Hetero bridged cyclic derivatives and their use in medicine

Abstract

Heterobicyclic derivatives and their use in medicine, in particular to a compound according to general formula (I-A) or a racemate, stereoisomer, tautomer thereof, a pharmaceutically acceptable salt thereof, and intermediates and processes for their preparation, and use in the manufacture of a medicament for the treatment of autoimmune or inflammatory diseases.(I-A).

Description

Technical Field

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

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

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

[0004] This invention provides a compound of general formula (IA) or its stereoisomers, a pharmaceutically acceptable salt, or a eutectic.

[0005] (IA);

[0006] In some embodiments, the compound represented by general formula (IA) is selected from the compound represented by general formula (I).

[0007] (I);

[0008] Indicates whether chemical bonds exist or not;

[0009] In some embodiments, the compound represented by formula (IA) or (I) is selected from the compound represented by formula (II).

[0010] (II);

[0011] In some implementation schemes, Selected from or ;

[0012] In some implementations, ring S is selected from ;

[0013] In some implementations, S1 or S2 is selected from N, CH or CR. s ;

[0014] In some implementations, n4 is selected from 0, 1, or 2;

[0015] In some embodiments, ring M is selected from a 5-membered heteroaryl group or a 5-membered unsaturated heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally surrounded by 1 to 4 R groups. m replace;

[0016] In some embodiments, the compound represented by formula (I) is selected from the compounds represented by formulas (Ia) and (Ib).

[0017] In some embodiments, the compound represented by general formula (IA) is selected from the compounds represented by (Ic), (Id), and (Ie). ;

[0018] In some implementation schemes, R m Each element is independently selected from deuterium, halogens, CN, =O, =S, OH, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4- to 7-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic alkyl is optionally surrounded by 1 to 4 R... k replace;

[0019] In some implementation schemes, R m Each element is independently selected from deuterium, halogens, CN, =O, =S, OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4- to 7-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic alkyl is optionally surrounded by 1 to 4 R... kreplace;

[0020] In some implementation schemes, R m Each of the following is independently selected from deuterium, F, Cl, Br, CN, OH, methyl, ethyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl groups are optionally selected by 1 to 4 of the following: deuterium, halogen, CF3, CHF2, CH2F, CD3, CHD2, CH2D, and C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0021] In some implementation schemes, R m Each is independently selected from deuterium, F, Cl, Br, CN, methyl, ethyl, cyclopropyl, CF3, CHF2, CH2F, CD3, CHD2, CH2D, CH2CD3, CH2CF3;

[0022] In some implementations, X is selected from N, O, S, C(R) x ), C(R x )2 or N(R x );

[0023] In some implementation schemes, R x Each is independently selected from H, -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-6 cycloalkyl, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0024] In some implementation schemes, R x Selected from H, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH(CH3)2, -C(=O)-cyclopropyl, methyl, ethyl, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, cyclopropyl, or cyclobutyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0025] In some implementation schemes, R x Each is independently selected from H, -C(=O)-C 1-4 Alkyl, -C(=O)-C 3-6 cycloalkyl, C 1-4 Alkyl, C 3-6 cycloalkyl, -C 1-2 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0026] In some implementation schemes, R x The group is selected from H, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH(CH3)2, -C(=O)-cyclopropyl, methyl, ethyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, cyclopropyl, and cyclobutyl 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, or ethyl.

[0027] In some implementation schemes, R x Selected from CF3, CD3, or cyclopropyl;

[0028] In some implementations, Q is selected from C, C(R) q1 ), C(R q1 2. C(=O), C(=S), C=N(R) q2 C=C(R) q3 )2, S(=O), S(=O) (=NH), S(=O)2;

[0029] In some implementation schemes, R q1 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;

[0030] In some implementation schemes, R q1 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;

[0031] In some implementation schemes, R q2 R q3 Each element is independently selected from H, CN, OH, NH2, and 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;

[0032] In some implementation schemes, R q2 R q3 Each element is independently selected from H, CN, OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6Cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0033] In some implementation schemes, R q1 The group is selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, or cyclopropyl, wherein the methyl, ethyl, or cyclopropyl group is optionally replaced by 1 to 4 groups selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0034] In some implementation schemes, R q2 The methyl, ethyl, methoxy, and ethoxy groups are selected from H, OH, CN, NH2, methyl, ethyl, methoxy, and ethoxy groups, wherein the methyl, ethyl, methoxy, and ethoxy groups are optionally replaced by 1 to 4 deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, and C groups. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0035] In some implementation schemes, R q1 The group is selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl or cyclopropyl, wherein the methyl, ethyl or cyclopropyl group is optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl;

[0036] In some implementation schemes, R q2 The group is selected from H, OH, CN, NH2, methyl, ethyl, methoxy, ethoxy, wherein the methyl, ethyl, methoxy, ethoxy group is optionally replaced by 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl;

[0037] In some implementations, W is selected from -CR w1 R w2 -、-(CR w1 R w2 )2-;

[0038] In some implementation schemes, R w1 R w2 Each element is independently selected from H, deuterium, halogens, and C. 1-6 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally surrounded by 1 to 4 R groups. kreplace;

[0039] As an option, R w1 R w2 Direct connection forms C 3-6 cycloalkyl group, wherein the cycloalkyl group is optionally surrounded by 1 to 4 R groups k replace;

[0040] In some implementation schemes, R w1 R w2 Each element is independently selected from H, deuterium, halogens, and C. 1-4 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0041] In some implementations, R is an option w1 R w2 Direct connection forms C 3-6 cycloalkyl group, wherein the cycloalkyl group is optionally surrounded by 1 to 4 R groups k replace;

[0042] In some implementations, W is selected from -CH2-, -CH(CH3)-, -CH(CF3)-, -CH(CD3)-, -CFH-, -CF2-, -CH2CH2-, or ;

[0043] In some implementation schemes, ring A is selected from 5-membered heteroaryl groups, , , , , In some embodiments, ring A is selected from thienyl, furanyl, pyrroleyl, thiazolyl, oxazolyl, pyrazolyl, and others. , , , , In some implementations, Z1 is selected from N or C(R). z1 );

[0044] In some implementations, Z2 is selected from N or C(R) z2 );

[0045] In some implementations, Z3 is selected from N or C(R) z3 );

[0046] In some implementations, Z4 is selected from N or C;

[0047] In some implementations, Z5 is selected from N or C;

[0048] In some implementations, Z6 is selected from N or C;

[0049] In some implementations, Z3 is selected from N;

[0050] In some implementation schemes, R 1 Selected from , , , ;

[0051] In some implementation schemes, R 1 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0052] In some implementation schemes, R 1 Selected from , , , , , , , , , , , , , , , , , , ;

[0053] In some implementation schemes, R 1a Selected from C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0054] In some implementation schemes, R 1b R 1c R 1d Each was independently selected from C 1-6 Alkyl, C 3-6 cycloalkyl, NH2, NHC1-6 Alkyl, N(C) 1-6 Alkyl)2, NHC 3-6 Carbocyclic group, N(C) 3-6 2, NH- (4-6 membered heterocyclic group), 4- to 10 membered heterocyclic group linked by a nitrogen atom, wherein the NH, alkyl, cycloalkyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0055] As an option, R 1a With R 1b Direct linkage forms a 4- to 7-membered heterocyclic group, wherein the heterocyclic group is optionally bounded by 1 to 4 R... k replace;

[0056] In some implementation schemes, R 1a R 1c R 1d Each was independently selected from C 1-4 Alkyl or C 3-6 Cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally composed of 1 to 4 elements selected from deuterium, halogen, halogen, CN, C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 Substituents of cycloalkyl groups;

[0057] In some implementation schemes, R 1b R 1c R 1d Each was independently selected from C 1-4 Alkyl, C 3-6 cycloalkyl, NH2, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, NHC 3-6 cycloalkyl, N(C) 3-6 2, NH- (4-6 membered heterocyclic group), or 4- to 10-membered heterocyclic group linked by a nitrogen atom, wherein the NH, alkyl, cycloalkyl, or heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace;

[0058] As an option, R 1a With R 1b Direct linkage forms a 4- to 7-membered heterocyclic group, wherein the heterocyclic group is optionally bounded by 1 to 4 R... k replace;

[0059] In some implementation schemes, R 1aThe methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups are selected from methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups, wherein 1 to 4 of the methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups are selected from deuterium, halogen, CN, or C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 Substituents of cycloalkyl groups;

[0060] In some implementation schemes, R 1b R 1c R 1d Each of the following groups, independently selected from NH2 and optionally substituted, is: methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, NH-isopropyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -NH-oxacyclobutyl. , , , , When substituted, it is selected from 1 to 4 elements chosen from deuterium, halogen, halogen, CN, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, OH, CH2OH, CF3CH2, CH3OCH2, CF3, CHF2, CH2F, CH2CN, NH2, -NHCH3, -N(CH3)2, CONH2, -CONHCH3, -CON(CH3)2 , , , , , , , , The substituents are replaced;

[0061] In some implementation schemes, R 1b R 1c R 1dEach group is independently selected from NH2 and optionally substituted with one of the following groups: methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -NH-oxacyclobutyl, , , , , When substituted, it is replaced by 1 to 4 radicals selected from deuterium, F, Cl, Br, CN, methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, oxetyl, aziroxy, ethynyl, OH, CH2OH, CF3CH2, CH3OCH2, CF3, CHF2, CH2F, CH2CN, NH2, -NHCH3, -N(CH3)2, CONH2, -CONHCH3, -CON(CH3)2. , , , , , , , , The substituents are replaced;

[0062] As an option, R 1a With R 1b Direct connection to form 4 to 7-membered heterocyclic alkyl groups (e.g. Selected from , The heterocyclic alkyl group is optionally surrounded by 1 to 4 R... k replace;

[0063] In some implementation schemes, R 3 Selected from H, deuterium, halogens, CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, ynyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0064] In some implementation schemes, R 3 Selected from H, deuterium, halogens, CN, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, ynyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0065] In some implementation schemes, R 3 Selected from H, deuterium, F, Cl, methyl, deuterated methyl or fluoromethyl;

[0066] In some implementations, ring S is selected from C 6-10 Aryl or 5 to 10-membered heteroaryl groups;

[0067] In some embodiments, the ring S is selected from phenyl, benzo[3]C 4-6 Carbocyclic, benzo4- to 6-membered heterocyclic, 5- to 6-membered heteroaryl or 8- to 10-membered fused-ring heteroaryl;

[0068] In some embodiments, ring S is selected from phenyl or 5- to 6-membered heteroaryl groups;

[0069] In some embodiments, the ring S is selected from phenyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl.

[0070] In some implementations, ring S is selected from , , , Left side and R 1 Direct connection;

[0071] In some implementation schemes, Selected from , , , , , , , , , , , , Left side and R 1 Direct connection;

[0072] In some embodiments, the ring T is selected from phenyl, 5- to 6-membered heteroaryl, benzo[C] 4-6 Carbocyclic, benzo4- to 6-membered heterocyclic or 8- to 10-membered fused-ring heteroaryl;

[0073] In some embodiments, the ring T is selected from phenyl, thienyl, furanyl, pyridyl, pyrimidinyl, pyridoneyl, benzocyclopentyl, imidazopyridyl, pyrazolopyridyl, and pyrrolopyridyl.

[0074] In some embodiments, the ring T is selected from phenyl, thiophene, or pyridinyl;

[0075] In some implementation schemes, Selected from , , , , , , , , , , , , , , , , or ;

[0076] In some implementation schemes, Selected from ;

[0077] R t2 The methyl or ethyl group is selected from methyl or ethyl, wherein the methyl or ethyl group is optionally substituted by 1 to 5 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl.

