Diaryl ether derivative as well as preparation method and application thereof

Abstract

The invention discloses a diaryl ether derivative as well as a preparation method and application thereof. The invention provides a compound shown in a general formula (I), and a stereoisomer or pharmaceutically acceptable salt thereof. The compound provided by the invention has better selectivity to the kappa opioid receptor, has more excellent pharmacodynamic and / or pharmacokinetic properties, is good in safety, and can be used for treating and / or preventing diseases related to the kappa opioid receptor.

Description

Technical Field

[0001] This application relates to, but is not limited to, the field of pharmaceutical technology, specifically to a diaryl ether derivative, its preparation method, and its application. Background Technology

[0002] Opioid receptors belong to the G protein-coupled receptor superfamily and are generally classified into four subtypes: μ-opioid receptors (MOR), delta-opioid receptors (DOR), κ-opioid receptors (KOR), and pain-sensitive peptide / orphanone FQ (N / OFQ) receptors. Opioid receptors exhibit high sequence homology; however, their pharmacological and physiological effects differ significantly when activated by selective endogenous and exogenous ligands (Fredriksson, R. et al., Mol. Pharmacol. 2003, 63, 1256-1272; Waldhoer, M. et al., Annu. Rev. Biochem. 2004, 73, 953-990.). KOR is a type of G protein-coupled receptor. αi / o Coupled receptors are primarily activated by endogenous dynorphin-opioid peptides (Chavkin, C. et al., Science 1982, 215, 413-415; Bruchas, MR et al., Brain Res. 2010, 1314, 44-55.). KOR is distributed throughout the spinal cord, brainstem, and human brain (Simonin, F. et al., Proc. Natl. Acad. Sci. USA 1995, 92, 7006-7010.). In the brain, it is mainly expressed in the anterior cingulate cortex, amygdala, insula, putamen, neocortex, caudate nucleus, thalamus, globus pallidus, pons, substantia nigra, and hippocampus (Pfeiffer, A. et al., Brain Res. 1982, 248, 87-96.; Delay-Goyet, P. et al., Brain Res. 1987, 414, 8-14.). Extensive evidence from preclinical and clinical studies suggests that KOR is associated with a variety of neuropsychiatric and neurological disorders, such as depression, epilepsy, Alzheimer's disease, substance and alcohol abuse, and schizophrenia (Carlezon, W.A. et al., J. Pharmacol. Exp. Ther. 2005, 316, 440-447.; Ranganathan, M. et al., Biol. Psychiatry 2012, 72, 871-879.; Van't Veer, A. et al., Psychopharmacology 2013, 229, 435-452.).

[0003] Activation of κ opioid receptors (KOR) leads to aversion to stress and is involved in key neural circuits that regulate many neurobehavioral disorders (Margolis EB et al, J Neurosci. 2003, 23, 9981-9986.). Preclinical studies have shown that blocking or knocking out KOR can significantly reduce aversion responses to stress (McLaughlin JP et al, J Neurosci. 2003, 23, 5674-5683.), drug withdrawal (Walker BM et al, Addict Biol. 2011, 16, 116-119.), and pain (Navratilova E. et al, Pain. 2019, 160, 824-832.), and has demonstrated antidepressant effects in preclinical models (Wells AM et al, J Neurosci Off J Soc Neurosci. 2017, 37, 7656-7668.), suggesting that selective KOR antagonists hold promise for development into clinically effective therapeutic agents. While no KOR antagonists have yet been approved for clinical use, some related drugs have entered clinical trials.

[0004] Early KOR antagonists included Nor-BNI, GNTI, and JDTic. JDTic entered clinical trials for cocaine abuse treatment, but was discontinued due to its potential to cause tachycardia. Furthermore, monotherapy with Nor-BNI, GNTI, or JDTic could continuously block KOR for up to 3 weeks, with delayed central onset and poor drug-like properties (Bruchas MR et al, J Biol Chem. 2007, 282, 29803-29811.; Carroll FI et al, J Med Chem. 2013, 56, 2178-2195.). Therefore, medicinal chemists focused on developing short-acting KOR antagonists with improved pharmacokinetics for the treatment of depression, anxiety, and addictive disorders. The most representative ones are PF-04455242 (Verhoest PR et al, J Med Chem. 2011, 54, 5868-5877), BTRX-335140 (Guerrero M. et al, J Med Chem. 2019, 62, 1761-1780; WO2018170492A1) and Aticaprant (WO2009094260A1), among which BTRX-335140 and Aticaprant are currently undergoing phase III clinical trials. PCT applications WO2018053222A1, WO2015109080A1, WO2018096510A1, WO2020092996A1, WO2011090473A1, WO2013086496A2, WO2013040321A1, WO2016086149A1, and WO2019183556A1, among others, have disclosed numerous small molecule compounds as short-acting KOR antagonists for the treatment of depression, anxiety, and addictive disorders. Therefore, developing novel, clinically effective KOR antagonists is of great significance. Summary of the Invention

[0005] This invention provides a novel diaryl ether derivative with κ opioid receptor antagonistic activity, which can be used to treat and / or prevent diseases related to κ opioid receptors.

[0006] To address this, the present invention adopts the following technical solution:

[0007] In one aspect, the present invention provides a compound having the general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof;

[0008]

[0009] in,

[0010] R 1 Selected from H, C1-6 Alkyl, C 3-8 Cycloalkyl, 4-7 membered heterocycloalkyl, -C 1-3 Alkylene-C 3-8 cycloalkyl and -C 1-3 alkylene-4-7-membered heterocyclic alkyl, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-7 membered heterocycloalkyl, -C 1-3 Alkylene-C 3-8 cycloalkyl and -C 1-3 Each of the alkylene-4-7-membered heterocyclic alkyl groups is independently and optionally surrounded by one or more R a Substitution, the 4-7 membered heterocyclic alkyl and -C 1-3 Each alkylene-4-7-membered heterocyclic alkyl group independently contains one to two heteroatoms selected from N, O, and S;

[0011] R 2 Each is independently selected from H, halogen, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-3 alkyl), -N(C) 1-3 Alkyl)2, C 3-8 Cycloalkyl, 4-7 membered heterocycloalkyl, -C 1-3 Alkylene-C 3-8 cycloalkyl and -C 1-3 alkylene-4-7-membered heterocyclic alkyl; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-7 membered heterocycloalkyl, -C 1-3 Alkylene-C 3-8 cycloalkyl and -C 1-3 Each of the alkylene-4-7-membered heterocyclic alkyl groups is independently and optionally surrounded by one or more R b Substitution; the 4-7 membered heterocyclic alkyl group and -C 1-3 Each alkylene-4-7-membered heterocyclic alkyl group independently contains one to two heteroatoms selected from N, O, and S;

[0012] R 3 Each is independently selected from H, halogen, -OH, C 1-3 Alkyl, C 1-3 Alkyl groups and oxo groups (C=O);

[0013] R 4 Each is independently selected from H, halogen, -OH, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups;

[0014] R 5 Each is independently selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups;

[0015] m is 0, 1, or 2;

[0016] n is 0, 1, or 2;

[0017] p is 1, 2, or 3;

[0018] q can be 0, 1, 2, or 3;

[0019] r can be 0, 1, 2, or 3;

[0020] X is selected from CR 6 R 7 and O;

[0021] Y 1 Y 2 Y 3 and Y 4 Each is independently selected from CH and N; and Y is specified. 1 Y 2 Y 3 and Y 4 Only two values ​​can be N simultaneously;

[0022] R 6 and R 7 Each is independently selected from H, halogen, -OH, C 1-3 Alkyl and C 1-3 Alkoxy;

[0023] R a and R b Each is independently selected from halogens, -OH, -NH2, and -NH(C). 1-3 alkyl), -N(C) 1-3 Alkyl)2 and C 1-3 alkyl;

[0024] The configuration of the carbon atom at position * is R configuration, S configuration, or a mixture of R and S configurations.

[0025] In some embodiments of the present invention, the C 1-6 The alkyl group is independently selected from methyl, ethyl, n-propyl or isopropyl, preferably methyl and ethyl.

[0026] In some embodiments of the present invention, the C 1-3 The alkylene group is independently selected from methylene, ethylene, n-propylene, or isopropylene, preferably methylene.

[0027] In some embodiments of the present invention, the C 1-3 The alkyl group is independently selected from methyl, ethyl, n-propyl or isopropyl, preferably methyl and ethyl.

[0028] In some embodiments of the present invention, the C 1-3 The alkoxy group is independently selected from methoxy, ethoxy, n-propoxy, or isopropoxy, preferably from methoxy and ethoxy.

[0029] In some embodiments of the present invention, the C 1-6 The alkyl halogroup is independently selected from C14 substituted with one or more halogens. 1-6 Alkyl groups, preferably C substituted with one or more halogens. 1-3 Alkyl groups, such as -CH2F, -CH2Cl, -CHF2, -CHCl2, -CCl3, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 or -CF2CF3.

[0030] In some embodiments of the present invention, the C 1-6 The alkoxy group is independently selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy, preferably methoxy.

[0031] In some embodiments of the present invention, the C 1-6 The haloalkoxy group is independently selected from C atoms substituted with one or more halogens. 1-6 Alkoxy groups, preferably C groups substituted with one or more halogens. 1-3 Alkyl groups, such as -OCH2F, -OCH2Cl, -OCHF2, -OCHCl2, -OCCl3, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3 or -OCF2CF3.

[0032] In some embodiments of the invention, the halogen is independently selected from fluorine, chlorine, bromine or iodine.

[0033] In some embodiments of the present invention, the C 3-8 Cycloalkyl groups can be C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0034] In some embodiments of the present invention, the -C 1-3 Alkylene-C 3-8 Cycloalkyl groups can be -CH2-C 3-6 cycloalkyl, for example

[0035] In some embodiments of the present invention, the 4-7 membered heterocyclic alkyl group may be a 4-6 membered heterocyclic alkyl group, such as oxocyclic butyl or tetrahydropyranyl.

[0036] In some embodiments of the present invention, the heteroatom of the 4-7 member heterocyclic group is selected from N or O, preferably O, and the number of heteroatoms is 1 or 2.

[0037] In some embodiments of the present invention, the -C 1-3 Alkylene-4-7-membered heterocyclic alkyl groups can be -CH2-4-6-membered heterocyclic alkyl groups, for example...

[0038] In some embodiments of the present invention, the above-mentioned R 1 Selected from H, C 1-3 Alkyl, -C 1-3 Alkylene-C 3-6 cycloalkyl and -C 1-3 alkylene-4-6-membered heterocyclic alkyl, wherein the C 1-3 Alkyl, -C 1-3 Alkylene-C 3-6 cycloalkyl and -C 1-3 Each alkylene-4-6-membered heterocyclic alkyl group is independently and optionally surrounded by one or more R a Instead, the -C 1-3 Alkylene-4-6-membered heterocyclic alkyl groups independently contain one to two heteroatoms selected from N, O, and S;

[0039] Preferably, R 1 Selected from H, C 1-3 Alkyl, -CH2-C 3-6 Cycloalkyl and -CH2-4-6-membered heterocycloalkyl, wherein the C 1-3 Alkyl groups are formed by one or more R groups a The -CH2-4-6-membered heterocyclic alkyl group independently comprises one to two heteroatoms selected from N, O and S.

[0040] In some embodiments of the present invention, the above-mentioned R 1 Selected from H, C 1-3 Alkyl, C 3-6 cycloalkyl, -C 1-3 Alkylene-C 3-6 cycloalkyl and -C 1-3 alkylene-4-6-membered heterocyclic alkyl, wherein -C 1-3 Alkylene-4-6-membered heterocyclic alkyl groups independently contain one to two heteroatoms selected from N, O, and S;

[0041] In some embodiments of the present invention, the above-mentioned R 1 Selected from H, methyl, ethyl, n-propyl, isopropyl, Preferably, R 1 Selected from H, methyl, and ethyl.

[0042] In some embodiments of the present invention, the above-mentioned R 1 Selected from H, methyl, ethyl, n-propyl, isopropyl,

[0043] Preferably, R 1 Selected from ethyl and isopropyl.

[0044] In some embodiments of the present invention, the above-mentioned R 2 Each is independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocyclic alkyl; wherein the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocyclic alkyl groups are each independently and optionally influenced by one or more R groups. b Substitution; the 4-6 membered heterocyclic alkyl group independently comprises 1 to 2 heteroatoms selected from N, O and S.

[0045] In some embodiments of the present invention, the above-mentioned R 2 Each is independently selected from H, halogen, C 1-3 Alkyl and C 1-3 Alkoxy; wherein the C 1-3 Alkyl and C 1-3 Each alkoxy group is independently and optionally influenced by one or more R groups. b replace;

[0046] Better, R 2 Each is independently selected from H, halogens, and C. 1-3 Alkyl; wherein the C 1-3 Alkyl groups are optionally surrounded by one or more R b replace.

[0047] In some embodiments of the present invention, the above-mentioned R 2 Each is independently selected from H, fluorine, chlorine, bromine, methyl, ethyl and Preferably, the above-mentioned R 2 Each is independently selected from H and methyl.

[0048] In some embodiments of the present invention, the above-mentioned R 3 Each is independently selected from H, halogens, and C. 1-3 alkyl.

[0049] In some embodiments of the present invention, the above-mentioned R 3 Each is independently selected from H and halogens, such as H and fluorine.

[0050] In some embodiments of the present invention, the above-mentioned R 3 Each is independently represented by H.

[0051] In some embodiments of the present invention, the above-mentioned R 4 Each is independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkyl groups.

[0052] In some embodiments of the present invention, the above-mentioned R 4 Each is independently selected from H and halogens, such as H and fluorine.

[0053] In some embodiments of the present invention, the above-mentioned R 5 Each is independently selected from H, halogens, and C. 1-3 Alkyl group, preferably H.

[0054] In some embodiments of the present invention, X may be CR. 6 R 7 For example, CH2.

[0055] In some embodiments of the present invention, X may be 0.

[0056] In some embodiments of the present invention, m is 0; in other embodiments of the present invention, m is 1; and in still other embodiments of the present invention, m is 2.

