl, propynyl, -NHC(=O)CH3, -NHS(=O)2CH3, =CR 1a R 1b Thiophene, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazoleyl, oxadiazolyl, thiadiazolyl, triazoleyl, isothiazolyl, isoxazolyl, vinyl, ethynyl, propynyl, propargyl, thiophene, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazoleyl, oxadiazolyl, thiadiazolyl, triazoleyl, isothiazolyl, isoxazolyl, optionally with 1 to 4 R k replace; R y Each of the following is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, thiophene, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazole, oxadiazolyl, thiazolyl, triazolel, -P(=O)(methyl)2, -P(=O)(ethyl)2, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl, thiophene, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazole, oxadiazolyl, thiazolyl, and triazolel groups are optionally selected from 1 to 4 of the following: deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups; R z1 R z2 R 1a R 1b Each element is independently selected from H, deuterium, F, Cl, Br, and methyl, wherein the methyl group is optionally coated with 1 to 3 R atoms. k replace; As an option, R z1 R z2 Together with the carbon atoms attached thereto, they form cyclopropyl and cyclobutyl groups, wherein the cyclopropyl and cyclobutyl groups are optionally bonded by 1 to 3 R atoms. k replace; R 10 Each of the following elements is independently selected from H, deuterium, methyl, ethyl, vinyl, ethynyl, propynyl, propynyl, -CH2-propynyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-bicyclo[1,1,1]pentane, -CH2-bicyclo[1,1,0]butane, -CH2-O-cyclopropyl, -CH2CH2-O-cyclopropyl, oxacyclobutyl, and aziridine, wherein CH2, methyl, ethyl, vinyl, ethynyl, propynyl, propynyl, propynyl, cyclopropyl, cyclobutyl, oxacyclobutyl, aziridine, bicyclo[1,1,1]pentane, and bicyclo[1,1,0]butane are optionally surrounded by 1 to 4 R atoms. k replace; R 10a Selected from -CH2-propynyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-bicyclo[1,1,1]pentane, -CH2-bicyclo[1,1,0]butane, -CH2-O-cyclopropyl, -CH2CH2-O-cyclopropyl, oxacyclobutyl, aziridine, wherein the CH2-propynyl, cyclopropyl, cyclobutyl, oxacyclobutyl, aziridine, bicyclo[1,1,1]pentane, or bicyclo[1,1,0]butane is optionally surrounded by 1 to 4 R-terminals. k replace; R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 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, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetrahydrofuran The following groups are used: -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, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxacyclobutyl, tetrahydrofuranyl are optionally surrounded by 1 to 4 R groups. k replace; R 2a Selected from CN, OH, SF5, NH2, cyclopropyl, cyclobutyl, methyl, CF3, CHF2, CH2F, CD3, CHD2, CH2D, wherein the cyclopropyl, cyclobutyl, and methyl groups are optionally coated with 1 to 3 R groups. k replace; R 3a Selected from CN, OH, SF5, NH2, cyclopropyl, and cyclobutyl, wherein the cyclopropyl and cyclobutyl groups are optionally coated with 1 to 3 R groups. k replace; R 5a Selected from -SF5, -OCF2Cl, -OCH2CHF2, -OCH2CF3, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -S-CH2-cyclopropyl, -S-CH2-cyclobutyl, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, wherein the methyl, ethyl, cyclopropyl, and cyclobutyl groups are optionally surrounded by 1 to 4 R groups. k Instead, the -CH2- is optionally replaced by 1 to 2 R k replace; R 6a R 8a Each of the following is independently selected from CN, -S-methyl, -S-ethyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, cyclopropyl, and cyclobutyl groups are optionally surrounded by 1 to 3 R groups. k replace; R 7a Selected from F, CN, -S-methyl, -S-ethyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, cyclopropyl, and cyclobutyl groups are optionally surrounded by 1 to 3 R groups. k replace; As an option, R 2 With R 3 R 3 With R 9 Together with the atoms or framework attached to it, a cyclopentyl group is formed, wherein the cyclopentyl group is optionally surrounded by 1 to 4 R atoms. k replace; As an option, R 5 With R 6 R 7 With R 8 R 6 With R 7 Together with its associated skeleton, it forms a cyclopentyl or pyrrolidinyl group, wherein the cyclopentyl or pyrrolidinyl group is optionally surrounded by 1 to 3 R groups. k replace; Alternatively, in ring C1, U and W, W and X, V and X, and their associated skeletons together form an imidazole group, a pyrrole group, a triazole group, a cyclopentyl group, or a pyrrole alkyl group, wherein the imidazole group, pyrrole group, triazole group, cyclopentyl group, or pyrrole alkyl group is optionally surrounded by 1 to 3 R groups. k replace; R k Each group is independently selected from deuterium, =O, F, Cl, Br, I, CN, OH, NH2, 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 methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and pyrrolyl groups are optionally selected from 1 to 4 elements selected from 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, Each independently selected n1 is independently selected from 0, 1, or 2; or Each independently selected n4 are each independently selected from 1, 2, and 3; or Each independently selected n3 is independently selected from 0 and 1; Q is independently selected from C (=O), C (=S), and Q. 1a ; Q 1a Selected from C(=O)-N(R) q1 ), S(=O)(=N(R) q2 )); R 11 Each is independently selected from H and deuterium; Z is independently selected from -CH2- or Z. 1a ; Z 1a Selected from -CH2-CH2-, -CR z1 R z2 -、-CHR z2 -or can be chosen by 1 to 3 Rs k The following groups are substituted: R z1 R z2 Each element is independently selected from deuterium, F, Cl, Br, and methyl, wherein the methyl group is optionally coated with 1 to 3 R atoms. k replace; Selected from Selected from Selected from n2 is selected from 2; As an option, Selected from Selected from Selected from R k Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, -CH2OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, 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, Q 1a Selected from C(=O)-NH, S(=O)(=NH); Z 1a Selected from -CH2-CH2-, -CF2-, -C(CH3)2-, -CHCH3-, or optionally by 1 to 3 Rs k The following groups are substituted: Selected from R 5a The derivative is selected from -SF5, -OCF2Cl, -OCH2CHF2, -OCF2CHF2, -OCH2CF3, -SCH2CHF2, -SCF2CHF2, -S-methyl, -S-CHF2, -S-CF3, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -S-CH2-cyclopropyl, -S-CH2-cyclobutyl, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, wherein the cyclopropyl and cyclobutyl groups are optionally substituted with 1 to 3 deuterium, F, Cl, Br, CN, OH, methyl, CF3, CHF2, CH2F; R 1 Each is independently selected from deuterium, F, Cl, Br, CN, OH, -C(=O)OH, -C(=O)NH2, -C(=O)N(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, CF3, CHF2, CH2F, CH2OH, CD3, -CH2CHF2, -CF2CHF2, -CH2CF3, -C H2CH2OCH3, -CH2CH2OCH2CH2OCH2CH3, cyclopropyl, oxacyclobutyl, tetrahydrofuranyl, -CH2-cyclopropyl, -CH2CH2O-cyclopropyl, -CH2-oxacyclobutyl, -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 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 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, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, -S-methyl, -S-ethyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, oxacyclobutyl, tetrahydrofuranyl; R y Each element is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, CF3, CHF2, CH2F, P(=O)(CH3)2, methyl, ethyl, methoxy, ethoxy, cyclopropyl. The methyl, ethyl, methoxy, ethoxy, cyclopropyl groups mentioned above It may be substituted by 1 to 4 substances selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, and methyl.

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.

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 a racemic, stereoisomer, tautomer, pharmaceutically acceptable salt thereof, or the composition according to claim 8, 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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