Aza compound and composition and application thereof

Abstract

The invention discloses a compound with a general formula I and a composition and application thereof. The compound with the general formula I has the following structure, and pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds thereof. # imgabs0 #

Description

[0001] This application is filed with the China Patent Office on June 9, 2023, with application number 202310682400.4 and the invention name “Benzodiazepine The entire contents of the Chinese patent application entitled "Compounds and compositions thereof and applications thereof" are incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of pharmaceutical technology and specifically relates to an azepine Compounds, compositions and applications thereof. Background Art

[0003] Benzodiazepines Barbiturates are a class of sedatives and hypnotics developed in the late 1950s. Because their toxic side effects are less than those of barbiturates, they have become the first choice for sedation, hypnosis and antianxiety in clinical practice.

[0004] Benzodiazepines The mechanism of action of these drugs is: there is a specific binding site in the brain that has a high affinity for diazepam. The distribution of GABA receptors is the most dense in the cortex, followed by the limbic system and midbrain, and then the brainstem and spinal cord. This distribution is consistent with the central inhibitory neurotransmitter GABA (GABA) A The distribution of receptors is basically the same. Drugs can enhance GABAergic neurotransmission function and synaptic inhibition effect, enhance GABA and GABA A It combines with other steroid receptors and has anti-anxiety, sedative and hypnotic effects. Summary of the Invention

[0005] The purpose of the present invention is to provide a class of nitrogen Compounds, and the aza Pharmaceutical compositions of compounds of the type, and the aza Uses of compounds.

[0006] In a first aspect, the present invention provides a compound of formula I, and pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates, and deuterated compounds thereof:

[0007]

[0008] wherein Y is selected from N or -CF;

[0009] A is selected from N or CH;

[0010] M does not exist, or forms a cyclic ring with the adjacent carbon to form a saturated / unsaturated alicyclic ring, a saturated / unsaturated heterocyclic ring, an aromatic ring or a heteroaromatic ring;

[0011] When M does not exist, R x -H, halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl; when M forms a cyclic ring with the adjacent carbon, R x does not exist;

[0012] n1 is 0, 1, or 2;

[0013] The H on the above saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring can be substituted by the following groups: halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 alkyl);

[0014] Q is selected from O, S-Rxx, N or R3 is selected from -H, C 1-5 The H on the alkyl group may be substituted by the following groups: -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, 3-8 membered heterocycloalkyl, -COO(C 0-10 Alkyl), wherein the heterocycloalkyl contains at least one N, O, or S as a ring atom;

[0015] When Q is N, R3, Q, the N atom and the C atom therebetween form a five-membered aromatic heterocycle or a six-membered aromatic heterocycle having at least two heteroatoms; optionally, the five-membered aromatic heterocycle is an imidazole group; optionally, the six-membered aromatic heterocycle is a pyridine group;

[0016] L is absent, or L is selected from C 2-8 Olefinic bond or C 1-8 Alkylene, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -CF3, -OCH2F, -OCHF2, -OCF3, C 1-10Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, -CO(C 0-10 Alkyl), -COO(C 0-10 alkyl);

[0017] When Q is N or When A is N, Q, A, L and the atoms therebetween form a five-membered or six-membered nitrogen-containing heterocyclic ring;

[0018] n is 0 or 1. When n is 0, it means that the -CO- group does not exist;

[0019] X is absent, or when n is 1, X is O, when n is 0, X is selected from O, substituted / unsubstituted N-alkyl, substituted / unsubstituted N-heterocycloalkyl;

[0020] R4 is selected from -H, halogen, -CN, -CF3, -OCH2F, -OCHF2, -OCF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl, aryl, N-heterocyclic aromatic group, O-heterocyclic aromatic group, S-heterocyclic aromatic group, -SO2(C 0-10 alkyl), -SO(C 0-10 Alkyl), -SO2O(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO2(C 3-10 Cycloalkyl), -SO2-aryl, -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl), -CO(C 3-10 Cycloalkyl), -CO(3-6 membered heterocycloalkyl), -(C 0-10 alkyl)COO(C 0-10 Alkyl), -COO(C 3-10 Cycloalkyl), -COO (3-6 membered heterocycloalkyl), alkenyl, alkynyl, wherein the heterocycloalkyl contains at least one N, O, or S as a ring atom, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -NO2, -CF3, C 1-3 Straight chain alkyl, -OC 0-10 Alkyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, -N(C 0-10Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -COO(C 3-10 Cycloalkyl), -COO(heterocycloalkyl), -CO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -OCOO(C 0-10 alkyl), phenyl, N heterocyclic aromatic group, O heterocyclic aromatic group, S heterocyclic aromatic group, alkenyl group, alkynyl group.

[0021] Preferably, Y is N.

[0022] In formula I Indicates a single bond or a double bond.

[0023] In the present invention, M and adjacent carbon atoms form a cyclic ring, which means that M and adjacent carbon atoms form a cyclic ring and are fused with the seven-membered ring of the parent core structure to form a cyclic ring. M and adjacent carbon atoms can form a single ring or a cyclic ring.

[0024] When Q is O, it is connected to the parent nucleus through a double bond. When Q is S, it is connected to the parent nucleus through a single bond. When Q is N or When , it is connected to the parent nucleus through a single bond or a double bond.

[0025] In order to more clearly indicate the position of M and the adjacent carbon atoms, the atoms of the parent nucleus of the compound of formula I are numbered as follows:

[0026]

[0027] When M is absent, the compound of formula I has the following structure:

[0028]

[0029] M forms a cyclic ring with the adjacent carbon atoms, which means that M forms a ring with the carbon atom at position 6 or carbon atom at position 7 to form a saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring.

[0030] Preferably, the compound, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, have the following structural formula:

[0031]

[0032] wherein Y is selected from N or -CF;

[0033] R1, R2 are each independently selected from -H, halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, or R1, R2 and the C atom between R1 and R2 form a five-membered aromatic heterocycle, a six-membered aromatic heterocycle or an aromatic ring, wherein the five-membered aromatic heterocycle is selected from furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, thiazole, and the six-membered aromatic heterocycle is selected from pyridine, pyridazine, pyrimidine, and pyrazine. Optionally, the H on the five-membered aromatic heterocycle, the six-membered aromatic heterocycle or the aromatic ring may be substituted by the following groups: halogen, -CN, -CF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 1-10 Alkyl, C 3-10 Cycloalkyl, N heterocycloalkyl, O heterocycloalkyl, S heterocycloalkyl; Optionally, the aromatic ring is selected from a six-membered aromatic ring;

[0034] Q is selected from O, S or N, R3 is selected from -H, C 1-5 The H on the alkyl group may be substituted by the following groups: -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, 3-8 membered heterocycloalkyl, -COO(C 0-10 Alkyl), wherein the heterocycloalkyl contains at least one N, O, or S as a ring atom;

[0035] When Q is N, R3, Q, the N atom and the C atom therebetween form a five-membered aromatic heterocycle or a six-membered aromatic heterocycle having at least two heteroatoms; optionally, the five-membered aromatic heterocycle is an imidazole group;

[0036] L is absent, or L is selected from C 2-8 Olefinic bond or C 1-8 Alkylene, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -CF3, -OCH2F, -OCHF2, -OCF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, -CO(C 0-10 Alkyl), -COO(C 0-10 alkyl);

[0037] When Q is N and A is N, Q, A, L and the atoms therebetween form a five-membered or six-membered nitrogen-containing heterocyclic ring;

[0038] n is 0 or 1. When n is 0, it means that the -CO- group does not exist;

[0039] X is absent, or when n is 1, X is O, when n is 0, X is selected from O, substituted / unsubstituted N-alkyl, substituted / unsubstituted N-heterocycloalkyl;

[0040] R4 is selected from -H, halogen, -CN, -CF3, -OCH2F, -OCHF2, -OCF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl, aryl, N-heterocyclic aromatic group, O-heterocyclic aromatic group, S-heterocyclic aromatic group, -SO2(C 0-10 alkyl), -SO(C 0-10 Alkyl), -SO2O(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO2(C 3-10 Cycloalkyl), -SO2-aryl, -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl), -CO(C 3-10 Cycloalkyl), -CO(3-6 membered heterocycloalkyl), -(C 0-10 alkyl)COO(C 0-10 Alkyl), -COO(C 3-10 Cycloalkyl), -COO (3-6 membered heterocycloalkyl), alkenyl, alkynyl, wherein the heterocycloalkyl contains at least one N, O, or S as a ring atom, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -NO2, -CF3, C 1-3 Straight chain alkyl, -OC 0-10 Alkyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -COO(C 3-10 Cycloalkyl), -COO(heterocycloalkyl), -CO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -OCOO(C 0-10alkyl), phenyl, N heterocyclic aromatic group, O heterocyclic aromatic group, S heterocyclic aromatic group, alkenyl group, alkynyl group.

[0041] Preferably, the compound, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, have the following structural formula:

[0042]

[0043] wherein Y is selected from N or -CF;

[0044] R1 and R2 are each independently selected from -H, -F, -Cl, -Br, -NO2, -CN, -CF3, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, or R1, R2 and the C atom between R1 and R2 form a five-membered aromatic heterocycle, a six-membered aromatic heterocycle or a benzene ring, the five-membered aromatic heterocycle is selected from: furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, thiazole, the six-membered aromatic heterocycle is selected from: pyridine, pyridazine, pyrimidine, pyrazine. Optionally, the H on the five-membered aromatic heterocycle, the six-membered aromatic heterocycle or the benzene ring can be substituted by the following groups: halogen, -CN, -CF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 1-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl;

[0045] Q is selected from O or N, R3 is selected from -H, C 1-5 The H on the alkyl group may be substituted by the following groups: -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, 3-8 membered heterocycloalkyl, wherein the heterocycloalkyl contains at least one N, O, or S as a ring atom;

[0046] When Q is N, R3, Q and the N atom and C atom therebetween form a five-membered aromatic heterocycle or a six-membered aromatic heterocycle having at least two heteroatoms;

[0047] L is absent, or L is selected from C 2-4 Olefinic bond or C 1-8Alkylene, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -CF3, -OCH2F, -OCHF2, -OCF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, 3-10 membered cycloalkyl, -CO(C 0-10 Alkyl), -COO(C 0-10 alkyl);

[0048] R a Selected from -H, C 1-10 Straight chain / branched chain alkyl, OR b , R b Selected from C 1-10 Straight chain / branched chain alkyl, C 3-10 Cycloalkyl, 3-8 membered heterocycloalkyl, aryl, heteroaryl, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -CH3, -C2H5, -OC 1-5 、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -CO(C 0-10 alkyl), -OCO(C 0-10 Alkyl), vinyl, propadienyl, ethynyl, further, the above alkyl part can be -CN, -OCH2F, -OCHF2, -OCF3, -OC 0-10 Alkyl, C 3-4 cycloalkyl substitution;

[0049] R c Selected from -H, -C 1-10 Straight chain / branched chain alkyl, -C 3-10 Cycloalkyl, -CH2CO(C 0-10 alkyl), -CH2COO(C 0-6 alkyl), -CH2COO(C 3-6 Cycloalkyl), -CH2COO(C 3-6 Heterocycloalkyl), -CH2CON(C 0-10 Alkyl)(C 0-10 Alkyl), benzyl, aryl, the H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -NO2, C 1-10 Straight chain / branched alkyl, 3-6 membered heterocyclic alkyl, -OC 1-5 Alkyl, -N(C 1-3 Alkyl)(C 1-3 Alkyl), C 2-8 alkenyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl; or R c Selected from Rc1 、R c2 、R c3 Independently selected from C 1-10 Straight chain / branched chain alkyl, -OC 0-5 Alkyl, -O(C 3-6 Cycloalkyl), -O(C 3-6 Heterocycloalkyl), C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, -N(C 0-10 Alkyl)(C 0-10 alkyl), alkenyl, alkynyl, aryl, heteroaryl, the H on the above groups can be halogen, -CN, -CH3, -C2H5, -OCH3, -N(C 1-3 Alkyl)(C 1-3 Alkyl), -C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, vinyl substituted, the above alkyl part can be replaced by -CN, -OCF3, -OC 0-10 Alkyl, C 3-4 cycloalkyl substitution;

[0050] R d1 and R d2 Each independently selected from H, C 1-10 Straight chain / branched alkyl, -COO(C 0-10 alkyl), -CO(C 0-10 alkyl), 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, aryl, or R d1 and R d2 The N atoms between them form a 3-6 membered heterocyclic alkyl group. The H on the above group can be replaced by the following groups: halogen, -CN, -NO2, C 1-3 Straight chain / branched chain alkyl, -OC 1-3 Alkyl, C 3-6 Cycloalkyl, -(C 0-10 alkyl)COO(C 0-10 alkyl), -CO(C 0-10 alkyl), aryl, -N(C 1-3 Alkyl)(C 1-3 Alkyl), the alkyl part can be -CN, -OCF3, -OC 0-10 、-CO(C 0-10 Alkyl), C 3-4 Cycloalkyl, aryl substitution;

[0051] R e1 and R e2 Each independently selected from H, C 1-3 Straight chain / branched chain alkyl.

[0052] In one embodiment of the present invention, the compound, and pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds thereof, have the following structural formula:

[0053]

[0054] Wherein, Y, Q, R1, R2, and R3 are substituted as shown above.

[0055] m is an integer between 0 and 4;

[0056] R5 is selected from -H, halogen, -CN, -CF3, -CO(C 0-10 Alkyl), -COO(C 0-10 alkyl);

[0057] R6 is selected from -H, C 1-10 Straight chain / branched chain alkyl, C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, aryl, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -CH3, -C2H5, -OCH3, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -CO(C 0-10 alkyl), -OCO(C 0-10 Alkyl), vinyl, propadienyl, ethynyl, further, the alkyl part can be -CN, -OCH2F, -OCHF2, -OCF3, -OC 0-10 Alkyl, C 3-4 Cycloalkyl substitution.

[0058] Furthermore, the compound, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds have the following structural formula:

[0059]

[0060] wherein Y is selected from N or -CF; P is N or CH;

[0061] m is an integer between 0 and 4;

[0062] R7 is selected from -H, -F, -Cl, -Br, -I, -NO2, -CN, alkenyl, alkynyl, -CF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl;

[0063] R8 is selected from -H, -CN, -CF3, C 1-4Straight chain / branched chain alkyl, C 3-10 cycloalkyl;

[0064] R9 is selected from -H, -F, -Cl, -Br, -I, -NO2, -CN, alkenyl, alkynyl, -CF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl;

[0065] R 10 Selected from -H, C 1-3 A straight chain / branched alkyl group, the H on which the alkyl group is replaced by -N(C 1-3 Alkyl)(C 1-3 Alkyl), five-membered or six-membered N heterocycloalkyl;

[0066] R5 is selected from -H, halogen, -CN, -CF3, -CO(C 0-10 Alkyl), -COO(C 0-10 alkyl);

[0067] R 6’ and R 6” Each independently selected from -H, C 1-10 Straight chain / branched chain alkyl, C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, aryl, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -CH3, -C2H5, -OCH3, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -CO(C 0-10 alkyl), -OCO(C 0-10 Alkyl), vinyl, propadienyl, ethynyl, further, the alkyl part can be -CN, -OCH2F, -OCHF2, -OCF3, -OC 0-10 Alkyl, C 3-4 Cycloalkyl substitution.

[0068] Furthermore, the compound, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, have the following structural formula:

[0069]

[0070] wherein Y is selected from N or -CF, and P is N or CH;

[0071] m1 is an integer between 0 and 2;

[0072] R 11Selected from -F, -Cl, -Br, -I, -NO2, ethynyl, -CF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl;

[0073] R 6a Selected from or C 1-4 Alkyl, the H on the alkyl can be -F, -OCH3, C 3-6 Cycloalkyl substitution, R 6a1 Selected from -H, -CN, -CH3, -C2H5, vinyl, propadienyl, ethynyl; R 6a2 Selected from vinyl, ethynyl, -COCH3, -COC2H5, 3-4 membered epoxyalkyl; R 6a3 Selected from -CH3, -C2H5, -OCH3, -OC2H5.

[0074] R 12 Selected from -F, -Cl, -Br, -I, -NO2, ethynyl, -CF3;

[0075] R 13 、R 13’ 、R 13” Each independently selected from -H, C 1-3 Straight chain / branched alkyl, the H on the alkyl can be replaced by -N(C 1-3 Alkyl)(C 1-3 Alkyl), five-membered or six-membered N heterocycloalkyl;

[0076] R 6b Selected from -H, -CH3, -C2H5, propyl, isopropyl, butyl, tert-butyl, 3-4 membered saturated cycloOalkyl, the H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -CH3, -C2H5, -OCH3, C 3-4 Cycloalkyl, 3-6 membered heterocycloalkyl, -CO(C 1-3 alkyl), -OCO(C 1-3 Further, the alkyl portion may be substituted by -OCH3, -OC2H5.

[0077] R 14 Selected from -H, halogen, -NO2, -CN, -CF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10Alkyl, C 3-10 Cycloalkyl;

[0078] R 6c Selected from -H, C 1-5 Straight chain / branched chain alkyl, -OC 0-5 Alkyl, C 3-6 Cycloalkyl, -O heterocycloalkyl, the H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -CH3, -C2H5, -OCH3, C 3-4 Cycloalkyl, vinyl, ethynyl.

[0079] T is C, N, O or S;

[0080] R 15 Selected from -H, halogen, -NO2, -CN, -CF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl;

[0081] R 6d Selected from -H, C 1-5 Straight chain / branched chain alkyl, -OC 0-5 Alkyl, C 3-6 Cycloalkyl, -O heterocycloalkyl, the H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -CH3, -C2H5, -OCH3, C 3-4 Cycloalkyl, vinyl, ethynyl.

[0082] In one embodiment of the present invention, the compound, and pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds thereof, have the following structural formula:

[0083]

[0084] Wherein, Y, Q, L, R1, R2, and R3 groups are substituted as shown above.

[0085] R 16 Selected from C 1-10 Straight chain / branched chain alkyl, -OC 0-5 Alkyl, -O(C 3-4 Cycloalkyl), -O(C 3-4 Heterocycloalkyl), -C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, -N(C 0-10 Alkyl)(C 0-10alkyl), vinyl, ethynyl, aryl, pyridyl, imidazolyl, the H on the above groups can be halogen, -CN, -CH3, -C2H5, -OCH3, -N(C 1-3 Alkyl)(C 1-3 Alkyl), -C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, vinyl substituted, the above alkyl part can be replaced by -CN, -OCF3, -OC 0-10 Alkyl, C 3-4 Cycloalkyl substitution.

[0086] Furthermore, the compound, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, have the following structural formula:

[0087]

[0088] wherein Y is selected from N or -CF; P is N or CH;

[0089] m is an integer between 0 and 4;

[0090] R7 is selected from -H, -F, -Cl, -Br, -I, -NO2, -CN, alkenyl, alkynyl, -CF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl;

[0091] R8 is selected from -H, -CN, -CF3, C 1-4 Straight chain / branched chain alkyl, C 3-10 cycloalkyl;

[0092] R9 is selected from -H, -F, -Cl, -Br, -I, -NO2, -CN, alkenyl, alkynyl, -CF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl;

[0093] R 10 Selected from -H, C 1-3 A straight chain / branched alkyl group, the H on which the alkyl group is replaced by -N(C 1-3 Alkyl)(C 1-3 alkyl), five-membered or six-membered N-heterocycloalkyl.

[0094] R 16’、R 16” 、R 16* 、R 16** R 16# and R 16## Each independently selected from C 1-10 Straight chain / branched chain alkyl, -OC 0-5 Alkyl, -O(C 3-4 Cycloalkyl), -O(C 3-4 Heterocycloalkyl), C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, -N(C 0-10 Alkyl)(C 0-10 alkyl), vinyl, ethynyl, aryl, pyridyl, imidazolyl, the H on the above groups can be halogen, -CN, -CH3, -C2H5, -OCH3, -N(C 1-3 Alkyl)(C 1-3 Alkyl), -C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, vinyl substituted, the above alkyl part can be replaced by -CN, -OCF3, -OC 0-10 Alkyl, C 3-4 Cycloalkyl substitution.

[0095] Furthermore, the compound, and its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds, has the following structural formula:

[0096]

[0097] wherein Y is selected from N or -CF;

[0098] m1 is an integer between 0 and 2;

[0099] R 17 and R 18 Independently selected from -F, -Cl, -Br, -I, -NO2, ethynyl, -CF3;

[0100] R 16a1 and R 16a2 Each independently selected from C 1-5 Straight chain / branched chain alkyl, -OC 1-3 Alkyl, -O(C 3-4 Cycloalkyl), -O(C 3-4 Heterocycloalkyl), C 3-6 Cycloalkyl, 3-6 membered N heterocycloalkyl, 3-6 membered O heterocycloalkyl, -N(C 0-10 Alkyl)(C 0-10 alkyl), vinyl, ethynyl, aryl, pyridyl, imidazolyl, the H on the above groups can be halogen, -CN, -CH3, -C2H5, -OCH3, -N(C 1-3 Alkyl)(C1-3 alkyl), vinyl substituted.

[0101] R 16b1 and R 16b2 Each independently selected from C 1-5 Straight chain / branched chain alkyl, -OC 1-3 Alkyl, C 3-6 Cycloalkyl, aryl, -N(C 1-3 Alkyl)(C 1-3 The H on the above groups can be replaced by halogen, -CN, -CH3, -C2H5, or -OCH3.

[0102] R 16c1 and R 16c2 Each independently selected from C 1-5 Straight chain / branched chain alkyl, -OC 1-3 Alkyl, C 3-6 Cycloalkyl, aryl.

[0103] In one embodiment of the present invention, the compound, and pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds thereof, have the following structural formula:

[0104]

[0105] Wherein, Y, Q, R1, R2, and R3 are substituted as shown above.

[0106] m is an integer between 0 and 4;

[0107] R 19 Selected from -H, -C 1-10 Straight chain / branched chain alkyl, -C 3-10 Cycloalkyl, -CH2CO(C 1-5 alkyl), -CH2COO(C 1-5 alkyl), -CH2COO(C 3-6 Cycloalkyl), -CH2COO(C 3-6 Heterocycloalkyl), -CH2CON(C 1-3 Alkyl)(C 1-3 alkyl), benzyl, aryl, the H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -NO2, -CH3, -C2H5, -C3H7, 3-6 membered heterocycloalkyl, -OC 1-3 Alkyl, -N(C 1-3 Alkyl)(C 1-3 alkyl), vinyl, imidazolyl, oxazolyl, thiazolyl, pyridyl.

[0108] Furthermore, the compound, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, have the following structural formula:

[0109]

[0110] wherein Y is selected from N or -CF; P is N or CH;

[0111] m is an integer between 0 and 4;

[0112] R7 is selected from -H, -F, -Cl, -Br, -I, -NO2, -CN, alkenyl, alkynyl, -CF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl;

[0113] R8 is selected from -H, -CN, -CF3, C 1-4 Straight chain / branched chain alkyl, C 3-10 cycloalkyl;

[0114] R9 is selected from -H, -F, -Cl, -Br, -I, -NO2, -CN, alkenyl, alkynyl, -CF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl;

[0115] R 10 Selected from -H, C 1-3 A straight chain / branched alkyl group, the H on which the alkyl group is replaced by -N(C 1-3 Alkyl)(C 1-3 alkyl), five-membered or six-membered N-heterocycloalkyl.

[0116] R 19’ and R 19” Each independently selected from -H, -C 1-10 Straight chain / branched chain alkyl, -C 3-10 Cycloalkyl, -CH2CO(C 1-5 alkyl), -CH2COO(C 1-5 alkyl), -CH2COO(C 3-6 Cycloalkyl), -CH2COO(C 3-6 Heterocycloalkyl), -CH2CON(C 1-3 Alkyl)(C 1-3alkyl), benzyl, aryl, the H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -NO2, -CH3, -C2H5, -C3H7, 3-6 membered heterocycloalkyl, -OC 1-3 Alkyl, -N(C 1-3 Alkyl)(C 1-3 alkyl), vinyl, imidazolyl, oxazolyl, thiazolyl, pyridyl.

[0117] Furthermore, the compound, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, have the following structural formula:

[0118]

[0119] wherein Y is selected from N or -CF; P is N or CH;

[0120] m1 is an integer between 0 and 2;

[0121] R 17 and R 18 Independently selected from -F, -Cl, -Br, -I, -NO2, ethynyl, -CF3;

[0122] R 19a1 and R 19a2 Each independently selected from -H, C 1-3 Straight chain / branched chain alkyl, C 3-6 Cycloalkyl, -CH2CO(C 1-3 alkyl), -CH2COO(C 1-3 alkyl), -CH2COO(C 3-6 Heterocycloalkyl), -CH2CON(C 1-3 Alkyl)(C 1-3 Alkyl), benzyl, aryl, the H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -NO2, -CH3, -C2H5, -C3H7, -OC 1-3 Alkyl, -N(C 1-3 Alkyl)(C 1-3 alkyl), vinyl, imidazolyl, thiazolyl, pyridyl.

[0123] In one embodiment of the present invention, the compound, and pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds thereof, have the following structural formula:

[0124]

[0125] Wherein, Y, Q, R1, R2, and R3 are substituted as shown above.

[0126] m is an integer between 0 and 4;

[0127] R 20a and R 20b Each independently selected from H, C 1-10 Straight chain / branched alkyl, -COO(C 0-10 alkyl), -CO(C 0-10 Alkyl), C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, aryl, or R d1 and R d2 The N atoms between them form a 3-6 membered N heterocycloalkyl group. The H on the above group can be replaced by the following groups: -F, -Cl, -CN, -NO2, -CH3, -C2H5, -OC 1-3 Alkyl, C 3-6 Cycloalkyl, -(C 0-3 alkyl)COO(C 0-5 alkyl), -CO(C 0-5 Alkyl), -N(C 1-3 Alkyl)(C 1-3 Alkyl), aryl, the alkyl part can be -CN, -OCF3, -OC 0-3 Alkyl, -CO(C 0-5 Alkyl), C 3-4 Cycloalkyl, aryl substitution.

[0128] Furthermore, the compound, and its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds, have the following structural formula:

[0129]

[0130] wherein Y is selected from N or -CF; P is N or CH;

[0131] m is an integer between 0 and 4;

[0132] R7 is selected from -H, -F, -Cl, -Br, -I, -NO2, -CN, alkenyl, alkynyl, -CF3;

[0133] R8 is selected from -H, -CN, -CF3, C 1-4 Straight chain / branched chain alkyl, C 3-10 cycloalkyl;

[0134] R9 is selected from -H, -F, -Cl, -Br, -I, -NO2, -CN, alkenyl, alkynyl, -CF3;

[0135] R 10 Selected from -H, C 1-3 A straight chain / branched alkyl group, the H on which the alkyl group is replaced by -N(C 1-3Alkyl)(C 1-3 alkyl), five-membered or six-membered N-heterocycloalkyl.

[0136] R 20a’ 、R 20a” 、R 20b’ and R 20b” Each independently selected from H, C 1-10 Straight chain / branched alkyl, -COO(C 0-10 alkyl), -CO(C 0-10 Alkyl), C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, aryl, or R d1 and R d2 The N atoms between them form a 3-6 membered N heterocycloalkyl group. The H on the above group can be replaced by the following groups: -F, -Cl, -CN, -NO2, -CH3, -C2H5, -OC 1-3 Alkyl, C 3-6 Cycloalkyl, -(C 0-3 alkyl)COO(C 0-5 alkyl), -CO(C 0-5 Alkyl), -N(C 1-3 Alkyl)(C 1-3 Alkyl), aryl, the alkyl part can be -CN, -OCF3, -OC 0-3 Alkyl, -CO(C 0-5 Alkyl), C 3-4 Cycloalkyl, aryl substitution.

[0137] Furthermore, the compound, and its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds, have the following structural formula:

[0138]

[0139] wherein Y is selected from N or -CF;

[0140] m1 is an integer between 0 and 2;

[0141] R 21 Selected from -F, -Cl, -Br, -I, -NO2, ethynyl, -CF3;

[0142] R 22a and R 22b Each independently selected from -H, C 1-3 Straight chain / branched alkyl, -COO(C 1-3 alkyl), -CO(C 1-3 Alkyl), C 3-5Cycloalkyl, 3-6 membered heterocycloalkyl, aryl, the H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -NO2, -CH3, -C2H5, -OCH3, -(C 0-3 alkyl)COO(C 1-3 alkyl).

[0143] m2 is an integer between 1 and 3;

[0144] R 23 Selected from -H, C 1-3 Straight chain / branched alkyl, -COO(C 1-3 alkyl), -CO(C 1-3 Alkyl), C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, -N(C 0-3 Alkyl)(C 0-3 Alkyl), aryl, the H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -NO2, -CH3, -C2H5, -OC 1-3 Alkyl, C 3-6 Cycloalkyl, -(C 0-3 alkyl)COO(C 0-5 alkyl), -CO(C 0-5 alkyl), aryl.

[0145] Preferably, the compound, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, have the following structural formula:

[0146]

[0147] wherein Y is selected from N or -CF;

[0148] M does not exist, or forms a cyclic ring with the adjacent carbon to form a saturated / unsaturated alicyclic ring, a saturated / unsaturated heterocyclic ring, an aromatic ring or a heteroaromatic ring;

[0149] When M does not exist, R x -H, halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N heterocycloalkyl, O heterocycloalkyl, S heterocycloalkyl; preferably, R x -H, halogen, -NO2, -CN, -CF3, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-6Straight chain / branched chain alkyl, -N(C 0-6 Alkyl)(C 0-6 Alkyl), -OC 0-6 Alkyl, C 3-6 Cycloalkyl, N heterocycloalkyl, O heterocycloalkyl, S heterocycloalkyl; More preferably, R x -H, halogen, -NO2, -CN, -CF3, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Straight chain / branched chain alkyl, -N(C 0-3 Alkyl)(C 0-3 Alkyl), -OC 0-3 Alkyl, C 3-6 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl; when M forms a cyclic ring with the adjacent carbon, R x does not exist;

[0150] n1 is 0, 1, or 2;

[0151] The H on the above saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring can be substituted by the following groups: halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 Preferably, the H on the above saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring can be substituted by the following groups: halogen, -NO2, -CN, -CF3, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Straight chain / branched chain alkyl, -N(C 0-6 Alkyl)(C 0-6 Alkyl), -OC 0-6 Alkyl, C 3-6 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 Further preferably, the H on the above saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring can be substituted by the following groups: halogen, -NO2, -CN, -CF3, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Straight chain / branched chain alkyl, -N(C 0-3 Alkyl)(C 0-3Alkyl), -OC 0-3 Alkyl, C 3-6 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 alkyl);

[0152] Q is selected from O, S-Rxx, N or R3 is selected from -H, C 1-5 The H on the alkyl group may be substituted by the following groups: -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, 3-8 membered heterocycloalkyl, -COO(C 0-10 alkyl); preferably, the H on the alkyl may be substituted by the following groups: -N(C 1-6 Alkyl)(C 1-6 Alkyl), -OC 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -COO(C 1-6 The heterocycloalkyl group contains at least one N, O, or S as a ring atom;

[0153] Rxx is selected from H, C 1-5 The straight chain / branched alkyl group is preferably H or methyl; the H on the alkyl group may be substituted by the following groups: halogen, nitro, cyano, -OC 0-10 alkyl;

[0154] When Q is N, R3, Q and the N atom and C atom therebetween form a five-membered aromatic heterocycle or a six-membered aromatic heterocycle having at least two heteroatoms; optionally, the five-membered aromatic heterocycle is an imidazole group; the H of the imidazole group may be substituted by the following groups: halogen, cyano, -C 0-10 Alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl; Preferably, the H of the imidazole group may be substituted by the following groups: halogen, cyano, -C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 Alkyl), -OC 1-6 Alkyl; Optionally, the six-membered aromatic heterocycle is a pyridine group; the H of the pyridine group may be substituted by the following groups: halogen, cyano, -C 0-10 Alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl; Preferably, the H of the pyridine group may be substituted by the following groups: halogen, cyano, -C 1-6Alkyl, -N(C 1-6 Alkyl)(C 1-6 Alkyl), -OC 1-6 alkyl;

[0155] L is absent, or L is selected from C 2-8 Olefinic bond or C 1-8 Alkylene, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -CF3, -OCH2F, -OCHF2, -OCF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, -CO(C 0-10 Alkyl), -COO(C 0-10 alkyl);

[0156] When Q is N or When Q, L and the atoms therebetween form a five-membered or six-membered nitrogen-containing heterocyclic ring;

[0157] n is 0 or 1. When n is 0, it means that the -CO- group does not exist;

[0158] X is absent, or when n is 1, X is O, when n is 0, X is selected from O, substituted / unsubstituted N-alkyl, substituted / unsubstituted N-heterocycloalkyl;

[0159] R4 is selected from -H, halogen, -CN, -CF3, -OCH2F, -OCHF2, -OCF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl, aryl, N-heterocyclic aromatic group, O-heterocyclic aromatic group, S-heterocyclic aromatic group, -SO2(C 0-10 alkyl), -SO(C 0-10 Alkyl), -SO2O(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO2(C 3-10 Cycloalkyl), -SO2-aryl, -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl), -CO(C 3-10 Cycloalkyl), -CO(3-6 membered heterocycloalkyl), -(C 0-10 alkyl)COO(C 0-10Alkyl), -COO(C 3-10 Cycloalkyl), -COO (3-6 membered heterocycloalkyl), alkenyl, alkynyl, wherein the heterocycloalkyl contains at least one N, O, or S as a ring atom, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -NO2, -CF3, C 1-3 Straight chain alkyl, -OC 0-10 Alkyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -COO(C 3-10 Cycloalkyl), -COO(heterocycloalkyl), -CO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -OCOO(C 0-10 alkyl), phenyl, N heterocyclic aromatic group, O heterocyclic aromatic group, S heterocyclic aromatic group, alkenyl group, alkynyl group.

[0160] Preferably, the compound, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, have the following structural formula:

[0161]

[0162] wherein Y is selected from N or -CF;

[0163] M does not exist, or forms a cyclic ring with the adjacent carbon to form a saturated / unsaturated alicyclic ring, a saturated / unsaturated heterocyclic ring, an aromatic ring or a heteroaromatic ring;

[0164] The H on the above saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring can be substituted by the following groups: halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 Preferably, the H on the above saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring can be substituted by the following groups: halogen, -CN, -NO2, -NHCO(C 0-10 alkyl), CF3, C 1-10 Straight chain alkyl, -OC0-10 alkyl;

[0165] Q is selected from N or R3 is selected from -H, C 1-5 The H on the alkyl group may be substituted by the following groups: -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, 3-8 membered heterocycloalkyl, -COO(C 0-10 alkyl); preferably, the H on the alkyl may be substituted by the following groups: -N(C 1-6 Alkyl)(C 1-6 Alkyl), -OC 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -COO(C 1-6 The heterocycloalkyl group contains at least one N, O, or S as a ring atom;

[0166] When Q is N, R3, Q, the N atom and the C atom therebetween form a five-membered aromatic heterocycle or a six-membered aromatic heterocycle having at least two heteroatoms; optionally, the five-membered aromatic heterocycle is an imidazole group; optionally, the six-membered aromatic heterocycle is a pyridine group;

[0167] Preferably, Q is N, R3 and the adjacent triaza The N atom and Q together form an imidazole structure.

[0168] Preferably, R3 and Q do not form a ring, and Q is N or -NCO(C 0-10 When Q is N, Q is connected to the parent nucleus through a double bond. When Q is -NCO(C 0-10 When Q is connected to the parent nucleus via a single bond.

[0169] Preferably, the compound, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, have the following structural formula:

[0170]

[0171] wherein Y is selected from N or -CF;

[0172] M does not exist, or forms a cyclic ring with the adjacent carbon to form a saturated / unsaturated alicyclic ring, a saturated / unsaturated heterocyclic ring, an aromatic ring or a heteroaromatic ring;

[0173] n1 is 0, 1, or 2;

[0174] The H on the above saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring can be substituted by the following groups: halogen, -NO2, -CN, -CF3, C2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 Preferably, the H on the above saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring can be substituted by the following groups: halogen, -CN, -NO2, -NHCO(C 0-10 alkyl), CF3, C 1-3 Straight chain alkyl, -OC 0-10 alkyl;

[0175] R y1 Selected from -H, -CN, -CF3, C 1-4 Straight chain / branched chain alkyl, C 3-10 cycloalkyl; preferably methyl;

[0176] R y2 Selected from -H, C 1-3 A straight chain / branched alkyl group, the H on which the alkyl group is replaced by -N(C 1-3 Alkyl)(C 1-3 Alkyl), -COO(C 0-5 alkyl), five-membered or six-membered N-heterocycloalkyl; preferably, the H on the alkyl can be substituted by N(C 1-3 Alkyl)(C 1-3 Alkyl), -COO(C 1-3 alkyl), five-membered or six-membered N-heterocycloalkyl.

[0177] Preferably, the compound, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, have the following structural formula:

[0178]

[0179] wherein Y is selected from N or -CF;

[0180] M does not exist, or forms a cyclic ring with the adjacent carbon to form a saturated / unsaturated alicyclic ring, a saturated / unsaturated heterocyclic ring, an aromatic ring or a heteroaromatic ring;

[0181] When M does not exist, R x -H, halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl; when M forms a cyclic ring with the adjacent carbon, R x does not exist;

[0182] n1 is 0, 1, or 2;

[0183] The H on the above saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring can be substituted by the following groups: halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 alkyl);

[0184] Q is selected from O, S-Rxx or N, R3 is selected from -H, C 1-5 The H on the alkyl group may be substituted by the following groups: -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, 3-8 membered heterocycloalkyl, -COO(C 0-10 Alkyl), wherein the heterocycloalkyl contains at least one N, O, or S as a ring atom;

[0185] When Q is N, R3, Q and the N atom and C atom therebetween form a five-membered aromatic heterocycle or a six-membered aromatic heterocycle having at least two heteroatoms;

[0186] Rxx is selected from H, C 1-5 The straight chain / branched alkyl group is preferably H or methyl; the H on the alkyl group may be substituted by the following groups: halogen, nitro, cyano, -OC 0-10 alkyl;

[0187] L is absent, or L is selected from C 2-4 Olefinic bond or C 1-8 Alkylene, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -CF3, -OCH2F, -OCHF2, -OCF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, 3-10 membered cycloalkyl, -CO(C0-10 Alkyl), -COO(C 0-10 alkyl);

[0188] R f Selected from -H, C 1-10 Straight chain / branched chain alkyl, OR j , R j Selected from C 1-10 Straight chain / branched chain alkyl, C 3-10 Cycloalkyl, 3-8 membered heterocycloalkyl, aryl, heteroaryl, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -CH3, -C2H5, -OC 1-5 、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -CO(C 0-10 alkyl), -OCO(C 0-10 Alkyl), vinyl, propadienyl, ethynyl, further, the above alkyl part can be -CN, -OCH2F, -OCHF2, -OCF3, -OC 0-10 Alkyl, C 3-4 cycloalkyl substitution;

[0189] R g Selected from -H, -C 1-10 Straight chain / branched chain alkyl, -C 3-10 Cycloalkyl, -CH2CO(C 0-10 alkyl), -CH2COO(C 0-6 alkyl), -CH2COO(C 3-6 Cycloalkyl), -CH2COO(C 3-6 Heterocycloalkyl), -CH2CON(C 0-10 Alkyl)(C 0-10 Alkyl), benzyl, aryl, the H on the above groups can be replaced by the following groups: -F, -Cl, -CN, -NO2, C 1-10 Straight chain / branched alkyl, 3-6 membered heterocyclic alkyl, -OC 1-5 Alkyl, -N(C 1-3 Alkyl)(C 1-3 Alkyl), C 2-8 alkenyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, phenyl; or R g Selected from R c1 、R c2 、R c3 Independently selected from C 1-10 Straight chain / branched chain alkyl, -OC 0-5 Alkyl, -O(C 3-6 Cycloalkyl), -O(C 3-6 Heterocycloalkyl), C 3-10Cycloalkyl, 3-6 membered heterocycloalkyl, -N(C 0-10 Alkyl)(C 0-10 alkyl), alkenyl, alkynyl, aryl, heteroaryl, the H on the above groups can be halogen, -CN, -CH3, -C2H5, -OCH3, -N(C 1-3 Alkyl)(C 1-3 Alkyl), -C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, vinyl substituted, the above alkyl part can be replaced by -CN, -OCF3, -OC 0-10 Alkyl, C 3-4 cycloalkyl substitution;

[0190] R h1 and R h2 Each independently selected from H, C 1-10 Straight chain / branched alkyl, -COO(C 0-10 alkyl), -CO(C 0-10 alkyl), 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, aryl, or R h1 and R h2 The N atoms between them form a 3-6 membered heterocyclic alkyl group. The H on the above group can be replaced by the following groups: halogen, -CN, -NO2, C 1-3 Straight chain / branched chain alkyl, -OC 1-3 Alkyl, C 3-6 Cycloalkyl, -(C 0-10 alkyl)COO(C 0-10 alkyl), -CO(C 0-10 alkyl), aryl, -N(C 1-3 Alkyl)(C 1-3 Alkyl), the alkyl part can be -CN, -OCF3, -OC 0-10 、-CO(C 0-10 Alkyl), C 3-4 Cycloalkyl, aryl substitution;

[0191] R j is selected from halogen, cyano, aryl, heteroaryl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; the H on the above groups may be substituted by the following groups: halogen, -CN, -NO2, C 1-10 Straight chain / branched chain alkyl, -OC 1-10 alkyl.

[0192] Preferably, the compound, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, have the following structural formula:

[0193]

[0194] wherein Y is selected from N or -CF;

[0195] M does not exist, or forms a cyclic ring with the adjacent carbon to form a saturated / unsaturated alicyclic ring, a saturated / unsaturated heterocyclic ring, an aromatic ring or a heteroaromatic ring;

[0196] When M does not exist, R x -H, halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl; when M forms a cyclic ring with the adjacent carbon, R x does not exist;

[0197] n1 is 0, 1, or 2;

[0198] The H on the above saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring can be substituted by the following groups: halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 alkyl);

[0199] Q is selected from O, S-Rxx or N, R3 is selected from -H, C 1-5 The H on the alkyl group may be substituted by the following groups: -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, 3-8 membered heterocycloalkyl, -COO(C 0-10 Alkyl), wherein the heterocycloalkyl contains at least one N, O, or S as a ring atom;

[0200] When Q is N, R3, Q and the N atom and C atom therebetween form a five-membered aromatic heterocycle or a six-membered aromatic heterocycle having at least two heteroatoms;

[0201] Rxx is selected from H, C 1-5 A straight chain / branched alkyl group, preferably a methyl group; the H on the alkyl group may be substituted by the following groups: halogen, nitro, cyano, -OC 0-10 alkyl;

[0202] m1, m2, and m3 are independently selected from integers of 0 to 5; preferably integers of 1 to 5, more preferably integers of 1 to 3;

[0203] R5', R5", R5'" are independently selected from -H, halogen, -CN, -CF3, -C 1-10 Alkyl, -CO(C 0-10 Alkyl), -COO(C 0-10 Alkyl); preferably -H, halogen, -CN, -CF3, -C 1-6 Alkyl, -CO(C 0-6 Alkyl), -COO(C 0-6 alkyl);

[0204] R f 'Selected from -H, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 alkyl), OR j ', R j 'Selected from C 1-10 Straight chain / branched chain alkyl, C 3-10 Cycloalkyl, 3-8 membered heterocycloalkyl, aryl, heteroaryl, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -CH3, -C2H5, -OC 1-5 、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -CO(C 0-10 alkyl), -OCO(C 0-10 Alkyl), vinyl, propadienyl, ethynyl, further, the above alkyl part can be -CN, -OCH2F, -OCHF2, -OCF3, -OC 0-10 Alkyl, C 3-4 cycloalkyl substitution;

[0205] Preferably, R f 'Selected from -H, C 1-6 Straight chain / branched chain alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), OR j ', R j 'Selected from C 1-6 Straight chain / branched chain alkyl, C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 3-5 membered heterocyclic group containing N, O and / or S, 3-5 membered heteroaryl group containing N, O and / or S; wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -CH3, -C2H5, -OC 1-5 、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -CO(C0-10 alkyl), -OCO(C 0-10 Alkyl), vinyl, propadienyl, ethynyl, further, the above alkyl part can be -CN, -OCH2F, -OCHF2, -OCF3, -OC 0-10 Alkyl, C 3-4 cycloalkyl substitution;

[0206] R g 'Selected from -H, -C 1-10 Straight chain / branched chain alkyl, -C 3-10 Cycloalkyl, -CH2CO(C 0-10 alkyl), -CH2COO(C 0-6 alkyl), -CH2COO(C 3-6 Cycloalkyl), -CH2COO(C 3-6 Heterocycloalkyl), -CH2CON(C 0-10 Alkyl)(C 0-10 Alkyl), benzyl, aryl, the H on the above groups can be replaced by the following groups: -F, -Cl, -CN, -NO2, C 1-10 Straight chain / branched alkyl, 3-6 membered heterocyclic alkyl, -OC 1-5 Alkyl, -N(C 1-3 Alkyl)(C 1-3 Alkyl), C 2-8 alkenyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, phenyl; or R g 'Selected R c1 、R c2 、R c3 Independently selected from C 1-10 Straight chain / branched chain alkyl, -OC 0-5 Alkyl, -O(C 3-6 Cycloalkyl), -O(C 3-6 Heterocycloalkyl), C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, -N(C 0-10 Alkyl)(C 0-10 alkyl), alkenyl, alkynyl, aryl, heteroaryl, the H on the above groups can be halogen, -CN, -CH3, -C2H5, -OCH3, -N(C 1-3 Alkyl)(C 1-3 Alkyl), -C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, vinyl substituted, the above alkyl part can be replaced by -CN, -OCF3, -OC 0-10 Alkyl, C 3-4 cycloalkyl substitution;

[0207] Preferably, R g 'Selected from -H, -C1-6 Straight chain / branched chain alkyl, -C 3-6 Cycloalkyl; H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -NO2, C 1-6 Straight chain / branched alkyl, 3-6 membered heterocyclic alkyl, -OC 1-5 Alkyl, -N(C 1-3 Alkyl)(C 1-3 Alkyl), C 2-8 alkenyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, phenyl; or R g 'Selected R c1 Selected from C 1-6 Straight chain / branched chain alkyl, -OC 1-5 Alkyl, -O(C 3-6 Cycloalkyl), -O(C 3-6 Heterocycloalkyl), C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), alkenyl, alkynyl, aryl, heteroaryl, the H on the above groups can be halogen, -CN, -CH3, -C2H5, -OCH3, -N(C 1-3 Alkyl)(C 1-3 Alkyl), -C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, vinyl substituted, the above alkyl part can be replaced by -CN, -OCF3, -OC 0-10 Alkyl, C 3-4 cycloalkyl substitution;

[0208] R i ' is selected from halogen, cyano, phenyl, 5-6 membered heteroaryl containing N, O and / or S, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; preferably, R i ' is selected from halogen, cyano, phenyl, pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, triazolyl, isoxazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the following groups:

[0209]

[0210] The above R i The H on the group can be substituted by the following groups: halogen, -CN, -NO2, C 1-6 Straight chain / branched chain alkyl, -OC 1-6 alkyl;

[0211] Indicates the connection location.

[0212] Preferably, the compound, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, have the following structural formula:

[0213]

[0214] wherein Y is selected from N or -CF; P' is N or CH;

[0215] M does not exist, or forms a cyclic ring with the adjacent carbon to form a saturated / unsaturated alicyclic ring, a saturated / unsaturated heterocyclic ring, an aromatic ring or a heteroaromatic ring;

[0216] When M does not exist, R x -H, halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl; when M forms a cyclic ring with the adjacent carbon, R x does not exist;

[0217] n1 is 0, 1, or 2;

[0218] The H on the above saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring can be substituted by the following groups: halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 alkyl);

[0219] R8' is selected from -H, halogen, -CN, -NO2, -CF3, C 1-4 Straight chain / branched chain alkyl, C 3-10 cycloalkyl;

[0220] R 10 'Selected from -H, C 1-3 A straight chain / branched alkyl group, the H on which the alkyl group is replaced by -N(C 1-3 Alkyl)(C 1-3 alkyl), -CO(C 0-10 Alkyl), -COO(C 0-10Alkyl), five-membered or six-membered N heterocycloalkyl;

[0221] Q' is selected from =O or -S-Rxx; Rxx is selected from H, C 1-3 The H on the alkyl group may be substituted by the following groups: halogen, nitro, cyano, -OC 0-10 alkyl;

[0222] m1, m2, and m3 are independently selected from integers of 0 to 4;

[0223] R5', R5", R5'" are independently selected from -H, halogen, -CN, -CF3, -C 1-10 Alkyl, -CO(C 0-10 Alkyl), -COO(C 0-10 alkyl);

[0224] R f 'Selected from -H, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 alkyl), OR j ', R j 'Selected from C 1-10 Straight chain / branched chain alkyl, C 3-10 Cycloalkyl, 3-8 membered heterocycloalkyl, aryl, heteroaryl, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -CH3, -C2H5, -OC 1-5 、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -CO(C 0-10 alkyl), -OCO(C 0-10 Alkyl), vinyl, propadienyl, ethynyl, further, the above alkyl part can be -CN, -OCH2F, -OCHF2, -OCF3, -OC 0-10 Alkyl, C 3-4 cycloalkyl substitution;

[0225] R g 'Selected from -H, -C 1-10 Straight chain / branched chain alkyl, -C 3-10 Cycloalkyl, -CH2CO(C 0-10 alkyl), -CH2COO(C 0-6 alkyl), -CH2COO(C 3-6 Cycloalkyl), -CH2COO(C 3-6 Heterocycloalkyl), -CH2CON(C 0-10 Alkyl)(C 0-10 Alkyl), benzyl, aryl, the H on the above groups can be replaced by the following groups: -F, -Cl, -CN, -NO2, C 1-10Straight chain / branched alkyl, 3-6 membered heterocyclic alkyl, -OC 1-5 Alkyl, -N(C 1-3 Alkyl)(C 1-3 Alkyl), C 2-8 alkenyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, phenyl; or R g 'Selected R c1 、R c2 、R c3 Independently selected from C 1-10 Straight chain / branched chain alkyl, -OC 0-5 Alkyl, -O(C 3-6 Cycloalkyl), -O(C 3-6 Heterocycloalkyl), C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, -N(C 0-10 Alkyl)(C 0-10 alkyl), alkenyl, alkynyl, aryl, heteroaryl, the H on the above groups can be halogen, -CN, -CH3, -C2H5, -OCH3, -N(C 1-3 Alkyl)(C 1-3 Alkyl), -C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, vinyl substituted, the above alkyl part can be replaced by -CN, -OCF3, -OC 0-10 Alkyl, C 3-4 cycloalkyl substitution;

[0226] R i 'Selected from halogen, cyano, phenyl, 5-6 membered heteroaryl containing N, O and / or S, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; H on the above groups may be substituted by the following groups: halogen, -CN, -NO2, C 1-6 Straight chain / branched chain alkyl, -OC 1-6 alkyl.

[0227] The Y is N or -CF, preferably N.

[0228] The P' is N or CH, preferably CH.

[0229] The R8' is preferably -H, halogen, -CN, -NO2, -CF3, C 1-3 Straight chain / branched chain alkyl, C 3-6 The cycloalkyl group is more preferably H or methyl.

[0230] The R 10 'Selected from -H, C 1-3 A straight chain / branched alkyl group, the H on which the alkyl group is replaced by -N(C 1-3 Alkyl)(C 1-3 alkyl), -CO(C 1-3Alkyl), -COO(C 1-3 alkyl), piperazinyl, N-methylpiperazinyl or N-ethylpiperazinyl.

[0231] Q' is selected from ═O or —S—Rxx; Rxx is preferably H or methyl.

[0232] The m1, m2, and m3 are independently selected from integers of 0 to 4, preferably integers of 0 to 2. In some specific embodiments of the present invention, the m1, m2, and m3 are independently selected from 0, 1, 2, 3, or 4.

[0233] R5', R5", R5'" are independently selected from -H, halogen, -CN, -CF3, -C 1-6 Alkyl, -CO(C 1-6 Alkyl), -COO(C 1-6 Alkyl); preferably -H, halogen, -CN, -CF3, -C 1-3 Alkyl, -CO(C 1-3 Alkyl), -COO(C 1-3 alkyl).

[0234] R f 'Preferably -H, C 1-6 Straight chain / branched chain alkyl, -N(C 0-6 Alkyl)(C 0-6 alkyl), OR j '; More preferably -H, C 1-5 Straight chain / branched chain alkyl, -N(C 0-3 Alkyl)(C 0-3 alkyl), OR j ';R j 'Preferably C 1-6 Straight-chain / branched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furyl, pyrrolyl, pyridyl or the following groups:

[0235]

[0236] Among them, R j1 '、R j2 '、R j3 '、R j4 '、R j5 '、R j6 'Independently selected from H, halogen, -CN, -C 1-6 Straight chain / branched chain alkyl, -C 2-6 Straight chain / branched alkenyl, -OC 1-6 Straight chain / branched chain alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -CO(C 0-10 alkyl), -OCO(C0-10 alkyl), ethynyl;

[0237] Among them, the above R f The H on the group can be substituted by the following groups: halogen, -CN, -CH3, -C2H5, -OC 1-5 、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -CO(C 0-10 alkyl), -OCO(C 0-10 Alkyl), vinyl, propadienyl, ethynyl, further, the above alkyl part can be -CN, -OCH2F, -OCHF2, -OCF3, -OC 0-10 Alkyl, C 3-4 Cycloalkyl substitution.

[0238] R g 'Selected from -H, -C 1-6 Straight chain / branched chain alkyl, -C 3-6 Cycloalkyl, -CH2CO(C 1-6 alkyl), -CH2COO(C 0-6 alkyl), -CH2COO(C 3-6 Cycloalkyl), -CH2COO(C 3-6 Heterocycloalkyl), -CH2CON(C 0-6 Alkyl)(C 0-6 Alkyl), benzyl, aryl, the H on the above groups can be replaced by the following groups: -F, -Cl, -CN, -NO2, C 1-10 Straight chain / branched alkyl, 3-6 membered heterocyclic alkyl, -OH, -OC 1-5 Alkyl, -N(C 1-3 Alkyl)(C 1-3 Alkyl), C 2-8 alkenyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, phenyl; preferably, the H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -NO2, C 1-6 Straight chain / branched alkyl, 3-6 membered heterocyclic alkyl, -OH, -OC 1-5 Alkyl, -N(C 1-3 Alkyl)(C 1-3 Alkyl), C 2-3 alkenyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, phenyl;

[0239] or R g 'Selected R c1 、R c2 、R c3 Independently selected from C 1-10 Straight chain / branched chain alkyl, -OC 0-5Alkyl, -O(C 3-6 Cycloalkyl), -O(C 3-6 Heterocycloalkyl), C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, -N(C 0-10 Alkyl)(C 0-10 alkyl), alkenyl, alkynyl, aryl, heteroaryl; preferably, R c1 、R c2 、R c3 Independently selected from C 1-6 Straight chain / branched chain alkyl, -OC 1-6 Alkyl, -O(C 3-6 Cycloalkyl), -O(C 3-6 Heterocycloalkyl), C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -N(C 0-6 Alkyl)(C 0-6 alkyl), alkenyl, alkynyl, aryl, heteroaryl; further preferably, R c1 、R c2 、R c3 Independently selected from C 1-3 Straight chain / branched chain alkyl, -OC 1-3 Alkyl, -O(C 3-6 Cycloalkyl), -O(C 3-6 heterocycloalkyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-membered N- or O-containing heterocycloalkyl, 4-membered N- or O-containing heterocycloalkyl, 5-membered N- or O-containing heterocycloalkyl, 6-membered N- or O-containing heterocycloalkyl, -N(C 1-3 Alkyl)(C 1-3 alkyl), vinyl, ethynyl, phenyl, pyridyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl;

[0240] Preferably, the above R g The H on the group can be halogen, -CN, -CH3, -C2H5, -OCH3, -N(C 1-3 Alkyl)(C 1-3 Alkyl), -C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, vinyl substituted, the above alkyl part can be replaced by -CN, -OCF3, -OC 0-10 Alkyl, C 3-4 Cycloalkyl substitution.

[0241] R i 'Preferably halogen, cyano, phenyl, pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, triazolyl, isoxazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the following groups:

[0242]

[0243] The above R i The H on the group can be substituted by the following groups: halogen, -CN, -NO2, C 1-6 Straight chain / branched chain alkyl, -OC 1-6 alkyl;

[0244] Indicates the connection location.

[0245] Preferably, the M and the adjacent carbon atoms together form the following groups: 3-8 membered saturated / unsaturated alicyclic ring, 3-8 membered saturated / unsaturated heterocyclic ring, benzene, 5-membered or 6-membered monocyclic heteroaromatic ring, heteroaromatic ring formed by condensing a benzene ring with 1-2 5-membered or 6-membered monocyclic heteroaromatic groups, heteroaromatic ring formed by condensing 2-3 5-membered and / or 6-membered monocyclic heteroaromatic groups; wherein, the H on the above groups may be substituted by the following groups: halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 Alkyl); preferably, the H on the above groups can be substituted by the following groups: halogen, -CN, -NO2, -NHCO(C 0-10 alkyl), CF3, C 1-3 Straight chain alkyl, -OC 0-10 Alkyl; further preferably, the H on the above groups can be substituted by the following groups: halogen, -CN, -NO2, -NHCO(C 1-6 alkyl), CF3, C 1-3 Straight chain alkyl, -OC 1-6 alkyl.

[0246] Preferably, the heteroatoms of the 3- to 8-membered saturated / unsaturated alicyclic ring and the 3- to 8-membered saturated / unsaturated heterocyclic ring are selected from one or more of N, O, and S.

[0247] Preferably, the M and the adjacent carbon atoms together form the following groups: 3-6 membered saturated / unsaturated alicyclic ring, 3-6 membered saturated / unsaturated heterocyclic ring, benzene, pyrrole, thiophene, furan, pyridine, pyrimidine, pyrazine, triazine, imidazole, oxazole, thiazole, pyrazole, benzofuran, benzoxazole, benzimidazole, benzothiophene, benzothiazole, indole or imidazopyridine; wherein the H on the above groups can be substituted by the following groups: halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 Alkyl); preferably, the H on the above groups can be substituted by the following groups: halogen, -CN, -NO2, -NHCO(C 0-10 alkyl), CF3, C 1-3 Straight chain alkyl, -OC 0-10 alkyl.

[0248] Preferably, the 3- to 6-membered saturated / unsaturated alicyclic ring is selected from saturated / unsaturated cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0249] Preferably, the 3- to 6-membered saturated / unsaturated heterocycle is a saturated / unsaturated 3-membered heterocycle, 4-membered heterocycle, 5-membered heterocycle or 6-membered heterocycle containing one or more of N, O and S. Preferably, the heterocycle is a monocyclic heterocycle.

[0250] When M forms a heteroaromatic ring with the adjacent carbon, it can be fused to the parent core through the phenyl side or the heterocyclic group side in the heteroaromatic ring.

[0251] Preferably, the M forms any of the following structures with adjacent carbons:

[0252]

[0253] R 1x 、R 2x 、R 3x 、R 4x Each independently selected from H, halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 Alkyl); preferably H, halogen, -CN, -NO2, -NHCO(C 0-10 alkyl), CF3, C 1-3 Straight chain alkyl, -OC 0-10 Alkyl; preferably H, halogen, -CN, -NO2, -NHCO(C 0-6 alkyl), CF3, C 1-3 Straight chain alkyl, -OC 0-6 alkyl;

[0254] T1, T2, T3, T4, and T5 are independently selected from CR 24 , N, O or S;

[0255] T6 is selected from C, N, O or S;

[0256] R 24 Selected from H, halogen, -CN, -NO2, -NHCO(C 0-10 alkyl), CF3, C 1-3 Straight chain alkyl, -OC 0-10 Alkyl; preferably H, halogen, -CN, -NO2, -NHCO(C 0-6 alkyl), CF3, C 1-3 Straight chain alkyl, -OC 0-6 alkyl;

[0257] Indicates the connection location.

[0258] Further preferably, the M forms any of the following structures with the adjacent carbon:

[0259]

[0260] R 5x -R 23x Independently selected from the following groups: H, halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 alkyl); preferably: H, halogen, -C 1-3 Straight chain / branched chain alkyl, -OC 0-3 Linear / branched alkyl, -CF3, -CN, -NO2;

[0261] Indicates the connection location.

[0262] In a specific embodiment of the present invention, the following specific compounds are provided:

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277] In a second aspect, a pharmaceutical composition comprises the compound provided by the present invention and pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds thereof.

[0278] Preferably, the pharmaceutical composition further comprises pharmaceutically acceptable excipients, including but not limited to carriers, diluents, adhesives, lubricants, and wetting agents.

[0279] In certain embodiments, the pharmaceutical composition can be used alone or in combination with other active ingredients having anesthetic and / or analgesic effects.

[0280] The pharmaceutical composition can be administered to humans and / or animals.

[0281] The pharmaceutical composition is suitable for enteral or parenteral administration, such as intravenous, intramuscular, intradermal and subcutaneous administration. Therefore, the pharmaceutical composition also includes antioxidants, buffers, bacteriostats, and solutes that make the formulation isotonic with the recipient's blood, suspending agents, solubilizers, thickeners, stabilizers and preservatives.

[0282] The pharmaceutical composition of the present invention can be formulated into the following forms of pharmaceutical preparations: syrups, elixirs, suspensions, powders, granules, tablets, capsules, lozenges, aqueous solutions, creams, ointments, lotions, gels, emulsions, etc.

[0283] The pharmaceutical preparation is preferably in unit dosage form, comprising a therapeutically effective amount of a compound of Formula I, and pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates, and deuterated compounds thereof. The unit dosage form may be a capsule, tablet, or any other dosage form. Furthermore, the unit dosage form may be a packaged preparation, such as tablets, capsules, and powders packaged in vials or ampoules.

[0284] The amount of active ingredient in the unit dosage form can be varied or adjusted from 0.001 mg to 1000 mg, depending on the specific application and efficacy of the active ingredient. If necessary, other suitable active ingredients may also be included.

[0285] In a third aspect, a compound provided by the present invention and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds or the above-mentioned pharmaceutical compositions are used in the preparation of drugs having analgesic effects, and / or anesthetic, sedative, hypnotic effects, and / or capable of controlling status epilepticus.

[0286] The pharmaceutically acceptable salts of the present invention are acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, naphthate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydroxynaphthenate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, xinafoate, methanesulfonate or p-toluenesulfonate.

[0287] Preferably, the pharmaceutically acceptable salt of the present invention is selected from one of benzenesulfonate, p-toluenesulfonate, isethionate, sulfate, hydrochloride, methanesulfonate, hydrobromide, and naphthalenesulfonate.

[0288] The term C in the present invention 0-10 Alkyl, C0 alkyl refers to H, therefore, C 0-10 Alkyl includes H, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, C 10 alkyl.

[0289] The term C in the present invention 1-10Straight chain / branched chain alkyl, including methyl, ethyl, C3 straight chain / branched chain alkyl, C4 straight chain / branched chain alkyl, C5 straight chain / branched chain alkyl, C6 straight chain / branched chain alkyl, C7 straight chain / branched chain alkyl, C8 straight chain / branched chain alkyl, C9 straight chain / branched chain alkyl, C 10 Straight chain / branched chain alkyl.

[0290] The term C in the present invention 3-10 Cycloalkyl, including C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C7 cycloalkyl, C8 cycloalkyl, C9 cycloalkyl, C 10 Cycloalkyl.

[0291] The term halogen described in the present invention includes fluorine, chlorine, bromine and iodine.

[0292] The term heterocycloalkyl as used herein refers to a cycloalkyl group containing heteroatoms, wherein the heteroatoms include N, O, and S. The heterocycloalkyl group contains at least one N, O, or S as a ring atom, including a heterocycloalkyl group containing one N, O, or S as a ring atom, or two or more N, O, or S as ring atoms, or N and O, N and S, O and S, or N, O, and S as ring atoms.

[0293] The term aryl in the present invention refers to phenyl and benzyl, as well as other aromatic compounds with aromatic properties, including but not limited to aromatic compounds formed by the condensation of 2 to 4 phenyl groups.

[0294] The term heteroaryl as used herein refers to an aromatic heterocyclic compound containing one or more heteroatoms selected from N, O, and S, including but not limited to monocyclic aromatic heterocyclic compounds, aromatic heterocyclic compounds formed by condensing multiple monocyclic aromatic heterocyclic compounds, and aromatic heterocyclic compounds formed by condensing one or more phenyl groups with one or more monocyclic aromatic heterocyclic compounds.

[0295] The structure of the present invention When m≥2, each R5 substituent on the alkylene group is independently substituted, and the R5 substituents may be the same or different. DETAILED DESCRIPTION

[0296] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts are within the scope of protection of the present invention.

[0298] The raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercial products.

[0299] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker Avance III 400 nuclear magnetic spectrometer, with deuterated dimethyl sulfoxide (d6-DMSO) or deuterated methanol (CD3OD) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0300] LCMS analysis was performed using an Agilent LCMS 1260-6110 (ESI) column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm). Column temperature: 40°C; flow rate: 2.0 mL / min; mobile phase: gradient from 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA] over 3 minutes, maintained at these conditions for 1 minute, then to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] over 0.05 minutes, and maintained at these conditions for 0.7 minutes.

[0301] 1) Medicinal materials and reagents

[0302] The thin layer chromatography silica gel plate used was HSGF254 silica gel plate produced by Yantai Xinnuo Chemical Co., Ltd., with a thickness of 1 mm.

[0303] Thin layer chromatography (TLC) was performed using a silica gel product from Yantai Jiangyou Silica Gel Development Co., Ltd., with a specification of 0.2 ± 0.03 mm.

[0304] Column chromatography generally uses 100-200 mesh or 200-300 mesh silica gel produced by Rushan Sun Desiccant Co., Ltd. (Weihai, Shandong) as a carrier.

[0305] 2) Main instruments

[0306] Sartorius BSA124S electronic balance (Sartorius Scientific Instruments Beijing Co., Ltd.), 98-2 magnetic stirrer (Shanghai Silo Instruments Co., Ltd.), MS-H-PRO +CNC heating magnetic stirrer (Beijing Dalong Xingchuang Experimental Instrument Co., Ltd.), TDGC2-1 contact voltage regulator (Zhejiang Tianzheng Electric Co., Ltd.), WMNK-01 temperature controller (Shanghai Lulin Electric Co., Ltd.), ZF-I three-purpose UV instrument (Shanghai Anting Electronic Instrument Factory), R-201 rotary evaporator (Shanghai Shenshun Biotechnology Co., Ltd.), W201D constant temperature water bath (Shanghai Shenshun Biotechnology Co., Ltd.), SHB-III circulating water vacuum pump (Zhengzhou Huicheng Science and Technology Co., Ltd.), SHB-B95 mobile water pump (Zhengzhou Huicheng Science and Technology Co., Ltd.), DLSB-5 / 20℃ low-temperature cooling circulating pump (Gongyi Yuhua Instrument Co., Ltd.), 2XZ-2 rotary vane vacuum pump (Linhai Yonghao Vacuum Equipment Co., Ltd.).

[0307] Example 1 Preparation of Compounds 1 and 1D

[0308]

[0309] 1. Preparation of Compound 1-1

[0310] At -40°C, n-butyllithium (305 mL, 2.5 mol / L in hexane, 762.5 mmol) was added to tetrahydrofuran (280 mL). 2-Bromopyridine (132.6 g, 839.2 mmol) was slowly added dropwise and stirred for 1 hour. A solution of 2-amino-5-bromobenzoic acid (41.2 g, 190.7 mmol) in THF (280 mL) was added dropwise to the reaction system. After completion, the temperature was naturally raised to 0°C and the reaction was allowed to react for 3 hours. After completion of the reaction as monitored by TLC, saturated aqueous ammonium chloride (67 mL) and water (318 mL) were added to the reaction system, and the mixture was extracted with ethyl acetate (3 x 200 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 to 1 / 5) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3). Fractions with Rf = 0.5 to 0.6 were collected to obtain yellow solid compound 1-1 (34.7 g, yield 65.7%). ESI [M+H] + =277.1.

[0311] 2. Preparation of Compound 1-2

[0312] 1-1 (20.0 g, 72.2 mmol) and Boc-L-glutamic acid-5-methyl ester (20.8 g, 79.6 mmol) were dissolved in dichloromethane (100 mL). A solution of DCC (16.4 g, 79.5 mmol) in dichloromethane (40 mL) was added dropwise at -10°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, methyl tert-butyl ether (140 mL) was added to the reaction system and stirred for 5 minutes. The reaction system was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 2) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3). The fraction with Rf = 0.2 to 0.3 was collected to obtain compound 1-2 (35.5 g, 94.5% yield) as a white solid. ESI [M+H] + =520.1.

[0313] 3. Preparation of Compound 1-3

[0314] At 0°C, methanolic hydrochloric acid (170.7 mL, 4 mol / L, 682.8 mmol) was added dropwise to a solution of 1-2 (35.5 g, 68.2 mmol) in methanol (300 mL). After completion of the addition, the mixture was naturally warmed to room temperature and stirred for 20 hours. After the reaction was complete as monitored by TLC, the reaction solution was added dropwise to a solution of sodium bicarbonate (172.1 g, 2.05 mol) in acetonitrile (300 mL) and stirred at room temperature for 12 hours. After the reaction was complete as monitored by TLC, the reaction solution was filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). The fraction with Rf = 0.2 to 0.3 was collected to obtain compound 1-3 (24.1 g, yield 87.8%) as a white solid. ESI [M+H] + =402.1.

[0315] 4. Preparation of Compound 1-4

[0316] Under nitrogen, phosphorus oxychloride (40 g, 260.9 mmol) was dissolved in toluene (200 mL). The mixture was cooled to 5°C and morpholine (89.7 g, 1.025 mol) was slowly added dropwise, maintaining the temperature at 20°C. After completion of the addition, the mixture was allowed to warm to room temperature and stirred for 3 hours. Insoluble matter was filtered, and the filtrate was washed three times with toluene (3 × 35 mL). The combined filtrates were concentrated under reduced pressure to an oil. Toluene (64 mL) was added to the oil, and the mixture was heated until uniformly dissolved. Petroleum ether (29 mL) was added with stirring, followed by petroleum ether (116 mL). The mixture was cooled to room temperature and filtered. The filter cake was washed with petroleum ether and dried under reduced pressure to obtain dimorpholinophosphinic chloride as a white solid (40 g, 60.2% yield).

[0317] Lithium bis(trimethylsilyl)amide (72 mL, 1 mol / L, 72 mmol) was slowly added dropwise to a solution of 1-3 (24.1 g, 59.9 mmol) in tetrahydrofuran (280 mL) at -30°C and stirred for 1 hour. Dimorpholinophosphinic chloride (36.1 g, 141.8 mmol) was added portionwise and stirred at -10°C for 4 hours. Isopropanolamine (20.3 g, 270.3 mmol) was added dropwise to the reaction system, allowed to warm to room temperature, and stirred for 12 hours. After completion of the reaction as monitored by TLC, ice water (100 mL) was added to the reaction system and extracted with ethyl acetate (3 × 100 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 1-4 (20 g, yield 72.7%) as a white solid. ESI [M+H] + =459.1.

[0318] 5. Preparation of Compound 1-5

[0319] Dess-Martin reagent (45.8 g, 108.0 mmol) was added to a solution of 1-4 (20 g, 43.5 mmol) in acetone (200 mL) and stirred at room temperature for 12 hours. After the reaction was complete as monitored by TLC, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed with saturated sodium bicarbonate solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). The fraction with Rf = 0.2 to 0.3 was collected to obtain compound 1-5 as a white solid (12.7 g, yield 66.4%). ESI [M+H] + =439.1.

[0320] 6. Preparation of Compound 1-6

[0321] LiOH.H2O (619 mg, 14.8 mmol) and NaOH (536 mg, 13.4 mmol) were added sequentially to a solution of 1-5 (5.9 g, 13.4 mmol) in MeOH / H2O (50 mL, v / v = 1 / 1) at -10°C. The mixture was allowed to warm to room temperature and stirred for 5 hours. After completion of the reaction as monitored by TLC, the pH of the system was adjusted to 6-7 with 1 mol / L hydrochloric acid in an ice bath and extracted with ethyl acetate (3 x 70 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 1-6 (4.7 g, yield 82.3%) as a white solid. ESI [M+H] + =425.1.

[0322] 7. Preparation of target compound 1

[0323] Vinylmagnesium bromide (13.9 mL, 1.3 mol / L in THF, 18.1 mmol) was slowly added dropwise to a solution of 3-oxetanone (1 g, 13.9 mmol) in anhydrous tetrahydrofuran (20 mL) at 0°C and stirred for 30 minutes. After completion of the reaction as monitored by TLC, saturated ammonium chloride solution (15 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.2 to 0.3 were collected to obtain 3-vinyloxetane-3-ol (1.36 g, 97.9% yield).

[0324] 1-6 (634 mg, 1.49 mmol), DCC (463 mg, 2.24 mmol), and DMAP (274 mg, 2.24 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 15 minutes. 3-Vinyloxetane-3-ol (227.6 mg, 2.27 mmol) was added to the reaction system and stirring continued at room temperature for 12 hours. After the reaction was complete as monitored by TLC, methyl tert-butyl ether (10 mL) was added to the reaction system, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.2 to 0.3 were collected to obtain Compound 1 (290 mg, 38.3% yield) as a gray solid. ESI [M+H] + =507.1.

[0325] 1 H NMR(400MHz,DMSO-d6)δ8.55(d,J=4.0Hz,1H),8.11(d,J=7.9Hz,1H),7.95(td,J=7.8,1.7Hz,1H), 7.89(dd,J=8.7,2.3Hz,1H),7.66(d,J=8.7Hz,1H),7.60(d,J=2.3Hz,1H),7.54–7.46(m,1H),6.82 (d,J=1.0Hz,1H),6.23(dd,J=17.4,10.9Hz,1H),5.26(dd,J=25.2,14.2Hz,2H),4.70(d,J=6.0Hz, 2H), 4.60 (d, J = 7.5Hz, 2H), 4.07–4.02 (m, 1H), 2.87–2.68 (m, 2H), 2.63–2.50 (m, 2H), 2.30 (s, 3H).

[0326] 8. Preparation of target compound 1D

[0327] Compound 1 (192.7 mg, 0.38 mmol) was dissolved in ethyl acetate (15 mL), and a solution of benzenesulfonic acid (60.1 mg, 0.38 mmol) in ethanol (0.6 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction system was filtered, and the filter cake was dried under reduced pressure to obtain compound 1D (196.8 mg, yield 77.9%) as a white solid. ESI [M+H] + =507.1.

[0328] 1H NMR (400MHz, DMSO-d6) δ8.61–8.56(m,1H),8.15(d,J=7.9Hz,1H),8.05–7.94(m,2H),7.84(d,J=8.8Hz,1 H),7.74(d,J=2.3Hz,1H),7.62–7.58(m,2H),7.57–7.53(m,1H),7.44(s,1H),7.36–7.25(m,3H),6.25(d d,J=17.4,10.9Hz,1H),5.35–5.25(m,2H),4.71(dd,J=7.4,2.4Hz,2H),4.62(dd,J=7.3,3.1Hz,2H),4.3 3(dd,J=8.3,5.2Hz,1H),2.90–2.79(m,1H),2.77–2.64(m,2H),2.54–2.50(m,1H),2.39(d,J=0.8Hz,3H).

[0329] Example 2 Preparation of Compounds 2 and 2D

[0330]

[0331] 1. Preparation of Compound 2-1

[0332] Methylmagnesium bromide (23 mL, 3 mol / L in THF, 69 mmol) was slowly added dropwise to a solution of 3-oxetanone (4 g, 55.5 mmol) in anhydrous tetrahydrofuran (40 mL) at 0°C and stirred for 30 minutes. After completion of the reaction as monitored by TLC, saturated ammonium chloride solution (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 30 mL). The organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.2 to 0.3 were collected to obtain 3-methyloxetan-3-ol (2.91 g, 59.5% yield).

[0333] 2. Preparation of target compound 2

[0334] 1-6 (350 mg, 0.823 mmol), DCC (255 mg, 1.24 mmol), and DMAP (151 mg, 1.24 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 15 minutes. 3-Methyloxetan-3-ol (148 mg, 1.68 mmol) was added to the reaction system and stirring continued at room temperature for 12 hours. After the reaction was complete as monitored by TLC, methyl tert-butyl ether (10 mL) was added to the reaction system, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 2 (148 mg, 36.3% yield) as a white solid. ESI [M+H] + =495.1.

[0335] 1 H NMR (400MHz, CDCl3) δ8.58(d,J=3.9Hz,1H),8.21(d,J=7.9Hz,1H),7.88–7.77(m,2H),7.73(d,J=1.9Hz,1H),7.44–7.34(m,2H),7.08( s,1H),4.71(dd,J=7.1,3.9Hz,2H),4.46(d,J=7.6Hz,2H),4.20(brs,1H),3.00(brs,1H),2.85–2.81(m,3H),2.39(s,3H),1.66(s,3H).

[0336] 8. Preparation of target compound 2D

[0337] Compound 2 (148 mg, 0.30 mmol) was dissolved in ethyl acetate (35 mL), and a solution of benzenesulfonic acid (47.3 mg, 0.30 mmol) in ethanol (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction system was filtered, and the filter cake was dried under reduced pressure to obtain compound 2D (162.1 mg, yield 83.0%) as a white solid. ESI [M+H] + =495.1.

[0338] 1H NMR (400MHz, DMSO-d6) δ8.60–8.56(m,1H),8.14(d,J=7.9Hz,1H),8.04–7.95(m,2H),7.84(d,J= 8.7Hz,1H),7.74(d,J=2.3Hz,1H),7.62–7.57(m,2H),7.55(ddd,J=7.6,4.8,1.1Hz,1H),7.43(s ,1H),7.35–7.26(m,3H),4.62(d,J=6.1Hz,2H),4.43(d,J=7.7Hz,2H),4.34(dd,J=8.6,5.1Hz,1 H),2.84–2.71(m,1H),2.71–2.58(m,2H),2.52–2.50(m,1H),2.39(d,J=0.8Hz,3H),1.62(s,3H).

[0339] Example 3 Preparation of Compound 3

[0340]

[0341] 1. Preparation of Compound 3-1

[0342] At 0°C, ethynylmagnesium bromide (72.2 mL, 0.5 mol / L in THF, 36.1 mmol) was slowly added dropwise to a solution of 3-oxetanone (2 g, 27.8 mmol) in anhydrous tetrahydrofuran (30 mL) and stirred for 30 minutes. After completion of the reaction as monitored by TLC, saturated ammonium chloride solution (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 30 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 3-1 (1.32 g, 48.5% yield) as a colorless oil. ESI [M+H] + =99.1.

[0343] 2. Preparation of compound 3-2

[0344] 3-1 (1.07 g, 10.9 mmol) was dissolved in dioxane (30 mL), and paraformaldehyde (811 mg, 27.0 mmol), diisopropylamine (1.965 g, 19.4 mmol), and cuprous bromide (770 mg, 5.37 mmol) were added. The mixture was stirred at 90°C for 1 hour. After the reaction was complete as monitored by TLC, the reaction system was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 2) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). The fraction with Rf = 0.3 to 0.4 was collected to obtain compound 3-2 (72 mg, 5.9% yield) as a colorless oil. ESI [M+H] + =113.1.

[0345] 3. Preparation of target compound 3

[0346] 1-6 (100 mg, 0.235 mmol), DCC (73 mg, 0.354 mmol), and DMAP (43.2 mg, 0.354 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 15 minutes. 3-2 (26.6 mg, 0.237 mmol) was added to the reaction system and stirring continued at room temperature for 12 hours. After the reaction was complete as monitored by TLC, methyl tert-butyl ether (2 mL) was added to the reaction system, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 3 (57.4 mg, 47.0% yield) as a white solid. ESI [M+H] + =519.1.

[0347] 1 H NMR (400MHz, CDCl3) δ8.58(d,J=4.6Hz,1H),8.20(d,J=7.9Hz,1H),7.88–7.76(m,2H),7.73(s,1H),7.42–7.31(m,2H),7.06(s,1H),5.57(t,J =6.6Hz,1H),4.99–4.94(m,2H),4.78–4.75(m,2H),4.72–4.68(m,2H), 4.20–4.18(m,1H),3.02–3.00(m,1H),2.88–2.86(m,3H),2.39(s,3H).

[0348] Example 4 Preparation of Compound 4

[0349]

[0350] 1-6 (80 mg, 0.188 mmol), DCC (58.3 mg, 0.283 mmol), and DMAP (34.5 mg, 0.282 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 15 minutes. 3-Oxetanol (28 mg, 0.378 mmol) was added to the reaction system and stirring continued at room temperature for 12 hours. After the reaction was complete as monitored by TLC, methyl tert-butyl ether (2 mL) was added to the reaction system, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 4 (42.5 mg, 46.9% yield) as a white solid. ESI [M+H] + =481.0.

[0351] 1 H NMR (400MHz, CDCl3) δ8.58(d,J=4.0Hz,1H),8.18(d,J=8.0Hz,1H),7.82(td,J=7.8, 1.7Hz,1H),7.76(dd,J=8.6,2.1Hz,1H),7.70(d,J=2.1Hz,1H),7.40–7.35(m,1H),7 .34(d,J=8.6Hz,1H),6.99(s,1H),5.48–5.38(m,1H),4.85(dd,J=11.6,6.8Hz,2H), 4.67–4.55(m,2H),4.13(s,1H),2.97–2.95(m,1H),2.91–2.76(m,3H),2.37(s,3H).

[0352] Example 5 Preparation of Compounds 5, 6, 6D, 7 and 7D

[0353]

[0354] 1. Preparation of target compound 5

[0355] 1-6 (3 g, 7.05 mmol), DCC (2.89 g, 14.0 mmol), and DMAP (1.71 g, 14.0 mmol) were dissolved in dichloromethane (30 mL) and stirred at room temperature for 15 minutes. 3-Methylbutynol-3-ol (1.18 g, 14.0 mmol) was added to the reaction system and stirring continued at room temperature for 12 hours. After the reaction was complete as monitored by TLC, methyl tert-butyl ether (30 mL) was added to the reaction system, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 5 (1.8 g, 51.9% yield) as a white solid. ESI [M+H] + =491.0.

[0356] 1 H NMR (400MHz, DMSO-d6) δ8.54(d,J=4.0Hz,1H),8.11(d,J=7.9Hz,1H),7.94(td,J=7.8,1.7Hz,1H),7.88(dd,J=8.7,2.3Hz,1H),7.66(d,J=8.7Hz,1H ),7.60(d,J=2.3Hz,1H),7.54–7.47(m,1H),6.81(d,J=1.1Hz,1H),4.05(t ,J=6.6Hz,1H),3.47(s,1H),2.73–2.52(m,4H),2.30(s,3H),1.58(s,6H).

[0357] 2. Preparation of target compound 6

[0358] Compound 5 (600 mg, 1.22 mmol) was dissolved in dichloromethane (10 mL), and mercuric sulfate / sulfuric acid / silica gel (600 mg) was added. The mixture was stirred at room temperature for 12 hours. After the reaction was complete as monitored by TLC, the reaction system was neutralized with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (3×10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (methanol / dichloromethane (v / v) = 1 / 30) and the fraction with Rf = 0.4-0.5 was collected to obtain compound 6 (267.1 mg, yield 42.9%) as a white solid. ESI [M+H] + =509.2.

[0359] 1H NMR (400MHz, DMSO-d6) δ8.54(d,J=4.0Hz,1H),8.11(d,J=7.9Hz,1H),7.95(td,J=7.8,1.7Hz,1H),7.88(dd,J=8.7,2.3Hz,1H),7.66(d,J=8.7Hz,1H ),7.60(d,J=2.3Hz,1H),7.54–7.46(m,1H),6.83(s,1H),4.11–4.02(m,1H ),2.86–2.51(m,4H),2.30(s,3H),2.01(s,3H),1.37(s,3H),1.36(s,3H).

[0360] 3. Preparation of target compound 6D

[0361] Compound 6 (199 mg, 0.391 mmol) was dissolved in ethyl acetate (10 mL), and a solution of benzenesulfonic acid (61.9 mg, 0.391 mmol) in ethanol (0.6 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction system was filtered, and the filter cake was dried under reduced pressure to obtain compound 6D (236.4 mg, 90.6% yield) as a white solid. ESI [M+H] + =509.1.

[0362] 1 H NMR (400MHz, DMSO-d6) δ8.57(d,J=4.1Hz,1H),8.14(d,J=7.9Hz,1H),8.02–7.94(m ,2H),7.82(d,J=8.8Hz,1H),7.72(d,J=2.3Hz,1H),7.62–7.57(m,2H),7.57–7.51(m ,1H),7.37(s,1H),7.34–7.25(m,3H),4.29–4.28(m,1H),2.86–2.75(m,1H),2.71–2 .59(m,2H),2.51–2.50(m,1H),2.38(s,3H),2.04(s,3H),1.40(s,3H),1.38(s,3H).

[0363] 4. Preparation of target compound 7

[0364] Compound 5 (600 mg, 1.22 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature, and Lindela's catalyst (600 mg, 5% Pd) was added. The mixture was stirred under hydrogen for 12 hours. After the reaction was complete as monitored by TLC, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product residue was purified by preparative TLC (methanol / dichloromethane (v / v) = 1 / 30) and the fraction with Rf = 0.3-0.4 was collected to obtain compound 7 (369.8 mg, 61.4% yield) as a white solid. ESI [M+H] + =493.2.

[0365] 1 H NMR (400MHz, CDCl3) δ8.57(d,J=3.7Hz,1H),8.21(d,J=7.9Hz,1H),7.84–7.80(m ,1H),7.78–7.76(m,1H),7.69(s,1H),7.37(dd,J=7.1,4.8Hz,2H),7.01(s,1H),6 .01(dd,J=17.5,10.8Hz,1H),5.09(d,J=17.5Hz,1H),4.99(d,J=10.8Hz,1H),4. 22–4.19(m,1H),2.95–2.94(m,1H),2.77–2.75(m,3H),2.38(s,3H),1.46(s,6H).

[0366] 5. Preparation of target compound 7D

[0367] Compound 7 (220 mg, 0.446 mmol) was dissolved in ethyl acetate (2.2 mL), and a solution of benzenesulfonic acid (70.7 mg, 0.446 mmol) in ethanol (0.7 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction system was filtered, and the filter cake was dried under reduced pressure to obtain compound 7D (251.5 mg, yield 86.6%) as a white solid. ESI [M+H] + =493.1.

[0368] 1H NMR (400MHz, DMSO-d6) δ8.57(d,J=4.1Hz,1H),8.13(d,J=7.9Hz,1H),8.03–7.94( m,2H),7.81(d,J=8.9Hz,1H),7.71(s,1H),7.62–7.57(m,2H),7.56–7.51(m,1H), 7.38–7.26(m,4H),6.04(dd,J=17.5,10.9Hz,1H),5.13(d,J=17.5Hz,1H),5.01(d d,J=10.9,0.9Hz,1H),4.26(s,1H),2.62–2.50(m,4H),2.37(s,3H),1.45(s,6H).

[0369] Example 6 Preparation of Compound 9

[0370]

[0371] 1. Preparation of compound 9-2

[0372] At 0°C, NaH (26.7 mg, 60%, 0.667 mmol) was slowly added to a solution of 9-1 (197 mg, 0.556 mmol) in dry tetrahydrofuran (5 mL) and stirred for 30 minutes. Iodomethane (118.3 mg, 0.833 mmol) was added to the reaction system, which was naturally warmed to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 to 1 / 10) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10). Fractions with Rf = 0.4 to 0.5 were collected to obtain compound 9-2 (124 mg, 60.5% yield) as a white solid. ESI[M+H] + =369.2.

[0373] 2. Preparation of compound 9-3

[0374] TBAF (176 mg, 0.673 mmol) was added to a solution of 9-2 (124 mg, 0.336 mmol) in tetrahydrofuran (5 mL) at 0°C, allowed to warm to room temperature, and stirred for 12 hours. After the reaction was complete as monitored by TLC, ice water (10 mL) was added to the reaction system and extracted with ethyl acetate (3×10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 2) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). The fraction with Rf = 0.3 to 0.4 was collected to obtain compound 9-3 (38.0 mg, yield 86.8%) as a colorless oil. ESI [M+H] + =131.2.

[0375] 3. Preparation of target compound 9

[0376] 1-6 (100 mg, 0.235 mmol), DCC (73.0 mg, 0.354 mmol), and DMAP (43.2 mg, 0.353 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 15 minutes. 9-3 (30.6 mg, 0.235 mmol) was added to the reaction system and stirring continued at room temperature for 12 hours. After the reaction was complete as monitored by TLC, methyl tert-butyl ether (2 mL) was added to the reaction system, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 2 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 3 / 1). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 9 (81.7 mg, 64.6% yield) as a white solid. ESI [M+H] + =537.2.

[0377] 1 H NMR(400MHz, CDCl3)δ8.57(d,J=4.0Hz,1H),8.22–8.20(m,1H),7.85–7.83(m,2H),7.76–7.65(m,1H),7.54–7.29(m,2H), 7.26–7.13(m,1H),4.47–4.44(m,1H),4.17–3.91(m,2H),3.30(s,5H),3.17–2.63(m,4H),2.39(s,3H),1.85–1.71(m,6H).

[0378] Example 7 Preparation of Compound 10

[0379]

[0380] 1-6 (100 mg, 0.235 mmol), DCC (73 mg, 0.354 mmol), and DMAP (43.2 mg, 0.354 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 15 minutes. 2,2-Difluoroethanol (21.3 mg, 0.260 mmol) was added to the reaction system and stirring continued at room temperature for 12 hours. After the reaction was complete as monitored by TLC, methyl tert-butyl ether (2 mL) was added to the reaction system, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (methanol / dichloromethane (v / v) = 1 / 30) and the fraction with Rf = 0.4-0.5 was collected to obtain compound 10 (90.1 mg, yield 78.3%) as a colorless oil. ESI [M+H] + =489.0.

[0381] 1 H NMR(400MHz, CDCl3)δ8.58(d,J=4.0Hz,1H),8.22–8.19(m,1H),7.86(t,J=7.8Hz,2H),7.80(s,1H),7.42(dd,J=7.3,5.0Hz,2H), 7.28–7.26(m,1H),6.10–5.70(m,1H),4.40–4.37(m,1H),4.32–4.16(m,2H),3.22–3.17(m,1H),3.09–2.80(m,3H),2.44(s,3H).

[0382] Example 8 Preparation of Compound 11

[0383]

[0384] 1-6 (81 mg, 0.190 mmol), bromomethyl acetate (35.1 mg, 0.229 mmol), and cesium carbonate (93 mg, 0.285 mmol) were dissolved in DMF (2 mL) and stirred at 60°C for 2 hours. After the reaction was complete as monitored by TLC, the reaction solution was poured into ice water and extracted with ethyl acetate (3×15 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (methanol / dichloromethane (v / v) = 1 / 30) and the fraction with Rf = 0.3-0.4 was collected to obtain compound 11 (39.1 mg, yield 41.3%) as a white solid. ESI [M+H] + =497.2.

[0385] 1H NMR(400MHz, CDCl3)δ8.58(d,J=4.7Hz,1H),8.19(d,J=7.9Hz,1H),7.87–7.77(m,2H),7.75(s,1H),7.43–7.33(m,2H) ,7.12(s,1H),5.75–5.66(m,2H),4.28–4.26(m,1H),3.06–3.04(m,1H),2.92–2.88(m,3H),2.40(s,3H),2.06(s,3H).

[0386] Example 9 Preparation of Compound 12

[0387]

[0388] 1. Preparation of Compound 12-1

[0389] 1-5 (632 mg, 1.44 mmol), trimethylethynylsilane (2.82 g, 28.7 mmol), and PdCl2(PPh3)2 (101.1 mg, 0.144 mmol) were dissolved in a mixed solvent of triethylamine (20 mL) and acetonitrile (30 mL) and stirred at 70°C for 4 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 12-1 (627 mg, 95.4% yield) as a white solid. ESI [M+H] + =457.2.

[0390] 2. Preparation of compound 12-2

[0391] At 0°C, TBAF (538.5 mg, 2.06 mmol) was added to a solution of 12-1 (627 mg, 1.37 mmol) in tetrahydrofuran (5 mL), the mixture was naturally warmed to room temperature, and stirred for 2 hours. After the reaction was complete as monitored by TLC, ice water (10 mL) was added to the reaction system and extracted with ethyl acetate (3×15 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (methanol / dichloromethane (v / v) = 1 / 10) and the fraction with Rf = 0.3-0.4 was collected to obtain compound 12-2 (287.5 mg, yield 54.5%) as a yellow solid. ESI [M+H] + =385.2.

[0392] 3. Preparation of Compound 12-3

[0393] LiOH.H2O (34.5 mg, 0.822 mmol) and NaOH (29.9 mg, 0.747 mmol) were added sequentially to a solution of 12-2 (287.5 mg, 0.748 mmol) in MeOH / THF / H2O (10 mL, v / v / v = 1 / 1 / 1) at -20°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, the pH of the system was adjusted to 6-7 with 1 mol / L hydrochloric acid in an ice bath, followed by extraction with ethyl acetate (3 x 50 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by preparative TLC (methanol / dichloromethane (v / v) = 1 / 8), and fractions with Rf = 0.3-0.4 were collected to afford compound 12-3 (267.9 mg, 96.7% yield) as a white solid. ESI [M+H] + =371.1.

[0394] 4. Preparation of target compound 12

[0395] At 0°C, 12-3 (146.5 mg, 0.396 mmol), dimethyl chloromethyl carbonate (148.4 mg, 1.19 mmol), and potassium carbonate (129.5 mg, 0.937 mmol) were dissolved in DMF (3 mL), naturally warmed to room temperature, and stirred for 4 hours. After the reaction was complete as monitored by TLC, water (10 mL) was added to the reaction system and extracted with ethyl acetate (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) and the fraction with Rf = 0.2-0.3 was collected to obtain compound 12 (49.4 mg, yield 27.2%) as a white solid. ESI [M+H] + =459.1.

[0396] 1H NMR (400MHz, DMSO-d6) δ8.53(d,J=4.0Hz,1H),8.09(d,J=7.9Hz,1H),7.98–7.90(m,1H),7.77(dd,J=8.4,1.9Hz,1H),7.70(d,J=8.4Hz,1H),7.51– 7.48(m,2H),6.82(d,J=1.0Hz,1H),5.71(s,2H),4.32(s,1H),4.06–4.02 (m,1H),3.73(s,3H),2.85–2.73(m,2H),2.66–2.50(m,2H),2.31(s,3H).

[0397] Example 10 Preparation of Compound 13

[0398]

[0399] 1. Preparation of Compound 13-1

[0400] At 0°C, NaH (175 mg, 60%, 4.37 mmol) was slowly added to a solution of 1-3 (1.6 g, 3.98 mmol) in dry DMF (15 mL) and stirred for 30 minutes. Iodomethane (623 mg, 4.39 mmol) was added to the reaction system and stirred for 1 hour. After the reaction was complete as monitored by TLC, the reaction solution was poured into ice water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 11). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 13-1 (1.603 g, 96.8% yield) as a white solid. ESI [M+H] + =416.1.

[0401] 2. Preparation of Compound 13-2

[0402] LiOH.H2O (177.7 mg, 4.23 mmol) and NaOH (154 mg, 3.85 mmol) were added sequentially to a solution of 13-1 (1.603 g, 3.85 mmol) in MeOH / THF / H2O (20 mL, v / v / v = 1 / 1 / 1) at -20°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, the pH of the system was adjusted to 6-7 with 1 mol / L hydrochloric acid in an ice bath, followed by extraction with ethyl acetate (3 x 50 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 30 to 1 / 10) and monitored by TLC (ethanol / dichloromethane (v / v) = 1 / 10). The fractions with Rf = 0.2 to 0.3 were collected to obtain compound 13-2 (1.54 g, yield 99.4%) as a white solid. ESI [M+H] + =402.1.

[0403] 3. Preparation of target compound 13

[0404] 13-2 (100 mg, 0.249 mmol), DCC (77 mg, 0.373 mmol), and DMAP (46 mg, 0.377 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 15 minutes. 3-Vinyloxetane-3-ol (50 mg, 0.499 mmol) was added to the reaction system and stirring continued at room temperature for 12 hours. After the reaction was complete as monitored by TLC, methyl tert-butyl ether (2 mL) was added to the reaction system, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 3 / 1) and the fraction with Rf = 0.3-0.4 was collected to obtain compound 13 (39.0 mg, yield 32.4%) as a white solid. ESI [M+H] + =484.1.

[0405] 1H NMR(400MHz, CDCl3)δ8.74(s,1H),8.19(d,J=7.9Hz,1H),8.04–8.02(m,1H),7.69(d,J=8.7Hz, 1H),7.59–7.57(m,1H),7.44(s,1H),7.28–7.26(m,1H),6.17(dd,J=17.4,10.9Hz,1H),5.29(d ,J=17.4Hz,1H),5.23(d,J=11.0Hz,1H),4.78(d,J=7.1Hz,2H),4.66(dd,J=7.4,3.2Hz,2H),3. 76(t,J=6.8Hz,1H),3.43(s,3H),2.74(t,J=6.9Hz,2H),2.69–2.59(m,1H),2.56–2.47(m,1H).

[0406] Example 11 Preparation of Compounds 14-16

[0407]

[0408] The preparation method of target compounds 14-16 is similar to that of compound 13 in Example 10, using 13-2 and the corresponding alcohol as raw materials to prepare the corresponding ester.

[0409] Compound 14: 80 mg, ESI [M+H] + =472.1.

[0410] 1 H NMR (400MHz, CDCl3) δ8.69(d,J=4.1Hz,1H),8.18(d,J=7.8Hz,1H),7.94(t,J=7.2Hz,1H),7.68(dd,J=8.8,2.1Hz,1H),7.49(d,J=2. 0Hz,2H),7.24(s,1H),4.71(d,J=7.1Hz,2H),4.46(d,J=7.6Hz,2H),3.74–3.72(m,1H),3.42(s,3H),2.71–2.43(m,4H),1.65(s,3H).

[0411] Compound 15: 102.7 mg, ESI [M+H] + =496.0.

[0412] 1H NMR (400MHz, CDCl3) δ8.65(d,J=4.2Hz,1H),8.17(d,J=7.9Hz,1H),7.86(t,J=7.3Hz,1H),7 .66(dd,J=8.8,2.2Hz,1H),7.52(d,J=2.2Hz,1H),7.46–7.38(m,1H),7.24(d,J=8.8Hz,1H) ,5.58(t,J=6.6Hz,1H),4.97(d,J=6.6Hz,2H),4.76(t,J=7.0Hz,2H),4.71(t,J=6.6Hz,2H) ,3.73–3.68(m,1H),3.40(s,3H),2.72–2.65(m,2H),2.63–2.55(m,1H),2.53–2.45(m,1H).

[0413] Compound 16: 65.6 mg, ESI [M+H] + =458.1.

[0414] 1 H NMR (400MHz, CDCl3) δ8.69 (d, J = 4.4Hz, 1H), 8.16 (d, J = 7.8Hz, 1H), 7.93 (t, J = 7. 5Hz,1H),7.67(dd,J=8.8,2.0Hz,1H),7.49–7.47(m,2H),7.26–7.25(m,1H),5.5 2–5.36(m,1H),4.85(dd,J=11.9,6.7Hz,2H),4.60(t,J=6.4Hz,2H),3.75–3.72( m,1H),3.41(s,3H),2.71(t,J=7.1Hz,2H),2.66–2.55(m,1H),2.54–2.44(m,1H).

[0415] Example 12 Preparation of Compounds 17, 17E, 18, 19 and 19E

[0416]

[0417] 1. Preparation of target compound 17

[0418] 13-2 (1.0 g, 2.49 mmol), DCC (1.03 g, 4.99 mmol), and DMAP (610 mg, 4.99 mmol) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 15 minutes. 3-Methylbutynol-3-ol (420 mg, 4.99 mmol) was added to the reaction system and stirring continued at room temperature for 12 hours. After the reaction was complete as monitored by TLC, methyl tert-butyl ether (10 mL) was added to the reaction system, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 17 (621.0 mg, 53.3% yield) as a white solid. ESI [M+H] + =468.0.

[0419] 1 H NMR (400MHz, CDCl3) δ8.66(d,J=3.9Hz,1H),8.20(d,J=7.7Hz,1H),7.91(t,J=7.1Hz,1H),7.65(dd,J=8.8,2.1Hz,1H),7.48–7.42(m,2H) ,7.24(d,J=8.8Hz,1H),3.75(t,J=6.5Hz,1H),3.41(s,3H),2.66–2.57(m,3H),2.53–2.44(m,1H),2.40(s,1H),1.61(s,3H),1.61(s,3H).

[0420] 2. Preparation of target compound 17E

[0421] Compound 17 (218 mg, 0.465 mmol) was dissolved in diethyl ether (10 mL). A solution of p-toluenesulfonic acid monohydrate (88.3 mg, 0.464 mmol) in acetone (0.5 mL) was added dropwise at -70°C and stirred for 20 minutes. The reaction mixture was filtered and the filter cake was dried under reduced pressure to obtain a yellow solid, Compound 17E (258.3 mg, 86.6% yield). ESI [M+H] + =468.2.

[0422] 1H NMR (400MHz, DMSO-d6) δ8.62(d,J=4.1Hz,1H),8.12(d,J=7.9Hz,1H),8.03(td,J=7.7,1.6H z,1H),7.82(dd,J=8.8,2.4Hz,1H),7.62–7.56(m,1H),7.53(t,J=5.8Hz,2H),7.47(d,J=8.1 Hz,2H),7.11(d,J=7.9Hz,2H),3.71(dd,J=8.0,5.5Hz,1H),3.45(s,1H),3.31(s,3H),2.55 –2.50(m,1H),2.47–2.30(m,2H),2.29(s,3H),2.26–2.16(m,1H),1.55(s,3H),1.55(s,3H).

[0423] 3. Preparation of target compound 18

[0424] Compound 17 (310 mg, 0.662 mmol) was dissolved in dichloromethane (10 mL), and mercuric sulfate / sulfuric acid / silica gel (310 mg) was added. The mixture was stirred at room temperature for 12 hours. After the reaction was complete as monitored by TLC, the reaction system was neutralized with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (3×10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (methanol / dichloromethane (v / v) = 1 / 30) and the fraction with Rf = 0.3-0.4 was collected to obtain compound 18 (284 mg, yield 88.2%) as a white solid. ESI [M+H] + =486.2.

[0425] 1 H NMR(400MHz,DMSO-d6)δ8.61–8.56(m,1H),8.12(d,J=7.9Hz,1H),7.97(td, J=7.8,1.7Hz,1H),7.81(dd,J=8.9,2.4Hz,1H),7.57–7.50(m,2H),7.48(d,J =2.4Hz,1H),3.71(dd,J=8.3,5.5Hz,1H),3.31(s,3H),2.66–2.51(m,2H),2 .39–2.30(m,1H),2.28–2.14(m,1H),1.96(s,3H),1.34(s,3H),1.32(s,3H).

[0426] 4. Preparation of target compound 19

[0427] Compound 17 (300 mg, 0.641 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature, and Lindela's catalyst (300 mg, 5% Pd) was added. The mixture was stirred under hydrogen for 12 hours. After the reaction was complete as monitored by TLC, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (methanol / dichloromethane (v / v) = 1 / 30) and the fraction with Rf = 0.3-0.4 was collected to obtain compound 19 (296 mg, 98.2% yield) as a white solid. ESI [M+H] + =470.2.

[0428] 1 H NMR (400MHz, DMSO-d6) δ8.58(d,J=4.0Hz,1H),8.11(d,J=7.9Hz,1H),7.96(td,J= 7.8,1.8Hz,1H),7.81(dd,J=8.8,2.4Hz,1H),7.54–7.51(m,2H),7.48(d,J=2.4Hz, 1H),5.97(dd,J=17.5,10.9Hz,1H),5.08(d,J=17.5Hz,1H),4.97(dd,J=10.9,0.9 Hz,1H),3.67(dd,J=8.2,5.6Hz,1H),3.30(s,3H),2.44–2.14(m,4H),1.39(s,6H).

[0429] 5. Preparation of target compound 19E

[0430] The preparation method of compound 19E was similar to that of compound 17E in Example 12, using 19 and p-toluenesulfonic acid monohydrate as raw materials.

[0431] Compound 19E: 265.1 mg, ESI [M+H] + =470.2.

[0432] 1H NMR (400MHz, DMSO-d6) δ8.62(d,J=4.3Hz,1H),8.11(d,J=7.9Hz,1H),8.05–8.02(m,1H),7.83(dd ,J=8.9,2.4Hz,1H),7.63–7.57(m,1H),7.55–7.51(m,2H),7.47(d,J=8.1Hz,2H),7.11(d,J=7.8H z,2H),5.97(dd,J=17.5,10.9Hz,1H),5.12–5.05(m,1H),4.97(dd,J=10.9,0.9Hz,1H),3.69(dd, J=7.9,5.6Hz,1H),3.30(s,3H),2.48–2.30(m,3H),2.29(s,3H),2.24–2.19(m,1H),1.39(s,6H).

[0433] Example 13 Preparation of Compound 20

[0434]

[0435] m-CPBA (56 mg, 0.325 mmol) was added portionwise to a solution of 19 (100 mg, 0.213 mmol) in dichloromethane (5 mL) and stirred at room temperature for 12 hours. After the reaction was complete as monitored by TLC, ice water (10 mL) was added to the reaction system and extracted with dichloromethane (3×15 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) to obtain compound 20 (84.3 mg, yield 81.5%) as a white solid. ESI [M+H] + =486.2.

[0436] 1 H NMR (400MHz, DMSO-d6) δ8.19(d,J=5.8Hz,1H),7.79–7.73(m,2H),7.63–7.49(m,3H),7.22(d,J=2.3Hz,1H),6.02–5.93(m,1H),5.11–5.04(m,1H) ),4.96(dd,J=10.9,0.9Hz,1H),3.66(dd,J=8.3,5.5Hz,1H),3.32(s,3H ),2.43–2.35(m,2H),2.32–2.25(m,1H),2.20–2.15(m,1H),1.39(s,6H).

[0437] Example 14 Preparation of Compounds 21-23

[0438]

[0439] 1. Preparation of Compound 23-1

[0440] Dissolve 1-1 (630 mg, 2.27 mmol) and (S)-6-tert-butyl 2-fluorenylmethyloxycarbonylaminoadipate (1 g, 2.28 mmol) in dichloromethane (10 mL). Add a solution of DCC (705 mg, 3.42 mmol) in dichloromethane (2 mL) dropwise at -10°C. After completion of the addition, the mixture was naturally warmed to room temperature and stirred for 12 hours. After the reaction was complete as monitored by TLC, methyl tert-butyl ether (12 mL) was added to the reaction system and stirred for 5 minutes. The reaction system was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was used directly in the next reaction without purification. ESI [M+H] + =642.1.

[0441] 2. Preparation of target compound 21

[0442] The crude compound from the previous step was dissolved in a mixed solvent of morpholine and dichloromethane (10 mL, v / v = 1 / 1) and stirred at room temperature for 24 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 10) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). The fractions with Rf = 0.2 to 0.3 were collected to obtain compound 21 (294 mg, 2-step yield 28.2%) as a white solid. ESI [M+H] + =458.2.

[0443] 1 H NMR (400MHz, CDCl3) δ8.69(s,1H),8.13(brs,1H),8.11(d,J=7.7Hz,1H),7.91(t,J=7.3Hz,1H),7.62(d,J=8.5Hz,1H),7.52–7.50(m ,1H),7.48–7.46(m,1H),7.05(d,J=7.7Hz,1H),3.63(s,1H),2.33–2.17(m,2H),1.93–1.80(m,2H),1.76–1.58(m,2H),1.44(s,9H).

[0444] 3. Preparation of target compound 22

[0445] NaH (25.2 mg, 60%, 0.63 mmol) was slowly added to a solution of 21 (264 mg, 0.576 mmol) in dry DMF (3 mL) at -10°C and stirred for 30 minutes. Iodomethane (89.6 mg, 0.631 mmol) was added to the reaction system and stirred for 1 hour. After the reaction was complete as monitored by TLC, the reaction solution was poured into ice water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (methanol / dichloromethane (v / v) = 1 / 10) and the fraction with Rf = 0.3-0.4 was collected to obtain compound 22 (152 mg, 55.9% yield) as a white solid. ESI [M+H] + =472.2.

[0446] 1 H NMR(400MHz, CDCl3)δ8.66(s,1H),8.23–8.17(m,1H),7.95–7.85(m,1H),7.66(d,J=8.8Hz,1H),7.52–7.40(m,2H),7.24 (d,J=9.0Hz,1H),3.62–3.58(m,1H),3.41(s,3H),2.40–2.27(m,3H),2.25–2.15(m,1H),1.84–1.80(m,2H),1.44(s,9H).

[0447] 4. Preparation of Compound 23-2

[0448] Trifluoroacetic acid (0.55 mL) was added to a solution of 22 (130 mg, 0.275 mmol) in dichloromethane (3.25 mL) at 0°C and stirred for 3 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The residue was dissolved in water, the pH of the system was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution, and then extracted with ethyl acetate (3×10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (methanol / dichloromethane (v / v) = 1 / 8) and the fraction with Rf = 0.3-0.4 was collected to obtain compound 23-2 (95 mg, yield 82.9%) as a white solid. ESI [M+H] + =416.1.

[0449] 5. Preparation of target compound 23

[0450] 23-2 (52 mg, 0.125 mmol), DCC (50.5 mg, 0.245 mmol), and DMAP (29.9 mg, 0.245 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 15 minutes. 3-Methyloxetan-3-ol (22.0 mg, 0.250 mmol) was added to the reaction system and stirring continued at room temperature for 12 hours. After the reaction was complete as monitored by TLC, methyl tert-butyl ether (2 mL) was added to the reaction system, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The product was purified by preparative TLC (methanol / dichloromethane (v / v) = 1 / 10) and the fraction with Rf = 0.3-0.4 was collected to obtain compound 23 (26.7 mg, 43.9% yield) as a white solid. ESI [M+H] + =486.2.

[0451] 1 H NMR(400MHz,DMSO-d6)δ8.58(d,J=4.5Hz,1H),8.09(d,J=7.9Hz,1H),7.96(td ,J=7.8,1.7Hz,1H),7.80(dd,J=8.8,2.4Hz,1H),7.53–7.50(m,3H),4.60(d,J= 6.9Hz,2H),4.40(d,J=7.5Hz,2H),3.63(dd,J=8.2,5.3Hz,1H),3.30(s,3H),2 .39(t,J=7.4Hz,2H),2.17–1.98(m,2H),1.74–1.70(m,1H),1.62–1.56(m,4H).

[0452] Example 15 Preparation of Compound 24

[0453]

[0454] The preparation method of compound 24 is similar to that of compound 23 in Example 14, using 23-2 and oxetan-3-ol as raw materials.

[0455] Compound 24: 14.5 mg, ESI [M+H] + =472.2.

[0456] 1H NMR (400MHz, DMSO-d6) δ8.58(d,J=4.0Hz,1H),8.09(d,J=7.9Hz,1H),7.96(td,J= 7.7,1.7Hz,1H),7.80(dd,J=8.8,2.4Hz,1H),7.55–7.49(m,3H),5.37–5.30(m,1H) ,4.77(t,J=7.3Hz,2H),4.51–4.41(m,2H),3.63(dd,J=8.3,5.5Hz,1H),3.30(s,3H ),2.44(t,J=7.5Hz,2H),2.12–2.00(m,2H),1.80–1.70(m,1H),1.65–1.55(m,1H).

[0457] Example 16 Preparation of Compounds 26-28

[0458]

[0459] 1. Preparation of Compound 28-1

[0460] At -70°C, n-butyllithium (179 mL, 2.5 mol / L in hexane, 447.5 mmol) was added dropwise to a solution of 2-bromopyridine (71.95 g, 455.4 mmol) in toluene (492 mL). After completion of the addition, the mixture was stirred for 30 minutes. A solution of 2-aminobenzonitrile (23.5 g, 198.9 mmol) in toluene (163 mL) was added dropwise to the reaction system, allowed to warm to room temperature, and stirred for 12 hours. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water and extracted with ethyl acetate (3 x 200 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 to 1 / 5) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3). Fractions with Rf = 0.4 to 0.6 were collected to obtain compound 28-1 (12.4 g, yield 31.4%) as a white solid. ESI [M+H] + =199.1.

[0461] 2. Preparation of Compound 28-2

[0462] Trifluoroacetic anhydride (16.1 g, 76.7 mmol) was added to a solution of 28-1 (12.73 g, 64.2 mmol) in chloroform (408 mL) and stirred at 42°C for 5 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The residue was dissolved in water, and the pH of the system was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution, followed by extraction with ethyl acetate (3 × 100 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 to 1 / 5) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3). Fractions with Rf = 0.4 to 0.6 were collected to obtain compound 28-2 (10.8 g, 57.2% yield) as a white solid. ESI [M+H] + =295.1.

[0463] 3. Preparation of Compound 28-3

[0464] Potassium nitrate (5.565 g, 55.0 mmol) was dissolved in concentrated sulfuric acid (50 mL) and added dropwise to a solution of 28-2 (10.6 g, 36.0 mmol) in concentrated sulfuric acid (50 mL) at 0°C, maintaining the temperature at no more than 10°C. After the addition, the mixture was allowed to warm to room temperature and stirred for 4 hours. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water and the pH was adjusted to 8-9 with 25% aqueous sodium hydroxide solution. The mixture was then extracted with ethyl acetate (3 x 60 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 to 1 / 2) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). Fractions with Rf = 0.4 to 0.6 were collected to obtain compound 28-3 (9.5 g, 77.7% yield) as a yellow solid. ESI [M+H] + =340.1.

[0465] 4. Preparation of Compound 28-4

[0466] 28-3 (9.5 g, 28.0 mmol) and potassium carbonate (7.71 g, 55.8 mmol) were added to a mixed solvent of methanol and water (100 mL, v / v = 1 / 1) and stirred at 70°C for 2 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. Ice water was added to the residue and filtered. The filter cake was washed three times with water and dried in vacuo to obtain compound 28-4 (6.8 g, yield 99.8%) as a yellow solid. ESI [M+H] + =244.1.

[0467] 5. Preparation of Compound 28-5

[0468] Thionyl chloride (30 mL) was added to a solution of Fmoc-L-glutamic acid methyl ester (13.3 g, 34.7 mmol) in chloroform (100 mL) and stirred at 50°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform (50 mL) and added dropwise to a solution of 28-4 (4.21 g, 17.3 mmol) and pyridine (1.35 g, 17.1 mmol) in chloroform (40 mL). The mixture was stirred at 60°C for 2 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 to 1 / 5) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). The fractions with Rf = 0.4 to 0.5 were collected to obtain compound 28-5 (7.7 g, 73.1% yield) as a white solid. ESI [M+H] + =609.2.

[0469] 6. Preparation of target compound 26

[0470] Compound 28-5 (7.67 g, 12.6 mmol) was dissolved in a mixed solvent of morpholine (13 mL) and dichloromethane (67 mL) and stirred at room temperature for 24 hours. After the reaction was complete as monitored by TLC, ice water (30 mL) was added to the reaction system. The mixture was extracted with dichloromethane (3 × 30 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). The fraction with Rf = 0.3 to 0.4 was collected to obtain compound 26 (2.2 g, yield 47.4%) as a white solid. ESI [M+H] + =369.2.

[0471] 1 H NMR (400MHz, CDCl3) δ9.05–8.90(m,1H),8.60–8.57(m,1H),8.39–8.27(m,2H),8.20(d,J=7.9Hz,1H),7.90–7.86(m,1 H),7.46–7.41(m,1H),7.25–7.14(m,1H),3.83–3.78(m,1H),3.67–3.66(m,3H),2.75–2.65(m,2H),2.65–2.44(m,2H).

[0472] 7. Preparation of target compound 27

[0473] NaH (215 mg, 60%, 5.37 mmol) was slowly added to a solution of 26 (1.8 g, 4.89 mmol) in dry DMF (20 mL) at -10°C and stirred for 30 minutes. Iodomethane (764 mg, 5.38 mmol) was added to the reaction system and stirred for 1 hour. After the reaction was complete as monitored by TLC, the reaction solution was poured into ice water (40 mL) and extracted with ethyl acetate (3 × 30 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.4 to 0.5 were collected to obtain compound 27 (1.505 g, 80.5% yield) as a white solid. ESI [M+H] + =383.2.

[0474] 1 H NMR(400MHz, CDCl3)δ8.62(s,1H),8.41(d,J=9.0Hz,1H),8.34–8.21(m,2H),7.96–7.94(m,1H),7.50 (d,J=9.0Hz,2H),3.79–3.77(m,1H),3.65(s,3H),3.49(s,3H),2.71–2.58(m,3H),2.57–2.46(m,1H).

[0475] 8. Preparation of target compound 28

[0476] At 0°C, sodium ethoxide (219.5 mg, 3.23 mmol) was added to a mixed solution of 27 (857 mg, 2.24 mmol) in EtOH / THF (18 mL, v / v = 1 / 1), the temperature was naturally raised to room temperature, and the mixture was stirred for 8 hours. After the reaction was complete as monitored by TLC, ice water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 30 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) and the fraction with Rf = 0.2-0.3 was collected to obtain compound 28 (242.9 mg, yield 27.3%) as a white solid. ESI [M+H] + =397.2.

[0477] 1H NMR (400MHz, DMSO-d6) δ8.57(d,J=4.7Hz,1H),8.45(dd,J=9.2,2.8Hz,1H),8.22( d,J=2.7Hz,1H),8.19(d,J=7.9Hz,1H),8.00(td,J=7.8,1.7Hz,1H),7.79(d,J=9. 2Hz,1H),7.57–7.54(m,1H),4.04(q,J=7.1Hz,2H),3.80–3.74(m,1H),3.38(s,3H ),2.59–2.53(m,1H),2.45–2.35(m,2H),2.31–2.21(m,1H),1.14(t,J=7.1Hz,3H).

[0478] Example 17 Preparation of Compound 29

[0479]

[0480] 1. Preparation of Compound 29-1

[0481] LiOH.H2O (64.3 mg, 1.53 mmol) and NaOH (55.7 mg, 1.39 mmol) were added sequentially to a solution of 27 (532 mg, 1.39 mmol) in MeOH / THF / H2O (7 mL, v / v / v = 1 / 1 / 1) at -10°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, the pH of the system was adjusted to 6-7 with 1 mol / L dilute hydrochloric acid and extracted with ethyl acetate (3 x 30 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 10) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). The fractions with Rf = 0.3 to 0.4 were collected to obtain compound 29-1 (254 mg, yield 49.6%) as a white solid. ESI [M+H] + =369.1.

[0482] 2. Preparation of target compound 29

[0483] 29-1 (50 mg, 0.136 mmol), DCC (39.6 mg, 0.192 mmol), and DMAP (23.5 mg, 0.192 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 15 minutes. 3-Methyloxetan-3-ol (12.5 mg, 0.142 mmol) was added to the reaction system and stirring continued at room temperature for 12 hours. After the reaction was complete as monitored by TLC, methyl tert-butyl ether (2 mL) was added to the reaction system, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) and the fraction with Rf = 0.2-0.3 was collected to obtain compound 29 (15.4 mg, yield 25.9%) as a white solid. ESI [M+H] + =439.2.

[0484] 1 H NMR (400MHz, CDCl3) δ8.67(s,1H),8.44(d,J=8.9Hz,1H),8.34–8.28(m,1H),8.27–8.23(m,1H),8.10–8.06(m,1H),7.64–7.58(m,1H),7.54–7 .52(m,1H),4.71(d,J=6.7Hz,2H),4.47(d,J=7.5Hz,2H),3.80–3.73(m ,1H),3.52(s,3H),2.70–2.58(m,3H),2.55–2.46(m,1H),1.66(s,3H).

[0485] Example 18 Preparation of Compounds 30-32

[0486]

[0487] The preparation method of target compound 30-32 is similar to that of compound 29 in Example 17, using 29-1 and the corresponding alcohol as raw materials to prepare the corresponding ester.

[0488] Compound 30: 18.8 mg, ESI [M+H] + =451.2.

[0489] 1H NMR (400MHz, CDCl3) δ8.64(s,1H),8.42(d,J=8.7Hz,1H),8.33–8.27(m,2H),8.01–7.95(m,1H),7.55–7.50(m,2H),6.18(dd,J=17.3,10.8Hz, 1H),5.31–5.22(m,2H),4.79(dd,J=7.2,3.0Hz,2H),4.70–4.64(m,2H) ,3.78–3.74(m,1H),3.51(s,3H),2.73–2.60(m,3H),2.55–2.45(m,1H).

[0490] Compound 31: 23.1 mg, ESI [M+H] + =425.2.

[0491] 1 H NMR (400MHz, CDCl3) δ8.62(s,1H),8.41(d,J=9.0Hz,1H),8.34(s,1H),8.27(d,J=7.5Hz,1H),7.96–7.90(m,1H),7.54–7.42(m,2H),5.4 6–5.38(m,1H),4.86(dd,J=11.2,6.6Hz,2H),4.62–4.59(m,2H),3.78–3.74(m,1H),3.49(s,3H),2.76–2.57(m,3H),2.55–2.45(m,1H).

[0492] Compound 32: 41.4 mg, ESI [M+H] + =435.1.

[0493] 1 H NMR (400MHz, DMSO-d6) δ8.57 (ddd, J=4.8, 1.7, 0.9Hz, 1H), 8.44 (dd, J=9.2, 2. 8Hz,1H),8.22–8.20(m,2H),8.00(td,J=7.7,1.8Hz,1H),7.80(d,J=9.2Hz,1H ),7.55(ddd,J=7.5,4.8,1.1Hz,1H),3.76(dd,J=7.8,5.5Hz,1H),3.44(s,1H) ,3.39(s,3H),2.49–2.29(m,3H),2.27–2.21(m,1H),1.56(s,3H),1.55(s,3H).

[0494] Example 19 Preparation of Compounds 34-37

[0495]

[0496] 1. Preparation of Compound 37-1

[0497] BOC-L-serine (18.0 g, 87.7 mmol) was dissolved in dichloromethane (180 mL), and DIEA (13.6 g, 105.2 mmol) and acetic anhydride (9.78 g, 95.8 mmol) were added. The mixture was stirred at room temperature for 18 hours. After completion of the reaction as monitored by TLC, water (50 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 100 mL). The organic phase was washed with 1% dilute hydrochloric acid, saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 37-1 (16.7 g, 77.0% yield) as a colorless oil. ESI [M+H] + =248.1.

[0498] 2. Preparation of compound 37-2

[0499] Compound 1-1 (12.4 g, 44.7 mmol) and compound 37-1 (16.7 g, 67.5 mmol) were dissolved in dichloromethane (100 mL). A solution of DCC (18.5 g, 89.7 mmol) in dichloromethane (40 mL) was added dropwise at -10°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, methyl tert-butyl ether (140 mL) was added to the reaction system and stirred for 5 minutes. The reaction system was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 2) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 37-2 (10.5 g, 46.3% yield) as a white solid. ESI [M+H]+ = 506.1.

[0500] 3. Preparation of Compound 37-3

[0501] Trifluoroacetic acid (10 mL) was added to a solution of 37-2 (10.5 g, 20.7 mmol) in dichloromethane (20 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 2 hours. After completion of the reaction as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was used directly in the next reaction without purification.

[0502] 4. Preparation of target compound 34

[0503] The crude compound from the previous step was dissolved in acetonitrile (100 mL), sodium bicarbonate (52.0 g, 619 mmol) was added, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete as monitored by TLC, the reaction solution was filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 2) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). The fraction with Rf = 0.2 to 0.3 was collected to obtain compound 34 (6.3 g, 78.3% yield for two steps) as a white solid. ESI [M+H] + =388.2.

[0504] 1 H NMR (400MHz, DMSO-d6) δ10.85(s,1H),8.57(dd,J=4.0,0.8Hz,1H),8.04(d,J=7.9Hz,1H),7.97(td,J=7.7,1.7Hz,1H),7.7 5(dd,J=8.7,2.3Hz,1H),7.55–7.49(m,2H),7.19(d,J=8.8Hz,1H),4.72–4.58(m,2H),3.93(t,J=6.4Hz,1H),2.03(s,3H).

[0505] 5. Preparation of Compound 37-4 and Target Compound 35

[0506] NaH (716 mg, 60%, 17.9 mmol) was slowly added to a solution of 34 (6.3 g, 16.2 mmol) in dry DMF (60 mL) at -20°C and stirred for 30 minutes. Iodomethane (2.54 g, 17.9 mmol) was added to the reaction system and stirring continued at -20°C for 1 hour. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water (120 mL) and extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) to obtain compound 37-4 (2.86 g, 43.8% yield) as a white solid and compound 35 (62.8 mg, 1.2% yield) as a yellow solid.

[0507] Compound 37-4: ESI[M+H] + =402.1.

[0508] Compound 35: ESI[M+H] + =328.2.

[0509] 1H NMR (400MHz, DMSO-d6) δ10.77(s,1H),8.69–8.58(m,1H),8.13(d,J=7.9Hz,1H),8.01(td,J=7.8,1.7Hz,1H),7.71(dd,J=8 .7,2.3Hz,1H),7.56(ddd,J=7.5,4.8,1.1Hz,1H),7.42(d,J=2.3Hz,1H),7.19(d,J=8.7Hz,1H),5.19(s,1H),4.99(s,1H).

[0510] 6. Preparation of target compounds 36 and 37

[0511] LiOH.H₂O (450 mg, 10.7 mmol) was added to a solution of 37-4 (2.86 g, 7.11 mmol) in THF / H₂O (25 mL, v / v = 1 / 1) at 0°C. The mixture was allowed to warm to room temperature and stirred for 2 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 30 mL). The organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) to afford compound 36 (1.2 g, 49.3% yield) as a yellow solid and compound 37 (1.01 g, 39.4% yield) as a colorless oil.

[0512] Compound 36: ESI[M+H] + =342.2.

[0513] 1 H NMR (400MHz, DMSO-d6) δ8.63(d,J=4.7Hz,1H),8.19(d,J=7.9Hz,1H),8.01(td,J=7.8,1.7Hz,1H),7.78(dd,J=8.8, 2.4Hz,1H),7.61–7.55(m,1H),7.50(d,J=2.4Hz,1H),7.48(d,J=8.9Hz,1H),5.10(s,1H),4.92(s,1H),3.32(s,3H).

[0514] Compound 37: ESI[M+H] + =360.2.

[0515] 1H NMR (400MHz, DMSO-d6) δ8.58(d,J=4.0Hz,1H),8.15(d,J=7.9Hz,1H),7.96(td,J=7.8,1.7Hz,1H),7.82(dd,J=8.8,2.4Hz,1H),7.55( d,J=8.9Hz,1H),7.53–7.50(m,2H),4.71(t,J=5.8Hz,1H),4.21–4.15(m,1H),4.03–3.94(m,1H),3.65(t,J=6.5Hz,1H),3.30(s,3H).

[0516] Example 20 Preparation of Compound 40

[0517]

[0518] Propionyl chloride (38.7 mg, 0.418 mmol) was added dropwise to a solution of 37 (100 mg, 0.278 mmol) and triethylamine (56.3 mg, 0.556 mmol) in dichloromethane (2 mL) at -10°C and stirred for 2 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system and extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.4 to 0.5 were collected to obtain compound 40 (73.5 mg, 63.6% yield) as a white solid. ESI [M+H] + =416.0.

[0519] 1 H NMR (400MHz, DMSO-d6) δ8.59(ddd,J=4.8,1.7,0.9Hz,1H),8.08(d,J=7.9Hz,1H),7.97(td,J=7.7,1.8Hz,1H),7.83(dd,J=8.8,2. 4Hz,1H),7.58–7.49(m,3H),4.72–4.59(m,2H),3.97(t,J=6.5Hz,1H),3.32(s,3H),2.31(q,J=7.5Hz,2H),1.02(t,J=7.5Hz,3H).

[0520] Example 21 Preparation of Compounds 41-43

[0521]

[0522] The preparation methods of target compounds 41-43 are similar to compound 40 in Example 20, using compound 37 and the corresponding acyl chloride as raw materials to prepare the corresponding esters.

[0523] Compound 41: 72.4 mg, ESI [M+H] + =430.0.

[0524] 1 H NMR (400MHz, DMSO-d6) δ8.59(d,J=4.1Hz,1H),8.06(d,J=7.9Hz,1H),7.97(td,J=7.7,1.7Hz,1H),7.83(dd,J=8.9,2.4H z,1H),7.59–7.50(m,3H),4.71–4.59(m,2H),3.99(t,J=6.5Hz,1H),3.32(s,3H),2.57–2.51(m,1H),1.09–1.04(m,6H).

[0525] Compound 42: 19.7 mg, ESI [M+H] + =464.0.

[0526] 1 H NMR (400MHz, DMSO-d6) δ8.59(d,J=4.0Hz,1H),8.07(d,J=7.9Hz,1H),7.99–7.91(m,3H),7.84(dd,J=8.9,2 .4Hz,1H),7.65(t,J=7.4Hz,1H),7.58–7.50(m,5H),4.97–4.87(m,2H),4.19(t,J=6.4Hz,1H),3.34(s,3H).

[0527] Compound 43: 54.1 mg, ESI [M+H] + =436.0.

[0528] 1 H NMR (400MHz, DMSO-d6) δ8.59(d,J=4.0Hz,1H),8.09(d,J=7.9Hz,1H),7.97(td,J=7.7,1.7Hz,1H),7.84(dd ,J=8.9,2.4Hz,1H),7.60–7.49(m,3H),4.78(d,J=6.5Hz,2H),4.40(s,2H),4.05–4.00(m,1H),3.32(s,3H).

[0529] Example 22 Preparation of Compounds 44 and 45

[0530]

[0531] 3-Chloropropionyl chloride (53.1 mg, 0.418 mmol) was added dropwise to a solution of 37 (100 mg, 0.278 mmol) and triethylamine (56.3 mg, 0.556 mmol) in dichloromethane (2 mL) at -10°C and stirred for 2 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10) to obtain compound 44 (9.5 mg, 7.6% yield) and compound 45 (19.5 mg, 17.0% yield) as a white solid.

[0532] Compound 44: ESI[M+H] + =450.0.

[0533] 1 H NMR (400MHz, DMSO-d6) δ8.62–8.57(m,1H),8.10(d,J=7.9Hz,1H),7.97(td,J=7.7,1.8Hz,1H),7.83(dd,J=8.9,2.4Hz,1H),7 .59–7.49(m,3H),4.77–4.70(m,2H),3.99(t,J=6.4Hz,1H),3.79(t,J=6.2Hz,2H),3.32(s,3H),2.83(dd,J=6.5,5.8Hz,2H).

[0534] Compound 45: ESI[M+H] + =414.0.

[0535] 1 H NMR (400MHz, DMSO-d6) δ8.59(ddd,J=4.8,1.6,0.9Hz,1H),8.07(d,J=7.9Hz,1H),7.97(td,J=7.7,1.8Hz,1H),7.83(dd,J=8.8,2.4Hz,1H),7.60–7.49(m ,3H),6.35(dd,J=17.3,1.6Hz,1H),6.19(dd,J=17.3,10.3Hz,1H),5.95(dd ,J=10.3,1.6Hz,1H),4.80–4.71(m,2H),4.04(t,J=6.5Hz,1H),3.32(s,3H).

[0536] Example 23 Preparation of Compound 46

[0537]

[0538] 2-Picolidinecarboxylic acid (51.4 mg, 0.418 mmol), DCC (86.1 mg, 0.417 mmol), and DMAP (68 mg, 0.557 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 15 minutes. Compound 37 (100 mg, 0.278 mmol) was added to the reaction system and stirred at room temperature for 12 hours. After the reaction was complete as monitored by TLC, methyl tert-butyl ether (2 mL) was added to the reaction system, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 46 (39.1 mg, 30.3% yield) as a white solid. ESI [M+H] + =465.0.

[0539] 1 H NMR (400MHz, DMSO-d6) δ8.72–8.70(m,1H),8.63–8.58(m,1H),8.10–8.03(m,2H),7.99–7.93(m,2H),7.85(dd,J=8.9,2.4Hz,1H),7.64(d dd,J=7.5,4.7,1.3Hz,1H),7.59–7.56(m,2H),7.53(ddd,J=7.5,4.8,1.2Hz,1H),5.02–4.91(m,2H),4.19(t,J=6.4Hz,1H),3.33(s,3H).

[0540] Example 24 Preparation of Compounds 47-49, 51

[0541]

[0542] The preparation methods of compounds 47-49 and 51 are similar to those of compound 46 in Example 23, using compound 37 and the corresponding carboxylic acid as raw materials to prepare the corresponding esters.

[0543] Compound 47: 48.3 mg, ESI [M+H] + =465.1.

[0544] 1H NMR (400MHz, DMSO-d6) δ8.80–8.79(m,2H),8.62–8.57(m,1H),8.07(d,J=7.9Hz,1H),7.95(td,J=7.7,1 .8Hz,1H),7.86–7.82(m,3H),7.59–7.49(m,3H),5.01–4.92(m,2H),4.22(t,J=6.3Hz,1H),3.34(m,3H).

[0545] Compound 48: 72.3 mg, ESI [M+H] + =465.1.

[0546] 1 H NMR (400MHz, DMSO-d6) δ9.03(s,1H),8.75(d,J=4.7Hz,1H),8.53(d,J=4.1Hz,1H),8.23(d,J=8.0Hz,1H),8.01(d,J=8.0Hz ,1H),7.89(t,J=7.7Hz,1H),7.81–7.75(m,1H),7.52–7.45(m,4H),4.96–4.83(m,2H),4.16(t,J=6.3Hz,1H),3.28(s,3H).

[0547] Compound 49: 32.3 mg, ESI [M+H] + =434.0.

[0548] 1 H NMR (400MHz, DMSO-d6) δ8.61–8.57(m,1H),8.09–8.02(m,1H),8.02–7.94(m,1H),7.84(dd,J=8.9,2.4Hz,1H),7.5 7–7.52(m,3H),5.31–5.25(m,1H),4.88–4.68(m,2H),4.06(dd,J=9.6,3.2Hz,1H),3.32(s,3H),1.51–1.42(m,3H).

[0549] Compound 51: 22.7 mg, ESI [M+H] + =426.1.

[0550] 1H NMR (400MHz, DMSO-d6) δ8.62(d,J=4.2Hz,1H),8.09(d,J=7.9Hz,1H),8.00(td,J=7.7,1.7Hz,1H),7.86(dd ,J=8.9,2.3Hz,1H),7.63–7.50(m,3H),4.83–4.71(m,2H),4.06(t,J=6.3Hz,1H),3.34(s,3H),2.04(s,3H).

[0551] Example 25 Preparation of Compound 53

[0552]

[0553] 1. Preparation of compound 53-1

[0554] NaOH (232 mg, 5.8 mmol) was added to a solution of ethyl fluoroacetate (530 mg, 5.0 mmol) in EtOH / H₂O (7 mL, v / v = 1 / 1) and stirred at room temperature for 16 hours. After completion of the reaction as monitored by TLC, the pH of the system was adjusted to 6-7 with 1 mol / L hydrochloric acid and extracted with diethyl ether (3 x 30 mL). The organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford Compound 53-1 (150 mg, 38.5% yield) as a colorless oil.

[0555] 2. Preparation of Compound 53

[0556] 53-1 (116.1 mg, 1.49 mmol), DCC (592.4 mg, 2.87 mmol), and DMAP (526.0 mg, 4.31 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 15 minutes. 37 (50 mg, 0.139 mmol) was added to the reaction system and stirring continued at room temperature for 12 hours. After the reaction was complete as monitored by TLC, methyl tert-butyl ether (2 mL) was added to the reaction system, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 53 (5.6 mg, yield 9.6%) as a white solid. ESI [M+H] + =420.0.

[0557] 1H NMR (400MHz, DMSO-d6) δ8.62(d,J=4.0Hz,1H),8.11(d,J=7.9Hz,1H),8.00(td,J=7.7,1.7Hz,1H),7.86(dd,J=8. 9,2.4Hz,1H),7.59-7.56(m,3H),5.06(d,J=46.2Hz,2H),4.84-4.81(m,2H),4.06(t,J=6.4Hz,1H),3.34(s,3H).

[0558] Example 26 Preparation of Compound 54

[0559]

[0560] Ethyl chloroformate (272.1 mg, 2.51 mmol) was added dropwise to a solution of 37 (300 mg, 0.833 mmol), pyridine (198.3 mg, 2.51 mmol), and DMAP (101.9 mg, 0.834 mmol) in dichloromethane (5 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100-1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 20). Fractions with Rf = 0.3-0.4 were collected to obtain an off-white solid compound 54 (170.3 mg, yield 47.3%). ESI [M+H] + =432.2.

[0561] 1 H NMR (400MHz, DMSO-d6) δ8.59(d,J=4.0Hz,1H),8.07(d,J=7.9Hz,1H),8.00–7.93(m,1H),7.84(dd,J=8.9,2.4Hz,1H),7.58–7.51 (m,3H),4.77–4.73(m,1H),4.70–4.65(m,1H),4.13(q,J=7.1Hz,2H),4.02(t,J=6.4Hz,1H),3.31(s,3H),1.20(t,J=7.1Hz,3H).

[0562] Example 27 Preparation of Compound 55

[0563]

[0564] The preparation method of target compound 55 is similar to that of compound 54 in Example 26, using compound 37 and isopropyl chloroformate as raw materials.

[0565] Compound 55: 279.7 mg, ESI [M+H] + =446.0.

[0566] 1 H NMR (400MHz, DMSO-d6) δ8.60–8.58(m,1H),8.09–8.03(m,1H),7.97(td,J=7.7,1.8Hz,1H),7.84(dd,J=8.9 ,2.4Hz,1H),7.58–7.50(m,3H),4.81–4.63(m,3H),4.01(t,J=6.4Hz,1H),3.31(s,3H),1.28–1.20(m,6H).

[0567] Example 28 Preparation of Compounds 56 and 57

[0568]

[0569] 1. Preparation of Compound 56-1

[0570] p-Nitrophenyl chloroformate (505.3 mg, 2.51 mmol) was added to a solution of 37 (300 mg, 0.833 mmol), pyridine (193.1 mg, 2.44 mmol), and DMAP (102 mg, 0.835 mmol) in dichloromethane (5 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 56-1 (272.8 mg, yield 62.4%) as a white solid. ESI [M+H] + =525.1.

[0571] 2. Preparation of target compound 56

[0572] Dimethylamine (0.095 mL, 2 mol / L in THF, 0.19 mmol) was added to a solution of 56-1 (100 mg, 0.19 mmol) and DIEA (24.6 mg, 0.19 mmol) in dichloromethane (2 mL) and stirred at room temperature for 12 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system and extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 56 (34.8 mg, 42.4% yield) as a white solid. ESI [M+H] + =431.1.

[0573] 1 H NMR (400MHz, DMSO-d6) δ8.61(d,J=4.1Hz,1H),8.09(d,J=7.9Hz,1H),7.99(td,J=7.7,1.7Hz,1H),7.85(dd,J=8.8,2.4Hz,1H),7.58(d,J=8 .9Hz,1H),7.56-7.54(m,2H),4.69(dd,J=10.9,5.9Hz,1H),4.60(dd,J=10.8,7.1Hz,1H),3.97(t,J=6.5Hz,1H),3.34(s,3H),2.82(s,6H).

[0574] 3. Preparation of target compound 57

[0575] The preparation method of target compound 57 is similar to that of compound 56 in Example 28, using compound 56-1 and N-ethylmethylamine as raw materials.

[0576] Compound 57: 62.1 mg, ESI [M+H] + =445.1.

[0577] 1H NMR (400MHz, DMSO-d6) δ8.61–8.56(m,1H),8.07(d,J=7.9Hz,1H),8.00–7.93(m,1H),7.83(dd,J=8.8,2.4Hz,1H),7.56(d,J=8.9Hz,1 H),7.53–7.52(m,2H),4.67–4.60(m,2H),3.95(t,J=6.5Hz,1H),3.32(s,3H),3.25–3.15(m,2H),2.78(s,3H),1.00(t,J=7.0Hz,3H).

[0578] Example 29 Preparation of Compounds 58 and 61

[0579]

[0580] 1. Preparation of target compound 58

[0581] Methanesulfonyl chloride (572.5 mg, 5.0 mmol) was added dropwise to a solution of 37 (359 mg, 0.997 mmol), pyridine (395 mg, 4.99 mmol), and DMAP (122 mg, 0.999 mmol) in dichloromethane (10 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 20). Fractions with Rf = 0.3 to 0.4 were collected to afford compound 58 (190 mg, 43.5% yield) as a white solid. ESI[M+H] + =438.0.

[0582] 1 H NMR (400MHz, CDCl3) δ8.65(d,J=3.8Hz,1H),8.16(d,J=7.9Hz,1H),7.88-7.84(m,1H),7.69(dd,J=8.8,2.2Hz,1H),7.54(d,J=2.3Hz,1H),7.42(dd, J=6.9,4.9Hz,1H),7.28-7.25(m,1H),5.08(dd,J=10.1,7.0Hz,1H),4.88 (dd,J=10.1,6.1Hz,1H),4.05(t,J=6.5Hz,1H),3.42(s,3H),3.16(s,3H).

[0583] 2. Preparation of target compound 61

[0584] At 0°C, NaH (47.2 mg, 60%, 1.18 mmol) was slowly added to a solution of hydroxyacetone (88.6 mg, 1.20 mmol) in dry DMF (3 mL) and stirred for 30 minutes. Compound 58 (172 mg, 0.392 mmol) was added to the reaction system and stirring continued at 0°C for 5 hours. After the reaction was complete as monitored by TLC, the reaction solution was poured into ice water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (methanol / dichloromethane (v / v) = 1 / 20) and the fraction with Rf = 0.3-0.4 was collected to obtain compound 61 (8.2 mg, 5.0% yield) as a white solid. ESI [M+H] + =416.0.

[0585] 1 H NMR (400MHz, DMSO-d6) δ8.60–8.56(m,1H),7.98–7.97(m,2H),7.82(dd,J=8.8,2.4Hz,1H),7.56–7.50(m,2H),7.46(d,J=2.4Hz,1H),5.2 6(d,J=5.3Hz,1H),4.17(dd,J=11.5,5.7Hz,1H),3.86(t,J=6.9Hz,1H),3.31(s,3H),2.55–2.50(m,1H),2.43–2.38(m,1H),2.19(s,3H).

[0586] Example 30 Preparation of Compounds 62, 63, 66-69

[0587]

[0588] The preparation methods of compounds 62, 63, 66-69 were similar to those of compound 58 in Example 29, using compound 37 and corresponding sulfonyl chlorides as raw materials.

[0589] Compound 62: 18.5 mg, ESI [M+H] + =452.0.

[0590] 1H NMR (400MHz, DMSO-d6) δ8.62–8.58(m,1H),8.10(d,J=7.9Hz,1H),7.99(td,J=7.7,1.7Hz,1H),7.84(dd,J=8.8,2.4Hz,1H) ,7.59–7.50(m,3H),4.82–4.73(m,2H),4.11(dd,J=7.0,5.7Hz,1H),3.47–3.41(m,2H),3.32(s,3H),1.27(t,J=7.3Hz,3H).

[0591] Compound 63: 15.8 mg, ESI [M+H] + =466.0.

[0592] 1 H NMR (400MHz, DMSO-d6) δ8.58(d,J=4.0Hz,1H),8.07(d,J=7.9Hz,1H),7.97(td,J=7.7,1.7Hz,1H),7.82(dd,J=8.9,2.4H z,1H),7.59–7.47(m,3H),4.83–4.69(m,2H),4.09(t,J=6.3Hz,1H),3.78–3.65(m,1H),3.30(s,3H),1.32–1.28(m,6H).

[0593] Compound 66: 17.1 mg, ESI [M+H] + =500.0.

[0594] 1 H NMR(400MHz, DMSO-d6)δ8.60(d,J=4.1Hz,1H),8.02–7.96(m,3H),7.92(d,J=7.9Hz,1H),7.88–7.79(m,2H ),7.71(t,J=7.7Hz,2H),7.58–7.50(m,3H),4.73–4.60(m,2H),4.02(dd,J=7.2,5.4Hz,1H),3.29(s,3H).

[0595] Compound 67: 26.6 mg, ESI [M+H] + =534.0.

[0596] 1H NMR (400MHz, DMSO-d6) δ8.60(d,J=4.2Hz,1H),7.98–7.96(m,3H),7.90(d,J=7.9Hz,1H),7.85(dd,J=8. 9,2.4Hz,1H),7.79–7.77(m,2H),7.60–7.51(m,3H),4.73–4.63(m,2H),4.08–3.98(m,1H),3.29(s,3H).

[0597] Compound 68: 80.3 mg, ESI [M+H] + =534.1.

[0598] 1 H NMR (400MHz, DMSO-d6) δ8.60(d,J=4.6Hz,1H),8.14(d,J=8.0Hz,1H),8.04–7.97(m,2H),7.85(dd,J=8.9,2.4Hz,1H),7.79–7.78( m,2H),7.66–7.59(m,1H),7.58–7.53(m,2H),7.51(d,J=2.3Hz,1H),4.79–4.69(m,2H),4.04(dd,J=7.7,4.9Hz,1H),3.28(s,3H).

[0599] Compound 69: 106.0 mg, ESI [M+H] + =534.2.

[0600] 1 H NMR(400MHz,DMSO-d6)δ8.60(d,J=4.3Hz,1H),8.03–8.00(m,1H),7.98–7.96(m,2H),7.94–7.88(m,2H),7.85(dd,J=8.9,2.4Hz,1 H),7.73(t,J=8.0Hz,1H),7.57–7.52(m,2H),7.51(d,J=2.4Hz,1H),4.77–4.66(m,2H),4.04(dd,J=7.3,5.2Hz,1H),3.29(s,3H).

[0601] Example 31 Preparation of Compound 71

[0602]

[0603] Methyl acetoacetate (68 mg, 0.586 mmol) was added to a solution of sodium methoxide (32 mg, 0.592 mmol) in methanol (3 mL) and stirred at room temperature for 30 minutes. Compound 36 (200 mg, 0.584 mmol) was added to the reaction system and stirring continued at room temperature for 16 hours. After completion of the reaction as monitored by TLC, the pH of the system was adjusted to 6-7 with 1 mol / L hydrochloric acid under ice-cooling, and then extracted with ethyl acetate (3 x 50 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.2-0.3 were collected to obtain compound 71 (113.0 mg, 42.2% yield) as a white solid. ESI [M+H] + =458.2.

[0604] 1 H NMR(400MHz, DMSO-d6)δ8.58(d,J=4.6Hz,1H),8.05–7.96(m,2H),7.81(dd,J=8.6,2.2Hz,1H),7.56–7.50(m,2H),7.48(dd,J=9.5,2.4Hz,1H),3.95 –3.91(m,1H),3.76–3.71(m,1H),3.67(s,1.5H),3.61(s,1.5H),3.30(s, 3H),2.68–2.57(m,1H),2.45–2.40(m,1H),2.27(s,1.5H),2.20(s,1.5H).

[0605] Example 32 Preparation of Compound 72

[0606]

[0607] The preparation method of compound 72 is similar to that of compound 71 in Example 31, using compound 36 and dimethyl malonate as raw materials.

[0608] Compound 72: 165.4 mg, ESI [M+H] + =474.2.

[0609] 1H NMR (400MHz, DMSO-d6) δ8.58(d,J=4.4Hz,1H),8.04(d,J=7.8Hz,1H),8.00–7.97(m,1H),7.82(dd,J=8.8,2.4Hz,1H),7.56–7.50 (m,2H),7.49(d,J=2.4Hz,1H),3.85–3.73(m,2H),3.67(s,3H),3.60(s,3H),3.30(s,3H),2.71–2.62(m,1H),2.50–2.45(m,1H).

[0610] Example 33 Preparation of Compound 73

[0611]

[0612] Compound 36 (95 mg, 0.278 mmol), methyl azetidine-3-carboxylate hydrochloride (63.3 mg, 0.418 mmol), DBU (46.5 mg, 0.305 mmol), and sodium bicarbonate (44.3 mg, 0.527 mmol) were dissolved in methanol (2 mL) and stirred at 50°C for 2 hours. After the reaction was complete as monitored by TLC, ice water (10 mL) was added to the reaction system and extracted with ethyl acetate (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (methanol / dichloromethane (v / v) = 1 / 30) and the fraction with Rf = 0.3-0.4 was collected to obtain compound 73 (71.5 mg, 56.3% yield) as a white solid. ESI [M+H] + =457.1.

[0613] 1 H NMR(400MHz, DMSO-d6)δ8.58(s,1H),8.04–7.98(m,2H),7.81(d,J=8.3Hz,1H),7.53–7.49( m,3H),3.62(s,3H),3.60–3.37(m,4H),3.31–3.29(m,1H),3.28(s,3H),3.22–3.05(m,3H).

[0614] Example 34 Preparation of Compounds 74 and 75

[0615]

[0616] The preparation methods of compounds 74 and 75 are similar to those of compound 73 in Example 33, using compound 36 and the corresponding amine (or its salt) as raw materials.

[0617] Compound 74: 121.2 mg, ESI [M+H] + =574.2.

[0618] 1 H NMR(400MHz,DMSO-d6)δ8.80–8.20(m,1H),8.01–7.71(m,3H),7.65–7.29(m, 6H),7.21–7.10(m,2H),4.57–4.37(m,1H),3.32–3.30(m,1H),3.28(s,3H),3. 20–2.80(m,4H),2.48–2.37(m,1H),2.30–1.97(m,1H),1.81–1.79(m,2H),1. 69–1.51(m,2H),1.50–1.28(m,1H),1.20–1.04(m,1H),0.86(t,J=7.4Hz,3H).

[0619] Compound 75: 70.3 mg, ESI [M+H] + =485.1.

[0620] 1 H NMR (400MHz, DMSO-d6) δ8.58(d,J=4.6Hz,1H),8.05(d,J=7.9Hz,1H),7.99–7.95(m,1H),7.85–7.78(m,1H),7.59–7.49(m,3H),3.78–3.75(m,1H) ),3.58(s,3H),3.30(s,3H),3.10–2.95(m,1H),2.92–2.75(m,2H),2.42 –2.23(m,2H),2.22–1.95(m,2H),1.82–1.62(m,2H),1.57–1.38(m,2H).

[0621] Example 35 Preparation of Compounds 76 and 77

[0622]

[0623] 1. Preparation of Compound 76-1

[0624] Compound 36 (170 mg, 0.497 mmol), aniline (69.75 mg, 0.749 mmol), and DBU (83.6 mg, 0.549 mmol) were dissolved in methanol (2 mL) and stirred at 50°C for 2 hours. After the reaction was complete as monitored by TLC, ice water (10 mL) was added to the reaction system and extracted with ethyl acetate (3×10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (methanol / dichloromethane (v / v) = 1 / 30) and the fraction with Rf = 0.3-0.4 was collected to obtain compound 76-1 (198.6 mg, 91.8% yield) as a white solid. ESI [M+H] + =435.1.

[0625] 2. Preparation of target compound 76

[0626] Ethyl chloroformate (45 mg, 0.415 mmol) was added to a solution of 76-1 (90.1 mg, 0.207 mmol) and cesium carbonate (135 mg, 0.414 mmol) in acetonitrile (2 mL) and stirred at room temperature for 30 minutes. After the reaction was complete as monitored by TLC, ice water (10 mL) was added to the reaction system and extracted with ethyl acetate (3×10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (methanol / dichloromethane (v / v) = 1 / 30) and the fraction with Rf = 0.3-0.4 was collected to obtain compound 76 (35.66 mg, 34.0% yield) as a white solid. ESI [M+H] + =507.1.

[0627] 1 H NMR(400MHz, DMSO-d6)δ8.59–8.53(m,1H),7.90(td,J=7.8,1.8Hz,1H),7.80(dd,J=8.8, 2.4Hz,1H),7.71(d,J=7.9Hz,1H),7.53–7.49(m,2H),7.48(d,J=2.3Hz,1H),7.38–7.32( m,2H),7.31–7.29(m,2H),7.25–7.21(m,1H),4.48–4.34(m,1H),4.29(dd,J=14.2,3.8Hz ,1H),4.07–3.95(m,2H),3.90(dd,J=9.3,3.8Hz,1H),3.28(s,3H),1.04(t,J=7.1Hz,3H).

[0628] 3. Preparation of target compound 77

[0629] At 0°C, propionyl chloride (28.2 mg, 0.305 mmol) was added dropwise to a solution of 76-1 (88.5 mg, 0.203 mmol) and triethylamine (41.1 mg, 0.406 mmol) in dichloromethane (2 mL). The mixture was allowed to warm to room temperature and stirred for 1 hour. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system and extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (methanol / dichloromethane (v / v) = 1 / 50) and the fraction with Rf = 0.3-0.4 was collected to obtain compound 77 (34.48 mg, 34.5% yield) as a white solid. ESI [M+H] + =491.1.

[0630] 1 H NMR (400MHz, DMSO-d6) δ8.56(d,J=4.7Hz,1H),7.89(t,J=7.8Hz,1H),7.81(dd,J=8.8,2.1Hz,1H),7.69(d,J=7.7Hz,1H),7.55–7.47(m,3H),7.46–7.4 2(m,2H),7.38–7.34(m,3H),4.46(d,J=11.2Hz,1H),4.27–4.20(m,1H),3. 96(d,J=6.8Hz,1H),3.27(s,3H),1.99–1.85(m,2H),0.85(t,J=7.1Hz,3H).

[0631] Example 36 Preparation of Compounds 79 and 80

[0632]

[0633] The preparation method of compounds 79 and 80 is similar to that of compound 76 in Example 35. Compound 36 is reacted with the corresponding amine to obtain intermediate 79-1, which is then reacted with ethyl chloroformate to obtain the target compound.

[0634] Compound 79: 68.0 mg, ESI [M+H] + =471.1.

[0635] 1H NMR(400MHz, DMSO-d6)δ8.58(d,J=4.7Hz,1H),8.05–7.94(m,2H),7.82(dd,J=8.9,2.4Hz,1H),7.55–7.51(m,3H),4.15–3 .90(m,4H),3.80–3.77(m,1H),3.31(s,3H),2.59–2.55(m,1H),1.10–1.06(m,3H),0.81–0.78(m,2H),0.68–0.64(m,2H).

[0636] Compound 80: 68.0 mg, ESI [M+H] + =445.0.

[0637] 1 H NMR(400MHz, DMSO-d6)δ8.59(d,J=4.1Hz,1H),8.08–8.05(m,1H),7.97(td,J=7.7,1.7Hz,1H),7.83(dd,J= 8.9,2.4Hz,1H),7.57–7.50(m,3H),4.06–3.81(m,5H),3.31(s,3H),3.03-2.93(m,3H),1.16-0.99(m,3H).

[0638] Example 37 Preparation of Compound 81

[0639]

[0640] 1. Preparation of Compound 81-1

[0641] Compound 36 (376.2 mg, 1.10 mmol), 1-Boc-4-aminopiperidine (440 mg, 2.20 mmol), and DBU (183.7 mg, 1.21 mmol) were dissolved in methanol (4 mL) and stirred at 50°C for 1 hour. After the reaction was complete as monitored by TLC, ice water (15 mL) was added to the reaction system and extracted with ethyl acetate (3 × 15 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (methanol / dichloromethane (v / v) = 1 / 10) and the fraction with Rf = 0.3-0.4 was collected to obtain compound 81-1 (408 mg, yield 68.4%) as a white solid. ESI [M+H] + =542.2.

[0642] 2. Preparation of Compound 81-2

[0643] At 0°C, propionyl chloride (83.25 mg, 0.90 mmol) was added dropwise to a solution of 81-1 (408 mg, 0.752 mmol) and DIEA (193.9 mg, 1.50 mmol) in THF (4 mL). The mixture was allowed to warm to room temperature and stirred for 1 hour. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system and extracted with ethyl acetate (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 to 1 / 10) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 81-2 (438 mg, 97.3% yield) as a white solid. ESI [M+H] + =598.3.

[0644] 3. Preparation of Compound 81-3

[0645] Trifluoroacetic acid (5 mL) was added to a solution of 81-2 (438 mg, 0.732 mmol) in dichloromethane (10 mL) and stirred at room temperature for 30 minutes. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The residue was dissolved in water, the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution, and then extracted with dichloromethane (3×15 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (methanol / dichloromethane (v / v) = 1 / 10) and the fraction with Rf = 0.3-0.4 was collected to obtain compound 81-3 (348 mg, yield 95.4%) as a white solid. ESI [M+H] + =498.2.

[0646] 4. Preparation of target compound 81

[0647] Methyl 3-bromopropionate (100.8 mg, 0.604 mmol) was added to a solution of 81-3 (200 mg, 0.401 mmol) and DIEA (156 mg, 1.21 mmol) in dichloromethane (3 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (methanol / dichloromethane (v / v) = 1 / 10) and the fraction with Rf = 0.3-0.4 was collected to obtain compound 81 (46.8 mg, 20.0% yield) as a white solid. ESI [M+H] + =584.1.

[0648] 1 H NMR (400MHz, DMSO-d6) δ8.58(d,J=4.6Hz,1H),8.08(d,J=7.7Hz,0.5H),7.98(t,J=7.9Hz,1H),7.91(d,J=8.0Hz,0.5H),7.82(td,J=8. 6,2.3Hz,1H),7.57–7.50(m,2H),7.49(d,J=2.1Hz,1H),4.38–4.28(m,0.5H),4.05–3.95(m,1H),3.93–3.80(m,1H),3.79–3.70(m,1H), 3.63–3.60(m,0.5H),3.60(s,1.5H),3.54(s,1.5H),3.31(s,3H),2.97–2.90(m,1H),2.85–2.66(m,2H),2.62–2.55(m,1H),2.41–2.30 (m,3H),2.09–2.00(m,1H),1.98–1.69(m,3H),1.65–1.50(m,1H),1.45–1.31(m,2H),0.99(t,J=8.0Hz,1.5H),0.88(t,J=8.0Hz,1.5H).

[0649] Example 38 Preparation of Compound 82

[0650]

[0651] 1. Preparation of Compound 82-1

[0652] Dissolve N-tert-Butyloxycarbonyl-4-piperidone (10.0 g, 50.2 mmol) and cyclopropylamine (5.73 g, 100.4 mmol) in dichloromethane (150 mL) and stir at room temperature for 2 hours. Add NaBH(OAc)₃ (31.9 g, 150.5 mmol) to the reaction system and continue stirring at room temperature for 10 hours. After the reaction is complete as monitored by TLC, add saturated aqueous sodium bicarbonate (100 mL) to the reaction system and extract with ethyl acetate (3 x 100 mL). The organic phase is washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 to 1 / 2) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). The fractions with Rf = 0.3 to 0.4 were collected to obtain compound 82-1 (9.9 g, yield 82.1%) as a white solid. ESI [M+H] + =241.1.

[0653] 2. Preparation of Compound 82-2

[0654] Propionyl chloride (920 mg, 9.94 mmol) was added to a solution of 82-1 (1.20 g, 5.0 mmol) and DIEA (1.94 g, 15.0 mmol) in dry tetrahydrofuran (25 mL) and stirred at room temperature for 2 hours. After completion of the reaction as monitored by TLC, ice water (50 mL) was added to the reaction system and extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 to 1 / 3) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3). The fraction with Rf = 0.3 to 0.4 was collected to obtain compound 82-2 (1.33 g, yield 89.9%) as a colorless oil. ESI [M+H] + =297.2.

[0655] 3. Preparation of Compound 82-3

[0656] Trifluoroacetic acid (2.57 g, 22.5 mmol) was added to a solution of 82-2 (1.33 g, 4.49 mmol) in dichloromethane (10 mL) and stirred at room temperature for 3 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The residue was dissolved in water, the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate, and then extracted with ethyl acetate (3×50 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100-1 / 10) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). The fraction with Rf = 0.3-0.4 was collected to obtain compound 82-3 (684 mg, yield 77.7%) as a colorless oil. ESI [M+H] + =197.1.

[0657] 4. Preparation of target compound 82

[0658] Compound 36 (100 mg, 0.292 mmol), 82-3 (86.0 mg, 0.438 mmol), and DBU (49.0 mg, 0.322 mmol) were dissolved in methanol (2 mL) and stirred at 50°C for 1 hour. After the reaction was complete as monitored by TLC, ice water (15 mL) was added to the reaction system and extracted with ethyl acetate (3×15 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 2 / 1) and the fraction with Rf = 0.2-0.3 was collected to obtain compound 82 (77.7 mg, 49.4% yield) as a white solid. ESI [M+H] + =538.2.

[0659] 1 H NMR(400MHz,DMSO-d6)δ8.97–8.52(m,1H),8.33–7.79(m,4H),7.71–7.46(m,2H),3.90–3.71(m,1H),3.60–3.46(m,1H),3.31(s,3H),3.30–3.2 8(m,1H),3.25–2.75(m,3H),2.60–2.52(m,1H),2.49–2.33(m,3H),2.35 -1.75(m,3H),1.52-1.25(m,2H),1.02–0.90(m,3H),0.81–0.71(m,4H).

[0660] Example 39 Preparation of Compounds 83 and 88

[0661]

[0662] 1. Preparation of Compound 88-1

[0663] NaH (2.146 g, 60%, 53.6 mmol) was slowly added to a solution of BOC-L-serine (5.0 g, 24.4 mmol) in dry DMF (60 mL) at 0°C and stirred for 30 minutes. Benzyl bromide (4.67 g, 27.3 mmol) was added to the reaction system, which was naturally warmed to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water (100 mL), the pH was adjusted to 6-7 with 1 mol / L dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (3 × 100 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 10) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 88-1 (6.8 g, yield 94.5%) as a colorless oil. ESI [M+H] + =296.2.

[0664] 2. Preparation of Compound 88-2

[0665] Compound 1-1 (2.76 g, 9.96 mmol) and compound 88-1 (4.42 g, 15.0 mmol) were dissolved in dichloromethane (30 mL). A solution of DCC (3.09 g, 15.0 mmol) in dichloromethane (10 mL) was added dropwise at -10°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, methyl tert-butyl ether (40 mL) was added to the reaction system and stirred for 5 minutes. The reaction system was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 2) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 88-2 (4.857 g, 88.0% yield) as a white solid. ESI [M+H]+ = 554.1.

[0666] 3. Preparation of Compound 88-3

[0667] Trifluoroacetic acid (20 mL) was added to a solution of 88-2 (4.857 g, 8.76 mmol) in dichloromethane (40 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 2 hours. After completion of the reaction as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was used directly in the next reaction without purification.

[0668] 4. Preparation of Compound 88-4

[0669] The crude compound from the previous step was dissolved in acetonitrile (50 mL), sodium bicarbonate (22.1 g, 263.1 mmol) was added, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete as monitored by TLC, the reaction solution was filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). The fractions with Rf = 0.2 to 0.3 were collected to obtain compound 88-4 as a white solid (2.491 g, two-step yield 65.2%). ESI [M+H] + =436.1.

[0670] 5. Preparation of target compound 83

[0671] NaH (275 mg, 60%, 6.87 mmol) was added to a solution of 88-4 (2.49 g, 5.71 mmol) in dry DMF (30 mL) at -20°C and stirred for 30 minutes. Iodomethane (975 mg, 6.87 mmol) was added to the reaction system and stirring continued at -20°C for 1 hour. After the reaction was complete as monitored by TLC, the reaction solution was poured into ice water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 83 (2.47 g, 96.1% yield) as a white solid. ESI [M+H] + =450.4.

[0672] 1 H NMR (400MHz, DMSO-d6) δ8.61(d,J=4.6Hz,1H),8.10(d,J=7.9Hz,1H),7.99(td,J=7.8,1.7Hz,1H),7.84(dd,J=8.8,2.4Hz,1H),7.56–7.53(m,3H) ,7.37–7.34(m,4H),7.32–7.26(m,1H),4.62(s,2H),4.25(dd,J=9.6,6.0 Hz, 1H), 4.08 (dd, J=9.6, 6.9Hz, 1H), 3.87 (t, J=6.3Hz, 1H), 3.32 (s, 3H).

[0673] 6. Preparation of Compound 37

[0674] At 0°C, aluminum trichloride (7.19 g, 53.9 mmol) was slowly added to a solution of 83 (2.43 g, 5.40 mmol) in dichloromethane (50 mL). The mixture was allowed to warm to room temperature and stirred for 3 hours. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water (50 mL), filtered, and the filtrate extracted with dichloromethane (3 × 60 mL). The organic phase was washed with 5% aqueous sodium bicarbonate solution, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 10) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 37 (1.15 g, 59.2% yield) as a colorless oil. ESI [M+H] + =360.2.

[0675] 7. Preparation of target compound 88

[0676] NaH (67 mg, 60%, 1.67 mmol) was slowly added to a solution of 37 (200 mg, 0.555 mmol) in dry DMF (3 mL) at 0°C and stirred for 30 minutes. Ethyl bromoacetate (186 mg, 1.11 mmol) was added to the reaction system, the temperature was raised to 50°C, and the mixture was stirred for 12 hours. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) and the fraction with Rf = 0.2-0.3 was collected to obtain compound 88 (11.5 mg, 4.6% yield) as a white solid. ESI [M+H] + =446.2.

[0677] 1 H NMR (400MHz, DMSO-d6) δ8.59(d,J=4.2Hz,1H),8.08(d,J=7.6Hz,1H),7.99-7.95(m,1H),7.83(dd,J=8.8,2.5Hz,1H),7.56-7.51(m,3H),4.2 7(dd,J=10.3,6.0Hz,1H),4.23(s,2H),4.15-4.14(m,1H),4.10(q,J=7.3Hz,2H),3.88(t,J=6.4Hz,1H),3.30(s,3H),1.18(t,J=7.1Hz,3H).

[0678] Example 40 Preparation of Compounds 84-87

[0679]

[0680] Compounds 84-87 were prepared similarly to compound 83 in Example 39, using BOC-L-serine and various substituted benzyl bromides to yield the corresponding carboxylic acids. The carboxylic acids were condensed with compound 1-1, followed by Boc removal, ring closure, and N-methylation to yield the target compounds.

[0681] Compound 84: 18.9 mg, ESI [M+H] + =464.1.

[0682] 1 H NMR(400MHz,DMSO-d6)δ8.60(d,J=4.2Hz,1H),8.09(d,J=7.9Hz,1H),7.99(td ,J=7.7,1.7Hz,1H),7.83(dd,J=8.8,2.4Hz,1H),7.57–7.50(m,3H),7.24(d,J =7.9Hz,2H),7.16(d,J=7.8Hz,2H),4.56(s,2H),4.22(dd,J=9.7,6.0Hz,1H), 4.05(dd,J=9.7,6.8Hz,1H),3.83(t,J=6.4Hz,1H),3.31(s,3H),2.30(s,3H).

[0683] Compound 85: 13.5 mg, ESI [M+H] + =484.0.

[0684] 1 H NMR (400MHz, DMSO-d6) δ8.60(d,J=4.1Hz,1H),8.09(d,J=7.9Hz,1H),7.99(td,J=7.7,1.7Hz,1H),7.83(dd,J=8.8,2.4Hz,1H),7.56–7. 53(m,3H),7.49–7.34(m,4H),4.61(s,2H),4.25(dd,J=9.7,6.0Hz,1H),4.07(dd,J=9.6,6.8Hz,1H),3.87(t,J=6.4Hz,1H),3.32(s,3H).

[0685] Compound 86: 24.2 mg, ESI [M+H] + =480.1.

[0686] 1H NMR(400MHz,DMSO-d6)δ8.60(d,J=4.2Hz,1H),8.09(d,J=7.9Hz,1H),7.99(td ,J=7.8,1.7Hz,1H),7.83(dd,J=8.8,2.4Hz,1H),7.55-7.52(m,3H),7.28(d,J =8.6Hz,2H),6.91(d,J=8.6Hz,2H),4.53(s,2H),4.21(dd,J=9.6,6.1Hz,1H), 4.03(dd,J=9.6,6.8Hz,1H),3.82(t,J=6.4Hz,1H),3.75(s,3H),3.31(s,3H).

[0687] Compound 87: 51.2 mg, ESI [M+H] + =492.2.

[0688] 1 H NMR (400MHz, DMSO-d6) δ8.60(d,J=4.3Hz,1H),8.09(d,J=7.9Hz,1H),7.98(td,J=7.7 ,1.7Hz,1H),7.83(dd,J=8.8,2.4Hz,1H),7.57–7.50(m,3H),7.27(d,J=8.1Hz,2H),7. 22(d,J=8.1Hz,2H),4.56(s,2H),4.21(dd,J=9.6,6.0Hz,1H),4.05(dd,J=9.6,6.9Hz, 1H),3.85(t,J=6.4Hz,1H),3.31(s,3H),2.94–2.83(m,1H),1.21(s,3H),1.19(s,3H).

[0689] Example 41 Preparation of Compound 91

[0690]

[0691] 37 (300 mg, 0.833 mmol), p-nitrobenzyl bromide (198.6 mg, 0.919 mmol), and silver oxide (232.4 mg, 1.00 mmol) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 18 hours. After the reaction was complete as monitored by TLC, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) and the fraction with Rf = 0.2-0.3 was collected to obtain compound 91 (21.7 mg, 5.3% yield) as a white solid. ESI [M+H] + =495.1.

[0692] 1 H NMR (400MHz, DMSO-d6) δ8.61(d,J=4.2Hz,1H),8.23(d,J=8.7Hz,2H),8.11(d,J=7.9Hz,1H),8.01-7.98(m,1H),7.84(dd,J=8.9,2.3Hz,1H),7.6 5(d,J=8.7Hz,2H),7.57-7.54(m,3H),4.79(s,2H),4.30(dd,J=9.7,5.9Hz,1H),4.14(dd,J=9.7,6.9Hz,1H),3.93(t,J=6.4Hz,1H),3.33(s,3H).

[0693] Example 42 Preparation of Compound 95

[0694]

[0695] 1. Preparation of Compound 95-1

[0696] Lithium bis(trimethylsilyl)amide (5.98 mL, 1 mol / L, 5.98 mmol) was slowly added dropwise to a solution of 88-4 (2.24 g, 5.13 mmol) in tetrahydrofuran (20 mL) at -30°C and stirred for 1 hour. Dimorpholinophosphinic chloride (2.99 g, 11.7 mmol) was added portionwise and stirred at -10°C for 4 hours. Isopropanolamine (1.68 g, 22.4 mmol) was added dropwise to the reaction system, allowed to warm to room temperature, and stirred for 12 hours. After completion of the reaction as monitored by TLC, ice water (20 mL) was added to the reaction system and extracted with ethyl acetate (3 × 20 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 95-1 (1.6 g, yield 63.2%) as a white solid. ESI [M+H] + =493.1.

[0697] 5. Preparation of target compound 95

[0698] Dess-Martin reagent (3.5 g, 8.25 mmol) was added to a solution of 95-1 (1.6 g, 3.24 mmol) in acetone (20 mL) and stirred at room temperature for 12 hours. After the reaction was complete as monitored by TLC, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). The fraction with Rf = 0.2 to 0.3 was collected to obtain compound 95 (1.164 g, yield 75.8%) as a white solid. ESI [M+H] + =473.1.

[0699] 1 H NMR (400MHz, DMSO-d6) δ8.56–8.52(m,1H),8.08(d,J=7.9Hz,1H),7.95(td,J =7.7,1.8Hz,1H),7.88(dd,J=8.7,2.3Hz,1H),7.66–7.63(m,2H),7.51–7.48 (m,1H),7.43–7.32(m,4H),7.30–7.26(m,1H),6.80(d,J=0.9Hz,1H),4.68(s ,2H),4.40–4.32(m,2H),4.23(dd,J=7.5,5.3Hz,1H),2.30(d,J=0.8Hz,3H).

[0700] Example 43 Preparation of Compound 96

[0701]

[0702] 1. Preparation of Compound 96-1

[0703] Lithium bis(trimethylsilyl)amide (2.7 mL, 1 mol / L, 2.7 mmol) was slowly added dropwise to a solution of 84-4 (1.0 g, 2.22 mmol) in tetrahydrofuran (10 mL) at -30°C and stirred for 1 hour. Dimorpholinophosphinic chloride (1.34 g, 5.26 mmol) was added portionwise and stirred at -10°C for 4 hours. Isopropanolamine (752 mg, 10.0 mmol) was added dropwise to the reaction system, allowed to warm to room temperature, and stirred for 12 hours. After completion of the reaction as monitored by TLC, ice water (20 mL) was added to the reaction system and extracted with ethyl acetate (3 × 20 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 20). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 96-1 (811 mg, yield 72.0%) as a white solid. ESI [M+H] + =507.1.

[0704] 2. Preparation of target compound 96

[0705] Dess-Martin reagent (1.698 g, 4.0 mmol) was added to a solution of 96-1 (811 mg, 1.60 mmol) in acetone (20 mL) and stirred at room temperature for 12 hours. After the reaction was complete as monitored by TLC, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). The fraction with Rf = 0.2 to 0.3 was collected to obtain compound 96 (228.7 mg, yield 29.4%) as a white solid. ESI [M+H] + =487.2.

[0706] 1H NMR(400MHz, DMSO-d6)δ8.56(d,J=4.2Hz,1H),8.09(d,J=7.9Hz,1H),7.97(td,J=7.8, 1.7Hz,1H),7.90(dd,J=8.7,2.3Hz,1H),7.67(d,J=8.7Hz,1H),7.64(d,J=2.3Hz,1H),7 .51(dd,J=6.5,4.9Hz,1H),7.28(d,J=7.9Hz,2H),7.17(d,J=7.8Hz,2H),6.81(s,1H), 4.64(s,2H),4.44–4.31(m,2H),4.22(dd,J=7.3,5.4Hz,1H),2.31(s,3H),2.30(s,3H).

[0707] Example 44 Preparation of Compounds 97, 97B and 97D

[0708]

[0709] 1. Preparation of Compound 97-1

[0710] At 0°C, aluminum trichloride (2.44 g, 18.3 mmol) was slowly added to a solution of 95 (866 mg, 1.83 mmol) in dichloromethane (50 mL). The mixture was allowed to warm to room temperature and stirred for 3 hours. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water (50 mL), filtered, and the filtrate extracted with dichloromethane (3 × 60 mL). The organic phase was washed with 5% aqueous sodium bicarbonate solution, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 10) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 97-1 (620 mg, 88.4% yield) as a white solid. ESI [M+H] + =383.1.

[0711] 2. Preparation of target compound 97

[0712] Isobutyryl chloride (125 mg, 1.17 mmol) was added dropwise to a solution of 97-1 (300 mg, 0.783 mmol) and triethylamine (159 mg, 1.57 mmol) in dichloromethane (3 mL) at -10°C and stirred for 2 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system and extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.4 to 0.5 were collected to obtain compound 97 (208 mg, 58.6% yield) as a white solid. ESI [M+H] + =453.1.

[0713] 1 H NMR (400MHz, DMSO-d6) δ8.57–8.53(m,1H),8.04(d,J=7.9Hz,1H),7.95(td,J=7.7,1.7Hz,1H),7.90( dd,J=8.7,2.3Hz,1H),7.68(d,J=8.7Hz,1H),7.64(d,J=2.3Hz,1H),7.50(ddd,J=7.5,4.8,1.2Hz,1H ),6.83(d,J=1.1Hz,1H),4.93(dd,J=10.9,8.0Hz,1H),4.84(dd,J=11.0,5.4Hz,1H),4.36(dd,J=7.9 ,5.4Hz,1H),2.60-2.53(m,1H),2.31(d,J=0.7Hz,3H),1.11(d,J=7.0Hz,3H),1.09(d,J=7.0Hz,3H).

[0714] 3. Preparation of target compound 97B

[0715] Compound 97 (109.8 mg, 0.242 mmol) was dissolved in acetone (10 mL), and a solution of sulfuric acid (23.7 mg, 0.242 mmol) in acetone (1 mL) was added dropwise. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was filtered, and the filter cake was dried under reduced pressure to obtain compound 97B (85.5 mg, 64.0% yield) as a white solid. ESI [M+H] + =453.1.

[0716] 1H NMR(400MHz, DMSO-d6)δ8.59(d,J=4.7Hz,1H),8.08(d,J=7.9Hz,1H),8.04–7.96(m, 2H),7.80(d,J=8.7Hz,1H),7.75(d,J=2.2Hz,1H),7.55(dd,J=6.3,4.9Hz,1H),7.20 (s,1H),4.95(dd,J=11.0,7.3Hz,1H),4.87(dd,J=11.1,6.0Hz,1H),4.58(t,J=6.7H z,1H),2.60–2.52(m,1H),2.38(s,3H),1.14(d,J=5.2Hz,3H),1.12(d,J=5.2Hz,3H).

[0717] 4. Preparation of target compound 97D

[0718] Compound 97 (27.2 mg, 0.06 mmol) was dissolved in ethyl acetate (1 mL), and a solution of benzenesulfonic acid (9.47 mg, 0.06 mmol) in ethanol (0.1 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filter cake was dried under reduced pressure to obtain compound 97D (10.3 mg, yield 28.1%) as a white solid. ESI [M+H] + =453.1.

[0719] 1 H NMR(400MHz, DMSO-d6)δ8.57(d,J=4.6Hz,1H),8.06(d,J=7.8Hz,1H),8.01–7.93(m,2H),7. 77(d,J=8.7Hz,1H),7.72(d,J=2.2Hz,1H),7.60–7.58(m,2H),7.56–7.51(m,1H),7.35–7.2 8(m,3H),7.14(s,1H),4.93(dd,J=11.1,7.4Hz,1H),4.85(dd,J=11.1,6.0Hz,1H),4.54(t, J=6.6Hz,1H),2.61–2.54(m,1H),2.35(s,3H),1.11(d,J=5.6Hz,3H),1.10(d,J=5.6Hz,3H).

[0720] Example 45 Preparation of Compounds 98 and 98D

[0721]

[0722] Compounds 98 and 98D were prepared similarly to compounds 97 and 97D in Example 44, using compound 97-1 and propionyl chloride as raw materials to prepare 98, which was then reacted with benzenesulfonic acid to prepare 98D.

[0723] Compound 98: 73.1 mg, ESI [M+H] + =439.0.

[0724] 1 H NMR (400MHz, DMSO-d6) δ8.55(ddd,J=4.8,1.7,0.9Hz,1H),8.06(d,J=7.9Hz,1H),7.95(t d,J=7.7,1.8Hz,1H),7.90(dd,J=8.7,2.3Hz,1H),7.68(d,J=8.7Hz,1H),7.66(d,J=2.3H z,1H),7.50(ddd,J=7.5,4.8,1.2Hz,1H),6.83(d,J=1.1Hz,1H),4.98–4.82(m,2H),4.34 (dd,J=7.5,5.7Hz,1H),2.38–2.32(m,2H),2.31(d,J=0.8Hz,3H),1.05(t,J=7.5Hz,3H).

[0725] Compound 98D: 9.3 mg, ESI [M+H] + =439.1.

[0726] 1 H NMR (400MHz, DMSO-d6) δ8.57(d,J=4.0Hz,1H),8.08(d,J=8.0Hz,1H),8.01–7.93(m,2H),7.77(d,J=8.7Hz,1H),7.73(d,J=2.3Hz,1H),7.62–7.5 7(m,2H),7.56–7.50(m,1H),7.34–7.26(m,3H),7.16(s,1H),4.94–4.85 (m,2H),4.53(t,J=6.3Hz,1H),2.39–2.32(m,5H),1.05(t,J=7.5Hz,3H).

[0727] Example 46 Preparation of Compound 99

[0728]

[0729] The preparation method of target compound 99 is similar to that of compound 97 in Example 44, using compound 97-1 and acetyl chloride as raw materials.

[0730] Compound 99: 42.8 mg, ESI [M+H] + =425.0.

[0731] 1 H NMR(400MHz,DMSO-d6)δ8.55(ddd,J=4.8,1.7,0.9Hz,1H),8.08–8.06(m,1H),7 .95(td,J=7.7,1.8Hz,1H),7.90(dd,J=8.7,2.3Hz,1H),7.68(d,J=8.7Hz,1H), 7.66(d,J=2.3Hz,1H),7.50(ddd,J=7.5,4.8,1.2Hz,1H),6.83(d,J=1.1Hz,1H) ,4.95–4.84(m,2H),4.34(t,J=6.6Hz,1H),2.31(d,J=0.8Hz,3H),2.05(s,3H).

[0732] Example 47 Preparation of Compound 100

[0733]

[0734] Benzenesulfonyl chloride (691.1 mg, 3.91 mmol) was added to a solution of 97-1 (300 mg, 0.783 mmol), pyridine (302.3 mg, 3.82 mmol), and DMAP (287.4 mg, 2.35 mmol) in dichloromethane (5 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100-1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 20). Fractions with Rf = 0.3-0.4 were collected to obtain a light yellow solid compound 100 (126.4 mg, yield 30.9%). ESI [M+H] + =523.1.

[0735] 1H NMR (400MHz, DMSO-d6) δ8.55(d,J=4.2Hz,1H),8.03(d,J=7.5Hz,2H),7.97(t,J=7.0Hz,1H),7.92–7.88(m,2H),7.83(t,J=7.4Hz,1H),7.73(t,J=7. 7Hz,2H),7.66(d,J=8.7Hz,1H),7.63(d,J=2.2Hz,1H),7.55–7.49(m,1H), 6.81(s,1H),4.94–4.79(m,2H),4.42(dd,J=7.8,5.0Hz,1H),2.30(s,3H).

[0736] Example 48 Preparation of Compounds 101 and 101D

[0737]

[0738] 1. Preparation of target compound 101

[0739] 3-Oxetanecarboxylic acid (80 mg, 0.784 mmol), DCC (162 mg, 0.785 mmol), and DMAP (192 mg, 1.57 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 15 minutes. 97-1 (200 mg, 0.522 mmol) was added to the reaction system and stirring continued at room temperature for 12 hours. After the reaction was complete as monitored by TLC, methyl tert-butyl ether (2 mL) was added to the reaction system, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 20). Fractions with Rf = 0.3 to 0.4 were collected to obtain Compound 101 (81.5 mg, 33.4% yield) as a white solid. ESI [M+H] + =467.1.

[0740] 1H NMR (400MHz, DMSO-d6) δ8.55(d,J=4.0Hz,1H),8.05(d,J=7.9Hz,1H),7.95(td,J=7.7,1. 8Hz,1H),7.90(dd,J=8.7,2.3Hz,1H),7.68(d,J=8.7Hz,1H),7.65(d,J=2.3Hz,1H),7.50( ddd,J=7.5,4.8,1.2Hz,1H),6.84(d,J=1.1Hz,1H),5.04–4.91(m,2H),4.74–4.69(m,2H), 4.67–4.62(m,2H),4.40(dd,J=7.4,5.7Hz,1H),3.96–3.90(m,1H),2.31(d,J=0.8Hz,3H).

[0741] 2. Preparation of target compound 101D

[0742] Compound 101 (81.5 mg, 0.174 mmol) was dissolved in ethyl acetate (1 mL), and a solution of benzenesulfonic acid (27.8 mg, 0.176 mmol) in ethanol (0.1 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filter cake was dried under reduced pressure to obtain Compound 101D (60.8 mg, 55.7% yield) as a white solid. ESI [M+H] + =467.0.

[0743] 1 H NMR(400MHz,DMSO-d6)δ8.56(d,J=4.0Hz,1H),8.06(d,J=7.9Hz,1H),8.00–7.9 1(m,2H),7.75(d,J=8.7Hz,1H),7.70(d,J=2.3Hz,1H),7.62–7.56(m,2H),7.56 –7.47(m,1H),7.35–7.25(m,3H),7.08(s,1H),5.04–4.91(m,2H),4.74–4.69(m ,2H),4.68–4.63(m,2H),4.53(t,J=6.5Hz,1H),3.96–3.90(m,1H),2.34(s,3H).

[0744] Example 49 Preparation of Compound 102

[0745]

[0746] The preparation method of compound 102 is similar to that of compound 101 in Example 48, using compound 97-1 and 2-fluoropropionic acid as raw materials.

[0747] Compound 102: 61.6 mg, ESI [M+H] + =457.3.

[0748] 1 H NMR(400MHz,DMSO-d6)δ8.57(d,J=4.1Hz,1H),8.07(dd,J=7.9,3.9Hz,1H),8 .00–7.96(m,1H),7.93(dd,J=8.7,2.3Hz,1H),7.71(d,J=8.7Hz,1H),7.67(d, J=2.2Hz,1H),7.56–7.48(m,1H),6.86(d,J=1.0Hz,1H),5.38–5.16(m,1H),5. 12–4.94(m,2H),4.45(dd,J=7.3,5.7Hz,1H),2.34(s,3H),1.57–1.47(m,3H).

[0749] Example 50 Preparation of Compounds 103 and 103D

[0750]

[0751] 1. Preparation of target compound 103

[0752] Ethyl chloroformate (128 mg, 1.18 mmol) was added dropwise to a solution of 97-1 (150 mg, 0.391 mmol), pyridine (90.7 mg, 1.15 mmol), and DMAP (48 mg, 0.393 mmol) in dichloromethane (2 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100-1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 20). Fractions with Rf = 0.3-0.4 were collected to obtain compound 103 (138 mg, yield 77.4%) as a white solid. ESI [M+H] + =455.0.

[0753] 1H NMR (400MHz, DMSO-d6) δ8.55 (dd, J=3.9, 0.8Hz, 1H), 8.05 (d, J=7.9Hz, 1H), 7.9 5(td,J=7.7,1.7Hz,1H),7.90(dd,J=8.7,2.3Hz,1H),7.69–7.66(m,2H),7.51(d dd,J=7.5,4.8,1.2Hz,1H),6.83(d,J=1.1Hz,1H),4.97–4.92(m,2H),4.39(t,J= 6.6Hz, 1H), 4.15 (q, J = 7.0Hz, 2H), 2.31 (d, J = 0.8Hz, 3H), 1.23 (t, J = 7.1Hz, 3H).

[0754] 2. Preparation of target compound 103D

[0755] Compound 103 (125 mg, 0.275 mmol) was dissolved in ethyl acetate (4 mL), and a solution of benzenesulfonic acid (43.6 mg, 0.276 mmol) in ethyl acetate (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filter cake was dried under reduced pressure to obtain Compound 103D (120 mg, yield 71.2%) as a white solid. ESI [M+H] + =455.0.

[0756] 1 H NMR (400MHz, DMSO-d6) δ8.61–8.56(m,1H),8.08(d,J=7.9Hz,1H),8.03–7.94(m,2H),7.80(d,J=8.7Hz,1H),7.76(d,J=2.3Hz,1H),7.62–7.49 (m,3H),7.36–7.26(m,4H),4.95(d,J=6.7Hz,2H),4.64(t,J=6.5Hz,1H),4.17(q,J=7.1Hz,2H),2.37(d,J=0.7Hz,3H),1.23(t,J=7.1Hz,3H).

[0757] Example 51 Preparation of Compound 104

[0758]

[0759] The preparation method of compound 104 is similar to that of compound 103 in Example 50, using compound 97-1 and isopropyl chloroformate.

[0760] Compound 104: 68.8 mg, ESI [M+H] + =469.0.

[0761] 1 H NMR (400MHz, DMSO-d6) δ8.55(dd,J=3.9,0.8Hz,1H),8.05(d,J=7.9Hz,1H),7.95(td,J =7.7,1.7Hz,1H),7.90(dd,J=8.7,2.3Hz,1H),7.69–7.66(m,2H),7.51(ddd,J=7.5,4. 8,1.2Hz,1H),6.83(d,J=1.1Hz,1H),5.00–4.88(m,2H),4.86–4.75(m,1H),4.39(dd,J =7.4,5.7Hz,1H),2.31(d,J=0.7Hz,3H),1.25(d,J=6.2Hz,3H),1.23(d,J=6.2Hz,3H).

[0762] Example 52 Preparation of Compound 105

[0763]

[0764] At 0°C, p-nitrophenyl chloroformate (157 mg, 0.779 mmol) was added to a solution of 97-1 (100 mg, 0.261 mmol), pyridine (61.7 mg, 0.780 mmol), and DMAP (63.6 mg, 0.521 mmol) in dichloromethane (2 mL). The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, dimethylamine (0.4 mL, 2 mol / L in THF, 0.8 mmol) and DIEA (33.6 mg, 0.26 mmol) were added to the reaction system and stirring continued at room temperature for 2 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 105 as a white solid (47.2 mg, yield 39.8%). ESI [M+H] + =454.3.

[0765] 1H NMR (400MHz, DMSO-d6) δ8.57(d,J=4.0Hz,1H),8.08(d,J=7.8Hz,1H),7.99–7.96(m,1H),7.92(dd,J=8.7,2.3Hz,1H),7.70(d,J=8.7 Hz,1H),7.67(d,J=2.3Hz,1H),7.56–7.48(m,1H),6.86(s,1H),4.91–4.83(m,2H),4.34(t,J=6.5Hz,1H),2.85(s,6H),2.33(s,3H).

[0766] Example 53 Preparation of Compounds 109 and 110

[0767]

[0768] 1. Preparation of target compound 109

[0769] NaH (60.6 mg, 60%, 1.51 mmol) was added to a solution of 88-4 (300 mg, 0.688 mmol) in dry DMF (5 mL) at 0°C and stirred for 30 minutes. 2-Diethylamino-1-bromoethane hydrobromide (216 mg, 0.828 mmol) was added to the reaction system, which was naturally warmed to room temperature and stirred for 2 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system and the mixture was extracted with ethyl acetate (3 × 30 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 10) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 109 (161 mg, 43.7% yield) as a white solid. ESI [M+H] + =535.4.

[0770] 1H NMR (400MHz, DMSO-d6) δ8.62(d,J=4.3Hz,1H),8.10(d,J=8.0Hz,1H),7.97(t,J=7.8Hz,1H),7.81 (dd,J=8.8,2.2Hz,1H),7.71(d,J=9.0Hz,1H),7.60(d,J=2.2Hz,1H),7.55–7.50(m,1H),7.36–7. 35(m,4H),7.31–7.28(m,1H),4.61(s,2H),4.32–4.14(m,2H),4.05(dd,J=9.5,6.6Hz,1H),3.84( t,J=6.5Hz,1H),3.74–3.71(m,1H),2.37–2.35(m,2H),2.25–2.22(m,4H),0.67(t,J=6.9Hz,6H).

[0771] 2. Preparation of Compound 110-1

[0772] At 0°C, aluminum trichloride (401 mg, 3.01 mmol) was slowly added to a solution of 109 (161 mg, 0.301 mmol) in dichloromethane (10 mL). The mixture was allowed to warm to room temperature and stirred for 3 hours. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water (10 mL), filtered, and the filtrate was extracted with dichloromethane (3 × 20 mL). The organic phase was washed with 5% aqueous sodium bicarbonate solution, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 10) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 110-1 (84 mg, 62.7% yield) as a white solid. ESI [M+H] + =445.1.

[0773] 3. Preparation of target compound 110

[0774] Propionyl chloride (13.0 mg, 0.141 mmol) was added dropwise to a solution of 110-1 (42 mg, 0.094 mmol) and triethylamine (19.1 mg, 0.189 mmol) in dichloromethane (2 mL) at 0°C and stirred for 2 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system and extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 110 (10.6 mg, 22.4% yield) as a syrupy solid. ESI [M+H] + =501.1.

[0775] 1 H NMR (400MHz, DMSO-d6) δ8.63(d,J=4.7Hz,1H),8.10(d,J=7.9Hz,1H),7.97(t,J=7.0Hz,1H),7.83(dd ,J=8.8,2.3Hz,1H),7.76(d,J=8.9Hz,1H),7.63(d,J=2.2Hz,1H),7.57–7.51(m,1H),4.73(dd,J=10.7 ,6.4Hz,1H),4.65(dd,J=10.8,6.7Hz,1H),4.20(dd,J=14.0,6.9Hz,1H),3.96(t,J=6.6Hz,1H),3.80 –3.70(m,1H),2.38(t,J=6.0Hz,2H),2.35–2.17(m,6H),1.03(t,J=7.5Hz,3H),0.66(t,J=7.1Hz,6H).

[0776] Example 54 Preparation of Compound 111

[0777]

[0778] The preparation method of target compound 111 is similar to that of compound 110 in Example 53, using 110-1 and isobutyryl chloride as raw materials.

[0779] Compound 111: 26.2 mg, ESI [M+H] + =515.2.

[0780] 1H NMR (400MHz, DMSO-d6) δ8.63(d,J=4.7Hz,1H),8.10(d,J=7.8Hz,1H),7.98(t,J=7.2Hz,1H),7.83 (dd,J=8.9,2.2Hz,1H),7.77(d,J=8.9Hz,1H),7.62(d,J=2.1Hz,1H),7.57–7.48(m,1H),4.73–4.6 4(m,2H),4.23–4.16(m,1H),3.99(t,J=6.6Hz,1H),3.84–3.64(m,1H),2.57–2.52(m,1H),2.42–2. 38(m,2H),2.32–2.13(m,4H),1.09(d,J=2.4Hz,3H),1.08(d,J=2.4Hz,3H),0.68(t,J=7.0Hz,6H).

[0781] Example 55 Preparation of Compounds 113 and 114

[0782]

[0783] 1. Preparation of Compound 114-1

[0784] 1-1 (2.76 g, 9.96 mmol) and Boc-L-aspartic acid 4-methyl ester (3.70 g, 15.0 mmol) were dissolved in dichloromethane (30 mL). A solution of DCC (3.09 g, 15.0 mmol) in dichloromethane (10 mL) was added dropwise at -10°C. The mixture was naturally warmed to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, methyl tert-butyl ether (40 mL) was added to the reaction system and stirred for 5 minutes. The reaction system was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 2) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 114-1 (3.356 g, 66.5% yield) as a white solid. ESI [M+H]+ = 506.1.

[0785] 2. Preparation of Compound 114-2

[0786] Trifluoroacetic acid (15 mL) was added to a solution of 114-1 (3.356 g, 6.63 mmol) in dichloromethane (30 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 2 hours. After completion of the reaction as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was used directly in the next reaction without purification.

[0787] 3. Preparation of Compound 114-3

[0788] The crude compound from the previous step was dissolved in acetonitrile (40 mL), sodium bicarbonate (31.8 g, 378.5 mmol) was added, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete as monitored by TLC, the reaction solution was filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 2) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). The fraction with Rf = 0.2 to 0.3 was collected to obtain compound 114-3 as a white solid (2.48 g, two-step yield 96.4%). ESI [M+H] + =388.1.

[0789] 4. Preparation of target compound 113

[0790] NaH (320 mg, 60%, 8.0 mmol) was slowly added to a solution of 114-3 (2.48 g, 6.39 mmol) in dry DMF (30 mL) at -20°C and stirred for 30 minutes. Iodomethane (1.136 g, 8.0 mmol) was added to the reaction system and stirring continued at -20°C for 1 hour. After the reaction was complete as monitored by TLC, the reaction solution was poured into ice water (60 mL) and extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) to obtain compound 113 (2.459 g, 95.7% yield) as a white solid. ESI [M+H] + =402.0.

[0791] 1 H NMR (400MHz, DMSO-d6) δ8.62–8.58(m,1H),8.03(d,J=7.9Hz,1H),7.96(td,J=7.7,1.7Hz,1H),7.85(dd,J=8.9,2.4Hz,1H),7.58(d,J=8. 9Hz,1H),7.55–7.49(m,2H),4.09(t,J=7.1Hz,1H),3.61(s,3H),3.32(s,3H),3.25(dd,J=16.6,7.5Hz,1H),3.09(dd,J=16.6,6.6Hz,1H).

[0792] 5. Preparation of target compound 114

[0793] At 0°C, sodium isopropoxide (307 mg, 20% in THF, 0.748 mmol) was added dropwise to a solution of 113 (200 mg, 0.497 mmol) in isopropanol (2 mL), allowed to warm to room temperature, and stirred for 1 hour. After the reaction was complete as monitored by TLC, ice water (10 mL) was added to the reaction solution, which was then extracted with ethyl acetate (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) and the fraction with Rf = 0.2-0.3 was collected to obtain compound 114 (71.0 mg, 33.2% yield) as a white solid. ESI [M+H] + =430.0.

[0794] 1 H NMR (400MHz, DMSO-d6) δ8.59(ddd,J=4.8,1.7,0.9Hz,1H),8.05–8.00(m,1H),7.99–7.93(m,1H),7.84(dd,J=8.9,2.4Hz,1H),7.58(d,J=8.9Hz,1H),7. 55–7.49(m,2H),4.92–4.86(m,1H),4.08(t,J=7.1Hz,1H),3.31(s,3H),3.1 8(dd,J=16.5,7.5Hz,1H),3.04(dd,J=16.5,6.8Hz,1H),1.24–1.14(m,6H).

[0795] Example 56 Preparation of Compound 115

[0796]

[0797] 1. Preparation of Compound 115-1

[0798] Dissolve N-Boc-L-homoserine (9.0 g, 41.1 mmol) in ethanol (70 mL), add a solution of sodium hydroxide (1.769 g, 44.2 mmol) in water (21 mL), and stir at room temperature for 24 hours. The reaction mixture is concentrated under reduced pressure, and the resulting white solid is dissolved in DMF (42 mL). Benzyl bromide (14 g, 81.9 mmol) is added to the above system, and stirring is continued at room temperature for 46 hours. After the reaction is complete as monitored by TLC, ice water (50 mL) is added to the reaction system, and extraction is performed with ethyl acetate (3 × 30 mL). The organic phase is washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 2) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 115-1 (2.34 g, 18.4% yield) as a colorless oil. ESI [M+H] + = 310.1.

[0799] 2. Preparation of Compound 115-2

[0800] 115-1 (2.34 g, 7.56 mmol) was dissolved in dichloromethane (31 mL), and DIEA (2.14 g, 16.6 mmol) and acetic anhydride (1.53

[0801] g, 15.0 mmol) and stirred at room temperature for 18 hours. After the reaction was complete as monitored by TLC, ice water (50 mL) was added to the reaction system and extracted with dichloromethane (3×30 mL). The organic phase was washed with 1% dilute hydrochloric acid, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 115-2 (1.2 g, yield 45.1%) as a colorless oil. ESI [M+H] + =352.2.

[0802] 3. Preparation of Compound 115-3

[0803] 115-2 (1.2 g, 3.41 mmol) was dissolved in methanol (10 mL) at room temperature, and palladium hydroxide on carbon (200 mg, 10%) was added. The mixture was stirred under hydrogen for 12 hours at room temperature. After completion of the reaction as monitored by TLC, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 115-3 (769 mg, 86.2% yield) as a white solid. ESI [M+H] + = 262.1.

[0804] 4. Preparation of Compound 115-4

[0805] Compound 1-1 (1.2 g, 4.33 mmol) and compound 115-3 (769 mg, 2.94 mmol) were dissolved in dichloromethane (12 mL). A solution of DCC (910 mg, 4.41 mmol) in dichloromethane (2 mL) was added dropwise at -10°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, methyl tert-butyl ether (14 mL) was added to the reaction system and stirred for 5 minutes. The reaction system was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 2) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 115-4 (1.42 g, 92.7% yield) as a white solid. ESI [M+H]+ = 520.1.

[0806] 5. Preparation of Compound 115-5

[0807] Trifluoroacetic acid (7.3 mL) was added to a solution of 115-4 (1.42 g, 2.73 mmol) in dichloromethane (14.6 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 2 hours. After completion of the reaction as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was used directly in the next reaction without purification.

[0808] 6. Preparation of Compound 115-6

[0809] The crude compound from the previous step was dissolved in acetonitrile (30 mL), sodium bicarbonate (8.62 g, 102.6 mmol) was added, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete as monitored by TLC, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 2) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). The fractions with Rf = 0.2 to 0.3 were collected to obtain compound 115-6 as a white solid (525 mg, two-step yield 47.8%). ESI [M+H] + =402.1.

[0810] 7. Preparation of target compound 115

[0811] NaH (78.5 mg, 60%, 1.96 mmol) was slowly added to a solution of 115-6 (525 mg, 1.31 mmol) in dry DMF (10 mL) at -20°C and stirred for 30 minutes. Iodomethane (279 mg, 1.97 mmol) was added to the reaction system and stirring continued at -20°C for 1 hour. After the reaction was complete as monitored by TLC, the reaction solution was poured into ice water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 115 (395 mg, 72.7% yield) as a white solid. ESI [M+H] + =416.0.

[0812] 1 H NMR (400MHz, DMSO-d6) δ8.58(d,J=4.0Hz,1H),8.09(d,J=7.9Hz,1H),7.97(td,J=7.7,1.8Hz,1H),7.82(dd,J=8.9,2.4H z,1H),7.59–7.47(m,3H),4.26-4.16(m,2H),3.76(dd,J=7.9,5.7Hz,1H),3.31(s,3H),2.41–2.27(m,2H),1.94(s,3H).

[0813] Example 57 Preparation of Compound 116

[0814]

[0815] 1. Preparation of Compound 116-1

[0816] 1-1 (4.46 g, 16.1 mmol) and BOC-O-benzyl-L-homoserine (5.0 g, 16.2 mmol) were dissolved in dichloromethane (45 mL). A solution of DCC (5.0 g, 24.2 mmol) in dichloromethane (15 mL) was added dropwise at -10°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, methyl tert-butyl ether (60 mL) was added to the reaction system and stirred for 5 minutes. The reaction system was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 2) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 116-1 (4.037 g, 44.1% yield) as a white solid. ESI [M+H]+ = 568.1.

[0817] 2. Preparation of Compound 116-2

[0818] Trifluoroacetic acid (10.1 mL) was added to a solution of 116-1 (4.037 g, 7.10 mmol) in dichloromethane (30.3 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 2 hours. After completion of the reaction as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was used directly in the next reaction without purification.

[0819] 3. Preparation of Compound 116-3

[0820] The crude compound from the previous step was dissolved in acetonitrile (50 mL), sodium bicarbonate (22.0 g, 261.9 mmol) was added, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete as monitored by TLC, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). The fractions with Rf = 0.2 to 0.3 were collected to obtain compound 116-3 as a white solid (3.029 g, two-step yield 94.7%). ESI [M+H] + =450.1.

[0821] 4. Preparation of target compound 116

[0822] NaH (385.7 mg, 60%, 9.64 mmol) was added to a solution of 116-3 (3.029 g, 6.73 mmol) in dry DMF (30 mL) at -20°C and stirred for 30 minutes. Iodomethane (1.053 g, 7.42 mmol) was added to the reaction system and stirring continued at -20°C for 1 hour. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 116 (2.903 g, 92.9% yield) as a white solid. ESI[M+H] + =464.3.

[0823] 1 H NMR(400MHz, DMSO-d6)δ8.60(d,J=4.7Hz,1H),8.00–7.93(m,2H),7.84(dd,J=8.9,2.2Hz,1H),7.56–7.52(m,2H),7.49(d,J=2.2Hz,1H),7.29–7.22( m,3H),7.17(d,J=7.4Hz,2H),4.46(d,J=12.3Hz,1H),4.38(d,J=12.4Hz,1 H),3.85–3.77(m,1H),3.65–3.64(m,2H),3.31(s,3H),2.40–2.28(m,2H).

[0824] Example 58 Preparation of Compound 117

[0825] Method A:

[0826]

[0827] Method B:

[0828]

[0829] Method C:

[0830]

[0831] Method A:

[0832] Sodium borohydride (581 mg, 15.4 mmol) was added portionwise to a solution of 113 (2.045 g, 5.08 mmol) in methanol (30 mL) and stirred at room temperature for 12 hours. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water (50 mL) and extracted with ethyl acetate (3 × 40 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 10) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 117 (439 mg, 23.1% yield) as a white solid.

[0833] Method B:

[0834] LiOH.H₂O (49 mg, 1.17 mmol) was added to a solution of 115 (323 mg, 0.776 mmol) in THF / H₂O (5 mL, v / v = 1 / 1) at 0°C and stirred for 30 minutes. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction solution, which was then extracted with ethyl acetate (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 10) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.2 to 0.3 were collected to afford compound 117 (249 mg, 85.7% yield) as a white solid.

[0835] Method C:

[0836] At 0°C, aluminum trichloride (5.83 g, 43.7 mmol) was slowly added to a solution of 116 (2.903 g, 6.25 mmol) in dichloromethane (70 mL). The mixture was allowed to warm to room temperature and stirred for 3 hours. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water (70 mL), filtered, and the filtrate was extracted with dichloromethane (3 × 70 mL). The organic phase was washed with 5% aqueous sodium bicarbonate solution, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 10) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 117 (2.08 g, 88.9% yield) as a white solid. ESI [M+H] + =374.0.

[0837] 1H NMR (400MHz, DMSO-d6) δ8.58(ddd,J=4.8,1.7,0.9Hz,1H),8.09(d,J=7.9Hz,1H),7.96(td,J=7.7,1.8Hz,1H),7.81(dd,J=8.8,2.4 Hz,1H),7.57–7.48(m,3H),4.40(t,J=5.2Hz,1H),3.79(t,J=6.9Hz,1H),3.59(q,J=6.0Hz,2H),3.30(s,3H),2.21(q,J=6.7Hz,2H).

[0838] Example 59 Preparation of Compound 118

[0839]

[0840] Difluoroacetic anhydride (112 mg, 0.643 mmol) was added dropwise to a solution of 117 (120 mg, 0.321 mmol), triethylamine (65.0 mg, 0.642 mmol), and DMAP (78.5 mg, 0.643 mmol) in dichloromethane (2 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 2 hours. After completion of the reaction as monitored by TLC, ice water (5 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100-1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 20). Fractions with Rf = 0.3-0.4 were collected to obtain compound 118 (24.0 mg, 16.5% yield) as a white solid. ESI [M+H] + =452.0.

[0841] 1 H NMR (400MHz, DMSO-d6) δ8.58(ddd,J=4.8,1.7,0.9Hz,1H),8.11(d,J=7.9Hz,1H),7.97(td,J=7.7,1.8Hz,1H),7.82(dd,J=8.9,2.4Hz,1H),7.5 6–7.50(m,2H),7.49(d,J=2.4Hz,1H),6.37(t,J=52.7Hz,1H),4.51–4.46(m,2H),3.82(dd,J=8.0,5.6Hz,1H),3.31(s,3H),2.48–2.37(m,2H).

[0842] Example 60 Preparation of Compound 120

[0843]

[0844] 3-Oxetanecarboxylic acid (41 mg, 0.402 mmol), DCC (82.8 mg, 0.401 mmol), and DMAP (49.1 mg, 0.402 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 15 minutes. Compound 117 (100 mg, 0.267 mmol) was added to the reaction system and stirred at room temperature for 12 hours. After the reaction was complete as monitored by TLC, methyl tert-butyl ether (2 mL) was added to the reaction system, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 10) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 120 (46.1 mg, 37.6% yield) as a white solid. ESI [M+H] + =458.0.

[0845] 1 H NMR (400MHz, DMSO-d6) δ8.58(ddd,J=4.8,1.7,0.9Hz,1H),8.10–8.08(m,1H),7.97(td,J=7.7,1.8Hz,1H),7.81(dd,J=8.9,2.4Hz,1H),7.56– 7.48(m,3H),4.65–4.61(m,2H),4.53–4.48(m,2H),4.39–4.25(m,2H), 3.87–3.81(m,1H),3.80–3.71(m,1H),3.31(s,3H),2.45–2.32(m,2H).

[0846] Example 61 Preparation of Compounds 121-123

[0847]

[0848] The preparation methods of compounds 121-123 were similar to those of compound 120 in Example 60, using compound 117 and corresponding carboxylic acids as raw materials to prepare the corresponding esters.

[0849] Compound 121: 80.5 mg, ESI [M+H] + =442.0.

[0850] 1H NMR (400MHz, DMSO-d6) δ8.61–8.56(m,1H),8.10(d,J=7.9Hz,1H),7.96(td,J=7.7,1.8Hz,1H),7.82(dd,J=8.8,2.4Hz,1H),7.56–7.47(m,3H) ,4.24(t,J=6.8Hz,2H),3.73(dd,J=8.1,5.5Hz,1H),3.31(s,3H),2.45 –2.28(m,2H),1.58–1.51(m,1H),0.85–0.76(m,2H),0.75–0.65(m,2H).

[0851] Compound 122: 22.7 mg, ESI [M+H] + =448.0.

[0852] 1 H NMR(400MHz, DMSO-d6)δ8.62–8.56(m,1H),8.13–8.08(m,1H),8.01–7.92(m,1H),7.82(dd,J=8.9,2.4Hz,1H),7.54–7.51(m,2H),7 .49(t,J=2.4Hz,1H),5.23–5.03(m,1H),4.40–4.33(m,2H),3.82–3.72(m,1H),3.31(s,3H),2.47–2.34(m,2H),1.40–1.30(m,3H).

[0853] Compound 123: 18.0 mg, ESI [M+H] + =484.0.

[0854] 1 H NMR (400MHz, DMSO-d6) δ8.62–8.55(m,1H),8.10(d,J=7.9Hz,1H),7.97(td,J=7.7,1.8Hz,1H),7.82(dd,J=8.9,2.4Hz,1H),7.55–7.50 (m,2H),7.48(d,J=2.4Hz,1H),4.37–4.33(m,2H),3.78(dd,J=8.3,5.4Hz,1H),3.62(q,J=11.0Hz,2H),3.31(s,3H),2.45–2.33(m,2H).

[0855] Example 62 Preparation of Compound 124

[0856]

[0857] Propionyl chloride (21 mg, 0.227 mmol) was added dropwise to a solution of 117 (56.7 mg, 0.152 mmol) and triethylamine (30.7 mg, 0.303 mmol) in dichloromethane (2 mL) at -10°C and stirred for 2 hours. After completion of the reaction as monitored by TLC, ice water (50 mL) was added to the reaction system and extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 20). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 124 (37.3 mg, 57.2% yield) as an off-white solid. ESI [M+H] + =430.0.

[0858] 1 H NMR (400MHz, DMSO-d6) δ8.61–8.56(m,1H),8.09(d,J=7.9Hz,1H),7.97(td,J=7.7,1.8Hz,1H),7.81(dd,J=8.9,2.4Hz,1H),7.55–7.45 (m,3H),4.30–4.16(m,2H),3.75(dd,J=8.0,5.7Hz,1H),3.31(s,3H),2.42–2.29(m,2H),2.23(q,J=7.5Hz,2H),0.93(t,J=7.5Hz,3H).

[0859] Example 63 Preparation of Compounds 125-129

[0860]

[0861] The preparation methods of target compounds 125-129 were similar to those of compound 124 in Example 62, using compound 117 and the corresponding acyl chloride as raw materials to prepare the corresponding esters.

[0862] Compound 125: 49.1 mg, ESI [M+H] + =444.1.

[0863] 1H NMR (400MHz, DMSO-d6) δ8.58 (ddd, J=4.8, 1.7, 0.9Hz, 1H), 8.10 (d, J=7.9Hz, 1H),7.97(td,J=7.7,1.8Hz,1H),7.81(dd,J=8.9,2.4Hz,1H),7.56–7.50(m, 2H),7.48(d,J=2.4Hz,1H),4.34–4.16(m,2H),3.73(dd,J=8.2,5.6Hz,1H),3 .31(s,3H),2.45–2.31(m,3H),0.95(d,J=7.1Hz,3H),0.93(d,J=7.1Hz,3H).

[0864] Compound 126: 17.6 mg, ESI [M+H] + =484.0.

[0865] 1 H NMR (400MHz, DMSO-d6) δ8.59–8.58(m,1H),8.12(d,J=7.9Hz,1H),7.97(td,J=7.7,1.8Hz,1H),7.81(dd,J=8.9,2.4Hz,1H),7.54– 7.52(m,2H),7.46(d,J=2.4Hz,1H),6.81(s,1H),4.58–4.41(m,2H),3.81(dd,J=8.4,5.4Hz,1H),3.31(s,3H),2.48–2.32(m,2H).

[0866] Compound 127: 33.1 mg, ESI [M+H] + =450.0.

[0867] 1 H NMR (400MHz, DMSO-d6) δ8.59(ddd,J=4.8,1.7,0.9Hz,1H),8.10(d,J=7.9Hz,1H),7.97(td,J=7.7,1.8Hz,1H),7.82(dd,J=8.9,2.4Hz,1H ),7.55–7.51(m,2H),7.49(d,J=2.4Hz,1H),4.41–4.33(m,2H),4.32(s,2H),3.81(dd,J=8.0,5.6Hz,1H),3.31(s,3H),2.46–2.35(m,2H).

[0868] Compound 128: 21.4 mg, ESI [M+H] + =492.0.

[0869] 1 H NMR(400MHz,DMSO-d6)δ8.61–8.56(m,1H),8.10(d,J=7.9Hz,1H),7.97(td, J=7.7,1.8Hz,1H),7.80(dd,J=8.9,2.4Hz,1H),7.57–7.49(m,2H),7.44(d,J =2.4Hz,1H),4.39–4.33(m,1H),4.28–4.22(m,1H),3.79(dd,J=8.3,5.5Hz, 1H),3.54(s,2H),3.31(s,3H),2.46–2.29(m,2H),1.07(s,3H),1.06(s,3H).

[0870] Compound 129: 24.5 mg, ESI [M+H] + =517.9.

[0871] 1 H NMR (400MHz, DMSO-d6) δ8.61–8.57(m,1H),8.14(d,J=7.9Hz,1H),7.98(td,J=7.7,1.8Hz,1H),7.81(dd,J=8.9,2.4Hz,1H) ,7.54–7.52(m,2H),7.46(d,J=2.4Hz,1H),4.74–4.57(m,2H),3.84(dd,J=8.2,5.4Hz,1H),3.31(s,3H),2.55–2.44(m,2H).

[0872] Example 64 Preparation of Compound 130

[0873]

[0874] 3-Chloropropionyl chloride (26.0 mg, 0.205 mmol) was added dropwise to a solution of 117 (50 mg, 0.134 mmol) and triethylamine (27.0 mg, 0.267 mmol) in dichloromethane (2 mL) at 0°C and stirred for 2 hours. After completion of the reaction as monitored by TLC, ice water (5 mL) was added to the reaction system and extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 20). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 130 (22.1 mg, 38.6% yield) as a white solid. ESI [M+H] +=428.0.

[0875] 1 H NMR (400MHz, DMSO-d6) δ8.61–8.57(m,1H),8.10(d,J=7.9Hz,1H),7.97(td,J=7.7,1 .8Hz,1H),7.81(dd,J=8.9,2.4Hz,1H),7.55–7.50(m,2H),7.49(d,J=2.4Hz,1H),6. 26(dd,J=17.3,1.7Hz,1H), 6.12(dd,J=17.3,10.2Hz,1H), 5.89(dd,J=10.2,1.7Hz, 1H),4.39–4.23(m,2H),3.79(dd,J=8.1,5.5Hz,1H),3.31(s,3H),2.48–2.36(m,2H).

[0876] Example 65 Preparation of Compound 131

[0877]

[0878] Ethyl chloroformate (87.3 mg, 0.804 mmol) was added dropwise to a solution of 117 (100 mg, 0.267 mmol), pyridine (61.9 mg, 0.783 mmol), and DMAP (32.7 mg, 0.268 mmol) in dichloromethane (2 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100-1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 20). Fractions with Rf = 0.3-0.4 were collected to obtain compound 131 (90.0 mg, yield 75.5%) as a white solid. ESI [M+H] + =446.0.

[0879] 1H NMR (400MHz, DMSO-d6) δ8.58(d,J=4.7Hz,1H),8.11(d,J=7.8Hz,1H),7.97(t,J=7.8Hz,1H),7.82(dd,J=8.9,2.2Hz,1H),7.57–7.46(m ,3H),4.31(t,J=6.5Hz,2H),4.05(q,J=7.0Hz,2H),3.75(dd,J=8.2,5.4Hz,1H),3.31(s,3H),2.44–2.27(m,2H),1.14(t,J=7.1Hz,3H).

[0880] Example 66 Preparation of Compound 132

[0881]

[0882] The preparation method of compound 132 is similar to that of compound 131 in Example 65, using compound 117 and isopropyl chloroformate as raw materials.

[0883] Compound 132: 84.5 mg, ESI [M+H] + =460.1.

[0884] 1 H NMR (400MHz, DMSO-d6) δ8.61–8.55(m,1H),8.11(d,J=7.9Hz,1H),7.97(td,J =7.7,1.8Hz,1H),7.82(dd,J=8.9,2.4Hz,1H),7.55–7.50(m,2H),7.48(d,J=2 .4Hz,1H),4.76–4.61(m,1H),4.32–4.29(m,2H),3.73(dd,J=8.3,5.4Hz,1H), 3.31(s,3H),2.45–2.24(m,2H),1.15(d,J=5.0Hz,3H),1.14(d,J=5.0Hz,3H).

[0885] Example 67 Preparation of Compounds 133-135

[0886]

[0887] 1. Preparation of Compound 133-1

[0888] p-Nitrophenyl chloroformate (810 mg, 4.02 mmol) was added to a solution of 117 (500 mg, 1.34 mmol), pyridine (310 mg, 3.92 mmol), and DMAP (163.5 mg, 1.34 mmol) in dichloromethane (5 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 133-1 (369.9 mg, 51.3% yield) as a white solid. ESI[M+H] + =539.1.

[0889] 2. Preparation of target compound 133

[0890] Cyclopropanol (10.8 mg, 0.186 mmol) was added to a solution of 133-1 (100 mg, 0.185 mmol) and DMAP (22.6 mg, 0.185 mmol) in dichloromethane (2 mL) and stirred at room temperature for 12 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system and extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 133 (56.1 mg, 66.0% yield) as a white solid. ESI [M+H] + =458.0.

[0891] 1H NMR (400MHz, DMSO-d6) δ8.58(ddd,J=4.8,1.7,0.9Hz,1H),8.11(d,J=7.9Hz,1H),7.97(td,J=7.7,1.8Hz,1H),7.82(dd,J=8.9,2.4Hz,1H),7.56–7.50( m,2H),7.49(d,J=2.4Hz,1H),4.32(t,J=6.6Hz,2H),4.04–3.94(m,1H),3.7 4(dd,J=8.2,5.4Hz,1H),3.31(s,3H),2.46–2.32(m,2H),0.67–0.54(m,4H).

[0892] 3. Preparation of target compound 134

[0893] The preparation method of compound 134 is similar to that of compound 133 in Example 67, using compound 133-1 and oxetan-3-ol as raw materials.

[0894] Compound 134: 56.7 mg, ESI [M+H] + =474.0.

[0895] 1 H NMR (400MHz, DMSO-d6) δ8.58(ddd,J=4.8,1.7,0.9Hz,1H),8.14–8.09(m,1H),7.97(td,J=7.7,1.8Hz,1H),7.82(dd,J=8.9,2.4Hz,1H),7.56–7.48 (m,3H),5.34–5.24(m,1H),4.76–4.67(m,2H),4.50–4.39(m,2H),4.36–4 .32(m,2H),3.77(dd,J=8.2,5.4Hz,1H),3.31(s,3H),2.44–2.34(m,2H).

[0896] 4. Preparation of target compound 135

[0897] 133-1 (100 mg, 0.185 mmol) and DIEA (24.0 mg, 0.186 mmol) were dissolved in dichloromethane (2 mL), and dimethylamine (0.1 mL, 2 mol / L in THF, 0.2 mmol) was added. The mixture was stirred at room temperature for 12 hours. After the reaction was complete as monitored by TLC, ice water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). The fraction with Rf = 0.2 to 0.3 was collected to obtain compound 135 (54.5 mg, yield 66.0%) as a white solid. ESI [M+H] + =445.0.

[0898] 1 H NMR (400MHz, DMSO-d6) δ8.59–8.57(m,1H),8.09(dd,J=7.9,1.0Hz,1H),7.97(td,J=7.7,1.8Hz,1H),7.81(dd,J=8.8,2.4Hz,1H ),7.55–7.48(m,3H),4.21–4.12(m,2H),3.76(dd,J=7.8,5.8Hz,1H),3.30(s,3H),2.74(s,3H),2.70(s,3H),2.40–2.32(m,2H).

[0899] Example 68 Preparation of Compounds 136 and 137

[0900]

[0901] Isopropylsulfonyl chloride (268 mg, 1.88 mmol) was added to a solution of 117 (70.0 mg, 0.187 mmol), pyridine (72.3 mg, 0.914 mmol), and DMAP (137.4 mg, 1.12 mmol) in dichloromethane (2 mL). The mixture was stirred at room temperature for 12 hours. After completion of the reaction as monitored by TLC, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 20) to give yellow solid compound 136 (7.6 mg, yield 8.5%) and off-white solid compound 137 (10.7 mg, yield 11.5%).

[0902] Compound 136: ESI [M+H] + =480.1.

[0903] 1 H NMR(400MHz,DMSO-d6)δ8.61(d,J=4.2Hz,1H),8.16(d,J=7.9Hz,1H),8.00(td ,J=7.8,1.7Hz,1H),7.84(dd,J=8.9,2.4Hz,1H),7.59–7.52(m,2H),7.48(d,J= 2.4Hz,1H),4.59–4.39(m,2H),3.82(dd,J=8.6,5.1Hz,1H),3.55–3.49(m,1H) ,3.34(s,3H),2.51–2.36(m,2H),1.22(d,J=6.8Hz,3H),1.19(d,J=6.8Hz,3H).

[0904] Compound 137: ESI[M+H] + =498.0.

[0905] 1 H NMR (400MHz, DMSO-d6) δ8.60(d,J=4.6Hz,1H),8.15(d,J=7.9Hz,1H),7.99(t,J=7.7Hz,1H),7.82(d,J=8.9Hz,1H),7.56–7.53 (m,2H),7.47(dd,J=6.1,2.2Hz,1H),4.48–4.25(m,2H),3.86–3.83(m,1H),3.33(s,3H),2.50–2.34(m,2H),1.58–1.51(m,6H).

[0906] Example 69 Preparation of Compounds 138 and 140

[0907]

[0908] 1. Preparation of target compound 138

[0909] Methanesulfonyl chloride (62.9 mg, 0.549 mmol) was added dropwise to a solution of 117 (165 mg, 0.441 mmol) and triethylamine (106.8 mg, 1.06 mmol) in dichloromethane (2 mL) at 0°C and stirred for 1 hour. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 138 (57.0 mg, yield 28.6%) as a yellow solid. ESI [M+H] + =452.2.

[0910] 1 H NMR (400MHz, DMSO-d6) δ8.61(d,J=4.7Hz,1H),8.16(d,J=7.9Hz,1H),8.02–7.96(m,1H),7.86–7.81(m,1H ),7.58–7.50(m,3H),4.55–4.44(m,2H),3.85–3.80(m,1H),3.34(s,3H),3.16(s,3H),2.60–2.38(m,2H).

[0911] 2. Preparation of target compound 140

[0912] N-Phenyl-N-(4-piperidinyl)propionamide (43.5 mg, 0.187 mmol) was added to a solution of 138 (57 mg, 0.126 mmol) and DIEA (32.6 mg, 0.253 mmol) in dichloromethane (2 mL) and stirred at room temperature for 48 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system and extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 140 (13.2 mg, 17.8% yield) as a white solid. ESI [M+H] + =588.2.

[0913] 1H NMR(400MHz, DMSO-d6)δ8.56(d,J=4.1Hz,1H),8.05(d,J=7.9Hz,1H),7.96–7.93(m,1H),7. 78(dd,J=8.9,2.4Hz,1H),7.54–7.49(m,1H),7.46–7.43(m,5H),7.20–7.16(m,2H),4.49-4 .47(m,1H),3.64–3.60(m,1H),3.25(s,3H),3.12–2.73(m,2H),2.44–2.34(m,2H),2.30-1. 90(m,4H),1.82-1.80(m,2H),1.75–1.60(m,2H),1.23–1.01(m,2H),0.87(t,J=7.4Hz,3H).

[0914] Example 70 Preparation of Compounds 144, 145 and 145D

[0915]

[0916] 1. Preparation of Compound 145-1

[0917] At -30°C, lithium bis(trimethylsilyl)amide (9.08 mL, 1 mol / L, 9.08 mmol) was slowly added to a solution of 116-3 (3.4 g, 7.55 mmol) in THF (40 mL) and stirred for 1 hour. Dimorpholinophosphinic chloride (4.54 g, 17.8 mmol) was added portionwise and stirred at -10°C for 4 hours. Isopropanolamine (2.56 g, 34.1 mmol) was added dropwise to the reaction system, allowed to warm to room temperature, and stirred for 12 hours. After completion of the reaction as monitored by TLC, ice water (40 mL) was added to the reaction system and extracted with ethyl acetate (3 × 40 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 145-1 (3.254 g, yield 84.9%) as a white solid. ESI [M+H] + =507.1.

[0918] 2. Preparation of target compound 144

[0919] Dess-Martin reagent (6.817 g, 16.1 mmol) was added to a solution of 145-1 (3.254 g, 6.41 mmol) in acetone (40 mL) and stirred at room temperature for 12 hours. After the reaction was complete as monitored by TLC, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with saturated sodium bicarbonate solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). The fraction with Rf = 0.2 to 0.3 was collected to obtain compound 144 (2.312 g, yield 74.0%) as a white solid. ESI [M+H] + =487.1.

[0920] 1 H NMR(400MHz, DMSO-d6)δ8.54–8.53(m,1H),7.96(d,J=7.7Hz,1H),7.94–7.86(m, 2H),7.66(d,J=8.7Hz,1H),7.58(d,J=2.3Hz,1H),7.52–7.42(m,1H),7.29–7.19( m,5H),6.80(d,J=1.1Hz,1H),4.48(d,J=12.3Hz,1H),4.41(d,J=12.3Hz,1H),4. 10(t,J=7.1Hz,1H),3.82–3.69(m,2H),2.59–2.54(m,2H),2.29(d,J=0.8Hz,3H).

[0921] 3. Preparation of Compound 145-2

[0922] At 0°C, aluminum trichloride (6.326 g, 47.4 mmol) was slowly added to a solution of 144 (2.312 g, 4.74 mmol) in dichloromethane (50 mL). The mixture was allowed to warm to room temperature and stirred for 3 hours. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water (50 mL), filtered, and the filtrate extracted with dichloromethane (3 × 60 mL). The organic phase was washed with 5% aqueous sodium bicarbonate solution, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 10) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 145-2 (1.7 g, 90.2% yield) as a white solid. ESI [M+H] + =397.1.

[0923] 4. Preparation of target compound 145

[0924] Acetyl chloride (55.1 mg, 0.702 mmol) was added dropwise to a solution of 145-2 (300 mg, 0.755 mmol) and triethylamine (153 mg, 1.512 mmol) in dichloromethane (3 mL) at -10°C and stirred for 2 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system and extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.4 to 0.5 were collected to obtain compound 145 (248 mg, 74.8% yield) as a white solid. ESI [M+H] + =439.1.

[0925] 1 H NMR (400MHz, DMSO-d6) δ8.54 (ddd, J=4.8, 1.7, 0.9Hz, 1H), 8.08 (d, J=7.9Hz, 1H), 7. 94(td,J=7.7,1.8Hz,1H),7.89(dd,J=8.7,2.3Hz,1H),7.66(d,J=8.7Hz,1H),7.62(d ,J=2.3Hz,1H),7.49(ddd,J=7.5,4.8,1.2Hz,1H),6.82(d,J=1.1Hz,1H),4.35-4.31( m,2H),4.12(t,J=7.0Hz,1H),2.65-2.59(m,2H),2.30(d,J=0.8Hz,3H),1.97(s,3H).

[0926] 5. Preparation of target compound 145D

[0927] Compound 145 (248 mg, 0.565 mmol) was dissolved in ethyl acetate (20 mL), and a solution of benzenesulfonic acid (89.6 mg, 0.566 mmol) in ethyl acetate (1 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filter cake was dried under reduced pressure to obtain Compound 145D (281.2 mg, 83.4% yield) as a white solid. ESI [M+H] + =439.1.

[0928] 1H NMR (400MHz, CD3OD) δ9.42(d,J=4.6Hz,1H),8.95(d,J=7.9Hz,1H),8.84(ddd,J=9.3,8.3,1.8Hz,2H),8.70(d,J=8.7Hz,1H),8.61(d,J =2.2Hz,1H),8.47–8.33(m,4H),8.18–8.10(m,3H),5.28–5.21(m,2H),5.17–5.10(m,1H),3.63–3.39(m,2H),3.23(s,3H),2.81(s,3H).

[0929] Example 71 Preparation of Compounds 146-149

[0930]

[0931] The preparation method of compounds 146-149 is similar to that of compound 145 in Example 70, and they are prepared by first using compound 145-2 and the corresponding acyl chloride as raw materials.

[0932] Compound 146: 38.8 mg, ESI [M+H] + =467.1

[0933] 1 H NMR (400MHz, DMSO-d6) δ8.54(ddd,J=4.8,1.7,0.9Hz,1H),8.08(d,J=7.9Hz,1H),7.95(td,J=7.7, 1.8Hz,1H),7.89(dd,J=8.7,2.3Hz,1H),7.66(d,J=8.7Hz,1H),7.60(d,J=2.3Hz,1H),7.49(ddd,J= 7.5,4.8,1.2Hz,1H),6.82(d,J=1.1Hz,1H),4.44–4.33(m,2H),4.09(dd,J=8.2,5.9Hz,1H),2.72–2 .52(m,2H),2.49–2.43(m,1H),2.30(d,J=0.8Hz,3H),1.00(d,J=4.4Hz,3H),0.98(d,J=4.4Hz,3H).

[0934] Compound 147: 51.7 mg, ESI [M+H] + =453.1

[0935] 1H NMR (400MHz, DMSO-d6) δ8.56–8.51(m,1H),8.08(d,J=7.9Hz,1H),7.94(td,J=7.7,1.8H z,1H),7.89(dd,J=8.7,2.3Hz,1H),7.66(d,J=8.7Hz,1H),7.61(d,J=2.3Hz,1H),7.49(d dd,J=7.5,4.8,1.1Hz,1H),6.82(d,J=1.1Hz,1H),4.47–4.28(m,2H),4.11(t,J=7.0Hz, 1H),2.65–2.59(m,2H),2.30(d,J=0.8Hz,3H),2.29–2.24(m,2H),0.96(t,J=7.5Hz,3H).

[0936] Compound 148: 90.1 mg, ESI [M+H] + =473.0

[0937] 1 H NMR (400MHz, DMSO-d6) δ8.58–8.50(m,1H),8.09(d,J=7.9Hz,1H),7.95(td,J=7. 8,1.7Hz,1H),7.89(dd,J=8.7,2.3Hz,1H),7.66(d,J=8.7Hz,1H),7.61(d,J=2.3H z,1H),7.50(ddd,J=7.5,4.8,1.1Hz,1H),6.82(d,J=1.0Hz,1H),4.56–4.44(m,2 H), 4.35 (s, 2H), 4.16 (t, J = 7.0Hz, 1H), 2.69–2.62 (m, 2H), 2.30 (d, J = 0.7Hz, 3H).

[0938] Compound 149: 101.7 mg, ESI [M+H] + =515.4

[0939] 1H NMR (400MHz, DMSO-d6) δ8.56(d,J=4.2Hz,1H),8.10(d,J=7.9Hz,1H),7.97(td,J=7.8 ,1.6Hz,1H),7.89(dd,J=8.7,2.3Hz,1H),7.67(d,J=8.7Hz,1H),7.57(d,J=2.3Hz,1H ),7.51(dd,J=6.9,5.3Hz,1H),6.84(s,1H),4.55–4.48(m,1H),4.47–4.33(m,1H),4. 17(dd,J=8.5,5.7Hz,1H),3.60(s,2H),2.73–2.60(m,2H),2.32(s,3H),1.13(s,6H).

[0940] Example 72 Preparation of Compounds 150 and 151

[0941]

[0942] 3-Chloropropionyl chloride (58.7 mg, 0.462 mmol) was added dropwise to a solution of 145-2 (100 mg, 0.252 mmol) and triethylamine (51 mg, 0.504 mmol) in dichloromethane (2 mL) at 0°C and stirred for 2 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10) to afford Compound 150 (21.1 mg, 17.2% yield) and Compound 151 (19.0 mg, 16.7% yield) as a white solid.

[0943] Compound 150: ESI [M+H] + =487.0.

[0944] 1H NMR (400MHz, DMSO-d6) δ8.58–8.51(m,1H),8.08(d,J=7.9Hz,1H),7.95(td,J=7.7,1.8H z,1H),7.88(dd,J=8.7,2.3Hz,1H),7.65(d,J=8.7Hz,1H),7.58(d,J=2.3Hz,1H),7.50(d dd,J=7.5,4.8,1.1Hz,1H),6.82(d,J=1.1Hz,1H),4.52–4.38(m,2H),4.19–4.11(m,1H) ,3.71(t,J=6.1Hz,2H),2.77(t,J=6.1Hz,2H),2.71–2.59(m,2H),2.30(d,J=0.7Hz,3H).

[0945] Compound 151: ESI [M+H] + =451.1.

[0946] 1 H NMR (400MHz, DMSO-d6) δ8.54(d,J=3.9Hz,1H),8.09(d,J=7.9Hz,1H),7.94(td,J=7.7,1.7Hz,1H ),7.89(dd,J=8.7,2.3Hz,1H),7.66(d,J=8.7Hz,1H),7.61(d,J=2.3Hz,1H),7.49(dd,J=6.4,4.9 Hz,1H),6.82(d,J=1.0Hz,1H),6.29(dd,J=17.3,1.6Hz,1H),6.15(dd,J=17.3,10.2Hz,1H),5.9 0(dd,J=10.2,1.7Hz,1H),4.49–4.44(m,2H),4.21–4.10(m,1H),2.73–2.60(m,2H),2.30(s,3H).

[0947] Example 73 Preparation of Compound 152

[0948]

[0949] Benzoic acid (46.2 mg, 0.378 mmol), DCC (78 mg, 0.378 mmol), and DMAP (61.6 mg, 0.504 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 15 minutes. 145-2 (100 mg, 0.252 mmol) was added to the reaction system and stirring continued at room temperature for 12 hours. After the reaction was complete as monitored by TLC, methyl tert-butyl ether (2 mL) was added to the reaction system, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 20). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 152 (58.8 mg, 46.6% yield) as a white solid. ESI [M+H] + =501.1.

[0950] 1 H NMR (400MHz, DMSO-d6) δ8.56–8.51(m,1H),8.07(d,J=7.9Hz,1H),7.92–7.90(m,3H),7.89–7.86(m,1H),7.68–7.60(m,2H),7.58(d,J=2.3Hz ,1H),7.51–7.45(m,3H),6.83(d,J=1.1Hz,1H),4.64(t,J=6.8Hz,2H),4.24(dd,J=8.2,5.7Hz,1H),2.85–2.73(m,2H),2.31(d,J=0.7Hz,3H).

[0951] Example 74 Preparation of Compound 153

[0952]

[0953] The preparation method of compound 153 is similar to that of compound 152 in Example 73, using compound 145-2 and 3-oxetanecarboxylic acid as raw materials.

[0954] Compound 153: 17.6 mg, ESI [M+H] + =481.1

[0955] 1H NMR (400MHz, DMSO-d6) δ8.58–8.53(m,1H),8.08(d,J=7.9Hz,1H),7.95(td,J=7.7,1.8Hz,1H),7. 89(dd,J=8.7,2.3Hz,1H),7.66(d,J=8.7Hz,1H),7.61(d,J=2.3Hz,1H),7.50(ddd,J=7.5,4.8,1. 2Hz,1H),6.82(d,J=1.1Hz,1H),4.65(dd,J=8.7,5.9Hz,2H),4.54(dd,J=12.1,5.8Hz,2H),4.50– 4.40(m,2H),4.13(t,J=7.0Hz,1H),3.90–3.82(m,1H),2.68–2.62(m,2H),2.30(d,J=0.8Hz,3H).

[0956] Example 75 Preparation of Compound 154

[0957]

[0958] Ethyl chloroformate (66 mg, 0.608 mmol) was added dropwise to a solution of 145-2 (80 mg, 0.201 mmol), pyridine (47 mg, 0.594 mmol), and DMAP (25 mg, 0.205 mmol) in dichloromethane (2 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100-1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 20). Fractions with Rf = 0.3-0.4 were collected to obtain compound 154 (42.3 mg, 44.8% yield) as a white solid. ESI [M+H] + =469.1.

[0959] 1H NMR (400MHz, DMSO-d6) δ8.54 (ddd, J=4.8, 1.6, 0.8Hz, 1H), 8.09 (d, J=7.9Hz, 1H), 7. 94(td,J=7.7,1.8Hz,1H),7.91–7.87(m,1H),7.68–7.64(m,1H),7.61(d,J=2.3Hz,1 H),7.49(ddd,J=7.5,4.8,1.2Hz,1H),6.82(d,J=1.1Hz,1H),4.44(t,J=6.6Hz,2H), 4.15–4.00(m,3H),2.72–2.57(m,2H),2.30(d,J=0.8Hz,3H),1.16(t,J=7.1Hz,3H).

[0960] Example 76 Preparation of Compound 155

[0961]

[0962] The preparation method of compound 155 is similar to that of compound 154 in Example 75, using compound 145-2 and isopropyl chloroformate as raw materials.

[0963] Compound 155: 45.7 mg, ESI [M+H] + =483.1

[0964] 1 H NMR (400MHz, DMSO-d6) δ8.57–8.51(m,1H),8.10(d,J=7.9Hz,1H),7.94(td,J=7.7,1.8Hz,1H),7 .89(dd,J=8.7,2.3Hz,1H),7.66(d,J=8.7Hz,1H),7.60(d,J=2.3Hz,1H),7.50(ddd,J=7.5,4.8, 1.1Hz,1H),6.82(d,J=1.1Hz,1H),4.80–4.66(m,1H),4.43(t,J=6.6Hz,2H),4.09(dd,J=8.1,6. 0Hz,1H),2.69–2.59(m,2H),2.30(d,J=0.8Hz,3H),1.18(d,J=2.7Hz,3H),1.16(d,J=2.7Hz,3H).

[0965] Example 77 Preparation of Compounds 156, 156D, 157, 158, 159 and 159D

[0966]

[0967] 1. Preparation of Compound 156-1

[0968] At 0°C, p-nitrophenyl chloroformate (487 mg, 2.42 mmol) was added to a solution of 145-2 (320 mg, 0.805 mmol), pyridine (186.2 mg, 2.35 mmol), and DMAP (98 mg, 0.802 mmol) in dichloromethane (5 mL). The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 156-1 (404 mg, yield 89.2%) as a white solid. ESI [M+H] + =562.1.

[0969] 2. Preparation of target compound 156

[0970] Compound 156-1 (200 mg, 0.356 mmol) and DIEA (46.0 mg, 0.356 mmol) were dissolved in dichloromethane (2 mL). Dimethylamine (0.356 mL, 2 mol / L in THF, 0.712 mmol) was added and stirred at room temperature for 12 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system and extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 20). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 156 (144.7 mg, 86.9% yield) as a white solid. ESI [M+H] + =468.1.

[0971] 1H NMR (400MHz, DMSO-d6) δ8.54(ddd,J=4.8,1.7,0.9Hz,1H),8.08(d,J=7.9Hz,1H),7.94(t d,J=7.7,1.8Hz,1H),7.88(dd,J=8.7,2.3Hz,1H),7.66(d,J=8.7Hz,1H),7.62(d,J=2.3Hz ,1H),7.49(ddd,J=7.5,4.8,1.2Hz,1H),6.81(d,J=1.1Hz,1H),4.39–4.25(m,2H),4.11(d d,J=7.9,6.1Hz,1H),2.76(s,3H),2.75(s,3H),2.69–2.56(m,2H),2.30(d,J=0.8Hz,3H).

[0972] 3. Preparation of target compound 156D

[0973] Compound 156 (144.7 mg, 0.309 mmol) was dissolved in ethyl acetate (10 mL), and a solution of benzenesulfonic acid (49.0 mg, 0.31 mmol) in ethyl acetate (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filter cake was dried under reduced pressure to obtain compound 156D (117.4 mg, 60.7% yield) as a white solid. ESI [M+H] + =468.1.

[0974] 1 H NMR(400MHz, DMSO-d6)δ8.60(d,J=4.1Hz,1H),8.13(d,J=7.9Hz,1H),8.06–7. 95(m,2H),7.86(d,J=8.7Hz,1H),7.78(d,J=1.3Hz,1H),7.63–7.59(m,2H),7. 57(dd,J=6.6,5.0Hz,1H),7.46(s,1H),7.36–7.24(m,3H),4.45–4.34(m,2H), 4.32–4.23(m,1H),2.79(s,3H),2.77(s,3H),2.74–2.59(m,2H),2.41(s,3H).

[0975] 4. Preparation of target compound 157

[0976] The preparation method of compound 157 was similar to that of compound 156 in Example 77, using compound 156-1 and N-ethylmethylamine as raw materials.

[0977] Compound 157: 45.5 mg, ESI [M+H]+ =482.1.

[0978] 1 H NMR (400MHz, DMSO-d6) δ8.57–8.51(m,1H),8.09(d,J=7.9Hz,1H),7.94(td,J=7.7,1.8Hz,1H ),7.88(dd,J=8.7,2.3Hz,1H),7.66(d,J=8.7Hz,1H),7.61(d,J=2.3Hz,1H),7.49(ddd,J=7.5 ,4.8,1.2Hz,1H),6.81(d,J=1.1Hz,1H),4.32(t,J=6.4Hz,2H),4.10(dd,J=8.0,6.0Hz,1H), 3.15–3.10(m,2H),2.73(s,3H),2.68–2.54(m,2H),2.30(d,J=0.8Hz,3H),0.95–0.82(m,3H).

[0979] 5. Preparation of target compound 158

[0980] The preparation method of compound 158 is similar to that of compound 156 in Example 77, using compound 156-1 and N-isopropylmethylamine as raw materials.

[0981] Compound 158: 44.6 mg, ESI [M+H] + =496.1.

[0982] 1 H NMR (400MHz, DMSO-d6) δ8.57–8.53(m,1H),8.09(d,J=7.9Hz,1H),7.94(td,J=7.7,1. 8Hz,1H),7.88(dd,J=8.7,2.3Hz,1H),7.66(d,J=8.7Hz,1H),7.60(d,J=2.3Hz,1H),7. 49(ddd,J=7.5,4.8,1.2Hz,1H),6.81(d,J=1.1Hz,1H),4.33(t,J=6.6Hz,2H),4.27–3 .94(m,2H),2.68–2.60(m,2H),2.59(s,3H),2.30(d,J=0.8Hz,3H),0.96–0.91(m,6H).

[0983] 5. Preparation of target compounds 159 and 159D

[0984] The preparation methods of compounds 159 and 159D were similar to those of compounds 156 and 156D in Example 77, respectively. Compound 156-1 and dimethylhydroxylamine hydrochloride were used as raw materials to prepare 159, which was then reacted with benzenesulfonic acid to prepare 159D.

[0985] Compound 159: 144.7 mg, ESI [M+H] + =484.1

[0986] 1 H NMR (400MHz, DMSO-d6) δ8.59–8.51(m,1H),8.10(d,J=7.9Hz,1H),7.95(td,J=7.7,1. 8Hz,1H),7.88(dd,J=8.7,2.3Hz,1H),7.66(d,J=8.7Hz,1H),7.62(d,J=2.3Hz,1H),7. 49(ddd,J=7.5,4.8,1.1Hz,1H),6.82(d,J=1.1Hz,1H),4.49–4.34(m,2H),4.13(dd,J =8.1,5.9Hz,1H),3.47(s,3H),3.01(s,3H),2.71–2.60(m,2H),2.30(d,J=0.7Hz,3H).

[0987] Compound 159D: 63.3 mg, ESI [M+H] + =484.1

[0988] 1 H NMR (400MHz, DMSO-d6) δ8.59–8.58(m,1H),8.15(d,J=7.6Hz,1H),8.01–7.98(m,2H),7.79–7.74(m,2H),7.64–7.59(m,2H) ,7.57–7.52(m,1H),7.37–7.23(m,4H),4.46–4.41(m,3H),3.50(s,3H),3.03(s,3H),2.79–2.62(m,2H),2.38–2.35(m,3H).

[0989] Example 78 Preparation of Compound 160

[0990]

[0991] 1. Preparation of Compound 160-1

[0992] 1-1 (2.341 g, 8.45 mmol) and BOC-glycine (2.23 g, 12.7 mmol) were dissolved in dichloromethane (30 mL). A solution of DCC (2.62 g, 12.7 mmol) in dichloromethane (10 mL) was added dropwise at -10°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, methyl tert-butyl ether (40 mL) was added to the reaction system and stirred for 5 minutes. The reaction system was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 160-1 (2.5 g, yield 68.1%) as a white solid. ESI [M+H] + =434.1.

[0993] 2. Preparation of Compound 160-2

[0994] Trifluoroacetic acid (10 mL) was added to a solution of 160-1 (2.5 g, 5.76 mmol) in dichloromethane (30 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 2 hours. After completion of the reaction as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was used directly in the next reaction without purification.

[0995] 3. Preparation of Compound 160-3

[0996] The crude compound from the previous step was dissolved in acetonitrile (30 mL), sodium bicarbonate (18.9 g, 225 mmol) was added, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete as monitored by TLC, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). The fractions with Rf = 0.2 to 0.3 were collected to obtain compound 160-3 as a white solid (672 mg, two-step yield 36.9%). ESI [M+H] + =316.0.

[0997] 4. Preparation of Compound 160-4

[0998] NaH (110.6 mg, 60%, 2.76 mmol) was slowly added to a solution of 160-3 (672 mg, 2.13 mmol) in dry DMF (6 mL) at -20°C and stirred for 30 minutes. Iodomethane (392.6 mg, 2.77 mmol) was added to the reaction system and stirring continued at -20°C for 1 hour. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 160-4 (450 mg, 64.1% yield) as a white solid. ESI[M+H] + =330.1.

[0999] 6. Preparation of Compound 160-5

[1000] LDA (0.926 mL, 2 mol / L in THF, 1.85 mmol) was slowly added dropwise to a solution of 160-4 (450 mg, 1.36 mmol) in dry tetrahydrofuran (8 mL) at -60°C and stirred for 15 minutes. Acetaldehyde (0.85 mL, 5 mol / L in THF, 4.25 mmol) was added to the reaction system and stirring continued at -60°C for 1 hour. After the reaction was complete as monitored by TLC, saturated aqueous ammonium chloride (10 mL) was added to the reaction system and extracted with ethyl acetate (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (CH2Cl2 / MTBE / MeOH / Et3N = 50 / 50 / 2.5 / 0.5) to afford compound 160-5 (180 mg, 35.3% yield) as a white solid. ESI [M+H] + =374.1.

[1001] 7. Preparation of target compound 160

[1002] 2-Fluoropropionic acid (18.5 mg, 0.201 mmol), DCC (41.4 mg, 0.201 mmol), and DMAP (32.7 mg, 0.268 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 15 minutes. Compound 160-5 (50 mg, 0.134 mmol) was added to the reaction system and stirred at room temperature for 12 hours. After completion of the reaction as monitored by TLC, methyl tert-butyl ether (2 mL) was added to the reaction system, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 160 (9.9 mg, 16.5% yield) as a white solid. ESI [M+H] + =448.1.

[1003] 1 H NMR (400MHz, DMSO-d6) δ8.62(d,J=4.6Hz,1H),8.15(d,J=7.7Hz,1H),8.01(t,J=7.7Hz,1H),7.86(dd,J=8.8,2.2Hz,1H),7.61(d ,J=8.9Hz,1H),7.58–7.55(m,2H),5.80–5.64(m,1H),5.22–5.08(m,1H),3.83(t,J=8.8Hz,1H),3.33(s,3H),1.48–1.28(m,6H).

[1004] Example 79 Preparation of Compound 162

[1005]

[1006] 1. Preparation of Compound 162-1

[1007] At 0°C, p-nitrophenyl chloroformate (80.8 mg, 0.401 mmol) was added to a solution of 160-5 (50 mg, 0.134 mmol), pyridine (31 mg, 0.392 mmol), and DMAP (32.7 mg, 0.268 mmol) in dichloromethane (2 mL). The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 2) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 162-1 (60 mg, yield 83.3%) as a white solid. ESI [M+H] + =539.1.

[1008] 2. Preparation of target compound 162

[1009] Compound 162-1 (60 mg, 0.111 mmol) and DIEA (14.4 mg, 0.111 mmol) were dissolved in dichloromethane (2 mL). Dimethylamine (0.17 mL, 2 mol / L in THF, 0.34 mmol) was added and stirred at room temperature for 12 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system and extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 20). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 162 (16.9 mg, 34.1% yield) as a white solid. ESI [M+H] + =445.1.

[1010] 1 H NMR (400MHz, DMSO-d6) δ8.61(d,J=4.4Hz,1H),8.14(d,J=7.9Hz,1H),8.00(td,J=7.7,1.5Hz,1H),7.85(dd,J=8.8,2.3Hz,1H),7.59(d,J =8.9Hz,1H),7.58–7.53(m,2H),5.49–5.43(m,1H),3.76(d,J=7.6Hz,1H),3.33(s,3H),2.81(s,3H),2.76(s,3H),1.44(d,J=6.3Hz,3H).

[1011] Example 80 Preparation of Compounds 164 and 165

[1012]

[1013] 1. Preparation of Compound 165-1

[1014] Dissolve 160-3 (1.616 g, 5.11 mmol) in glacial acetic acid (20 mL), add potassium acetate (1.004 g, 10.23 mmol), iodine (1.303 g, 5.13 mmol), and manganese dioxide (1.454 g, 16.7 mmol), and stir at 80°C for 2 hours. After the reaction is complete, as monitored by TLC, the reaction solution is filtered and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl acetate (30 mL). The organic phase is washed with 10% aqueous sodium thiosulfate solution, saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 165-1 (1.03 g, yield 53.9%) as a white solid. ESI [M+H] + =374.1.

[1015] 2. Preparation of target compound 164

[1016] NaH (141 mg, 60%, 3.52 mmol) was slowly added to a solution of 165-1 (1.013 g, 2.71 mmol) in dry DMF (10 mL) at -20°C and stirred for 30 minutes. Iodomethane (385 mg, 2.71 mmol) was added to the reaction system and stirring continued at -20°C for 1 hour. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 164 (550 mg, 52.3% yield) as an off-white solid. ESI[M+H] + =388.0.

[1017] 1H NMR (400MHz, DMSO-d6) δ8.64(d,J=4.0Hz,1H),8.13(d,J=7.9Hz,1H),8.02(td,J=7.8,1.7Hz,1H),7.90( dd,J=8.9,2.4Hz,1H),7.65(d,J=8.9Hz,1H),7.61–7.55(m,2H),5.93(s,1H),3.37(s,3H),2.23(s,3H).

[1018] 3. Preparation of Compound 165-2

[1019] At 5°C, a solution of sodium hydroxide (102.3 mg, 2.56 mmol) in water (5 mL) was added to a solution of 164 (450 mg, 1.16 mmol) in ethanol (10 mL) and stirred for 1 hour. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 20). The fraction with Rf = 0.3 to 0.4 was collected to obtain compound 165-2 (350 mg, yield 87.2%) as a white solid. ESI [M+H] + =346.1.

[1020] 4. Preparation of target compound 165

[1021] p-Nitrophenyl chloroformate (175 mg, 0.868 mmol) was added to a solution of 165-2 (100 mg, 0.289 mmol), pyridine (67 mg, 0.847 mmol), and DMAP (35.5 mg, 0.291 mmol) in dichloromethane (3 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, dimethylamine (0.87 mL, 2 mol / L in THF, 1.74 mmol) and DIEA (37 mg, 0.286 mmol) were added to the reaction system and stirring continued at room temperature for 2 hours. After completion of the reaction as monitored by TLC, water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100-1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.3-0.4 were collected to obtain an off-white solid compound 165 (2.5 mg, yield 2.1%). ESI [M+H]+ =417.1.

[1022] 1 H NMR (400MHz, DMSO-d6) δ8.63(d,J=4.6Hz,1H),8.11(d,J=7.9Hz,1H),8.00(td,J=7.7,1.6Hz,1H),7.89(dd,J= 8.9, 2.4Hz, 1H), 7.62 (d, J = 8.9Hz, 1H), 7.59-7.56 (m, 2H), 5.84 (s, 1H), 3.35 (s, 3H), 3.09 (s, 3H), 2.86 (s, 3H).

[1023] Example 81 Preparation of Compound 166

[1024]

[1025] Isopropyl chloroformate (52.3 mg, 0.427 mmol) was added dropwise to a solution of 165-2 (80 mg, 0.231 mmol) and DIEA (94.1 mg, 0.728 mmol) in dichloromethane (2 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 166 (21.4 mg, 21.4% yield) as a pale yellow solid. ESI [M+H] + =432.1.

[1026] 1 H NMR (400MHz, DMSO-d6) δ8.51(d,J=4.7Hz,1H),8.05(d,J=2.1Hz,1H),7.84–7.79(m,2H),7.54(d,J=8.6Hz,1H),7.41–7.30 (m,1H),7.17(d,J=8.0Hz,1H),6.89(s,1H),5.11–5.05(m,1H),2.80(s,3H),1.36(d,J=6.2Hz,3H),1.32(d,J=6.2Hz,3H).

[1027] Example 82 Preparation of Compound 167

[1028]

[1029] Isobutyryl chloride (32.3 mg, 0.303 mmol) was added dropwise to a solution of 165-2 (70 mg, 0.202 mmol) and triethylamine (41 mg, 0.405 mmol) in dichloromethane (2 mL) at 0°C and stirred for 1 hour. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system and extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 167 (42.7 mg, 50.7% yield) as a white solid. ESI [M+H] + =416.1.

[1030] 1 H NMR (400MHz, DMSO-d6) δ8.49(d,J=4.3Hz,1H),8.01(d,J=2.2Hz,1H),7.85–7.76(m,2H),7.55(d,J=8.6Hz,1H),7. 38–7.31(m,1H),7.16–7.08(m,2H),3.58–3.51(m,1H),2.83(s,3H),1.26(d,J=6.8Hz,3H),1.16(d,J=6.7Hz,3H).

[1031] Example 83 Preparation of Compounds 169-172

[1032]

[1033] 1. Preparation of Compound 169-1

[1034] Sodium borohydride (1.3 g, 34.4 mmol) was added portionwise to a solution of 1-5 (1.0 g, 2.28 mmol) in methanol (15 mL) at 0°C and stirred for 8 hours. After the reaction was complete as monitored by TLC, ice water (30 mL) was added to the reaction system and extracted with ethyl acetate (3×30 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 10) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). The fraction with Rf = 0.3 to 0.4 was collected to obtain compound 169-1 (266 mg, yield 28.4%) as a white solid. ESI [M+H] + =411.1.

[1035] 2. Preparation of target compound 169

[1036] Propionyl chloride (20.2 mg, 0.218 mmol) was added dropwise to a solution of compound 169-1 (60 mg, 0.146 mmol) and triethylamine (30 mg, 0.296 mmol) in dichloromethane (2 mL) at 0°C and stirred for 1 hour. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system and extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.4 to 0.5 were collected to obtain compound 169 (29.6 mg, 43.4% yield) as a white solid. ESI [M+H] + =467.1.

[1037] 1 H NMR (400MHz, DMSO-d6) δ8.54(ddd,J=4.8,1.7,0.9Hz,1H),8.08(d,J=7.9Hz,1H),7.94(td,J=7.7 ,1.8Hz,1H),7.88(dd,J=8.7,2.3Hz,1H),7.65(d,J=8.7Hz,1H),7.61(d,J=2.3Hz,1H),7.49(ddd ,J=7.5,4.8,1.2Hz,1H),6.80(d,J=1.1Hz,1H),4.19–4.09(m,2H),4.02(dd,J=8.2,6.0Hz,1H),2 .42–2.32(m,2H),2.31–2.24(m,5H),2.03–1.90(m,1H),1.88–1.80(m,1H),1.00(t,J=7.5Hz,3H).

[1038] 3. Preparation of Compound 170

[1039] The preparation method of target compound 170 is similar to that of compound 169 in Example 83, using compound 169-1 and isobutyryl chloride as raw materials.

[1040] Compound 170: 37.3 mg, ESI [M+H] + =481.1.

[1041] 1H NMR (400MHz, DMSO-d6) δ8.57–8.51(m,1H),8.08(d,J=7.9Hz,1H),7.94(td,J=7.7,1.8Hz,1H),7.87(dd,J =8.7,2.3Hz,1H),7.65(d,J=8.7Hz,1H),7.61(d,J=2.3Hz,1H),7.49(ddd,J=7.5,4.8,1.2Hz,1H),6.80(d ,J=1.1Hz,1H),4.13(t,J=6.5Hz,2H),4.02(dd,J=8.0,6.1Hz,1H),2.48–2.43(m,1H),2.42–2.31(m,2H), 2.29(d,J=0.8Hz,3H),1.94–1.91(m,1H),1.89–1.80(m,1H),1.06(d,J=1.2Hz,3H),1.04(d,J=1.2Hz,3H).

[1042] 4. Preparation of Compound 171-1

[1043] At 0°C, p-nitrophenyl chloroformate (215 mg, 1.07 mmol) was added to a solution of 169-1 (146 mg, 0.355 mmol), pyridine (55 mg, 0.695 mmol), and DMAP (87 mg, 0.712 mmol) in dichloromethane (5 mL). The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 171-1 (120 mg, 58.6% yield) as a white solid. ESI[M+H] + =576.1.

[1044] 5. Preparation of target compound 171

[1045] Compound 171-1 (60 mg, 0.104 mmol) and DIEA (13 mg, 0.101 mmol) were dissolved in dichloromethane (2 mL), and dimethylamine (0.1 mL, 2 mol / L in THF, 0.2 mmol) was added. The mixture was stirred at room temperature for 2 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 10) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 171 (13.7 mg, 27.3% yield) as a white solid. ESI [M+H] + =482.1.

[1046] 1 H NMR (400MHz, DMSO-d6) δ8.54(d,J=4.0Hz,1H),8.08(d,J=8.0Hz,1H),7.94(td,J= 7.7,1.7Hz,1H),7.87(dd,J=8.7,2.3Hz,1H),7.65(d,J=8.7Hz,1H),7.60(d,J=2. 3Hz,1H),7.49(dd,J=6.4,4.8Hz,1H),6.80(d,J=1.0Hz,1H),4.10–4.07(m,2H),4 .04–3.98(m,1H),2.78(s,6H),2.41–2.32(m,2H),2.30(s,3H),1.98–1.79(m,2H).

[1047] 6. Preparation of target compound 172

[1048] The preparation method of target compound 172 is similar to that of compound 171 in Example 83, using compound 171-1 and N-isopropylmethylamine as raw materials.

[1049] Compound 172: 22.9 mg, ESI [M+H] + =510.2.

[1050] 1H NMR (400MHz, DMSO-d6) δ8.54(d,J=4.0Hz,1H),8.08(d,J=7.9Hz,1H),7.94(td,J=7.7,1.7Hz,1 H),7.88(dd,J=8.7,2.3Hz,1H),7.65(d,J=8.7Hz,1H),7.61(d,J=2.3Hz,1H),7.49(ddd,J=7.5 ,4.8,1.1Hz,1H),6.81(s,1H),4.22(s,1H),4.10–4.08(m,2H),4.05–3.98(m,1H),2.64(s,3H) ,2.40–2.33(m,2H),2.30(s,3H),1.99–1.89(m,1H),1.85–1.81(m,1H),1.03(d,J=6.7Hz,6H).

[1051] Example 84 Preparation of Compounds 173 and 174

[1052]

[1053] 1. Preparation of Compound 174-1

[1054] Lithium bis(trimethylsilyl)amide (8.3 mL, 1 mol / L, 8.3 mmol) was slowly added dropwise to a solution of 88-4 (3.0 g, 6.88 mmol) in tetrahydrofuran (30 mL) at -30°C and stirred for 1 hour. Dimorpholinophosphinic chloride (4.14 g, 16.3 mmol) was added portionwise and stirred at -10°C for 4 hours. After completion of the reaction as monitored by TLC, ice water (40 mL) was added to the reaction system and the mixture was extracted with ethyl acetate (3 × 40 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was used directly in the next reaction without purification.

[1055] 2. Preparation of target compound 173

[1056] The crude compound from the previous step was dissolved in dioxane (30 mL), and acetohydrazide (2.7 g, 36.4 mmol) was added. After stirring at room temperature for 2 hours, the temperature was raised to 100°C and stirring was continued for 5 hours. The reaction solution was poured into ice water (40 mL) and extracted with ethyl acetate (3×40 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 10) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). The fraction with Rf = 0.3 to 0.4 was collected to obtain Compound 173 (1.395 g, 42.8% yield for two steps) as a pale yellow solid. ESI [M+H] + =474.1.

[1057] 1 H NMR (400MHz, DMSO-d6) δ8.56(d,J=4.3Hz,1H),8.10(d,J=7.8Hz,1H),8.00–7.96(m,2H),7.79(d,J=8.8Hz,1H),7.68(d,J=2.1Hz ,1H),7.57–7.48(m,1H),7.45–7.35(m,4H),7.32–7.29(m,1H),4.72(s,2H),4.52–4.43(m,2H),4.41–4.36(m,1H),2.55(s,3H).

[1058] 3. Preparation of Compound 174-2

[1059] At 0°C, aluminum trichloride (3.79 g, 28.4 mmol) was slowly added to a solution of 173 (1.345 g, 2.84 mmol) in dichloromethane (30 mL). The mixture was allowed to warm to room temperature and stirred for 3 hours. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water (50 mL), filtered, and the filtrate extracted with dichloromethane (3 × 60 mL). The organic phase was washed with 5% aqueous sodium bicarbonate solution, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 10) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 174-2 (650 mg, 59.7% yield) as a white solid. ESI [M+H] + =384.1.

[1060] 4. Preparation of target compound 174

[1061] Isobutyryl chloride (22.1 mg, 0.207 mmol) was added dropwise to a solution of 174-2 (80 mg, 0.208 mmol) and triethylamine (52.7 mg, 0.521 mmol) in dichloromethane (3 mL) at -10°C and stirred for 2 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system and extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.4 to 0.5 were collected to obtain compound 174 (46.8 mg, 49.5% yield) as a white solid. ESI [M+H] + =454.1.

[1062] 1 H NMR (400MHz, DMSO-d6) δ8.57(d,J=4.5Hz,1H),8.07(d,J=7.9Hz,1H),8.02–7.94(m,2H),7.82(d,J=8.7Hz,1H),7.71(d,J=2.2Hz,1H),7.54(dd,J=6.5, 4.9Hz,1H),4.98(dd,J=11.0,7.7Hz,1H),4.90(dd,J=11.0,5.6Hz,1H),4.6 3(dd,J=7.5,5.7Hz,1H),2.63–2.58(m,1H),2.57(s,3H),1.15–1.12(m,6H).

[1063] Example 85 Preparation of Compound 175

[1064]

[1065] 3-Oxetanecarboxylic acid (39.9 mg, 0.391 mmol), DCC (80.7 mg, 0.391 mmol), and DMAP (95.6 mg, 0.783 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 15 minutes. Compound 174-2 (100 mg, 0.260 mmol) was added to the reaction system and stirred at room temperature for 12 hours. After completion of the reaction as monitored by TLC, methyl tert-butyl ether (2 mL) was added to the reaction system, stirred for 5 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 10) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 175 (36.5 mg, 29.9% yield) as a white solid. ESI [M+H] + =468.1.

[1066] 1 H NMR (400MHz, DMSO-d6) δ8.57(d,J=4.1Hz,1H),8.08(d,J=7.9Hz,1H),8.02–7.94(m,2H),7.82(d,J=8.7Hz,1H),7.71(d,J =2.3Hz,1H),7.57–7.50(m,1H),5.09–4.99(m,2H),4.76–4.72(m,2H),4.71–4.66(m,3H),4.01–3.94(m,1H),2.57(s,3H).

[1067] Example 86 Preparation of Compound 176

[1068]

[1069] Isopropyl chloroformate (95.6 mg, 0.780 mmol) was added dropwise to a solution of 174-2 (100 mg, 0.260 mmol), pyridine (60.3 mg, 0.762 mmol), and DMAP (31.9 mg, 0.261 mmol) in dichloromethane (2 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, ice water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100-1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 20). Fractions with Rf = 0.3-0.4 were collected to obtain compound 176 (45.4 mg, 37.1% yield) as a white solid. ESI [M+H]+ =470.1.

[1070] 1 H NMR (400MHz, DMSO-d6) δ8.58(d,J=4.8Hz,1H),8.08(d,J=7.9Hz,1H),8.02–7.95(m,2H),7.82(d,J=8.7Hz,1H),7.72(d,J=2 .3Hz,1H),7.58–7.50(m,1H),5.05–4.95(m,2H),4.89–4.79(m,1H),4.67(t,J=6.5Hz,1H),2.57(s,3H),1.29–1.25(m,6H).

[1071] Example 87 Preparation of Compound 177

[1072]

[1073] At 0°C, p-nitrophenyl chloroformate (158 mg, 0.784 mmol) was added to a solution of 174-2 (100 mg, 0.260 mmol), pyridine (60.3 mg, 0.762 mmol), and DMAP (63.7 mg, 0.521 mmol) in dichloromethane (5 mL). The mixture was allowed to warm to room temperature and stirred for 12 hours. After the reaction was complete as monitored by TLC, dimethylhydroxylamine hydrochloride (153 mg, 1.57 mmol) and DIEA (202 mg, 1.56 mmol) were added to the reaction system and stirring continued at room temperature for 2 hours. After the reaction was complete as monitored by TLC, ice water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 20) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 177 (66.3 mg, 54.1% yield) as a white solid. ESI [M+H] + =471.2.

[1074] 1H NMR (400MHz, DMSO-d6) δ8.58(d,J=4.2Hz,1H),8.08(d,J=7.9Hz,1H),8.02–7.96(m,2H),7.83(d,J=8.7Hz,1H),7.71(d,J= 2.2Hz,1H),7.54(dd,J=6.4,4.9Hz,1H),5.04–4.93(m,2H),4.66(t,J=6.6Hz,1H),3.63(s,3H),3.12(s,3H),2.57(s,3H).

[1075] Example 88 Preparation of Compound 178

[1076]

[1077] 1. Preparation of Compound 178-1

[1078] Potassium nitrate (15.3 g, 151.3 mmol) was dissolved in concentrated sulfuric acid (50 mL) and added dropwise to a solution of methyl 2,4-difluorobenzoate (20.0 g, 116.2 mmol) in concentrated sulfuric acid (200 mL) at 0°C, with the temperature controlled to not exceed 10°C. After the addition, the mixture was allowed to warm to room temperature and stirred for 1 hour. After the reaction was complete as monitored by TLC, the reaction solution was poured into ice and filtered. The filter cake was washed three times with water and dried under vacuum to obtain compound 178-1 (24.5 g, yield 97.1%). ESI [M+H] + =218.1.

[1079] 2. Preparation of Compound 178-2

[1080] 178-1 (24.5 g, 112.8 mmol) was dissolved in ethanol (250 mL), and potassium carbonate (43.6 g, 315.5 mmol) and 2-ethylhexyl 3-mercaptopropionate (24.6 g, 112.8 mmol) were added. The mixture was stirred at 50°C for 1 hour. After completion of the reaction as monitored by TLC, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 to 1 / 10) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 178-2 (41.9 g, 89.4% yield) as a white solid. ESI [M+H]+ = 416.1.

[1081] 3. Preparation of Compound 178-3

[1082] 178-2 (41.0 g, 98.7 mmol) was dissolved in DMSO (400 mL), and potassium carbonate (20.5 g, 148.3 mmol) and 2,4-dimethoxybenzylamine (16.5 g, 98.7 mmol) were added. The mixture was stirred at 90°C for 2 hours. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water and extracted with ethyl acetate (3 × 200 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 to 1 / 10) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 178-3 (44.6 g, yield 80.3%). ESI [M+H]+ = 563.3.

[1083] 4. Preparation of Compound 178-4

[1084] Zinc powder (13.0 g, 198.8 mmol) was added portionwise to a mixture of 178-3 (37.6 g, 66.8 mmol) in methanol / saturated aqueous ammonium chloride (500 mL, v / v = 4 / 1) and stirred at room temperature for 1 hour. After the reaction was complete as monitored by TLC, the reaction system was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 to 1 / 10) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3). Fractions with Rf = 0.2 to 0.3 were collected to obtain compound 178-4 (26.3 g, yield 73.9%). ESI [M+H] + =533.2.

[1085] 5. Preparation of Compound 178-5

[1086] Acetyl chloride (1.7 g, 21.7 mmol) was added dropwise to a solution of compound 178-4 (14.4 g, 27.0 mmol) and DIEA (6.98 g, 54.0 mmol) in dichloromethane (150 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 2 hours. After completion of the reaction as monitored by TLC, ice water (100 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (3 × 100 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 178-5 (4.2 g, 27.0% yield). ESI [M+H] + =575.3.

[1087] 6. Preparation of Compound 178-6

[1088] At room temperature, 178-5 (4.2 g, 7.31 mmol) was dissolved in tetrahydrofuran (42 mL), and a solution of sodium methoxide (1.18 g, 21.8 mmol) in methanol (20 mL) was added dropwise. The mixture was stirred for 30 minutes. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was used directly in the next reaction without purification. ESI [M+H] + =373.1.

[1089] 7. Preparation of Compound 178-7

[1090] The crude compound from the previous step was dissolved in dichloromethane (30 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred at 37°C for 2 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The residue was dissolved in water, the pH of the system was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution, and then extracted with EtOAc (3×30 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (methanol / dichloromethane (v / v) = 1 / 100-1 / 30) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 30). The fraction with Rf = 0.4-0.5 was collected to obtain compound 178-7 (1.6 g, 98.5% yield for two steps). ESI [M+H] + =223.1.

[1091] 8. Preparation of Compound 178-8

[1092] LiOH.H2O (360 mg, 8.58 mmol) and NaOH (378 mg, 9.45 mmol) were added sequentially to a solution of 178-7 (1.6 g, 7.20 mmol) in THF / MeOH / H2O (20 mL, v / v / v = 1 / 1 / 1) at 0°C. The temperature was slowly raised to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, the pH of the system was adjusted to 6-7 with 1 mol / L hydrochloric acid in an ice bath, followed by extraction with ethyl acetate (3 x 30 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 10) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound 178-8 (1.3 g, yield 86.7%) as a white solid. ESI [M+H] + =209.1.

[1093] 9. Preparation of Compounds 178-9 and 178-10

[1094] 2-Bromopyridine (347.6 mg, 2.2 mmol) was added dropwise to a solution of n-butyllithium (0.8 mL, 2.5 mol / L inhexane, 2.0 mmol) in tetrahydrofuran (3 mL) at -40°C. The mixture was stirred for 30 minutes. A solution of 178-8 (111 mg, 0.533 mmol) in tetrahydrofuran (2 mL) was added dropwise to the reaction system, naturally warmed to 0°C, and stirred for 3 hours. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water and extracted with ethyl acetate (3 x 20 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.3 to 0.5 were collected to obtain compound 178-9 (10 mg, yield 6.97%) and compound 178-10 (31.7 mg, yield 18.3%). 178-9: ESI [M+H] + =270.1.178-10:ESI[M+H] + =326.1.

[1095] 10. Preparation of Compound 178-11

[1096] Compound 178-9 (10 mg, 0.037 mmol) and Boc-L-glutamic acid-5-methyl ester (12.6 mg, 0.048 mmol) were dissolved in dichloromethane (2 mL). A solution of DCC (17.6 mg, 0.085 mmol) in dichloromethane (1 mL) was added dropwise at -10°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, methyl tert-butyl ether (3 mL) was added to the reaction system and stirred for 5 minutes. The reaction system was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) and the fraction with Rf = 0.2-0.3 was collected to obtain compound 178-11 (16.2 mg, yield 85.1%). ESI [M+H] + =513.2.

[1097] 11. Preparation of Compound 178-12

[1098] Trifluoroacetic acid (1 mL) was added to a solution of 178-11 (16.2 mg, 0.032 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 hour. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was used directly in the next reaction without purification. ESI [M+H] + =413.1.

[1099] 12. Preparation of Compound 178-13

[1100] The crude compound from the previous step was dissolved in acetonitrile (2 mL), sodium bicarbonate (80 mg, 0.952 mmol) was added, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete as monitored by TLC, the reaction solution was filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 4 / 1) and the fraction with Rf = 0.2-0.3 was collected to obtain compound 178-13 (12.0 mg, two-step yield 96.3%). ESI [M+H] + =395.1.

[1101] 13. Preparation of target compound 178

[1102] NaH (1.34 mg, 60%, 0.033 mmol) was added to a solution of 178-13 (12.0 mg, 0.03 mmol) in dry DMF (2 mL) at -10°C and stirred for 30 minutes. Iodomethane (4.76 mg, 0.033 mmol) was added to the reaction system and stirring continued at -10°C for 1 hour. After the reaction was complete as monitored by TLC, the reaction solution was poured into ice water (5 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (methanol / dichloromethane (v / v) = 1 / 10) and fractions with Rf = 0.4-0.5 were collected to obtain the target compound 178 (7.2 mg, 57.9% yield). ESI [M+H] + =409.1.

[1103] 1 H NMR (400MHz, DMSO-d6) δ8.55(d,J=4.0Hz,1H),8.29(s,1H),8.14(d,J=7.9Hz,1H),8.01–7.95(m,1H),7.78(s,1H),7.52(ddd,J=7.5,4.8, 1.1Hz,1H),3.75(dd,J=7.8,5.6Hz,1H),3.57(s,3H),3.37(s,3H),2.81(s,3H),2.52–2.42(m,2H),2.41–2.30(m,1H),2.29–2.22(m,1H).

[1104] Example 89 Preparation of Compound 179

[1105]

[1106] 1. Preparation of Compound 179-1

[1107] Compound 178-10 (31.7 mg, 0.097 mmol) and Boc-L-glutamic acid-5-methyl ester (33.0 mg, 0.126 mmol) were dissolved in dichloromethane (2 mL). A solution of DCC (26.0 mg, 0.126 mmol) in dichloromethane (1 mL) was added dropwise at -10°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, methyl tert-butyl ether (3 mL) was added to the reaction system and stirred for 5 minutes. The reaction system was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) and the fraction with Rf = 0.2-0.3 was collected to obtain compound 179-1 (51.1 mg, yield 92.2%). ESI [M+H] +=569.2.

[1108] 2. Preparation of Compound 179-2

[1109] Trifluoroacetic acid (1 mL) was added to a solution of 179-1 (51.1 mg, 0.09 mmol) in dichloromethane (2 mL) and stirred at room temperature for 1 hour. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was used directly in the next reaction without purification. ESI [M+H] + =469.2.

[1110] 3. Preparation of Compound 179-3

[1111] The crude compound from the previous step was dissolved in acetonitrile (2 mL), sodium bicarbonate (226 mg, 2.69 mmol) was added, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete as monitored by TLC, the reaction solution was filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 5 / 1) and the fraction with Rf = 0.2-0.3 was collected to obtain compound 179-3 (34.9 mg, two-step yield 86.2%). ESI [M+H] + =451.2.

[1112] 4. Preparation of target compound 179

[1113] NaH (3.7 mg, 60%, 0.092 mmol) was added to a solution of 179-3 (34.9 mg, 0.077 mmol) in dry DMF (2 mL) at -10°C and stirred for 30 minutes. Iodomethane (13.2 mg, 0.093 mmol) was added to the reaction system and stirring continued at -10°C for 1 hour. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water (5 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (methanol / dichloromethane (v / v) = 1 / 10) and fractions with Rf = 0.4-0.5 were collected to obtain the target compound 179 (16.4 mg, 45.6% yield). ESI [M+H] + =465.2.

[1114] 1H NMR (400MHz, DMSO-d6) δ8.55(d,J=4.2Hz,1H),8.30(s,1H),8.14(d,J=7.9Hz,1H ),8.02–7.94(m,1H),7.80(s,1H),7.56–7.49(m,1H),3.80–3.73(m,1H),3.57(s ,3H),3.38(s,3H),3.11(t,J=7.5Hz,2H),2.52–2.41(m,2H),2.36–2.34(m,1H), 2.30–2.19(m,1H),1.87–1.75(m,2H),1.38–1.32(m,4H),0.87(t,J=7.0Hz,3H).

[1115] Example 90 Preparation of Compounds 180 and 181

[1116]

[1117] 1. Preparation of Compound 181-1

[1118] 178-4 (11.9 g, 22.3 mmol) was dissolved in methanol (120 mL), and ethyl trifluoroacetate (9.53 g, 67.1 mmol) and triethylamine (2.26 g, 22.3 mmol) were added. The mixture was stirred at room temperature for 12 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 to 1 / 3) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3). The fractions with Rf = 0.4 to 0.5 were collected to obtain compound 181-1 (6.2 g, yield 44.1%). ESI [M+H] + =629.2.

[1119] 2. Preparation of Compound 181-2

[1120] At room temperature, 181-1 (6.2 g, 9.86 mmol) was dissolved in tetrahydrofuran (62 mL), and a solution of sodium methoxide (1.75 g, 32.4 mmol) in methanol (20 mL) was added dropwise. The mixture was stirred for 30 minutes. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The crude product was used directly in the next reaction without purification. ESI [M+H] + =427.1.

[1121] 3. Preparation of Compound 181-3

[1122] The crude compound from the previous step was dissolved in dichloromethane (40 mL), trifluoroacetic acid (20 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. The residue was dissolved in water, the pH of the system was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution, and then extracted with EtOAc (3×50 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 to 1 / 2) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). The fraction with Rf = 0.2-0.3 was collected to obtain compound 181-3 (1.224 g, 44.9% yield for two steps). ESI [M+H] + =277.0.

[1123] 4. Preparation of Compound 181-4

[1124] NaOH (348 mg, 8.69 mmol) was added to a solution of 181-3 (1.2 g, 4.34 mmol) in THF / MeOH / H₂O (12 mL, v / v / v = 1 / 1 / 1) at 0°C. The mixture was slowly warmed to room temperature and stirred for 4 hours. After completion of the reaction as monitored by TLC, the pH of the system was adjusted to 6-7 with 1 mol / L hydrochloric acid in an ice bath, followed by extraction with ethyl acetate (3 × 30 mL). The organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100-1 / 10) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.3-0.4 were collected to obtain compound 181-4 (1.05 g, 92.2% yield). ESI[M+H] + =263.0.

[1125] 5. Preparation of Compound 181-5

[1126] 2-Bromopyridine (2.222 g, 14.1 mmol) was added dropwise to a solution of n-butyllithium (5.11 mL, 2.5 mol / L inhexane, 12.8 mmol) in tetrahydrofuran (10 mL) at -40°C. The mixture was stirred for 30 minutes. A solution of 181-4 (908 mg, 3.46 mmol) in tetrahydrofuran (2 mL) was added dropwise to the reaction system, which was naturally warmed to -10°C and stirred for 3 hours. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water and extracted with ethyl acetate (3 × 20 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 to 1 / 10) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). The fractions with Rf = 0.2 to 0.4 were collected to obtain compound 181-5 (506 mg, yield 45.2%). ESI [M+H] + =324.0.

[1127] 6. Preparation of Compound 181-6

[1128] Compound 181-5 (506 mg, 1.57 mmol) and 5-methyl Boc-L-glutamic acid ester (613 mg, 2.35 mmol) were dissolved in dichloromethane (5 mL). A solution of DCC (484 mg, 2.35 mmol) in dichloromethane (2 mL) was added dropwise at -10°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. After completion of the reaction as monitored by TLC, methyl tert-butyl ether (7 mL) was added to the reaction system and stirred for 5 minutes. The reaction system was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 to 1 / 2) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). Fractions...

Claims

1. A compound of general formula I, and pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds thereof: in, Y is selected from N or -CF; A is selected from N or CH; M does not exist, or forms a ring with the adjacent carbon to form a saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring; When M does not exist, R x -H, halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl; when M forms a cyclic ring with the adjacent carbon, R x does not exist; n1 is 0, 1 or 2; The H on the above saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring can be substituted by the following groups: halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 alkyl); Q is selected from O, S-Rxx, N or R3 is selected from -H, C 1-5 A straight chain / branched alkyl group, wherein the H on the alkyl group may be substituted by the following groups: -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, 3-8 membered heterocycloalkyl, -COO(C 0-10 Alkyl), wherein the heterocycloalkyl contains at least one N, O, or S as a ring atom; Rxx is selected from H, C 1-5 A straight chain / branched alkyl group, wherein the H on the alkyl group may be substituted by the following groups: halogen, nitro, cyano, -OC 0-10 alkyl; When Q is N, R3, Q, the N atom and the C atom therebetween form a five-membered aromatic heterocyclic ring or a six-membered aromatic heterocyclic ring having at least two heteroatoms; L does not exist, or L is selected from C 2-8 Olefinic bond or C 1-8 Alkylene, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -CF3, -OCH2F, -OCHF2, -OCF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, -CO(C 0-10 Alkyl), -COO(C 0-10 alkyl); When Q is N or When A is N, Q, A, L and the atoms therebetween form a five-membered or six-membered nitrogen-containing heterocyclic ring; n is 0 or 1. When n is 0, it means that the -CO- group does not exist; X is absent, or when n is 1, X is O, when n is 0, X is selected from O, substituted / unsubstituted N-alkyl, substituted / unsubstituted N-heterocycloalkyl; R4 is selected from -H, halogen, -CN, -CF3, -OCH2F, -OCHF2, -OCF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl, aryl, N heteroaromatic, O heteroaromatic, S heteroaromatic, -SO2(C 0-10 Alkyl), -SO(C 0-10 Alkyl), -SO2O(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO2(C 3-10 Cycloalkyl), -SO2-aryl, -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 alkyl), -CO(C 3-10 Cycloalkyl), -CO(3-6 membered heterocycloalkyl), -(C 0-10 alkyl)COO(C 0-10 Alkyl), -COO(C 3-10 Cycloalkyl), -COO (3-6 membered heterocycloalkyl), alkenyl, alkynyl, wherein the heterocycloalkyl contains at least one N, O, S as a ring atom, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -NO2, -CF3, C 1-3 Straight chain alkyl, -OC 0-10 Alkyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -COO(C 3-10 Cycloalkyl), -COO(heterocycloalkyl), -CO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -OCOO(C 0-10 alkyl), phenyl, N heterocyclic aromatic group, O heterocyclic aromatic group, S heterocyclic aromatic group, alkenyl group, alkynyl group.

2. The compound according to claim 1, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, whose structural formula is as follows: in, Y is selected from N or -CF; R1 and R2 are each independently selected from -H, halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, or R1, R2 and the C atom between R1 and R2 form a five-membered aromatic heterocycle, a six-membered aromatic heterocycle or an aromatic ring, wherein the five-membered aromatic heterocycle is selected from furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, thiazole, and the six-membered aromatic heterocycle is selected from pyridine, pyridazine, pyrimidine, pyrazine; optionally, the H on the five-membered aromatic heterocycle, the six-membered aromatic heterocycle or the aromatic ring may be substituted by the following groups: halogen, -CN, -CF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl; Q is selected from O or N, R3 is selected from -H, C 1-5 A straight chain / branched alkyl group, wherein the H on the alkyl group may be substituted by the following groups: -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, 3-8 membered heterocycloalkyl, wherein the heterocycloalkyl contains at least one N, O, S as a ring atom; When Q is N, R3, Q, the N atom and the C atom therebetween form a five-membered aromatic heterocyclic ring or a six-membered aromatic heterocyclic ring having at least two heteroatoms; L does not exist, or L is selected from C 2-8 Olefinic bond or C 1-8 Alkylene, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -CF3, -OCH2F, -OCHF2, -OCF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, -CO(C 0-10 Alkyl), -COO(C 0-10 alkyl); n is 0 or 1. When n is 0, it means that the -CO- group does not exist; X is absent, or when n is 1, X is O, when n is 0, X is selected from O, substituted / unsubstituted N-alkyl, substituted / unsubstituted N-heterocycloalkyl; R4 is selected from -H, halogen, -CN, -CF3, -OCH2F, -OCHF2, -OCF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl, aryl, N heteroaromatic, O heteroaromatic, S heteroaromatic, -SO2(C 0-10 Alkyl), -SO(C 0-10 Alkyl), -SO2O(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO2(C 3-10 Cycloalkyl), -SO2-aryl, -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl), -CO(C 3-10 Cycloalkyl), -CO(3-6 membered heterocycloalkyl), -(C 0-10 alkyl)COO(C 0-10 Alkyl), -COO(C 3-10 Cycloalkyl), -COO (3-6 membered heterocycloalkyl), alkenyl, alkynyl, wherein the heterocycloalkyl contains at least one N, O, S as a ring atom, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -NO2, -CF3, C 1-3 Straight chain alkyl, -OC 0-10 Alkyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -COO(C 3-10 Cycloalkyl), -COO(heterocycloalkyl), -CO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -OCOO(C 0-10 alkyl), phenyl, N heterocyclic aromatic group, O heterocyclic aromatic group, S heterocyclic aromatic group, alkenyl group, alkynyl group.

3. The compound according to claim 2, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, whose structural formula is as follows: in, Y is selected from N or -CF; R1 and R2 are each independently selected from -H, -F, -Cl, -Br, -NO2, -CN, -CF3, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, or R1, R2 and the C atom between R1 and R2 form a five-membered aromatic heterocycle, a six-membered aromatic heterocycle or a benzene ring, wherein the five-membered aromatic heterocycle is selected from furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, thiazole, and the six-membered aromatic heterocycle is selected from pyridine, pyridazine, pyrimidine, pyrazine; optionally, the H on the five-membered aromatic heterocycle, the six-membered aromatic heterocycle or the benzene ring may be substituted by the following groups: halogen, -CN, -CF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl; Q is selected from O or N, R3 is selected from -H, C 1-5 A straight chain / branched alkyl group, wherein the H on the alkyl group may be substituted by the following groups: -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, 3-8 membered heterocycloalkyl, wherein the heterocycloalkyl contains at least one N, O, S as a ring atom; When Q is N, R3, Q, the N atom and the C atom therebetween form a five-membered aromatic heterocyclic ring or a six-membered aromatic heterocyclic ring having at least two heteroatoms; L does not exist, or L is selected from C 2-4 Olefinic bond or C 1-8 Alkylene, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -CF3, -OCH2F, -OCHF2, -OCF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, 3-10 membered cycloalkyl, -CO(C 0-10 Alkyl), -COO(C 0-10 alkyl); R a Selected from -H, C 1-10 Straight chain / branched chain alkyl, -OR b , R b Selected from C 1-10 Straight chain / branched chain alkyl, C 3-10 Cycloalkyl, 3-8 membered heterocycloalkyl, aryl, heteroaryl, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -CH3, -C2H5, -OC 1-5 , C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -CO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), vinyl, propadienyl, ethynyl, and further, the alkyl part can be -CN, -OCH2F, -OCHF2, -OCF3, -OC 0-10 Alkyl, C 3-4 Cycloalkyl substitution; R c Selected from -H, C 1-10 Straight chain / branched chain alkyl, C 3-10 Cycloalkyl, -CH2CO(C 0-10 alkyl), -CH2COO(C 0-6 alkyl), -CH2COO(C 3-6 Cycloalkyl), -CH2COO(C 3-6 Heterocycloalkyl), -CH2CON(C 0-10 Alkyl)(C 0-10 alkyl), benzyl, aryl, the H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -NO2, C 1-10 Straight chain / branched chain alkyl, 3-6 membered heterocyclic alkyl, -OC 1-5 Alkyl, -N(C 1-3 Alkyl)(C 1-3 Alkyl), C 2-8 alkenyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl; or R c Selected from R c1 , R c2 , R c3 Independently selected from C 1-10 Straight chain / branched chain alkyl, -OC 0-5 Alkyl, -O(C 3-6 Cycloalkyl), -O(C 3-6 Heterocycloalkyl), C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, -N(C 0-10 Alkyl)(C 0-10 alkyl), alkenyl, alkynyl, aryl, heteroaryl, the H on the above groups can be halogen, -CN, -CH3, -C2H5, -OCH3, -N(C 1-3 Alkyl)(C 1-3 Alkyl), -C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, vinyl substituted, the alkyl part can be -CN, -OCF3, -OC 0-10 Alkyl, C 3-4 Cycloalkyl substitution; R d1 and R d2 Each independently selected from H, C 1-10 Straight chain / branched chain alkyl, -COO(C 0-10 alkyl), -CO(C 0-10 alkyl), 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, aryl, or R d1 and R d2 The N atoms between them form a 3-6 membered heterocycloalkyl group. The H on the above group can be substituted by the following groups: halogen, -CN, -NO2, C 1-3 Straight chain / branched chain alkyl, -OC 1-3 Alkyl, C 3-6 Cycloalkyl, -(C 0-10 alkyl)COO(C 0-10 alkyl), -CO(C 0-10 alkyl), aryl, -N(C 1-3 Alkyl)(C 1-3 Alkyl), the alkyl part can be -CN, -OCF3, -OC 0-10 Alkyl, -CO(C 0-10 Alkyl), C 3-4 Cycloalkyl, aryl substitution; R e1 and R e2 Each independently selected from H, C 1-3 Straight chain / branched chain alkyl.

4. The compound according to claim 3, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, which have the following structural formula: m is an integer between 0 and 4; R5 is selected from -H, halogen, -CN, -CF3, -CO(C 0-10 Alkyl), -COO(C 0-10 alkyl); R6 is selected from -H, C 1-10 Straight chain / branched chain alkyl, C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, aryl, wherein The H on the above groups can be substituted by the following groups: halogen, -CN, -CH3, -C2H5, -OCH3, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -CO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), vinyl, propadienyl, ethynyl, and further, the alkyl portion may be -CN, -OCH2F, -OCHF2, -OCF3, -OC 0-10 Alkyl, C 3-4 Cycloalkyl substitution; R 16 Selected from C 1-10 Straight chain / branched chain alkyl, -OC 0-5 Alkyl, -O(C 3-4 Cycloalkyl), -O(C 3-4 Heterocycloalkyl), C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, -N(C 0-10 Alkyl)(C 0-10 alkyl), vinyl, ethynyl, aryl, pyridyl, imidazolyl, the H on the above groups can be halogen, -CN, -CH3, -C2H5, -OCH3, -N(C 1-3 Alkyl)(C 1-3 Alkyl), -C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, vinyl substituted, the alkyl part can be -CN, -OCF3, -OC 0-10 Alkyl, C 3-4 Cycloalkyl substitution; R 19 Selected from -H, -C 1-10 Straight chain / branched chain alkyl, -C 3-10 Cycloalkyl, -CH2CO(C 1-5 alkyl), -CH2COO(C 1-5 alkyl), -CH2COO(C 3-6 Cycloalkyl), -CH2COO(C 3-6 Heterocycloalkyl), -CH2CON(C 1-3 Alkyl)(C 1-3 alkyl), benzyl, aryl, the H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -NO2, -CH3, -C2H5, -C3H7, 3-6 membered heterocycloalkyl, -OC 1-3 Alkyl, -N(C 1-3 Alkyl)(C 1-3 alkyl), vinyl, imidazolyl, oxazolyl, thiazolyl, pyridyl; R 20a and R 20b Each independently selected from H, C 1-10 Straight chain / branched chain alkyl, -COO(C 0-10 alkyl), -CO(C 0-10 Alkyl), C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, aryl, or R d1 and R d2 The N atoms between them form a 3-6-membered N-heterocycloalkyl group. The H on the above group can be replaced by the following groups: -F, -Cl, -CN, -NO2, -CH3, -C2H5, -OC 1-3 Alkyl, C 3-6 Cycloalkyl, -(C 0-3 alkyl)COO(C 0-5 alkyl), -CO(C 0-5 Alkyl), -N(C 1-3 Alkyl)(C 1-3 Alkyl), aryl, the alkyl part can be -CN, -OCF3, -OC 0-3 Alkyl, -CO(C 0-5 Alkyl), C 3-4 Cycloalkyl, aryl substitution.

5. The compound according to claim 4, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, which have the following structural formula: in, Y is selected from N or -CF; P is N or CH; m is an integer between 0 and 4; R7 is selected from -H, -F, -Cl, -Br, -I, -NO2, -CN, alkenyl, alkynyl, -CF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl; R8 is selected from -H, -CN, -CF3, C 1-4 Straight chain / branched chain alkyl, C 3-10 cycloalkyl; R9 is selected from -H, -F, -Cl, -Br, -I, -NO2, -CN, alkenyl, alkynyl, -CF 3、 , C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl; R 10 Selected from -H, C 1-3 A straight chain or branched chain alkyl group, wherein the H on the alkyl group may be replaced by -N(C 1-3 Alkyl)(C 1-3 Alkyl), five-membered or six-membered N-heterocycloalkyl; R 6’ and R 6” Each independently selected from -H, C 1-10 Straight chain / branched chain alkyl, C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, aryl, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -CH3, -C2H5, -OCH3, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -CO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), vinyl, propadienyl, ethynyl, and further, the alkyl portion may be -CN, -OCH2F, -OCHF2, -OCF3, -OC 0-10 Alkyl, C 3-4 Cycloalkyl substitution; R 16’ , R 16” , R 16* , R 16** R 16# and R 16## Each independently selected from C 1-10 Straight chain / branched chain alkyl, -OC 0-5 Alkyl, -O(C 3-4 Cycloalkyl), -O(C 3-4 Heterocycloalkyl), C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, -N(C 0-10 Alkyl)(C 0-10 alkyl), vinyl, ethynyl, aryl, pyridyl, imidazolyl, the H on the above groups can be halogen, -CN, -CH3, -C2H5, -OCH3, -N(C 1-3 Alkyl)(C 1-3 Alkyl), -C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, vinyl substituted, the alkyl part can be -CN, -OCF3, -OC 0-10 Alkyl, C 3-4 Cycloalkyl substitution; R 19’ and R 19” Each independently selected from -H, -C 1-10 Straight chain / branched chain alkyl, -C 3-10 Cycloalkyl, -CH2CO(C 1-5 alkyl), -CH2COO(C 1-5 alkyl), -CH2COO(C 3-6 Cycloalkyl), -CH2COO(C 3-6 Heterocycloalkyl), -CH2CON(C 1-3 Alkyl)(C 1-3 alkyl), benzyl, aryl, the H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -NO2, -CH3, -C2H5, -C3H7, 3-6 membered heterocycloalkyl, -OC 1-3 Alkyl, -N(C 1-3 Alkyl)(C 1-3 alkyl), vinyl, imidazolyl, oxazolyl, thiazolyl, pyridyl; R 20a’ , R 20a” , R 20b’ and R 20b” Each independently selected from H, C 1-10 Straight chain / branched chain alkyl, -COO(C 0-10 alkyl), -CO(C 0-10 Alkyl), C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, aryl, or R d1 and R d2 The N atoms between them form a 3-6-membered N-heterocycloalkyl group. The H on the above group can be replaced by the following groups: -F, -Cl, -CN, -NO2, -CH3, -C2H5, -OC 1-3 Alkyl, C 3-6 Cycloalkyl, -(C 0-3 alkyl)COO(C 0-5 alkyl), -CO(C 0-5 Alkyl), -N(C 1-3 Alkyl)(C 1-3 Alkyl), aryl, the alkyl part can be -CN, -OCF3, -OC 0-3 Alkyl, -CO(C 0-5 Alkyl), C 3-4 Cycloalkyl, aryl substitution.

6. The compound according to claim 5, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, which have the following structural formula: in, Y is selected from N or -CF; P is N or CH; m1 is an integer between 0 and 2; R 11 Selected from -F, -Cl, -Br, -I, -NO2, ethynyl, -CF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl; R 6a Selected from or C 1-4 Alkyl, the H on the alkyl can be -F, -OCH3, C 3-6 Cycloalkyl substitution, R 6a1 is selected from -H, -CN, -CH3, -C2H5, vinyl, propadienyl, ethynyl; R 6a2 Selected from vinyl, ethynyl, -COCH3, -COC2H5, 3-4-membered epoxyalkyl; R 6a3 Selected from -CH3, -C2H5, -OCH3, -OC2H5; R 12 Selected from -F, -Cl, -Br, -I, -NO2, ethynyl, -CF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl; R 13 , R 13’ , R 13” Each independently selected from -H, C 1-3 Straight chain / branched alkyl, the H on the alkyl can be replaced by -N(C 1-3 Alkyl)(C 1-3 Alkyl), five-membered or six-membered N-heterocycloalkyl; R 6b Selected from -H, -CH3, -C2H5, propyl, isopropyl, butyl, tert-butyl, 3-4 membered saturated cycloalkyl, the H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -CH3, -C2H5, -OCH3, C 3-4 Cycloalkyl, 3-6 membered heterocycloalkyl, -CO(C 1-3 Alkyl), -OCO(C 1-3 Alkyl), vinyl, ethynyl, further, the alkyl part may be substituted by -OCH3, -OC2H5; R 14 Selected from -H, halogen, -NO2, -CN, -CF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl; R 6c Selected from -H, C 1-5 Straight chain / branched chain alkyl, -OC 0-5 Alkyl, C 3-6 Cycloalkyl, -O heterocycloalkyl, the H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -CH3, -C2H5, -OCH3, C 3-4 Cycloalkyl, vinyl, ethynyl; T is C, N, O or S; R 15 Selected from -H, halogen, -NO2, -CN, -CF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl; R 6d Selected from -H, C 1-5 Straight chain / branched chain alkyl, -OC 0-5 Alkyl, C 3-6 Cycloalkyl, -O heterocycloalkyl, the H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -CH3, -C2H5, -OCH3, C 3-4 Cycloalkyl, vinyl, ethynyl.

7. The compound according to claim 5, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, which have the following structural formula: in, Y is selected from N or -CF; m1 is an integer between 0 and 2; R 17 、R'17、R"17、R 18 , R' 18 , R” 18 Each independently selected from -F, -Cl, -Br, -I, -NO2, ethynyl, -CF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl; R 16a1 and R 16a2 Each independently selected from C 1-5 Straight chain / branched chain alkyl, -OC 1-3 Alkyl, -O(C 3-4 Cycloalkyl), -O(C 3-4 Heterocycloalkyl), C 3-6 Cycloalkyl, 3-6 membered N heterocycloalkyl, 3-6 membered O heterocycloalkyl, -N(C 0-10 Alkyl)(C 0-10 alkyl), vinyl, ethynyl, aryl, pyridyl, imidazolyl, the H on the above groups can be halogen, -CN, -CH3, -C2H5, -OCH3, -N(C 1-3 Alkyl)(C 1-3 Alkyl), vinyl substituted; R 16b1 and R 16b2 Each independently selected from C 1-5 Straight chain / branched chain alkyl, -OC 1-3 Alkyl, C 3-6 Cycloalkyl, aryl, -N(C 1-3 Alkyl)(C 1-3 Alkyl), the H on the above groups can be replaced by halogen, -CN, -CH3, -C2H5, -OCH3; R 16c1 and R 16c2 Each independently selected from C 1-5 Straight chain / branched chain alkyl, -OC 1-3 Alkyl, C 3-6 Cycloalkyl, aryl.

8. The compound according to claim 5, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, which have the following structural formula: in, Y is selected from N or -CF; m1 is an integer between 0 and 2; R 17 and R 18 independently selected from -F, -Cl, -Br, -I, -NO2, ethynyl, -CF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl; R 19a1 and R 19a2 Each independently selected from -H, C 1-3 Straight chain / branched chain alkyl, C 3-6 Cycloalkyl, -CH2CO(C 1-3 alkyl), -CH2COO(C 1-3 alkyl), -CH2COO(C 3-6 Heterocycloalkyl), -CH2CON(C 1-3 Alkyl)(C 1-3 alkyl), benzyl, aryl, the H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -NO2, -CH3, -C2H5, -C3H7, -OC 1-3 Alkyl, -N(C 1-3 Alkyl)(C 1-3 alkyl), vinyl, imidazolyl, thiazolyl, pyridyl.

9. The compound according to claim 5, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, which have the following structural formula: in, Y is selected from N or -CF; m1 is an integer between 0 and 2; R 21 and R'21 are each independently selected from -F, -Cl, -Br, -I, -NO2, ethynyl, -CF 3、 C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl; R 22a and R 22b Each independently selected from -H, C 1-3 Straight chain / branched chain alkyl, -COO(C 1-3 alkyl), -CO(C 1-3 Alkyl), C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, aryl, the H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -NO2, -CH3, -C2H5, -OCH3, -(C 0-3 alkyl)COO(C 1-3 alkyl); m2 is an integer between 1 and 3; R 23 Selected from -H, C 1-3 Straight chain / branched chain alkyl, -COO(C 1-3 alkyl), -CO(C 1-3 Alkyl), C 3-5 Cycloalkyl, 3-6 membered heterocycloalkyl, -N(C 0-3 Alkyl)(C 0-3 Alkyl), aryl, the H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -NO2, -CH3, -C2H5, -OC 1-3 Alkyl, C 3-6 Cycloalkyl, -(C 0-3 alkyl)COO(C 0-5 alkyl), -CO(C 0-5 Alkyl), aryl.

10. The compound according to claim 1, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, which have the following structural formula: in, Y is selected from N or -CF; M does not exist, or forms a ring with the adjacent carbon to form a saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring; When M does not exist, R x -H, halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl; when M forms a cyclic ring with the adjacent carbon, R x does not exist; n1 is 0, 1 or 2; The H on the above saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring can be substituted by the following groups: halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 alkyl); Q is selected from O, S-Rxx, N or R3 is selected from -H, C 1-5 A straight chain / branched alkyl group, wherein the H on the alkyl group may be substituted by the following groups: -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, 3-8 membered heterocycloalkyl, -COO(C 0-10 Alkyl), wherein the heterocycloalkyl contains at least one N, O, or S as a ring atom; Rxx is selected from H, C 1-5 A straight chain / branched alkyl group, wherein the H on the alkyl group may be substituted by the following groups: halogen, nitro, cyano, -OC 0-10 alkyl; When Q is N, R3, Q, the N atom and the C atom therebetween form a five-membered aromatic heterocyclic ring or a six-membered aromatic heterocyclic ring having at least two heteroatoms; L does not exist, or L is selected from C 2-8 Olefinic bond or C 1-8 Alkylene, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -CF3, -OCH2F, -OCHF2, -OCF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, -CO(C 0-10 Alkyl), -COO(C 0-10 alkyl); When Q is N or When A is N, Q, A, L and the atoms therebetween form a five-membered or six-membered nitrogen-containing heterocyclic ring; n is 0 or 1. When n is 0, it means that the -CO- group does not exist; X is absent, or when n is 1, X is O, when n is 0, X is selected from O, substituted / unsubstituted N-alkyl, substituted / unsubstituted N-heterocycloalkyl; R4 is selected from -H, halogen, -CN, -CF3, -OCH2F, -OCHF2, -OCF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, heterocycloalkyl, aryl, N heteroaromatic, O heteroaromatic, S heteroaromatic, -SO2(C 0-10 Alkyl), -SO(C 0-10 Alkyl), -SO2O(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -SO2(C 3-10 Cycloalkyl), -SO2-aryl, -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl), -CO(C 3-10 Cycloalkyl), -CO(3-6 membered heterocycloalkyl), -(C 0-10 alkyl)COO(C 0-10 Alkyl), -COO(C 3-10 Cycloalkyl), -COO (3-6 membered heterocycloalkyl), alkenyl, alkynyl, wherein the heterocycloalkyl contains at least one N, O, S as a ring atom, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -NO2, -CF3, C 1-3 Straight chain alkyl, -OC 0-10 Alkyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -COO(C 3-10 Cycloalkyl), -COO(heterocycloalkyl), -CO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -OCOO(C 0-10 alkyl), phenyl, N heterocyclic aromatic group, O heterocyclic aromatic group, S heterocyclic aromatic group, alkenyl group, alkynyl group.

11. The compound according to claim 1 or 10, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, characterized in that: The M and the adjacent carbon form the following groups: a 3-8-membered saturated / unsaturated alicyclic ring, a 3-8-membered saturated / unsaturated heterocyclic ring, benzene, a 5-membered or 6-membered monocyclic heteroaromatic ring, a heteroaromatic ring formed by condensing a benzene ring with 1-2 5-membered or 6-membered monocyclic heteroaromatic groups, or a heteroaromatic ring formed by condensing 2-3 5-membered and / or 6-membered monocyclic heteroaromatic groups; Among them, the H on the above groups can be replaced by the following groups: halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 alkyl).

12. The compound according to claim 11, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, characterized in that: The M and the adjacent carbon form the following group: a 3- to 6-membered saturated / unsaturated alicyclic ring, a 3- to 6-membered saturated / unsaturated heterocyclic ring, benzene, pyrrole, thiophene, furan, pyridine, pyrimidine, pyrazine, triazine, imidazole, oxazole, thiazole, pyrazole, benzofuran, benzoxazole, benzimidazole, benzothiophene, benzothiazole, indole or imidazopyridine; The heteroatom of the above 3-6 membered saturated / unsaturated heterocyclic ring is selected from one or more of N, O and S; Among them, the H on the above groups can be replaced by the following groups: halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 alkyl).

13. The compound according to claim 10, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, which have the following structural formula: in, Y is selected from N or -CF; M does not exist, or forms a ring with the adjacent carbon to form a saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring; The H on the above saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring can be substituted by the following groups: halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 alkyl); Q is selected from N or R3 is selected from -H, C 1-5 A straight chain / branched alkyl group, wherein the H on the alkyl group may be substituted by the following groups: -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, 3-8 membered heterocycloalkyl, -COO(C 0-10 Preferably, the H on the alkyl group may be substituted by the following groups: -N(C 1-6 Alkyl)(C 1-6 Alkyl), -OC 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -COO(C 1-6 The heterocycloalkyl group contains at least one N, O, or S as a ring atom; When Q is N, R3, Q, the N atom and the C atom therebetween form a five-membered aromatic heterocyclic ring or a six-membered aromatic heterocyclic ring having at least two heteroatoms.

14. The compound according to claim 13, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, which have the following structural formula: in, Y is selected from N or -CF; M does not exist, or forms a ring with the adjacent carbon to form a saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring; n1 is 0, 1 or 2; The H on the above saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring can be substituted by the following groups: halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 alkyl); R y1 Selected from -H, -CN, -CF3, C 1-4 Straight chain / branched chain alkyl, C 3-10 cycloalkyl; R y2 Selected from -H, C 1-3 A straight chain or branched chain alkyl group, wherein the H on the alkyl group may be replaced by -N(C 1-3 Alkyl)(C 1-3 Alkyl), -COO(C 0-5 alkyl), five-membered or six-membered N-heterocycloalkyl.

15. The compound according to claim 10, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, which have the following structural formula: in, Y is selected from N or -CF; M does not exist, or forms a ring with the adjacent carbon to form a saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring; When M does not exist, R x -H, halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl; when M forms a cyclic ring with the adjacent carbon, R x does not exist; n1 is 0, 1 or 2; The H on the above saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring can be substituted by the following groups: halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 alkyl); Q is selected from O, S-Rxx or N, R3 is selected from -H, C 1-5 A straight chain / branched alkyl group, wherein the H on the alkyl group may be substituted by the following groups: -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, 3-8 membered heterocycloalkyl, -COO(C 0-10 Alkyl), wherein the heterocycloalkyl contains at least one N, O, or S as a ring atom; When Q is N, R3, Q, the N atom and the C atom therebetween form a five-membered aromatic heterocyclic ring or a six-membered aromatic heterocyclic ring having at least two heteroatoms; Rxx is selected from H, C 1-5 A straight chain / branched alkyl group, wherein the H on the alkyl group may be substituted by the following groups: halogen, nitro, cyano, -OC 0-10 alkyl; L does not exist, or L is selected from C 2-4 Olefinic bond or C 1-8 Alkylene, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -CF3, -OCH2F, -OCHF2, -OCF3, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, 3-10 membered cycloalkyl, -CO(C 0-10 Alkyl), -COO(C 0-10 alkyl); R f Selected from -H, C 1-10 Straight chain / branched chain alkyl, OR j , R j Selected from C 1-10 Straight chain / branched chain alkyl, C 3-10 Cycloalkyl, 3-8 membered heterocycloalkyl, aryl, heteroaryl, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -CH3, -C2H5, -OC 1-5 , C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -CO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), vinyl, propadienyl, ethynyl, and further, the alkyl part can be -CN, -OCH2F, -OCHF2, -OCF3, -OC 0-10 Alkyl, C 3-4 Cycloalkyl substitution; R g Selected from -H, -C 1-10 Straight chain / branched chain alkyl, -C 3-10 Cycloalkyl, -CH2CO(C 0-10 alkyl), -CH2COO(C 0-6 alkyl), -CH2COO(C 3-6 Cycloalkyl), -CH2COO(C 3-6 Heterocycloalkyl), -CH2CON(C 0-10 Alkyl)(C 0-10 alkyl), benzyl, aryl, the H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -NO2, C 1-10 Straight chain / branched chain alkyl, 3-6 membered heterocyclic alkyl, -OC 1-5 Alkyl, -N(C 1-3 Alkyl)(C 1-3 Alkyl), C 2-8 alkenyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, phenyl; or R g Selected from R c1 , R c2 , R c3 Independently selected from C 1-10 Straight chain / branched chain alkyl, -OC 0-5 Alkyl, -O(C 3-6 Cycloalkyl), -O(C 3-6 Heterocycloalkyl), C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, -N(C 0-10 Alkyl)(C 0-10 alkyl), alkenyl, alkynyl, aryl, heteroaryl, the H on the above groups can be halogen, -CN, -CH3, -C2H5, -OCH3, -N(C 1-3 Alkyl)(C 1-3 Alkyl), -C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, vinyl substituted, the alkyl part can be -CN, -OCF3, -OC 0-10 Alkyl, C 3-4 Cycloalkyl substitution; R h1 and R h2 Each independently selected from H, C 1-10 Straight chain / branched chain alkyl, -COO(C 0-10 alkyl), -CO(C 0-10 alkyl), 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, aryl, or R h1 and R h2 The N atoms between them form a 3-6 membered heterocycloalkyl group. The H on the above group can be substituted by the following groups: halogen, -CN, -NO2, C 1-3 Straight chain / branched chain alkyl, -OC 1-3 Alkyl, C 3-6 Cycloalkyl, -(C 0-10 alkyl)COO(C 0-10 alkyl), -CO(C 0-10 alkyl), aryl, -N(C 1-3 Alkyl)(C 1-3 Alkyl), the alkyl part can be -CN, -OCF3, -OC 0-10 、-CO(C 0-10 Alkyl), C 3-4 Cycloalkyl, aryl substitution; R j is selected from halogen, cyano, aryl, heteroaryl, 3-6-membered cycloalkyl or 3-6-membered heterocycloalkyl; the H on the above groups may be substituted by the following groups: halogen, -CN, -NO2, C 1-10 Straight chain / branched chain alkyl, -OC 1-10 alkyl.

16. The compound according to claim 15, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, which have the following structural formula: in, Y is selected from N or -CF; M does not exist, or forms a ring with the adjacent carbon to form a saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring; When M does not exist, R x -H, halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl; when M forms a cyclic ring with the adjacent carbon, R x does not exist; n1 is 0, 1 or 2; The H on the above saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring can be substituted by the following groups: halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 alkyl); Q is selected from O, S-Rxx or N, R3 is selected from -H, C 1-5 A straight chain / branched alkyl group, wherein the H on the alkyl group may be substituted by the following groups: -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, 3-8 membered heterocycloalkyl, -COO(C 0-10 Alkyl), wherein the heterocycloalkyl contains at least one N, O, or S as a ring atom; When Q is N, R3, Q, the N atom and the C atom therebetween form a five-membered aromatic heterocyclic ring or a six-membered aromatic heterocyclic ring having at least two heteroatoms; Rxx is selected from H, C 1-5 A straight chain / branched alkyl group, wherein the H on the alkyl group may be substituted by the following groups: halogen, nitro, cyano, -OC 0-10 alkyl; m1, m2, and m3 are independently selected from integers of 0 to 5; R5', R5", R5'" are independently selected from -H, halogen, -CN, -CF3, -C 1-10 Alkyl, -CO(C 0-10 Alkyl), -COO(C 0-10 alkyl); R f 'Selected from -H, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 alkyl), OR j ', R j 'Selected from C 1-10 Straight chain / branched chain alkyl, C 3-10 Cycloalkyl, 3-8 membered heterocycloalkyl, aryl, heteroaryl, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -CH3, -C2H5, -OC 1-5 , C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -CO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), vinyl, propadienyl, ethynyl, and further, the alkyl part can be -CN, -OCH2F, -OCHF2, -OCF3, -OC 0-10 Alkyl, C 3-4 Cycloalkyl substitution; R g 'Selected from -H, -C 1-10 Straight chain / branched chain alkyl, -C 3-10 Cycloalkyl, -CH2CO(C 0-10 alkyl), -CH2COO(C 0-6 alkyl), -CH2COO(C 3-6 Cycloalkyl), -CH2COO(C 3-6 Heterocycloalkyl), -CH2CON(C 0-10 Alkyl)(C 0-10 alkyl), benzyl, aryl, the H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -NO2, C 1-10 Straight chain / branched chain alkyl, 3-6 membered heterocyclic alkyl, -OC 1-5 Alkyl, -N(C 1-3 Alkyl)(C 1-3 Alkyl), C 2-8 alkenyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, phenyl; or R g 'Selected from R c1 , R c2 , R c3 Independently selected from C 1-10 Straight chain / branched chain alkyl, -OC 0-5 Alkyl, -O(C 3-6 Cycloalkyl), -O(C 3-6 Heterocycloalkyl), C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, -N(C 0-10 Alkyl)(C 0-10 alkyl), alkenyl, alkynyl, aryl, heteroaryl, the H on the above groups can be halogen, -CN, -CH3, -C2H5, -OCH3, -N(C 1-3 Alkyl)(C 1-3 Alkyl), -C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, vinyl substituted, the alkyl part can be -CN, -OCF3, -OC 0-10 Alkyl, C 3-4 Cycloalkyl substitution; R i ' is selected from halogen, cyano, phenyl, 5-6 membered heteroaryl containing N, O and / or S, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; the H on the above groups may be substituted by the following groups: halogen, -CN, -NO2, C 1-6 Straight chain / branched chain alkyl, -OC 1-6 alkyl.

17. The compound according to claim 16, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, which have the following structural formula: in, Y is selected from N or -CF; P' is N or CH; M does not exist, or forms a ring with the adjacent carbon to form a saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring; When M does not exist, R x -H, halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl; when M forms a cyclic ring with the adjacent carbon, R x does not exist; n1 is 0, 1 or 2; The H on the above saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring can be substituted by the following groups: halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 alkyl); R8' is selected from -H, halogen, -CN, -NO2, -CF3, C 1-4 Straight chain / branched chain alkyl, C 3-10 cycloalkyl; R 10 'Selected from -H, C 1-3 A straight chain or branched chain alkyl group, wherein the H on the alkyl group may be replaced by -N(C 1-3 Alkyl)(C 1-3 alkyl), -CO(C 0-10 Alkyl), -COO(C 0-10 Alkyl), five-membered or six-membered N-heterocycloalkyl; Q' is selected from =O or -S-Rxx; Rxx is selected from H, C 1-3 A straight chain / branched alkyl group, wherein the H on the alkyl group may be substituted by the following groups: halogen, nitro, cyano, -OC 0-10 alkyl; m1, m2, and m3 are independently selected from integers of 0 to 4; R5', R5", R5'" are independently selected from -H, halogen, -CN, -CF3, -C 1-10 Alkyl, -CO(C 0-10 Alkyl), -COO(C 0-10 alkyl); R f 'Selected from -H, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 alkyl), OR j ', R j 'Selected from C 1-10 Straight chain / branched chain alkyl, C 3-10 Cycloalkyl, 3-8 membered heterocycloalkyl, aryl, heteroaryl, wherein the H on the above groups can be substituted by the following groups: halogen, -CN, -CH3, -C2H5, -OC 1-5 , C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -CO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), vinyl, propadienyl, ethynyl, and further, the alkyl part can be -CN, -OCH2F, -OCHF2, -OCF3, -OC 0-10 Alkyl, C 3-4 Cycloalkyl substitution; R g 'Selected from -H, -C 1-10 Straight chain / branched chain alkyl, -C 3-10 Cycloalkyl, -CH2CO(C 0-10 alkyl), -CH2COO(C 0-6 alkyl), -CH2COO(C 3-6 Cycloalkyl), -CH2COO(C 3-6 Heterocycloalkyl), -CH2CON(C 0-10 Alkyl)(C 0-10 alkyl), benzyl, aryl, the H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -NO2, C 1-10 Straight chain / branched chain alkyl, 3-6 membered heterocyclic alkyl, -OC 1-5 Alkyl, -N(C 1-3 Alkyl)(C 1-3 Alkyl), C 2-8 alkenyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, phenyl; or R g 'Selected from R c1 , R c2 , R c3 Independently selected from C 1-10 Straight chain / branched chain alkyl, -OC 0-5 Alkyl, -O(C 3-6 Cycloalkyl), -O(C 3-6 Heterocycloalkyl), C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, -N(C 0-10 Alkyl)(C 0-10 alkyl), alkenyl, alkynyl, aryl, heteroaryl, the H on the above groups can be halogen, -CN, -CH3, -C2H5, -OCH3, -N(C 1-3 Alkyl)(C 1-3 Alkyl), -C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, vinyl substituted, the alkyl part can be -CN, -OCF3, -OC 0-10 Alkyl, C 3-4 Cycloalkyl substitution; R i ' is selected from halogen, cyano, phenyl, 5-6 membered heteroaryl containing N, O and / or S, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; the H on the above groups may be substituted by the following groups: halogen, -CN, -NO2, C 1-6 Straight chain / branched chain alkyl, -OC 1-6 alkyl.

18. The compound according to claim 17, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, characterized in that: The Y is selected from N or -CF; P' is N or CH; M does not exist, or forms a ring with the adjacent carbon to form a saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring; When M does not exist, R x -H, halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl; when M forms a cyclic ring with the adjacent carbon, R x does not exist; n1 is 0, 1 or 2; The H on the above saturated / unsaturated alicyclic ring, saturated / unsaturated heterocyclic ring, aromatic ring or heteroaromatic ring can be substituted by the following groups: halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 alkyl); R8' is selected from H or methyl; R 10 'Selected from -H, C 1-3 A straight chain or branched chain alkyl group, wherein the H on the alkyl group may be replaced by -N(C 1-3 Alkyl)(C 1-3 alkyl), -CO(C 1-3 Alkyl), -COO(C 1-3 alkyl), piperazinyl, N-methylpiperazinyl or N-ethylpiperazinyl; Q' is selected from =O or -S-Rxx; Rxx is selected from H or methyl; m1, m2, and m3 are independently selected from integers of 0 to 4; R5', R5", R5'" are independently selected from -H, halogen, -CN, -CF3, -C 1-6 Alkyl, -CO(C 1-6 Alkyl), -COO(C 1-6 alkyl); R f 'Selected from -H, C 1-6 Straight chain / branched chain alkyl, -N(C 0-6 Alkyl)(C 0-6 alkyl), OR j ', R j 'Selected from C 1-6 Straight-chain / branched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl, pyrrolyl, pyridyl or the following groups: R j1 '、R j2 '、R j3 '、R j4 '、R j5 '、R j6 'Independently selected from H, halogen, -CN, -C 1-6 Straight chain / branched chain alkyl, -C 2-6 Straight chain / branched chain alkenyl, -OC 1-6 Straight chain / branched chain alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -CO(C 0-10 Alkyl), -OCO(C 0-10 alkyl), ethynyl; Among them, the above R f The H on the group can be substituted by the following groups: halogen, -CN, -CH3, -C2H5, -OC 1-5 , C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -CO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), vinyl, propadienyl, ethynyl, and further, the alkyl part can be -CN, -OCH2F, -OCHF2, -OCF3, -OC 0-10 Alkyl, C 3-4 Cycloalkyl substitution; R g 'Selected from -H, -C 1-6 Straight chain / branched chain alkyl, -C 3-6 Cycloalkyl, -CH2CO(C 1-6 alkyl), -CH2COO(C 0-6 alkyl), -CH2COO(C 3-6 Cycloalkyl), -CH2COO(C 3-6 Heterocycloalkyl), -CH2CON(C 0-6 Alkyl)(C 0-6 alkyl), benzyl, aryl, the H on the above groups can be substituted by the following groups: -F, -Cl, -CN, -NO2, C 1-10 Straight chain / branched chain alkyl, 3-6 membered heterocyclic alkyl, -OH, -OC 1-5 Alkyl, -N(C 1-3 Alkyl)(C 1-3 Alkyl), C 2-8 alkenyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, phenyl; or R g 'Selected from R c1 , R c2 , R c3 Independently selected from C 1-10 Straight chain / branched chain alkyl, -OC 0-5 Alkyl, -O(C 3-6 Cycloalkyl), -O(C 3-6 Heterocycloalkyl), C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, -N(C 0-10 Alkyl)(C 0-10 alkyl), alkenyl, alkynyl, aryl, heteroaryl, the H on the above groups can be halogen, -CN, -CH3, -C2H5, -OCH3, -N(C 1-3 Alkyl)(C 1-3 Alkyl), -C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, vinyl substituted, the alkyl part can be -CN, -OCF3, -OC 0-10 Alkyl, C 3-4 Cycloalkyl substitution; R i ' is selected from halogen, cyano, phenyl, pyrrolyl, thienyl, furanyl, imidazolyl, thiazolyl, triazolyl, isoxazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the following groups: The above R i The H on the group can be replaced by the following groups: halogen, -CN, -NO2, C 1-6 Straight chain / branched chain alkyl, -OC 1-6 alkyl; Indicates the connection location.

19. The compound according to any one of claims 10 to 18, and its pharmaceutically acceptable salt, stereoisomer, prodrug, solvate and deuterated compound, characterized in that: The M and the adjacent carbons together form any of the following structures: R 1x , R 2x , R 3x , R 4x Each independently selected from: H, halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 alkyl); T1, T2, T3, T4, T5 are independently selected from CR 24 , N, O or S; T6 is selected from C, N, O or S; R 24 Selected from H, halogen, -CN, -NO2, -NHCO(C 0-10 alkyl), CF3, C 1-3 Straight chain alkyl, -OC 0-10 alkyl; Indicates the connection location.

20. The compound according to claim 19, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, characterized in that: The M and the adjacent carbon form any of the following structures: R 5x -R 23x Each independently selected from the following groups: H, halogen, -NO2, -CN, -CF3, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Straight chain / branched chain alkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -OC 0-10 Alkyl, C 3-10 Cycloalkyl, N-heterocycloalkyl, O-heterocycloalkyl, S-heterocycloalkyl, -NHCO(C 0-10 alkyl); Indicates the connection location.

21. The compound according to claim 1, and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds, which have the following structural formula:

22. A pharmaceutical composition comprising the compound according to any one of claims 1 to 21 and a pharmaceutically acceptable salt, stereoisomer, prodrug, solvate and deuterated compound thereof.

23. Use of a compound according to any one of claims 1 to 21 and its pharmaceutically acceptable salts, stereoisomers, prodrugs, solvates and deuterated compounds or a pharmaceutical composition according to claim 22 in the preparation of a drug having analgesic effect, and / or anesthetic, sedative, hypnotic effect, and / or capable of controlling status epilepticus.

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