[0078] In some implementation schemes, R 2 R z1 R z2 R z3 Each element is independently selected from H, deuterium, halogens, CN, OH, 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, -S(=O)C 1-6 Alkyl group, -S(=O)C 3-7 Carbocyclic group, -NHS(=O)C 1-6 Alkyl group, -S(=O)2C 1-6 Alkyl group, -S(=O)2C 3-7 Carbocyclic group, -NHS(=O)2C 1-6 Alkyl group, -S(=O)2NHC 1-6 Alkyl, -P(=O)(C 1-6 Alkyl)2, wherein the alkylene, alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 Rk replace;

[0079] As an option, R 2 R z3 Direct connection forms C 4-6 A carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0080] As an option, R 2 R z1 Direct connection forms C 4-6 A carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0081] In some implementation schemes, R 2 R z1 R z2 R z3 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, -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, wherein the alkylene, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R k replace;

[0082] As an option, R 2 R z3 Direct connection forms C 4-6 A carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. kreplace;

[0083] As an option, R 2 R z1 Direct connection forms C 4-6 A carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0084] In some implementation schemes, R 2 R z1 R z2 R z3 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 Alkylene-4 to 7-membered heterocyclic group, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0085] In some implementation schemes, R s R t Each element is independently selected from deuterium, halogens, CN, OH, NH2, SF5, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-7 carbonyl group, -OC 1-4 Alkylene-C 3-7 carbonyl group, -SC 3-7 carbonyl group, -SC 1-4 Alkylene-C 3-7 Carbocyclic group, -C 0-4 Alkylene-C 3-7 Carbocyclic group, -C 0-4 Alkyl-4 to 7-membered heterocyclic groups, -S(=O)C 1-6 Alkyl group, -S(=O)C 3-7 Carbocyclic group, -NHS(=O)C1-6 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 5 R k replace;

[0086] In some implementation schemes, R s R t Each element is independently selected from deuterium, halogens, CN, OH, NH2, SF5, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 1-2 Alkylene-C 3-6 cycloalkyl, -SC 3-6 cycloalkyl, -SC 1-2 Alkylene-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, -S(=O)C 1-4 Alkyl group, -S(=O)C 3-6 cycloalkyl, -NHS(=O)C 1-4 Alkyl group, -S(=O)2C 1-4 Alkyl group, -S(=O)2C 3-6 cycloalkyl, -NHS(=O)2C 1-4 Alkyl group, -S(=O)2NHC 1-4 Alkyl, -P(=O)(C 1-4 Alkyl)2, phenyl or 5 to 6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, carbocyclic, heterocyclic, phenyl or heteroaryl group is optionally surrounded by 1 to 5 R groups. k replace;

[0087] In some implementation schemes, R s R tEach of these groups is independently selected from deuterium, F, Cl, Br, CN, OH, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -S-CH 2-Cyclopropyl, -S-CH2-Cyclobutyl, -P(=O)(CH3)2, phenyl, thiophene, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazole, pyrazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl, wherein CH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, phenyl, thiophene, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazole, pyrazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl are optionally surrounded by 1 to 5 R k replace;

[0088] In some implementation schemes, R s Each is independently selected from deuterium, F, Cl, Br, CN, OH, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -P(=O)(CH3)2, thiazolyl, oxazolyl, imidazole, pyrazolyl, thiadiazole The group consisting of methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, thiazolyl, oxazolyl, imidazole, pyrazolyl, thiazolyl, oxazolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazolyl, or triazolyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, or ethoxy.

[0089] In some implementation schemes, R 2 R z1 R z2 Each of the following is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl groups are optionally selected by 1 to 4 of the following: deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, and C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0090] In some implementation schemes, R 2 R z1 R z2 Each of the following groups is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl 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, or ethyl.

[0091] In some implementation schemes, R 2 R z1 R z2 Each of the following groups is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl 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, ethyl, methoxy, or ethoxy.

[0092] In some implementation schemes, R 2 Selected from H, R z1 Selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, CF3, CHF2, CH2F, CD3, CHD2, CH2D, cyclopropyl;

[0093] In some implementation schemes, R t1 Selected from H, deuterium, halogens, CN, OH, NH2, SF5, 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, -OC 1-2 Alkylene-C 3-6 cycloalkyl, -SC 3-6 cycloalkyl, -SC 1-2 Alkylene-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, -S(=O)C 1-4 Alkyl group, -S(=O)C 3-6cycloalkyl, -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, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 5 R k replace;

[0094] In some implementation schemes, R t1 Selected from H, deuterium, F, Cl, Br, CN, OH, NH2, SF5, 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, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -S-CH2-cyclopropyl, -S-CH2-cyclobutyl, oxacyclobutyl, tetrahydrofuranyl, -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, or tetrahydrofuranyl is optionally surrounded by 1 to 5 R... k replace;

[0095] In some implementation schemes, R t1 The molecule is selected from SF5, methyl, ethyl, methoxy, ethoxy, -S-methyl, -S-ethyl, -O-cyclopropyl, -O-cyclobutyl, -OCH2-cyclopropyl, -OCH2-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -SCH2-cyclopropyl, -SCH2-cyclobutyl, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl group is optionally substituted by 1 to 5 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl;

[0096] In some implementation schemes, R k Each element is independently selected from deuterium, O, halogens, CN, OH, COOH, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic groups, -O-4 to 7-membered heterocyclic groups, -NH-C 3-6 Carbocyclic groups, -NH-4 to 7-membered heterocyclic groups, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 alkylene-4 to 7-membered heterocyclic groups, C 3-6 The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic group may optionally contain 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 alkoxy- or cyano-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, halogen-substituted C 1-6 Substituents of alkyl groups;

[0097] In some implementation schemes, R k Each element is independently selected from deuterium, O, 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 The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic group may optionally contain 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 alkoxy- or cyano-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, halogen-substituted C 1-6 Substituents of alkyl groups;

[0098] In some implementation schemes, R kEach of the following groups is independently selected from deuterium, =O, F, Cl, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl Cyclopentyl, cyclohexyl, oxecyclobutyl, oxecyclopentyl, oxecyclohexyl, aziroxybutyl, pyrrolylyl, piperidinyl, piperazine, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxecyclobutyl, oxecyclopentyl, oxecyclohexyl, aziroxybutyl, pyrrolylyl, piperidinyl, piperazine are optionally selected from 1 to 4 elements selected from deuterium, halogen, CN, OH, NH2, C. 1-4 Alkyl, C 1-4 alkoxy- or cyano-substituted C 1-4 Alkyl, hydroxyl substituted C 1-4 Alkyl, halogen-substituted C 1-4 Substituents of alkyl groups;

[0099] In some implementation schemes, R k Each of these groups is independently selected from deuterium, =O, NH2, F, Cl, Br, I, CN, OH, -CH2OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, N(CH3)2, NH(CH3), methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl The methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxecyclobutyl, oxecyclopentyl, oxecyclohexyl, oxecyclobutyl, pyrrolyl, piperidinyl, and piperazine groups are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, -CH2CN, -CH2F, -CH2OH, CF3, and CHF2.

[0100] In some implementations, n1 and n2 are each independently selected from 0, 1, 2, 3 or 4;

[0101] In some implementation schemes, Selected from 1 to 3 Rs m One of the following groups is substituted: , , , , , , , , ;

[0102] In some implementation schemes, Selected from , , , , , ;

[0103] In some embodiments, ring S is selected from phenyl or 5- to 6-membered heteroaryl groups;

[0104] In some implementations, ring S is selected from , , , Left side and R 1 Direct connection;

[0105] In some implementations, Y is selected from N or CH;

[0106] In some implementations, n3 is selected from 0, 1, 2, or 3;

[0107] Optionally, the general formula (IA) is not... .

[0108] As a first embodiment of the present invention, the compound represented by the above general formulas (IA) and (I), or its racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is used.

[0109] Selected from or ;

[0110] Ring M is selected from a 5-membered heteroaryl group or a 5-membered unsaturated heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally surrounded by 1 to 4 R groups. m replace;

[0111] R m Each element is independently selected from deuterium, halogens, CN, =O, =S, OH, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4- to 7-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic alkyl is optionally surrounded by 1 to 4 R... k replace;

[0112] X is selected from N, O, S, C(R) x ), C(R x )2 or N(R x );

[0113] R x Each is independently selected from H, -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-6 cycloalkyl, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0114] Q is selected from C, C(R) q1 ), C(R q1 2. C(=O), C(=S), C=N(R) q2 C=C(R) q3 )2, S(=O), S(=O) (=NH), S(=O)2; R q1 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;

[0115] R q2 R q3 Each element is independently selected from H, CN, OH, NH2, and 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;

[0116] W is selected from -CR w1 R w2 -、-(CR w1 R w2 )2-;

[0117] R w1 R w2 Each element is independently selected from H, deuterium, halogens, and C. 1-6 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0118] As an option, R w1 R w2 Direct connection forms C 3-6 cycloalkyl group, wherein the cycloalkyl group is optionally surrounded by 1 to 4 R groupsk replace;

[0119] Cycle A is selected from 5-membered heteroaryl groups, , , , , ;

[0120] Z1 is selected from N or C(R) z1 );

[0121] Z2 is selected from N or C(R) z2 );

[0122] Z3 is selected from N or C(R) z3 );

[0123] Z4 is selected from N or C;

[0124] Z5 is selected from N or C; Z6 is selected from N or C;

[0125] R 1 Selected from , , , ;

[0126] R 1a Selected from C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0127] R 1b R 1c R 1d Each was independently selected from C 1-6 Alkyl, C 3-6 cycloalkyl, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, NHC 3-6 Carbocyclic group, N(C) 3-6 2, NH- (4-6 membered heterocyclic group), 4- to 10 membered heterocyclic group linked by a nitrogen atom, wherein the NH, alkyl, cycloalkyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0128] As an option, R 1a With R 1b Direct linkage forms a 4- to 7-membered heterocyclic group, wherein the heterocyclic group is optionally bounded by 1 to 4 R... k replace;

[0129] R 3 Selected from H, deuterium, halogens, CN, C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, ynyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0130] Ring S is selected from C 6-10 Aryl or 5 to 10-membered heteroaryl groups;

[0131] The ring T is selected from phenyl, 5- to 6-membered heteroaryl, and benzo[C]. 4-6 Carbocyclic, benzo4- to 6-membered heterocyclic or 8- to 10-membered fused-ring heteroaryl;

[0132] R 2 R z1 R z2 R z3 Each element is independently selected from H, deuterium, halogens, CN, OH, 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, -S(=O)C 1-6 Alkyl group, -S(=O)C 3-7 Carbocyclic group, -NHS(=O)C 1-6 Alkyl group, -S(=O)2C 1-6 Alkyl group, -S(=O)2C 3-7 Carbocyclic group, -NHS(=O)2C 1-6 Alkyl group, -S(=O)2NHC 1-6 Alkyl, -P(=O)(C 1-6 Alkyl)2, wherein the alkylene, alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R k replace;

[0133] As an option, R 2 R z3 Direct connection forms C 4-6 A carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0134] As an option, R 2 R z1 Direct connection forms C 4-6A carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0135] R s R t Each element is independently selected from deuterium, halogens, CN, OH, NH2, SF5, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-7 carbonyl group, -OC 1-4 Alkylene-C 3-7 carbonyl group, -SC 3-7 carbonyl group, -SC 1-4 Alkylene-C 3-7 Carbocyclic group, -C 0-4 Alkylene-C 3-7 Carbocyclic group, -C 0-4 Alkyl-4 to 7-membered heterocyclic groups, -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 5 R k replace;

[0136] R k Each element is independently selected from deuterium, O, 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 1-4alkylene-4 to 7-membered heterocyclic groups, C 3-6 The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic group may optionally contain 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 alkoxy- or cyano-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, halogen-substituted C 1-6 Substituents of alkyl groups;

[0137] n1 and n2 are each independently selected from 0, 1, 2, 3 or 4.

[0138] As a second embodiment of the present invention, the compound represented by the above general formula (IA) or its racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof

[0139] R m Each element is independently selected from deuterium, halogens, CN, =O, =S, OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4- to 7-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic alkyl is optionally surrounded by 1 to 4 R... k replace;

[0140] R x Each is independently selected from H, -C(=O)-C 1-4 Alkyl, -C(=O)-C 3-6 cycloalkyl, C 1-4 Alkyl, C 3-6 cycloalkyl, -C 1-2 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0141] R q1 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;

[0142] R q2 R q3 Each element is independently selected from H, CN, OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6Cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0143] R 1a Selected from C 1-4 Alkyl or C 3-6 Cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally composed of 1 to 4 elements selected from deuterium, halogen, halogen, CN, C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 Substituents of cycloalkyl groups;

[0144] R 1b R 1c R 1d Each was independently selected from C 1-4 Alkyl, C 3-6 cycloalkyl, NH2, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, NHC 3-6 cycloalkyl, N(C) 3-6 2, NH- (4-6 membered heterocyclic group), or 4- to 10-membered heterocyclic group linked by a nitrogen atom, wherein the NH, alkyl, cycloalkyl, or heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace;

[0145] As an option, R 1a With R 1b Direct linkage forms a 4- to 7-membered heterocyclic group, wherein the heterocyclic group is optionally bounded by 1 to 4 R... k replace;

[0146] R w1 R w2 Each element is independently selected from H, deuterium, halogens, and C. 1-4 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0147] As an option, R w1 R w2 Direct connection forms C 3-6 cycloalkyl group, wherein the cycloalkyl group is optionally surrounded by 1 to 4 R groups k replace;

[0148] R 3 Selected from H, deuterium, halogens, CN, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6Cycloalkyl, wherein the alkyl, alkenyl, ynyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0149] The ring S is selected from phenyl, benzo[3]C 4-6 Carbocyclic, benzo4- to 6-membered heterocyclic, 5- to 6-membered heteroaryl or 8- to 10-membered fused-ring heteroaryl;

[0150] R 2 R z1 R z2 R z3 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, -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, wherein the alkylene, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R k replace;

[0151] As an option, R 2 R z3 Direct connection forms C 4-6 A carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0152] As an option, R 2 R z1 Direct connection forms C 4-6 A carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0153] R s R t Each element is independently selected from deuterium, halogens, CN, OH, NH2, SF5, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 1-2 Alkylene-C 3-6 cycloalkyl, -SC 3-6 cycloalkyl, -SC 1-2 Alkylene-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, -S(=O)C 1-4 Alkyl group, -S(=O)C 3-6 cycloalkyl, -NHS(=O)C 1-4 Alkyl group, -S(=O)2C 1-4 Alkyl group, -S(=O)2C 3-6 cycloalkyl, -NHS(=O)2C 1-4 Alkyl group, -S(=O)2NHC 1-4 Alkyl, -P(=O)(C 1-4 Alkyl)2, phenyl or 5 to 6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, carbocyclic, heterocyclic, phenyl or heteroaryl group is optionally surrounded by 1 to 5 R groups. k replace;

[0154] R k Each element is independently selected from deuterium, O, 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 1-2alkylene-4 to 7-membered heterocyclic groups, C 3-6 The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic group may optionally contain 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 alkoxy- or cyano-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, halogen-substituted C 1-6 Substituents of alkyl groups;

[0155] The definitions of the remaining functional groups are the same as those in the first embodiment of the present invention.

[0156] As a third embodiment of the present invention, the compounds represented by the above general formulas (IA) and (I), or their racemic mixtures, stereoisomers, tautomers, or pharmaceutically acceptable salts, are used.

[0157] Selected from , , , , , , , , , , ;

[0158] Selected from 1 to 3 Rs m One of the following groups is substituted: , , , , , , , , ;

[0159] Selected from , , , , , ;

[0160] R w1 R w2 Each of the following groups is independently selected from H, deuterium, F, Cl, Br, methyl, ethyl, and cyclopropyl, wherein the methyl, ethyl, and cyclopropyl groups are optionally surrounded by 1 to 4 R groups. k replace;

[0161] As an option, Rw1 R w2 Direct linkage to form cyclopropyl and cyclobutyl groups, wherein the cyclopropyl and cyclobutyl groups are optionally coupled with 1 to 4 R groups. k replace;

[0162] The ring S is selected from phenyl or 5- to 6-membered heteroaryl groups;

[0163] Selected from , , , , , , , , , , , , , , , , or ;

[0164] Y is selected from N or CH;

[0165] R 1a The methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups are selected from methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups, wherein 1 to 4 of the methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups are selected from deuterium, halogen, CN, or C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 Substituents of cycloalkyl groups;

[0166] R 1b R 1c R 1d Each of the following groups, independently selected from NH2 and optionally substituted, is: methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, NH-isopropyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -NH-oxacyclobutyl. , , , , When substituted, it is selected from 1 to 4 elements chosen from deuterium, halogen, halogen, CN, and C. 1-4 Alkyl, C 2-4 alkenyl, C2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, OH, CH2OH, CF3CH2, CH3OCH2, CF3, CHF2, CH2F, CH2CN, NH2, -NHCH3, -N(CH3)2, CONH2, -CONHCH3, -CON(CH3)2 , , , , , , , , The substituents are replaced;

[0167] As an option, R 1a With R 1b Direct linkage forms 4- to 7-membered heterocyclic alkyl groups, wherein the heterocyclic alkyl group is optionally bounded by 1 to 4 R groups. k replace;

[0168] R t1 Selected from H, deuterium, halogens, CN, OH, NH2, SF5, 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, -OC 1-2 Alkylene-C 3-6 cycloalkyl, -SC 3-6 cycloalkyl, -SC 1-2 Alkylene-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, -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 1-4Alkyl)2, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 5 R k replace;

[0169] n3 is selected from 0, 1, 2, or 3;

[0170] The definitions of the remaining functional groups are the same as those in the first or second embodiment of the present invention.

[0171] As a fourth embodiment of the present invention, the compound represented by the above general formulas (IA) and (I), or its racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is used.

[0172] R m Each of the following is independently selected from deuterium, F, Cl, Br, CN, OH, methyl, ethyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl groups are optionally selected by 1 to 4 of the following: deuterium, halogen, CF3, CHF2, CH2F, CD3, CHD2, CH2D, and C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0173] W is selected from -CH2-, -CH(CH3)-, -CH(CF3)-, -CH(CD3)-, -CFH-, -CF2-, -CH2CH2- or ;R 2 R z1 R z2 Each of the following is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl groups are optionally selected by 1 to 4 of the following: deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, and C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0174] R x Selected from H, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH(CH3)2, -C(=O)-cyclopropyl, methyl, ethyl, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, cyclopropyl, or cyclobutyl group is optionally surrounded by 1 to 4 R groups. k replace;

[0175] R q1The group is selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, or cyclopropyl, wherein the methyl, ethyl, or cyclopropyl group is optionally replaced by 1 to 4 groups selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0176] R q2 The methyl, ethyl, methoxy, and ethoxy groups are selected from H, OH, CN, NH2, methyl, ethyl, methoxy, and ethoxy groups, wherein the methyl, ethyl, methoxy, and ethoxy groups are optionally replaced by 1 to 4 deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, and C groups. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0177] The ring S is selected from phenyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl.

[0178] R 1 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ;

[0179] R s 、R tEach of these groups is independently selected from deuterium, F, Cl, Br, CN, OH, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -S-CH 2-Cyclopropyl, -S-CH2-Cyclobutyl, -P(=O)(CH3)2, phenyl, thiophene, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazole, pyrazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl, wherein CH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, phenyl, thiophene, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazole, pyrazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl are optionally surrounded by 1 to 5 R k replace;

[0180] R t1 Selected from H, deuterium, F, Cl, Br, CN, OH, NH2, SF5, 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, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -S-CH2-cyclopropyl, -S-CH2-cyclobutyl, oxacyclobutyl, tetrahydrofuranyl, -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, or tetrahydrofuranyl is optionally surrounded by 1 to 5 R... k replace;

[0181] R kEach of the following groups is independently selected from deuterium, =O, F, Cl, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl Cyclopentyl, cyclohexyl, oxecyclobutyl, oxecyclopentyl, oxecyclohexyl, aziroxybutyl, pyrrolylyl, piperidinyl, piperazine, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxecyclobutyl, oxecyclopentyl, oxecyclohexyl, aziroxybutyl, pyrrolylyl, piperidinyl, piperazine are optionally selected from 1 to 4 elements selected from deuterium, halogen, CN, OH, NH2, C. 1-4 Alkyl, C 1-4 alkoxy- or cyano-substituted C 1-4 Alkyl, hydroxyl substituted C 1-4 Alkyl, halogen-substituted C 1-4 Substituents of alkyl groups;

[0182] Preferably, R k Each of these groups is independently selected from deuterium, =O, NH2, F, Cl, Br, I, CN, OH, -CH2OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, N(CH3)2, NH(CH3), methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl The methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxecyclobutyl, oxecyclopentyl, oxecyclohexyl, oxecyclobutyl, pyrrolyl, piperidinyl, and piperazine groups are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, -CH2CN, -CH2F, -CH2OH, CF3, and CHF2.

[0183] The definitions of the remaining functional groups are the same as those in the first, second, or third embodiments of the present invention.

[0184] As a fifth embodiment of the present invention, the compound represented by the above general formulas (IA) and (I), or its racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, is used.

[0185] R mEach is independently selected from deuterium, F, Cl, Br, CN, methyl, ethyl, cyclopropyl, CF3, CHF2, CH2F, CD3, CHD2, CH2D, CH2CD3, CH2CF3;

[0186] Ring S is selected from , , , Left side and R 1 Direct connection;

[0187] R t1 The molecule is selected from SF5, methyl, ethyl, methoxy, ethoxy, -S-methyl, -S-ethyl, -O-cyclopropyl, -O-cyclobutyl, -OCH2-cyclopropyl, -OCH2-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -SCH2-cyclopropyl, -SCH2-cyclobutyl, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl group is optionally substituted by 1 to 5 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl;

[0188] R x The group is selected from H, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH(CH3)2, -C(=O)-cyclopropyl, methyl, ethyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, cyclopropyl, and cyclobutyl 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, or ethyl.

[0189] R q1 The group is selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl or cyclopropyl, wherein the methyl, ethyl or cyclopropyl group is optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl;

[0190] R q2 The group is selected from H, OH, CN, NH2, methyl, ethyl, methoxy, ethoxy, wherein the methyl, ethyl, methoxy, ethoxy group is optionally replaced by 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl;

[0191] R 2 R z1 R z2Each of the following groups is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl 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, ethyl, methoxy, or ethoxy.

[0192] Preferably, R s Each is independently selected from deuterium, F, Cl, Br, CN, OH, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -P(=O)(CH3)2, thiazolyl, oxazolyl, imidazole, pyrazolyl, thiadiazole The group consisting of methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, thiazolyl, oxazolyl, imidazole, pyrazolyl, thiazolyl, oxazolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazolyl, or triazolyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, or ethoxy.

[0193] The definitions of the remaining functional groups are the same as those in the first, second, third, or fourth embodiments of the present invention.

[0194] As a sixth embodiment of the present invention, the compound represented by general formula (IA) or (I) above, or its racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (IA) or (I) is selected from the compound represented by general formula (II).

[0195] (II);

[0196] R x Selected from CF3, CD3, or cyclopropyl;

[0197] S1 or S2 is selected from N, CH or CR s ;

[0198] n4 is selected from 0, 1, or 2;

[0199] R s Each is independently selected from deuterium, F, Cl, Br, CN, OH, methyl, ethyl, methoxy, and cyclopropyl;

[0200] R 1The definition is the same as the corresponding definition in the first, second, or third embodiment of the present invention;

[0201] Preferably, R 1 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0202] More preferably, R 1 Selected from , , , , , , , , , , , , , , , , , , .

[0203] 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, preferably the compound structure shown in Table E-1.

[0204] Table E

[0205]

[0206] Table E-1

[0207]

[0208] 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.

[0209] 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.

[0210] 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").

[0211] 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 disease or condition being treated (e.g., autoimmune diseases or inflammatory diseases, preferably psoriasis, rheumatoid arthritis, Crohn's disease, and ulcerative colitis). 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.

[0212] 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.

[0213] 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, rheumatoid arthritis, Crohn's disease and ulcerative colitis).

[0214] 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.

[0215] 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.

[0216] 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, rheumatoid arthritis, Crohn's disease, and ulcerative colitis).

[0217] This invention relates to the use of the above-described pharmaceutical composition in the preparation of medicaments for treating autoimmune diseases or inflammatory diseases (preferably psoriasis, rheumatoid arthritis, Crohn's disease, and ulcerative colitis).

[0218] The amounts of racemic, stereoisomer, tautomer, and pharmaceutically acceptable salts of the compounds of this invention are converted in each case as free bases.

[0219] Synthesis Method 1:

[0220]

[0221] 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 iodomethane under alkaline conditions to give the corresponding general formula (Z4). General formula (Z4) reacts with pinacol diborate under palladium catalysis to give the corresponding general formula (Z5). General formula (Z5) and general formula (Z6) are coupled under palladium catalysis to give the corresponding general formula (Ia').

[0222] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0223] The compounds of this invention include their racemic, stereoisomer, tautomer, deuterated, solvated, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal.

[0224] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0225] The carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds described in this invention include their isotopic forms. That is, the carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds described in this invention may be optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 11 C 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 15 O、 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S, 35 S and 36 S, nitrogen isotopes include 13 N、 14 N and 15 N, isotopes of fluorine include 17 F, 18 F and 19 F, isotopes of chlorine include 35 Cl、 36 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br, an isotope of iodine, includes 123 I, 125 I, phosphorus isotopes include 31 P, 32 P.

[0226] “CN” refers to cyano.

[0227] "Halogen" refers to F, Cl, Br or I.

[0228] "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".

[0229] "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.

[0230] "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.

[0231] "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.

[0232] "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.

[0233] "Alkenyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon double bonds. The main chain has, but is not limited to, 2 to 10, 2 to 6, or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-... The alkenyl group can be monovalent, divalent, trivalent, or tetravalent, including methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene.

[0234] "Alynyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon triple bonds. The main chain comprises 2 to 10 carbon atoms, including but not limited to having 2 to 6 carbon atoms on the main chain, or 2 to 4 carbon atoms on the main chain. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, and 4-pentynyl. The alkynyl group can be monovalent, divalent, trivalent, or tetravalent. Examples of alkynyl groups include: 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-hepynyl, 2-hepynyl, 3-hepynyl, 4-hepynyl, 1-octyynyl, 3-octyynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.

[0235] "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.

[0236] "Carbocyclic group" or "carbocyclic ring" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered quaternary system. The carbocyclic group can be attached to an aromatic or non-aromatic ring, and the ring can be optionally a monocyclic, fused, bridged, or spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, etc. , , or "Carbocyclic group" or "carbon ring" can be monovalent, divalent, trivalent or tetravalent.

[0237] "Heterocyclic group" or "heterocyclic" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered quaternary system, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The C, N, S or Se selectively substituted in the ring of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused, or spirocyclic ring. Non-limiting examples include epoxyethyl, azirropropyl, oxacyclobutyl, azirrobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxahexacycloyl, azirroheptyl, pyridinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithioyl, dihydrofuranyl, dihydropyranyl, dithiapentylcycloyl. Tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophene, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl, , , , , , , , , , , , "Heterocyclic group" or "heterocyclic ring" can be monovalent, divalent, trivalent or tetravalent.