[0057] In some embodiments of the present invention, n is 0; in other embodiments of the present invention, n is 1; and in still other embodiments of the present invention, n is 2.

[0058] In some embodiments of the present invention, n is 0 or 1.

[0059] In some embodiments of the present invention, p is 1; in other embodiments of the present invention, p is 2; and in still other embodiments of the present invention, p is 3.

[0060] In some embodiments of the present invention, p is selected from 1 and 2.

[0061] In some embodiments of the present invention, q is 0; in other embodiments of the present invention, q is 1; in other embodiments of the present invention, q is 2; and in other embodiments of the present invention, q is 3.

[0062] In some embodiments of the present invention, q is selected from 0, 1 and 2, preferably 0 or 1.

[0063] In some embodiments of the present invention, r is 0 or 1, preferably 0.

[0064] In some embodiments of the present invention, the above-mentioned R 6 and R 7 Each is independently H; in other embodiments of the invention, the above-mentioned R 6 and R 7 Each is an independent halogen; the above R 6 and R 7 Each independently is C 1-3 alkyl.

[0065] In some embodiments of the present invention, the above-mentioned R 6 and R 7 Each is independently selected from H, fluorine, chlorine, bromine, iodine, and methyl; preferably, R 6 and R 7 Each is independently selected from H and fluorine.

[0066] In some embodiments of the present invention, the above-mentioned R 6 and R 7 Each is independently selected from H, halogens, and C. 1-3 Alkyl group, preferably H.

[0067] In some embodiments of the present invention, the above-mentioned Y 1 Y 2 Y 3 and Y 4 Each variable is independently represented by CH, and other variables are as defined in this invention.

[0068] In some embodiments of the present invention, the above-mentioned Y 1 Y 2 Y 3 and Y 4 Three of them are randomly selected as CH, and the other is N. Other variables are as defined in this invention.

[0069] In some embodiments of the present invention, the above-mentioned Y 1 Y 2 Y 3 Each is independently represented by CH and Y. 4 Let N be the variable, and other variables be as defined in this invention.

[0070] In some embodiments of the present invention, the above-mentioned Y 1 Y 2 Y 3 and Y 4Two of them are randomly selected as CH, and the other two are N. Other variables are as defined in this invention.

[0071] In some embodiments of the present invention, the above-mentioned Y 2 and Y 3 Each is independently represented by CH and Y. 1 and Y 4 Each variable is independently represented by N, and other variables are as defined in this invention.

[0072] In some embodiments of the present invention, the above-mentioned Y 3 and Y 4 Each is independently represented by CH and Y. 1 and Y 2 Each variable is independently represented by N, and other variables are as defined in this invention.

[0073] In some embodiments of the present invention, structural units Selected from Preferably, structural unit for

[0074] In some embodiments of the present invention, structural units Selected from Preferably, structural unit Selected from

[0075] In some embodiments of the present invention, structural units Selected from

[0076] Preferably, structural unit Selected from More preferably, structural unit Selected from

[0077] In some embodiments of the present invention, structural units for Preferred For example

[0078] In some embodiments of the present invention, the above-mentioned R a and R b Each is independently selected from halogens, -OH, and C. 1-3 alkyl.

[0079] In some embodiments of the present invention, the above-mentioned Ra and R b Each is independently selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, and isopropyl; preferably, R a and R b Each is independently selected from fluorine and methyl.

[0080] In some embodiments of the present invention, the carbon atom at the * position has an R configuration. In other embodiments of the present invention, the carbon atom at the * position has an S configuration.

[0081] In some embodiments of the present invention, the present invention provides compounds represented by the above general formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, wherein the compounds represented by formula (I) have the structural features of formula (II):

[0082]

[0083] Among them, R 1 R 2 R 3 R 4 R 5 m, n, p, q, r, X, Y 1 Y 2 Y 3 and Y 4 As defined above.

[0084] In some embodiments of the present invention, the present invention provides compounds represented by the above general formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein the compounds represented by formula (I) have the structural features of formula (III-1):

[0085]

[0086] Among them, R 1 R 2 R 3 R 4 , m, n, * and q are as defined above.

[0087] In some embodiments of the present invention, the present invention provides compounds represented by the above general formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compounds represented by formula (I) have the structural features of formula (III-2):

[0088]

[0089] Where R 1 Selected from H, C 1-3 Alkyl, -C 1-3 Alkylene-C 3-6 cycloalkyl and -C 1-3alkylene-4-6-membered heterocyclic alkyl, wherein the C1-3 alkyl group, -C 1-3 Alkylene-C 3-6 cycloalkyl and -C 1-3 Each alkylene-4-6-membered heterocyclic alkyl group is independently and optionally surrounded by one or more R a Instead, the -C 1-3 The alkylene-4-6-membered heterocyclic alkyl group independently comprises one to two heteroatoms selected from N, O, and S; preferably, R 1 Selected from H, methyl, ethyl, n-propyl, isopropyl, More preferably, R 1 Selected from H, methyl, and ethyl;

[0090] R 2 Each is independently selected from H, halogens, and C. 1-3 Alkyl; wherein the C 1-3 Alkyl groups are optionally surrounded by one or more R b Replacement; preferably, R 2 Each is independently selected from H, fluorine, chlorine, bromine, methyl, ethyl and More preferably, the above-mentioned R 2 Each is independently selected from H and methyl;

[0091] R 3 Selected from H;

[0092] R 4 Selected from H and halogens; preferably, R 4 Selected from H and fluorine;

[0093] m is 0, 1, or 2;

[0094] n is 0;

[0095] q is 0 or 1;

[0096] R a and R b Each is independently selected from fluorine, chlorine, bromine, and iodine; preferably, R a and R b Each is independently selected from fluorine.

[0097] In some embodiments of the present invention, the present invention provides compounds represented by the above general formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compounds represented by formula (I) have the structural features of formula (III-2):

[0098]

[0099] Where R 1 Selected from H, C 1-3 Alkyl, C 3-6cycloalkyl, -C 1-3 Alkylene-C 3-6 cycloalkyl and -C 1-3 alkylene-4-6-membered heterocyclic alkyl, wherein -C 1-3 Alkylene-4-6-membered heterocyclic alkyl groups independently contain one to two heteroatoms selected from N, O, and S;

[0100] R 2 Each is independently selected from H, halogens, and C. 1-3 Alkyl; wherein the C 1-3 Alkyl groups are optionally surrounded by one or more R b replace;

[0101] R 3 Selected from H;

[0102] R 4 Selected from H and halogens;

[0103] m is 0, 1, or 2;

[0104] n is 0;

[0105] q is 0 or 1;

[0106] R a and R b Each is independently selected from fluorine, chlorine, bromine, and iodine.

[0107] In some embodiments of the present invention, the present invention provides compounds represented by the above general formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compounds represented by formula (I) have the structural features of formula (IV-1):

[0108]

[0109] Among them, R 1 Selected from H, C 1-3 Alkyl, -CH2-C 3-6 Cycloalkyl and -CH2-4-6-membered heterocycloalkyl, wherein the C 1-3 Alkyl groups are formed by one or more R groups a The -CH2-4-6-membered heterocyclic alkyl group independently comprises one to two heteroatoms selected from N, O, and S;

[0110] R 2 Each is independently selected from H, halogens, and C. 1-3 Alkyl; wherein the C 1-3 Alkyl groups are optionally surrounded by one or more R b replace;

[0111] m is 0, 1, or 2;

[0112] p is 1 or 2;

[0113] q is 0 or 1;

[0114] R 4 Selected from H and halogens;

[0115] R a and R b Each is independently selected from fluorine, chlorine, bromine, and iodine;

[0116] Y 1 Y 2 Y 3 and Y 4 Each is independently selected from CH and N; and Y is specified. 1 Y 2 Y 3 and Y 4 Only two values ​​can be N simultaneously;

[0117] The configuration of the carbon atom at position * is R configuration, S configuration, or a mixture of R and S configurations.

[0118] In some embodiments of the present invention, the present invention provides compounds represented by the above general formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein the compounds represented by formula (I) have the structural features of formula (IV-2):

[0119]

[0120] Among them, structural units Selected from Preferably, structural unit Selected from

[0121] p is 1 or 2;

[0122] q is 0 or 1;

[0123] R 4 Selected from H and halogens;

[0124] Y 1 Y 2 Y 3 and Y 4 Each is independently selected from CH and N; and Y is specified. 1 Y 2 Y 3 and Y 4 Only two values ​​can be N simultaneously.

[0125] In some embodiments of the present invention, the present invention provides compounds represented by the above general formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein the compounds represented by formula (I) have the structural features of formula (V):

[0126]

[0127] Among them, R 1 Selected from H, C 1-3 Alkyl and -CH2-C 3-6 cycloalkyl;

[0128] R 2 Selected from H, methyl and trifluoromethyl; m is selected from 0, 1 and 2.

[0129] In some embodiments of the present invention, the present invention provides a compound having the general formula (I) as any of the following compounds:

[0130]

[0131] In some embodiments of the present invention, the present invention provides a compound having the general formula (I) as any of the following compounds:

[0132]

[0133]

[0134] In another aspect, the present invention also provides a method for preparing a compound represented by general formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the method for preparing the compound represented by general formula (I) comprises the following steps:

[0135] Compound (IA) and compound (IB) undergo a reductive amination reaction in an acidic system in the presence of borohydrides (such as sodium borohydride, sodium cyanoborohydride, sodium borohydride acetate, etc.) to obtain compound (I).

[0136]

[0137] In the above preparation methods, the groups in formulas (IA), (IB) and (I) are defined as above.

[0138] In another aspect, the present invention also provides a pharmaceutical composition comprising a compound of formula (I) of the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient. In a specific embodiment, the compound of formula (I) of the present invention is provided in the pharmaceutical composition in an effective amount. In a specific embodiment, the compound of formula (I) of the present invention is provided in a therapeutically effective amount. In a specific embodiment, the compound of formula (I) of the present invention is provided in a preventatively effective amount.

[0139] In another aspect, the present invention also provides the use of a compound of general formula (I) of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention in the preparation of a κ opioid receptor inhibitor or a medicament for the prevention and / or treatment of diseases related to κ opioid receptors.

[0140] In some embodiments of the present invention, the diseases associated with the κ opioid receptor are selected from depression, anxiety disorders, addictive disorders, epilepsy, schizophrenia, cognitive impairment, Alzheimer's disease, and pain.

[0141] In another aspect, the present invention also provides a compound represented by general formula (I) of the present invention, its stereoisomers or pharmaceutically acceptable salts thereof, or the use of the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention and / or treatment of diseases;

[0142] The diseases mentioned are selected from depression, anxiety, addictive disorders, epilepsy, schizophrenia, cognitive impairment, Alzheimer's disease, and pain.

[0143] The terms used to describe this invention in the specification and claims are defined as follows. If the meaning of a particular term defined in this application differs from the meaning commonly understood by those skilled in the art, the meaning defined in this application shall prevail; if not defined in this application, it shall have the meaning commonly understood by those skilled in the art. In this application, compound names correspond to their structural formulas. When a compound name and structural formula differ, the structural formula shall prevail, or the name shall be deduced based on the specific circumstances of the invention and the knowledge of those skilled in the art.

[0144] In this paper, the numerical ranges defined in the substituents, such as 1-3, 1-6, 3-6, 3-8, 4-6, 4-7, etc., indicate the integers within that range. For example, 1 to 3 means 1, 2, or 3; 1-6 means 1, 2, 3, 4, 5, or 6; and 3-6 means 3, 4, 5, or 6.

[0145] "Halogen" refers to fluorine, chlorine, bromine, or iodine atoms.

[0146] "Alkyl" refers to a straight-chain or branched monovalent saturated hydrocarbon group.

[0147] “C1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. 1-3 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, 3-pentyl, pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl, and n-hexyl. The alkyl group in this application is preferably C10. 1-3 alkyl.

[0148] “C 1-6 "Alkoxy" refers to the group -OR, where R is C 1-6 Alkyl group. In some embodiments, C 1-3 Alkoxy groups are particularly preferred. Specific alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, and 1,2-dimethylbutoxy.

[0149] “C 1-6 "Halogenated alkyl" refers to the above "C 1-6 "alkyl" refers to an alkyl group that is substituted with one or more halogen groups. "C" 1-3 "Halogenated alkyl" refers to the above "C 1-3 An alkyl group is a substituent of one or more halogen groups. In a haloalkyl group, some or all hydrogen atoms may be substituted with halogens. Exemplary haloalkyl groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CH F CH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, etc.

[0150] “C 1-6 "Haloalkoxy" refers to the above "C" 1-6 "Alkoxy" is substituted by one or more halogen groups. "C" 1-3 "Haloalkoxy" refers to the above "C" 1-3 The alkyl group is substituted with one or more halogen groups. In the alkyl halogroup, some or all hydrogen atoms may be substituted with halogens. Exemplary alkyl halogroups include, but are not limited to: -OCF3, -OCH2F, -OCHF2, -OCH F CH2F, -OCH2CHF2, -OCF2CF3, -OCCl3, -OCH2Cl, -OCHCl2, etc.

[0151] “C 3-8"Cycloalkyl" refers to a saturated cyclic hydrocarbon group having 3 to 8 ring carbon atoms, including monocyclic and bicyclic groups, wherein bicyclic groups include spirocyclic, fused, and bridged rings. In some embodiments, "C 3-6 "Cycloalkyl" is preferred, and it is a saturated cyclic hydrocarbon group having 3 to 6 ring carbon atoms. An exemplary C 3-8 Cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0152] "4-7 membered heterocyclic alkyl" refers to a saturated cyclic group consisting of 4 to 7 ring atoms, where 1, 2, or 3 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. The 4-7 membered heterocyclic alkyl is a monocyclic system. In some embodiments, 4-6 membered heterocyclic alkyl is preferred. Examples of 4-7 membered heterocyclic alkyl groups include, but are not limited to, azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyryl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxane, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl, homopiperidinyl, or dioxaneheptyl, etc.

[0153] “C 1-3 "Alkylene" refers to a saturated, straight-chain or branched divalent hydrocarbon group having 1-3 carbon atoms, and can be substituted or unsubstituted. "C" 1-3 "alkylene" includes, but is not limited to, methylene, ethylene, or propylene.

[0154] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0155] "Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of the compounds of the present invention as defined above, and the salt possesses the desired pharmacological activity. Such salts include acid addition salts that form with inorganic or organic acids. Pharmaceutically acceptable salts also include base addition salts, which can be formed in the presence of acidic protons capable of reacting with inorganic or organic bases.

[0156] The term "optional" means that an event or condition described subsequently may occur but is not required, and the description includes both the possibility that said event or condition occurs and the possibility that said event or condition does not occur. For example, the term "optionally substituted by one or more substituents" means that it may or may not be substituted. When substituted, it means that any one or more hydrogen atoms on a particular atom are substituted by a substituent.

[0157] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by 1-2 Rs, the group can optionally be substituted by up to two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0158] The term "therapeutic effective dose" refers to the amount given to a patient that is sufficient to effectively treat the disease. Therapeutic effective doses will vary depending on the type of compound, the type of disease, the severity of the disease, the patient's age, etc., but may be adjusted as appropriate by those skilled in the art.

[0159] The term "pharmaceutical excipients" refers to all substances contained in pharmaceutical preparations other than the active pharmaceutical ingredient, and are generally divided into two main categories: excipients and additives. For details, please refer to the *Pharmacopoeia of the People's Republic of China (2020 Edition)* and *Handbook of Pharmaceutical Excipients* (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0160] The term "treatment" refers to eliminating the cause of an illness or relieving symptoms.

[0161] The term "prevention" refers to reducing the risk of developing a disease.

[0162] The term "patient" refers to any animal, typically a mammal such as a human, that requires treatment or prevention of disease. Mammals include, but are not limited to: cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans.

[0163] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0164] The positive effects of this invention are that the compounds of this invention have better selectivity for κ opioid receptors, better pharmacodynamic and / or pharmacokinetic properties, good safety, and can be used to treat and / or prevent diseases related to κ opioid receptors. Attached Figure Description

[0165] Figure 1 The graph shows the antidepressant effect of compound 5 in a mouse forced swimming test model.

[0166] Figure 2 This is a dose-response diagram of the antidepressant effect of compound 5 in a mouse forced swimming test model. Detailed Implementation

[0167] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0168] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). 1 HNMR data were collected and recorded at 600 MHz using a Bruker Avance Neo 600 MHz liquid superconducting NMR spectrometer. DMSO-d6 was used as the solvent, and TMS (δ=0) was used as the internal standard to report chemical shift δ values ​​(ppm).

[0169] LC-MS was performed using Waters acquity UPLC h-class and ACQUITY QDa MS.

[0170] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods. This application uses the following abbreviations: TLC: Thin-layer chromatography; 1 1H NMR: Proton nuclear magnetic resonance spectroscopy; LC-MS: Liquid chromatography-mass spectrometry; DMSO-d6: Deuterated dimethyl sulfoxide; DMSO: Dimethyl sulfoxide; Wt: Mass fraction. Compounds were named according to conventional nomenclature rules in the art, and commercially available reagents were named according to the supplier's catalog.

[0171] Preparation of intermediate 1:

[0172]

[0173] Step 1: 4-Hydroxybenzaldehyde (5.00 g, 40.97 mmol), 3,4-difluorobenzonitrile (5.70 g, 40.97 mmol), and potassium carbonate (11.4 g, 81.94 mmol) were placed in a single-necked flask and dissolved in dimethylacetamide (20 mL). The mixture was heated to 100 °C and stirred for 2 hours. TLC analysis showed that the reactants had essentially reacted completely. After the reaction was complete, the reaction system was cooled to room temperature. Under stirring, the reaction solution was slowly poured into an ice-water mixture (250 mL). A large amount of brown solid precipitated out. The mixture was filtered, and the filter cake was washed with a small amount of water and dried to obtain 9.38 g of a yellow solid intermediate, P3, with a yield of 95%. LC-MS (ESI) m / z: 242.55 (M+H) + .

[0174] Step 2: Take intermediate P3 (5.00 g, 20.74 mmol) and potassium carbonate (5.8 g, 41.48 mmol) in a single-necked flask (100 mL). Add dimethyl sulfoxide (35 mL) to the reaction flask. While stirring at room temperature, add 30% hydrogen peroxide (4.70 g, 41.48 mmol) to the reaction system. Stir at room temperature for at least 10 hours until the reactants are essentially complete. Dilute with water, extract three times with ethyl acetate, combine the organic phases, wash once with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and remove the solvent from the organic phase by rotary evaporation under reduced pressure to obtain the crude product. Purify by silica gel column chromatography (mobile phase: ethyl acetate and petroleum ether, ratio 1:99–20:80) to obtain intermediate 1 as a white solid, 3.50 g, yield 65%. LC-MS (ESI) m / z: 260.27 (M+H) + .

[0175] Preparation of intermediate 2:

[0176]

[0177] Step 1: 4-Hydroxy-2-methoxybenzaldehyde (10.00 g, 65.72 mmol) was dissolved in a 250 mL single-necked flask with N,N-dimethylacetamide (50 mL). Then, 3,4-difluorobenzonitrile (10.97 g, 78.87 mmol) and potassium carbonate (18.17 g, 131.45 mmol) were added. The mixture was stirred at 100 °C for 3 hours. After the reaction was complete, the reaction solution was allowed to return to room temperature. The solution was then poured into an ice-water mixture and stirred slowly for 2 hours, resulting in the precipitation of a large amount of solid. This solid was filtered, washed with water, and the filter cake was transferred to a clean crystallizing dish and dried in an oven at 50 °C to obtain 17.79 g of a yellow solid, with a yield of 99.78%. LC-MS (ESI) m / z: 272.13 (M+H) + .

[0178] Step 2: Intermediate P5 (17.79 g, 65.59 mmol) was placed in a single-necked flask (250 mL), dissolved in dimethyl sulfoxide (80 mL), and then potassium carbonate (9.06 g, 65.59 mmol) was added. Under stirring in an ice-water bath, 30% hydrogen peroxide (14.87 g, 131.17 mmol) was slowly added. The reaction was carried out at room temperature for 15 hours, and the conversion was confirmed to be complete by LC-MS. After the reaction was complete, water and a small amount of ethyl acetate were added to the reaction solution, and the mixture was stirred for 30 minutes. A large amount of solid precipitated out. The solid was filtered and washed with water. The filter cake was transferred to a clean crystallizing dish and dried in an oven at 50 °C to obtain 17.00 g of a pale yellow solid, with a yield of 89.62%. LC-MS (ESI) m / z: 290.14 (M+H) + .

[0179] Preparation of intermediate 3:

[0180]

[0181] Step 1: Intermediate 2 (2.00 g, 6.91 mmol) was dissolved in a 100 mL single-necked flask with 20 mL dichloromethane. The mixture was cooled to approximately -70 °C, and a dichloromethane solution of boron tribromide (5.20 g, 20.74 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred for 30 minutes, then allowed to return to room temperature naturally before stirring for another 15 hours. The reaction was confirmed to be complete by LC-MS. After the reaction was complete, the reaction solution was transferred to ice water, and the pH of the system was adjusted to approximately 7–8 with sodium bicarbonate aqueous solution. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was purified by slurrying with a petroleum ether:ethyl acetate (10:1) mixture to obtain 1.78 g of a yellow solid, with a yield of 93.54%. LC-MS (ESI) m / z: 276.12 (M+H) + .

[0182] Preparation of intermediate 4:

[0183]

[0184] Step 1: Intermediate 3 (0.10 g, 0.36 mmol) was dissolved in a single-necked flask (50 mL) with N,N-dimethylformamide (15 mL), followed by the addition of potassium carbonate (0.10 g, 0.72 mmol) and iodoethane (68.00 mg, 0.44 mmol). The mixture was stirred at room temperature for 15 hours, and the conversion of the starting material was confirmed by LC-MS. After the reaction was complete, a small amount of water was added to quench the reaction mixture. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a yellow oily crude product. The crude product was purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–70:30) to obtain 85.36 mg of a yellow solid, yield 77.60%. LC-MS (ESI) m / z: 304.16 (M+H) + .

[0185] Preparation of Example 1:

[0186]

[0187] Step 1: Take 2.00 g (10.04 mmol) of (S)-2-formylpyrrolidine-1-carbonyl tert-butyl ester in a single-necked flask (100 mL), dilute with 20 mL of methanol, and add 40.18% acetone aldehyde. Wt (2.13 g, 12.05 mmol), ammonia (25% Wt, 3.00 mL), stirred at room temperature for 1 hour, then heated to 65℃ for 10 hours. LC-MS showed that the reactants were essentially completely reacted. After the reaction, water was added to dilute the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–66:34) to give 0.62 g of a white solid product, yield 25%. LC-MS (ESI) m / z: 196.26 (Mt-Bu). + .

[0188] Step 2: Intermediate B1 (0.33 g, 1.31 mmol) was placed in a single-necked flask (100 mL), dissolved in ethyl acetate (5 mL), and stirred at room temperature. 8M hydrochloric acid-ethanol (1.00 mL) was added to the reaction system, and the mixture was stirred at room temperature for 10 hours. TLC analysis showed that the reactants had essentially reacted completely. After the reaction, the reaction solution was filtered, washed with ethyl acetate, and dried to obtain 0.24 g of a white solid. This solid was dissolved in water (10 mL), and the pH was adjusted to 7–8 with saturated sodium bicarbonate solution while stirring at room temperature. Then, ethyl acetate (15 mL) was added for extraction three times. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain 0.20 g of a white solid product, with a yield of 100%. LC-MS (ESI) m / z: 152.22 (M+H) + .

[0189] Step 3: C1 (0.20 g, 1.32 mmol) was placed in a single-necked flask (50 mL), diluted with 1,2-dichloroethane (10 mL), and intermediate 1 (0.34 g, 1.32 mmol), sodium triacetoxyborohydride (0.42 g, 1.98 mmol), and acetic acid (0.12 g, 1.98 mmol). The mixture was heated to 65 °C and stirred for 15 hours. TLC analysis showed that the reactants had essentially reacted completely. After the reaction was complete, saturated sodium bicarbonate solution was added to the reaction flask to quench the reaction. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain a white solid compound 1, 102.32 mg, yield 20%. LC-MS (ESI) m / z: 395.35 (M+H) + . 1 H NMR (600MHz, DMSO-d6) δ8.04(s,1H),7.86(dd,J=12.0,2.1Hz,1H),7.72(dd,J=8.6,2 .1Hz,1H),7.50(s,1H),7.31(d,J=8.4Hz,2H),7.07(t,J=8.4Hz,1H),7.01-6.92(m,2 H),6.63(s,1H),3.65(d,J=13.2Hz,1H),3.53(t,J=7.6Hz,1H),3.23(d,J=13.2Hz,1H ), 2.91(td,J=8.2,2.6Hz,1H),2.20(q,J=8.5Hz,1H),2.10(s,3H),1.88-1.66(m,4H).

[0190] Preparation of Example 2:

[0191]

[0192] Step 1: Same as Step 1 in Example 1, except that an equimolar amount of acetone aldehyde is replaced with an equimolar amount of glyoxal.

[0193] Step 2: Intermediate B2 (1.00 g, 4.21 mmol) was placed in a single-necked flask (100 mL), dissolved in tetrahydrofuran (10 mL), cooled to 0 °C, and sodium hydroxide (60% wt, 0.20 g, 5.06 mmol) was added. The mixture was stirred for 10 minutes, and iodomethane (0.71 g, 5.06 mmol) was added dropwise. After the addition was complete, the reaction was continued to be stirred at room temperature for 36 hours. TLC showed that the starting material had basically reacted completely. The reaction solution was slowly poured into an ice-water mixture (100 mL) to quench the reaction, and extracted three times with ethyl acetate. The organic phases were combined, washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (mobile phase: ethyl acetate and petroleum ether, ratio 1:99–20:80) to obtain 0.86 g of white solid intermediate C2, yield 81%.

[0194] Step 3: Intermediate C2 (0.86 g, 3.41 mmol) was placed in a single-necked flask (100 mL), diluted and dissolved with ethyl acetate (5 mL), and 8M hydrochloric acid-ethanol solution (1.0 mL) was added dropwise. After the addition was complete, the reaction was continued to be stirred at room temperature for more than 8 hours. TLC showed that the starting material had basically reacted completely. The reaction solution was filtered, washed with ethyl acetate, and the filter cake was simply dried and dissolved in water. Sodium hydroxide aqueous solution was added to adjust the pH to 7-8, and then extracted three times with acetic acid. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain a pale yellow solid intermediate D2 (0.50 g), yield 97%. LC-MS (ESI) m / z: 152.25 (M+H) + .

[0195] Step 4: Intermediate D2 (500.00 mg, 3.31 mmol) was placed in a single-necked flask (50 mL), diluted with 1,2-dichloroethane (15 mL), and then intermediate 1 (858.00 mg, 3.31 mmol), sodium triacetoxyborohydride (1.05 g, 4.96 mmol), and acetic acid (298.00 mg, 4.96 mmol) were added. The mixture was stirred at room temperature for 15 hours. TLC analysis showed that the reaction proceeds were essentially complete. The reaction was quenched by adding saturated sodium bicarbonate solution to the reaction flask. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to give 2,351 mg of a white solid compound, yield 27%. LC-MS (ESI) m / z: 395.46 (M+H) + . 1 H NMR(600MHz,DMSO-d6)δ8.03(s,1H),7.86(dd,J=11.9,2.1Hz,1H),7.76-7.68(m,1H),7 .48(s,1H),7.30-7.20(m,2H),7.08(t,J=8.4Hz,1H),7.04(d,J=1.2Hz,1H),7.00-6.92 (m,2H),6.76(d,J=1.2Hz,1H),3.74(t,J=8.2Hz,1H),3.72(s,3H),3.58(d,J=13.3Hz,1 H), 3.23 (d, J = 13.3Hz, 1H), 3.01-2.86 (m, 1H), 2.20 (q, J = 8.6Hz, 1H), 2.14-1.72 (m, 4H).

[0196] Preparation of Example 3:

[0197]

[0198] Step 1: Intermediate B2 (1.00 g, 4.21 mmol) was placed in a single-necked flask (100 mL), dissolved in tetrahydrofuran (10 mL), cooled to 0 °C, and sodium hydroxide (60% wt, 0.2 g, 5.06 mmol) was added. The mixture was stirred for 10 minutes, and iodoethane (0.79 g, 5.06 mmol) was added dropwise. After the addition was complete, the reaction was continued at room temperature for 36 hours. TLC analysis showed that the starting material had essentially reacted completely. The reaction solution was slowly poured into an ice-water mixture (100 mL) to quench the reaction, and extracted three times with ethyl acetate. The organic phases were combined, washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (mobile phase: ethyl acetate and petroleum ether, ratio 1:99–20:80) to obtain 0.41 g of white solid intermediate C3, yield 37%.

[0199] Step 2: Intermediate C3 (0.41 g, 1.56 mmol) was placed in a single-necked flask (100 mL), diluted and dissolved with ethyl acetate (5 mL), and 8M hydrochloric acid-ethanol solution (1.0 mL) was added dropwise. After the addition was complete, the reaction was stirred at room temperature for more than 8 hours. TLC analysis showed that the starting material had basically reacted completely. The reaction solution was filtered, washed with ethyl acetate, filtered, and simply dried before being dissolved in water. The pH was adjusted to 7-8 with sodium hydroxide aqueous solution, and then extracted three times with acetic acid. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain a pale yellow solid intermediate D3 (0.24 g), yield 93%. LC-MS (ESI) m / z: 166.28 (M+H) + .

[0200] Step 3: Intermediate D3 (240.00 mg, 1.45 mmol) was placed in a single-necked flask (50 mL), diluted with 1,2-dichloroethane (15 mL), and then intermediate 1 (377.00 mg, 1.45 mmol), sodium triacetoxyborohydride (0.46 g, 2.18 mmol), and acetic acid (298.00 mg, 4.96 mmol) were added. The mixture was stirred at room temperature for 15 hours. TLC analysis showed that the reaction proceeds were essentially complete. The reaction was quenched by adding saturated sodium bicarbonate solution to the reaction flask. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain a white solid compound 3, 148.00 mg, yield 25%. LC-MS (ESI) m / z: 409.50 (M+H) + . 1H NMR (600MHz, DMSO-d6) δ8.03(s,1H),7.86(dd,J=11.8,2.1Hz,1H),7.73(dd,J=8.6,2.1Hz,1H),7. 49(s,1H),7.30-7.22(m,2H),7.16(d,J=1.3Hz,1H),7.08(t,J=8.4Hz,1H),7.00-6.95(m,2H),6.84 (d,J=1.3Hz,1H),4.20-4.06(m,2H),3.78(t,J=7.8Hz,1H),3.61(d,J=13.2Hz,1H),3.26(d,J=13. 3Hz, 1H), 2.96 (td, J = 8.1, 2.7Hz, 1H), 2.29-2.07 (m, 2H), 1.94-1.72 (m, 3H), 1.30 (t, J = 7.3Hz, 3H).

[0201] Preparation of Example 4

[0202]

[0203] Step 1: (S)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (Al, 10.00 g, 50.19 mmol) was dissolved in a single-necked flask (250 mL) with methanol (50 mL). Glyoxal (5.80 g, 100.38 mmol) and 25% ammonia (19.08 g, 125.47 mmol) were added, and the mixture was stirred at room temperature for 15 hours. LC-MS analysis showed that the reaction proceeds were essentially complete. After the reaction, the reaction solution was poured into ice water and extracted twice with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to give 7.81 g of a yellow solid, yield 65.62%. LC-MS (ESI) m / z: 238.29 (M+H) + .

[0204] Step 2: Intermediate B2 (2.00 g, 8.43 mmol) was placed in a single-necked flask (100 mL) and dissolved in ethyl acetate (20 mL). Under stirring at room temperature, 4M ethyl acetate hydrochloride (6.32 mL, 25.28 mmol) was added to the system. The mixture was stirred at room temperature for 15 hours. TLC analysis showed that the reactants had essentially reacted completely. After the reaction was complete, the mixture was evaporated to dryness, then dissolved and diluted with methanol. An appropriate amount of ammonia was added to adjust the pH to 7–8. The solvent and ammonia were removed by vacuum evaporation using a rotary evaporator, followed by two evaporations with methanol, yielding 0.87 g of a yellow oily liquid (the crude product was used directly in the next step), with a yield of 75.26%. LC-MS (ESI) m / z: 138.15 (M+H) + .

[0205] Step 3: Intermediate D4 (0.20 g, 1.46 mmol) was dissolved in methanol (14 mL) in a single-necked flask (50 mL), followed by intermediate 1 (0.38 g, 1.46 mmol), sodium cyanoborohydride (0.18 g, 2.92 mmol), and acetic acid (1 mL). The mixture was stirred at room temperature for 15 hours. LC-MS analysis showed that the reactants had essentially reacted completely. After the reaction, the reaction solution was poured into water and extracted three times with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The organic phase was then subjected to rotary evaporation under reduced pressure to remove the solvent, yielding a crude product. This crude product was purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–60:40) to obtain 98.00 mg of a colorless, transparent liquid, with a yield of 17.67%. LC-MS (ESI) m / z: 381.33 (M+H) + . 1 H NMR(600MHz,DMSO-d6)δ8.04(s,1H),7.86(dt,J=11.8,1.8Hz,1H),7.72(d, J=8.5Hz,1H),7.49(s,1H),7.43(d,J=8.2Hz,1H),7.34-7.28(m,1H),7.05-7 .01(m,1H),7.01-6.96(m,1H),3.68-3.59(m,1H),3.52(s,1H),3.22(d,J=13 .3Hz,0H),2.91(q,J=5.2,3.5Hz,0H),2.25-2.04(m,1H),1.40-1.32(m,1H).

[0206] Preparation of Example 5

[0207]

[0208] Step 1: Intermediate B2 (0.50 g, 2.11 mmol) was dissolved in a single-necked flask (50 mL) with tetrahydrofuran (15 mL). The mixture was cooled to 0 °C, and sodium hydride (0.10 g, 2.53 mmol) was added. The mixture was allowed to return to room temperature, and 2-iodopropane (0.43 g, 2.53 mmol) was added. The mixture was stirred at room temperature for 15 hours. LC-MS analysis showed that the starting material showed almost no movement and a product peak was observed. After the reaction was terminated, the reaction solution was quenched with water and extracted 2–3 times with ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 0.25 g of a pale yellow oily liquid, yield 42.37%. LC-MS (ESI) m / z: 280.33 (M+H) + .

[0209] Step 2: Intermediate C5 (0.25 g, 0.86 mmol) was placed in a single-necked flask (50 mL) and dissolved in ethyl acetate (10 mL). Under stirring at room temperature, 4M hydrochloric acid-ethanol (1.10 mL, 4.43 mmol) was added to the system, and the reaction was continued for 15 hours. TLC analysis showed that the reactants were essentially completely reacted. After the reaction, the solvent was removed by rotary evaporation under reduced pressure, followed by two distillations with ethyl acetate. The mixture was then dissolved and diluted with methanol, and the pH was adjusted to 7–8 with a suitable amount of ammonia. The solvent and ammonia were removed by rotary evaporation under reduced pressure, followed by one distillation with methanol. The mixture was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 0.15 g of a pale yellow oily liquid, yield 93.75%. LC-MS (ESI) m / z: 180.24 (M+H) + .

[0210] Step 3: Intermediate D5 (0.15 g, 0.84 mmol) was dissolved in a single-necked flask (50 mL) with 1,2-dichloroethane (15 mL), followed by intermediate 1 (0.21 g, 0.81 mmol), sodium triacetoxyborohydride (0.87 g, 4.11 mmol), and acetic acid (0.07 g, 1.23 mmol). The mixture was stirred at 60 °C for 15 hours. LC-MS analysis showed that the reaction was essentially complete. After the reaction, saturated sodium bicarbonate solution was added to quench the reaction mixture, and the pH was adjusted to 7–8. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–40:60) to obtain 178.90 mg of a colorless, transparent oily liquid, with a yield of 52.33%. LC-MS (ESI) m / z: 423.35 (M+H)+ . 1 H NMR (600MHz, DMSO-d6) δ8.02(s,1H),7.85(dd,J=11.8,2.0Hz,1H),7.72(d,J=8.6Hz,1H),7.48(s,1H),7.27(d ,J=8.3Hz,3H),7.10(t,J=8.4Hz,1H),6.99(d,J=8.1Hz,2H),6.81(s,1H),5.00(h,J=6.7Hz,1H),3.75(t,J=7.9 Hz,1H),3.64(d,J=13.4Hz,1H),3.19(d,J=13.3Hz,1H),3.03-2.88(m,1H),2.14(q,J=8.7,8.2Hz,2H),1.91(d ,J=6.3Hz,1H),1.86(d,J=7.7Hz,1H),1.79(q,J=6.7,4.1Hz,1H),1.35(d,J=6.7Hz,3H),1.32(d,J=6.6Hz,3H).

[0211] Example 6

[0212]

[0213] Step 1: Intermediate B2 (0.50 g, 2.11 mmol) was placed in a single-necked flask (50 mL), dissolved and diluted with N,N-dimethylformamide (15 mL), and then cesium carbonate (2.06 g, 6.33 mmol) and iodocyclopropane (1.42 g, 8.44 mmol) were added. The mixture was stirred at 100 °C for at least 15 hours. LC-MS analysis showed partial conversion of the starting material and the presence of a product peak. After the reaction was terminated, a small amount of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–4:1) to obtain 0.47 g of a yellow oily liquid, yield 80.80%. LC-MS (ESI) m / z: 278.24 (M+H) + .

[0214] Step 2: Intermediate C6 (0.47 g, 1.69 mmol) was placed in a single-necked flask (50 mL), dissolved and diluted with ethyl acetate (10 mL), and stirred at room temperature. Then, 4M ethyl acetate hydrochloride (1.27 mL, 5.07 mmol) was added to the system, and the mixture was stirred at room temperature for 15 hours. TLC analysis showed that the reactants had essentially reacted completely. After the reaction, the solvent was removed by rotary evaporation under reduced pressure, followed by two distillations with ethyl acetate. The mixture was then dissolved and diluted with methanol, and the pH was adjusted to 7–8 with the addition of a suitable amount of ammonia. The solvent and ammonia were removed by rotary evaporation under reduced pressure, followed by two distillations with methanol, yielding 0.26 g of a pale yellow oily liquid (the crude product was used directly in the next step), with a yield of 86.58%. LC-MS (ESI) m / z: 178.20 (M+H) + .

[0215] Step 3: Intermediate D6 (0.15 g, 0.85 mmol) was dissolved in a single-necked flask (50 mL) with methanol (14 mL). Then, intermediate 1 (0.22 g, 0.85 mmol), sodium cyanoborohydride (0.16 g, 2.55 mmol), and acetic acid (1 mL) were added. The mixture was stirred at room temperature for 15 hours. LC-MS analysis showed that the reaction was essentially complete. After the reaction, the solvent was removed by rotary evaporation under reduced pressure. Water was added, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The organic phase was then evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–60:40) to give 76.00 mg of a colorless, transparent liquid, yielding 21.36%. LC-MS (ESI) m / z: 421.27 (M+H) + . 1H NMR (600MHz, DMSO-d6) δ8.02(s,1H),7.85(dq,J=11.8,1.9Hz,1H),7.72(dd,J=8.5,2.1Hz,1H),7.49(s,1H),7.37(dd,J=16.4 ,8.2Hz,1H),7.28-7.21(m,1H),7.12(d,J=9.1Hz,0H),7.10-7.05(m,1H),7.05-7.00(m,1H),7.00-6.97(m,1H),6.75(s,1H),3 .94(t,J=7.9Hz,1H),3.65(d,J=13.2Hz,1H),3.58(dq,J=7.5,3.8Hz,1H),2.96(td,J=8.7,2.9Hz,1H),2.31(q,J=8.5Hz,1H), 2.14(dq,J=17.4,8.1Hz,1H), 2.03(dt,J=12.8,6.3Hz,0H), 1.95-1.86(m,1H), 1.81(td,J=9.1,4.6Hz,1H), 1.09-0.71(m,3H).

[0216] Example 7

[0217]

[0218] Step 1: Intermediate B2 (0.50 g, 2.11 mmol) was placed in a single-necked flask (50 mL), dissolved and diluted with tetrahydrofuran (15 mL), and cooled to 0 °C. Sodium hydride (0.10 g, 2.53 mmol) and bromomethylcyclopropane (0.34 g, 2.53 mmol) were added to the system, and the mixture was stirred at room temperature for 15 hours. LC-MS analysis showed that the starting material showed almost no movement and a product peak was observed. After the reaction was terminated, the reaction solution was quenched with water, extracted 2–3 times with ethyl acetate, and the organic phases were combined. The mixture was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 0.41 g of a pale yellow oily liquid, yield 67.21%. LC-MS (ESI) m / z: 292.33 (M+H) + .

[0219] Step 2: Intermediate C7 (0.41 g, 1.41 mmol) was placed in a single-necked flask (50 mL), dissolved and diluted with ethyl acetate (10 mL), and stirred at room temperature. Then, 4M hydrochloric acid-ethanol (1.76 mL, 7.03 mmol) was added to the system, and the mixture was stirred at room temperature for 15 hours. TLC analysis showed that the reaction was essentially complete. After the reaction, the solvent was removed by rotary evaporation under reduced pressure, followed by two distillations with ethyl acetate. The mixture was then dissolved and diluted with methanol, and the pH was adjusted to 7–8 with a suitable amount of ammonia. The solvent and ammonia were removed by rotary evaporation under reduced pressure, followed by one distillation with methanol. The mixture was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 0.22 g of a pale yellow oily liquid, yield 81.48%. LC-MS (ESI) m / z: 192.23 (M+H) + .

[0220] Step 3: Intermediate D7 (0.22 g, 1.15 mmol) was placed in a single-necked flask (50 mL), dissolved and diluted with 1,2-dichloroethane (15 mL), and then intermediate 1 (0.29 g, 1.12 mmol), sodium triacetoxyborohydride (1.20 g, 5.67 mmol), and acetic acid (0.10 g, 1.70 mmol) were added. The mixture was stirred at 60 °C for 15 hours. LC-MS analysis showed that the reaction was essentially complete. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction mixture, and the pH was adjusted to 7–8. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–40:60) to obtain 82.90 mg of a colorless, transparent oily liquid, with a yield of 17.09%. LC-MS (ESI) m / z: 435.38 (M+H) + . 1HNMR (600MHz, DMSO-d6) δ8.04(s,1H),7.86(dd,J=11.9,2.1Hz,1H),7.72(dd,J=8.6,2.0Hz,1H),7.49(s,1H),7.25(d ,J=8.2Hz,2H),7.11-7.04(m,2H),6.98(d,J=8.2Hz,2H),6.83(s,1H),3.82(td,J=13.6,7.4Hz,2H),3.74(dd,J=13.8 ,7.7Hz,1H),3.60(d,J=13.3Hz,1H),3.27(d,J=13.3Hz,1H),2.97(td,J=8.3,3.3Hz,1H),2.31(q,J=8.2Hz,1H),2.16 -2.06(m,1H),1.80(td,J=8.7,8.2,3.9Hz,1H),1.49(dd,J=28.5,12.8Hz,2H),1.19-1.05(m,3H),0.98-0.84(m,2H).

[0221] Example 8

[0222]

[0223] Step 1: Intermediate B2 (0.50 g, 2.11 mmol) was dissolved in a single-necked flask (50 mL) with 15 mL of tetrahydrofuran. The mixture was cooled to 0 °C, and sodium hydride (0.10 g, 2.53 mmol) and bromomethylcyclobutane (0.38 g, 2.53 mmol) were added. The mixture was stirred at room temperature for 15 hours. LC-MS analysis showed that the starting material showed almost no movement and a product peak was observed. After the reaction was terminated, the reaction solution was quenched with water and extracted 2–3 times with ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 0.35 g of a pale yellow oily liquid, yield 54.35%. LC-MS (ESI) m / z: 306.31 (M+H) + .

[0224] Step 2: Intermediate C8 (0.35 g, 1.13 mmol) was placed in a single-necked flask (50 mL) and dissolved in ethyl acetate (10 mL). Under stirring at room temperature, 4M hydrochloric acid-ethanol (1.41 mL, 5.57 mmol) was added to the system, and the reaction was continued for 15 hours. TLC analysis showed that the reactants were essentially completely reacted. After the reaction, the solvent was removed by rotary evaporation under reduced pressure, followed by two distillations with ethyl acetate. The mixture was then dissolved and diluted with methanol, and the pH was adjusted to 7–8 with a suitable amount of ammonia. The solvent and ammonia were removed by rotary evaporation under reduced pressure, followed by one distillation with methanol. The mixture was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 0.15 g of a pale yellow oily liquid, with a yield of 63.82%. LC-MS (ESI) m / z: 206.31 (M+H) + .

[0225] Step 3: Intermediate D8 (0.15 g, 0.73 mmol) was placed in a single-necked flask (50 mL), dissolved and diluted with 1,2-dichloroethane (15 mL), and then intermediate 1 (0.19 g, 0.73 mmol), sodium triacetoxyborohydride (0.78 g, 5.56 mmol), and acetic acid (0.07 g, 1.11 mmol) were added. The mixture was stirred at 60 °C for 15 hours. LC-MS analysis showed that the reaction was essentially complete. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction mixture, and the pH was adjusted to 7–8. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–40:60) to obtain 195 mg of a colorless, transparent oily liquid, with a yield of 59.45%. LC-MS (ESI) m / z: 449.33 (M+H) + . 1H NMR (600MHz, DMSO-d6) δ8.03(s,1H),7.85(dd,J=11.9,2.2Hz,1H),7.72(dd,J=8.5,2.0Hz,1H),7.48(s,1H),7.25(d,J=8 .2Hz,2H),7.09(t,J=8.4Hz,1H),7.02(s,1H),6.99(d,J=8.2Hz,2H),6.78(s,1H),4.04(d,J=7.5Hz,2H),3.77(t,J=7.7Hz ,1H),3.59(d,J=13.4Hz,1H),3.24(d,J=13.3Hz,1H),2.95(t,J=8.6Hz,1H),2.62(t,J=7.8Hz,1H),2.25(q,J=8.3Hz,1H), 2.16-2.07(m,1H),1.91(d,J=7.1Hz,2H),1.81(dtd,J=14.7,10.4,4.8Hz,4H),1.73(dt,J=17.9,9.0Hz,2H),1.23(s,1H).

[0226] Example 9

[0227]

[0228] Step 1: Intermediate B2 (0.50 g, 2.11 mmol) was dissolved in a single-necked flask (50 mL) with 15 mL of tetrahydrofuran. The mixture was cooled to 0 °C, and sodium hydride (0.10 g, 2.53 mmol) and bromomethylcyclopentane (0.41 g, 2.53 mmol) were added. The mixture was stirred at room temperature for 15 hours. LC-LCMS analysis showed that the starting material showed almost no movement and a product peak was observed. After the reaction was terminated, the reaction solution was quenched with water and extracted 2–3 times with ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 0.27 g of a pale yellow oily liquid, yield 40.12%. LC-MS (ESI) m / z: 320.37 (M+H) + .

[0229] Step 2: Intermediate C9 (0.27 g, 0.83 mmol) was placed in a single-necked flask (50 mL), dissolved and diluted with ethyl acetate (10 mL), and stirred at room temperature. Then, 4M hydrochloric acid-ethanol (1.04 mL, 4.17 mmol) was added to the system, and the reaction was continued at room temperature for 15 hours. TLC analysis showed that the reaction was essentially complete. After the reaction, the solvent was removed by rotary evaporation under reduced pressure, followed by two distillations with ethyl acetate. The mixture was then dissolved and diluted with methanol, and the pH was adjusted to 7–8 with a suitable amount of ammonia. The solvent and ammonia were removed by rotary evaporation under reduced pressure, followed by one distillation with methanol. The mixture was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 0.10 g of a pale yellow oily liquid, yield 54.05%. LC-MS (ESI) m / z: 220.31 (M+H) + .

[0230] Step 3: Intermediate D9 (0.10 g, 0.46 mmol) was placed in a single-necked flask (50 mL), dissolved and diluted with 1,2-dichloroethane (15 mL), and then intermediate 1 (0.12 g, 0.46 mmol), sodium triacetoxyborohydride (0.49 g, 2.29 mmol), and acetic acid (0.04 g, 0.69 mmol) were added. The mixture was stirred at 60 °C for 15 hours. LC-MS analysis showed that the reaction was essentially complete. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction mixture, and the pH was adjusted to 7–8. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–40:60) to obtain 100 mg of a colorless, transparent oily liquid, with a yield of 47.39%. LC-MS (ESI) m / z: 463.35 (M+H) + . 1H NMR (600MHz, DMSO-d6) δ8.03(s,1H),7.86(dd,J=11.8,2.1Hz,1H),7.72(dd,J=8.5,2.0Hz,1H),7.49(s,1H),7.24(d,J= 8.2Hz,2H),7.13-7.05(m,2H),6.97(d,J=8.2Hz,2H),6.81(s,1H),3.95(dd,J=13.7,7.4Hz,1H),3.88(dd,J=13.7,8.0Hz ,1H),3.79(t,J=7.7Hz,1H),3.60(d,J=13.3Hz,1H),3.25(d,J=13.3Hz,1H),2.96(td,J=8.5,3.3Hz,1H),2.25(dq,J=26 .1,8.1Hz,2H),2.11(ddt,J=9.5,6.7,3.5Hz,1H),1.91(s,3H),1.65-1.56(m,4H),1.53-1.43(m,2H),1.23-1.11(m,2H).

[0231] Example 10

[0232]

[0233] Step 1: Intermediate B2 (0.50 g, 2.11 mmol) was dissolved in a single-necked flask (50 mL) with 15 mL of tetrahydrofuran. The mixture was cooled to 0 °C, and sodium hydride (0.10 g, 2.53 mmol) and bromomethylcyclohexane (0.45 g, 2.53 mmol) were added to the system. The mixture was stirred at room temperature for 15 hours. LC-MS analysis showed that the starting material showed almost no movement and a product peak was observed. After the reaction was terminated, the reaction solution was quenched with water and extracted 2–3 times with ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 0.25 g of a pale yellow oily liquid, yield 35.56%. LC-MS (ESI) m / z: 334.37 (M+H) + .

[0234] Step 2: Intermediate C10 (0.25 g, 0.76 mmol) was placed in a single-necked flask (50 mL) and dissolved in ethyl acetate (10 mL). Under stirring at room temperature, 4M hydrochloric acid-ethanol (0.95 mL, 3.81 mmol) was added to the system, and the reaction was continued for 15 hours. TLC analysis showed that the reaction was essentially complete. After the reaction, the solvent was removed by rotary evaporation under reduced pressure, followed by two distillations with ethyl acetate. The mixture was then dissolved and diluted with methanol, and the pH was adjusted to 7–8 with a suitable amount of ammonia. The solvent and ammonia were removed by rotary evaporation under reduced pressure, followed by one distillation with methanol. The mixture was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 0.10 g of a pale yellow oily liquid, yield 56.50%. LC-MS (ESI) m / z: 234.33 (M+H) + .

[0235] Step 3: Intermediate D10 (0.16 g, 0.69 mmol) was placed in a single-necked flask (50 mL), dissolved in 1,2-dichloroethane (15 mL), and then intermediate 1 (0.18 g, 0.69 mmol), sodium triacetoxyborohydride (0.83 g, 3.45 mmol), and acetic acid (0.06 g, 1.04 mmol) were added. The mixture was stirred at 60 °C for 15 hours. LC-MS analysis showed that the reaction was essentially complete. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction mixture, and the pH was adjusted to 7–8. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–40:60) to obtain 195.30 mg of a colorless, transparent oily liquid, with a yield of 59.72%. LC-MS (ESI) m / z: 477.38 (M+H) + . 1H NMR (600MHz, DMSO-d6) δ8.04(s,1H),7.86(dd,J=11.9,2.1Hz,1H),7.73(dd,J=8.5,2.0Hz,1H),7.49(s,1H),7.24(d,J=8.1Hz,2H),7.21(s ,1H),7.08(t,J=8.6Hz,1H),6.97(d,J=8.2Hz,2H),6.83(s,1H),4.00-3.88(m,2H),3.79(t,J=8.0Hz,1H),3.60(d,J=13.3Hz,1H),3.38(s,5 H),3.25(d,J=13.3Hz,1H),2.96(dt,J=8.6,4.4Hz,1H),2.24(q,J=8.4Hz,1H),2.13(dq,J=12.4,3.3Hz,1H),1.91(d,J=2.4Hz,2H),1.86(p, J=7.2Hz,1H),1.83-1.75(m,1H),1.11(tq,J=7.9,4.9,3.8Hz,1H),0.53(ddt,J=15.9,12.8,6.5Hz,2H),0.36(ddp,J=12.4,9.2,4.5Hz,2H).

[0236] Example 11

[0237]

[0238] Step 1: Intermediate B2 (0.50 g, 2.11 mmol) was dissolved in a single-necked flask (50 mL) with 15 mL of tetrahydrofuran. The mixture was cooled to 0 °C, and sodium hydride (0.10 g, 2.53 mmol) and 4-bromomethyltetrahydrofuran (0.45 g, 2.53 mmol) were added to the system. The mixture was stirred at room temperature for 15 hours. LC-MS analysis showed that the starting material showed almost no movement and a product peak was observed. After the reaction was terminated, the reaction solution was quenched with water and extracted 2–3 times with ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 0.16 g of a pale yellow oily liquid, yield 22.63%. LC-MS (ESI) m / z: 336.37 (M+H) + .

[0239] Step 2: Intermediate C11 (0.16 g, 0.47 mmol) was placed in a single-necked flask (50 mL), dissolved and diluted with ethyl acetate (10 mL), and stirred at room temperature. Then, 4M hydrochloric acid-ethanol (0.59 mL, 2.36 mmol) was added to the system, and the reaction was continued at room temperature for 15 hours. TLC analysis showed that the reaction was essentially complete. After the reaction, the solvent was removed by rotary evaporation under reduced pressure, followed by two distillations with ethyl acetate. The mixture was then dissolved and diluted with methanol, and the pH was adjusted to 7–8 with the addition of a suitable amount of ammonia. The solvent and ammonia were removed by rotary evaporation under reduced pressure, followed by one distillation with methanol. The mixture was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 0.10 g of a pale yellow oily liquid, yield 89.29%. LC-MS (ESI) m / z: 236.31 (M+H) + .

[0240] Step 3: Intermediate D11 (0.10 g, 0.43 mmol) was placed in a single-necked flask (50 mL), dissolved and diluted with 1,2-dichloroethane (15 mL), and then intermediate 1 (0.11 g, 0.43 mmol), sodium triacetoxyborohydride (0.45 g, 2.12 mmol), and acetic acid (0.04 g, 0.64 mmol) were added. The mixture was stirred at 60 °C for 15 hours. LC-MS analysis showed that the reaction was essentially complete. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction mixture, and the pH was adjusted to 7–8. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–40:60) to obtain 82.90 mg of a colorless, transparent oily liquid, with a yield of 40.33%. LC-MS (ESI) m / z: 479.37 (M+H) + . 1HNMR(600MHz,DMSO-d6)δ8.03(s,1H),7.86(d,J=11.8Hz,1H),7.72(d,J=8.5Hz,1H),7.49(s,1H),7.25(d,J=8.1Hz,2H),7 .12-7.06(m,2H),6.98(d,J=8.2Hz,2H),6.82(s,1H),3.90(dd,J=13.9,7.3Hz,1H),3.81(p,J=7.2,6.5Hz,4H),3.60(d,J=1 3.3Hz,1H),3.27(d,J=13.3Hz,1H),3.20(t,J=11.7Hz,2H),2.96(td,J=8.3,3.2Hz,1H),2.31(q,J=8.1Hz,1H),2.12(td,J= 11.2, 9.4, 5.7Hz, 1H), 1.91 (s, 2H), 1.80 (td, J = 8.1, 3.8Hz, 1H), 1.37 (t, J = 14.0Hz, 2H), 1.22 (dp, J = 18.9, 6.9, 6.2Hz, 3H).

[0241] Example 12

[0242]

[0243] Step 1: Intermediate B2 (0.50 g, 2.11 mmol) was placed in a single-necked flask (50 mL), dissolved and diluted with tetrahydrofuran (15 mL), and cooled to 0 °C. Sodium hydride (0.10 g, 2.53 mmol) and fluoroiodomethane (0.40 g, 2.53 mmol) were added to the system, and the mixture was stirred at room temperature for 15 hours. LC-MS analysis showed that the starting material showed almost no movement and a product peak was observed. After the reaction was terminated, the reaction solution was quenched with water, extracted 2–3 times with ethyl acetate, and the organic phases were combined. The mixture was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 0.39 g of a pale yellow oily liquid, yield 68.78%. LC-MS (ESI) m / z: 270.22 (M+H) + .

[0244] Step 2: Intermediate C12 (0.39 g, 1.44 mmol) was placed in a single-necked flask (50 mL), dissolved and diluted with ethyl acetate (10 mL), and stirred at room temperature. Then, 4M hydrochloric acid-ethanol (1.80 mL, 7.20 mmol) was added to the system, and the reaction was continued at room temperature for at least 15 hours. TLC analysis showed that the reaction was essentially complete. After the reaction, the solvent was removed by rotary evaporation under reduced pressure, followed by two distillations with ethyl acetate. The mixture was then dissolved and diluted with methanol, and the pH was adjusted to 7–8 with the addition of ammonia. The solvent and ammonia were removed by rotary evaporation under reduced pressure, followed by one distillation with methanol. The mixture was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 0.24 g of a pale yellow oily liquid, with a yield of 99%. LC-MS (ESI) m / z: 170.17 (M+H) + .

[0245] Step 3: Intermediate D12 (0.24 g, 1.43 mmol) was placed in a single-necked flask (50 mL), dissolved and diluted with 1,2-dichloroethane (15 mL), and then intermediate 1 (0.37 g, 1.43 mmol), sodium triacetoxyborohydride (1.51 g, 7.13 mmol), and acetic acid (0.13 g, 2.14 mmol) were added. The mixture was stirred at 60 °C for at least 15 hours. LC-MS analysis showed that the reaction was essentially complete. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction mixture, and the pH was adjusted to 7–8. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–40:60) to obtain 62.90 mg of a colorless, transparent oily liquid, with a yield of 10.75%. LC-MS (ESI) m / z: 413.30 (M+H) + . 1H NMR (600MHz, DMSO-d6) δ8.03(s,1H),7.85(dd,J=11.9,2.1Hz,1H),7.72(dd,J=8.6,2.0Hz,1H),7.48(s,1 H),7.35(s,1H),7.25(d,J=8.2Hz,2H),7.08(t,J=8.4Hz,1H),6.97(d,J=8.2Hz,2H),6.88(s,1H),6.47(d d,J=52.6,8.1Hz,1H),6.14(dd,J=52.2,8.1Hz,1H),3.81(t,J=8.1Hz,1H),3.59(d,J=13.1Hz,1H),3.25( d,J=13.1Hz,1H),2.95(t,J=7.6Hz,1H),2.25-2.13(m,2H),1.88(s,1H),1.85-1.75(m,1H),1.23(s,1H).

[0246] Example 13

[0247]

[0248] Step 1: Intermediate B2 (0.50 g, 2.11 mmol) was placed in a single-necked flask (50 mL), dissolved and diluted with tetrahydrofuran (15 mL), and cooled to 0 °C. Sodium hydride (0.10 g, 2.53 mmol) and 1-fluoro-2-iodoethane (0.44 g, 2.53 mmol) were added to the system, and the mixture was stirred at room temperature for 15 hours. LC-MS analysis showed that the starting material showed almost no movement and a product peak was observed. After the reaction was terminated, the reaction solution was quenched with water, extracted 2–3 times with ethyl acetate, and the organic phases were combined. The mixture was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 0.41 g of a pale yellow oily liquid, yield 68.68%. LC-MS (ESI) m / z: 284.23 (M+H) + .

[0249] Step 2: Intermediate C13 (0.41 g, 1.45 mmol) was placed in a single-necked flask (50 mL) and dissolved in ethyl acetate (10 mL). Under stirring at room temperature, 4M hydrochloric acid-ethanol (1.81 mL, 7.27 mmol) was added to the system, and the reaction was continued for 15 hours. TLC analysis showed that the reactants were essentially completely reacted. After the reaction, the solvent and hydrochloric acid gas were removed by rotary evaporation under reduced pressure, followed by two distillations with ethyl acetate. The mixture was then dissolved and diluted with methanol, and the pH was adjusted to 7–8 with the addition of a suitable amount of ammonia. The solvent and ammonia gas were removed again by rotary evaporation under reduced pressure, followed by one distillation with methanol. The mixture was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 0.27 g of a pale yellow oily liquid, with a yield of 100%. LC-MS (ESI) m / z: 184.25 (M+H) + .

[0250] Step 3: Intermediate D13 (0.27 g, 1.47 mmol) was placed in a single-necked flask (50 mL), dissolved and diluted with 1,2-dichloroethane (15 mL), and then intermediate 1 (0.38 g, 1.47 mmol), sodium triacetoxyborohydride (1.56 g, 7.37 mmol), and acetic acid (0.13 g, 2.21 mmol) were added. The mixture was stirred at 60 °C for 15 hours. LC-MS analysis showed that the reaction was essentially complete. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction mixture, and the pH was adjusted to 7–8. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–40:60) to obtain 59.60 mg of a colorless, transparent oily liquid, with a yield of 9.49%. LC-MS (ESI) m / z: 427.41 (M+H) + . 1H NMR (600MHz, DMSO-d6) δ8.03(s,1H),7.86(dd,J=11.8,2.1Hz,1H),7.72(dd,J=8.5,2.0Hz,1H),7.49(s,1H),7.25(d,J=8.2Hz,2H ),7.16(s,1H),7.09(t,J=8.4Hz,1H),6.97(d,J=8.2Hz,2H),6.84(s,1H),4.75(t,J=4.8Hz,1H),4.67(t,J=4.8Hz,1H),4.64-4.52 (m,1H),4.40(ddt,J=28.6,15.5,4.7Hz,1H),3.78(t,J=8.2Hz,1H),3.59(d,J=13.2Hz,1H),3.22(d,J=13.2Hz,1H),2.99-2.89(m, 1H), 2.20 (q, J=8.5Hz, 1H), 2.11 (ddt, J=12.3, 8.9, 3.5Hz, 1H), 1.91-1.84 (m, 1H), 1.78 (dt, J=9.8, 4.4Hz, 1H), 1.29-1.17 (m, 1H).

[0251] Example 14

[0252]

[0253] Step 1: Intermediate B2 (0.50 g, 2.11 mmol) was placed in a single-necked flask (50 mL), dissolved and diluted with tetrahydrofuran (15 mL), and cooled to 0 °C. Sodium hydride (0.10 g, 2.53 mmol) and 1,1-difluoro-2-iodoethane (0.48 g, 2.53 mmol) were added to the system, and the mixture was stirred at room temperature for 15 hours. LC-MS analysis showed that the starting material showed almost no movement and a product peak was observed. After the reaction was terminated, the reaction solution was quenched with water, extracted 2–3 times with ethyl acetate, and the organic phases were combined. The mixture was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 0.35 g of a pale yellow oily liquid, yield 55.12%. LC-MS (ESI) m / z: 302.22 (M+H) + .

[0254] Step 2: Intermediate C14 (0.35 g, 1.16 mmol) was placed in a single-necked flask (50 mL), dissolved and diluted with ethyl acetate (10 mL), and stirred at room temperature. Then, 4M hydrochloric acid-ethanol (1.45 mL, 5.81 mmol) was added to the system, and the reaction was continued for 15 hours at room temperature. TLC analysis showed that the reaction was essentially complete. After the reaction, the solvent and hydrochloric acid gas were removed by rotary evaporation under reduced pressure, followed by two distillations with ethyl acetate. The mixture was then dissolved and diluted with methanol, and the pH was adjusted to 7–8 with the addition of a suitable amount of ammonia. The solvent and ammonia gas were removed by rotary evaporation under reduced pressure, followed by one distillation with methanol. The mixture was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 0.20 g of a pale yellow oily liquid, yield 86.96%. LC-MS (ESI) m / z: 202.22 (M+H) + .

[0255] Step 3: Intermediate D14 (0.20 g, 1.00 mmol) was placed in a single-necked flask (50 mL), dissolved and diluted with 1,2-dichloroethane (15 mL), and then intermediate 1 (0.26 g, 1.00 mmol), sodium triacetoxyborohydride (1.06 g, 4.99 mmol), and acetic acid (0.09 g, 1.50 mmol) were added. The mixture was stirred at 60 °C for at least 15 hours. LC-MS analysis showed that the reaction was essentially complete. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction mixture, and the pH was adjusted to 7–8. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–40:60) to obtain 114.90 mg of a colorless, transparent oily liquid, with a yield of 26.00%. LC-MS (ESI) m / z: 445.28 (M+H) + . 1H NMR (600MHz, DMSO-d6) δ8.03(s,1H),7.86(d,J=11.8Hz,1H),7.73(d,J=8.4Hz,1H),7.49(s,1H),7.28(dd,J=30.7,8.2Hz ,2H),7.13(s,1H),7.09(t,J=8.6Hz,1H),6.98(d,J=8.1Hz,2H),6.87(s,1H),6.35(tt,J=55.1,3.7Hz,1H),4.81(qd,J=15 .5,3.6Hz,1H),4.53(qd,J=15.7,3.5Hz,1H),3.82(t,J=8.0Hz,1H),3.60(dd,J=24.9,13.1Hz,1H),3.25(dd,J=13.3,6.6H z,1H),3.03-2.85(m,1H),2.24(p,J=9.9,9.3Hz,1H),2.12(ddt,J=14.4,8.9,4.6Hz,1H),1.90(s,1H),1.87-1.69(m,2H).

[0256] Example 15

[0257]

[0258] Step 1: (S)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (3.00 g, 15.06 mmol) was dissolved in a 100 mL single-necked flask, dissolved in 30 mL of methanol, followed by the addition of 1.43 g (16.56 mmol) of 2,3-butanedione and 5.28 g (25.09 mmol) of 25% ammonia. The mixture was heated to 65 °C and stirred for 15 hours. LC-MS analysis showed that the reaction was essentially complete. After the reaction, the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 2.67 g of a pale yellow oily liquid, yielding 66.75%. LC-MS (ESI) m / z: 266.28 (M+H) + .

[0259] Step 2: Intermediate B15 (2.67 g, 10.04 mmol) was placed in a single-necked flask (100 mL) and dissolved in ethyl acetate (25 mL). Under stirring at room temperature, 4M hydrochloric acid-ethanol (7.53 mL, 30.12 mmol) was added to the system. The mixture was stirred at room temperature for at least 15 hours. TLC analysis showed that the reaction was essentially complete. After the reaction, the solvent was removed by rotary evaporation under reduced pressure, followed by two distillations with ethyl acetate. The mixture was then dissolved and diluted with methanol, and the pH was adjusted to 7–8 with a suitable amount of ammonia. The solvent and ammonia were removed by rotary evaporation under reduced pressure, followed by one distillation with methanol. The mixture was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 1.63 g of a pale yellow oily liquid, with a yield of 98%. LC-MS (ESI) m / z: 166.18 (M+H) + .

[0260] Step 3: Intermediate D15 (0.23 g, 1.41 mmol) was placed in a single-necked flask (50 mL), dissolved and diluted with 1,2-dichloroethane (15 mL), and then intermediate 1 (0.36 g, 1.41 mmol), sodium triacetoxyborohydride (1.49 g, 7.05 mmol), and acetic acid (0.13 g, 2.11 mmol) were added. The mixture was stirred at 60 °C for 15 hours. LC-MS analysis showed that the reaction was essentially complete. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction mixture, and the pH was adjusted to 7–8. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 186.00 mg of a white solid product, with a yield of 32.69%. LC-MS (ESI) m / z: 409.38 (M+H) + . 1 H NMR (600MHz, DMSO-d6) δ8.04(s,1H),7.86(d,J=11.9Hz,1H),7.72(d,J=9.4Hz,1H),7.49( s,1H),7.30(d,J=8.3Hz,2H),7.07(t,J=8.4Hz,1H),6.97(d,J=8.2Hz,2H),3.66(d,J=13. 2Hz,1H),3.50(t,J=7.6Hz,1H),3.26(d,J=13.2Hz,1H),3.16(s,1H),2.20(q,J=8.6Hz,1H ), 2.07 (q, J = 9.3Hz, 1H), 2.02 (s, 6H), 1.91 (s, 1H), 1.86-1.78 (m, 2H), 1.76-1.70 (m, 1H).

[0261] Example 16

[0262]

[0263] Step 1: (S)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (1.00 g, 5.02 mmol) and methanol (20 mL) were placed in a single-necked flask (100 mL). Under stirring at room temperature, 1,1-dibromo-3,3,3-trifluoroacetone (1.48 g, 5.48 mmol) and 25% ammonia (2.81 g, 20.07 mmol) were added to the reaction system. The reaction was continued for 16 hours, and TLC analysis showed that the reactants had essentially reacted completely. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure to obtain a large amount of brown solid. The solid was dissolved in ethyl acetate (50 mL), filtered, and the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow crude solid product. This crude product was purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:1–35:1) to obtain 1.36 g of a light yellow solid product, with a yield of 88.88%. LC-MS (ESI) m / z: 306.19 (M+H) + .

[0264] Step 2: Intermediate B16 (0.76 g, 2.49 mmol) and solvent ethyl acetate (4 mL) were placed in a single-necked flask (50 mL). Under stirring at room temperature, 4M hydrochloric acid ethanol (2 mL) was added to the reaction system, and the reaction was continued for 16 minutes. TLC analysis showed that the reactants had essentially reacted completely. After the reaction, the solvent was removed by rotary evaporation under reduced pressure, followed by two distillations with ethyl acetate. The mixture was then dissolved and diluted with methanol, and the pH was adjusted to 7–8 with the addition of a suitable amount of ammonia. The solvent and ammonia were removed by rotary evaporation under reduced pressure, followed by one distillation with methanol. The product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 0.40 g of a colorless, transparent liquid product, with a yield of 78.43%. LC-MS (ESI) m / z: 206.21 (M+H) + .

[0265] Step 3: Intermediate D16 (0.40 g, 1.95 mmol) and solvent 1,2-DCE (10 mL) were placed in a single-necked flask (50 mL). Intermediate 1 (0.51 g, 1.95 mmol) and glacial acetic acid (0.17 g, 2.83 mmol) were added to the reaction system under stirring at room temperature. The mixture was heated to 65 °C and stirred for 2 hours. Sodium triacetoxyborohydride (0.83 g, 3.90 mmol) was then added to the reaction system, and stirring continued for 16 hours. TLC analysis showed that the reactants had essentially reacted completely. After the reaction was complete, a saturated potassium bicarbonate aqueous solution was added to the reaction flask to quench the reaction. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 200:1–25:1) to obtain 110.6 mg of a white solid product, with a yield of 12.66%. LC-MS (ESI) m / z: 449.36 (M+H) + ; 1 H NMR(600MHz,DMSO-d6)δ12.55(s,1H),8.03(s,1H),7.86(dd,J=12.0,2.4Hz,1H),7 .73(s,1H),7.66(s,1H),7.49(s,1H),7.36(d,J=8.2Hz,1H),7.31(d,J=8.3Hz,2H), 7.07(t,J=8.4Hz,1H),6.98(s,1H),5.21(t,J=5.7Hz,1H),4.49(d,J=5.1Hz,1H),3. 68-3.58(m,2H),2.95(td,J=8.2,2.7Hz,1H),2.30-2.13(m,2H),1.89-1.81(m,2H).

[0266] Example 17

[0267]

[0268] Step 1: Intermediate 2 (100 mg, 0.35 mmol) was dissolved in a single-necked flask (50 mL) with 14 mL of methanol. Then, intermediate D3 (57.13 mg, 0.35 mmol), sodium cyanoborohydride (65.17 mg, 1.04 mmol), and acetic acid (1 mL) were added. The mixture was stirred at room temperature for 15 hours. LC-MS analysis showed that the starting material was essentially completely converted. After the reaction, the mixture was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed from the organic phase by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–60:40) to obtain 76.40 mg of a colorless, transparent liquid, yielding 50.40%. LC-MS (ESI) m / z: 439.30 (M+H) + . 1 HNMR(600MHz,DMSO-d6)δ8.03(s,1H),7.86(dt,J=12.0,1.9Hz,1H),7.72(d,J=8.5Hz,1H),7.49(s,1H),7.23(d,J=8.2Hz,1H ),7.19(s,1H),7.12-7.03(m,1H),6.87(s,1H),6.73(d,J=2.1Hz,1H),6.50(dt,J=8.3,2.0Hz,1H),4.13(ddq,J=35.6,14.3, 7.2Hz,2H),3.92-3.77(m,1H),3.54(d,J=13.9Hz,1H),3.17(s,0H),3.06(t,J=7.9Hz,1H),2.20(dq,J=63.1,9.9,9.1Hz,2H) ,1.89(dd,J=18.2,5.2Hz,3H),1.81(q,J=10.6Hz,1H),1.51-1.31(m,0H),1.27(td,J=7.3,1.6Hz,3H),1.23(t,J=3.2Hz,1H).

[0269] Example 18

[0270]

[0271] Step 1: Intermediate 3 (211.38 mg, 0.76 mmol) was dissolved in a single-necked flask (50 mL) with 14 mL of methanol. Then, intermediate D3 (126.90 mg, 0.76 mmol), sodium cyanoborohydride (144.78 mg, 2.30 mmol), and acetic acid (1 mL) were added. The mixture was stirred at room temperature for 15 hours. LC-MS analysis showed that the starting material was essentially completely converted. After the reaction, the mixture was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–60:40) to obtain 137.80 mg of a colorless, transparent liquid, yielding 42.27%. LC-MS (ESI) m / z: 425.37 (M+H) + . 1 H NMR(600MHz,DMSO-d6)δ8.03(s,1H),7.85(dt,J=11.9,1.8Hz,1H),7.72(d,J=8.5Hz,1H),7.49 (s,1H),7.22(d,J=1.8Hz,1H),7.13(td,J=8.4,1.4Hz,1H),7.06(d,J=7.9Hz,1H),6.91(d,J=1. 6Hz,1H),6.40-6.33(m,2H),4.01-3.93(m,3H),3.76(t,J=8.1Hz,1H),3.34(s,2H),3.10(d,J=1 2.9Hz, 1H), 2.93 (t, J = 8.4Hz, 1H), 2.35-2.24 (m, 2H), 1.80 (d, J = 7.9Hz, 1H), 1.37-1.29 (m, 3H).

[0272] Example 19

[0273]

[0274] Step 1: Intermediate 4 (85.36 mg, 0.28 mmol) was dissolved in a single-necked flask (50 mL) with 10 mL of methanol. Then, intermediate D3 (46.51 mg, 0.28 mmol), sodium cyanoborohydride (53.06 mg, 0.84 mmol), and acetic acid (0.5 mL) were added. The mixture was stirred at room temperature for 15 hours. LC-MS analysis showed that the reaction was essentially complete. After the reaction, the mixture was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–60:40) to obtain 56.50 mg of a colorless, transparent liquid, yielding 44.36%. LC-MS (ESI) m / z: 453.34 (M+H) + . 1 H NMR(600MHz,DMSO-d6)δ8.03(s,0H),7.85(dd,J=11.9,2.1Hz,0H),7.72(d,J=8.5Hz,0H),7.48(s,0H),7.2 3(d,J=8.4Hz,0H),7.16(s,0H),7.09(t,J=8.4Hz,0H),6.83(s,0H),6.71(d,J=2.3Hz,0H),6.51(d,J=8.3Hz ,0H),4.13(ddt,J=34.3,14.0,7.0Hz,1H),3.94(p,J=9.2,8.3Hz,1H),3.82(s,0H),3.54(d,J=14.0Hz,0H) ,3.06(t,J=8.1Hz,0H),2.23(d,J=8.4Hz,0H),2.19-2.09(m,0H),1.82(t,J=8.8Hz,0H),1.32-1.18(m,3H).

[0275] Example 20

[0276]

[0277] Step 1: Intermediate B15 (1.50 g, 5.66 mmol) and solvent tetrahydrofuran (20 mL) were placed in a clean, dry single-necked flask (100 mL). The mixture was dissolved by sonication. Under ice bath stirring, 60% sodium hydroxide (0.27 g, 6.78 mmol) was added to the reaction system. The mixture was heated to room temperature and stirred for 0.5 hours. Iodomethane (0.96 g, 6.78 mmol) was then added to the reaction system, and stirring continued at room temperature for 16 hours. TLC analysis showed that the reactants had essentially reacted completely. After the reaction was complete, water was added to the reaction flask to quench the reaction, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 200:1–30:1) to obtain 1.10 g of a yellow oily liquid product, with a yield of 69.62%. LC-MS (ESI) m / z: 280.26 (M+H) + .

[0278] Step 2: Intermediate C20 (0.55 g, 2.07 mmol) and solvent ethyl acetate (4 mL) were placed in a single-necked flask (50 mL). Under stirring at room temperature, 4M hydrochloric acid-ethanol (2 mL) was added to the reaction system, and the reaction was continued for 16 hours. TLC analysis showed that the reactants had essentially reacted completely. After the reaction, the solvent and hydrochloric acid gas were removed by rotary evaporation under reduced pressure, followed by two distillations with ethyl acetate. The mixture was then dissolved and diluted with methanol, and the pH was adjusted to 7–8 with the addition of a suitable amount of ammonia. The solvent and ammonia gas were removed again by rotary evaporation under reduced pressure, followed by one distillation with methanol. The product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 0.28 g of a colorless, transparent liquid product, with a yield of 80.00%. LC-MS (ESI) m / z: 180.20 (M+H) + .

[0279] Step 3: Intermediate D20 (0.28 g, 1.56 mmol) and solvent 1,2-DCE (10 mL) were placed in a single-necked flask (50 mL). Intermediate 1 (0.40 g, 1.56 mmol) and glacial acetic acid (0.14 g, 2.34 mmol) were added to the reaction system under stirring at room temperature. The mixture was heated to 65 °C and stirred for 2 hours. Sodium triacetoxyborohydride (0.66 g, 3.12 mmol) was then added to the reaction system, and stirring continued for 16 hours. TLC analysis showed that the reactants had essentially reacted completely. After the reaction was complete, a saturated potassium bicarbonate aqueous solution was added to the reaction flask to quench the reaction. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 200:1–25:1) to obtain 78.3 mg of a white solid product, with a yield of 11.87%. LC-MS (ESI) m / z: 423.36 (M+H) + ; 1 H NMR(600MHz,DMSO)δ8.03(s,1H),7.85(d,J=11.7Hz,1H),7.72(d,J=8.4Hz,1H),7.49(s,1H), 7.24(d,J=8.1Hz,2H),7.06(dd,J=18.2,9.9Hz,1H),6.96(d,J=8.1Hz,2H),3.61(dd,J=13.5, 5.6Hz,1H),3.57(s,3H),3.22-3.15(m,1H),2.94(t,J=7.7Hz,1H),2.12(dt,J=13.2,8.6Hz,1 H), 2.03 (d, J = 7.2Hz, 3H), 1.96 (d, J = 15.2Hz, 3H), 1.93-1.72 (m, 4H), 1.20 (d, J = 30.5Hz, 2H).

[0280] Example 21

[0281]

[0282] Step 1: Intermediate B15 (1.50 g, 5.66 mmol) and solvent tetrahydrofuran (20 mL) were placed in a clean, dry single-necked flask (100 mL). The mixture was dissolved by sonication. Under ice bath stirring, 60% sodium hydroxide (0.27 g, 6.78 mmol) was added to the reaction system. The mixture was heated to room temperature and stirred for 0.5 hours. Iodoethane (1.06 g, 6.78 mmol) was then added to the reaction system, and stirring continued at room temperature for 16 hours. TLC analysis showed that the reactants had essentially reacted completely. After the reaction was complete, water was added to the reaction flask to quench the reaction, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 200:1–30:1) to obtain 1.15 g of a yellow oily liquid product, with a yield of 69.69%. LC-MS (ESI) m / z: 294.28 (M+H) + .

[0283] Step 2: Intermediate C21 (0.61 g, 2.07 mmol) and solvent ethyl acetate (4 mL) were placed in a single-necked flask (50 mL). Under stirring at room temperature, 4M hydrochloric acid-ethanol (2 mL) was added to the reaction system, and the reaction was continued for 16 hours. TLC analysis showed that the reactants had essentially reacted completely. After the reaction, the solvent and hydrochloric acid gas were removed by rotary evaporation under reduced pressure, followed by two distillations with ethyl acetate. The mixture was then dissolved and diluted with methanol, and the pH was adjusted to 7–8 with the addition of a suitable amount of ammonia. The solvent and ammonia gas were removed again by rotary evaporation under reduced pressure, followed by one distillation with methanol. The product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:0–80:20) to obtain 0.31 g of a colorless, transparent liquid product, with a yield of 75.50%. LC-MS (ESI) m / z: 194.31 (M+H) + .

[0284] Step 3: Take intermediate D21 (0.31 g, 1.60 mmol) and solvent 1,2-dichloroethane (10 mL) in a single-necked flask (50 mL). Under stirring at room temperature, add intermediate 1 (0.42 g, 1.60 mmol) and glacial acetic acid (0.15 g, 2.40 mmol) to the reaction system. Heat to 65 °C and stir for 2 hours. Add sodium triacetoxyborohydride (0.68 g, 3.20 mmol) to the reaction system and continue stirring for 16 hours. TLC showed that the starting materials had basically reacted completely. After the reaction was complete, a saturated potassium bicarbonate aqueous solution was added to the reaction flask to quench the reaction, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 200:1–25:1) to give 83.5 mg of a white solid product, with a yield of 11.93%. LC-MS (ESI) m / z: 437.38 (M+H) + ; 1 H NMR (600MHz, DMSO) δ8.04(s,1H),7.86(d,J=11.8Hz,1H),7.73(d,J=8.5Hz,1H),7.50(s,1H),7.26(d,J=8.2Hz,2H ),7.13-7.06(m,1H),6.97(d,J=8.1Hz,2H),4.19(dq,J=14.2,6.9Hz,1H),3.90(dq,J=14.2,7.0Hz,1H),3.68(t,J =7.5Hz,1H),3.62(d,J=13.3Hz,1H),3.25(d,J=13.2Hz,1H),2.95(t,J=7.3Hz,1H),2.23-2.14(m,1H),2.07(s,3H ), 2.00 (d, J = 14.6Hz, 3H), 1.90 (d, J = 8.6Hz, 1H), 1.89-1.83 (m, 2H), 1.78 (d, J = 9.1Hz, 1H), 1.18 (t, J = 7.1Hz, 3H).

[0285] Comparative Example 1

[0286]

[0287] Step 1: (S)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (1.00 g, 5.02 mmol), p-toluenesulfonylmethylisocyanate (978.90 mg, 5.02 mmol), and anhydrous methanol (20 mL) were placed in a clean, dry single-necked flask (100 mL). Anhydrous potassium carbonate (2.07 g, 15.06 mmol) was added with stirring at room temperature. The mixture was heated to 80 °C and stirred for 8 hours. TLC analysis showed that the reaction proceeds were essentially complete. After the reaction was complete, the reaction solution was slowly poured into water (200 mL) under stirring. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:1–70:1) to obtain 950.00 mg of a yellow solid product, yield 79.43%. LC-MS (ESI) m / z: 239.24 (M+H) + .

[0288] Step 2: Intermediate B22 (950.00 mg, 4.01 mmol) was placed in a single-necked flask (100 mL), and anhydrous dichloromethane (20 mL) and 37% hydrochloric acid solution (5 mL) were added. The mixture was stirred at room temperature for 4 hours. LC-LCMS analysis showed that the reaction proceeds were essentially complete. Ammonia solution was added to the reaction flask to neutralize the reaction and adjust the pH to neutral. The mixture was then extracted three times with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain 350.00 mg of crude yellow oily liquid, which was directly used in the next step of the reaction, with a yield of 63.60%. LC-MS (ESI) m / z: 139.04 (M+H) + .

[0289] Step 3: Intermediate D22 (350.00 mg, 2.53 mmol) was placed in a single-necked flask (100 mL), and anhydrous 1,2-dichloroethane (20 mL) was added. Intermediate 1 (784.77 mg, 3.03 mmol), anhydrous acetic acid (227.70 mg, 3.79 mmol), and sodium triacetoxyborohydride (1.60 g, 7.59 mmol) were added with stirring at room temperature. The mixture was heated to 65 °C and stirred for 15 hours. LC-MS analysis showed that the reaction was essentially complete. After the reaction, the reaction solution was directly evaporated to dryness, and the sample was loaded onto a silica gel column for purification (mobile phase: dichloromethane and methanol, ratio 100:1–80:1) to obtain a white solid product of 380.00 mg, yield 39.34%. LC-MS (ESI) m / z: 382.28 (M+H) + . 1H NMR (600MHz, DMSO) δ8.28(s,1H),8.03(s,1H),7.85(d,J=11.9Hz,1H),7.72(d,J =8.5Hz,1H),7.48(s,1H),7.26(d,J=8.1Hz,2H),7.09(t,J=8.4Hz,1H),7.04(s,1 H),6.98(d,J=8.1Hz,2H),3.76-3.66(m,2H),2.87(d,J=6.6Hz,1H),2.30(q,J=8. 4Hz, 1H), 2.14 (dd, J = 19.5, 7.9Hz, 1H), 1.96-1.73 (m, 3H), 1.23 (d, J = 5.3Hz, 1H).

[0290] Comparative Example 2

[0291]

[0292] Step 1: Take intermediate A2-1 (1.00 g, 4.65 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.33 g, 6.97 mmol), 1-hydroxybenzotriazole (753.48 mg, 5.58 mmol) and anhydrous tetrahydrofuran (20 mL) into a clean, dry single-necked flask (100 mL) and stir at room temperature for 20 minutes. Then add acetylhydrazine (344.50 mg, 4.65 mmol) and N,N-diisopropylethylamine (2.99 g, 23.25 mmol) and stir at room temperature for 16 hours. The reaction was found to be basically complete by TLC. After the reaction was complete, the reaction solution was slowly poured into water (200 mL) under stirring. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (mobile phase: dichloromethane and methanol, ratio 100:1–50:1) to obtain 500.00 mg of a white solid product, yield 39.60%. LC-MS (ESI) m / z: 272.22 (M+H) + .

[0293] Step 2: Intermediate A2-2 (500.00 mg, 1.82 mmol) was placed in a single-necked flask (100 mL). Anhydrous tetrahydrofuran (40 mL) was added to the reaction flask. While stirring at room temperature, Lawson's reagent (2.20 g, 5.45 mmol) was added to the reaction system. The temperature was raised to 50 °C, and the reaction was continued with stirring for 15 hours. TLC analysis showed that the reactants had essentially reacted completely. After the reaction was complete, the reaction solution was directly evaporated to dryness and purified by silica gel column chromatography (mobile phase: petroleum ether and ethyl acetate, ratio 5:1–2:1) to obtain 400.00 mg of a white solid product, yield 80.50%. LC-MS (ESI) m / z: 270.20 (M+H) + .

[0294] Step 3: Intermediate B23 (400.00 mg, 1.48 mmol) was placed in a single-necked flask (100 mL), and anhydrous dichloromethane (20 mL) and 37% hydrochloric acid solution (5 mL) were added. The mixture was stirred at room temperature for 4 hours. LC-MS analysis showed that the reaction proceeds were essentially complete. Ammonia solution was added to the reaction flask to neutralize the reaction and adjust the pH to neutral. The mixture was then extracted three times with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain 150.00 mg of a crude yellow oily liquid, which was directly used in the next step of the reaction, yielding a yield of 59.60%. LC-MS (ESI) m / z: 170.13 (M+H) + .

[0295] Step 4: Intermediate D23 (150.00 mg, 0.89 mmol) was placed in a single-necked flask (100 mL), and anhydrous 1,2-dichloroethane (20 mL) was added. Intermediate 1 (276.61 mg, 1.06 mmol), anhydrous acetic acid (80.00 mg, 1.33 mmol), and sodium triacetoxyborohydride (563.37 mg, 2.67 mmol) were added under stirring at room temperature. The mixture was heated to 65 °C and stirred for 15 hours. LC-MS analysis showed that the reaction was essentially complete. After the reaction, the reaction solution was directly evaporated to dryness, and the sample was loaded onto a silica gel column for purification (mobile phase: dichloromethane and methanol, ratio 100:1–80:1) to obtain 300.00 mg of a white solid product, yield 81.80%. LC-MS (ESI) m / z: 413.28 (M+H) +. 1H NMR(600MHz,DMSO)δ8.03(s,1H),7.86(d,J=11.9Hz,1H),7.72(d,J=8.5Hz,1H),7.4 9(s,1H),7.32(d,J=7.7Hz,2H),7.09(t,J=8.2Hz,1H),7.01(d,J=7.3Hz,2H),4.06( t,J=7.4Hz,1H),3.81(d,J=13.2Hz,1H),3.43(d,J=13.2Hz,1H),2.95(d,J=6.4Hz,1 H), 2.65 (d, J = 33.7Hz, 3H), 2.40-2.30 (m, 2H), 1.78 (ddd, J = 19.1, 14.2, 7.1Hz, 3H).

[0296] Bioactivity test

[0297] Example 1 of bioactivity testing: KOR receptor binding assay

[0298] 1. Experimental materials

[0299] KOR membrane (constructed by WuXi AppTec); 3H Diprenorphine purchased from PerkinElmer; U-50488 purchased from Sigma-Aldrich; Tris-HCl purchased from Sigma-Aldrich; PEI (Polyethyleneimine) purchased from Sigma-Aldrich; Microscint 20 cocktail purchased from PerkinElmer; Polypropylene 96-well plate purchased from Agilent Technologies; Bravo automated liquid handling platform purchased from Agilent Technologies; ECHO 555 automated sample handling system purchased from Labcyte; Unifilter-96GF / C filter plates purchased from PerkinElmer; TopSeal-A top sealing membrane purchased from PerkinElmer; Cell harvest C961961 purchased from PerkinElmer; MicroBeta2 microplate radioactivity counter purchased from PerkinElmer.

[0300] 2. Experimental Methods

[0301] 1) Preparation of membranes and radioactive ligands

[0302]

[0303]

[0304] 2) Compound configuration

[0305] Test compounds: Starting from 10 μM, 4-fold serial dilutions were performed at 8 sites.

[0306] Reference compound U-50488: Starting from 1 μM, perform 8 4-fold serial dilutions.

[0307] 3) Experimental Procedure

[0308] a) Transfer 1 μL of compound / high concentration control / low concentration control to the assay plate.

[0309] b) Dispense 100 μL of membrane stock solution into the test plate.

[0310] c) Add 100 μL of radioactive ligand.

[0311] d) Seal the 96-well plate. Shake at 300 rpm for 1 hour at room temperature.

[0312] e) At room temperature, soak the Unifilter-96GF / C filter plate in 50 μL of 0.3% PEI per well for at least 0.5 h.

[0313] f) After the binding assay was completed, the reaction mixture was filtered through a GF / C plate using a Perkin Elmer Filtermate Harvester and then washed four times with cold wash buffer.

[0314] g) Dry the filter plate at 50°C for 1 hour.

[0315] h) After drying, seal the bottom of the filter plate pores with Perkin Elmer Unifilter-96 back sealing tape. Add 50 μL Perkin Elmer Microscint 20. Seal the top of the filter plate with Perkin Elmer TopSeal-A sealing membrane.

[0316] i) Tritium hydrogen captured on the filter using the Perkin Elmer MicroBeta2 Reader.

[0317] j) Calculate the inhibition rate using the following formula: % Inhibition rate = (1 - (Assay well - Average_LC) / (Average_HC - Average_LC)) * 100%.

[0318] k) Data were analyzed using Prism 5. A "log(inhibitor) vs. response—variable slope" model was used to fit the data to obtain the IC50 of the test compound. 50 Value and Ki value.

[0319] 3. Experimental Results:

[0320] The compounds of the present invention were tested in the above KOR receptor binding assay, and the results of the compounds in the representative examples are summarized in Table 1 below.

[0321] Table 1. KOR receptor binding assay results of compounds from representative examples.

[0322]

[0324] Experiment Example 2: KOR Cell Functional Detection Experiment

[0325] 1. Experimental materials

[0326] KOR (HEK293 cells) were constructed by WuXi AppTec; Fluo-4 Direct Calcium assay kit was purchased from Invitrogen; HEPES was purchased from Gibco; HBSS was purchased from Gibco; u-69593 was purchased from Aladdin Scientific; and the positive reference compound Aticaprant was purchased from TargetMol.

[0327]

[0328] Cell culture plates were purchased from Greiner; multi-well cell plates were purchased from Greiner; the automated sample handling system Liquidhandler: Echo 555 was purchased from Labcyte; and the real-time fluorescence detection system FLIPR was purchased from Molecular Device.

[0329] 2. Experimental Methods

[0330] Day 1: Planting Board

[0331] Culture medium: 90% DMEM (dulbecco's modified eagle medium), 10% FBS, 300 μg / mL LG418 (Geneticin), 2 μg / mL Blasticidin.

[0332] HEK293 cells expressing high levels of KOR were diluted to 10^6 cells / mL using culture medium. Then, 20 μL was transferred to each well of a cell plate (Greiner #781090). The final cell density was 20,000 cells / well.

[0333] the next day:

[0334] 1) Preparation of assay buffer: 20 mM HEPES and 1X HBSS.

[0335] EC80 Detection

[0336] 2) Dilute the agonist reference compound u-69593 10-fold at a ratio of 1:5 in assay buffer. Dilute the test compound in DMSO. Transfer 500 nmL of the compound solution to a compound plate (Greiner #781280). Add 30 μL of assay buffer to the compound plate (Greiner #781280).

[0337] 3) Remove EC from the incubator 80 Test plate, and use a pipette to transfer 20 μL of 2X Fluo-4 Direct TM Gently dispense the unwashed loading buffer into 384-well cell culture plates. The final volume in the cell plate is 40 μL.

[0338] 4) Incubate at 37℃ in a 5% CO2 cell culture incubator for 50 minutes, then incubate at room temperature for 10 minutes.

[0339] 5) Remove EC from the incubator 80 The test plate is placed into the FLIPR testing system. The multi-well plate is then placed into the FLIPR instrument.

[0340] 6) Run the protocol on FLIPRTETRA and calculate EC 80 .

[0341] Testing of the compounds of this invention

[0342] 7) Dilute the antagonist reference compound, nor-Binaltorphimine dihydrochloride, in DMSO at a ratio of 1:5. Dilute the test compound in DMSO. Transfer 500 nL of the test compound solution to a compound plate (Greiner #781280).

[0343] 8) Add 30 μL of assay buffer to each well of the compound plate (Greiner #781280). Add 20 μL of 2X Fluo-4 Direct to the cell plate. TM No-rinse loading buffer.

[0344] 9) Incubate at 37℃ in a 5% CO2 cell culture incubator for 50 minutes, then incubate at room temperature for 10 minutes.

[0345] 10) Dilute the agonist reference compound with assay buffer to obtain 6X EC 80 And transfer 30uL to EC 80 In the compound plate.

[0346] 11) Remove the cell plate from the incubator and place it in the FLIPR. Place the EC 80 compound plate into the FLIPR instrument.

[0347] a. Run the program on the FLIPR TETRA

[0348] b. Transfer 10 μL of the agonist reference compound from the EC 80 compound plate to the cell plate.

[0349] c. Read the fluorescence signal.

[0350] d. Calculate "maximum - minimum" from readings 1 to 90 to generate the final signal for % effect calculation, from which the IC 50 value of the compound is obtained.

[0351] 3. Experimental results:

[0352] The compounds of the present invention were tested in the above KOR receptor cell function detection test, and the test results of the representative example compounds are summarized in Table 2 below.

[0353] Table 2 KOR antagonistic functional test results of representative example compounds

[0354] Compound number of the examples <![CDATA[IC 50 (nM)]]> Aticaprant 25.99 Compound 1 5.083 Compound 3 9.90 Compound 6 14.37

[0355] Experimental Example 3. Mouse forced swimming test

[0356] Experimental purpose

[0357] In the mouse forced swimming model, evaluate the effect of the test compound on the mobility of mice as a measure of the antidepressant effect. Compared with the blank control, the lower the immobility, the more significant the antidepressant effect.

[0358] Experimental animals

[0359] Animal species: C57 / BL6 mice

[0360] Animal grade: SPF grade

[0361] Sex: Male

[0362] Number: 40

[0363] Animal body weight range: 22 - 24 g

[0364] Animal source: Hunan Slack Jingda Experimental Animal Co., Ltd.

[0365] Experimental animal production license number: SCXK(Xiang)2019 - 0004

[0366] Drugs and reagents

[0367] Test sample

[0368] Table 3 Information on test samples

[0369] name batch number Properties Storage conditions Manufacturer Aticaprant NA solid normal temperature TargetMol

[0370] solvent

[0371] Table 4 Solvent Information

[0372]

[0373] instrument

[0374] Table 5 Instrument Information

[0375]

[0376] