Muscarinic m4 receptor agonist and use thereof

Abstract

A CHRM4 receptor agonist and the use thereof. Specifically, disclosed in the present invention are a compound as shown in formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof; and the use thereof in the preparation of a drug for treating / preventing a CHRM4-mediated disease, wherein each group in formula (I) is as defined in the description.

Description

A muscarinic M4 receptor agonist and its uses Technical Field

[0001] This invention belongs to the pharmaceutical field, and particularly relates to a small molecule compound with CHRM4 receptor agonist activity, its stereoisomers, deuterated derivatives, solvates, cocrystals or pharmaceutically acceptable salts, and their use in the preparation of medicaments for treating related diseases. Background Technology

[0002] mAChRs are widely distributed throughout the human body, mediating numerous physiological functions in the cardiovascular, renal, gastrointestinal, pulmonary, central, and peripheral nervous systems based on their location and receptor subtypes. mAChRs are typically expressed in various parts of the brain, and their functions are involved in a wide range of brain circuits, including regulating neuronal excitability, synaptic plasticity, and acetylcholine release. All five mAChRs are expressed in brain neurons and glial cells, but receptor abundance varies by region. The muscarinic acetylcholine receptor M4 (also known as muscarinic 4 or CHRM4) is a protein encoded by the CHRM4 gene in humans. The M4 receptor is primarily expressed in the brain. Key brain regions where M4 receptor expression occurs are the striatum, cortex, and hippocampus, with the highest expression occurring in the striatum (approximately 46%), where M4 is the predominant muscarinic subtype. M4 is occasionally expressed in the periphery (e.g., testes, skin, and colon). Summary of the Invention

[0003] The purpose of this invention is to provide a small molecule compound with CHRM4 activity, which has the advantages of novel structure, good efficacy, high bioavailability, few side effects, rapid onset of action, and long-lasting effect.

[0004] This invention relates to a compound of formula (I), its stereoisomer or pharmaceutically acceptable salt,

[0005] Among them, ring A is selected from:

[0006] In some implementations, ring A is selected from ring A1;

[0007] In some implementations, ring A is selected from...

[0008] In some implementations, ring A is selected from ring A2;

[0009] In some implementations, ring A is selected from one of the following structures:

[0010] Ring B is selected from C. 3-6Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups, wherein the cycloalkyl groups or heterocyclic alkyl groups are optionally surrounded by 0-5 R groups. B replace;

[0011] In some embodiments, ring B is selected from cyclopropyl, cyclobutyl, azircyclobutyl, azircyclopentyl, and azircyclohexyl, wherein the cyclopropyl, cyclobutyl, azircyclobutyl, azircyclopentyl, and azircyclohexyl groups are optionally surrounded by 1-3 R groups. B replace;

[0012] In some embodiments, ring B is selected from cyclopropyl, azircyclobutyl, and azircyclohexyl, wherein the cyclopropyl, azircyclobutyl, and azircyclohexyl groups are optionally surrounded by 1-3 R groups. B replace;

[0013] In some implementations, ring B is selected from 1-3 R... B The following groups are substituted: in, The terminal is connected to L1;

[0014] In some embodiments, ring B is selected from the following groups:

[0015] Ring C is selected from:

[0016] In some implementations, the C ring is selected from 1-3 R rings. C The following groups are substituted:

[0017] In some embodiments, the C ring is selected from the following groups:

[0018] R a1 R b R c R d Each element is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 alkyl;

[0019] In some implementations, R a1 R b R c R d Each is independently selected from hydrogen;

[0020] X1 is selected from -N-, -CR x1 -;

[0021] In some implementations, X1 is selected from -N-;

[0022] In some implementations, X1 is selected from -CR x1 -;

[0023] R x1 Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups;

[0024] In some implementations, R x1 Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Alkoxy;

[0025] In some implementations, R x1 Selected from hydrogen, deuterium, halogens, and C 1-4 Alkyl, C 1-4 Alkoxy;

[0026] In some implementations, R x1 Selected from hydrogen, deuterium, halogens, and C 1-2 alkyl;

[0027] In some implementations, R x1 Selected from hydrogen, deuterium, F, Cl, methyl, and ethyl;

[0028] In some implementations, R x1 Selected from hydrogen;

[0029] X2 and X3 are each independently selected from -N-, -CH-, and -CR. C -;

[0030] In some implementations, X2 and X3 are each independently selected from -N- and -CH-.

[0031] In some implementations, X2 and X3 are each independently selected from -N-;

[0032] In some implementations, X2 and X3 are each independently selected from -CR C -;

[0033] R1, R2, R3, and R4 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, =O, amino, nitro, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6Deuterated alkoxy, C 1-6 Haloalkoxy, -C(=O)NR A1 R A2 -C 1-6 Alkyl-C(=O)NR A1 R A2 -NR A1 R A2 -NR A1 C(=O)C 1-6 Alkyl, -NR A1 C(=O)OC 1-6 Alkyl, -NR A1 C(=O)NR A1 R A2 -S(=O)2-NR A1 R A2 -S(=O)2-C 1-6 Alkyl, -SF5, -SCF3, =CH2, =CF2, =CH-CH3, =C-(CH3)2, C 3-6 Cycloalkyl, -O-(CH2) r -C 3-6 cycloalkyl, -NR A1 -C 3-6 cycloalkyl, -NR A1 C(=O)-C 3-6 Cycloalkyl, -C(=O)NR A1 -C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -NR A1 C(=O)-(4-6 membered heterocyclic alkyl groups), C 6-8 Aryl, -NR A1 -(5-6-membered heteroaryl) or 5-6-membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace;

[0034] In some implementations, R1, R2, R3, and R4 are each independently selected from hydrogen, deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-8 aryl or 5-6 heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace;

[0035] In some implementations, R1, R2, R3, and R4 are each independently selected from hydrogen, deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-8 aryl or 5-6 heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace;

[0036] In some implementations, R1, R2, R3, and R4 are each independently selected from hydrogen, deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, wherein the alkyl group is optionally further radicalized with 1-5 R groups. a replace;

[0037] In some embodiments, R1, R2, R3, and R4 are each independently selected from hydrogen, deuterium, F, Cl, Br, -CH3, -CH2CH3, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, and -CH2CH2F;

[0038] R5 is selected from deuterium, halogen, hydroxyl, nitro, and C. 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, -C(=O)NR A1 R A2 -C 1-6 Alkyl-C(=O)NR A1 R A2 -NR A1 C(=O)C 1-6 Alkyl, -NR A1 C(=O)OC 1-6 Alkyl, -NR A1 C(=O)NR A1 R A2 -S(=O)2-NR A1 R A2 -S(=O)2-C 1-6 Alkyl, -SF5, -SCF3, =CH2, =CF2, =CH-CH3, =C-(CH3)2, -NR A1 -C 3-6 cycloalkyl, -NR A1 C(=O)-C 3-6 Cycloalkyl, -C(=O)NR A1 -C 3-6cycloalkyl, -NR A1 C(=O)-(4-6 membered heterocyclic alkyl groups), C 6-8 Aryl, -NR A1 -(5-6-membered heteroaryl) or 5-6-membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace;

[0039] In some implementations, R5 is selected from deuterium, halogens, and C. 2-6 alkenyl, C 2-6 alkynyl, -NR A1 C(=O)-C 3-6 Cycloalkyl, -C(=O)NR A1 -C 3-6 cycloalkyl, -NR A1 C(=O)-(4-6 membered heterocyclic alkyl groups), C 6-8 Aryl, -NR A1 -(5-6-membered heteroaryl) or 5-6-membered heteroaryl, wherein the alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace;

[0040] In some implementations, R5 is selected from deuterium, halogens, and C. 6-8 Aryl or 5-6 heteroaryl, wherein the aryl or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace;

[0041] In some embodiments, R5 is selected from 5-6 heteroaryl groups, wherein the heteroaryl group is optionally further surrounded by 1-5 R groups. a replace;

[0042] In some embodiments, R5 is selected from a five-membered heteroaryl group, which is optionally further surrounded by 1-5 R5 groups. a replace;

[0043] In some implementations, R5 is selected from those optionally further replaced by 1-3 Ra. r can be independently selected from 0, 1, 2, 3, 4, or 5;

[0044] In some implementations, r is independently selected from 0, 1, 2, or 3;

[0045] In some implementations, r is independently selected from 0 or 1;

[0046] R A1 R A2 Each element is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups;

[0047] In some implementations, R A1 R A2 Each element is independently selected from hydrogen, deuterium, halogens, and carbon. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Halogenated alkoxy groups;

[0048] In some implementations, R A1 R A2 Each is independently selected from hydrogen, deuterium, F, Cl, Br, -CH3, -CH2CH3, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CD3, -CHD2, -CH2D, -CH2CD3, -CH2CHD2, -CH2CH2D, -OCH3, -OCH2CH3, -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCH2CHF2, -OCH2CH2F, -OCD3, -OCHD2, -OCH2D, -OCH2CD3, -OCH2CHD2, -OCH2CH2D;

[0049] In some implementations, R A1 R A2 Each element is independently selected from hydrogen, deuterium, and C. 1-4 alkyl;

[0050] In some implementations, R A1 R A2 Each is independently selected from hydrogen, -CH3, and -CH2CH3;

[0051] L1 is selected from -C(=O)-C 1-4 Alkyl, -C(=O)-O-, -C(=O)-S-, C 2-4 alkenyl, C 2-4 alkynyl group;

[0052] In some implementations, L1 is selected from -C(=O)-C 1-4 Alkyl, -C(=O)-O-, -C(=O)-S-;

[0053] In some implementations, L1 is selected from -C(=O)-C1-2 Alkyl, -C(=O)-O-, -C(=O)-S-;

[0054] In some implementations, L1 is selected from -C(=O)-CH2-, -C(=O)-O-, and -C(=O)-S-.

[0055] In some implementations, L1 is selected from -C(=O)-CH2-;

[0056] L2 is selected from the bond;

[0057] Each R B Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-8 aryl or 5-6 heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace;

[0058] In some implementations, each R B Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-8 aryl or 5-6 heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace;

[0059] In some implementations, each R B Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4Deuterated alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. a replace;

[0060] In some implementations, each R B Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. a replace;

[0061] In some implementations, each R B Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-4 Alkyl, C 1-4 alkoxy groups, wherein the alkyl or alkoxy group is optionally further surrounded by 1-5 R groups. a replace;

[0062] In some implementations, each R B Each element is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, wherein the alkyl or alkoxy group is optionally further surrounded by 1-3 R groups. a replace

[0063] In some implementations, each R B Each element is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl groups, wherein the alkyl group is optionally further oxidized by 1-5 R groups. a replace;

[0064] In some implementations, each R B Each is independently selected from hydrogen, deuterium, F, Cl, -CH3, -CH2CH3, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, and -CH2CH2F;

[0065] In some implementations, each R B Each is independently selected from hydrogen, -CH3, -CF3, -CHF2, and -CH2F;

[0066] Each R CEach group is independently selected from deuterium, hydroxyl, cyano, halogen, amino, nitro, -SCF3, -SCH2CF3, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy groups, -O-(CH2) r -C 3-6 Cycloalkyl, -O-(CH2) r -(3-8 membered heterocyclic alkyl groups), -C(=O)-C 3-6 cycloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 quinary heteroaryl, 5-6 quinary heterocyclic 5-6 quinary heteroaryl, -NR A1 -(5-6 quinone heteroaryl groups), -NR A1 -C 1-6 Alkyl group, -CH=CR c1 R c2 -NR A1 -(CH2) r -C 3-6 Cycloalkyl, -O-(CH2) r -5-6-membered heteroaryl, wherein the alkenyl, alkynyl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further characterized by 1-5 R groups. a replace;

[0067] In some implementations, each R C Each group is independently selected from deuterium, hydroxyl, cyano, halogen, amino, nitro, -SCF3, -SCH2CF3, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy groups, -O-(CH2) r -C 3-6 Cycloalkyl, -O-(CH2) r -(3-8 membered heterocyclic alkyl groups), -C(=O)-C 3-6 cycloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 quinary heteroaryl, 5-6 quinary heterocyclic 5-6 quinary heteroaryl, -NRA1 -(5-6 quinone heteroaryl groups), -NR A1 -C 1-6 Alkyl group, -CH=CR c1 R c2 -NR A1 -(CH2) r -C 3-6 Cycloalkyl, wherein the alkenyl, alkynyl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further characterized by 1-5 R groups. a replace;

[0068] In some implementations, each R C Each element is independently selected from deuterium, halogens, -SCF3, -SCH2CF3, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy groups, -O-(CH2) r -C 3-6 Cycloalkyl, -O-(CH2) r -(3-6 membered heterocyclic alkyl groups), C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-8 Aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclic 5-6 membered heteroaryl, 4-6 membered heterocyclic alkyl spiro-3-4 membered cycloalkyl, -NR A1 -(5-6 quinone heteroaryl groups), -NR A1 -C 1-6 Alkyl group, -CH=CR c1 R c2 -NR A1 -(CH2) r -C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further characterized by 1-5 R groups. a replace;

[0069] In some implementations, each R C Each element is independently selected from deuterium, halogens, -SCF3, -SCH2CF3, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2- 6-acetylinyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy groups, -O-(CH2) r-C 3-6 Cycloalkyl, -O-(CH2) r -(3-6 membered heterocyclic alkyl groups), C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-8 Aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclic 5-6 membered heteroaryl, 4-6 membered heterocyclic alkyl spiro-3-4 membered cycloalkyl, -NR A1 -(5-6 quinone heteroaryl groups), -NR A1 -C 1-6 Alkyl group, -CH=CR c1 R c2 -NR A1 -(CH2) r -C 3-6 Cycloalkyl, -O-(CH2) r -5-6-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace;

[0070] In some implementations, each R C Each element is independently selected from deuterium, halogens, -SCF3, and C. 1-6 Alkyl, C 1-6 Haloalkyl, -O-(CH2) r -C 3-6 Cycloalkyl, -O-(CH2) r -(3-6 membered heterocyclic alkyl groups), C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-8 Aryl or 5-6-membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace;

[0071] In some implementations, each R C Each is independently selected from halogens, -SCF3, C 1-6 Alkyl, C 1-6 Haloalkyl, -O-(CH2) r -C 3-6 Cycloalkyl, -O-(CH2) r -(3-6 membered heterocyclic alkyl groups), C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, or 5-6-membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace;

[0072] In some implementations, each R CEach is independently selected from F, Cl, -SCF3, Br, -CH3, -CH2CH3, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, and -O-(CH2). r -C 3-6 Cycloalkyl, -O-(CH2) r -(3-6 membered heterocyclic alkyl groups), C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, or 5-6-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace;

[0073] In some implementations, each R C Each is independently selected from F, Cl, -SCF3, -CH3, -CH2CH3, -CF3, -CHF2, -CH2F, and -O-(CH2). r -C 3-6 Cycloalkyl, -O-(CH2) r -(3-6 membered heterocyclic alkyl groups), C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, or 5-6-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace;

[0074] In some implementations, each R C Each is independently selected from vinyl, ethynyl, F, -SCF3, -SCH2CF3, -CH3, -CF3, -OCF3, -OCHF2,

[0075] Alternatively, two R atoms on the same atom B Two R atoms on the same atom C Two R atoms on adjacent atoms B Two R atoms on adjacent atoms C Together with the atoms attached to it, they form C 3-8 Carbon rings or 3-8 membered heterocycles, wherein the carbon rings or heterocycles may optionally be further divided into 1-5 R groups. a replace;

[0076] In some implementations, two R atoms on the same atom B Two R atoms on the same atom C Two R atoms on adjacent atoms B Two R atoms on adjacent atoms C Together with the atoms attached to it, they form C 3-6Carbon rings or 3-6 membered heterocycles, wherein the carbon rings or heterocycles may optionally be further divided by 1-5 R groups. a replace;

[0077] R a Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, nitro, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, -C(=O)-C 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl group, -(CH2) r -S(=O)2-C 1-6 Alkyl, =CH2, =CHF, =CF2, =CH-CH3, =C-(CH3)2, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, -O-(CH2) r -C 3-6 Cycloalkyl, -SCF3, -NR A1 -C 1-6 Alkyl, C 6-10 aryl or 5-10 heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further selected from 1-5 groups selected from deuterium, halogen, cyano, amino, =O, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or deuterated C 1-6 The alkoxy group is substituted; in some embodiments, R a Each is independently selected from deuterium, halogen, cyano, hydroxyl, amino, nitro, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, -C(=O)-C 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl group, -(CH2) r -S(=O)2-C 1-6Alkyl, =CH2, =CHF, =CF2, =CH-CH3, =C-(CH3)2, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, -O-(CH2) r -C 3-6 Cycloalkyl, -SCF3, -NR A1 -C 1-6 Alkyl, C 6-10 aryl or 5-10 heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further selected from 1-5 groups selected from deuterium, halogen, cyano, amino, =O, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or deuterated C 1-6 The alkoxy group is replaced;

[0078] In some implementations, R a Each is independently selected from deuterium, halogen, cyano, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy group, -(CH2) r -S(=O)2-C 1-6 Alkyl, =CF2, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-8 aryl or 5-6 heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further selected from 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, =O, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or deuterated C 1-6 The alkoxy group is replaced;

[0079] In some implementations, R a Selected from deuterium, halogens, cyano groups, and C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Haloalkoxy group, -(CH2) r -S(=O)2-C1-6 Alkyl, =CF2, C 3-6 Cycloalkyl, 5-6-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, and heteroaryl groups are optionally further selected from 1-5 deuterium, halogen, C 1-4 Alkyl groups are substituted;

[0080] In some implementations, R a Selected from deuterium, F, Cl, Br, cyano, -CH3, -CH2CH3, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CD3, -CHD2, -CH2D, -CH2CD3, -CH2CHD2, -CH2CH2D, -OCH3, - OCH2CH3, -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCH2CHF2, -OCH2CH2F, -OCD3, -OCHD2, -OCH2D, -OCH2CD3, -OCH2CHD2, -OCH2CH2D, -(CH2)-S(=O)2-C 1-2 Alkyl group, -S(=O)2-C 1-2 Alkyl, =CH2, =CHF, =CF2, =CH-CH3, =C-(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-6-membered heteroaryl, -O-cyclopropyl, -O-cyclobutyl, -SCF3, -N(CH3)2, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and 5-6-membered heteroaryl groups are optionally further selected by 1-5 elements selected from deuterium, halogen, C 1-4 Alkyl groups are substituted;

[0081] R c1 R c2 Together with the connected carbon atoms, they form 4-6 membered carbon rings;

[0082] In some implementations, R c1 R c2 Together with the attached carbon atom, they form cyclobutyl, cyclopentyl, and cyclohexyl groups;

[0083] n is selected from 1, 2, 3, 4, or 5;

[0084] In some implementations, n is independently selected from 1, 2, or 3;

[0085] In some implementations, n is independently selected from 1 or 2.

[0086] This invention relates to a compound of formula (I), its stereoisomer or pharmaceutically acceptable salt,

[0087] Among them, ring A is selected from:

[0088] Ring B is selected from C. 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups, wherein the cycloalkyl groups or heterocyclic alkyl groups are optionally surrounded by 0-5 R groups. B replace;

[0089] Ring C is selected from:

[0090] R a1 R b R c R d Each element is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 alkyl;

[0091] X1 is selected from -N-, -CR x1 -;

[0092] R x1 Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups;

[0093] X2 and X3 are each independently selected from -N-, -CH-, and -CR. C -;

[0094] R1, R2, R3, and R4 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, =O, amino, nitro, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, -C(=O)NR A1 R A2 -C 1-6 Alkyl-C(=O)NR A1 R A2 -NR A1 R A2 -NR A1 C(=O)C 1-6 Alkyl, -NR A1 C(=O)OC 1-6 Alkyl, -NR A1 C(=O)NR A1 RA2 -S(=O)2-NR A1 R A2 -S(=O)2-C 1-6 Alkyl, -SF5, -SCF3, =CH2, =CF2, =CH-CH3, =C-(CH3)2, C 3-6 Cycloalkyl, -O-(CH2) r -C 3-6 cycloalkyl, -NR A1 -C 3-6 cycloalkyl, -NR A1 C(=O)-C 3-6 Cycloalkyl, -C(=O)NR A1 -C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -NR A1 C(=O)-(4-6 membered heterocyclic alkyl groups), C 6-8 Aryl, -NR A1 -(5-6-membered heteroaryl) or 5-6-membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace;

[0095] R5 is selected from deuterium, halogen, hydroxyl, nitro, and C. 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, -C(=O)NR A1 R A2 -C 1-6 Alkyl-C(=O)NR A1 R A2 -NR A1 C(=O)C 1-6 Alkyl, -NR A1 C(=O)OC 1-6 Alkyl, -NR A1 C(=O)NR A1 R A2 -S(=O)2-NR A1 R A2 -S(=O)2-C 1-6 Alkyl, -SF5, -SCF3, =CH2, =CF2, =CH-CH3, =C-(CH3)2, -NR A1 -C 3-6 cycloalkyl, -NR A1 C(=O)-C 3-6 Cycloalkyl, -C(=O)NR A1 -C 3-6cycloalkyl, -NR A1 C(=O)-(4-6 membered heterocyclic alkyl groups), C 6-8 Aryl, -NR A1 -(5-6-membered heteroaryl) or 5-6-membered heteroaryl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace;

[0096] r can be independently selected from 0, 1, 2, 3, 4, or 5;

[0097] R A1 R A2 Each element is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups;

[0098] L1 is selected from -C(=O)-C 1-4 Alkyl, -C(=O)-O-, -C(=O)-S-, C 2-4 alkenyl, C 2-4 alkynyl group;

[0099] L2 is selected from the bond;

[0100] Each R B Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-8 aryl or 5-6 heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace;

[0101] Each R C Each group is independently selected from deuterium, hydroxyl, cyano, halogen, amino, nitro, -SCF3, -SCH2CF3, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy groups, -O-(CH2) r -C 3-6 Cycloalkyl, -O-(CH2) r -(3-8 membered heterocyclic alkyl groups), -C(=O)-C 3-6 cycloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 quinary heteroaryl, 5-6 quinary heterocyclic 5-6 quinary heteroaryl, -NR A1 -(5-6 quinone heteroaryl groups), -NR A1 -C 1-6 Alkyl group, -CH=CR c1 R c2 -NR A1 -(CH2) r -C 3-6 Cycloalkyl, -O-(CH2) r -5-6-membered heteroaryl, wherein the alkenyl, alkynyl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further characterized by 1-5 R groups. a Replace; in some implementations, each R C Each group is independently selected from deuterium, hydroxyl, cyano, halogen, amino, nitro, -SCF3, -SCH2CF3, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy groups, -O-(CH2) r -C 3-6 Cycloalkyl, -O-(CH2) r -(3-8 membered heterocyclic alkyl groups), -C(=O)-C 3-6 cycloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 quinary heteroaryl, 5-6 quinary heterocyclic 5-6 quinary heteroaryl, -NR A1 -(5-6 quinone heteroaryl groups), -NR A1 -C 1-6 Alkyl group, -CH=CR c1 R c2 -NR A1 -(CH2)r -C 3-6 Cycloalkyl, wherein the alkenyl, alkynyl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further characterized by 1-5 R groups. a replace;

[0102] Alternatively, two R atoms on the same atom B Two R atoms on the same atom C Two R atoms on adjacent atoms B Two R atoms on adjacent atoms C Together with the atoms attached to it, they form C 3-8 Carbon rings or 3-8 membered heterocycles, wherein the carbon rings or heterocycles may optionally be further divided into 1-5 R groups. a replace;

[0103] R a Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, nitro, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, -C(=O)-C 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl group, -(CH2) r -S(=O)2-C 1-6 Alkyl, =CH2, =CHF, =CF2, =CH-CH3, =C-(CH3)2, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, -O-(CH2) r -C 3-6 Cycloalkyl, -SCF3, -NR A1 -C 1-6 Alkyl, C 6-10 aryl or 5-10 heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further selected from 1-5 groups selected from deuterium, halogen, cyano, amino, =O, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or deuterated C 1-6 The alkoxy group is substituted; or R a Each is independently selected from deuterium, halogen, cyano, hydroxyl, amino, nitro, =O, C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, -C(=O)-C 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl group, -(CH2) r -S(=O)2-C 1-6 Alkyl, =CH2, =CHF, =CF2, =CH-CH3, =C-(CH3)2, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, -O-(CH2) r -C 3-6 Cycloalkyl, -SCF3, -NR A1 -C 1-6 Alkyl, C 6-10 aryl or 5-10 heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further selected from 1-5 groups selected from deuterium, halogen, cyano, amino, =O, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or deuterated C 1-6 The alkoxy group is replaced;

[0104] R c1 R c2 Together with the connected carbon atoms, they form 4-6 membered carbon rings;

[0105] n is selected from 1, 2, 3, 4 or 5.

[0106] In some specific embodiments, the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt, wherein,

[0107] R a1 R b R c R d Each is independently selected from hydrogen;

[0108] X1 is selected from -N- and -CH-;

[0109] R1, R2, R3, and R4 are each independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-8 aryl or 5-6 heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace;

[0110] R5 is selected from deuterium, halogens, and C. 2-6 alkenyl, C 2-6 alkynyl, -NR A1 C(=O)-C 3-6 Cycloalkyl, -C(=O)NR A1 -C 3-6 cycloalkyl, -NR A1 C(=O)-(4-6 membered heterocyclic alkyl groups), C 6-8 Aryl, -NR A1 -(5-6-membered heteroaryl) or 5-6-membered heteroaryl, wherein the alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace;

[0111] R A1 Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups.

[0112] In some specific embodiments, the compound, its stereoisomer or pharmaceutically acceptable salt, wherein,

[0113] L1 is selected from -C(=O)-C 1-2 Alkyl, -C(=O)-O-, -C(=O)-S-;

[0114] Ring B is selected from cyclopropyl, cyclobutyl, azirrobutyl, azirropentyl, and azirrohexyl, wherein the cyclopropyl, cyclobutyl, azirrobutyl, azirropentyl, and azirrohexyl groups are optionally surrounded by 1-3 R groups. B replace;

[0115] Each R B Each element is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkoxy, C 1-6Halogenated alkoxy groups, wherein the alkyl or alkoxy group is optionally further surrounded by 1-3 R groups. a replace;

[0116] Alternatively, two R atoms on the same atom B Two R atoms on adjacent atoms B Together with the atoms attached to it, they form C 3-6 Carbon rings or 4-6 membered heterocycles, wherein the carbon rings or heterocycles may optionally be further divided by 1-3 R groups. a replace.

[0117] In some specific embodiments, the compound, its stereoisomer or pharmaceutically acceptable salt, wherein,

[0118] X2 and X3 are each independently selected from -N-, -CH-, and -CR. C -;

[0119] Each R C Each element is independently selected from deuterium, halogens, -SCF3, -SCH2CF3, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy groups, -O-(CH2) r -C 3-6 Cycloalkyl, -O-(CH2) r -(3-6 membered heterocyclic alkyl groups), C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-8 Aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclic 5-6 membered heteroaryl, 4-6 membered heterocyclic alkyl spiro-3-4 membered cycloalkyl, -NR A1 -(5-6 quinone heteroaryl groups), -NR A1 -C 1-6 Alkyl group, -CH=CR c1 R c2 -NR A1 -(CH2) r -C 3-6 Cycloalkyl, -O-(CH2) r -5-6-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further surrounded by 1-5 R groups. a Replace; in some implementations, each R C Each element is independently selected from deuterium, halogens, -SCF3, -SCH2CF3, and C. 1-6 Alkyl, C1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy groups, -O-(CH2) r -C 3-6 Cycloalkyl, -O-(CH2) r -(3-6 membered heterocyclic alkyl groups), C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-8 Aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclic 5-6 membered heteroaryl, 4-6 membered heterocyclic alkyl spiro-3-4 membered cycloalkyl, -NR A1 -(5-6 quinone heteroaryl groups), -NR A1 -C 1-6 Alkyl group, -CH=CR c1 R c2 -NR A1 -(CH2) r -C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further characterized by 1-5 R groups. a replace;

[0120] r can be independently selected from 0, 1, 2, or 3;

[0121] R c1 R c2 Together with the connected carbon atoms, they form 4-6 membered carbon rings;

[0122] Alternatively, two R atoms on the same atom C Two R atoms on adjacent atoms C Together with the atoms attached to it, they form C 3-6 Carbon rings or 4-6 membered heterocycles, wherein the carbon rings or heterocycles may optionally be further divided by 1-3 R groups. a replace;

[0123] n is selected from 1, 2, or 3.

[0124] In some specific embodiments, the compound, its stereoisomer or pharmaceutically acceptable salt, wherein,

[0125] R a Each is independently selected from deuterium, F, Cl, cyano, hydroxyl, amino, nitro, =O, C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4Deuterated alkoxy, C 1-4 Haloalkoxy, -C(=O)-C 1-2 Alkyl group, -NH-C(=O)-C 1-2 Alkyl group, -(CH2) r -S(=O)2-C 1-2 Alkyl, =CH2, =CHF, =CF2, =CH-CH3, =C-(CH3)2, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl or 5-10 heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further selected from 1-5 groups selected from deuterium, halogen, cyano, amino, =O, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl or deuterated C 1-3 The alkoxy group is replaced.

[0126] In some specific embodiments, the compound, its stereoisomer or pharmaceutically acceptable salt, wherein,

[0127] R a Each is independently selected from deuterium, F, Cl, cyano, hydroxyl, amino, nitro, =O, C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Haloalkoxy, -C(=O)-C 1-2 Alkyl group, -NH-C(=O)-C 1-2 Alkyl group, -(CH2) r -S(=O)2-C 1-2 Alkyl, =CH2, =CHF, =CF2, =CH-CH3, =C-(CH3)2, wherein the alkyl, alkenyl, alkynyl, or alkoxy group is optionally further selected from 1 to 5 groups selected from deuterium, halogen, cyano, amino, =O, C 1-3 Alkyl, Halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl or deuterated C 1-3 The alkoxy group is replaced.

[0128] In some specific embodiments, the compound, its stereoisomer or pharmaceutically acceptable salt, wherein,

[0129] Ring A is selected from one of the following structures: In some implementations, ring A is selected from one of the following structures:

[0130] B rings are selected from 1-3 R rings. B The following groups are substituted: in, The terminal is connected to L1;

[0131] C rings are selected from 1-3 R rings. C The following groups are substituted:

[0132] In some specific embodiments, the compound, its stereoisomer or pharmaceutically acceptable salt, wherein,

[0133] L1 is selected from -C(=O)-CH2-;

[0134] Ring B is selected from the following groups:

[0135] In some specific embodiments, the compound, its stereoisomer or pharmaceutically acceptable salt, wherein,

[0136] Among them, ring A is selected from one of the following structures:

[0137] L1 is selected from -C(=O)-CH2-;

[0138] L2 is selected from the bond;

[0139] Ring B is selected from the following groups:

[0140] C rings are selected from 2-3 R rings. C The following groups are substituted:

[0141] Each R C Each element is independently selected from deuterium, halogens, -SCF3, -SCH2CF3, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkoxy, C1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, preferably R C Each element is independently selected from deuterium, halogens, -SCF3, -SCH2CF3, and C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Deuterated alkoxy, C 1-4 Halogenated alkoxy groups, C 3-4 Cycloalkyl, more preferably each R C Each is independently selected from F, Cl, -SCF3, -CH3, -CH2CH3, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, cyclopropyl, and cyclobutyl.

[0142] In some specific embodiments, the compound, its stereoisomer, or a pharmaceutically acceptable salt, wherein the compound does not have the following structure:

[0143] In some specific embodiments, the compound, its stereoisomer or pharmaceutically acceptable salt, wherein,

[0144] Ring A is selected from the following structure:

[0145] L1 is selected from -C(=O)-CH2-;

[0146] L2 is selected from the bond;

[0147] Ring B is selected from the following groups:

[0148] C rings are selected from 1-3 R rings. C The following groups are substituted:

[0149] Each R C Each element is independently selected from deuterium, halogens, -SCF3, -SCH2CF3, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, preferably R C Each element is independently selected from deuterium, halogens, -SCF3, -SCH2CF3, and C. 1-4 Alkyl, C1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Deuterated alkoxy, C 1-4 Halogenated alkoxy groups, C 3-4 Cycloalkyl, more preferably each R C Each is independently selected from F, Cl, -SCF3, -CH3, -CH2CH3, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, cyclopropyl, and cyclobutyl.

[0150] In some specific embodiments, the compound, its stereoisomer, or a pharmaceutically acceptable salt, wherein the B ring is selected from... At that time, the C-ring is not of the following structure:

[0151] In some specific embodiments, the compound, its stereoisomer or pharmaceutically acceptable salt, wherein,

[0152] Ring A is selected from the following structure:

[0153] L1 is selected from -C(=O)-CH2-;

[0154] L2 is selected from the bond;

[0155] Ring B is selected from the following groups:

[0156] The C ring is selected from -O-(CH2). r -C 3-6 Cycloalkyl or -O-(CH2) r -(3-6 membered heterocyclic alkyl) substituted groups include the following: The cycloalkyl or heterocycloalkyl group thereon is optionally further reinforced with 1-3 R groups. a Replacement, r is selected from 0; and the C ring is optionally further replaced by 1-2 R C replace;

[0157] R a Selected from deuterium, halogen, cyano, hydroxyl, amino, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6Haloalkoxy, =CH2, =CHF, =CF2, =CH-CH3, =C-(CH3)2; preferably deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Haloalkoxy groups; more preferably deuterium, F, Cl, Br, cyano, -CH3, -CH2CH3, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CD3, -CHD2, -CH2D, -CH2CD3, -CH2CHD2, -CH2CH2D, -OCH3, -OCH2CH3, -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCH2CHF2, -OCH2CH2F, -OCD3, -OCHD2, -OCH2D, -OCH2CD3, -OCH2CHD2, -OCH2CH2D;

[0158] Each R C Each element is independently selected from deuterium, halogens, -SCF3, -SCH2CF3, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, preferably R C Each element is independently selected from deuterium, halogens, -SCF3, -SCH2CF3, and C. 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Deuterated alkoxy, C 1-4 Halogenated alkoxy groups, more preferably each R C Each is independently selected from F, Cl, -SCF3, -CH3, -CH2CH3, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, and -CH2CH2F.

[0159] In some specific embodiments, the compound, its stereoisomer, or a pharmaceutically acceptable salt, wherein the B ring is selected from... At that time, the C-ring is not of the following structure:

[0160] In some specific embodiments, the compound, its stereoisomer or pharmaceutically acceptable salt, is selected from one of the structures in Table A:

[0161] Table A

[0162] The present invention also provides a pharmaceutical composition or pharmaceutical formulation comprising the compound described in any of the foregoing embodiments, its stereoisomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient.

[0163] Furthermore, the compositions or pharmaceutical preparations of the present invention contain 1-1500 mg of the compound described in any of the foregoing embodiments, its stereoisomers or pharmaceutically acceptable salts, and carriers and / or excipients.

[0164] The present invention also provides the use of the compounds described in any of the foregoing embodiments, their stereoisomers or pharmaceutically acceptable salts, or the compositions described in any of the foregoing embodiments in the preparation of medicaments for treating / preventing CHRM4-mediated diseases, further wherein the CHRM4-mediated diseases are selected from Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorders, cognitive impairment, Parkinson's disease, Parkinson's disease-levodopa-induced dyskinesia, Huntington's disease, dyskinesia, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma, trisomy 21, cerebral amyloid angiopathy, dementia, Dutch amyloid hemorrhage, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes, autism, and atherosclerosis; preferably Alzheimer's disease, schizophrenia, pain, addiction, and sleep disorders.

[0165] This invention also provides a method for treating diseases in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound or a pharmaceutically acceptable salt of its stereoisomers as described in any of the preceding embodiments, preferably 1-1500 mg, wherein the disease is selected from Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorders, cognitive impairment, Parkinson's disease, Parkinson's disease-levodopa-induced dyskinesia, Huntington's disease, dyskinesia, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma, trisomy 21, cerebral amyloid angiopathy, dementia, Dutch amyloid hemorrhage, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes, autism, and atherosclerosis; wherein the disease is preferably Alzheimer's disease, schizophrenia, pain, addiction, and sleep disorders. In some embodiments, the mammals described in this invention include humans.

[0166] The term "effective amount" or "therapeutic effective amount" as used in this application means that administering a sufficient amount of the compound disclosed in this application will alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising the compound disclosed in this application required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective doses include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1- 20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5 -150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-20 0mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 2 0-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-25 0mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg;50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg. ;

[0167] This invention relates to a kit that may include a single-dose or multi-dose composition comprising a compound of the present invention or its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein the amount of the compound of the present invention or its stereoisomers or the pharmaceutically acceptable salt thereof is the same as that in the pharmaceutical composition described above.

[0168] In this invention, the amount of the compound of the invention or its stereoisomer or pharmaceutically acceptable salt is converted in each case as a free base.

[0169] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0170] Synthetic route

[0171] Patent documents such as WO2018002760A1 describe methods for preparing CHRM4 receptor agonists. Those skilled in the art can combine these documents with known organic synthesis techniques to prepare the compounds of this invention, using commercially available chemicals and / or compounds described in chemical literature as starting materials. "Commercially available chemicals" are obtained from legitimate commercial sources, and suppliers include: Titan Technology, Anengji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology, among others.

[0172] The index of known chemical substances prepared by the American Chemical Society's Chemical Abstracts Service allows for the selective identification of specific and similar reactants. These indexes are available in most public and university libraries, as well as online. Known but not commercially available chemicals can optionally be prepared by custom chemical synthesis plants, many of which offer custom synthesis services to standard chemical suppliers.

[0173] the term

[0174] Unless otherwise specified in this invention, the terminology used in this invention has the following meanings:

[0175] The carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen involved in the groups and compounds described in this invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen involved in the groups and compounds described in this invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), and tritium (T, also known as superheavy hydrogen), and the isotopes of oxygen include... 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, an isotope of fluorine 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br.

[0176] In this article, "halogen" refers to F, Cl, Br, I, or their isotopes.

[0177] "Halogen substitution" refers to the substitution of a hydrogen atom by one or more elements selected from F, Cl, Br, I, or their isotopes. The upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be substituted in the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and this upper limit. When the number of halogen substituents is greater than 1, the same or different halogens can be used for substitution.

[0178] "Deuterated" or "deuterated product" refers to the situation where hydrogen atoms on alkyl, cycloalkyl, alkylene, aryl, heteroaryl, mercapto, heterocycloalkyl, alkenyl, alkynyl, etc., groups are replaced by at least one isotope deuterium. The upper limit of the number of deuterated groups is equal to the sum of the number of hydrogen atoms that can be replaced by the substituted groups. Unless otherwise specified, the number of deuterated groups is any integer between 1 and the upper limit. Preferably, 1 to 20 deuterium atoms are substituted, more preferably 1 to 10 deuterium atoms are substituted, more preferably 1 to 6 deuterium atoms are substituted, and even more preferably 1 to 3 deuterium atoms are substituted.

[0179] "alkyl" refers to a monovalent straight-chain or branched saturated aliphatic hydrocarbon group, and unless otherwise specified, it is an alkyl group with 1 to 20 carbon atoms, preferably an alkyl group with 1 to 8 carbon atoms, more preferably an alkyl group with 1 to 6 carbon atoms, further preferably an alkyl group with 1 to 4 carbon atoms, and even more preferably an alkyl group with 1 to 2 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and their various branched isomers.

[0180] "alkylene" refers to divalent straight-chain and branched saturated alkyl groups. Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0181] "Cycloalkyl" refers to a monovalent non-aromatic, partially unsaturated or fully saturated, substituted or unsubstituted carbocyclic hydrocarbon group. Unless otherwise specified, it typically has 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 6 carbon atoms, and even more preferably 3 to 4 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. Or cycloheptyl, etc.

[0182] "Cycloalkylene" refers to the divalent group of "cycloalkyl", and non-limiting examples include cyclopropylene, cyclobutylene, etc.

[0183] "Heterocyclic" or "heterocyclic group" refers to a substituted or unsubstituted, saturated or unsaturated aromatic or non-aromatic ring. Unless otherwise specified, it contains 1 to 3 heteroatoms selected from N, O, or S, including monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic fused heterocycles, bicyclic spirocyclic heterocycles, tricyclic fused heterocycles, etc. Unless otherwise specified, it is a 3- to 14-membered heterocycle, more preferably a 4- to 12-membered heterocycle, even more preferably a 4- to 10-membered heterocycle, and even more preferably a 4- to 7-membered heterocycle. Its definition includes heterocyclic alkyl and heteroaryl groups. The N and S in the heterocyclic group ring can be oxidized to various oxidation states. Heterocyclic groups can be attached to heteroatoms or carbon atoms. Non-limiting examples include epoxyethyl, azirropropyl, oxacyclobutyl, azirrobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxohexyl, azirroheptyl, pyridinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazoleyl, piperidinyl, piperinyl, morpholinyl, thiomorpholinyl, 1,3-dithioyl, and dioxinyl. Hydrofuranyl, dihydropyranyl, dithiapentylyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl, wait.

[0184] "Hypo-heterocyclic group" is the divalent group corresponding to "heterocyclic group". Non-limiting examples include imidazolyl, piperidinyl, aziridinepropyl, etc.

[0185] "Carbocyclic" or "carbocyclic group" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic carbocyclic group, including monocyclic carbocyclic, bicyclic bridged ring, bicyclic fused ring, and bicyclic spirocyclic groups, etc. Unless otherwise specified, it has 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 6 carbon atoms. Its definition includes cycloalkyl and aryl groups. In non-limiting embodiments, monocyclic carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl. The double-ring bridge includes... Etc., double-ring parallel rings include etc., double-ring spiral rings include wait.

[0186] "Aryl" refers to a carbocyclic ring that has aromatic properties. Non-limiting examples include phenyl, naphthyl, etc.

[0187] "Alynyl" refers to a straight-chain or branched monovalent unsaturated hydrocarbon group containing one or more carbon-carbon triple bonds. Unless otherwise specified, alkynyl contains 2-6 carbon atoms, preferably 2-4 carbon atoms. Non-limiting examples include acetylenyl, propynyl, propynyl, etc.

[0188] "Alkenyl" refers to a straight-chain or branched monovalent unsaturated hydrocarbon group containing one or more carbon-carbon double bonds. Unless otherwise specified, alkynyl groups contain 2-6 carbon atoms, preferably 2-4 carbon atoms. Non-limiting examples include vinyl, propenyl, allyl, 2-butenyl, 1-butenyl, etc.

[0189] "Alkoxy" or "alkyloxy" refers to -O-alkyl, and unless otherwise specified, it is -OC. 1-8 Alkyl group, preferably -OC 1-6 Alkyl, more preferably -OC 1-4 Alkyl groups, more preferably -OC 1-2 Alkyl groups. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy.

[0190] "Haloalkoxy" refers to -O-haloalkyl, and unless otherwise specified, it is -O-haloC. 1-8 Alkyl groups, preferably -O-halogenated C 1-6Alkyl groups, more preferably -O-halogenated C 1-4 Alkyl groups, more preferably -O-halogenated C 1-2 Alkyl groups. Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, etc.

[0191] “C 1-4 "alkyl acyl" refers to C 1-4 Alkyl-C(O)-. Non-limiting examples include formyl, acetyl, and propionyl groups.

[0192] “C 1-4 "alkylsulfonyl" refers to C 1-4 Alkyl-S(O)2-. Non-limiting examples include methanesulfonyl, ethanesulfonyl, and propanesulfonyl.

[0193] "Heteroaromatic ring" or "heteroaryl" refers to a heterocyclic ring that is aromatic. Non-limiting examples include pyrazolyl, pyrimidinyl, thiazolyl, pyridinyl, furanyl, pyranone, pyridinone, etc.

[0194] "Heterocyclic alkyl" refers to a non-aromatic, partially unsaturated, or fully saturated heterocycle, generally having 4 to 12 ring members, preferably 4 to 10 ring members, more preferably 4 to 7 ring members, and even more preferably 5 or 6 ring members. In addition to a carbon atom, the heterocyclic alkyl also contains 1 to 3 heteroatoms selected from N, S, and O as ring members. Non-limiting examples include nitrogen-heterocyclic butyl, morpholino, piperazine, piperidinyl, tetrahydropyranyl, and oxocyclic butyl.

[0195] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or possibility that the event or environment may or may not occur. For example, "optionally substituted F alkyl" means that the alkyl group may but does not have to be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

[0196] When the specific structures or segments listed in this invention are further substituted, the hydrogen atoms shown in the specific structures may also be optionally substituted. For example, in general formulas (I), (II), etc., ring A is selected from those optionally further substituted with 1, 2, or 3 R atoms. A Replacement Include The hydrogen atom on the nitrogen in the structure can still be R A replace.

[0197] When the groups described in this invention are further substituted, the described groups include both individual groups and groups that are part of them. For example, when describing the further substitution of heteroaryl groups, the heteroaryl groups in the heterocycloalkyl benzoaryl groups may also be further substituted.

[0198] "Pharmaceutically acceptable salt" means that the compound of the present invention retains the bioavailability and properties of a free acid or a free base, wherein the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0199] "Pharmaceutical composition" means one or more of the compounds described herein or their stereoisomers, solvates, pharmaceutically acceptable salts or eutectics, mixed with other components, wherein the other components contain physiologically / pharmaceuticalally acceptable carriers and / or excipients.

[0200] "Carrier" refers to a system that does not cause significant stimulation to the organism and does not eliminate the biological activity and properties of the given compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug, and deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0201] "Excipient" refers to an agent that is not itself a therapeutic agent but is used as a diluent, excipient, binder, and / or medium to be added to a pharmaceutical composition to improve its disposal or storage properties or to allow or promote the formation of a unit dosage form of the compound or pharmaceutical composition for administration. As is known to those skilled in the art, pharmaceutical excipients can provide a variety of functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweeteners. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, and croscarmellose (e.g., sodium croscarmellose); (4) tragacanth gum powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter. (9) Oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) Diols, such as propylene glycol; (11) Polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) Esters, such as ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers, such as magnesium hydroxide and aluminum hydroxide; (15) Alginate; (16) Atherless water; (17) Isotonic saline; (18) Ringer's solution; (19) Ethanol; (20) pH buffer solution; (21) Polyesters, polycarbonates and / or polyanhydrides; and (22) Other non-toxic compatible substances used in pharmaceutical preparations.

[0202] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0203] The compounds of this invention can exist in specific geometric or stereoisomeric forms. All such compounds of this invention, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, are within the scope of this invention. Additional asymmetric carbon atoms may be present in the substituents of the compounds of this invention. All such isomers and mixtures thereof are included within the scope of this invention. In some embodiments, the preferred compounds are those isomers exhibiting superior biological activity. Purified or partially purified isomers and stereoisomers of the compounds of this invention, or racemic mixtures or diastereomer mixtures, are also included within the scope of this invention. Purification and separation of such substances can be achieved using standard techniques known in the art.

[0204] The following detailed description of the invention is intended to illustrate non-limiting embodiments, enabling other skilled in the art to more fully understand the technical solutions, principles, and practical applications of the invention, so that other skilled in the art can modify and implement the invention in many forms to best suit the requirements of a particular application. Attached Figure Description

[0205] Figure 1: Experimental results of spontaneous activity model induced by AMPH (amphetamine) in mice.

[0206] Figure 2: Results of the caffeine-induced hyperactivity model in rats. Detailed Implementation

[0207] The present invention will be described in detail below through embodiments. Unless otherwise specified, experimental methods under conventional conditions were used in the embodiments. The embodiments are provided to better illustrate the present invention, but should not be construed as limiting the invention to the examples given. Non-essential improvements and adjustments made to the implementation schemes by those skilled in the art based on the above description are still within the scope of protection of the present invention.

[0208] Unless otherwise specified, the raw materials were purchased from companies such as Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology.

[0209] The structure of the compounds was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using Bruker Avance III 400 and Bruker Avance 300 NMR spectrometers in the following solvents: deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), and deuterated methanol (CD₃OD). Tetramethylsilane (TMS) was used as the internal standard.

[0210] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0211] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM).

[0212] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) are 0.15mm-0.20mm in diameter, and the silica gel plates used for thin-layer chromatography separation and purification are 0.4mm-0.5mm in diameter.

[0213] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0214] TBSCl: tert-butyldimethylchlorosilane; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; TBAF: tetrabutylammonium fluoride; TsCl: p-toluenesulfonyl chloride; DIPEA: N,N-diisopropylethylamine; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; Pd2(dba)3: tris(dibenzylacetone)dipalladium; Xantphos: 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene; XPhos Pd G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II); HBTU: Benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate; Pd(dppf)Cl2: 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride; Selectfluor reagent: 1-chloromethyl-4-fluoro-1,4-diazotized bicyclo[2.2.2]octane di(tetrafluoroborate); TCFH: N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate; RuPhos Pd G3: Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II); RuPhos Pd G4: Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II); DMF: N,N-dimethylformamide

[0215] Example 1:

[0216] Step 1: Compound 1A (0.2 g, 0.74 mmol, synthesized according to the method described in patent WO2020139916) was dissolved in 1,4-dioxane (8 mL), followed by the addition of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (184 mg, 0.88 mmol), potassium carbonate (204 mg, 1.48 mmol), and water (2 mL). Under a nitrogen atmosphere, Pd(dppf)Cl2 (27 mg, 0.04 mmol) was added, and the mixture was then heated to 85 °C and stirred for 16 h. After the reaction was complete, the mixture was cooled to room temperature, extracted with water and ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to give compound 1B (211 mg, 90.51%). LC-MS (ESI): m / z = 316.1 [M+H] + .

[0217] Step 2: Compound 1B (211 mg, 0.67 mmol) was dissolved in dichloromethane (5 mL), and a hydrochloric acid-dioxane solution (4 M, 2 mL) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was directly concentrated under reduced pressure to obtain crude compound 1C (208 mg). No further purification was required, and it could be used directly for the next reaction. LC-MS (ESI): m / z = 216.1 [M+H] + .

[0218] Step 3: 1-(trifluoromethyl)cyclobutanol (750 mg, 5.38 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0 °C under nitrogen protection, and NaH (258 mg, 6.45 mmol, 60% wt) was added. After stirring for 30 min, compound 1D (1 g, 4.48 mmol) was added, and the mixture was then heated to 70 °C and reacted for 16 h. After the reaction was completed by TLC monitoring, saturated ammonium chloride aqueous solution was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 1E (680 mg, 44.25%).

[0219] 1 H NMR (400MHz, CDCl3) δ9.81-9.78(m,1H),9.27-9.24(m,1H),9.20-9.18(m,1H),4.89-4.77(m,2H),4.66-4.57(m,2H),4.02-3.83(m,2H).

[0220] Step 4: Compound 1E (680 mg, 1.98 mmol), ethyl trifluoroacetate of 3-azacyclobutane (713 mg, 2.97 mmol), cesium carbonate (1.29 g, 3.96 mmol), L-proline (22 mg, 0.19 mmol), and CuI (37 mg, 0.19 mmol) were dissolved sequentially in DMSO (20 mL). The mixture was reacted at 100 °C for 16 hours under a nitrogen atmosphere. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, and saturated ammonium chloride aqueous solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 1F (600 mg, yield: 84.64%). LC-MS (ESI): m / z = 359.1 [M+H] + .

[0221] Step 5: Dissolve 1F (600 mg, 1.67 mmol) in a mixed solvent (tetrahydrofuran:water = 3:1 (20 mL)), add lithium hydroxide (200 mg, 8.35 mmol), and react at room temperature for 4 hours. After the reaction is complete as monitored by TLC, concentrate under reduced pressure to obtain 1 G of crude compound (240 mg). LC-MS (ESI): m / z = 331.1 [M+H] + .

[0222] Step 6: Compound 1G (120 mg) was dissolved in DMF (10 mL), and TEA (147 mg, 1.45 mmol) and HATU (165 mg, 0.43 mmol) were added. The mixture was stirred at room temperature for 5 minutes, and then compound 1C (100 mg, 0.40 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 1 (100 mg, yield 52.27%). LC-MS (ESI): m / z = 528.3 [M+H] + .

[0223] 1 H NMR (400MHz, CDCl3) δ8.19-8.15(m,1H),8.11-8.07(m,1H),7.84-7.81(m,1H ),6.05-5.98(m,1H),5.70-5.65(m,1H),4.80-4.74(m,4H),4.23-4.15(m,2H ),3.96(s,3H),3.69-3.63(m,2H),3.32-3.20(m,1H),2.93-2.83(m,2H),2.8 3-2.76(m,2H),2.62-2.54(m,2H),2.48(d,J=4.3Hz,3H),1.98-1.83(m,2H).

[0224] Example 2:

[0225] Step 1: 2A (40 g, 214 mmol) was dissolved in methanol (600 mL) at room temperature. A methanol solution of sodium methoxide (225 mmol) was added dropwise at 0 °C. After the addition was complete, the reaction proceeded at room temperature for 16 h. After the reaction was complete, a large amount of solid precipitated. The solid was filtered, and the filtrate was concentrated under reduced pressure to remove most of the methanol. Water was added, and the mixture was extracted with dichloromethane. The organic phase was concentrated under reduced pressure to obtain crude compound 2B (40 g). LC-MS (ESI): m / z = 183.1 [M+H] + .

[0226] Step 2: 2B (40 g, 219 mmol), triethylamine (34 g, 329 mmol), and 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (8.01 g, 10.95 mmol) were dissolved sequentially in methanol (350 mL) at room temperature. The mixture was then reacted at 100 °C for 16 h under a CO atmosphere (3 MPa). After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 2C (30 g, 66%). LC-MS (ESI): m / z = 207.1 [M+H] + .

[0227] Step 3: 2C (30 g, 145.5 mmol) was dissolved in methanol (500 mL) at room temperature, and Raney nickel (8.54 g) was added. The reaction was carried out at room temperature for 16 h under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 2D (7.5 g, 29%). LC-MS (ESI): m / z = 179.1 [M+H] + .

[0228] Step 4: 2D (7.5 g, 42.1 mmol), di-tert-butyl dicarbonate (13.8 g, 63.1 mmol), and triethylamine (8.5 g, 84.2 mmol) were dissolved sequentially in tetrahydrofuran (80 mL) at room temperature. 4-Dimethylaminopyridine (1.03 g, 8.43 mmol) was added at 0 °C, and the mixture was reacted at room temperature for 16 h. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 2E (11 g, 94%). LC-MS (ESI): m / z = 179.1 [M+H-Boc] + .

[0229] Step 5: 2E (11 g, 39.5 mmol) was dissolved in THF (100 mL) at room temperature, and borane dimethyl sulfide (12.1 g, 158 mmol) was added. The mixture was heated to 70 °C and reacted for 4 h. After the reaction was complete, the mixture was cooled to room temperature, and methanol was slowly added dropwise under ice bath to quench the reaction. After quenching, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 2F (5.5 g, 53%). LC-MS (ESI): m / z = 265.1 [M+H] + .

[0230] Step 6: Dissolve 2F (5.5 g, 20.8 mmol) in concentrated hydrochloric acid (60 mL) at room temperature, heat to 100 °C and react for 16 h. After the reaction is complete, concentrate under reduced pressure to remove the concentrated hydrochloric acid to obtain crude compound 2G (3 g). LC-MS (ESI): m / z = 151.1 [M+H] + .

[0231] Step 7: Dissolve 2g (3g, 20mmol) in 50mL H2O at room temperature. Adjust the pH to 8-9 by adding sodium carbonate in portions at room temperature. Then add di-tert-butyl dicarbonate (6.55g, 30mmol) and continue the reaction at room temperature for 3 hours. After the reaction is complete, a large amount of solid precipitates. Filter the mixture, collect the solid on the filter cake, and concentrate the solid under reduced pressure to obtain compound 2H (4.5g, 90%). LC-MS (ESI): m / z = 251.1 [M+H] + .

[0232] Step 8: 2H (4.5 g, 17.9 mmol) was dissolved in dichloromethane (100 mL) at room temperature, and lithium tert-butoxide (7.16 g, 89.5 mmol) was added. Then, difluorobromomethyltrimethylsilane (12.7 g, 62.6 mmol) was added at 0 °C. After the addition was complete, the reaction mixture was allowed to react at room temperature for 16 h. After the reaction was complete, the reaction solution was evaporated to dryness, then water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 2I (4.95 g, 92%). LC-MS (ESI): m / z = 301.2 [M+H] + .

[0233] Step 9: Dissolve 2I (0.5 g, 1.66 mmol) in dichloromethane (10 mL) at room temperature, add dioxane hydrochloride (0.62 mL, 2.49 mmol, 4 M), and react at room temperature for 16 h. Concentrate the reaction solution under reduced pressure to obtain the hydrochloride salt of compound 2J (0.3 g). LC-MS (ESI): m / z = 201.2 [M+H] + .

[0234] Step 10: At room temperature, 2 J of hydrochloride (0.040 g, 0.17 mmol), 1 G (0.067 g, 0.20 mmol), N,N-diisopropylethylamine (0.11 g, 0.85 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.097 g, 0.26 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the reaction was carried out at room temperature for 16 h. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine and concentrated under reduced pressure to obtain the crude product. The crude product was further purified by preparative HPLC to obtain compound 2 (0.050 g, 49%). LC-MS (ESI): m / z = 513.1 [M+H] + .

[0235] 1H NMR (400MHz, CDCl3) δ7.97-7.64(m,2H),6.34-6.30(m,1H),6.01(dd,1H),5.67(d,1H),4.90-4.85(m,2H),4.56-4.50(m,2H),4.18(t,2H),3.68 -3.61(m,2H),3.28-3.20(m,1H),2.92-2.82(m,2H),2.76(dd,2H),2.62 -2.54(m,2H),2.17-2.14(m,3H),2.02-1.93(m,1H),1.90-1.82(m,1H).

[0236] Example 3:

[0237] Compound 3 (65 mg, 27%) was synthesized from 3A (140 mg, 0.51 mmol, synthesized according to the method described in patent WO2024088409) and 1C (110 mg, 0.51 mmol) following the procedure in step 6 of Example 1. LC-MS (ESI): m / z = 472.2 [M+H] + .

[0238] 1 H NMR (400MHz, CDCl3) δ8.29-8.26(m,1H),8.19-8.14(m,1H),8.11-8.07(m,1H ),6.63-6.60(m,1H),6.40-6.36(m,1H),4.86-4.71(m,4H),4.65-4.29(m,1H) ,4.14-4.08(m,1H),3.98-3.95(m,3H),3.83-3.53(m,1H),3.46-2.87(m,1H) ,2.84-2.68(m,2H),2.52-2.44(m,3H),1.63-1.59(m,1H),1.47-1.42(m,2H).

[0239] Example 4:

[0240] Step 1: Dissolve 4A (50g, 261.79mmol) in methanol (500mL), and add a methanol solution of sodium methoxide (261.79mmol) dropwise while maintaining the temperature at 20°C. After the addition is complete, stir at room temperature for 16 hours. A solid precipitates during the reaction. Add water (1000mL), filter, wash the solid with water (300mL), and dry to obtain 4B (40g, 81.90%).

[0241] 1H NMR (400MHz, CDCl3) δ7.58 (d, 1H), 4.11 (s, 3H).

[0242] Step 2: Dissolve 4B (25 g, 134.00 mmol) and iodine (68.02 g, 268 mmol) in tetrahydrofuran (250 mL). Under a nitrogen atmosphere, at -78 °C, add diisopropylaminolithium (43.06 g, 402 mmol) dropwise. After the addition is complete, continue stirring for 1 h, then slowly raise the temperature to room temperature and stir for 2 h. Add sodium thiosulfate aqueous solution, extract with ethyl acetate, wash the combined organic phases with saturated brine, concentrate the organic phase under reduced pressure, and separate by silica gel column chromatography to obtain 4C (35 g, 83.59%). 1 H NMR (400MHz, CDCl3) 4.10 (s, 3H).

[0243] Step 3: 4C (34 g, 108.81 mmol), methylboric acid (32.57 g, 544.05 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (7.96 g, 10.88 mmol), and potassium phosphate (46.19 g, 217.62 mmol) were dissolved sequentially in a mixed solvent of 1,4-dioxane (350 mL) and water (30 mL). The mixture was heated to 80 °C and reacted for 16 h under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to remove most of the 1,4-dioxane. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 4D (14, 64.14%). 1 H NMR (400MHz, CDCl3) δ4.08 (s, 3H), 2.47 (d, 3H).

[0244] Step 4: 4D (13 g, 64.81 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (4.74 g, 6.48 mmol), and triethylamine (9.84 g, 97.22 mmol) were dissolved in methanol (150 mL) under a CO atmosphere (3 MPa) and the mixture was heated to 100 °C and reacted for 16 h. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and then water was added. The mixture was extracted with dichloromethane, and the organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 4E (7 g, 48.18%). LC-MS (ESI): m / z = 225.1 [M + H - 100] + .

[0245] Step 5: 4E (7 g, 31.22 mmol) and Raney nickel (1.83 g, 31.22 mmol) were dissolved sequentially in methanol (140 mL) and reacted at 40 °C for 16 h under a H2 atmosphere. After the reaction was complete, DCM (50 mL) was added, the mixture was filtered, the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure to obtain crude 4F (6 g, 97.95%). LC-MS (ESI): m / z = 197.1 [M+H] + .

[0246] Step 6: 4F (6 g, 30.58 mmol), di-tert-butyl dicarbonate (10.01 g, 45.87 mmol), and triethylamine (4.64 g, 45.87 mmol) were dissolved sequentially in tetrahydrofuran (60 mL). 4-Dimethylaminopyridine (DMAP) (0.37 g, 3.06 mmol) was added, and the mixture was reacted at room temperature for 2 h. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with dilute hydrochloric acid (pH = 2-3), then washed with saturated brine, and concentrated under reduced pressure to obtain crude product 4G (8 g, 88.28%). LC-MS (ESI): m / z = 297.1 [M+H] + .

[0247] Step 7: Dissolve 4G (6g, 20.25mmol) in tetrahydrofuran (60mL), add borane dimethyl sulfide complex (4.62g, 60.75mmol), and react at 70℃ for 3h. After the reaction is complete, cool to room temperature, quench with methanol (20mL) dropwise in an ice bath, and continue stirring for 2h after the addition is complete. Concentrate the reaction solution under reduced pressure, add water, extract with ethyl acetate, wash the organic phase with saturated brine, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 4H (4g, 69.97%). LC-MS (ESI): m / z = 283.1 [M+H] + .

[0248] Step 8: 4H (3 g, 10.63 mmol) and sodium iodide (7.17 g, 47.84 mmol) were dissolved in acetonitrile (60 mL), followed by the addition of trimethylchlorosilane (4.62 g, 42.52 mmol). The reaction was then heated to 85 °C for 3 h. After the reaction was complete, the mixture was cooled to room temperature, and water (40 mL), sodium bicarbonate (3.57 g, 42.52 mmol), and di-tert-butyl dicarbonate (3.48 g, 15.95 mmol) were added sequentially. The reaction was continued at room temperature for 16 h. The mixture was concentrated under reduced pressure to remove most of the acetonitrile, filtered, and the filter cake was washed with water and ethyl acetate. After drying, 4I (1.4 g, 49.11%) was obtained. LC-MS (ESI): m / z = 269.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ4.40-4.31(m,4H),2.09-2.05(m,3H),1.44(d,9H).

[0249] Step 9: Dissolve 4I (0.2 g, 0.75 mmol) in dichloromethane (10 mL), add triethylamine (0.3 g, 3.0 mmol), then lower the temperature to -70 °C under a nitrogen atmosphere, and add trifluoromethanesulfonic anhydride (0.42 g, 1.5 mmol) dropwise. After the addition is complete, continue the reaction for 2 h. After the reaction is complete, quench with water, extract with dichloromethane, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate to obtain the crude product. Purify the crude product by silica gel column chromatography to obtain compound 4J (0.17 g, 56.96%). LC-MS (ESI): m / z = 401.1 [M+H] + .

[0250] Step 10: Compound 4J (0.17 g, 0.40 mmol), 1-methyl-1H-pyrazole-4-boric acid (0.11 g, 0.84 mmol), tetrakis(triphenylphosphine)palladium (97 mg, 0.084 mmol), and sodium carbonate (0.13 g, 1.26 mmol) were dissolved sequentially in toluene (5 mL) and water (1 mL). The mixture was heated to 100 °C and stirred for 6 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature. The reaction solution was filtered through diatomaceous earth. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 4K (0.13 g, 92.11%). LC-MS (ESI): m / z = 333.2 [M+H] + .

[0251] Step 11: Compound 4K (0.13 g, 0.39 mmol) was dissolved in dichloromethane (1 mL), and HCl (4 M in 1,4-dioxane, 2 mL) was added dropwise. The mixture was stirred at room temperature for 2 hours after the addition was complete. The solution was concentrated under reduced pressure to obtain compound 4L (115 mg; the crude product was used directly in the next step). LC-MS (ESI): m / z = 233.2 [M+H] + .

[0252] Step 12: 4 L of crude product (60 mg), compound 4M (79 mg, 0.32 mmol, synthesized according to the method described in patent WO2024088408), N,N-diisopropylethylamine (0.13 g, 1.05 mmol), N-methylimidazole (86 mg, 1.05 mmol), and TCFH (0.12 g, 0.42 mmol) were dissolved in DMF (5 mL) sequentially, and the reaction was carried out at room temperature for 16 h. After the reaction was complete, water and ethyl acetate were added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 4 (51 mg, 54.55%). LC-MS (ESI): m / z = 466.3 [M+H] + .

[0253] 1 H NMR (400MHz, CDCl3) δ8.11-8.09(m,1H),8.00-7.96(m,1H),7.84(d,1H),4.77-4.74(m,4H),4.50-4.45(m,2H) ,3.99-3.94(m,5H),3.29-3.25(m,1H),2.82-2.78(m,2H),2.27(s,3H),2.04-1.99(m,1H),1.01-0.89(m,4H).

[0254] Example 5:

[0255] Step 1: Compound 3,3-difluorocyclobutanol (5.26 g, 48.63 mmol) was dissolved in tetrahydrofuran (80 mL), cooled to 0 °C, and then NaH (2.07 g, 51.87 mmol) was added. After stirring for 30 min, compound 1D (7.23 g, 32.42 mmol) was added, and the mixture was allowed to rise naturally to room temperature for 4 hours. After the reaction was completed by TLC monitoring, saturated ammonium chloride aqueous solution was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 5A (9.01 g, yield: 89.11%). LC-MS (ESI): m / z = 312.1 [M+H] + .

[0256] Step 2: 5A (6.0 g, 19.29 mmol), methyl 3-azacyclobutane acetate (4.98 g, 38.57 mmol), cesium carbonate (18.86 g, 57.87 mmol), and Ruphos Pd G3 (1.68 g, 1.93 mmol) were dissolved in toluene (100 mL) sequentially. The mixture was reacted at 90 °C for 4 hours under a nitrogen atmosphere. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, and saturated ammonium chloride aqueous solution was added. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The residue was concentrated under reduced pressure and purified by silica gel column chromatography to give compound 5B (2.4 g, yield: 39.88%). LC-MS (ESI): m / z = 313.2 [M+H] + .

[0257] Step 3: 5B (2.30 g, 7.36 mmol) was dissolved in a mixed solvent (tetrahydrofuran:methanol:water = 3:1:1 (30 mL)), and lithium hydroxide (0.26 g, 11.04 mmol) was added. The reaction was carried out at room temperature for 4 hours. After the reaction was completed by TLC monitoring, the solution was concentrated under reduced pressure to obtain crude compound 5C (2.50 g). LC-MS (ESI): m / z = 305.2 [M+H] + .

[0258] Step 4: Using compound 4L (75 mg, 0.15 mmol) and compound 5C (0.11 g, 0.38 mmol) as starting materials, compound 5 (61 mg, 48.43%) was obtained according to the method in step 12 of Example 4. LC-MS (ESI): m / z = 513.2 [M+H] + .

[0259] 1 H NMR(400MHz,DMSO-d6)δ8.26-8.24(d,1H),7.95-7.94(s,1H),7.74-7.72 (d,1H),6.08(d,1H),5.67(d,1H),5.06-5.02(m,1H),4.86(s,1H),4.80(s ,1H),4.63(s,1H),4.56(s,1H),4.05(t,2H),3.91(s,3H),3.60-3.57(m,2 H),3.11-3.02(m,3H),2.83-2.82(m,2H),2.69-2.59(m,2H),2.24(s,3H).

[0260] Example 6:

[0261] Step 1: Compound 6A (2 g, 11.11 mmol, synthesized according to the method described in patent WO2022011274) was dissolved in acetonitrile (40 mL), and tert-butyl nitrite (1.14 g, 11.11 mmol) and CuBr (1.59 g, 11.11 mmol) were added. Under a nitrogen atmosphere, the mixture was heated to 50 °C and stirred for 16 h. After the reaction was completed, it was cooled to room temperature, quenched with saturated sodium carbonate aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to obtain compound 6B (300 mg, 11.11%).

[0262] Step 2: Compound 6B (300 mg, 1.23 mmol), methyl 3-azacyclobutane acetate trifluoroacetate (333 mg, 1.47 mmol), Ruphos-Pd-G3 (102 mg, 0.12 mmol), and cesium carbonate (801 mg, 2.46 mmol) were dissolved in toluene (10 mL). The mixture was heated to 100 °C under a nitrogen atmosphere and reacted for 16 h. After the reaction was complete, the mixture was cooled to room temperature, filtered through a diatomaceous earth liner, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 6C (315 mg, 87%). LC-MS (ESI): m / z = 293.0 [M+H] + .

[0263] Step 3: Using compound 6C (315 mg, 1.08 mmol) as the starting material, following step 5 of Example 1, crude compound 6D (337 mg) was obtained. No further purification was required; it was used directly in the next step. LC-MS (ESI): m / z = 279.0 [M+H] + .

[0264] Step 4: Using compound 6D (337 mg) and compound 1C (150 mg, 0.69 mmol) as starting materials, compound 6 (24 mg, 7.32%) was obtained following the procedure in Step 6 of Example 1. LC-MS (ESI): m / z = 476.1 [M+H] + .

[0265] 1 H NMR (400MHz, DMSO-d6) δ8.37-8.33(m,1H),8.27-8.23(m,1H),8.01-7.97(m,1H),6.90-6.84(m,1H),4.89-4.82(m ,2H),4.66-4.58(m,2H),4.40-4.32(m,2H),3.89(s,5H),3.18-3.07(m,1H),2.92-2.83(m,2H),2.45-2.41(m,3H).

[0266] Example 7:

[0267] Step 1: Using 7A (0.36 g, 2 mmol) and methyl 3-azacyclobutane acetate (0.31 g, 2.4 mmol) as starting materials, compound 7B (0.5 g, 92.11%) was synthesized according to the method described in Step 4 of Example 1. LC-MS (ESI): m / z = 276.2 [M+H] + .

[0268] Step 2: Using 7B (0.5 g, 1.82 mmol) as the starting material, compound 7C (470 mg, 99.05%) was synthesized according to the synthesis method in step 5 of Example 1. LC-MS (ESI): m / z = 262.1 [M+H] + .

[0269] Step 3: Using 7C (0.10 g, 0.46 mmol) and intermediate 1C (0.12 g, 0.46 mmol) as starting materials, compound 7 (90 mg, 42.26%) was obtained according to the synthesis method in step 6 of Example 1. LC-MS (ESI): m / z = 459.1 [M+H] + .

[0270] 1 H NMR (400MHz, CDCl3): δ8.65(s,1H),8.18-8.16(m,1H),8.10-8.08(m,1H),6.46(s,1H),4.79-4.70(m,4H),4 .45-4.40(m,2H),3.96(s,3H),3.91-3.90(m,2H),3.34-3.33(m,1H),2.85-2.81(m,2H),2.49-2.48(m,3H).

[0271] Example 8:

[0272] Step 1: Compound 8A (1.08 g, 5 mmol) and methyl 3-azacyclobutane acetate (0.71 g, 5.5 mmol) were dissolved in dichloromethane (20 mL). Triethylamine (0.75 g, 7.5 mmol) was added dropwise under ice bath conditions. After the addition was complete, the reaction mixture was stirred under ice bath conditions for 2 hours. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain compound 8B-1 (700 mg, yield 45.41%, Rf = 0.65 (PE / EA = 4 / 1)) and compound 8B-2 (210 mg, yield 13.62%, Rf = 0.60 (PE / EA = 4 / 1)). LC-MS (ESI): m / z = 310.2 [M+H] + .

[0273] Step 2: Compound 8B-1 (700 mg, 2.26 mmol), pinacol 1-cyclopropylborate (760 mg, 4.52 mmol), Pd(dppf)₂Cl₂ (165 mg, 0.23 mmol), and potassium carbonate (623 mg, 4.52 mmol) were dissolved sequentially in a mixed solvent of 1,4-dioxane (15 mL) and water (2 mL). The mixture was heated to 90 °C and reacted for 18 h under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was then separated by silica gel column chromatography to obtain compound 8C-1 (60 mg, 8.42%). LC-MS (ESI): m / z = 316.3 [M+H] + .

[0274] Compound 8C-2 (50 mg, 24.55%) was synthesized using the method described above, starting with compound 8B-2 (700 mg, 2.26 mmol). LC-MS (ESI): m / z = 316.2 [M+H] + .

[0275] Step 3: Using 8C-1 (60 mg, 0.19 mmol) as the starting material, compound 8D-1 (57 mg, 99.99%) was synthesized according to the method described in Step 5 of Example 1. LC-MS (ESI): m / z = 302.2 [M+H] + .

[0276] Compound 8D-2 (48 mg, 99.99%) was synthesized using compound 8C-2 (50 mg, 2.26 mmol) following the method described in step 5 of Example 1. LC-MS (ESI): m / z = 302.1 [M+H] + .

[0277] Step 4: Using 8D-1 (57 mg, 0.19 mmol) intermediate 1C (52 mg, 0.21 mmol) as a starting material, compound 8 (20 mg, 21.20%) was obtained by following the synthetic method in Step 6 of Example 1. LC-MS (ESI): m / z = 499.3 [M+H] + .

[0278] Compound 8: 1 H NMR (400MHz, CDCl3): δ8.32(s,1H),8.17-8.15(m,1H),8.10-8.08(m,1H),4.79-4.76(m,4H),4.63-4.61(m,2H) ),4.12-4.11(m,2H),3.96(s,3H),3.30-3.29(m,1H),2.85-2.80(m,2H),2.49-2.47(m,4H),1.33-1.23(m,4H).

[0279] Compound 9 (20 mg, 25.18%) was obtained from intermediate 1C (44 mg, 0.18 mmol) of 8D-2, following the synthetic method described in step 6 of Example 1. LC-MS (ESI): m / z = 499.3 [M+H] + .

[0280] Compound 9: 1 H NMR (400MHz, CDCl3): δ8.31-8.29(m,1H),8.17-8.10(m,2H),4.80-4.76(m,4H),4.49-4.42(m,2H),3.97(s,3H ),3.96-3.95(m,1H),3.26-3.24(m,1H),2.84-2.79(m,2H),2.50(s,3H),2.22-2.19(m,2H),1.33-1.22(m,4H).

[0281] Example 10:

[0282] Step 1: Dissolve 10B (synthesized according to the method described in patent WO202302532) (2.02 g, 16.82 mmol) in tetrahydrofuran (25 mL), then add sodium hydride (0.81 g, 33.63 mmol) in portions under an ice-water bath, and continue stirring for half an hour. Add 10A (2.5 g, 11.2 mmol), and react at room temperature for 3 hours. After the reaction is complete, dilute with water, extract with ethyl acetate, concentrate the organic phase, and separate the residue by column chromatography to obtain 10C (2.3 g, 63.5%. LC-MS (ESI): m / z = 324.0 [M+H]). + .

[0283] Step 2: 10C (2 g, 6.19 mmol), 10D (2.40 g, 18.57 mmol), cesium carbonate (6.05 g, 18.57 mmol), and Ruphos Pd G3 (0.52 g, 0.62 mmol) were dissolved sequentially in 1,4-dioxane (30 mL). The reaction was carried out at 95 °C for 6 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phase was concentrated. The residue was separated by column chromatography to obtain 10E (1.6 g, 79%). LC-MS (ESI): m / z = 325.1 [M+H] + .

[0284] Step 3: Dissolve 10E (1.6 g, 4.93 mmol) in methanol (4 mL), water (4 mL), and tetrahydrofuran (4 mL), then add lithium hydroxide (0.24 g, 9.86 mmol) and react at room temperature for 2 hours. After the reaction is complete, concentrate to obtain crude 10F (1.3 g). LC-MS (ESI): m / z = 311.0 [M+H] + .

[0285] Step 4: Compound 10F (0.26 g, 0.84 mmol) was dissolved in DMF (10 mL), and then 10 G (synthesized according to the method described in patent WO2018002760) (0.18 g, 0.70 mmol), N-methylimidazole (0.34 g, 4.2 mmol), and TCFH (0.24 g, 0.84 mmol) were added sequentially. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, and the organic phase was washed successively with saturated ammonium chloride aqueous solution and saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain compound 10 (80 mg, 23.79%). LC-MS (ESI): m / z = 477.1 [M+H] + .

[0286] 1H NMR(400MHz,DMSO-d6)δ7.72-7.71(m,1H),7.48-7.47(m,1H),7.06-6.78 (m,1H),6.07-6.05(m,1H),5.65-5.64(m,1H),5.20-5.16(m,1H),4.92-4 .88(m,2H),4.68-4.64(m,2H),4.07-4.03(m,2H),3.60-3.57(m,2H),3.1 4-3.08(m,3H),2.85-2.83(m,2H),2.73-2.67(m,2H),2.35-2.34(m,3H).

[0287] Example 11:

[0288] Compound 11 (31 mg, 18.51%) was obtained from starting materials compound 11A (100 mg, 0.34 mmol, synthesized according to the method described in patent WO2024088408) and compound 1C (88 mg, 0.41 mmol) following the procedure in step 6 of Example 1. LC-MS (ESI): m / z = 490.1 [M+H] + .

[0289] 1 H NMR (400MHz, CDCl3) δ8.21-8.14(m,2H),8.12-8.06(m,1H),6.54(s,1H),6.33-6.26(m,1H),4.82-4.74( m,4H),4.38-4.30(m,2H),3.96(s,3H),3.89-3.80(m,2H),3.36(s,1H),2.91-2.80(m,2H),2.49(s,3H).

[0290] Example 12:

[0291] Step 1: 12A (1.0 g, 11.6 mmol) was added to triethylamine trihydrofluoride (2.8 g, 17.4 mmol) at room temperature, and the mixture was heated to 120 °C and reacted for 16 h. After the reaction was complete, the mixture was cooled to room temperature, and sodium carbonate was added in portions to adjust the pH to 7–8. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 12B (12B-1 and 12B-2 are enantiomers) (400 mg, 32%). LC-MS (ESI): m / z = 107.2 [M+H] + .

[0292] Step 2: Using compound 12B (12B-1 and 12B-2 are enantiomers) (400 mg, 3.77 mmol) as the starting material, compound 12C (12C-1 and 12C-2 are enantiomers) (550 mg, 47%) was synthesized according to the method described in Step 1 of Example 10. LC-MS (ESI): m / z = 310.1 [M+H] + .

[0293] Step 3: Using 12C (12C-1 and 12C-2 are enantiomers) (550 mg, 1.78 mmol) as the starting material, compound 12D (12D-1 and 12D-2 are enantiomers) (400 mg, 69%) was synthesized according to the method described in Step 2 of Example 10. LC-MS (ESI): m / z = 325.2 [M+H] + .

[0294] Step 4: Using 12D (12D-1 and 12D-2 are enantiomers) (400 mg, 1.23 mmol) as the starting material, compound 12E (12E-1 and 12E-2 are enantiomers) (340 mg, 93%) was synthesized according to the method described in Step 3 of Example 10. LC-MS (ESI): m / z = 297.1 [M+H] + .

[0295] Step 5: Using 12E (12E-1 and 12E-2 are enantiomers) (340 mg, 1.15 mmol) and 2J (230 mg, 1.15 mmol) as raw materials, the enantiomer of compound 12 (450 mg) was obtained by referring to the synthesis method in step 10 of Example 2. The enantiomer of compound 12 was further separated by chiral HPLC to obtain compound 12 isomer 1 (212 mg, retention time 2.529 min, 39%) and compound 12 isomer 2 (192 mg, retention time 3.719 min, 35%).

[0296] Preparative chromatographic analysis method: Instrument: SHIMADZU LC-20AD; Column: Chiral OX column; Mobile phase system: A for n-Hexane; B for 0.1% IPAmin ethanol and acetonitrile (v / v = 3:1); Gradient: B for 45%; Flow rate: 1.0 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0297] Compound 12 isomer 1: LCMS m / z = 479.1 [M+H] + .

[0298] 1H NMR (400MHz, CDCl3) δ7.97-7.64(m,2H),6.35-6.29(m,1H),6.03-5.97(m,1H),5. 66-5.62(m,1H),5.58-5.50(m,1H),5.29-5.13(m,1H),4.91-4.83(m,2H),4.57-4. 47(m,2H),4.28-4.22(m,1H),4.17(t,2H),4.10-4.06(m,1H),4.02-3.97(m,1H),3 .93-3.88(m,1H),3.67-3.60(m,2H),3.29-3.18(m,1H),2.76(d,2H),2.16(d,3H).

[0299] Compound 12 isomer 2: LCMS m / z = 479.1 [M+H] + .

[0300] 1 H NMR (400MHz, CDCl3) δ7.98-7.63(m,2H),6.37-6.29(m,1H),6.03-5.97(m,1H),5. 65-5.62(m,1H),5.58-5.50(m,1H),5.29-5.13(m,1H),4.91-4.83(m,2H),4.57-4. 47(m,2H),4.28-4.22(m,1H),4.18(t,2H),4.10-4.06(m,1H),4.02-3.97(m,1H),3 .93-3.88(m,1H),3.67-3.60(m,2H),3.29-3.18(m,1H),2.76(d,2H),2.15(d,3H).

[0301] Example 13:

[0302] Step 1: Triphenylphosphine (9.6 g, 36.7 mmol) was dissolved in anhydrous tetrahydrofuran (120 mL) at room temperature. Then, diisopropyl azodicarbonate (7.4 g, 36.7 mmol) was added dropwise at 0 °C under a N2 atmosphere. After the addition was complete, the reaction was carried out at 0 °C for 1 h. Then, 12B (12B-1 and 12B-2 are enantiomers) (3.0 g, 28.3 mmol) and p-nitrobenzoic acid (4.7 g, 36.7 mmol) were added. After the addition was complete, the reaction was carried out at room temperature for 16 h. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 13A (1.5 g, 21%) (1.5 g, 21%). LC-MS (ESI): m / z = 256.2 [M+H] + .

[0303] Step 2: 13A (13A-1 and 13A-2 are enantiomers) (1.5 g, 5.88 mmol) was dissolved in methanol (60 mL) at room temperature, followed by the addition of potassium carbonate (4.0 g, 29.4 mmol). The reaction was carried out at room temperature for 3 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 13B (13B-1 and 13B-2 are enantiomers) (500 mg, 80%). LC-MS (ESI): m / z = 107.1 [M+H] + .

[0304] Step 3: Using 13B-1 and 13B-2 (500 mg, 4.71 mmol) as starting materials, compound 13C (13C-1 and 13C-2 are enantiomers) (600 mg, 41%) was obtained according to the synthesis method in Step 1 of Example 10. LC-MS (ESI): m / z = 310.1 [M+H] + .

[0305] Step 4: Using 13C (13C-1 and 13C-2 are enantiomers) (600 mg, 1.94 mmol) as the starting material, compound 13D (13D-1 and 13D-2 are enantiomers) (500 mg, 79%) was obtained by following the synthetic method in Step 2 of Example 10. LC-MS (ESI): m / z = 325.2 [M+H] + .

[0306] Step 5: Using 13D (13D-1 and 13D-2 are enantiomers) (500 mg, 1.54 mmol) as the starting material, compound 13E (13E-1 and 13E-2 are enantiomers) (430 mg, 94%) was synthesized according to the method described in Step 3 of Example 10. LC-MS (ESI): m / z = 297.1 [M+H]+ .

[0307] Step 6: Using 13E (13E-1 and 13E-2 are enantiomers) (430 mg, 1.45 mmol) and 2J (290 mg, 1.45 mmol) as raw materials, the enantiomer of compound 13 (600 mg) was obtained by referring to the synthesis method in step 10 of Example 2. The enantiomer of compound 13 was further separated by SFC to obtain compound 13 isomer 1 (267 mg, retention time 0.526 min, 38%) and compound 13 isomer 2 (248 mg, retention time 0.660 min, 36%).

[0308] Preparative chromatographic analysis method: Instrument: SHIMADZU LC-30AD SFC; Column: Chiral AD column; Mobile phase system: A for CO2; B for 0.05% DEA in ethanol and acetonitrile; Gradient: B for 50%; Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0309] Compound 13 isomer 1: LCMS m / z = 479.1 [M+H] + .

[0310] 1 H NMR (400MHz, CDCl3) δ7.97-7.62(m,2H),6.34-6.29(m,1H),6.00(dd,1H),5.74(d,1H),5.50-5.26(m,2H),4.90-4.83(m,2H),4.55 -4.49(m,2H),4.24-4.10(m,4H),4.10-4.01(m,1H),3.88(t,1H),3.68-3.60(m,2H),3.30-3.18(m,1H),2.75(d,2H),2.15(d,3H).

[0311] Compound 13 isomer 2: LCMS m / z = 479.1 [M+H] + .

[0312] 1H NMR (400MHz, CDCl3) δ7.97-7.62(m,2H),6.35-6.28(m,1H),6.00(dd,1H),5.74(d,1H),5.49-5.26(m,2H),4.91-4.83(m,2H),4.58 -4.47(m,2H),4.23-4.10(m,4H),4.09-4.00(m,1H),3.88(t,1H),3.68-3.59(m,2H),3.29-3.18(m,1H),2.75(d,2H),2.15(d,3H).

[0313] Example 14:

[0314] Step 1: Using 2,6-difluoro-4-iodopyridine (1 g, 4.15 mmol) as a starting material, compound 14A (1.1 g, 81%) was obtained by following the synthetic method described in Step 1 of Example 5. LC-MS (ESI): m / z = 330.1 [M+H] + .

[0315] Step 2: Using compound 14A (1.1 g, 3.34 mmol) as the starting material, compound 14B (0.85 g, 74%) was synthesized according to the method described in Step 2 of Example 5. LC-MS (ESI): m / z = 345.1 [M+H] + .

[0316] Step 3: Using compound 14B (100 mg, 0.29 mmol) as the starting material, compound 14C (90 mg, 98%) was synthesized according to the method described in Step 3 of Example 5. LC-MS (ESI): m / z = 317.1 [M+H] + .

[0317] Step 4: Using compound 14C (90 mg, 0.28 mmol) and compound 2J (57 mg, 0.28 mmol) as starting materials, compound 14 (64 mg, 46%) was synthesized according to the method described in Step 4 of Example 5. LC-MS (ESI): m / z = 499.2 [M+H] + .

[0318] 1H NMR (400MHz, CDCl3) δ7.97-7.64(m,1H),6.32(d,1H),5.49(s,2H),5.09-4.99(m,1H),4.87(d,2H),4.54(t,1H),4.51(s,1H) ),4.17(t,2H),3.67-3.62(m,2H),3.28-3.21(m,1H),3.12-3.02(m,2H),2.76(d,2H),2.73-2.58(m,2H),2.16-2.15(m,3H).

[0319] Example 15:

[0320] Using compound 2J (100 mg, 0.5 mmol) and compound 11A (148 mg, 0.5 mmol) as starting materials, compound 15 (70 mg, 30%) was obtained according to the procedure in step 6 of Example 1. LC-MS (ESI): m / z = 475.5 [M+H] + .

[0321] 1 H NMR(400MHz, CDCl3)δ8.17(d,1H),7.97-7.65(m,1H),6.51(d,1H),6.32(d,1H),6.23-6.21(m,1H),4.88 (d,2H),4.55-4.52(m,2H),4.24(t,2H),3.73-3.68(m,2H),3.36-3.21(m,1H),2.78(d,2H),2.16(d,3H).

[0322] Example 16:

[0323] Step 1: Compound 16A (1.5 g, 14.79 mmol) was dissolved in DMF (20 mL). Under a nitrogen atmosphere and controlled temperature of 0–5 °C, sodium hydride (0.59 g, 14.79 mmol) was added in portions. The mixture was then allowed to react at room temperature for 1 hour. 2-Fluoro-4-iodopyridine (3.0 g, 13.45 mmol) was added, and the reaction was continued at room temperature for 15 hours. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain compound 16B (1.8 g, 44%). LC-MS (ESI): m / z = 306.0 [M+H] + .

[0324] Step 2: Compound 16B (1.8 g, 5.90 mmol) and 2-iodobenzoic acid (3.3 g, 11.80 mmol) were dissolved in ethyl acetate (30 mL), and the mixture was heated to 75 °C and reacted for 6 hours. After the reaction was completed by TLC monitoring, the mixture was filtered, and the residue was purified by column chromatography to obtain compound 16C (1.5 g, 84%).

[0325] Step 3: Compound 16C (1.5 g, 4.95 mmol) was dissolved in dichloromethane (30 mL), and the solution was cooled to 0–5 °C. Diethylaminosulfur trifluoride (2.39 g, 14.85 mmol) was slowly added dropwise. After the addition was complete, the mixture was brought to room temperature and reacted for 5 hours. After the reaction was completed as monitored by TLC, the reaction solution was slowly poured into a saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated and purified by column chromatography to obtain compound 16D (0.9 g, 56%). LC-MS (ESI): m / z = 326.0 [M+H] + .

[0326] Step 4: Using compound 16D (0.9 g, 2.77 mmol) as the starting material, compound 16E (0.7 g, 74%) was synthesized according to the method described in step 2 of Example 10. LC-MS (ESI): m / z = 341.2 [M+H] + .

[0327] Step 5: Using compound 16E (0.7g, 2.06mmol) as the starting material, compound 16F (0.74g) was obtained by referring to the synthesis method in step 3 of Example 10. It was used directly in the next reaction without further purification.

[0328] Step 6: Using compound 16F (0.51 g, 1.27 mmol) and compound 2J (0.30 g, 1.27 mmol) as starting materials, the racemic mixture of compound 16 (370 mg) was obtained according to the synthesis method in step 10 of Example 2. Further chiral resolution yielded compound 16, isomer 1 (170 mg, 27%, retention time 1.406 min) and isomer 2 (173 mg, 27%, retention time 1.896 min).

[0329] Preparative Chromatographic Analysis Method: Instrument: SHIMADZU LC-30AD SFC; Column: Chiral AD column; Mobile Phase: A for CO2; B for 0.05% DEA in methanol; Gradient: B for 40%; Flow Rate: 3 mL / min; Column Temperature: 35℃; Wavelength: 220 nm

[0330] Compound 16, isomer 1, LC-MS (ESI): m / z = 495.2 [M+H] + .

[0331] 1 H NMR (400MHz, CDCl3) δ7.97-7.65(m,2H),6.32(d,1H),5.99(d,1H),5.62(s,1H),5.48(s,1H),4.88(s,1H),4.54-4.52 (m,2H),4.21-4.17(m,1H),3.68-3.63(m,2H),3.25-3.22(m,1H),2.76(d,2H),2.66-2.53(m,1H),2.39-2.03(m,8H).

[0332] Compound 16, isomer 2, LC-MS (ESI): m / z = 495.2 [M+H] + .

[0333] 1 H NMR (400MHz, CDCl3) δ7.97-7.65(m,2H),6.32(d,1H),6.00(d,1H),5.62(s,1H),5.50(s,1H),4.88(s,1H),4.54-4.52 (m,2H),4.22-4.18(m,1H),3.67-3.66(m,2H),3.27-3.23(m,1H),2.76(d,2H),2.63-2.54(m,1H),2.37-2.05(m,8H).

[0334] Example 17:

[0335] Step 1: Using 17A (200 mg, 0.83 mmol) and 10B (109 mg, 0.91 mmol) as starting materials, compound 17B (120 mg, 42%) was synthesized according to the method described in Step 1 of Example 10. LC-MS (ESI): m / z = 342.0 [M+H] + .

[0336] Step 2: Using 17B (120 mg, 0.35 mmol) and ethyl 2-(azacyclobutane-3-yl)acetate (60 mg, 0.42 mmol) as starting materials, compound 17C (100 mg, 80%) was synthesized according to the method described in Step 2 of Example 10. LC-MS (ESI): m / z = 357.1 [M+H] + .

[0337] Step 3: Using 17C (100 mg, 0.28 mmol) as the starting material, compound 17D (80 mg, 87%) was synthesized according to the method described in Step 3 of Example 10. LC-MS (ESI): m / z = 329.2 [M+H] + .

[0338] Step 4: Using 17D (80 mg, 0.24 mmol) and 2J (49 mg, 0.24 mmol) as starting materials, compound 17 (33 mg, 26%) was synthesized according to the method described in step 10 of Example 2. LC-MS (ESI): m / z = 511.1 [M+H] + .

[0339] 1 H NMR(400MHz, CDCl3)δ7.80(td,1H),7.62(d,1H),6.34-6.29(m,1H),5.62(d,1H),5.20-5.11(m,1H),4.91-4.84(m,2H),4.5 7-4.48(m,2H),4.35-4.27(m,2H),3.84-3.74(m,2H),3.28-3.17(m,1H),3.16-3.08(m,2H),2.80-2.70(m,4H),2.15(s,3H).

[0340] Example 18:

[0341] Step 1: Compound 18A (1.0 g, 7.24 mmol) (prepared according to the method described in patent CN113072546) was dissolved in tetrahydrofuran (20 mL). Under a nitrogen atmosphere, sodium hydride (0.26 g, 10.86 mmol) was added in portions at 0 °C, followed by a reaction at 0 °C for 1 hour. Then, 2-fluoro-4-iodopyridine (3.0 g, 13.45 mmol) was added, and the reaction was continued at 0 °C for another hour. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain compound 18B (1.2 g, 48.6%). LC-MS (ESI): m / z = 342.0 [M+H] + .

[0342] Step 2: Using compound 18B (1.0 g, 2.93 mmol) as the starting material, compound 18C (0.95 g, 91%) was synthesized according to the method described in Step 2 of Example 10. LC-MS (ESI): m / z = 357.2 [M+H] + .

[0343] Compound 18C (0.55 g, 1.54 mmol) was further chirally resolved to 18C-1 (28 mg, retention time 1.504 min) and 18C-2 (450 mg, retention time 2.293 min). Preparative chromatographic analysis: Instrument: Waters 150Prep-SFC; Column: Chiral AD column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in methanol; Gradient: B for 45%; Flow rate: 100 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0344] Step 3: Using compound 18C-2 (0.3 g, 0.84 mmol) as the starting material, crude compound 18D-2 (0.84 mmol) was obtained according to the synthesis method in step 3 of Example 10. This crude compound was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 329.1 [M+H] + .

[0345] Step 4: Using compound 18D-2 (0.84 mmol) and compound 2J (0.229 g, 0.84 mmol) as starting materials, compound 18 (200 mg, 48%) was synthesized according to the method described in step 10 of Example 2. LC-MS (ESI): m / z = 511.2 [M+H] + .

[0346] 1 H NMR (400MHz, CDCl3) δ7.98-7.63(m,2H),6.35-5.96(m,3H),5.62-5.61(m,1H),4.91-4.80(m,3H),4.55-4.51(m,2H),4.39-4.31(m,1H) ,4.18-4.14(m,2H),3.65-3.60(m,2H),3.26-3.17(m,1H),2.98-2.87(m,2H),2.76-2.75(m,2H),2.34-2.27(m,2H),2.19-2.13(m,3H).

[0347] Example 19:

[0348] Step 1: Using compound 19A (1 g, 6.41 mmol) (prepared according to the method described in patent WO2022094244) as the starting material, compound 19B (1.3 g, 57%) was synthesized according to the method described in Step 1 of Example 18. LC-MS (ESI): m / z = 360.0 [M+H] + .

[0349] Step 2: Using compound 19B (1.2 g, 3.34 mmol) as the starting material, compound 19C (1.1 g, 88%) was synthesized according to the method described in Step 2 of Example 10. LC-MS (ESI): m / z = 375.2 [M+H] + .

[0350] Compound 19C (0.45 g, 1.2 mmol) was further chirally resolved to 19C-1 (16 mg, retention time 1.02 min) and 19C-2 (340 mg, retention time 1.48 min). Preparative chromatographic analysis: Instrument: Waters 150Prep-SFC; Column: Chiral AD column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in methanol; Gradient: B for 45%; Flow rate: 100 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0351] Step 3: Using compound 19C-2 (0.3 g, 0.8 mmol) as the starting material, crude compound 19D-2 (0.8 mmol) was obtained according to the synthesis method in step 3 of Example 10. This crude product was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 347.1 [M+H] + .

[0352] Step 4: Using compound 19D-2 (0.8 mmol) and compound 2J (0.22 g, 0.8 mmol) as starting materials, compound 19 (200 mg, 47%) was synthesized according to the method described in step 10 of Example 2. LC-MS (ESI): m / z = 529.2 [M+H] + .

[0353] 1 H NMR (400MHz, CDCl3) δ7.99-7.62(m,2H),6.32(d,1H),5.98(dd,1H),5.62(d,1H),4.89-4.82(m,3H),4.55-4.51(m,2H),4.43-4.36(m ,1H),4.17(t,2H),3.66-3.61(m,2H),3.31-3.15(m,1H),3.06-2.92(m,2H),2.77-2.75(m,2H),2.43-2.33(m,2H),2.17-2.14(m,3H).

[0354] Example 20:

[0355] Step 1: At room temperature, benzyl alcohol (561 mg, 5.19 mmol) was dissolved in dioxane hydrochloride solution (4 M, 2 mL), and compound 20A (1.0 g, 4.33 mmol) was added. The mixture was then heated to 80 °C and reacted for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 20B (0.3 g, 39%). LC-MS (ESI): m / z = 177.2 [M+H] + .

[0356] Step 2: Using 20B (0.3 g, 1.70 mmol) as the starting material, compound 20C (0.19 g, 55.4%) was obtained by following the synthetic method in Step 3 of Example 16. LC-MS (ESI): m / z = 199.2 [M+H] + .

[0357] Step 3: Compound 20C (0.19 g, 0.95 mmol) was dissolved in diethyl ether, and palladium on carbon (10%, 120 mg) was added. The reaction was carried out under a hydrogen atmosphere at room temperature for 15 hours. After the reaction was complete, the mixture was filtered, and the filtrate (containing compound 20D) was used directly for the next step. LC-MS (ESI): m / z = 109.2 [M+H] + .

[0358] Step 4: Using compound 20D (filtrate from step 3) as the starting material, compound 20E (0.29 g, 76.2%) was obtained by referring to the synthesis method in step 1 of Example 16. LC-MS (ESI): m / z = 312.2 [M+H] + .

[0359] Step 5: Using compound 20E (0.29 g, 0.95 mmol) as the starting material, compound 20F (0.29 g, 94.5%) was synthesized according to the method described in step 2 of Example 10. LC-MS (ESI): m / z = 327.2 [M+H] + .

[0360] Step 6: Using compound 20F (0.29 g, 0.95 mmol) as the starting material, compound 20G (0.28 g, 99.6%) was synthesized according to the method described in step 3 of Example 10. This compound was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 299.2 [M+H] + .

[0361] Step 7: Using compound 20G (0.28g, 0.95mmol) and compound 2J (0.29g, 0.95mmol) as raw materials, compound 20 (120mg) was synthesized according to the method in step 10 of Example 2. The compound 20 isomer 1 (62mg, 32%, retention time 1.412min) and compound 20 isomer 2 (55mg, 31%, retention time 1.765min) were further chirally resolved to obtain compound 20 isomer 1 (62mg, 32%, retention time 1.412min) and compound 20 isomer 2 (55mg, 31%, retention time 1.765min).

[0362] Preparative chromatographic analysis method: Instrument: SHIMADZU LC-30AD SFC; Column: Chiral AD column; Mobile phase: A for CO2; B for 0.05% DEA in methanol; Gradient: B for 40%; Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0363] Isomer 1 of compound 20: LC-MS (ESI): m / z = 481.2 [M+H] + .

[0364] 1 H NMR (400MHz, CDCl3) δ8.01-7.98(m,1H),7.39-7.32(m,1H),7.04-6.89(m,1H),6.32-6.25(m,1H),6.25-6.22(m,1H),5.85-5.81(s,1H),4.84-4. 75(m,1H),4.57-4.50(m,1H),4.33-4.29(m,1H),4.27-4.22(m,1H),3.8 2-3.76(m,2H),3.55-3.47(m,2H),2.73-2.61(m,2H),2.59-2.28(m,8H).

[0365] Compound 20 isomer 2: LC-MS (ESI): m / z = 481.2 [M+H] + .

[0366] 1H NMR (400MHz, CDCl3) δ8.01-7.98(m,1H),7.39-7.32(m,1H),7.04-6.89(m,1H),6.32-6.25(m,1H),6.25-6.22(m,1H),5.85-5.81(s,1H),4.84-4. 75(m,1H),4.57-4.50(m,1H),4.33-4.29(m,1H),4.27-4.22(m,1H),3.8 2-3.76(m,2H),3.55-3.47(m,2H),2.73-2.61(m,2H),2.59-2.28(m,8H).

[0367] Example 21:

[0368] Step 1: Using compound 21A (900 mg, 6.42 mmol) as the starting material, compound 21B (1.91 g, 86.7%) was synthesized according to the method described in Step 1 of Example 16. LC-MS (ESI): m / z = 344.0 [M+H] + .

[0369] Step 2: Using compound 21B (1.05 g, 3.06 mmol) as the starting material, compound 21C (0.98 g, 89.3%) was obtained by following the synthetic method in Step 2 of Example 10. LC-MS (ESI): m / z = 359.2 [M+H] + .

[0370] Step 3: Using compound 21C (400 mg, 1.12 mmol) as the starting material, compound 21D (350 mg, 94.9%) was obtained by following the synthetic method in step 3 of Example 10. LC-MS (ESI): m / z = 331.1 [M+H] + .

[0371] Step 4: Using compound 21D (150 mg, 0.454 mmol) and compound 2J (108 mg, 0.454 mmol) as starting materials, the racemic mixture of compound 21 was obtained by referring to the synthesis method in step 10 of Example 2. The racemic mixture was further chirally resolved to obtain isomer 1 of compound 21 (58.3 mg, 25.1%, retention time 4.621 min) and isomer 2 of compound 21 (24.2 mg, 10.4%, retention time 5.436 min).

[0372] Preparative chromatographic analysis method: Instrument: SHIMADZU LC-20AD; Column: Chiral IA column; Mobile phase: A for n-Hexane; B for 0.1% IPAmin ethanol and acetonitrile; Gradient: B for 20%; Flow rate: 1 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0373] Isomer 1 of compound 21: LC-MS (ESI): m / z = 513.2 [M+H] + .

[0374] 1 H NMR(400MHz,Chloroform-d)δ7.99-7.62(m,2H),6.37-6.21(m,1H),6.05-5.92(m,1H),5.61(d,1H),5.14(q,1H),4.88(q,2H),4.61-4.4 4(m,2H),4.18(t,2H),3.75-3.58(m,2H),3.29-3.14(m,1H),2.85-2.70(m,2H),2.72-2.55(m,3H),2.32-2.23(m,2H),2.23-2.12(m,3H).

[0375] Compound 21 isomer 2: LC-MS (ESI): m / z = 513.2 [M+H] + .

[0376] 1 H NMR(400MHz,Chloroform-d)δ8.00-7.61(m,2H),6.32(d,1H),6.07-5.93(m,1H),5.54(s,1H),5.30-5.17(m,1H),4.88(s,2H),4.58-4.49(m ,2H),4.21(t,2H),3.69(q,2H),3.27(d,1H),3.04-2.92(m,1H),2.81- 2.73(m,2H),2.71-2.64(m,2H),2.51-2.39(m,2H),2.23-2.12(m,3H).

[0377] Example 22:

[0378] Step 1: Using compound 22A (900 mg, 7.37 mmol) as the starting material, compound 22B (2.03 g, 84.7%) was synthesized according to the method described in Step 1 of Example 16. LC-MS (ESI): m / z = 326.0 [M+H] + .

[0379] Step 2: Using compound 22B (1.05 g, 3.23 mmol) as the starting material, compound 22C (1.03 g, 93.6%) was obtained by following the synthetic method in Step 2 of Example 10. LC-MS (ESI): m / z = 341.2 [M+H] + .

[0380] Step 3: Using compound 22C (400 mg, 1.18 mmol) as the starting material, compound 22D (355 mg, 96.7%) was obtained by following the synthetic method in Step 3 of Example 10. LC-MS (ESI): m / z = 313.1 [M+H] + .

[0381] Step 4: Using compound 22D (150 mg, 0.480 mmol) and compound 2J (114 mg, 0.480 mmol) as raw materials, the racemic mixture of compound 22 was obtained by referring to the synthesis method in step 10 of Example 2. The racemic mixture was further chirally resolved to obtain isomer 1 of compound 22 (75.2 mg, 31.7%, retention time 2.024 min) and isomer 2 of compound 22 (37.1 mg, 15.6%, retention time 2.018 min).

[0382] Preparative chromatographic analysis method: Instrument: SHIMADZU LC-30AD SFC; Column: Chiral AS column; Mobile phase: A for CO2; B for 0.05% DEA in isopropanol; Gradient: B for 5-40%; Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0383] Compound 22 isomer 1: LC-MS (ESI): m / z = 495.2 [M+H] + .

[0384] 1H NMR(400MHz,Chloroform-d)δ7.97-7.64(m,2H),6.32(d,1H),6.04-5.95(m,1H),5.93-5.63(m,1H),5.61(d,1H),5.14(p,1H),4.92-4.84(m,2H), 4.56-4.50(m,2H),4.16(t,2H),3.66-3.59(m,2H),3.27-3.20(m,1H),2. 79-2.73(m,2H),2.62-2.54(m,2H),2.44-2.36(m,1H),2.19-2.08(m,5H).

[0385] Compound 22 isomer 2: LC-MS (ESI): m / z = 495.2 [M+H] + .

[0386] 1 H NMR(400MHz,Chloroform-d)δ7.97-7.64(m,2H),6.32(d,1H),6.05-5.74(m,2H),5.58(d,1H),5.21(q,1H),4.91-4.84(m,2H),4.57-4.5 0(m,2H),4.17(t,2H),3.69-3.58(m,2H),3.28-3.19(m,1H),2.82-2.64(m,3H),2.62-2.52(m,2H),2.36-2.30(m,2H),2.19-2.08(m,3H).

[0387] Example 23:

[0388] Step 1: Under a nitrogen atmosphere, compounds 23A (2.57 g, 10.0 mmol), 23B (1.29 g, 10.0 mmol), RuPhos Pd G3 (837 mg, 1.00 mmol), and cesium carbonate (9.77 g, 30.0 mmol) were dissolved in toluene (100 mL), stirred thoroughly, and then heated to 100 °C and reacted overnight. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 23C (424 mg, 16%). LC-MS (ESI): m / z = 259.1 [M+H] + .

[0389] Step 2: Under a nitrogen atmosphere, compound 23C (320 mg, 1.24 mmol), potassium cyclopropyltrifluoroborate (1.82 g, 12.4 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (98 mg, 0.124 mmol), and cesium carbonate (1.21 g, 3.72 mmol) were dissolved in 1,4-dioxane (100 mL) and water (30 mL). After stirring thoroughly, the mixture was heated to 100 °C and reacted overnight. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 23D (84 mg, 26%). LC-MS (ESI): m / z = 265.2 [M+H] + .

[0390] Step 3: Using compound 23D (84 mg, 0.318 mmol) as the starting material, crude compound 23E (116 mg) was obtained by following the synthesis method in step 5 of Example 1. LC-MS (ESI): m / z = 251.1 [M+H] + .

[0391] Step 4: Compound 23E (116 mg) and 1C (68 mg, 0.318 mmol) were dissolved in DMF (10 mL), and triethylamine (32 mg, 0.318 mmol) and N-methylimidazole (52 mg, 0.636 mmol) were added. After stirring until homogeneous, the mixture was cooled to 0 °C, and N,N,N',N'-tetramethylchloromethamine hexafluorophosphate (178 mg, 0.636 mmol) was added in portions. The mixture was then heated to room temperature and stirred for 30 minutes. The mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to obtain compound 23 (10 mg, yield 7%). LC-MS (ESI): m / z = 448.3 [M+H] + .

[0392] 1 H NMR (400MHz, CDCl3) δ8.18-8.16(m,1H),8.10-8.08(m,1H),7.95-7.92(m,1H),6.02-6.00(m,1H),4.80-4.76(m,4H) ,4.45-4.41(m,2H),3.96-3.91(m,5H),2.86-2.80(m,2H),2.48-2.47(m,3H),2.05-1.99(m,2H),1.07-0.92(m,4H).

[0393] Example 24:

[0394] Step 1: Using 24A (500 mg, 1.75 mmol, synthesized according to the method described in patent WO2021121282) as the starting material, 24B (470 mg, 81%) was obtained by following the synthesis method in Step 1 of Example 1. LC-MS (ESI): m / z = 332.1 [M+H] + .

[0395] Step 2: Using 24B (470 mg, 1.42 mmol) as the starting material, 24C (298 mg, 91%) was obtained according to the synthesis method in Step 2 of Example 1. LC-MS (ESI): m / z = 232.0 [M+H] + .

[0396] Step 3: Using 24C (100 mg, 0.42 mmol) and 4M (109 mg, 0.42 mmol) as starting materials, compound 24 (55 mg, 27%) was obtained by following the synthesis method in Step 6 of Example 1. LC-MS (ESI): m / z = 465.2 [M+H] + .

[0397] 1 H NMR (400MHz, CDCl3) δ8.15-8.13(m,1H),8.09-8.05(m,1H),7.85-7.82(m,1H),4.72-4.67(m,4H),4.51-4.45(m,2H),4.09 (s,3H),3.99-3.92(m,5H),3.32-3.21(m,1H),2.80-2.76(m,2H),2.08-2.01(m,1H),1.03-0.96(m,2H),0.96-0.88(m,2H).

[0398] Example 25:

[0399] Step 1: Using 25A (300 mg, 1.55 mmol) as the starting material, compound 25B (160 mg, 39%) was synthesized according to the method described in Step 1 of Example 10. LC-MS (ESI): m / z = 364.9 & 366.9 [M+H] + .

[0400] Step 2: Using 25B (160 mg, 0.60 mmol) and ethyl 2-(azacyclobutane-3-yl)acetate (104 mg, 0.72 mmol) as starting materials, compound 25C (135 mg, 68%) was synthesized according to the method described in Step 2 of Example 10. LC-MS (ESI): m / z = 328.1 [M+H]+ .

[0401] Step 3: Using 25C (135 mg, 0.41 mmol) as the starting material, compound 25D (105 mg, 85%) was synthesized according to the method described in Step 3 of Example 10. LC-MS (ESI): m / z = 300.2 [M+H] + .

[0402] Step 4: Using 25D (105 mg, 0.35 mmol) and 2J (70 mg, 0.35 mmol) as starting materials, compound 25 (56 mg, 33%) was synthesized according to the method described in step 10 of Example 2. LC-MS (ESI): m / z = 482.2 [M+H] + .

[0403] 1 H NMR(400MHz, CDCl3)δ8.14(d,1H),7.97-7.63(m,1H),6.32(d,1H),5.74-5.70(m,1H),5.36-5.24(m,1H),4.91-4.83(m,2H),4.58 -4.48(m,2H),4.26(t,2H),3.79-3.69(m,2H),3.37-3.24(m,1H),3.21-3.09(m,2H),2.78(d,2H),2.76-2.62(m,2H),2.15(d,3H).

[0404] Example 26:

[0405] Step 1: Compound 1A (270 mg, 1.0 mmol), 4-fluoro-1H-pyrazole (100 mg, 1.2 mmol), and cesium carbonate (490 mg, 1.5 mmol) were dissolved sequentially in N,N-dimethylformamide (10 mL). After stirring thoroughly, the mixture was heated to 100 °C and reacted for 5 hours. After the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain compound 26A (300 mg, yield 93.85%). LC-MS (ESI): m / z = 320.2 [M+H] + .

[0406] Step 2: Using 26A (300 mg, 0.94 mmol) as the starting material, compound 26B (230 mg, 99.99%) was synthesized according to the method described in Step 2 of Example 1. LC-MS (ESI): m / z = 220.2 [M+H] + .

[0407] Step 3: Using 26B (0.10 g, 0.46 mmol) and intermediate 4M (0.12 g, 0.46 mmol) as starting materials, compound 26 (80 mg, 38.76%) was obtained by following the synthetic method in Step 6 of Example 1. LC-MS (ESI): m / z = 453.2 [M+H] + .

[0408] 1 H NMR (400MHz, CDCl3) δ8.46-8.43(m,1H),7.85-7.84(m,1H),7.72-7.71(m,1H),4.84(s,3H),4.83-4.80(m,1H),4.55-4. 51(m,2H),4.02-4.01(m,2H),3.31-3.30(m,1H),2.85-2.79(m,2H),2.57(s,3H),2.19-2.18(m,1H),1.03-0.98(m,4H).

[0409] Example 27:

[0410] Step 1: Under a nitrogen atmosphere, compound 1A (269 mg, 1.00 mmol), 3-methylpyrazole (164 mg, 2.00 mmol), and cesium carbonate (975 mg, 3.00 mmol) were dissolved sequentially in N,N-dimethylformamide (20 mL). After stirring thoroughly, the mixture was heated to 100 °C and reacted overnight. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 27A (260 mg, 82%). LC-MS (ESI): m / z = 316.1 [M+H] + .

[0411] Step 2: Using compound 27A (260 mg, 0.825 mmol) as the starting material, crude compound 27B (220 mg) was obtained by referring to the synthesis method in Step 2 of Example 1. LC-MS (ESI): m / z = 216.2 [M+H] + .

[0412] Step 3: Using compound 27B (220 mg) and compound 4M (200 mg, 0.796 mmol) as starting materials, compound 27 (90 mg, 25% yield) was synthesized according to the method described in Step 4 of Example 23. LC-MS (ESI): m / z = 449.2 [M+H] + .

[0413] 1H NMR (400MHz, CDCl3) δ8.51-8.49(m,1H),7.85-7.84(m,1H),6.30-6.29(m,1H),4.82-4.78(m,4H),4.53-4.49(m,2H),4. 02-3.97(m,2H),3.30-3.27(m,1H),2.84-2.78(m,2H),2.55(s,3H),2.43(s,3H),2.18-2.09(m,1H),1.00-0.96(m,4H).

[0414] Example 28:

[0415] Step 1: Using compound 1A (220 mg, 0.81 mmol) and compound 28A (200 mg, 0.96 mmol) as starting materials, compound 28B (240 mg, 93.3%) was obtained by following the procedure in Step 1 of Example 1. LC-MS (ESI): m / z = 316.2.

[0416] Step 2: Using compound 28B (240 mg, 0.76 mmol) as the starting material, crude compound 28C (220 mg) was obtained by following the procedure in Step 2 of Example 1. No further purification was required; it was used directly in the next step. LC-MS (ESI): m / z = 216.2.

[0417] Step 3: Using compound 28C (110 mg) and 4M (110 mg, 0.43 mmol) as starting materials, compound 28 (46 mg, two-step yield 27%) was obtained by following the procedure in step 6 of Example 1. LC-MS (ESI): m / z = 449.2.

[0418] 1 H NMR(400MHz,DMSO-d6)δ8.00-7.96(m,1H),7.58-7.49(m,1H),6.98-6.95(m,1H),4.96-4.89(m,2H),4.73-4.65(m,2H),4.37-4.28 (m,2H),4.25(s,3H),3.94-3.85(m,2H),3.16-3.05(m,1H),2.92-2.84(m,2H),2.51(s,3H),1.97-1.89(m,1H),0.90-0.82(m,4H).

[0419] Example 29:

[0420] 3A-1, 3A-2, 3A-3, and 3A-4 were prepared by chiral separation of 3A using SFC. SFC separation method: Instrument: Waters 150Prep-SFC; Column: Chiralcel IG column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in MeOH; Gradient: 11% Phase B; Flow rate: 120 mL / min; Back pressure: 100 bar; Column temperature: 25℃; Wavelength: 220 nm. Retention times: 3A-1: tR = 0.858 min; 3A-2: tR = 0.889 min; 3A-3: tR = 0.992 min; 3A-4: tR = 1.136 min.

[0421] Compound 29-1 (31 mg, 50%) was obtained from 3A-1 (36 mg, 0.13 mmol) and 1C (28 mg, 0.13 mmol) using the synthetic method described in step 6 of Example 1. LC-MS (ESI): m / z = 472.2 [M+H] + .

[0422] 1 H NMR(400MHz, CDCl3)δ8.27(s,1H),8.18-8.14(m,1H),8.11-8.07(m,1H),6.61(s,1H),6.39(s,1H),4.79-4.72(m,4H),4.38-4.29(m, 1H),4.16-4.07(m,1H),3.96(s,3H),3.63-3.53(m,1H),2.95-2.88(m,1H),2.83-2.70(m,2H),2.49-2.45(m,3H),1.64-1.59(m,3H).

[0423] Compound 29-2 (33 mg, 0.12 mmol) was obtained from 3A-2 (34 mg, 0.12 mmol) and 1C (27 mg, 0.12 mmol) according to the synthetic method in step 6 of Example 1. LC-MS (ESI): m / z = 472.2 [M+H] + .

[0424] 1H NMR (400MHz, CDCl3) δ8.28(s,1H),8.18-8.14(m,1H),8.11-8.07(m,1H),6.62(s,1H),6.39(s,1H),4.81-4.70(m,4H),4.39-4. 31(m,1H),4.17-4.07(m,1H),3.96(s,3H),3.63-3.52(m,1H),2.97-2.89(m,1H),2.81-2.70(m,2H),2.48(s,3H),1.62(s,3H).

[0425] Compound 29-3 (35 mg, 39%) was obtained from 3A-3 (52 mg, 0.19 mmol) and 1C (41 mg, 0.19 mmol) using the synthetic method described in step 6 of Example 1. LC-MS (ESI): m / z = 472.2 [M+H] + .

[0426] 1 H NMR (400MHz, CDCl3) δ8.30-8.26(m,1H),8.19-8.15(m,1H),8.12-8.07(m,1H),6.62(s,1H),6.38(s,1H),4.85-4.75(m,4H),4.65-4.57 (m,1H),4.16-4.08(m,1H),3.97(s,3H),3.84-3.77(m,1H),3.46-3.37(m,1H),2.85-2.68(m,2H),2.51-2.47(m,3H),1.48-1.41(m,3H).

[0427] Compound 29-4 (35 mg, 44%) was obtained from 3A-4 (46 mg, 0.17 mmol) and 1C (36 mg, 0.19 mmol) using the synthetic method described in step 6 of Example 1. LC-MS (ESI): m / z = 472.1 [M+H] + .

[0428] 1H NMR(400MHz, CDCl3)δ8.28(s,1H),8.19-8.15(m,1H),8.12-8.07(m,1H),6.62(s,1H),6.38(s,1H),4.85-4.75(m,4H),4.65-4.57(m, 1H),4.15-4.07(m,1H),3.97(s,3H),3.83-3.77(m,1H),3.45-3.37(s,1H),2.86-2.68(m,2H),2.51-2.47(m,3H),1.48-1.41(m,3H).

[0429] Example 30:

[0430] Step 1: Using compound 30A (1.2 g, 4.98 mmol) and 3-fluorocyclobutane-1-ol (0.45 g, 5 mmol) as starting materials, compound 30B (0.7 g, 45%) was synthesized according to the method described in Step 1 of Example 18. LC-MS (ESI): m / z = 312.0 [M+H] + .

[0431] Step 2: Using compound 30B (0.7 g, 2.25 mmol) as the starting material, the racemic mixture of compound 30C (0.69 g, 93%) was obtained according to the synthetic method in Step 2 of Example 18. Further chiral resolution yielded 30C-1 (538 mg, retention time 1.120 min) and 30C-2 (75 mg, retention time 1.328 min). LC-MS (ESI): m / z = 327.1 [M+H] + .

[0432] Preparative chromatographic analysis method: Instrument: Waters 150Prep-SFC; Column: Chiral AD column; Mobile phase: A for CO2; B for methanol; Gradient: B for 20%; Flow rate: 120 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0433] Step 3: Using compound 30C-1 (0.2 g, 0.61 mmol) as the starting material, crude compound 30D-1 (0.61 mmol) was obtained according to the synthetic method in step 3 of Example 18. This crude compound was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 299.1 [M+H] + .

[0434] Starting with compound 30C-2 (0.075 g, 0.23 mmol), crude compound 30D-2 (0.23 mmol) was obtained according to the synthetic method in step 3 of Example 18. It was directly proceeded to the next reaction without purification. LC-MS (ESI): m / z = 299.1 [M+H] + .

[0435] Step 4: Using compound 30D-1 (crude product 0.61 mmol) and compound 2J (0.166 g, 0.61 mmol) as starting materials, compound 30-1 (120 mg, 41%) was synthesized according to the method described in Step 4 of Example 18. LC-MS (ESI): m / z = 481.2 [M+H] + .

[0436] 1 H NMR(400MHz,DMSO-d6)δ8.10-7.80(m,1H),6.33-6.32(m,1H),5.68-5.66(m,1H),5.54-5.53(m,1H),5.39-5.14(m,2H),4.92-4.39(m,4H ),4.09-4.04(m,2H),3.62-3.59(m,2H),3.09-3.00(m,1H),2.83-2.78(m,2H),2.65-2.54(m,2H),2.47-2.35(m,2H),2.17-2.11(m,3H).

[0437] Starting with compound 30D-2 (crude product 0.23 mmol) and compound 2J (0.063 g, 0.23 mmol), compound 30-2 (40 mg, 36%) was synthesized according to the method described in step four of Example 18. LC-MS (ESI): m / z = 481.2 [M+H] + .

[0438] 1 H NMR(400MHz,DMSO-d6)δ8.12-7.75(m,1H),6.33-6.32(m,1H),5.68-5.66(m,1H),5.56-5.55(m,1H),4.96-4.55(m,5H),4.40-4 .38(m,1H),4.09-4.04(m,2H),3.63-3.56(m,2H),3.10-3.01(m,1H),2.96-2.86(m,2H),2.84-2.78(m,2H),2.25-2.11(m,5H).

[0439] Example 31:

[0440] Step 1: Using compound 18C-1 (28 mg, 0.078 mmol) as the starting material, crude compound 18D-1 (0.078 mmol) was obtained according to the synthetic method in step 3 of Example 10. This crude compound was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 329.1 [M+H] + .

[0441] Step 2: Using compound 18D-1 (crude product 0.078 mmol) and compound 2J (0.028 g, 0.1 mmol) as starting materials, compound 31 (12 mg, 30.14%) was synthesized according to the method described in step 10 of Example 2. LC-MS (ESI): m / z = 511.2 [M+H] + .

[0442] 1 H NMR (400MHz, CDCl3) δ7.99-7.62(m,2H),6.36-5.97(m,3H),5.59(d,1H),5.32-5.27(m,1H),4.94-4.83(m,3H),4.56-4.52(m,2H) ,4.18(t,2H),3.67-3.62(m,2H),3.31-3.16(m,1H),2.77-2.75(m,2H),2.68-2.58(m,2H),2.55-2.49(m,2H),2.17-2.15(m,3H).

[0443] Example 32:

[0444] Step 1: Using compound 19C-1 (16 mg, 0.04 mmol) as the starting material, crude compound 19D-1 (0.04 mmol) was obtained according to the synthetic method in step 3 of Example 10. This crude compound was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 347.1 [M+H] + .

[0445] Step 2: Using compound 19D-1 (crude product 0.04 mmol) and compound 2J (16 mg, 0.06 mmol) as starting materials, compound 32 (6 mg, 28.38%) was synthesized according to the method described in step 10 of Example 2. LC-MS (ESI): m / z = 529.2 [M+H] + .

[0446] 1H NMR (400MHz, CDCl3) δ7.99-7.63(m,2H),6.33-6.32(m,1H),5.99-5.97(m,1H),5.58(s,1H),5.34-5.29(m,1H),4.98-4.90(m,1H),4.89-4. 86(m,2H),4.55-4.52(m,2H),4.19(t,2H),3.68-3.63(m,2H),3.30-3 .19(m,1H),2.81-2.65(m,4H),2.60-2.54(m,2H),2.16-2.15(m,3H).

[0447] Example 33:

[0448] Step 1: Under a nitrogen atmosphere at room temperature, compound 33A (2.0 g, 10.4 mmol) was dissolved in dichloromethane (25 mL). Diethylaminosulfur trifluoride (2.5 g, 15.6 mmol) was added dropwise to the reaction system at -78 °C. After the addition was complete, stirring was continued for 0.5 h, followed by a reaction at room temperature for 16 h. After the reaction was complete, saturated sodium bicarbonate aqueous solution was added dropwise to adjust the pH to 7. The mixture was extracted and separated. The aqueous phase was back-extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain compound 33B (1.03 g, 51%). LC-MS (ESI): m / z = 195.2 [M+H] + .

[0449] Step 2: At room temperature, compound 33B (1.03 g, 5.3 mmol) was dissolved in tetrahydrofuran (20 mL), Pd / C (206 mg, Pd content 10%) was added, and 5 drops of 6N HCl were added dropwise. The reaction was carried out under a hydrogen atmosphere for 24 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain compound 33C (350 mg, 63%). LC-MS (ESI): m / z = 105.2 [M+H] + .

[0450] Step 3: Using 33C (350 mg, 3.36 mmol) as the starting material, compound 33D (450 mg, 44%) was synthesized according to the method described in Step 1 of Example 10. LC-MS (ESI): m / z = 308.2 [M+H] + .

[0451] Step 4: Using 33D (450 mg, 1.47 mmol) and ethyl 2-(azacyclobutane-3-yl)acetate (231 mg, 1.61 mmol) as starting materials, the racemic mixture of compound 33E (300 mg, 63%) was obtained according to the synthesis method in step 2 of Example 10. Further resolution by SFC yielded 33E-1 (200 mg, retention time 1.315 min) and 33E-2 (80 mg, retention time 2.004 min). LC-MS (ESI): m / z = 323.2 [M+H] + .

[0452] Preparative Chromatographic Analysis Method: Instrument: SHIMADZU LC-30AD SFC; Column: Chiral IG column; Mobile Phase: A for CO2; B for 0.05% DEA in methanol; Gradient: B for 5-40%; Flow Rate: 3 mL / min; Column Temperature: 35℃; Wavelength: 220 nm

[0453] Step 5: Using compound 33E-1 (200 mg, 0.62 mmol) as the starting material, crude compound 33F-1 (0.62 mmol) was obtained according to the synthesis method in step 3 of Example 10. It was directly proceeded to the next reaction without further purification. LC-MS (ESI): m / z = 295.1 [M+H] + .

[0454] Starting with compound 33E-2 (80 mg, 0.25 mmol), crude compound 33F-2 (0.25 mmol) was obtained according to the synthetic method in step 3 of Example 10. It was directly proceeded to the next reaction without further purification. LC-MS (ESI): m / z = 295.1 [M+H] + .

[0455] Step 6: Using crude compound 33F-1 (0.62 mmol) and compound 2J (124 mg, 0.62 mmol) as starting materials, compound 33-1 (125 mg, 42%) was synthesized according to the method described in step 10 of Example 2. LC-MS (ESI): m / z = 477.1 [M+H] + .

[0456] 1H NMR (400MHz, CDCl3) δ7.95-7.62(m,2H),6.29(d,1H),5.94(dd,1H),5.57(d,1H),5.30-5.21(m,1H),4.89-4.82(m,2H),4.55-4.47 (m,2H),4.14(t,2H),3.64-3.57(m,2H),3.26-3.15(m,1H),2.85-2.71(m,4H),2.27-2.16(m,2H),2.13(dd,3H),1.57-1.49(m,3H).

[0457] Starting with crude compound 33F-2 (0.25 mmol) and compound 2J (50 mg, 0.25 mmol), compound 33-2 (50 mg, 42%) was synthesized according to step 10 of Example 2. LC-MS (ESI): m / z = 477.1 [M+H] + .

[0458] 1 H NMR (400MHz, CDCl3) δ7.97-7.63(m,2H),6.31(d,1H),5.97(dd,1H),5.62(d,1H),4.90-4.85(m,2H),4.84-4.76(m,1H),4.55-4.49(m,2H),4 .16(t,2H),3.69-3.58(m,2H),3.29-3.16(m,1H),2.79-2.73(m,2H),2 .72-2.65(m,2H),2.56-2.43(m,2H),2.15(dd,3H),1.55-1.44(m,3H).

[0459] Example 34:

[0460] Step 1: Using compound 34A (0.50 g, 5.55 mmol) as the starting material, compound 34B (0.81 g, 50%) was synthesized according to the method described in Step 1 of Example 18. LC-MS (ESI): m / z = 294.0 [M+H] + .

[0461] Step 2: Using compound 34B (0.81 g, 2.76 mmol) as the starting material, the racemic mixture (0.72 g) was obtained according to the synthesis method in Step 2 of Example 10. Further chiral resolution yielded compound 34C-1 (84.3 mg, 10%, retention time 1.422 min) and compound 34C-2 (536.2 mg, 63%, retention time 1.497 min). LC-MS (ESI): m / z = 309.2 [M+H] + .

[0462] Preparative chromatographic analysis method: Instrument: SHIMADZU LC-30AD SFC; Column: Chiral WHELK column; Mobile phase: A for CO2; B for 0.05% DEA in isopropanol; Gradient: B for 5-40%; Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0463] Step 3: Using compound 34C-1 (84.3 mg, 0.27 mmol) as the starting material, compound 34D-1 (80.0 mg, 100%) was obtained by referring to the synthesis method in step 3 of Example 10. It was used directly in the next reaction without further purification.

[0464] Starting with compound 34C-2 (536.2 mg, 1.74 mmol), compound 34D-2 (520.0 mg, 100%) was synthesized according to the third step of Example 10 and used directly in the next reaction without further purification.

[0465] Step 4: Using compound 34D-1 (40.0 mg, 0.14 mmol) as the starting material, compound 34-1 (15.0 mg, 23%) was synthesized according to the method described in step 10 of Example 2. LC-MS (ESI): m / z = 463.2 [M+H] + .

[0466] 1 H NMR (400MHz, CDCl3) δ7.97-7.65(m,2H),6.33(d,1H),5.99(dd,1H),5.61(d,1H),4.90-4.74(m,4H),4.54-4.52(m,2H),4 .23-4.19(m,2H),3.69-3.68(m,2H),3.27-3.24(m,1H),3.08-3.02(m,2H),2.77(d,2H),2.45-2.33(m,2H),2.16(d,3H).

[0467] Starting with compound 34D-2 (260 mg, 0.87 mmol), compound 34-2 (82.0 mg, 21%) was synthesized according to the method described in step 10 of Example 2. LC-MS (ESI): m / z = 463.2 [M+H] + .

[0468] 1 H NMR (400MHz, CDCl3) δ7.97-7.65(m,2H),6.32(d,1H),5.97(dd,1H),5.58(d,1H),5.37-5.19(m,2H),4.89-4.86(m,2H),4.55-4.51 (m,2H),4.19-4.15(m,2H),3.67-3.61(m,2H),3.27-3.20(m,1H),2.76(d,2H),2.76-2.64(m,2H),2.56-2.45(m,2H),2.15(d,3H).

[0469] Example 35:

[0470] Step 1: Using compound 35A (1.2 g, 4.98 mmol) and 3-fluorocyclobutane-1-ol (0.45 g, 5 mmol) as starting materials, compound 35B (0.7 g, 45%) was synthesized according to the method described in Step 1 of Example 10. LC-MS (ESI): m / z = 312.0 [M+H] + .

[0471] Step 2: Using compound 35B (0.7 g, 2.25 mmol) as the starting material, the racemic mixture of compound 35C (0.6 g, 81%) was synthesized according to the method described in Step 2 of Example 10. This was followed by one-step chiral resolution to obtain 35C-1 (395 mg, retention time 1.195 min) and 35C-2 (70 mg, retention time 1.502 min). LC-MS (ESI): m / z = 327.1 [M+H] + .

[0472] Preparative chromatographic analysis method: Instrument: Waters 150 Prep-SFC; Column: Chiral AD column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in methanol; Gradient: B for 25%; Flow rate: 110 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0473] Step 3: Using compound 35C-1 (0.2 g, 0.61 mmol) as the starting material, crude compound 35D-1 (0.61 mmol) was obtained according to the synthetic method in step 3 of Example 10. This crude product was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 299.1 [M+H] + .

[0474] Starting with compound 35C-2 (0.07 g, 0.21 mmol), crude compound 35D-2 (0.21 mmol) was obtained according to the synthetic method in step 3 of Example 10. This crude product was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 299.1 [M+H] + .

[0475] Step 4: Using compound 35D-1 (0.61 mmol) and compound 2J (0.166 g, 0.61 mmol) as starting materials, compound 35-1 (100 mg, 34%) was synthesized according to the method described in Step 4 of Example 10. LC-MS (ESI): m / z = 481.2 [M+H] + .

[0476] 1 H NMR (400MHz, CDCl3) δ7.98-7.61(m,2H),6.33-6.31(m,1H),5.60(d,1H),5.38-5.17(m,2H),4.91-4.86(m,2H),4.56-4.51(m,2H),4 .35-4.31(m,2H),3.83-3.78(m,2H),3.28-3.15(m,1H),2.79-2.76(m,2H),2.73-2.60(m,2H),2.54-2.41(m,2H),2.17-2.15(m,3H).

[0477] Starting with compound 35D-2 (0.21 mmol) and compound 2J (0.06 g, 0.21 mmol), compound 35-2 (35 mg, 12%) was synthesized according to the method described in step four of Example 10. LC-MS (ESI): m / z = 481.2 [M+H] + .

[0478] Compound 35-2 1H NMR (400MHz, CDCl3) δ7.99-7.61(m,2H),6.33-6.31(m,1H),5.63(d,1H),4.91-4.68(m,4H),4.56-4.51(m,2H),4.37-4.33 (m,2H),3.87-3.78(m,2H),3.27-3.20(m,1H),3.05-2.95(m,2H),2.79-2.76(m,2H),2.42-2.29(m,2H),2.17-2.15(m,3H).

[0479] Example 36:

[0480] Step 1: Compound 36A (3.0 g, 17.97 mmol) was dissolved in tetrahydrofuran (30 mL), cooled to -30 °C, and sodium methanethiol (6.93 g, 19.77 mmol, 20% aqueous solution) was slowly added dropwise. After the addition was complete, the reaction was continued at -30 °C for 2 hours. After the reaction was complete, saturated brine was added, and the mixture was extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain compound 36B (2.8 g, 87%). LC-MS (ESI): m / z = 179.0 [M+H] + .

[0481] Step 2: 3,3-Difluorocyclobutanol (1.82 g, 16.90 mmol) was dissolved in dry tetrahydrofuran (20 mL). Under nitrogen protection, the mixture was cooled to 0 °C, and sodium hydride (0.90 g, 22.4 mmol, 60% purity) was slowly added. After the addition was complete, the reaction was continued at 0 °C for 0.5 h. Then, 36B (2.0 g, 11.20 mmol) was added, and the mixture was allowed to rise naturally to room temperature for 2 h. After the reaction was complete, saturated ammonium chloride solution was added dropwise to quench the reaction. After complete quenching, the mixture was extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain compound 36C (0.8 g, 28%). LC-MS (ESI): m / z = 251.0 [M+H] + .

[0482] Step 3: Compound 36C (0.80 g, 3.20 mmol) was dissolved in dichloromethane (20 mL), and m-chloroperoxybenzoic acid (1.95 g, 9.60 mmol, 85% purity) was added. The reaction was allowed to proceed at room temperature for 15 h after the addition was complete. After the reaction was complete, saturated sodium sulfite solution was added dropwise to quench the reaction. After complete quenching, dichloromethane was added for extraction twice. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 36D (0.9 g, 100%). This compound was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 283.0 [M+H]+ .

[0483] Step 4: Compound 36D (0.90 g, 3.20 mmol) was dissolved in acetonitrile (20 mL), followed by the sequential addition of triethylamine (1.61 g, 15.95 mmol) and ethyl acetate trifluoroacetate of 2-(azacyclobutane-3-yl)ethyl acetate (1.23 g, 4.79 mmol). The reaction was carried out at room temperature for 3 h after the addition was complete. After the reaction was completed, the mixture was concentrated, and the residue was purified by column chromatography to give compound 36E (0.3 g, 27%). LC-MS (ESI): m / z = 346.2 [M+H] + .

[0484] Step 5: Using compound 36E (0.3 g, 0.87 mmol) as the starting material, compound 36F (0.35 g, 100%) was synthesized according to the method described in step 3 of Example 10. This compound was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 318.2 [M+H] + .

[0485] Step 6: Using compound 36F (0.17 g, 0.43 mmol) as the starting material, compound 36 (38.0 mg, 18%) was synthesized according to the method described in step 10 of Example 2. LC-MS (ESI): m / z = 500.2 [M+H] + .

[0486] 1 H NMR (400MHz, CDCl3) δ7.97-7.65(m,2H),6.33(d,1H),5.00-4.98(m,1H),4.88(d,2H),4.56-4.51 (m,4H),4.07-4.03(m,2H),3.33-3.28(m,1H),3.07-3.03(m,2H),2.85-2.73(m,4H),2.16(d,3H).

[0487] Example 37:

[0488] Step 1: Using compound 37A (1g, 11.9mmol) as the starting material, compound 37B (37B-1 and 37B-2 are enantiomers) (0.7g, 56%) was obtained by following the synthesis method in Step 1 of Example 12.

[0489] Step 2: Compound 37B (0.7 g, 6.73 mmol) was dissolved in dichloromethane (20 mL), and potassium tert-butoxide (1.13 g, 10.1 mmol) and p-toluenesulfonyl chloride (1.54 g, 8.08 mmol) were added. The reaction was carried out at room temperature for 3 h. After the reaction was completed, the mixture was quenched with water, and the layers were extracted and separated. The aqueous phase was back-extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 37C (37C-1 and 37C-2 ​​are enantiomers) (0.76 g, 40%). LC-MS (ESI): m / z = 259.1 [M+H] + .

[0490] Step 3: Compound 37C (0.76 g, 2.95 mmol) was dissolved in N,N-dimethylformamide (10 mL), and cesium carbonate (1.13 g, 5.9 mmol) was added. After stirring thoroughly, the mixture was heated to 90 °C and reacted for 2 h. After the reaction was completed, the mixture was quenched with water, extracted three times with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 37D (37D-1 and 37D-2 are enantiomers) (0.63, 82%). LC-MS (ESI): m / z = 260.1 [M+H] + .

[0491] Step 4: Using compound 37D (1.5 g, 5.77 mmol) as the starting material, 37E (1.2 g, 65%) was synthesized according to the method described in Step 3 of Example 5. Further separation by SFC yielded compounds 37E-1 (348 mg, retention time 1.327 min) and 37E-2 (308 mg, retention time 1.628 min). LC-MS (ESI): m / z = 323.2 [M+H] + .

[0492] Preparative chromatographic analysis method: Instrument: Waters 150Prep-SFC; Column: Chiral OX column; Mobile phase system: A for CO2; B for 0.1% NH3·H2O in methanol; Gradient: B for 30%; Flow rate: 100 mL / min; Column temperature: 35℃; Wavelength: 220 nm. Step 5: Using compound 37E-1 (100 mg, 0.31 mmol) as the starting material, compound 37F-1 (90 mg, 98%) was obtained according to the synthesis method in step 3 of Example 5. LC-MS (ESI): m / z = 295.2 [M+H] + .

[0493] Compound 37F-2 (90 mg, 98%) was obtained from compound 37E-2 (100 mg, 0.31 mmol) using the synthetic method described in step 3 of Example 5. LC-MS (ESI): m / z = 295.2 [M+H] + .

[0494] Step 6: Using compound 37F-1 (89 mg, 0.3 mmol) and compound 2J (61 mg, 0.3 mmol) as starting materials, isomer 1 of compound 37 (73 mg, 51%) was obtained according to the synthetic method in step 12 of Example 4. LC-MS (ESI): m / z = 477.2 [M+H] + .

[0495] 1 H NMR (400MHz, CDCl3) δ7.98-7.63(m,2H),6.32(d,1H),5.98(dd,1H),5.74(d,1H),5.31-5.05(m,2H),4.8 7(d,2H),4.54-4.51(m,2H),4.18-4.14(m,2H),3.65-3.59(m,2H),3.26-3.18(m,1H),2.75(d,2H),2.16 -2.15(m,3H),2.14-1.85(m,5H),1.70-1.60(m,1H).

[0496] Using compound 37F-2 (89 mg, 0.3 mmol) and compound 2J (61 mg, 0.3 mmol) as starting materials, isomer 2 of compound 37 (70 mg, 50%) was obtained according to the synthetic method in step 12 of Example 4. LC-MS (ESI): m / z = 477.2 [M+H] + .

[0497] 1 H NMR (400MHz, CDCl3) δ7.98-7.63(m,2H),6.31(d,1H),5.97(dd,1H),5.74(d,1H),5.29-5.06(m,2H),4.8 7(s,2H),4.54-4.51(m,2H),4.17-4.13(m,2H),3.64-3.59(m,2H),3.25-3.18(m,1H),2.75(d,2H),2.16 -2.15(m,3H),2.13-1.84(m,5H),1.68-1.60(m,1H).

[0498] Example 38:

[0499] Compound 38 (20 mg, 8% yield) was synthesized from compound 1C (108 mg, 0.500 mmol) and compound 20G (149 mg, 0.500 mmol) using the method described in step four of Example 23. LC-MS (ESI): m / z = 496.2 [M+H] + .

[0500] 1 H NMR (400MHz, CDCl3) δ8.18-8.16(m,1H),8.10-8.08(m,1H),7.82-7.81(m,1 H),6.03-5.99(m,1H),5.73-5.70(m,1H),5.49-5.42(m,1H),4.79-4.76(m, 4H),4.24-4.19(m,2H),3.96(s,3H),3.71-3.67(m,2H),3.29-3.25(m,1H), 2.83-2.78(m,2H),2.48-2.47(m,4H),2.43-2.22(m,2H),1.99-1.91(m,1H).

[0501] Example 39:

[0502] Step 1: Using 4,6-dichloropyrimidine (0.1 g, 0.67 mmol) and compound 10B (81 mg, 0.67 mmol) as starting materials, compound 39A (50 mg, 21%) was synthesized according to the method described in Step 1 of Example 5. LC-MS (ESI): m / z = 233.1 [M+H] + .

[0503] Step 2: Compound 39A (50 mg, 0.22 mmol) was dissolved in DMF (2 mL), and diisopropylethylamine (142 mg, 1.1 mmol) was added. The reaction was carried out at 70 °C for 20 h. After the reaction was completed, the mixture was cooled to room temperature, ethyl acetate was added, and the organic phase was washed three times with water. The residue was concentrated and purified by column chromatography to obtain compound 39B (60 mg, 84%). LC-MS (ESI): m / z = 326.1 [M+H] + .

[0504] Step 3: Using compound 39B (60 mg, 0.18 mmol) as the starting material, compound 39C (55 mg, 96%) was obtained by following the synthesis method in Step 3 of Example 5. LC-MS (ESI): m / z = 312.1 [M+H] + .

[0505] Step 4: Using compound 39C (55 mg, 0.18 mmol) and compound 2J (37 mg, 0.18 mmol) as starting materials, compound 39 (31 mg, 35%) was obtained by following the synthetic method in step 12 of Example 4. LC-MS (ESI): m / z = 494.2 [M+H] + .

[0506] 1 H NMR (400MHz, CDCl3) δ8.27(s,1H),7.97-7.65(m,1H),6.32(d,1H),5.47(s,1H),5.29-5.18(m,1H),4.88(d,2H),4 .55-4.52(m,2H),4.31(t,2H),3.78(t,2H),3.27-3.23(m,1H),3.20-3.09(m,2H),2.87-2.73(m,4H),2.16(s,3H).

[0507] Example 40:

[0508] Step 1: Using 13B (13B-1 and 13B-2) (500 mg, 4.71 mmol) as the starting material, compounds 40A (40A-1 and 40A-2) (510 mg, 33%) were synthesized according to the method described in Step 1 of Example 10. LC-MS (ESI): m / z = 328.1 [M+H] + .

[0509] Step 2: Using 40A (40A-1 and 40A-2) (510 mg, 1.58 mmol) as starting material, 40B (400 mg) was synthesized according to the method described in Step 2 of Example 10. Further separation by SFC yielded 40B-1 (200 mg, retention time 1.174 min, 37%) and 40B-2 (200 mg, retention time 1.701 min, 37%). LC-MS (ESI): m / z = 343.2 [M+H] + .

[0510] Preparative Chromatographic Analysis Method: Instrument: SHIMADZU LC-30AD SFC; Column: Chiral AD column; Mobile Phase: A for CO2; B for 0.05% DEA in methanol; Gradient: B for 5-40%; Flow Rate: 3 mL / min; Column Temperature: 35℃; Wavelength: 220 nm

[0511] Step 3: Using 40B-1 (200 mg, 0.58 mmol) as the starting material, compound 40C-1 (180 mg, 98%) was synthesized according to the method described in Step 3 of Example 10. LC-MS (ESI): m / z = 315.1 [M+H] + .

[0512] Following the procedures described above, compound 40C-2 (180 mg, 98%) was obtained from compound 40B-2 (200 mg, 0.58 mmol). LC-MS (ESI): m / z = 315.1 [M+H] + .

[0513] Step 4: Using 40C-1 (180 mg, 0.57 mmol) and 2J (115 mg, 0.57 mmol) as starting materials, isomer 1 (80 mg, 28%) of compound 40 was obtained by referring to the synthesis method in step 10 of Example 2. LCMS m / z = 497.1 [M+H] + .

[0514] 1 H NMR(400MHz, CDCl3)δ7.80(td,1H),7.61(d,1H),6.33-6.29(m,1H),5.75( d,1H),5.41-5.23(m,2H),4.89-4.84(m,2H),4.54(t,1H),4.52-4.49(m,1H ),4.37-4.27(m,2H),4.21-4.15(m,1H),4.14-3.99(m,2H),3.89-3.84(m, 1H),3.82-3.75(m,2H),3.28-3.17(m,1H),2.79-2.74(m,2H),2.16(s,3H).

[0515] Following the procedures described above, isomer 2 of compound 40 (80 mg, 28%) was obtained from compound 40C-2 (180 mg, 0.57 mmol). LCMS m / z = 497.1 [M+H] + .

[0516] 1H NMR(400MHz, CDCl3)δ7.80(td,1H),7.61(d,1H),6.34-6.29(m,1H),5.75(d,1H),5.43-5.23(m,2H),4.92-4.85(m,2H),4.57-4.48(m,2H),4 .36-4.27(q,2H),4.21-4.15(m,1H),4.14-3.99(m,2H),3.86(t,1H), 3.83-3.73(m,2H),3.29-3.16(m,1H),2.81-2.73(m,2H),2.16(s,3H).

[0517] Example 41:

[0518] Step 1: 41A (5 g, 19.53 mmol) and methyl 3-azacyclobutane acetate trifluoroacetate (4.41 g, 19.53 mmol) were dissolved in anhydrous ethanol (50 mL), and N,N-diisopropylethylamine (7.56 g, 58.59 mmol) was added. The reaction was carried out at room temperature for 1 h. After the reaction was complete, most of the solvent was removed by concentration under reduced pressure. Ethyl acetate and water were added for extraction. The organic layer was washed with saturated brine, concentrated, and the residue was purified by silica gel column chromatography to obtain 41B (5.2 g, 88%). LC-MS (ESI): m / z = 304.1 [M+H] + .

[0519] Step 2: 41B (1 g, 3.29 mmol), potassium vinyltrifluoroborate (485 mg, 3.62 mmol), Pd(dppf)Cl2 (240 mg, 0.33 mmol), and potassium carbonate (1.36 g, 9.87 mmol) were dissolved in a mixed solvent of 1,4-dioxane (15 mL) and water (1 mL). The reaction was carried out overnight at 90 °C under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, concentrated, and the residue was purified by silica gel column chromatography to obtain 41C (680 mg, 83%). LC-MS (ESI): m / z = 252.1 [M+H] + .

[0520] Step 3: Dissolve 41C (680 mg, 2.71 mmol) in a mixed solvent of acetone (15 mL) and water (10 mL). Add N-methylmorpholine-N-oxide (475 mg, 4.06 mmol) and potassium osmium tetroxide dihydrate (100 mg, 0.27 mmol) under ice bath conditions, and react overnight at room temperature. After the starting materials have reacted completely, add sodium periodate (1.16 g, 5.42 mmol), and continue reacting for 4 hours at room temperature. After the reaction is complete, add water, extract twice with ethyl acetate, wash the combined organic layers with saturated brine, concentrate, and purify the residue by silica gel column chromatography to obtain 41D (320 mg, 47%). LC-MS (ESI): m / z = 254.1 [M+H] + .

[0521] Step 4: 41D (320 mg, 1.26 mmol), sodium difluorochloroacetate (390 mg, 2.53 mmol), and triphenylphosphine (662 mg, 2.53 mmol) were dissolved in N-methylpyrrolidone (10 mL) under a nitrogen atmosphere and reacted overnight at 100 °C. After the reaction was complete, water was added, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, concentrated, and the residue was purified by silica gel column chromatography to obtain 41E (130 mg, 36%). LC-MS (ESI): m / z = 288.1 [M+H] + .

[0522] Step 5: Using 41E (130 mg, 0.45 mmol) as the starting material, 41F (114 mg, 92%) was obtained according to the synthesis method in Step 5 of Example 1. LC-MS (ESI): m / z = 274.1 [M+H] + .

[0523] Step 6: Using 41F (114 mg, 0.42 mmol) and 1C (90 mg, 0.42 mmol) as starting materials, compound 41 (34 mg, 17%) was synthesized according to the method described in Step 6 of Example 1. LC-MS (ESI): m / z = 471.3 [M+H] + .

[0524] 1 H NMR (400MHz, CDCl3) δ8.03-7.99(m,1H),7.97-7.92(m,1H),7.88-7.85(m,1H),5.22-5.15(m,1H),4.84 -4.75(m,4H),4.51-4.45(m,2H),4.00-3.93(m,5H),3.33-3.22(m,1H),2.83-2.77(m,2H),2.31(s,3H).

[0525] Example 42:

[0526] Step 1: Using 1A (500 mg, 1.86 mmol) and 2-methylthiazol-5-boronic acid pinacol ester (460 mg, 2.04 mmol) as starting materials, 42A (565 mg, 92%) was obtained according to the synthesis method in Step 1 of Example 1. LC-MS (ESI): m / z = 333.1 [M+H] + .

[0527] Step 2: Using 42A (565 mg, 1.70 mmol) as the starting material, 42B (380 mg, 83%) was obtained according to the synthesis method in Step 2 of Example 1. LC-MS (ESI): m / z = 233.1 [M+H] + .

[0528] Step 3: Using 42B (100 mg, 0.43 mmol) and 6D (120 mg, 0.43 mmol) as starting materials, compound 42 (45 mg, 21%) was obtained by following the synthesis method in Step 6 of Example 1. LC-MS (ESI): m / z = 493.3 [M+H] + .

[0529] 1 H NMR (400MHz, CDCl3) δ8.48-8.44(m,1H),8.15-8.13(m,1H),6.63-6.61(m,1H),4.83-4.77(m,4H),4.49 -4.42(m,2H),3.97-3.90(m,2H),3.36-3.27(m,1H),2.88-2.80(m,2H),2.78(s,3H),2.52-2.50(m,3H).

[0530] Example 43:

[0531] Compound 43 (31 mg, 16%) was obtained from 42B (100 mg, 0.43 mmol) and 4M (108 mg, 0.43 mmol) using the synthetic method described in step 6 of Example 1. LC-MS (ESI): m / z = 466.4 [M+H] + .

[0532] 1H NMR (400MHz, CDCl3) δ8.47-8.44(m,1H),7.86-7.84(m,1H),4.83-4.75(m,4H),4.52-4.46(m,2H),3.99-3.94(m,2H),3.31 -3.23(m,1H),2.84-2.78(m,2H),2.76(s,3H),2.52-2.50(m,3H),2.06-2.04(m,1H),1.02-0.97(m,2H),0.95-0.90(m,2H).

[0533] Example 44:

[0534] Step 1: Compound 41A (6 g, 23.45 mmol) was dissolved in methanol (120 mL). The mixture was cooled to 0–5 °C under nitrogen protection in an ice-water bath. A sodium methoxide methanol solution (30 wt%) was slowly added dropwise. After the addition was complete, the mixture was stirred in the ice-water bath for 1 hour. The reaction was monitored by TLC until completion. The reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 44B (4.4 g, 90.6%), which was used directly in the next step without further purification. LC-MS (ESI): m / z = 206.9 [M+H] + .

[0535] Step 2: Compound 44B was dissolved in tetrahydrofuran (88 mL), and Ni(DPPP)Cl2 (2.30 g, 4.25 mmol) and cyclobutylmagnesium bromide (46.8 mL, 23.39 mmol, 0.5 M in THF) were added. The mixture was refluxed at 70 °C for 3 hours under a nitrogen atmosphere. The reaction was monitored by TLC until complete. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 44C (2.2 g, 56.8%). LC-MS (ESI): m / z = 183.0 [M+H] + .

[0536] 1 H NMR (400MHz, DMSO-d6) δ8.51-8.48(m,1H),4.02(s,3H),3.69-3.57(m,1H),2.36-2.23(m,4H),2.06-1.93(m,1H),1.91-1.80(m,1H).

[0537] Step 3: Hydrobromic acid aqueous solution (30 mL, 48 wt%) was added to compound 44C (2.2 g, 12.08 mmol), and the mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction was monitored by TLC until completion. The reaction solution was quenched dropwise in saturated sodium bicarbonate aqueous solution, followed by extraction with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound 44D (1.6 g, 78.7%). LC-MS (ESI): m / z = 169.2 [M+H] + .

[0538] Step 4: Compound 44D (1.6 g, 9.51 mmol) was dissolved in acetonitrile (48 mL), and N,N-dimethylaniline (0.23 g, 1.90 mmol) and phosphorus oxychloride (2.19 g, 14.27 mmol) were added. The mixture was stirred at 85 °C for 3 hours under nitrogen protection. The reaction was monitored by TLC until completion. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography to obtain compound 44E (500 mg, 28.16%). LC-MS (ESI): m / z = 187.1 [M+H] + .

[0539] Step 5: Compound 44E (500 mg, 2.68 mmol) was dissolved in DMSO (15 mL), and triethylamine (813 mg, 8.04 mmol) and methyl 2-(azacyclobutane-3-yl)acetate trifluoroacetate (717 mg, 2.95 mmol) were added. The mixture was stirred at room temperature under nitrogen protection for 16 hours. The reaction was monitored by TLC until complete. The reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 44F (612 mg, 81.78%). LC-MS (ESI): m / z = 280.3 [M+H] + .

[0540] Step 6: Using compound 44F (612 mg, 2.19 mmol) as the starting material, crude compound 44E (682 mg) was obtained by following the synthesis method in step 5 of Example 1. No further purification was required; it was used directly in the next step. LC-MS (ESI): m / z = 266.1 [M+H] + .

[0541] Step 7: Using compound 1C (100 mg, 0.46 mmol) and compound 44E (200 mg) as starting materials, and referring to Step 6 of Example 1, compound 44E (48 mg, 22.34%) was obtained. LC-MS (ESI): m / z = 463.2 [M+H] + .

[0542] 1H NMR(400MHz,DMSO-d6)δ8.37-8.33(m,1H),8.08-8.05(m,1H),8.00-7.98(m,1H),4.90 -4.81(m,2H),4.67-4.58(m,2H),4.40-4.30(m,2H),3.96-3.90(m,2H),3.89(s,3H),3.52-3.41(m,1H),3.16 -3.07(m,1H),2.90-2.83(m,2H),2.44-2.42(m,3H),2.29-2.16(m,4H),1.98-1.89(m,1H),1.85-1.77(m,1H).

[0543] Example 45:

[0544] Step 1: In an autoclave, compound 45A (6.60 g, 43.20 mmol), triethylamine (6.84 g, 67.80 mmol), and 1,1'-bis(diphenylphosphine)ferrocene[palladium(II) dichloride] (1.59 g, 2.16 mmol) were dissolved in methanol (90 mL). After sealing the autoclave, carbon monoxide was introduced to replace the precipitate, and the pressure was increased to 2.5 MPa. The reaction was carried out at 110 °C for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, the pressure was released, and the reaction solution was concentrated. The residue was purified by silica gel column chromatography to obtain compound 45B (5.10 g, 67%). LC-MS (ESI): m / z = 177.0 [M+H] + .

[0545] Step 2: Compound 45B (5.10 g, 28.98 mmol) was dissolved in methanol (100 mL), Raney nickel was added, and the mixture was reacted overnight at room temperature under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 45C (3.90 g, 91%). LC-MS (ESI): m / z = 149.0 [M+H] + .

[0546] Step 3: Compound 45C (3.90 g, 26.31 mmol) was dissolved in tetrahydrofuran (60 mL), and 10 mol / L borane dimethyl sulfide complex (15 mL) was added. The mixture was then heated to 80 °C and reacted for 18 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. A 4 mol / L hydrochloric acid-methanol solution (90 mL) was added to the residue, and the mixture was then heated to 80 °C and reacted for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and dichloromethane (90 mL) and triethylamine (15 mL) were added to the residue. After stirring, p-toluenesulfonyl chloride (10.23 g, 53.67 mmol) was added, and the mixture was reacted overnight at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 45D (1.68 g, 13%). LC-MS (ESI): m / z = 289.3 [M+H] + .

[0547] Step 4: Under ice bath conditions, compound 45D (1.68 g, 5.82 mmol) was dissolved in dichloromethane (20 mL), and m-chloroperoxybenzoic acid (1.20 g, 6.93 mmol) was added. The mixture was then heated to room temperature and stirred for 2 hours. The reaction was quenched by adding saturated sodium thiosulfate solution. The mixture was extracted three times with dichloromethane. The combined organic phases were washed successively with saturated sodium bicarbonate aqueous solution, saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 45E (1.38 g, 78%). LC-MS (ESI): m / z = 305.1 [M+H] + .

[0548] Step 5: Under ice bath conditions, compound 45E (1.38 g, 1.94 mmol) was added in portions to a 30 mL solution of phosphorus oxychloride, followed by heating to 100 °C and stirring for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure to remove most of the phosphorus oxychloride, and the residue was then added dropwise to an ice-cold saturated sodium bicarbonate aqueous solution. The mixture was then extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 45F (1.44 g, 98%). LC-MS (ESI): m / z = 323.0 [M+H] + .

[0549] Step 6: Using compound 45F (0.39 g, 1.20 mmol) and 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (300 mg, 1.44 mmol) as starting materials, compound 45G (0.42 g, 95%) was synthesized according to the method described in Step 2 of Example 1. LC-MS (ESI): m / z = 369.1 [M+H] + .

[0550] Step 7: Compound 47G (0.42 g, 1.17 mmol) was dissolved in acetic acid solution of hydrogen bromide (50 mL), and phenol (354 mg, 3.81 mmol) was added. The mixture was heated to 100 °C and reacted for 18 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The residue was quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography to give compound 45H (150 mg, 61.41%). LC-MS (ESI): m / z = 215.1 [M+H] + .

[0551] Step 8: Using compound 45H (107 mg, 0.500 mmol) and compound 23E (166 mg, 0.500 mmol) as starting materials, compound 45 (71 mg, 32%) was synthesized according to the method described in Step 4 of Example 23. LC-MS (ESI): m / z = 447.3 [M+H] + .

[0552] 1 H NMR (400MHz, CDCl3) δ7.94-7.89(m,3H),7.20(s,1H),6.08-6.06(m,1H),4.81-4.75(m,4H),4.39-4.35(m,2H),3.95 (s,3H),3.88-3.84(m,2H),3.30-3.23(m,1H),2.84-2.80(m,2H),2.32(s,3H),1.95-1.92(m,1H),0.93-0.91(m,4H).

[0553] Example 46:

[0554] Step 1: Under nitrogen protection, compound 46A (1.50 g, 8.38 mmol), pinacol diborate (6.38 g, 25.1 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (613 mg, 0.838 mmol), and potassium acetate (2.47 g, 25.1 mmol) were dispersed in dry tetrahydrofuran (50 mL), and the mixture was heated to 80 °C and stirred overnight. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by vacuum to obtain crude product 46B (11.0 g). LC-MS (ESI): m / z = 227.1 [M+H] + .

[0555] Step 2: Using crude product 46B and compound 1A (1.36 g, 5.03 mmol) as starting materials, compound 46C (993 mg, 59%) was synthesized according to the method described in Step 1 of Example 1. LC-MS (ESI): m / z = 334.2 [M+H] + .

[0556] Step 3: Using compound 46C (993 mg, 2.98 mmol) as the starting material, crude product 46D (960 mg) was obtained by referring to the synthesis method in step 2 of Example 1. LC-MS (ESI): m / z = 234.1 [M+H] + .

[0557] Step 4: Using compound 4M (125 mg, 0.500 mmol) and crude 46D (188 mg) as starting materials, compound 46 (10 mg, 4%) was synthesized according to the method described in Step 4 of Example 23. LC-MS (ESI): m / z = 467.4 [M+H] + .

[0558] 1 H NMR (400MHz, CDCl3) δ7.95-7.93(m,1H),7.85-7.84(m,1H),4.80-4.76(m,4H),4.53-4.48(m,2H),4.01-3. 97(m,2H),3.83(s,3H),3.32-3.25(m,1H),2.83-2.78(m,2H),2.49(s,3H),2.12(s,1H),1.03-0.95(m,4H).

[0559] Example 47:

[0560] Step 1: Using compound 47A (1.50 g, 8.38 mmol) as the starting material, crude product 47B (11.5 g) was obtained by following the synthesis method in Step 1 of Example 46. LC-MS (ESI): m / z = 227.1 [M+H] + .

[0561] Step 2: Using crude product 47B and compound 1A (1.36 g, 5.03 mmol) as starting materials, compound 47C (383 mg, 23%) was synthesized according to the method described in Step 1 of Example 1. LC-MS (ESI): m / z = 334.2 [M+H] + .

[0562] Step 3: Using compound 47C (383 mg, 0.750 mmol) as the starting material, crude product 47D (350 mg) was obtained by referring to the synthesis method in step 2 of Example 1. LC-MS (ESI): m / z = 234.1 [M+H]+ .

[0563] Step 4: Using compound 4M (125 mg, 0.500 mmol) and crude 47D (175 mg) as starting materials, compound 47 (37 mg, 16%) was synthesized according to the method described in Step 4 of Example 23. LC-MS (ESI): m / z = 467.0 [M+H] + .

[0564] 1 H NMR (400MHz, CDCl3) δ8.06-8.04(m,1H),7.85-7.84(m,1H),4.79-4.77(m,4H),4.55-4.50(m,2H),4.01(s,2H) ,3.81-3.80(m,3H),3.33-3.26(m,1H),2.84-2.79(m,2H),2.50(s,3H),2.24-2.18(m,1H),1.05-0.98(m,4H).

[0565] Example 48:

[0566] Compound 48 (40 mg, 16%) was synthesized from compound 6D (139 mg, 0.500 mmol) and crude 47D (175 mg) using the method described in step four of Example 23. LC-MS (ESI): m / z = 494.4 [M+H] + .

[0567] 1 H NMR (400MHz, CDCl3) δ8.16-8.15(m,1H),8.08-8.06(m,1H),6.63-6.61(m,1H),4.81-4.77(m,4H),4.49-4. 45(m,2H),3.97-3.93(m,2H),3.81-3.80(m,3H),3.34-3.29(m,1H),2.86-2.81(m,2H),2.51-2.50(m,3H).

[0568] Example 49:

[0569] Step 1: 49A (1 g, 5.62 mmol), pinacol diboronate (2.85 g, 11.26 mmol), Pd2(dba)3 (514 mg, 0.56 mmol), tricyclohexylphosphine (392 mg, 1.40 mmol), and potassium acetate (1.65 g, 16.85 mmol) were dissolved in 1,4-dioxane (25 mL) under nitrogen atmosphere and reacted overnight at 90 °C. After the reaction was complete, the mixture was cooled to room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, concentrated, and the residue was purified by silica gel column chromatography to obtain 49B (560 mg, 70%). LC-MS (ESI): m / z = 144.1 [M+H] + .

[0570] Step 2: Using 49B (560 mg, 3.92 mmol) and 1A (1.05 g, 3.92 mmol) as raw materials, 49C (492 mg, 38%) was obtained according to the synthesis method in Step 1 of Example 1. LC-MS (ESI): m / z = 333.3 [M+H] + .

[0571] Step 3: Using 49C (492 mg, 1.48 mmol) as the starting material, 49D (290 mg, 84%) was obtained according to the synthesis method in Step 2 of Example 1. LC-MS (ESI): m / z = 233.1 [M+H] + .

[0572] Step 4: Using 49D (100 mg, 0.43 mmol) and 6D (120 mg, 0.43 mmol) as starting materials, compound 49 (44 mg, 21%) was obtained by following the synthesis method in Step 6 of Example 1. LC-MS (ESI): m / z = 493.2 [M+H] + .

[0573] 1 H NMR (400MHz, CDCl3) δ8.48-8.44(m,1H),8.21-8.18(m,1H),6.64-6.62(m,1H),4.82-4.76(m,4H),4.49 -4.41(m,2H),3.98-3.92(m,2H),3.36-3.28(m,1H),2.89-2.81(m,2H),2.78(s,3H),2.53-2.50(m,3H).

[0574] Example 50:

[0575] Step 1: Compound 50B (1.00 g, 10.2 mmol) and compound 50A (2.71 g, 11.2 mmol) were dissolved sequentially in THF (50 mL), and potassium tert-butoxide (1.72 g, 15.3 mmol) was added. The mixture was stirred at room temperature. After the starting material disappeared as monitored by TLC, the reaction was quenched by adding saturated ammonium chloride aqueous solution. The mixture was extracted three times with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 50C (2.07 g, 63.7%). LC-MS (ESI): m / z = 320.0 [M+H] + .

[0576] Step 2: Using compound 50C (1.00 g, 3.13 mmol) as the starting material, compound 50D (746 mg, 71.2%) was obtained according to the synthesis method described in Step 2 of Example 10. LC-MS (ESI): m / z = 335.2 [M+H] + .

[0577] Step 3: Using compound 50D (300 mg, 0.898 mmol) as the starting material, compound 50E (260 mg, 94.5%) was obtained by following the synthetic method in Step 3 of Example 10. LC-MS (ESI): m / z = 307.1 [M+H] + .

[0578] Step 4: Dissolve 4I (1 g, 3.73 mmol) in tetrahydrofuran (20 mL), add sodium tert-butoxide (1.79 g, 18.65 mmol), stir at room temperature for 20 min, then add difluorobromomethyltrimethylsilane (2.27 g, 11.19 mmol) dropwise. After the addition is complete, react at room temperature for 16 h. Dilute with water, extract three times with ethyl acetate, wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by silica gel column chromatography to obtain 50F (0.45 g, 37.93%).

[0579] 1 H NMR (400MHz, CDCl3) δ7.99-7.65(m,1H),4.80-4.67(m,2H),4.47-4.37(m,2H),2.14(d,3H),1.52(s,9H).

[0580] Step 5: Dissolve 50F (0.45 g, 1.41 mmol) in dioxane hydrochloride (5 mL, 4 M) and react at room temperature for 2 h. Concentrate the reaction solution under reduced pressure to obtain 50G (0.37 g). LC-MS (ESI): m / z = 219.1 [M+H] + .

[0581] Step 6: Using compound 50E (100 mg, 0.326 mmol) and compound 50G (129 mg, 0.392 mmol) as starting materials, compound 50 (132 mg, 79.8%) was synthesized according to the method described in step 10 of Example 2. LC-MS (ESI): m / z = 507.2 [M+H] + .

[0582] 1 H NMR(400MHz,Chloroform-d)δ8.00-7.66(m,1H),7.52(s,1H),7.40(s,1H),5.63(s,1H),5.55(d,1H),4.90-4.83(m ,2H),4.61-4.51(m,2H),4.20(t,2H),3.88(s,3H),3.70-3.58(m,2H),3.31-3.20(m,1H),2.76(d,2H),2.17(d,3H).

[0583] Example 51:

[0584] Step 1: Compound 50B (3.05 g, 31.1 mmol) and compound 35A (2.50 g, 10.4 mmol) were dissolved in THF (100 mL), and potassium tert-butoxide (1.75 g, 15.6 mmol) was added. The mixture was then heated to 60 °C and stirred overnight. After the starting material disappeared as monitored by TLC, the mixture was cooled to room temperature, and the reaction was quenched by adding saturated ammonium chloride aqueous solution. The mixture was extracted three times with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 51C (2.07 g, 74.3%). LC-MS (ESI): m / z = 320.0 [M+H] + .

[0585] Step 2: Using compound 51C (1.00 g, 3.13 mmol) as the starting material, compound 51D (463 mg, 44.1%) was obtained by following the synthetic method in Step 2 of Example 10. LC-MS (ESI): m / z = 335.2 [M+H] + .

[0586] Step 3: Using compound 51D (300 mg, 0.898 mmol) as the starting material, compound 51E (250 mg, 90.9%) was obtained by following the synthetic method in Step 3 of Example 10. LC-MS (ESI): m / z = 307.1 [M+H] + .

[0587] Step 4: Using compound 51E (100 mg, 0.326 mmol) and compound 2J (129 mg, 0.392 mmol) as starting materials, compound 51 (136 mg, 82.2%) was synthesized according to the method described in step 10 of Example 2. LC-MS (ESI): m / z = 507.2 [M+H] + .

[0588] 1 H NMR(400MHz,Chloroform-d)δ8.00-7.66(m,1H),7.69(d,1H),7.46(s,1H),7.38(s,1H),5.79(d,1H),4.91-4.84(m,2H),4.6 1-4.52(m,2H),4.40-4.30(m,2H),3.87(s,3H),3.85-3.79(m,2H),3.30-3.20(m,1H),2.82-2.75(m,2H),2.19-2.15(m,3H).

[0589] Example 52:

[0590] Compound 52 (78 mg, 37%) was obtained from 24C (100 mg, 0.42 mmol) and 6D (120 mg, 0.42 mmol) using the synthetic method described in step 6 of Example 1. LC-MS (ESI): m / z = 492.0 [M+H] + .

[0591] 1 H NMR (400MHz, CDCl3) δ8.16-8.12(m,2H),8.09-8.05(m,1H),6.62-6.59(m,1H),4.74-4.66(m,4H) ,4.48-4.41(m,2H),4.10-4.06(m,3H),3.99-3.89(m,5H),3.36-3.25(m,1H),2.83-2.78(m,2H).

[0592] Example 53:

[0593] Step 1: Compound 35A (5 g, 20.75 mmol) and 1,3-cyclopentanediol (2.12 g, 20.75 mmol) were dissolved in dry N,N-dimethylformamide (40 mL). Potassium tert-butoxide (3.48 g, 31.12 mmol) was added in portions at 0 °C. After the addition was complete, the reaction was carried out at room temperature for 5 hours. After the reaction was completed, the mixture was quenched with water, and then extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to give compound 53A (2.5 g, 37%). LC-MS (ESI): m / z = 324.0 [M+H] + .

[0594] Step 2: Using compound 53A (2 g, 6.19 mmol) as the starting material, compound 53B (1.4 g, 70%) was synthesized according to the method described in Step 2 of Example 16. LC-MS (ESI): m / z = 322.0 [M+H] + .

[0595] Step 3: Using compound 53B (1.4 g, 4.36 mmol) as the starting material, compound 53C (0.9 g, 60%) was synthesized according to the method described in Step 3 of Example 16. LC-MS (ESI): m / z = 344.0 [M+H] + .

[0596] Step 4: Using compound 53C (0.9 g, 2.62 mmol) as the starting material, compound 53D (0.65 g, 69%) was synthesized according to the method described in step 2 of Example 10. Further chiral resolution yielded 53D-1 (270 mg, retention time 1.185 min) and 53D-2 (255 mg, retention time 1.520 min). LC-MS (ESI): m / z = 359.1 [M+H] + .

[0597] Preparative chromatographic analysis method: Instrument: Waters 150Prep-SFC; Column: Chiral AD column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in methanol; Gradient: B for 25%; Flow rate: 110 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0598] Step 5: Using compound 53D-1 (0.12 g, 0.334 mmol) as the starting material, crude compound 53E-1 (0.334 mmol) was obtained according to the synthesis method in step 5 of Example 16. This crude compound was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 331.1 [M+H] + .

[0599] Starting with compound 53D-2 (0.12 g, 0.334 mmol), crude compound 53E-2 (0.334 mmol) was obtained according to the synthetic method in step 5 of Example 16. This crude product was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 331.1 [M+H] + .

[0600] Step 6: Using compound 53E-1 (0.334 mmol) and compound 2J (91 mg, 0.334 mmol) as starting materials, isomer 1 of compound 53 (100 mg, 58%) was synthesized according to the method described in Step 6 of Example 16. LC-MS (ESI): m / z = 513.2 [M+H] + .

[0601] 1 H NMR (400MHz, CDCl3) δ7.96-7.62(m,2H),6.32-3.31(m,1H),5.63(d,1H),5.40-5.35(m,1H),4.90-4.86(m,2H),4.55-4.51(m,2H),4.35-4. 24(m,2H),3.83-3.73(m,2H),3.30-3.13(m,1H),2.78-2.75(m,2H),2 .61-2.49(m,1H),2.39-2.18(m,3H),2.16(s,3H),2.13-1.96(m,2H).

[0602] Starting with compound 53E-2 (0.334 mmol) and compound 2J (91 mg, 0.334 mmol), isomer 2 (105 mg, 61%) of compound 53 was synthesized according to step 6 of Example 16. LC-MS (ESI): m / z = 513.2 [M+H] + .

[0603] 1 H NMR (400MHz, CDCl3) δ7.96-7.62(m,2H),6.32-3.31(m,1H),5.63(d,1H),5.40-5.35(m,1H),4.91-4.87(m,2H),4.55-4.51(m,2H),4.32-4. 28(m,2H),3.80-3.75(m,2H),3.25-3.18(m,1H),2.78-2.75(m,2H),2 .61-2.49(m,1H),2.39-2.18(m,3H),2.16(s,3H),2.13-1.96(m,2H).

[0604] Example 54:

[0605] Step 1: 54A (1.08 g, 6.15 mmol) was dissolved in DMF (5 mL), and ethyl 2-(azacyclobutane-3-yl)acetate (800 mg, 5.59 mmol) and DIPEA (2.17 g, 16.77 mmol) were added sequentially. The mixture was then heated to 100 °C and reacted for 16 hours. The reaction was stopped when the starting material disappeared as monitored by TLC. After cooling to room temperature, EA was added. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 54B (1.2 g, 71.79%). LC-MS (ESI): m / z = 301.0 [M+H] + .

[0606] Step 2: At room temperature, 54B (300 mg, 1.0 mmol) was dissolved in tetrahydrofuran, and (S)-1,1,1-trifluoropropane-2-amine (0.17 g, 1.50 mmol), Pd2(dba)3 (183 mg, 0.20 mmol), tBuXPhos (127 mg, 0.30 mmol), and sodium tert-butoxide (288 mg, 3.0 mmol) were added sequentially. The reaction was then carried out at 65 °C for 16 hours under a nitrogen atmosphere. The reaction was stopped when the starting material disappeared as monitored by TLC. The mixture was cooled to room temperature, and EA was added to the reaction solution. The organic phase was washed twice with water, and the aqueous phase was collected. The aqueous phase was washed twice with methyl tert-butyl ether, and the aqueous phase was concentrated. No purification was required to obtain compound 54C (190 mg, 62.65%). LC-MS (ESI): m / z = 304.2 [M+H] + .

[0607] Step 3: Using 54C (190 mg, 0.63 mmol) and 1C (149 mg, 0.69 mmol) as starting materials, compound 54 (65 mg, 20.73%) was obtained by following the synthetic method in Step 6 of Example 1. LC-MS (ESI): m / z = 501.1 [M+H] + .

[0608] 1H NMR (400MHz, CDCl3) δ8.18-8.16(d,1H),8.10-8.08(d,1H),7.61-7.60(d,1H),5.82-5.81(d,1H),5.30(s,1H),4.79(s,1H),4.76(s, 4H),4.29-4.25(t,3H),3.97(s,3H),3.78-3.73(m,2H),3.35-3.26(m,1H),2.84-2.80(m,2H),2.49-2.47(d,3H),1.47-1.46(d,3H).

[0609] Example 55:

[0610] Step 1: Using 55A (2.83 g, 21.52 mmol) as the starting material, compound 55B (2.9 g, 58.22%) was synthesized according to the method described in Step 1 of Example 54. LC-MS (ESI): m / z = 255.0 [M+H] + .

[0611] Step 2: Using 55B (254 mg, 1.0 mmol) as the starting material, and following the synthesis method described in Step 2 of Example 54, compound 55C (200 mg, 65.95%) was obtained. LC-MS (ESI): m / z = 304.2 [M+H] + .

[0612] Step 3: Using 55C (200 mg, 0.66 mmol) and 1C (156 mg, 0.73 mmol) as starting materials, compound 55 (60 mg, 18.18%) was obtained by following the synthetic method in Step 6 of Example 1. LC-MS (ESI): m / z = 501.1 [M+H] + .

[0613] 1 H NMR(400MHz, CDCl3)δ8.18-8.16(d,1H),8.10-8.08(d,1H),7.70-7.69(d,1H),5.81-5.80(d,1H),5.33(s,1H),4.79(s,1H),4.76(s,4H),4.47 -4.46(d,1H),4.24-4.20(t,2H),3.96(s,3H),3.71-3.67(m,2H),3.32 -3.21(m,1H),2.83-2.78(t,2H),2.48-2.47(d,3H),1.42-1.40(d,3H).

[0614] Example 56:

[0615] Compound 56 (52 mg, 23.32%) was synthesized from compound 45H (100 mg, 0.47 mmol) and compound 6D (155 mg, 0.56 mmol) according to step 6 of Example 1. LC-MS (ESI): m / z = 475.1 [M+H] + .

[0616] 1 H NMR (400MHz, DMSO-d6) δ8.26-8.21(m,2H),7.96-7.93(m,1H),7.44-7.41(m,1H),6.89-6.85(m,1H),4.86-4.79(m,2H),4.63-4 .56(m,2H),4.40-4.32(m,2H),3.95-3.89(m,2H),3.88-3.85(m,3H),3.19-3.08(m,1H),2.91-2.82(m,2H),2.31-2.25(m,3H).

[0617] Example 57:

[0618] Compound 57 (68 mg, 29.61%) was synthesized using compound 45H (100 mg, 0.47 mmol) and compound 6D (164 mg, 0.56 mmol) as starting materials, following the synthetic method in step 6 of Example 1. LC-MS (ESI): m / z = 489.0 [M+H] + .

[0619] 1 H NMR(400MHz,DMSO-d6)δ8.26-8.22(m,1H),8.12-8.08(m,1H),7.97-7.93 (m,1H),7.45-7.41(m,1H),6.61-6.57(m,1H),6.42-6.39(m,1H),4.86-4 .79(m,2H),4.62-4.57(m,2H),4.17-4.11(m,2H),3.89-3.84(m,3H),3.7 1-3.65(m,2H),3.17-3.08(m,1H),2.89-2.83(m,2H),2.31-2.25(m,3H).

[0620] Example 58:

[0621] Compound 58 (31 mg, 35%) was obtained from compounds 50G (55 mg, 0.18 mmol) and 11A (37 mg, 0.18 mmol) according to the synthetic method described in step 6 of Example 1. LC-MS (ESI): m / z = 493.1 [M+H] + .

[0622] 1 H NMR(400MHz, CDCl3)δ8.17(d,1H),7.99-7.67(m,1H),6.50(d,1H),6.23-6.21(m,1H),4.87(s,2H),4.59-4.58 (m,H),4.55(s,1H),4.24(t,2H),3.73-3.68(m,2H),3.33-3.26(m,1H),2.80-2.77(m,2H),2.18-2.16(m,3H).

[0623] Example 59:

[0624] Compound 59 (15 mg, 0.47 mmol) was obtained from 36F (150 mg, 0.47 mmol) and 1C (101 mg, 0.47 mmol) according to the synthetic method in step 12 of Example 4. LC-MS (ESI): m / z = 515.0 [M+H] + .

[0625] 1 H NMR (400MHz, CDCl3) δ8.18-8.16(d,1H),8.10-8.08(d,1H),7.75-7.74(d,1H),5.02-4.93(m,1H),4.79-4.76(d,4H),4. 55-4.51(t,2H),4.03-3.99(t,2H),3.97(s,3H),3.33-3.26(m,1H),3.10-3.00(m,2H),2.83-2.70(m,4H),2.48(d,3H).

[0626] Example 60:

[0627] Compound 60 (56 mg, 25.60%) was synthesized from compound 28C (100 mg, 0.46 mmol) and compound 10D (155 mg, 0.55 mmol) according to step 6 of Example 1. LC-MS (ESI): m / z = 476.1 [M+H] + .

[0628] 1 H NMR(400MHz,DMSO-d6)δ8.28-8.23(m,1H),7.53-7.49(m,1H),6.98-6.93(m,1H),6.90-6.84(m,1H),4.97-4.87(m,2H),4 .73-4.63(m,2H),4.40-4.32(m,2H),4.25(s,3H),3.97-3.88(m,2H),3.18-3.09(m,1H),2.93-2.84(m,2H),2.50(s,3H).

[0629] Example 61:

[0630] Step 1: 61A (3.00 g, 14.26 mmol) was dissolved in dimethyl sulfoxide (50 mL), and methyl 2-(azacyclobutane-3-yl)acetate trifluoroacetate (6.36 g, 15.69 mmol), triethylamine (2.89 g, 28.52 mmol), and potassium carbonate (4.93 g, 35.65 mmol) were added sequentially. The mixture was heated to 100 °C and reacted for 4 hours. After the reaction was complete, the mixture was diluted with water, extracted twice with ethyl acetate, and the organic phases were combined and concentrated. The residue was purified by column chromatography to obtain 61B (3.20 g, 74.05%). LC-MS (ESI): m / z = 302.9; 304.9 [M+H] + .

[0631] Step 2: Compound 61B (2.40 g, 7.92 mmol) and trifluoromethylthio(2,2-bipyridine)copper(I) (3.06 g, 9.50 mmol) were added to 1,4-dioxane (50 mL). After nitrogen purging, the mixture was heated to 90 °C and reacted for 12 hours. After the reaction was complete, the mixture was filtered. Ethyl acetate and saturated brine were added to the filtrate, and the mixture was extracted and separated. The aqueous phase was extracted again with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 61C (1.90 g, 74.00%). LC-MS (ESI): m / z = 325.0 [M+H] + .

[0632] Step 3: 61C (1.90 g, 5.86 mmol) was dissolved in a mixed solvent of methanol (1 mL), water (5 mL), and tetrahydrofuran (20 mL), then lithium hydroxide monohydrate (0.30 g, 7.03 mmol) was added, and the reaction was carried out at room temperature for 8 hours. After the reaction was complete, the solution was concentrated to dryness under reduced pressure. Dichloromethane and water were added, and the pH was adjusted to 3-5 with 1 mol / L hydrochloric acid. The mixture was extracted and separated. The aqueous phase was extracted again with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 61D (4.90 g, 98.49%). LC-MS (ESI): m / z = 311.0 [M+H] + .

[0633] Step 4: Using compound 50G (55 mg, 0.18 mmol) and compound 61D (37 mg, 0.18 mmol) as starting materials, compound 61 (22 mg, 24%) was synthesized according to the method described in Step 6 of Example 1. LC-MS (ESI): m / z = 511.1 [M+H] + .

[0634] 1 H NMR(400MHz, CDCl3)δ8.07(d,1H),7.99-7.67(m,1H),6.56(d,1H),4.87(s,2H),4.57(d,2H ),4.44-4.39(m,2H),3.97-3.84(m,2H),3.32-3.25(m,1H),2.80-2.78(m,2H),2.17(t,3H).

[0635] Example 62:

[0636] Starting with 2 J (50 mg, 0.16 mmol), compound 62 (21.0 mg, 26%) was obtained by following the synthetic method in step 10 of Example 2. LC-MS (ESI): m / z = 493.1 [M+H] + .

[0637] 1 H NMR(400MHz,DMSO-d6)δ8.17(dd,1H),7.96(t,1H),6.75(dd,1H),6.33(d,1H),4.92(s,1H), 4.64(d,2H),4.39(s,1H),4.29(s,2H),3.85(t,2H),3.10(s,1H),2.84(dd,2H),2.14(d,3H).

[0638] Example 63:

[0639] Compound 63 (42 mg, 25.86%) was obtained from compounds 61D (100 mg, 0.32 mmol) and 1C (88 mg, 0.41 mmol) according to step 6 of Example 1. LC-MS (ESI): m / z = 508.1 [M+H] + .

[0640] 1 H NMR(400MHz,DMSO-d6)δ8.37-8.33(m,1H),8.19-8.17(m,1H),8.00-7.98(m,1H),6.78-6.75(m,1H),4.89-4.81(m,2H),4.66-4 .57(m,2H),4.35-4.27(m,2H),3.91-3.89(m,3H),3.89-3.84(m,2H),3.17-3.06(m,1H),2.89-2.84(m,2H),2.45-2.40(m,3H).

[0641] Example 64:

[0642] Starting with compound 36F (50 mg, 0.16 mmol) and compound 58K (60 mg, 0.21 mmol), compound 64 (20.0 mg, 24.5%) was synthesized according to step 10 of Example 2. LC-MS (ESI): m / z = 518.2 [M+H] + .

[0643] 1 H NMR (400MHz, CDCl3) δ7.99-7.67(m,2H),5.03-4.98(m,1H),4.88(d,2H),4.58-4.55(m,4H) ,4.12-4.08(m,2H),3.36-3.29(m,1H),3.07-3.03(m,2H),2.84-2.76(m,4H),2.17(d,3H).

[0644] Example 65:

[0645] Step 1: Compound 65A (5.0 g, 23.58 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), purged with nitrogen three times, cooled to 0 °C, and sodium hydride (1.42 g, 35.38 mmol, 60% purity) was slowly added. After stirring for 30 minutes, iodomethane (6.70 g, 47.16 mmol) was added. After the addition was complete, the mixture was brought back to room temperature and reacted for 2 hours. Then, the mixture was cooled to 0 °C, and the reaction was quenched by slowly adding saturated ammonium chloride solution. The mixture was extracted twice with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain compound 65B (5.0 g, 93.8%).

[0646] Step 2: Compound 65B (3.5 g, 15.49 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), purged three times with nitrogen, and cooled to -78 °C. Butyllithium (9.30 mL, 23.23 mmol, 2.5 mol / L) was slowly added dropwise. After the addition was complete, the reaction continued for 30 min. N,N-dimethylformamide (2.26 g, 30.98 mmol) was added, followed by slow warming and reaction for 3 hours. After the reaction was complete, a saturated ammonium chloride aqueous solution was slowly added dropwise to quench the reaction. The mixture was extracted twice with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain compound 65C (0.40 g, 20.1%). LC-MS (ESI): m / z = 129.0 [M+H] + .

[0647] Step 3: Compound 65C (0.40 g, 3.12 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (1.27 g, 6.24 mmol, 85% purity) was added. The reaction was allowed to proceed at room temperature for 15 h. After the reaction was complete, the solution was concentrated under reduced pressure. The residue was then dissolved in methanol (20 mL), and potassium carbonate (2.16 g, 15.60 mmol) was added in portions. The reaction was allowed to proceed for 3 h. After the reaction was complete, water was added, and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to give compound 65D (0.15 g, 41.4%). LC-MS (ESI): m / z = 117.0 [M+H] + .

[0648] Step 4: Using compound 65D (0.15 g, 1.29 mmol) as the starting material, compound 65E (0.21 g, 50.9%) was synthesized according to the method described in Step 1 of Example 18. LC-MS (ESI): m / z = 320.0 [M+H] + .

[0649] Step 5: Using compound 65E (0.21 g, 0.66 mmol) as the starting material, compound 65F (0.17 g, 77.2%) was synthesized according to the method described in step 2 of Example 10. LC-MS (ESI): m / z = 335.2 [M+H] + .

[0650] Step 6: Using compound 65F (0.17 g, 0.51 mmol) as the starting material, compound 65G (0.20 g, 100%) was synthesized according to the method described in step 3 of Example 10. This unpurified compound was used directly in the next reaction. LC-MS (ESI): m / z = 307.1 [M+H] + .

[0651] Step 7: Using compound 65G (50.0 mg, 0.16 mmol) and compound 2J (52 mg, 0.19 mmol) as starting materials, compound 65 (35.0 mg, 43.8%) was synthesized according to the method described in step 10 of Example 2. LC-MS (ESI): m / z = 489.2 [M+H] + .

[0652] 1 H NMR (400MHz, CDCl3) δ7.97-7.65(m,2H),7.38(d,1H),6.33(d,1H),6.05(dd,1H),5.80(d,1H),4.89-4.87(m,2H ),4.55-4.52(m,2H),4.21(t,2H),3.75(s,3H),3.71-3.65(m,2H),3.28-3.24(m,1H),2.77(d,2H),2.17(d,3H).

[0653] Example 66:

[0654] Step 1: Compound 66A (380.00 mg, 3.11 mmol) and 2,5-difluoro-4-iodopyridine (824.39 mg, 9.42 mmol) were dissolved in tetrahydrofuran (5 mL), and potassium tert-butoxide (523.46 mg, 4.67 mmol) was added. The mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 66B (550.0 mg, 52%). LC-MS (ESI): m / z = 343.9 [M+H] + .

[0655] Step 2: Compound 66B (500.00 mg, 1.46 mmol), ethyl acetate trifluoroacetate of 2-(azacyclobutane-3-yl) (390.00 mg, 1.05 mmol), cesium carbonate (1.19 g, 3.65 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)(II) (110.00 mg, 0.15 mmol) were dissolved in 1,4-dioxane (10 mL), stirred until homogeneous, and reacted at 100 °C for 7 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography to obtain 66C (494.0 mg, 94%). Further separation by SFC yielded compound 66C-1 (358.5 mg, retention time 0.915 min) and compound 66C-2 (127.9 mg, retention time 1.001 min). LC-MS (ESI): m / z = 359.2 [M+H] + .

[0656] Preparative chromatographic analysis method: Instrument: Waters 150Prep-SFC; Column: Chiral OX column; Mobile phase system: A for CO2; B for 0.1% NH3·H2O in methanol; Gradient: B for 10%; Flow rate: 120 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0657] Step 3: Using compound 66C-1 (358.5 mg, 1.00 mmol) as the starting material, compound 66D-1 (322.8 mg, 98%) was synthesized according to the method described in Step 3 of Example 10. LC-MS (ESI): m / z = 331.2 [M+H] + .

[0658] Using compound 66C-2 (127.9 mg, 0.36 mmol) as the starting material, compound 66D-2 (112.0 mg, 95%) was synthesized according to the method described in step 3 of Example 10. LC-MS (ESI): m / z = 331.2 [M+H] + .

[0659] Step 4: Using compound 66D-1 (322.8 mg, 0.98 mmol) as the starting material, isomer 1 (52.0 mg, 11%) of compound 66 was synthesized according to the synthesis method in step 10 of Example 2. LC-MS (ESI): m / z = 513.1 [M+H] + .

[0660] 1 H NMR(400MHz,DMSO-d6)δ7.96(dd,1H),7.68(dd,1H),6.33(d,1H),6.07(td,1H),5.72(dd,1H),5.00(dd,1H),4.92(s,1H),4.64(d, 2H),4.39(s,1H),4.18(dd,2H),3.78-3.69(m,2H),3.06(s,1H),2.82(dd,2H),2.49-2.38(m,3H),2.15(d,3H),2.02-1.89(m,2H).

[0661] Using compound 66D-2 (112.0 mg, 0.22 mmol) as the starting material, isomer 2 (99.0 mg, 57%) was obtained according to the synthetic method in step 10 of Example 2. LC-MS (ESI): m / z = 513.1 [M+H] + .

[0662] 1 H NMR(400MHz,DMSO-d6)δ7.96(dd,1H),7.69(dd,1H),6.33(d,1H),6.20(td,1H),5.73(dd,1H),5.11(p,1H),4.93(s,1H),4.64(d,2 H),4.39(s,1H),4.18(dd,2H),3.74(t,2H),3.12-2.98(m,1H),2.82(dd,2H),2.77-2.60(m,1H),2.41(ddd,2H),2.27-2.10(m,5H).

[0663] Example 67:

[0664] Step 1: Compound 20B (5 g, 28.4 mmol) was dissolved in methanol, and sodium borohydride (2.1 g, 56.8 mmol) was added under ice bath conditions. After the addition was complete, the mixture was allowed to react at room temperature. After the reaction was complete, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 67A (5.0 g, 100%). LC-MS (ESI): m / z = 179.2 [M+H] + .

[0665] Step 2: Compound 67A (5 g, 28.4 mmol) was dissolved in methanol, and (1 g) palladium on carbon was added. The reaction was carried out under a hydrogen atmosphere for 6 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 67B, which was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 89.2 [M+H] + .

[0666] Step 3: Using compound 67B (2 g, 22.7 mmol) as the starting material, compound 67C (1.4 g, 21.2%) was synthesized according to the method described in Step 1 of Example 16. LC-MS (ESI): m / z = 292.2 [M+H] + .

[0667] Step 4: Using compound 67C (1.4 g, 4.81 mmol) as the starting material, compound 67D (1.2 g, 86.3%) was obtained by following the synthetic method in step 2 of Example 16. LC-MS (ESI): m / z = 290.2 [M+H] + .

[0668] Step 5: Compound 67D (0.7 g, 2.34 mmol) and difluoromethyl (2-pyridyl) sulfone (0.677 g, 3.51 mmol) were dissolved in DMF (10 mL). Under a nitrogen atmosphere, the mixture was cooled to -60 °C, and a solution of potassium tert-butoxide (0.4 g, 3.51 mmol) in DMF (5 mL) was added dropwise. After the addition was complete, the reaction mixture was raised to 0 °C and stirred for 1 hour. Concentrated hydrochloric acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with water, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 67E (120 mg, 12%). LC-MS (ESI): m / z = 324.2 [M+H] + .

[0669] Step 6: Using 67E (120 mg, 0.037 mmol) as the starting material, compound 67F (65 mg, 43.91%) was obtained by following the synthetic method in step 2 of Example 10. LC-MS (ESI): m / z = 325.2 [M+H] + .

[0670] Step 7: Using compound 67F (65 mg, 0.2 mmol) as the starting material, compound 67G was synthesized according to the method described in step 3 of Example 10. This compound was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 311.2 [M+H] + .

[0671] Step 8: Using compound 67G (64 mg, 0.2 mmol) and compound 2J (0.072 g, 0.2 mmol) as starting materials, compound 67 (racemic) (35 mg) was synthesized according to the method in step 10 of Example 2. Further chiral resolution yielded isomer 1 of compound 67 (18 mg, 32%, retention time 5.893 min) and isomer 2 of compound 67 (15 mg, 31%, retention time 5.898 min).

[0672] Preparative chromatographic analysis method: Instrument: SHIMADZU LC-30AD SFC; Column: Chiral AD column; Mobile phase: A for CO2; B for 0.05% DEA in methanol; Gradient: B for 40%; Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0673] Compound 67 isomer 1: LC-MS (ESI): m / z = 493.2 [M+H] + .

[0674] 1 H NMR (400MHz, CDCl3) δ7.99-7.81(m,1H),7.80-7.76(m,1H),6.30-6.27(m,1 H),6.05-5.99(m,1H),5.94(s,1H),5.70-5.59(m,1H),4.95-4.81(m,1H),4. 62-4.48(m,1H),4.33-4.16(m,1H),3.74-3.64(m,1H),3.34-3.16(m,1H),2. 85-2.55(m,3H),2.28-2.09(m,3H),1.33-1.16(m,4H),0.966-0.766(m,3H).

[0675] Compound 67 isomer 2: LC-MS (ESI): m / z = 493.2 [M+H] + .

[0676] 1H NMR (400MHz, CDCl3) δ7.99-7.81(m,1H),7.80-7.76(m,1H),6.30-6.27(m,1 H),6.05-5.99(m,1H),5.94(s,1H),5.70-5.59(m,1H),4.95-4.81(m,1H),4. 62-4.48(m,1H),4.33-4.16(m,1H),3.74-3.64(m,1H),3.34-3.16(m,1H),2. 85-2.55(m,3H),2.28-2.09(m,3H),1.33-1.16(m,4H),0.966-0.766(m,3H).

[0677] Example 68:

[0678] Step 1: Using compound 20D (0.135 g, 1.25 mmol) as the starting material, compound 68A (0.11 g, 62.2%) was synthesized according to the method described in Step 1 of Example 16. LC-MS (ESI): m / z = 330.2 [M+H] + .

[0679] Step 2: Using compound 68A (0.11 g, 0.34 mmol) as the starting material, compound 68B (0.14 g, 65.5%) was synthesized according to the method described in Step 2 of Example 10. LC-MS (ESI): m / z = 331.2 [M+H] + .

[0680] Step 3: Using compound 68B (0.14 g, 0.42 mmol) as the starting material, compound 68C was synthesized according to the method described in Step 3 of Example 10. This compound was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 317.2 [M+H] + .

[0681] Step 4: Using compound 68C (0.11 g, 0.42 mmol) and compound 2J (0.106 g, 0.42 mmol) as starting materials, the racemic mixture of compound 68 (104 mg) was obtained according to the synthesis method in step 10 of Example 2. This was then chirally resolved to obtain isomer 1 of compound 68 (62 mg, 32%, retention time 3.624 min) and isomer 2 of compound 68 (41 mg, 31%, retention time 3.618 min).

[0682] Preparative chromatographic analysis method: Instrument: SHIMADZU LC-30AD SFC; Column: Chiral AD column; Mobile phase: A for CO2; B for 0.05% DEA in methanol; Gradient: B for 40%; Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0683] Compound 68 isomer 1: LC-MS (ESI): m / z = 499.2 [M+H] + .

[0684] 1 H NMR (400MHz, CDCl3) δ8.01-7.98(m,1H),7.39-7.32(m,1H),7.04-6.89(m,1H),6.32-6.25(m,1H),5.84(s,1H),4.84-4.75(m,1H),4 .57-4.50(m,1H),4.33-4.29(m,1H),4.27-4.22(m,1H),3.82-3.76(m,2H),3.55-3.47(m,2H).2.73-2.61(m,2H),2.59-2.28(m,8H).

[0685] Compound 68 isomer 2: LC-MS (ESI): m / z = 499.2 [M+H] + .

[0686] 1 H NMR (400MHz, CDCl3) δ8.01-7.98(m,1H),7.39-7.32(m,1H),7.04-6.89(m,1H),6.32-6.25(m,1H),5.84(s,1H),4.84-4.75(m,1H),4 .57-4.50(m,1H),4.33-4.29(m,1H),4.27-4.22(m,1H),3.82-3.76(m,2H),3.55-3.47(m,2H),2.73-2.61(m,2H),2.59-2.28(m,8H).

[0687] Example 69:

[0688] Step 1: Compound 69A (1 g, 4.56 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The reaction was carried out at room temperature. After the reaction was complete, the solution was concentrated under reduced pressure to obtain crude compound 69B, which could be used directly in the next step without further purification. LC-MS (ESI): m / z = 120.2 [M+H]+ .

[0689] Step 2: Compound 69B (0.543 g, 4.56 mmol), 2,5-difluoro-4-iodopyridine (1.09 g, 4.56 mmol), and cesium carbonate (7.4 g, 22.8 mmol) were dissolved sequentially in DMF (20 mL), and the mixture was then heated to 110 °C and stirred overnight. After the reaction was complete, the mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 69C (0.11 g, 7.09%). LC-MS (ESI): m / z = 341.2 [M+H] + .

[0690] Step 3: Using compound 69C (0.11 g, 0.36 mmol) as the starting material, compound 69D (0.105 g, 95.5%) was synthesized according to the method described in Step 2 of Example 10. LC-MS (ESI): m / z = 342.2 [M+H] + .

[0691] Step 4: Using compound 69D (0.105 g, 0.3 mmol) as the starting material, compound 69E was synthesized according to the method described in step 3 of Example 10. No further purification was required; it was directly used in the next reaction. LC-MS (ESI): m / z = 328.2 [M+H] + .

[0692] Step 5: Using compound 69E (98 mg, 0.3 mmol) and compound 2J (0.088 g, 0.3 mmol) as starting materials, compound 69 (38 mg, 23%) was synthesized according to the method described in step 10 of Example 2. LC-MS (ESI): m / z = 510.2 [M+H] + .

[0693] 1 H NMR (400MHz, CDCl3) δ7.99-7.64(m,1H),7.64-7.60(m,1H),6.36(s,1H),5.25-5.15(m,1H),4.94-4.82(m,2H),4.75-4.61(m,1H),4.59-4. 48(m,2H),4.38-4.26(m,2H),4.20-4.07(m,1H),3.86-3.69(m,2H),3 .30-3.09(m,3H),2.85-2.71(m,2H),2.41-2.26(m,2H),2.15(s,3H).

[0694] Example 70:

[0695] Compound 70 (47 mg, 21.64%) was obtained from compound 28C (100 mg, 0.47 mmol) and compound 44G (147 mg, 0.56 mmol) according to step 6 of Example 1. LC-MS (ESI): m / z = 463.3 [M+H] + .

[0696] 1 H NMR(400MHz,DMSO-d6)δ8.10-8.05(m,1H),7.52-7.49(m,1H),6.98-6.94(m,1H),4.97-4.87(m,2H),4.74-4.65(m,2H),4.40-4.31(m,2H),4 .25(s,3H),3.98-3.87(m,2H),3.52-3.41(m,1H),3.19-3.07(m,1H), 2.93-2.84(m,2H),2.50(s,3H),2.32-2.13(m,4H),2.00-1.77(m,2H).

[0697] Example 71:

[0698] Compound 71 (40 mg, 16.44%) was obtained from 36F (150 mg, 0.47 mmol) and 28C (110 mg, 0.52 mmol) using the synthetic method described in step 12 of Example 4. LC-MS (ESI): m / z = 515.2 [M+H] + .

[0699] 1 H NMR (400MHz, CDCl3) δ7.75-7.74(d,1H),7.52(d,1H),7.08-7.05(m,1H),5.01-4.95(m,1H),4.83-4.81(d,4H),4.53-5. 51(t,2H),4.34(d,3H),4.02-3.99(m,2H),3.33-3.25(m,1H),3.10-2.99(m,2H),2.85-2.70(m,4H),2.55-2.54(d,3H).

[0700] Example 72:

[0701] Compound 72 (120 mg, 28%) was synthesized from compound 1C (195 mg, 0.910 mmol) and crude 34D (350 mg) using the method described in step four of Example 23. LC-MS (ESI): m / z = 478.2 [M+H] + .

[0702] 1 H NMR (400MHz, CDCl3) δ8.17-8.15(m,1H),8.10-8.08(m,1H),7.83-7.81(m,1H),6.00-5.98(m,1H),5.63-5.58(m,1H),5.39-5.20(m,2H),4.78 -4.76(m,4H),4.22-4.18(m,2H),3.96(s,3H),3.69-3.65(m,2H),3.28 -3.25(m,1H),2.83-2.78(m,2H),2.76-2.65(m,2H),2.57-2.47(m,5H).

[0703] Example 73:

[0704] Compound 73 (140 mg, 49%) was synthesized from compound 1C (123 mg, 0.573 mmol) and crude 35D (175 mg) using the method described in step four of Example 23. LC-MS (ESI): m / z = 496.3 [M+H] + .

[0705] 1 H NMR (400MHz, CDCl3) δ8.18-8.16(m,1H),8.10-8.08(m,1H),7.68-7.65(m,1H),5.64-5.79(m,1H),5.38-5.18(m,2H),4.79-4.76( m,4H),4.39-4.34(m,2H),3.96(s,3H),3.85(s,2H),3.30-3.25(m,1H),2.84-2.79(m,2H),2.75-2.64(m,2H),2.48-2.44(m,5H).

[0706] Biological testing

[0707] The DZ-01 of this invention is prepared according to the method described in Example 11 of Patent WO2018002760, and its structure is shown below:

[0708] The DZ-02 of this invention is prepared according to the method described in Example 42 of Patent WO2024088408, and its structure is shown below:

[0709] 1. Determination of the compound's PAM agonist activity against the M4 receptor

[0710] 1) Cell plating: M4-CHO cells were digested and collected, resuspended, counted, and then seeded into 384-well cell plates at a density of 1.2 × 10⁴ cells / 25 μL / well. The cell plates were then incubated at 37°C in a 5% CO₂ incubator for approximately 16-20 hours.

[0711] 2) Day 2: Prepare the Assay Buffer according to the FLIPR Calcium 6 Assay Kit instructions. Freeze-thaw 20×Component A to room temperature, dilute it with Assay Buffer to 1×loading buffer, and store at room temperature.

[0712] 3) Remove the culture medium from the cell plate, quickly add 40 μL of 1× loading buffer to each well, centrifuge, and then incubate the cell plate at 37°C in the dark for 120 min.

[0713] 4) Prepare working solutions for positive and test compounds, and prepare the Ach agonist compound (final concentration 3 nM). Mix the PAM compound and the Ach agonist solution at a 1:1 ratio, and transfer 20 μL / well to a 384-well compound source plate;

[0714] 5) Place the cell plate, compound source plate, and pipette tip into the corresponding positions on the FLIPR instrument. Use the FLIPR Tetra to add 10 μL of the diluted compound from step 4 into each well and collect data at wavelengths of 515 nm to 575 nm.

[0715] 6) Plot the signal value against the compound concentration, and use the nonlinear regression method in GraphPad Prism software to perform curve fitting and EC50 calculation.

[0716] The compounds of the present invention, such as those in the examples, have an EC50 of less than 500 nM against the M4 receptor. 50 EC values ​​of some preferred compounds 50 <300 nM, EC of some preferred compounds 50 <200 nM, EC of some preferred compounds 50 <100 nM, EC of some preferred compounds 50<50 nM. Experimental results for some specific compounds are shown in Table 1, where A represents EC. 50 <200nM; B indicates 200nM≤EC 50 <500nM, C represents 500nM≤EC 50 .

[0717] Table 1. Agonistaltic activity of compounds on M4 receptors

[0718] Conclusion: The compounds of this invention exhibit high agonistic activity against the M4 receptor.

[0719] 2. Pharmacokinetic assays in mice

[0720] 2.1 Experimental animals: Male C57 mice, 20-25g, were divided into intravenous and gavage groups.

[0721] 2.2 Experimental Design: On the day of the experiment, C57 mice were randomly divided into groups according to their body weight. One day before administration, mice were fasted but allowed free access to water for 12–14 hours. They were fed 4 hours after administration.

[0722] Table 2. Dosage Information Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Gavage administration solvent: 5% DMSO + 95% (0.5% MC);

[0723] Whole blood was collected at 0, 5, 15, 30 min, 1, 2, 4, and 7 h after oral administration, and brain tissue was collected at 5 min, 15 min, and 2 h. After centrifugation of the whole blood, plasma was separated. Brain tissue was rinsed with cold physiological saline to remove residual blood, dried, and homogenized. All samples were stored at -80℃ before quantitative analysis using LC-MS / MS.

[0724] Table 3. Pharmacokinetic parameters of the tested compounds in mice

[0725] Table 4. Pharmacokinetic parameters of the tested compounds in the mouse brain

[0726] Conclusion: The compounds of the present invention, such as the compounds in the examples, have favorable pharmacokinetic characteristics in mice.

[0727] 3. Rat pharmacokinetic test

[0728] 3.1 Experimental animals: Male SD rats, about 220g, 6-8 weeks old, were divided into intravenous and gavage groups.

[0729] 3.2 Experimental Design: On the day of the experiment, SD rats were randomly divided into groups according to their body weight. They were fasted for 12-14 hours before drug administration but allowed free access to water. They were fed 4 hours after drug administration.

[0730] Table 5. Dosage Information Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Gavage administration solvent: 5% DMSO + 95% (0.5% MC);

[0731] Whole blood was collected at 0, 5, 15, 30 min, 1, 2, 4, 6, 8, and 24 h after oral administration; brain tissue was collected at 5 min, 15 min, 2 h, and 24 h. After centrifugation of the whole blood, plasma was separated. Brain tissue was rinsed with cold physiological saline to remove residual blood, dried, and homogenized. All samples were stored at -80℃ before analysis, and quantitative analysis was performed using LC-MS / MS.

[0732] Table 6. Pharmacokinetic parameters of the tested compounds in rat plasma

[0733] Table 7. Pharmacokinetic parameters of the tested compounds in the rat brain

[0734] Conclusion: The compounds of the present invention, such as the compounds in the examples, have favorable pharmacokinetic characteristics in rats.

[0735] 4. Pharmacokinetics of Beagle Dogs

[0736] Experimental animals: Male beagle dogs, weighing approximately 8–11 kg, were divided into intravenous and gavage groups.

[0737] Experimental Methods: On the day of the experiment, beagles were randomly grouped according to body weight. They were fasted for 12–14 hours prior to administration but allowed free access to water. Food was given 4 hours after administration. Administration was performed according to Table 8.

[0738] Table 8. Dosage Information Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Gavage administration solvent: 5% DMSO + 95% (0.5% MC)

[0739] Blood samples (1 ml) were collected via jugular or limb veins before and after drug administration and placed in EDTAK2 centrifuge tubes. Plasma was collected by centrifugation at 5000 rpm and 4°C for 10 min. Blood collection time points for both the intravenous and gavage groups were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 h. All samples were stored at -80°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0740] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in dogs.

[0741] 5. Pharmacokinetics in monkeys

[0742] Experimental animals: male cynomolgus monkeys, 3-5 kg, 3-6 years old, divided into intravenous and gavage groups.

[0743] Experimental method: On the day of the experiment, monkeys were randomly divided into groups according to their body weight. They were fasted for 14-18 hours before administration but allowed free access to water. They were fed 4 hours after administration.

[0744] Table 9. Dosage Information Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Gavage administration solvent: 5% DMSO + 95% (0.5% MC)

[0745] Blood samples of 1.0 mL were collected from venous sites in the extremities before and after drug administration and placed in EDTAK2 centrifuge tubes. Plasma was collected by centrifugation at 5000 rpm and 4°C for 10 min. Blood collection time points for both the intravenous and gavage groups were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, and 24 h. All samples were stored at -80°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0746] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in monkeys.

[0747] 6. hERG potassium ion channel function test

[0748] Experimental platform: Electrophysiological manual patch-clamp system

[0749] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channels

[0750] Experimental Methods: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents at room temperature using whole-cell patch-clamp technique. Glass microelectrodes were fabricated from glass electrode blanks (BF150-86-10, Sutter) using a stretching device. The tip resistance after perfusion with electrode fluid was approximately 2-5 MΩ. The glass microelectrodes were inserted into the amplifier probe to connect to the patch-clamp amplifier. Clamp voltage and data recording were controlled and recorded using pClamp 10 software via computer, with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After obtaining whole-cell recordings, the cells were clamped at -80 mV to induce hERG potassium current (Ig). hERGThe step voltage was applied from -80 mV to +20 mV for 2 seconds, then repolarized to -50 mV for 1 second before returning to -80 mV. This voltage stimulation was applied every 10 seconds, and the drug administration process began after the hERG potassium current stabilized (at least 1 minute). Each test concentration of the compound was administered for at least 1 minute, and at least 2 cells (n≥2) were tested for each concentration.

[0751] Data processing: Data analysis and processing were performed using pClamp 10, GraphPad Prism 5, and Excel software. The inhibition degree of different compound concentrations on the hERG potassium current (the peak hERG tail current induced at -50mV) was calculated using the following formula: Inhibition% = [1 – (I / Io)] × 100%

[0752] Where Inhibition% represents the percentage of inhibition of hERG potassium current by the compound, and I and Io represent the amplitude of hERG potassium current before and after drug administration, respectively.

[0753] Compound IC 50 The following equation was used to fit and calculate the result using GraphPad Prism 5 software: Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0754] Where X is the Log value of the detected concentration of the test sample, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0755] Table 10. hERG inhibition of the tested compounds

[0756] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a weak inhibitory effect on hERG channels.

[0757] 7. Liver microsomal stability test

[0758] This experiment used liver microsomes from five genera—human, canine, rat, and mouse—as in vitro models to evaluate the metabolic stability of the test substance.

[0759] At 37°C, 1 μM of the test substance was co-incubated with microsomal protein and coenzyme NADPH. The reaction was terminated by adding ice-cold acetonitrile containing an internal standard after certain time intervals (5, 10, 20, 30, 60 min). The concentration of the test substance in the sample was detected by LC-MS / MS. T was calculated using the ln value of the drug residue in the incubation system and the incubation time. 1 / 2 Furthermore, the intrinsic clearance rate (CL) of liver microsomes was calculated. int(mic) and hepatic intrinsic clearance rate CLint(Liver) .

[0760] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good liver microsomal stability.

[0761] 8. CYP450 enzyme inhibition test

[0762] The aim of this study was to evaluate the effects of test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro assay system. Specific probe substrates for CYP450 isoenzymes were co-incubated with human liver microsomes and different concentrations of the test substances. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS) after sample processing, and the changes in CYP enzyme activity were measured. The IC50 values ​​were calculated. 50 The value is used to evaluate the inhibitory potential of the test substance against each CYP enzyme subtype.

[0763] Conclusion: The compounds of the present invention, such as the compounds in the examples, have weak inhibitory effects on CYP enzymes.

[0764] 9. Caco2 Permeability Test

[0765] The experiment used monolayers of Caco-2 cells, incubated in triple parallel in 96-well Transwell plates. A transport buffer solution (HBSS, 10 mM HEPES, pH 7.4±0.05) containing either the compound of the present invention (2 μM) or the control compounds digoxin (10 μM), naldolol (2 μM), and metoprolol (2 μM) was added to the dosing well on the apical or basal side. A transport buffer solution containing DMSO was added to the corresponding receiving well. After incubation at 37±1 °C for 2 hours, the cell plate was removed, and appropriate amounts of sample were transferred from both the apical and basal sides to new 96-well plates. Acetonitrile containing an internal standard was then added to precipitate the protein. The samples were analyzed using LC MS / MS to determine the concentrations of the compound of the present invention and the control compounds. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical to the basal side of the monolayer cells, and from the basal side to the apical side, thereby calculating the efflux rate. Leakage of fluorescein was used to evaluate the integrity of the monolayer cells after 2 hours of incubation.

[0766] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good permeability.

[0767] 10. Experiment on a mouse model of spontaneous activity induced by AMPH (amphetamine)

[0768] Male C57BL / 6J mice were weighed, randomly grouped, and numbered according to experimental requirements. Mice were removed from their cages and soothed for 3-5 minutes to allow them to become accustomed to the researchers' scent and temperature before being returned to their cages. This process was repeated for three consecutive days. On the day of activity recording, mice were moved to the behavioral room three hours in advance for acclimatization. The spontaneous activity test chamber was confirmed to be clean and odorless. Researchers set the appropriate parameters in the animal behavior analysis and recording software and recorded the mouse number, date, and other information. Before the experiment, mice were placed in the test chamber for 5 minutes to acclimatize. The mice to be tested were gently removed from their cages, given the test compound, and quickly placed in the central area of ​​the test chamber, with the chamber door immediately closed. The software was used to record the mice's movement within the test chamber. After 30 minutes, the mice were removed and injected intraperitoneally with 5 mpkJ. After AMPH, gently place the mouse into the central area of ​​the test chamber and immediately close the shielded chamber door; then record the mouse's movement trajectory over the next 90 minutes; after the test, remove the mouse from the test chamber and return it to its cage; during the experiment, remove the excrement left in the open field box by each mouse (clean the open field box by spraying 75% ethanol on paper towels and wiping it again with clean paper); repeat the above process until all mice have been tested; after the experiment, properly store the experimental apparatus and euthanize the mice. The results are shown in Figure 1.

[0769] Conclusion: In the mouse AMPH (amphetamine)-induced spontaneous activity model experiment, compound 6 was comparable to or better than DZ-01 at lower doses.

[0770] 11. Caffeine-induced hyperactivity model in rats

[0771] From Day 6 to Day 1, rats were removed from their cages and gently stroked for 3-5 minutes each day. This restraint method, simulating subcutaneous injection, allowed the animals to become familiar with the experimental procedure, environment, and the scent of the personnel. On Day 0, animals were weighed and grouped according to weight, and then placed in the behavioral testing room for acclimatization. From Day 1 to Day 3, before each test, the spontaneous activity testing chamber was confirmed to be clean and odorless. Researchers set the appropriate parameters in the animal behavior analysis and recording software, recording the rat's number, date, and other information. The rats to be tested were gently removed from their cages and quickly placed in the central area of ​​the testing chamber. The door of the shielded chamber was immediately closed, and any animals not yet in the testing room were removed. After the rats had acclimatized for at least 10-20 minutes, the animals in the drug-treated group were removed and administered the drug via gavage. The activity trajectory of the rats within the shielded chamber was recorded using the software. After recording the movement trajectory of each animal for 60 minutes, the rats were removed and subcutaneously injected with caffeine (5 ml / kg, 3 mg / ml) or saline (Vehicle group). They were then gently placed back into the central area of ​​the test chamber, and the door of the shielded chamber was immediately closed. The rats' movement trajectory was then recorded over the next 120 minutes. After the test, the rats were removed from the shielded chamber, returned to their cages, and the shielded chamber was cleaned.

[0772] Histograms were used to analyze the total activity distance over 120 minutes after modeling, and one-way ANOVA was used for significant difference analysis. *, P < 0.05, **, P < 0.01. The results are shown in Figure 2.

[0773] Conclusion: In the caffeine-induced hyperactivity model in rats, compound 6 was comparable to or better than DZ-01 at lower doses.

Claims

A compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt, in, Ring A is selected from: Ring B is selected from C. 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups, wherein the cycloalkyl groups or heterocyclic alkyl groups are optionally surrounded by 0-5 R groups. B replace; Ring C is selected from: R a1 R b R c R d Each element is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 alkyl; X1 is selected from -N-, -CR x1 -; R x1 Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups; X2 and X3 are each independently selected from -N-, -CH-, and -CR. C -; R1, R2, R3, and R4 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, =O, amino, nitro, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, -C(=O)NR A1 R A2 -C 1-6 Alkyl-C(=O)NR A1 R A2 -NR A1 R A2 -NR A1 C(=O)C 1-6 Alkyl, -NR A1 C(=O)OC 1-6 Alkyl, -NR A1 C(=O)NR A1 R A2 -S(=O)2-NR A1 R A2 -S(=O)2-C 1-6 Alkyl, -SF5, -SCF3, =CH2, =CF2, =CH-CH3, =C-(CH3)2, C 3-6 Cycloalkyl, -O-(CH2) r -C 3-6 cycloalkyl, -NR A1 -C 3-6 cycloalkyl, -NR A1 C(=O)-C 3-6 Cycloalkyl, -C(=O)NR A1 -C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -NR A1 C(=O)-(4-6 membered heterocyclic alkyl groups), C 6-8 Aryl, -NR A1 -(5-6-membered heteroaryl) or 5-6-membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace; R5 is selected from deuterium, halogen, hydroxyl, nitro, and C. 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, -C(=O)NR A1 R A2 -C 1-6 Alkyl-C(=O)NR A1 R A2 -NR A1 C(=O)C 1-6 Alkyl, -NR A1 C(=O)OC 1-6 Alkyl, -NR A1 C(=O)NR A1 R A2 -S(=O)2-NR A1 R A2 -S(=O)2-C 1-6 Alkyl, -SF5, -SCF3, =CH2, =CF2, =CH-CH3, =C-(CH3)2, -NR A1 -C 3-6 cycloalkyl, -NR A1 C(=O)-C 3-6 Cycloalkyl, -C(=O)NR A1 -C 3-6 cycloalkyl, -NR A1 C(=O)-(4-6 membered heterocyclic alkyl groups), C 6-8 Aryl, -NR A1 -(5-6-membered heteroaryl) or 5-6-membered heteroaryl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace; r can be independently selected from 0, 1, 2, 3, 4, or 5; R A1 R A2 Each element is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups; L1 is selected from -C(=O)-C 1-4 Alkyl, -C(=O)-O-, -C(=O)-S-, C 2-4 alkenyl, C 2-4 alkynyl group; L2 is selected from the bond; Each R B Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-8 aryl or 5-6 heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace; Each R C Each group is independently selected from deuterium, hydroxyl, cyano, halogen, amino, nitro, -SCF3, -SCH2CF3, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy groups, -O-(CH2) r -C 3-6 Cycloalkyl, -O-(CH2) r -(3-8 membered heterocyclic alkyl groups), -C(=O)-C 3-6 cycloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 quinary heteroaryl, 5-6 quinary heterocyclic 5-6 quinary heteroaryl, -NR A1 -(5-6 quinone heteroaryl groups), -NR A1 -C 1-6 Alkyl group, -CH=CR c1 R c2 -NR A1 -(CH2) r -C 3-6 Cycloalkyl, -O-(CH2) r -5-6-membered heteroaryl, wherein the alkenyl, alkynyl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further characterized by 1-5 R groups. a replace; Alternatively, two R atoms on the same atom B Two R atoms on the same atom C Two R atoms on adjacent atoms B Two R atoms on adjacent atoms C Together with the atoms attached to it, they form C 3-8 Carbon rings or 3-8 membered heterocycles, wherein the carbon rings or heterocycles may optionally be further divided into 1-5 R groups. a replace; R a Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, nitro, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, -C(=O)-C 1-6 Alkyl group, -NH-C(=O)-C 1-6 Alkyl group, -(CH2) r -S(=O)2-C 1-6 Alkyl, =CH2, =CHF, =CF2, =CH-CH3, =C-(CH3)2, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, -O-(CH2) r -C 3-6 Cycloalkyl, -SCF3, -NR A1 -C 1-6 Alkyl, C 6-10 aryl or 5-10 heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further selected from 1-5 groups selected from deuterium, halogen, cyano, amino, =O, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or deuterated C 1-6 The alkoxy group is replaced; R c1 R c2 Together with the connected carbon atoms, they form 4-6 membered carbon rings; n is selected from 1, 2, 3, 4 or 5. According to claim 1, the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt, wherein, R a1 R b R c R d Each is independently selected from hydrogen; X1 is selected from -N- and -CH-; R1, R2, R3, and R4 are each independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-8 aryl or 5-6 heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace; R5 is selected from deuterium, halogens, and C. 2-6 alkenyl, C 2-6 alkynyl, -NR A1 C(=O)-C 3-6 Cycloalkyl, -C(=O)NR A1 -C 3-6 cycloalkyl, -NR A1 C(=O)-(4-6 membered heterocyclic alkyl groups), C 6-8 Aryl, -NR A1 -(5-6-membered heteroaryl) or 5-6-membered heteroaryl, wherein the alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace; R A1 Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups. According to claim 1, the stereoisomer or pharmaceutically acceptable salt thereof, wherein, L1 is selected from -C(=O)-C 1-2 Alkyl, -C(=O)-O-, -C(=O)-S-; Ring B is selected from cyclopropyl, cyclobutyl, azirrobutyl, azirropentyl, and azirrohexyl, wherein the cyclopropyl, cyclobutyl, azirrobutyl, azirropentyl, and azirrohexyl groups are optionally surrounded by 1-3 R groups. B replace; Each R B Each element is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, wherein the alkyl or alkoxy group is optionally further surrounded by 1-3 R groups. a replace; Alternatively, two R atoms on the same atom B Two R atoms on adjacent atoms B Together with the atoms attached to it, they form C 3-6 Carbon rings or 4-6 membered heterocycles, wherein the carbon rings or heterocycles may optionally be further divided by 1-3 R groups. a replace. According to claim 1, the stereoisomer or pharmaceutically acceptable salt thereof, wherein, X2 and X3 are each independently selected from -N-, -CH-, and -CR. C -; Each R C Each element is independently selected from deuterium, halogens, -SCF3, -SCH2CF3, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy groups, -O-(CH2) r -C 3-6 Cycloalkyl, -O-(CH2) r -(3-6 membered heterocyclic alkyl groups), C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C 6-8 Aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclic 5-6 membered heteroaryl, 4-6 membered heterocyclic alkyl spiro-3-4 membered cycloalkyl, -NR A1 -(5-6 quinone heteroaryl groups), -NR A1 -C 1-6 Alkyl group, -CH=CR c1 R c2 -NR A1 -(CH2) r -C 3-6 Cycloalkyl, -O-(CH2) r -5-6-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further surrounded by 1-5 R groups. a replace; r can be independently selected from 0, 1, 2, or 3; Alternatively, two R atoms on the same atom C Two R atoms on adjacent atoms C Together with the atoms attached to it, they form C 3-6 Carbon rings or 4-6 membered heterocycles, wherein the carbon rings or heterocycles may optionally be further divided by 1-3 R groups. a replace; n is selected from 1, 2, or 3. According to claim 1, the stereoisomer or pharmaceutically acceptable salt thereof, wherein, Ring A is selected from one of the following structures: B rings are selected from 1-3 R rings. B The following groups are substituted: in, The terminal is connected to L1; C rings are selected from 1-3 R rings. C The following groups are substituted: According to claim 1, the stereoisomer or pharmaceutically acceptable salt thereof, wherein, L1 is selected from -C(=O)-CH2-; Ring B is selected from the following groups: The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt, is selected from one of the structures in Table A. A pharmaceutical composition or pharmaceutical preparation comprising the compound of any one of claims 1-7, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical composition or pharmaceutical preparation according to claim 8 comprises 1-1500 mg of the compound or its stereoisomer or pharmaceutically acceptable salt of any one of claims 1-7 and a carrier and / or excipient. The use of the compound of any one of claims 1-7, its stereoisomer or pharmaceutically acceptable salt, or the composition of claims 8-9 in the preparation of a medicament for treating / preventing CHRM4-mediated diseases. The use as described in claim 10, wherein the CHRM4-mediated diseases are selected from Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorders, cognitive impairment, Parkinson's disease, Parkinson's disease-levodopa-induced dyskinesia, Huntington's disease, dyskinesia, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma, trisomy 21, cerebral amyloid angiopathy, dementia, Dutch amyloid hemorrhage, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes, autism, and atherosclerosis; preferably Alzheimer's disease, schizophrenia, pain, addiction, and sleep disorders. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound or its stereoisomers, or a pharmaceutically acceptable salt, according to any one of claims 1-7, preferably 1-1500 mg, wherein the disease is selected from Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorders, cognitive impairment, Parkinson's disease, Parkinson's disease-levodopa-induced dyskinesia, Huntington's disease, dyskinesia, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma, trisomy 21, cerebral amyloid angiopathy, dementia, Dutch amyloid hemorrhage, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes, autism, and atherosclerosis; preferably Alzheimer's disease, schizophrenia, pain, addiction, and sleep disorders.

Images