[0238] "Spirocyclic" or "spirocyclic group" refers to a polycyclic group in which substituted or unsubstituted rings share a single atom (called a spiro atom). The number of ring atoms in a spirocyclic system includes, but is not limited to, 5 to 20, 6 to 14, 6 to 12, or 6 to 10. One or more rings may contain 0 or more (including but not limited to 1, 2, 3, or 4) double bonds, and optionally may contain 0 to 5 double bonds selected from N, O, or S (=O). n Heteroatoms (n is 0, 1, or 2). Non-limiting embodiments include:

[0239] "Spirocyclic" or "spirocyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0240] "Burying" or "burying group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with the other rings in the system. One or more rings may contain zero or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted. Each ring in the burying system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to those selected from N, S (=O)). n Or O, where n is 0, 1, or 2). The number of ring atoms in a cyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include:

[0241] "Cyclone" or "cyclone base" can be monovalent, divalent, trivalent, or tetravalent.

[0242] A “bridged ring” or “bridged ring group” refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain zero or more double bonds. Any ring in a bridged ring system may contain 0 to 5 groups selected from heteroatoms or containing heteroatoms (including but not limited to N, S(=O)n, or O, where n is 0, 1, or 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include: Cubicane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0243] "Carbon spirocyclic", "spirocyclic carbon cyclic", "spirocarbon cyclic", or "carbon spirocyclic" refers to a spirocyclic system composed only of carbon atoms.

[0244] "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.

[0245] "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.

[0246] "Hybrid monocyclic", "monocyclic heterocyclic group" or "hybrid monocyclic group" refers to the "heterocyclic group" or "heterocyclic" in a monocyclic system.

[0247] "Hydrocyclic ring", "hydrocyclic cyclic group", "fused cyclic heterocyclic group" or "fused heterocyclic group" refers to a "fused ring" containing heteroatoms.

[0248] "Heterospirocyclic", "heterospirocyclic group", "spirocyclic heterocyclic group" or "spiroheterocyclic group" refers to a "spirocycle" containing heteroatoms.

[0249] "Hybrid-bridged ring", "hybrid-bridged ring group", "bridged ring heterocyclic group" or "bridged heterocyclic group" refers to a "bridged ring" containing heteroatoms.

[0250] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring. Non-limiting embodiments include benzene rings, naphthalene rings, etc. The "aryl" or "aryl ring" can be monovalent, divalent, trivalent, or tetravalent. When it is divalent, trivalent, or tetravalent, the linker site is located on the aryl ring.

[0251] "Heteroaryl" or "heteroary ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or a group containing heteroatoms (including but not limited to N, O, S(=O)n or Se(=O)n, where n is 0, 1, or 2). The number of ring atoms in the heteroaryl ring includes, but is not limited to, 5 to 15, 5 to 10, or 5 to 6. The atoms C, N, and S on the ring may be optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, where n is 1 or 2). Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furanyl, thiophenyl, selenyl, pyridyl, pyranyl, N-alkylpyrrolithyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazoleyl, benzopyrazolyl, benzimidazoleyl, benzopyridyl, pyrrolopyridyl, pyridinoneyl, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbon ring or heterocycle, wherein the ring connected to the parent structure is an aryl ring. Non-limiting embodiments include: , , The definition of heteroaryl groups used in this paper is consistent with that in this paper. Heteroaryl groups can be monovalent, divalent, trivalent, or tetravalent. When they are divalent, trivalent, or tetravalent, the linking site is located on an aromatic ring.

[0252] "Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4, or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged cyclic, spirocyclic, fused cyclic, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, and ‒(CH2). m ‒C(=O)‒R a 、‒O‒(CH2) m ‒C(=O)‒R a 、‒(CH2) m ‒C(=O)‒NR b R c 、‒(CH2) m S(=O) n R a 、‒(CH2) m ‒Alkenyl‒R a OR d Or (CH2) m ‒Alkyne‒R a (where m and n are 0, 1, or 2), arylthio, thiocarbonyl, silyl, or ‒NR b R c Groups, wherein R b With R c Independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, R b With R c It can form five- or six-membered cycloalkyl or heterocyclic groups, R a With R d Each group is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic, carbonyl, ester, bridged cyclic, spirocyclic, or fused cyclic groups.

[0253] "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. kSubstitution. 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.

[0254] X-Y member rings (where X and Y are integers, and 3 ≤ X < Y, X < Y ≤ 20, selected from any integer between 4 and 20) include rings of the X, X+1, X+2, X+3, X+4…Y member categories. These rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterofused rings, heterospirocyclic rings, or heterobridged rings. For example, “4-7 member heteromonocyclic rings” refers to heteromonocyclic rings of 4, 5, 6, or 7 members, and “5-10 member heterofused rings” refers to heterofused rings of 5, 6, 7, 8, 9, or 10 members.

[0255] C x-y Carbocyclic rings (including aryl, cycloalkyl, monocyclic, spirocyclic, fused, or bridged carbocyclic rings) include C x C x+1 C x+2 C x+3 C x+4 …. C y A ring of elements (x is an integer, and 3 ≤ x < y, where y is any integer between 4 and 20), for example, C. 3‒6 "Cycloalkyl" refers to C3, C4, C5, or C6 cycloalkyl groups.

[0256] When a functional group has one or more connectable sites, any one or more of these sites can be linked to other functional groups via chemical bonds. When the chemical bond connection is non-directional and a hydrogen atom is present at the connectable site, the number of hydrogen atoms at that site decreases accordingly with the number of bonds being formed, resulting in a functional group with a corresponding valence. For example... This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... These four connection methods, even if an H atom is drawn on -N-, This also includes .For example This indicates that the R group on the piperidinyl group can be located on C or N, and at least includes [missing information]. For example, the general formula fragment is: When X is selected from CH2 or NH, it means that the R group on the general formula fragment can be located on C or X. When X is selected from CH2, the general formula fragment can be... , When X is selected from NH, the general formula fragment can be: .

[0257] Unless otherwise stated, key ( ) indicates that the configuration is not specified, meaning that if chiral isomers exist in the chemical structure, the bond ( ) can be ( )or( ), or simultaneously include ( )or( Two configurations. Using wedge-shaped solid line keys ( ) and wedge-shaped dashed key ( The absolute configuration of a solid center is represented by a solid line key (). ) and straight dashed line key ( ) represents the relative configuration of the solid center. (Key) ) indicates that no configuration is specified, which can be Z configuration or E configuration, or both configurations.

[0258] 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.

[0259] "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.

[0260] "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.

[0261] "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.

[0262] "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.

[0263] "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.

[0264] "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.

[0265] "Animals" refers to mammals, such as humans, companion animals, zoo animals, and livestock, with humans, horses, or dogs being preferred.

[0266] "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.

[0267] "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

[0268] 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.

[0269] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were measured in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0270] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0271] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM).

[0272] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used for TLC have a diameter of 0.15 mm to 0.20 mm, and the diameter of the plates used for TLC separation and purification is 0.4 mm to 0.5 mm.

[0273] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0274] To accomplish the objectives of this invention, compounds used in the reactions described herein are prepared from commercially available chemicals and / or compounds described in chemical literature, according to organic synthesis techniques known to those skilled in the art. "Commercially available chemicals" are obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai Maclean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Esa (China) Chemical Co., Ltd., THIAI (Shanghai) Chemical Industry Development Co., Ltd., Energie Chemicals, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.

[0275] Retention time: Unless otherwise specified in the embodiments, this represents the retention time corresponding to the analysis method.

[0276] Example 1: Preparation of Compound 1

[0277]

[0278] Step 1: Preparation of Compound 1

[0279] Compound 1A (20.0 mg, 0.05 mmol), compound 1B (23.6 mg, 0.08 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (3.65 mg, 0.005 mmol), and potassium carbonate (13.8 mg, 0.10 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2.5 mL) and water (0.5 mL). The reaction was carried out at 100 °C for 12 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted twice with ethyl acetate (20 mL × 2). The organic phases were combined and washed twice with water (20 mL × 2) and once with a saturated NaCl aqueous solution (20 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give compound 1 (10 mg, yield 37.26%).

[0280] LCMS m / z = 523.1 [M+H] +

[0281] 1 H NMR (400 MHz, CD3OD) δ 8.37 (dd, 1H), 7.74 (d, 1H), 7.64 (d, 1H), 7.53 – 7.42 (m, 5H), 7.27 (t, 1H), 7.16 – 7.10 (m, 2H), 6.41 (d, 1H), 5.18(d, 1H), 3.61 – 3.52 (m, 1H), 3.48 (s, 3H), 3.24 (s, 6H), 2.90 – 2.87 (m,1H).

[0282] Example 2: Preparation of Compound 2

[0283]

[0284] Step 1: Preparation of 2B

[0285] Compound 2A (2.19 g, 10.00 mmol) was dissolved in dichloromethane and cooled to 0 °C. Triethylamine (2.02 g, 20.00 mmol) was added, followed by dropwise addition of trifluoromethylsulfinyl chloride (2.28 g, 15.00 mmol). The reaction was carried out at room temperature for 2 hours. The mixture was diluted with water (20 mL) and extracted twice with dichloromethane (20 mL × 2). The organic phases were combined and washed twice with water (20 mL × 2) and once with a saturated NaCl aqueous solution (20 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give compound 2B (1.82 g, yield 54.32%).

[0286] LCMS m / z = 335.9 [M+H] +

[0287] Step 2: Preparation of 2C

[0288] Compound 2B (1.4 g, 4.2 mmol) and N-chlorosuccinimide (0.62 g, 4.6 mmol) were dissolved in acetonitrile. A THF solution of tetrabutylammonium fluoride (4.6 mL, 4.6 mmol, 1 M) was added at 0 °C, and the reaction was carried out at room temperature for 1 hour. Then, 3-(R)-fluoropyrrolidine (0.82 g, 9.2 mmol) was added, and the reaction was carried out for 2 hours. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography to give compound 2 (0.51 g, yield 28.98%).

[0289] LCMS m / z = 423.1 [M+H] +

[0290] Step 3: Preparation of Compound 2

[0291] Compound 2C (31.65 mg, 0.075 mmol), compound 2D (24.00 mg, 0.05 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (3.65 mg, 0.005 mmol), and potassium carbonate (20.70 mg, 0.15 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2.5 mL) and water (0.5 mL). The reaction was carried out at 100 °C for 12 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted twice with ethyl acetate (20 mL × 2). The organic phases were combined and washed twice with water (20 mL × 2) and once with a saturated NaCl aqueous solution (20 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give compound 2 (5 mg, yield 15.44%).

[0292] LCMS m / z = 650.1 [M+H] +

[0293] 1 H NMR (400 MHz, CD3OD) δ 8.37 (dd, 1H), 7.77 – 7.73 (s, 1H), 7.65 (d,1H), 7.56 – 7.42 (m, 5H), 7.27 (t, 1H), 7.15 – 7.13 (m, 2H), 6.41 (d, 1H),5.40 – 5.21 (m, 1H), 5.18 (d, 1H), 3.92 – 3.52 (m, 5H), 3.48 (s, 3H), 2.89(d, 1H), 2.36 – 2.04 (m, 2H).

[0294] Example 3: Preparation of Compound 3

[0295]

[0296] Compound 3 was prepared using the same method as compound 2, yielding compound 3 (10 mg).

[0297] LCMS m / z = 624.1 [M+H] +

[0298] 1H NMR (400 MHz, CD3OD) δ 8.40 – 8.34 (m, 1H), 7.75 – 7.71 (m, 1H), 7.66 (d, 1H), 7.49 – 7.36 (m, 4H), 7.20 (t, 1H), 6.95 (dd, 1H), 6.88 (dd,1H), 6.40 (d, 1H), 5.20 (d, 1H), 3.62 – 3.52 (m, 1H), 3.48 (s, 3H), 3.14 –3.08 (m, 6H), 2.89 (d, 1H).

[0299] Example 4: Preparation of Compound 4

[0300]

[0301] Compound 4 was prepared using the same method as compound 2, yielding compound 4 (5 mg).

[0302] LCMS m / z = 636.1 [M+H] +

[0303] 1 H NMR (400 MHz, CD3OD) δ 8.37 (dd, 1H), 7.75 – 7.71 (m, 1H), 7.66 (d,1H), 7.48 – 7.31 (m, 4H), 7.20 (t, 1H), 6.95 (dd, 1H), 6.87 (dd, 1H), 6.40(d, 1H), 5.20 (d, 1H), 3.62 – 3.52 (m, 1H), 3.48 (s, 3H), 2.89 (d, 1H), 2.76– 2.68 (m, 1H), 0.80 – 0.53 (m, 4H).

[0304] Example 5: Preparation of Compound 5

[0305]

[0306] Compound 5 was prepared using the same method as compound 2, yielding compound 5 (5 mg).

[0307] LCMS m / z = 608.1 [M+H] +

[0308] 1H NMR (400 MHz, CD3OD) δ 8.83 – 8.79 (m, 2H), 8.37 (dd, 1H), 7.80 (d,1H), 7.75 (d, 1H), 7.54 (dd, 1H), 7.51 – 7.45 (m, 2H), 7.31 (t, 1H), 6.45 (d,1H), 5.21 (d, 1H), 3.63 – 3.53 (m, 1H), 3.48 (s, 3H), 3.17 – 3.09 (m, 6H), 2.91 (d, 1H).

[0309] Compound 5 was obtained and then subjected to chiral resolution to yield compound 5-1 (2 mg, retention time of chiral analysis: 0.758 min) and compound 5-2 (2 mg, retention time of chiral analysis: 0.939 min). Resolution method: Instrument: CAS-05-Prep-SFC-F; Column: OX column; Mobile phase: A was CO2; B was 0.1% NH3•H2O methanol-acetonitrile solution; Flow rate: 120 mL / min; Column temperature: room temperature; Detection wavelength: 220 nm. Chiral analysis method: Instrument: CAS-05-ANA-SFC-D; Column: OX column; Mobile phase: A was CO2; B was 0.05% NH3•H2O methanol-acetonitrile solution; Flow rate: 3 mL / min; Column temperature: 35℃; Detection wavelength: 220 nm.

[0310] When compound 5-1 is structure 5-A, 5-2 is structure 5-B; conversely, when compound 5-1 is structure 5-B, 5-2 is structure 5-A.

[0311] 5-1: LCMS m / z = 608.2 [M+H] +

[0312] 1 H NMR (400 MHz, CD3OD) δ 8.81 (s, 2H), 8.39 – 8.34 (m, 1H), 7.82 – 7.73 (m 2H), 7.57 – 7.52 (m, 1H), 7.51 – 7.44 (m, 2H), 7.31 (t, 1H), 6.45 (d,1H), 5.21 (d, 1H), 3.63 – 3.53 (m, 1H), 3.48 (s, 3H), 3.13 (s, 6H), 2.91 (d,1H).

[0313] 5-2: LCMS m / z = 608.2 [M+H] +

[0314] 1 H NMR (400 MHz, CD3OD) δ 8.82 (s, 2H), 8.39 – 8.34 (m, 1H), 7.82 – 7.73 (m 2H), 7.58 – 7.52 (m, 1H), 7.51 – 7.45 (m, 2H), 7.31 (t, 1H), 6.45 (d,1H), 5.22 (d, 1H), 3.63 – 3.54 (m, 1H), 3.48 (s, 3H), 3.13 (s, 6H), 2.91 (d,1H).

[0315] Example 6: Preparation of Compound 6

[0316]

[0317] Step 1: Preparation of 6B

[0318] Compound 6A (1.0 g, 3.92 mmol) was dissolved in dichloromethane and cooled to 0 °C. Triethylamine (0.80 g, 7.84 mmol) was added, followed by dropwise addition of cyclopropylamine (0.23 g, 3.92 mmol). The reaction was carried out at room temperature for 2 hours. The mixture was diluted with water (20 mL) and extracted twice with dichloromethane (20 mL × 2). The organic phases were combined and washed twice with water (20 mL × 2) and once with a saturated NaCl aqueous solution (20 mL × 1). 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 give compound 6B (0.6 g, 55.0% yield).

[0319] LCMS m / z = 276.0 [M+H] +

[0320] Step 2: Preparation of Compound 6

[0321] 6B (20.65 mg, 0.075 mmol), compound 2D (24.00 mg, 0.05 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (3.65 mg, 0.005 mmol), and potassium carbonate (20.70 mg, 0.15 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2.5 mL) and water (0.5 mL). The reaction was carried out at 100 °C for 12 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted twice with ethyl acetate (20 mL × 2). The organic phases were combined and washed twice with water (20 mL × 2) and once with a saturated NaCl aqueous solution (20 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give compound 2 (1 mg, yield 3.64%).

[0322] LCMS m / z = 551.1 [M+H] +

[0323] Example 7: Preparation of Compound 7

[0324]

[0325] Step 1: Preparation of Compound 7

[0326] Compound 7A (30.22 mg, 0.10 mmol), compound 2D (48.13 mg, 0.05 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (3.65 mg, 0.005 mmol), and potassium carbonate (23.60 mg, 0.20 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2.5 mL) and water (0.5 mL). The reaction was carried out at 100 °C for 12 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted twice with ethyl acetate (20 mL × 2). The organic phases were combined and washed twice with water (20 mL × 2) and once with a saturated NaCl aqueous solution (20 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give compound 7 (10 mg, yield 17.36%).

[0327] LCMS m / z = 577.2[M+H] +

[0328] 1H NMR (400 MHz, CD3OD) δ 8.68 (s, 2H), 8.41 – 8.33 (m, 1H), 7.78 –7.68 (m, 2H), 7.54 – 7.11 (m, 4H), 6.43 (d, 1H), 5.20 (d, 1H), 3.63 – 3.52(m, 1H), 3.48 (s, 3H), 2.99 – 2.86 (m, 3H), 1.59 – 1.46 (m, 2H), 1.38 – 1.27(m, 2H), 1.26 – 1.11 (m, 4H).

[0329] Example 8: Preparation of Compound 8

[0330]

[0331] Compound 8 was prepared using the same method as compound 7, yielding compound 8 (10 mg).

[0332] LCMS m / z = 593.2 [M+H] +

[0333] 1 H NMR (400 MHz, CD3OD) δ 8.42 – 8.32 (m, 1H), 7.71 (s, 1H), 7.64 (d,1H), 7.51 – 7.36 (m, 3H), 7.27 (t, 1H), 7.21 (t, 1H), 6.95 – 6.82 (m, 2H),6.39 (d, 1H), 5.19 (d, 1H), 3.62 – 3.51 (m, 1H), 3.48 (s, 3H), 2.88 (d, 1H),2.80 – 2.69 (m, 2H), 1.35 – 1.22 (m, 2H), 1.20 – 1.04 (m, 6H).

[0334] Example 9: Preparation of Compound 9

[0335]

[0336] Step 1: Preparation of 9B

[0337] Compound 9A (1.0 g, 3.65 mmol) was dissolved in dichloromethane, cooled to 0 °C, and triethylamine (0.80 g, 7.84 mmol) was added. Ammonia-methanol solution (2 ml, 7 M) was then added dropwise, and the reaction was carried out at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give compound 6B (0.6 g, yield: 65.12%).

[0338] LCMS m / z = 253.9 [M+H] +

[0339] Step 2: Preparation of Compound 9

[0340] Compound 9B (25.41 mg, 0.10 mmol), compound 2D (48.13 mg, 0.05 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (3.65 mg, 0.005 mmol), and potassium carbonate (23.60 mg, 0.20 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2.5 mL) and water (0.5 mL). The reaction was carried out at 100 °C for 12 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted twice with ethyl acetate (20 mL × 2). The organic phases were combined and washed twice with water (20 mL × 2) and once with a saturated NaCl aqueous solution (20 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give compound 9 (10 mg, yield 18.98%).

[0341] LCMS m / z = 529.1 [M+H] +

[0342] 1 H NMR (400 MHz, CD3OD) δ 8.40 – 8.34 (m, 1H), 7.83 – 7.76 (m, 2H), 7.75 – 7.64 (m, 3H), 7.50 – 7.43 (m, 3H), 7.22 (t, 1H), 6.43 (d, 1H), 5.22(d, 1H), 3.63 – 3.53 (m, 1H), 3.49 (s, 3H), 2.94 – 2.87 (m, 1H).

[0343] Example 10: Preparation of Compound 10

[0344]

[0345] Compound 10 was prepared using the same method as compound 9, yielding compound 10 (10 mg).

[0346] LCMS m / z = 511.1 [M+H] +

[0347] 1 H NMR (400 MHz, CD3OD) δ 8.41 – 8.34 (m, 1H), 7.97 (d, 2H), 7.87 –7.84 (m, 1H), 7.78 (d, 2H), 7.72 (d, 1H), 7.62 – 7.56 (m, 1H), 7.50 – 7.44(m, 2H), 7.29 (t, 1H), 6.44 (d, 1H), 5.21 (d, 1H), 3.63 – 3.53 (m, 1H), 3.48(s, 3H), 2.91 (d, 1H).

[0348] Example 11: Preparation of Compound 11

[0349]

[0350] Step 1: Preparation of Compound 11

[0351] Compound 11A (29.10 mg, 0.10 mmol), compound 2D (48.13 mg, 0.05 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (3.65 mg, 0.005 mmol), and potassium carbonate (23.60 mg, 0.20 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2.5 mL) and water (0.5 mL). The reaction was carried out at 100 °C for 12 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted twice with ethyl acetate (20 mL × 2). The organic phases were combined and washed twice with water (20 mL × 2) and once with a saturated NaCl aqueous solution (20 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give compound 11 (10 mg, yield 17.66%).

[0352] LCMS m / z = 567.2 [M+H] +

[0353] 1H NMR (400 MHz, CD3OD) δ 8.40 – 8.33 (m, 1H), 7.71 (s, 1H), 7.65 (d,1H), 7.49 – 7.42 (m, 2H), 7.42 – 7.37 (m, 1H), 7.36 – 7.29 (m, 1H), 7.20 (t,1H), 6.94 – 6.81 (m, 2H), 6.40 (d, 1H), 5.19 (d, 1H), 3.62 – 3.51 (m, 1H), 3.50 – 3.40 (m, 5H), 3.29 – 3.22 (m, 2H), 2.89 (d, 1H), 2.42 – 2.19 (m, 4H).

[0354] Example 12: Preparation of Compound 12

[0355]

[0356] Compound 12 was prepared using the same method as compound 11, yielding compound 12 (10 mg).

[0357] LCMS m / z = 551.1 [M+H] +

[0358] 1 H NMR (400 MHz, CD3OD) δ 8.72 (s, 2H), 8.41 – 8.32 (m, 1H), 7.78 –7.70 (m, 2H), 7.53 – 7.42 (m, 3H), 7.30 (t, 1H), 6.43 (d, 1H), 5.21 (d, 1H),3.77 – 3.66 (m, 2H), 3.63 – 3.52 (m, 1H), 3.50 – 3.39 (m, 5H), 2.90 (d, 1H), 2.44 – 2.20 (m, 4H).

[0359] Example 13: Preparation of Compound 13

[0360]

[0361] Step 1: Preparation of Compound 13B

[0362] Compound 13A (38.81 mg, 0.10 mmol), compound 2D (48.13 mg, 0.05 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (3.65 mg, 0.005 mmol), and potassium carbonate (23.60 mg, 0.20 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2.5 mL) and water (0.5 mL). The reaction was carried out at 100 °C for 12 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted twice with ethyl acetate (20 mL × 2). The organic phases were combined and washed twice with water (20 mL × 2) and once with a saturated NaCl aqueous solution (20 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give compound 13B (20 mg, yield 30.15%).

[0363] LCMS m / z = 664.2 [M+H] +

[0364] Step 2: Preparation of Compound 13

[0365] 13B (20.0 mg, 0.03 mmol) was dissolved in tetrahydrofuran (2.5 mL), and tetrabutylammonium fluoride (0.1 mL, 1 M THF solution) was added dropwise at 0 °C. After the addition was complete, the mixture was brought to room temperature and the reaction was continued for 3 hours. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography to give compound 13 (10 mg, yield 57.72%).

[0366] LCMS m / z = 550.1 [M+H] +

[0367] 1 H NMR (400 MHz, CD3OD) δ 8.40 – 8.35 (m, 1H), 8.06 (d, 2H), 7.89 –7.86 (m, 1H), 7.81 (d, 2H), 7.75 – 7.70 (m, 1H), 7.63 – 7.58 (m, 1H), 7.50 –7.45 (m, 2H), 7.29 (t, 1H), 6.44 (d, 1H), 5.21 (d, 1H), 3.63 – 3.54 (m, 1H), 3.48 (s, 3H), 2.91 (d, 1H), 2.34 – 2.22 (m, 1H), 0.58 – 0.42 (m, 4H).

[0368] Example 14: Preparation of Compound 14

[0369]

[0370] Compound 14 was prepared using the same method as compound 4, yielding compound 14 (5 mg).

[0371] LCMS m / z = 620.2 [M+H] +

[0372] 1 H NMR (400 MHz, CD3OD) δ 8.77 (s, 2H), 8.40 – 8.35 (m, 1H), 7.80 –7.72 (m, 2H), 7.56 – 7.51 (m, 1H), 7.50 – 7.45 (m, 2H), 7.31 (t, 1H), 6.44(d, 1H), 5.21 (d, 1H), 3.62 – 3.53 (m, 1H), 3.48 (s, 3H), 2.91 (d, 1H), 2.82– 2.74 (m, 1H), 0.87 – 0.55 (m, 4H).

[0373] Example 15: Preparation of Compound 15

[0374]

[0375] Step 1: Preparation of Compound 15B

[0376] Substrate 9B (508 mg, 2 mmol), triethylamine (404 mg, 4 mmol), and 5 mL of dichloromethane were added sequentially to a reaction flask. TBSCl (474 ​​mg, 3 mmol) was then added under ice-water bath conditions, 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 obtain the target product 15B (660 mg, 90%).

[0377] Step 2: Preparation of compound 15C

[0378] Triphenylphosphine (577 mg, 2.2 mmol), hexachloroethane (520 mg, 2.2 mmol), and 5 mL of chloroform were added to a reaction flask and reacted at 70 °C for 5 hours. After cooling to room temperature, triethylamine (223 mg, 2.2 mmol) was added, and the reaction was continued for 10 minutes. Then, 15B (708 mg, 2 mmol) was added under ice-water bath conditions, and the reaction was continued for 30 minutes. Cyclopropylamine (114 mg, 2 mmol) and triethylamine (202 mg, 2 mmol) were added, and the reaction was continued for 30 minutes. The reaction was then allowed to proceed to room temperature overnight. The reaction solution was directly concentrated and subjected to silica gel column chromatography to obtain compound 15C (520 mg, 64%).

[0379] LCMS m / z = 407.0 [M+H] +

[0380] Step 3: Preparation of compounds 15D and 15E

[0381] Substrate 15C (83 mg, 0.2 mmol), 2d (97 mg, 0.2 mmol), Pd(dppf)Cl2 (15 mg, 0.02 mmol), potassium carbonate (56 mg, 0.1 mmol), 3 mL of dioxane, and 0.3 mL of water were added to a reaction flask. After purging the flask three times with nitrogen, the reaction mixture was incubated overnight at 100 °C. The reaction solution was directly concentrated and subjected to silica gel column chromatography to obtain compounds 15D (28 mg, 21%) and 15E (65 mg, 51%).

[0382] 15D: LCMS m / z = 682.3 [M+H] + , 15E: LCMS m / z = 642.3 [M+H] +

[0383] Step 4: Preparation of Compound 15

[0384] 15D (28 mg, 0.04 mmol) was dissolved in 3 mL of tetrahydrofuran, and a tetrahydrofuran solution of TBAF (1.0 M, 0.2 mL) was added. The reaction mixture was reacted for 2 hours. The reaction solution was directly concentrated and subjected to silica gel column chromatography to give compound 15 (12 mg, 53%).

[0385] LCMS m / z = 568.2 [M+H] +

[0386] 1H NMR (400 MHz, CD3OD) δ 8.41 – 8.34 (m, 1H), 7.89 – 7.78 (m, 3H), 7.78 – 7.66 (m, 2H), 7.52 – 7.43 (m, 3H), 7.22 (t, 1H), 6.43 (d, 1H), 5.22(d, 1H), 3.63 – 3.54 (m, 1H), 3.49 (s, 3H), 2.91 (d, 1H), 2.37 – 2.23 (m,1H), 0.63 – 0.43 (m, 4H).

[0387] Example 16: Preparation of Compound 16

[0388]

[0389] Step 1: Synthesis of compound 16b

[0390] 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 the addition of a dichloromethane solution of TMSCF2Br (61.6 g, 303.8 mmol). After the addition was complete, the reaction was continued under ice bath conditions for another 30 minutes. After concentration, ethyl acetate and water were added. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography to obtain compound 16b (28.5 g, 42%).

[0391] LCMS m / z = 446.1 [M+H] +

[0392] Step 4: Synthesis of compound 16c

[0393] 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%).

[0394] LCMS m / z = 224.0 [M+H] +

[0395] Step 5: Synthesis of compound 16d

[0396] 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%).

[0397] Step 6: Synthesis of compound 16e

[0398] 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%).

[0399] Step 7: Synthesis of compound 16f

[0400] 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%).

[0401] Step 8: Synthesis of 16g ​​of compound

[0402] 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.

[0403] Step 9: Synthesis of compound 16h

[0404] Zinc powder (13 g, 200 mmol), cuprous chloride (2.97 g, 30 mmol), and 40 mL of tetrahydrofuran were added sequentially to a reaction flask and reacted at 70 °C for 2 hours. The mixture was then cooled to room temperature, and ethyl bromoacetate (15.0 g, 90 mmol) was slowly added, with the reaction continuing at 50 °C for 1 hour. The reaction 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%).

[0405] Step 10: Synthesis of Compound 16i

[0406] 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 directly to obtain crude 16i.

[0407] LCMS m / z = 343.9, 346.0 [M+H] +

[0408] Step 11: Synthesis of Compound 16j

[0409] 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, 78% yield in two steps).

[0410] LCMS m / z = 500.8 [M+H] +

[0411] Step 12: Synthesis of compound 16k

[0412] 16kJ (3.2 g, 6.4 mmol) was dissolved in 25 mL of dichloromethane, and a toluene solution of DIBAL-H (1.5 M, 4.3 mL, 6.4 mmol) was added dropwise at -78 °C. The reaction was continued at this temperature for 40 minutes. The reaction was quenched by adding saturated ammonium chloride solution, and an appropriate amount of dichloromethane was added. After filtration and washing, the resulting organic phase was dried and concentrated to obtain the crude product of 16kJ.

[0413] Step 13: Synthesis of Compound 16l

[0414] 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).

[0415] Step 14: Synthesis of compound 16m

[0416] 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 was carried out 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).

[0417] LCMS m / z = 587.0 [M+H] +

[0418] Step 15: Synthesis of Compound 16n

[0419] 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%).

[0420] LCMS m / z = 436.0 [M+H] +

[0421] Step 16: Synthesis of Compound 16o

[0422] 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%).

[0423] LCMS m / z = 382.0 [M+H] +

[0424] Step 17: Synthesis of compound 16p

[0425] 16o (220 mg, 0.58 mmol) was dissolved in 10 mL of tetrahydrofuran. After cooling to -78 °C, a tetrahydrofuran solution of KHMDS (1.0 M, 1.16 mL, 1.16 mmol) was added dropwise. The reaction was allowed to proceed at this temperature for half an hour. 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%).

[0426] Step 18: Synthesis of compound 16q

[0427] 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%).

[0428] LCMS m / z = 488.1 [M+H] +

[0429] Step 19: Synthesis of Compound 16

[0430] Substrate 10b (18 mg, 0.075 mmol), 16q (25 mg, 0.05 mmol), Pd(dppf)Cl2 (3.7 mg, 0.005 mmol), potassium carbonate (14 mg, 0.1 mmol), 2 mL of dioxane, and 0.2 mL of water were added to a reaction flask. After purging the flask three times with nitrogen, the reaction mixture was incubated overnight at 100 °C. The reaction solution was directly concentrated and subjected to silica gel column chromatography to obtain compound 16 (18 mg, 70%).

[0431] LCMS m / z = 517.0 [M+H] +

[0432] 1H NMR (400 MHz, DMSO-d6) δ 7.94 – 7.87 (m, 2H), 7.85 – 7.79 (m, 2H), 7.77 – 7.68 (m, 2H), 7.59 – 7.54 (m, 1H), 7.49 (t, 1H), 7.45 – 7.34 (m, 3H), 5.84 (d, 1H), 5.34 (d, 1H), 3.53 – 3.42 (m, 1H), 3.35 (s, 3H), 2.90 (d, 1H).

[0433] Example 17: Preparation of Compound 17

[0434]

[0435] 15E (65 mg, 0.1 mmol) was dissolved in 3 mL of tetrahydrofuran, and a tetrahydrofuran solution of TBAF (1.0 M, 0.4 mL) was added to the solution, and the reaction was carried out for 2 hours. The reaction solution was directly concentrated and subjected to silica gel column chromatography to give compound 17 (32 mg, 61%).

[0436] LCMS m / z = 528.2 [M+H] +

[0437] 1 H NMR (400 MHz, DMSO-d6) δ 8.31 – 8.25 (m, 1H), 7.82 – 7.72 (m, 3H), 7.70 – 7.63 (m, 2H), 7.57 (t, 1H), 7.50 – 7.45 (m, 2H), 7.43 – 7.38 (m, 1H), 6.28 (d, 1H), 5.25 (d, 1H), 3.58 – 3.48 (m, 1H), 3.36 (s, 3H), 2.83 (d, 1H).

[0438] Example 18: Synthesis of Compound 18

[0439]

[0440] Compound 18 (13 mg) was obtained by synthesis according to Example 9.

[0441] LCMS m / z = 532.2 [M+H] +

[0442] 1 H NMR 1H NMR (400 MHz, DMSO-d6) δ 8.31 – 8.24 (m, 1H), 7.78 – 7.68(m, 5H), 7.59 – 7.38 (m, 6H), 6.28 (d, 1H), 5.25 (d, 1H), 3.59 – 3.47 (m,2H), 2.83 (d, 1H).

[0443] Example 19: Synthesis of Compound 19

[0444]

[0445] Compounds 19-P1 (15 mg) and 19-P2 (10 mg) were obtained by synthesis according to Example 15.

[0446] Compound 19-P1: LCMS m / z = 571.2 [M+H] +

[0447] 1 H NMR (400 MHz, CD3OD) δ 8.42 – 8.34 (m, 1H), 8.00 – 7.90 (m, 2H), 7.91 – 7.82 (m, 2H), 7.78 (d, 1H), 7.57 – 7.51 (m, 1H), 7.50 – 7.44 (m, 2H),7.22 (t, 1H), 6.45 (d, 1H), 5.25 (d, 1H), 3.64 – 3.54 (m, 1H), 2.93 (d, 1H),2.54 – 2.46 (m, 1H), 0.80 – 0.55 (m, 4H).

[0448] Compound 19-P2: LCMS m / z = 531.2 [M+H] +

[0449] 1 H NMR (400 MHz, CD3OD) δ 8.41 – 8.35 (m, 1H), 8.02 – 7.94 (m, 2H), 7.90 – 7.84 (m, 2H), 7.77 (d, 1H), 7.55 – 7.43 (m, 3H), 7.42 – 7.00 (m, 1H), 6.43 (d, 1H), 5.24 (d, 1H), 3.64 – 3.54 (m, 1H), 2.92 (d, 1H).

[0450] Example 20: Synthesis of Compound 20

[0451]

[0452] Compound 20 (11 mg) was obtained by synthesis according to Example 9.

[0453] LCMS m / z = 608.1 [M+H] +

[0454] 1 H NMR (400 MHz, CD3OD) δ 8.43 – 8.35 (m, 1H), 7.92 – 7.87 (m, 1H), 7.82 – 7.74 (m, 2H), 7.74 – 7.66 (m, 2H), 7.60 – 7.55 (m, 1H), 7.52 – 7.45(m, 2H), 7.22 (t, 1H), 6.52 (d, 1H), 5.35 (d, 1H), 3.68 – 3.57 (m, 1H), 3.48(s, 3H), 3.10 (s, 2H), 2.97 (d, 1H), 1.24 – 1.16 (m, 2H), 1.09 – 0.97 (m,2H).

[0455] Example 21: Synthesis of Compound 21

[0456]

[0457] Compound 21 (10 mg) was obtained by synthesis according to Example 9.

[0458] LCMS m / z = 654.1 [M+H] +

[0459] 1 H NMR (400 MHz, CD3OD) δ 8.40 – 8.34 (m, 1H), 7.85 – 7.80 (m, 1H), 7.76 – 7.65 (m, 4H), 7.51 – 7.43 (m, 3H), 7.21 (t, 1H), 6.43 (d, 1H), 5.21(d, 1H), 3.63 – 3.53 (m, 1H), 3.19 (s, 2H), 2.90 (d, 1H), 1.00 – 0.93 (m,2H), 0.90 – 0.83 (m, 2H).

[0460] Example 22: Synthesis of Compound 22

[0461]

[0462] Compound 22 (13 mg) was obtained by synthesis according to Example 9.

[0463] LCMS m / z = 625.3 [M+H] +

[0464] 1 H NMR (400 MHz, DMSO-d6) δ 8.31 – 8.23 ​​(m, 1H), 8.11 – 7.95 (m, 1H), 7.79 – 7.72 (m, 2H), 7.72 – 7.67 (m, 3H), 7.57 – 7.36 (m, 4H), 6.28 (d, 1H),5.25 (d, 1H), 3.60 – 3.46 (m, 1H), 2.90 – 2.77 (m, 3H), 2.61 (s, 2H), 0.59 –0.47 (m, 4H).

[0465] Example 23: Preparation of compound 23

[0466]

[0467] Compound 23 was prepared using the same method as compound 6, yielding compound 23 (10 mg).

[0468] LCMS m / z = 569.2 [M+H] +

[0469] 1 H NMR (400 MHz, CD3OD) δ 8.40 – 8.34 (m, 1H), 7.85 – 7.82 (m, 1H), 7.79 – 7.67 (m, 4H), 7.52 – 7.42 (m, 3H), 7.22 (t, 1H), 6.43 (d, 1H), 5.22(d, 1H), 3.63 – 3.53 (m, 1H), 3.49 (s, 3H), 2.91 (d, 1H), 2.29 – 2.22 (m,1H), 0.63 – 0.51 (m, 4H).

[0470] Example 24: Preparation of compound 24

[0471]

[0472] Compound 24 was prepared using the same method as compound 6, yielding compound 24 (10 mg).

[0473] LCMS m / z = 584.9 [M+H] +

[0474] 1 H NMR (400 MHz, CD3OD) δ 8.40 – 8.33 (m, 1H), 7.84 – 7.80 (m, 1H), 7.76 – 7.63 (m, 4H), 7.51 – 7.42 (m, 3H), 7.22 (t, 1H), 6.43 (d, 1H), 5.22(d, 1H), 3.63 – 3.53 (m, 1H), 3.48 (s, 3H), 3.36 – 3.25 (m, 4H), 2.90 (d,1H), 1.17 (t, 6H).

[0475] Example 25: Preparation of Compound 25

[0476]

[0477] Compound 25 was prepared using the same method as compound 6, yielding compound 25 (10 mg).

[0478] LCMS m / z = 583.2 [M+H] +

[0479] 1 H NMR (400 MHz, CD3OD) δ 8.40 -8.33 (m, 1H), 7.83 – 7.80 (m, 1H), 7.76 – 7.71 (m, 2H), 7.70 – 7.64 (m, 2H), 7.50 – 7.43 (m, 3H), 7.22 (t, 1H),6.42 (d, 1H), 5.22 (d, 1H), 3.63 – 3.53 (m, 1H), 3.48 (s, 3H), 2.92 – 2.89(m, 1H), 2.82 (d, 2H), 0.94 – 0.83 (m, 1H), 0.49 – 0.41 (m, 2H), 0.18 – 0.10(m, 2H).

[0480] Example 26: Preparation of Compound 26

[0481]

[0482] Compound 26 was prepared using the same method as compound 6, yielding compound 26 (10 mg).

[0483] LCMS m / z = 603.3 [M+H] +

[0484] 1 H NMR (400 MHz, CD3OD) δ 8.40 – 8.34 (m, 1H), 7.84 – 7.80 (m, 1H), 7.77 – 7.66 (m, 4H), 7.51 – 7.42 (m, 3H), 7.22 (t, 1H), 6.42 (d, 1H), 5.21(d, 1H), 3.62 – 3.53 (m, 1H), 3.05 (t, 2H), 2.90 (d, 1H), 2.44 (t, 2H), 2.22(s, 6H).

[0485] Example 27: Preparation of Compound 27

[0486]

[0487] Compound 27 was prepared using the same method as compound 6, yielding compound 27 (10 mg).

[0488] LCMS m / z = 614.2 [M+H] +

[0489] 1 H NMR (400 MHz, CD3OD) δ 8.40 – 8.34 (m, 1H), 7.85 – 7.80 (m, 1H), 7.78 – 7.67 (m, 4H), 7.52 – 7.43 (m, 3H), 7.21 (t, 1H), 6.43 (d, 1H), 5.21(d, 1H), 3.76 – 3.66 (m, 2H), 3.63 – 3.53 (m, 1H), 2.91 (d, 1H).

[0490] Example 28: Preparation of compound 28

[0491]

[0492] Compound 28 was prepared using the same method as compound 6, yielding compound 28 (10 mg).

[0493] LCMS m / z = 602.3 [M+H] +

[0494] 1 H NMR (400 MHz, CD3OD) δ 8.41 – 8.35 (m, 1H), 7.89 – 7.85 (m, 1H), 7.79 – 7.66 (m, 4H), 7.58 – 7.53 (m, 1H), 7.50 – 7.45 (m, 2H), 7.23 (t, 1H),6.49 (d, 1H), 5.30 (d, 1H), 4.89 – 4.81 (m, 1H), 4.66 – 4.58 (m, 1H), 4.53 –4.45 (m, 1H), 3.66 – 3.56 (m, 1H), 3.23 – 3.11 (m, 2H), 2.95 (d, 1H), 2.71 –2.49 (m, 2H).

[0495] Biological test cases

[0496] 1. TNF-α / TNFR1 binding assay

[0497] The inhibition of TNF-α / TNFR1 binding by the compound was tested using the TR-FRET method. Solutions of proteins TNF-α (ACRO, Cat #TNA-H82E3) and TNFR1 (ACRO, Cat #TN1-H5251) were prepared in reaction buffer PPI (Revvity, Cat #61DB10RDF). The final concentrations of TNF-α / TNFR1 in the reaction mixture were both 0.15 nM. The positive reference, adalimumab, was initially diluted 3-fold at a concentration of 1 μM, 10 doses. 0.1 μL of the diluted positive reference in reaction buffer was transferred to a 384-well plate (Grenier, Cat #784075) using acoustic liquid delivery technology (Echo655) and centrifuged at 1000 rpm for 1 min. 2.5 μL of TNF-α solution was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 min, then incubated at 25°C for 15 min. 2.5 μL of TNFR1 solution was transferred to the 384-well plate and centrifuged at 1000 rpm for 1 min. Transfer 5 μL of the streptavidin-Tb cryptate and PAb Anti-Human IgG-XL665 detection mixture to a 384 reaction plate and centrifuge at 1000 rpm for 1 minute. Incubate at 25°C for 60 minutes. Finally, read the HTRF signal (Ratio 665 / 620 nm) using a BMG high-throughput drug screening multi-mode microplate reader. Obtain the IC50 using GraphPad Prism software. 50 Values ​​and nonlinear regression.

[0498] Table 1. IC50 values ​​of the compounds of this invention for inhibiting TNF-α / TNFR1 binding. 50 (nM)

[0499] Compound numbering <![CDATA[IC 50 (nM)]]> Compound numbering <![CDATA[IC 50 (nM)]]> Compound 1 ＜50 Compound 15 ＜50 Compound 2 ＜50 Compound 16 ＜50 Compound 5 ＜50 Compound 17 ＜50 Compound 8 ＜50 Compound 19-P1 ＜50 Compound 9 ＜50 Compound 19-P2 ＜50 Compound 10 ＜50 Compound 24 ＜50 Compound 11 ＜50 Compound 15 ＜50 Compound 13 ＜50

[0500] Conclusion: The compounds of the present invention, such as those in the examples, exhibit good inhibitory activity against TNF-α / TNFR1 binding. For example, compounds 8, 11, and 19-P2 show IC50 values ​​for inhibiting TNF-α / TNFR1 binding. 50 Less than 30 nM, the IC50 of compounds 1, 9, 16, 18, and 24 on the inhibition of TNF-α / TNFR1 binding was [value missing]. 50 Less than 20 nM, the IC50 of compound 10 inhibits TNF-α / TNFR1 binding. 50 The IC50 value of compound 13 for inhibiting TNF-α / TNFR1 binding was 6.36 nM. 50 The IC50 value for the inhibition of TNF-α / TNFR1 binding by compound 15 was 9.82 nM. 50The IC50 value for the inhibition of TNF-α / TNFR1 binding by compound 19-P1 was 2.90 nM. 50 It is 6.96 nM.

[0501] 2. Detection experiment of Membrane TNFα and H_TNFR1 / H_TNFR2 reporter cells:

[0502] Cell line GM-C33297: Membrane Bound H_TNFα (cleavage-resistant) CHO-K1 Cell Line;

[0503] GM-C27615:H_TNFR2 Null Reporter Cell Line

[0504] GM-C25776: H_TNFR2 Reporter V2 Cell Line

[0505] Experimental methods:

[0506] 16-24 hours before the experiment, Membrane Bound H_TNFα CHO-K1 Cell Line cell pellets were collected by digestion and centrifugation. Cells were resuspended in complete culture medium, and cell density and viability were calculated. The appropriate cell density was adjusted by adding more complete culture medium. 100 μL cells / well were added to the center well using a multipipeline, and 100 μL PBS was added to the surrounding wells. The plates were then capped and incubated overnight. 1-2 hours before the experiment, effector cells (H_TNFR1 / H_TNFR2 reporter cell lines) were collected by centrifugation and resuspended in Assay Buffer. Cell density and viability were calculated, and the effector cell density was adjusted to an appropriate level by adding more Assay Buffer. Anti-TNFα drugs were serially diluted in Assay Buffer in sterile 96-well V plates. The overnight Membrane Bound H_TNFα CHO-K1 Cell Line plates were removed, the supernatant was discarded, and serially diluted drugs were added at 50 μL / well. The plates were incubated for 1 hour. One hour later, effector cells (H_TNFR1 / H_TNFR2 reporter cell line) were added at 50 μL per well, the plate was capped, and incubation continued for another 6 hours. Samples were collected and Luciferase was detected.

[0507] Conclusion: The compounds of the present invention, such as those in the examples, exhibit good inhibitory activity against mTNFα / TNFR1 binding.

[0508] 3. HT-29 cell apoptosis experiment

[0509] HT-29 (ATCC) cells were seeded at 12,000 cells / 100 μL / well in 96-well plates (corning, 3599) and allowed to adhere overnight. TNF-α (R&D, 210-TA-020) was diluted to a final concentration of 20 pg / mL using culture medium, and different concentrations of the compound were added (starting at 10 μM, serially diluted 3 times, setting 9 concentration points), and pre-incubated at 37°C for 1 hour. Transfer 100 μL of the pre-incubated mixture of TNF-α and the compound into 100 μL of cells. Add Z-VAD (MCE, HY-16658B) to a final concentration of 20 μM and AT406 (MCE, HY-15454) to 25 μM. Incubate at 37°C with 5% CO2 for 24 hours. Add CellCounting-Lite (vazyme, DD1102), shake for 2 minutes in the dark, and incubate at room temperature in the dark for 30 minutes. Read the luminescence signal value using a microplate reader.

[0510] Conclusion: The compounds of the present invention, such as those in the examples, have good inhibitory activity against HT-29 cells.

[0511] 4. Pharmacokinetics test in mice

[0512] Test animals: Male C57 mice, 20-25 g, 6 mice / compound. Purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0513] Experimental Design: On the day of the experiment, C57 mice were randomly assigned to groups according to body weight. They were fasted for 12-14 hours prior to drug administration but allowed free access to water. Food was given 4 hours after drug administration. Drug administration information is as follows:

[0514] Group quantity Test compounds Dosage (mg / kg) Dosage concentration (mg / mL) Dosage volume (mL / kg) Sample collection Administration method G1 3 compound 1 0.2 5 plasma vein G2 3 compound 3 0.3 10 plasma Gavage

[0515] Note: Intravenous administration solvent: 10% DMA + 10% Solutol + 80% Saline; Gavage administration solvent: 0.5% MC

[0516] DMA: Dimethylacetamide; Solutol: Polyethylene glycol-15-hydroxystearate; Saline: Physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose

[0517] 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.

[0518] Table 2 Mouse PK data

[0519] Compound numbering Dosage <![CDATA[AUC (h·ng·mL -1 )]]> <![CDATA[CL(mL·kg -1 ·min -1 )]]> <![CDATA[Vdss(L·kg -1 )]]> <![CDATA[T 1 / 2 (h)]]> Compound 19-P1 IV 1 mg / kg 342 48.8 0.834 0.573 Compound 19-P2 IV 1 mg / kg 1605 10.5 0.159 0.703

[0520] Conclusion: The compounds of the present invention, such as those in the examples, have good pharmacokinetic properties.

[0521] 5. CYP450 enzyme inhibition test

[0522] 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-M) 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).

[0523] Table 3. Inhibition results of the compounds of the present invention on various CYP enzyme isoforms (IC50) 50 Value (µM)

[0524] Compound numbering CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4-M Reference compound A 1.88 >30 20.1 >30 >30 Compound 19-P2 >30 >30 >30 >30 >30

[0525] 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.

[0526] Compare with the structure of compound A: .

[0527] 6. hERG potassium ion channel function test

[0528] Experimental platform: Electrophysiological manual patch-clamp system

[0529] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channels

[0530] Experimental Methods: CHO (Chinese Hamster Ovary) cells stably expressing the hERG potassium channel were used to record hERG potassium channel currents at room temperature using whole-cell patch-clamp technique. Glass microelectrodes were fabricated from glass electrode blanks (BF150-86-10, Sutter) using a stretching device. The tip resistance after perfusion with electrode fluid was approximately 2-5 MΩ. The glass microelectrodes were inserted into the amplifier probe to connect to the patch-clamp amplifier. Clamping voltage and data recording were controlled and recorded using pClamp 10 software via computer, with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After obtaining whole-cell recordings, the cells were clamped at -80 mV. The step voltage to induce hERG potassium current (IhERG) was applied from -80 mV with a 2-second depolarization voltage to +20 mV, followed by repolarization to -50 mV, held for 1 second, and then returned to -80 mV. This voltage stimulation is applied every 10 seconds. Once the hERG potassium current has stabilized (at least 1 minute), the dosing process begins. Each test concentration of the compound is administered for at least 1 minute, and at least 2 cells are tested for each concentration (n≥2).

[0531] Data processing: Data analysis and processing were performed using pClamp 10, GraphPad Prism 5, and Excel software. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula:

[0532] Inhibition % = [1 – (I / Io)]×100%

[0533] 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.

[0534] Compound IC 50 The following equations were fitted and calculated using GraphPad Prism 5 software:

[0535] Y=Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope))

[0536] 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.

[0537] Table 4. Inhibition results of the compounds of this invention on hERG (µM)

[0538] Compound numbering hERG (µM) Reference compound A 5.36 Compound 1 >40 Compound 18 25.7

[0539] Conclusion: The compounds of the present invention, such as those in the examples, do not exhibit significant hERG inhibitory activity.

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 (IA). (I-A); Selected from or ; Ring M is selected from a 5-membered heteroaryl group or a 5-membered unsaturated heterocyclic group, wherein the heteroaryl or heterocyclic group is optionally surrounded by 1 to 4 R groups. m replace; R m Each element is independently selected from deuterium, halogens, CN, =O, =S, OH, NH2, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4- to 7-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic alkyl is optionally surrounded by 1 to 4 R... k replace; X is selected from N, O, S, C(R) x ), C(R x )2 or N(R x ); R x Each is independently selected from H, -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-6 cycloalkyl, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace; Q is selected from C, C(R) q1 ), C(R q1 2. C(=O), C(=S), C=N(R) q2 C=C(R) q3 )2, S(=O), S(=O)(=NH), S(=O)2; R q1 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 R q3 Each element is independently selected from H, CN, OH, NH2, and 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; W is selected from -CR w1 R w2 -、-(CR w1 R w2 )2-; R w1 R w2 Each element is independently selected from H, deuterium, halogens, and C. 1-6 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R w1 R w2 Direct connection forms C 3-6 cycloalkyl group, wherein the cycloalkyl group is optionally surrounded by 1 to 4 R groups k replace; Cycle A is selected from 5-membered heteroaryl groups, , , , , ; Z1 is selected from N or C(R) z1 ); Z2 is selected from N or C(R) z2 ); Z3 is selected from N or C(R) z3 ); Z4 is selected from N or C; Z5 is selected from N or C; Z6 is selected from N or C; R 1 Selected from , , , ; R 1a Selected from C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace; R 1b R 1c R 1d Each is independently selected from C 1-6 Alkyl, C 3-6 cycloalkyl, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, NHC 3-6 Carbocyclic group, N(C) 3-6 2, NH- (4-6 membered heterocyclic group), 4- to 10 membered heterocyclic group linked by a nitrogen atom, wherein the NH, alkyl, cycloalkyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R 1a With R 1b Direct linkage forms a 4- to 7-membered heterocyclic group, wherein the heterocyclic group is optionally bounded by 1 to 4 R... k replace; R 3 Selected from H, deuterium, halogens, CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, ynyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace; Ring S is selected from C 6-10 Aryl or 5 to 10-membered heteroaryl; The ring T is selected from phenyl, 5- to 6-membered heteroaryl, and benzo[C]. 4-6 Carbocyclic, benzo4- to 6-membered heterocyclic or 8- to 10-membered fused-ring heteroaryl; R 2 R z1 R z2 R z3 Each element is independently selected from H, deuterium, halogens, CN, OH, 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, -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 R z3 Direct connection forms C 4-6 A carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R 2 R z1 Direct connection forms C 4-6 A carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R s R t Each element is independently selected from deuterium, halogens, CN, OH, NH2, SF5, and NHC. 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-7 carbonyl group, -OC 1-4 Alkylene-C 3-7 carbonyl group, -SC 3-7 carbonyl group, -SC 1-4 Alkylene-C 3-7 Carbocyclic group, -C 0-4 Alkylene-C 3-7 Carbocyclic group, -C 0-4 Alkyl-4 to 7-membered heterocyclic groups, -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 5 R k replace; R k Each element is independently selected from deuterium, O, 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 The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic group may optionally contain 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 alkoxy- or cyano-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, halogen-substituted C 1-6 Substituents of alkyl groups; n1 and n2 are each independently selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. R m Each element is independently selected from deuterium, halogens, CN, =O, =S, OH, NH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4- to 7-membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic alkyl is optionally surrounded by 1 to 4 R... k replace; R x Each is independently selected from H, -C(=O)-C 1-4 Alkyl, -C(=O)-C 3-6 cycloalkyl, C 1-4 Alkyl, C 3-6 cycloalkyl, -C 1-2 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace; R q1 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 R q3 Each element is independently selected from H, CN, OH, NH2, and 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 1a Selected from C 1-4 Alkyl or C 3-6 Cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally composed of 1 to 4 elements selected from deuterium, halogen, halogen, CN, C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 Substituents of cycloalkyl groups; R 1b R 1c R 1d Each is independently selected from C 1-4 Alkyl, C 3-6 cycloalkyl, NH2, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, NHC 3-6 Cycloalkyl, NH- (4-6 membered heterocyclic group), N(C 3-6 2. A 4- to 10-membered heterocyclic group linked by a nitrogen atom, wherein the NH, alkyl, cycloalkyl, or heterocyclic group is optionally surrounded by 1 to 4 R atoms. k replace; As an option, R 1a With R 1b Direct linkage forms a 4- to 7-membered heterocyclic group, wherein the heterocyclic group is optionally bounded by 1 to 4 R... k replace; R w1 R w2 Each element is independently selected from H, deuterium, halogens, and C. 1-4 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R w1 R w2 Direct connection forms C 3-6 cycloalkyl group, wherein the cycloalkyl group is optionally surrounded by 1 to 4 R groups k replace; R 3 Selected from H, deuterium, halogens, CN, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, ynyl, or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k replace; The ring S is selected from phenyl, benzo[3]C 4-6 Carbocyclic, benzo4- to 6-membered heterocyclic, 5- to 6-membered heteroaryl or 8- to 10-membered fused-ring heteroaryl; R 2 R z1 R z2 R z3 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, -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, wherein the alkylene, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic alkyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 4 R k replace; As an option, R 2 R z3 Direct connection forms C 4-6 A carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R 2 R z1 Direct connection forms C 4-6 A carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R s R t Each element is independently selected from deuterium, halogens, CN, OH, NH2, SF5, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 cycloalkyl, C 3-6 cycloalkyl, -OC 1-2 Alkylene-C 3-6 cycloalkyl, -SC 3-6 cycloalkyl, -SC 1-2 Alkylene-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, -S(=O)C 1-4 Alkyl group, -S(=O)C 3-6 cycloalkyl, -NHS(=O)C 1-4 Alkyl group, -S(=O)2C 1-4 Alkyl group, -S(=O)2C 3-6 Cycloalkyl, -NHS(=O)2C 1-4 Alkyl group, -S(=O)2NHC 1-4 Alkyl, -P(=O)(C 1-4 Alkyl)2, phenyl or 5 to 6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, carbocyclic, heterocyclic, phenyl or heteroaryl group is optionally surrounded by 1 to 5 R groups. k replace; R k Each element is independently selected from deuterium, O, 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 The alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic group may optionally contain 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 alkoxy- or cyano-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, halogen-substituted C 1-6 Alkyl groups are substituted.

3. The compound according to claim 2, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. Selected from , , , , , , , , , , ; Selected from 1 to 3 Rs m One of the following groups is substituted: , , , , , , , , ; Selected from , , , , , ; R w1 R w2 Each of the following groups is independently selected from H, deuterium, F, Cl, Br, methyl, ethyl, and cyclopropyl, wherein the methyl, ethyl, and cyclopropyl groups are optionally surrounded by 1 to 4 R groups. k replace; As an option, R w1 R w2 Direct linkage to form cyclopropyl and cyclobutyl groups, wherein the cyclopropyl and cyclobutyl groups are optionally coupled with 1 to 4 R groups. k replace; The ring S is selected from phenyl or 5- to 6-membered heteroaryl groups; Selected from , , , , , , , , , , , , , , , , or ; Y is selected from N or CH; R 1a The methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups are selected from methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups, wherein 1 to 4 of the methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups are selected from deuterium, halogen, CN, or C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 Substituents of cycloalkyl groups; R 1b R 1c R 1d Each of the following groups, independently selected from NH2 and optionally substituted, is: methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, NH-isopropyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -NH-oxacyclobutyl. , , , , When substituted, it is selected from 1 to 4 elements chosen from deuterium, halogen, halogen, CN, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, OH, CH2OH, CF3CH2, CH3OCH2, CF3, CHF2, CH2F, CH2CN, NH2, -NHCH3, -N(CH3)2, CONH2, -CONHCH3, -CON(CH3)2 , , , , , , , , The substituents are replaced; As an option, R 1a With R 1b Direct linkage forms 4- to 7-membered heterocyclic alkyl groups, wherein the heterocyclic alkyl group is optionally bounded by 1 to 4 R groups. k replace; R t1 Selected from H, deuterium, halogens, CN, OH, NH2, SF5, 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, -OC 1-2 Alkylene-C 3-6 cycloalkyl, -SC 3-6 cycloalkyl, -SC 1-2 Alkylene-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, -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, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, carbocyclic or heterocyclic group is optionally surrounded by 1 to 5 R k replace; n3 is selected from 0, 1, 2 or 3.

4. The compound according to claim 3, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, R m Each of the following is independently selected from deuterium, F, Cl, Br, CN, OH, methyl, ethyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl groups are optionally selected by 1 to 4 of the following: deuterium, halogen, CF3, CHF2, CH2F, CD3, CHD2, CH2D, and C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups; W is selected from -CH2-, -CH(CH3)-, -CH(CF3)-, -CH(CD3)-, -CFH-, -CF2-, -CH2CH2- or ; R 2 R z1 R z2 Each of the following is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl groups are optionally selected by 1 to 4 of the following: deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, and C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups; R x Selected from H, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH(CH3)2, -C(=O)-cyclopropyl, methyl, ethyl, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, cyclopropyl, or cyclobutyl group is optionally surrounded by 1 to 4 R groups. k replace; R q1 The group is selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, or cyclopropyl, wherein the methyl, ethyl, or cyclopropyl group is optionally replaced by 1 to 4 groups selected from 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 q2 The methyl, ethyl, methoxy, and ethoxy groups are selected from H, OH, CN, NH2, methyl, ethyl, methoxy, and ethoxy groups, wherein the methyl, ethyl, methoxy, and ethoxy groups are optionally replaced by 1 to 4 deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, and C groups. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups; The ring S is selected from phenyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrazolyl, pyrroleyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl. R 1 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； R s R t Each of these groups is independently selected from deuterium, F, Cl, Br, CN, OH, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -S-CH 2-Cyclopropyl, -S-CH2-Cyclobutyl, -P(=O)(CH3)2, phenyl, thiophene, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazole, pyrazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl, wherein CH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, phenyl, thiophene, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazole, pyrazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl are optionally surrounded by 1 to 5 R k replace; R t1 Selected from H, deuterium, F, Cl, Br, CN, OH, NH2, SF5, 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, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -S-CH2-cyclopropyl, -S-CH2-cyclobutyl, oxacyclobutyl, tetrahydrofuranyl, -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, or tetrahydrofuranyl is optionally surrounded by 1 to 5 R... k replace; R k Each of the following groups is independently selected from deuterium, =O, F, Cl, Br, I, CN, OH, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl Cyclopentyl, cyclohexyl, oxecyclobutyl, oxecyclopentyl, oxecyclohexyl, aziroxybutyl, pyrrolylyl, piperidinyl, piperazine, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxecyclobutyl, oxecyclopentyl, oxecyclohexyl, aziroxybutyl, pyrrolylyl, piperidinyl, piperazine are optionally selected from 1 to 4 elements selected from deuterium, halogen, CN, OH, NH2, C. 1-4 Alkyl, C 1-4 alkoxy- or cyano-substituted C 1-4 Alkyl, hydroxyl substituted C 1-4 Alkyl, halogen-substituted C 1-4 Substituents of alkyl groups; Preferably, R k Each of these groups is independently selected from deuterium, =O, NH2, F, Cl, Br, I, CN, OH, -CH2OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, N(CH3)2, NH(CH3), methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl The methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxecyclobutyl, oxecyclopentyl, oxecyclohexyl, azeoyl, pyrrolyl, piperidinyl, and piperazine groups are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, -CH2CN, -CH2F, -CH2OH, CF3, and CHF2.

5. The compound according to claim 4, or its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, R m Each is independently selected from deuterium, F, Cl, Br, CN, methyl, ethyl, cyclopropyl, CF3, CHF2, CH2F, CD3, CHD2, CH2D, CH2CD3, CH2CF3; Ring S is selected from , , , Left side and R 1 Direct connection; R t1 The molecule is selected from SF5, methyl, ethyl, methoxy, ethoxy, -S-methyl, -S-ethyl, -O-cyclopropyl, -O-cyclobutyl, -OCH2-cyclopropyl, -OCH2-cyclobutyl, -S-cyclopropyl, -S-cyclobutyl, -SCH2-cyclopropyl, -SCH2-cyclobutyl, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl or cyclobutyl group is optionally substituted by 1 to 5 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl; R x The group is selected from H, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH(CH3)2, -C(=O)-cyclopropyl, methyl, ethyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, cyclopropyl, and cyclobutyl 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, or ethyl. R q1 The group is selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl or cyclopropyl, wherein the methyl, ethyl or cyclopropyl group is optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl; R q2 The group is selected from H, OH, CN, NH2, methyl, ethyl, methoxy, ethoxy, wherein the methyl, ethyl, methoxy, ethoxy group is optionally replaced by 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl or ethyl; R 2 R z1 R z2 Each of the following groups is independently selected from H, deuterium, F, Cl, Br, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl 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, ethyl, methoxy, or ethoxy. Preferably, R s Each is independently selected from deuterium, F, Cl, Br, CN, OH, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -P(=O)(CH3)2, thiazolyl, oxazolyl, imidazole, pyrazolyl, thiadiazole The group consisting of methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, thiazolyl, oxazolyl, imidazole, pyrazolyl, thiazolyl, oxazolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazolyl, or triazolyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, NH2, CF3, CHF2, CH2F, CD3, CHD2, CH2D, methyl, ethyl, methoxy, or ethoxy.

6. The compound according to claim 1, or a racemic, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (IA) is selected from the compound represented by general formula (II). (II); R x Selected from CF3, CD3, or cyclopropyl; S1 or S2 is selected from N, CH or CR s ; n4 is selected from 0, 1, or 2; R s Each is independently selected from deuterium, F, Cl, Br, CN, OH, methyl, ethyl, methoxy, and cyclopropyl; R 1 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； Preferably, R 1 Selected from , , , , , , , , , , , , , , , , , , .

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

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

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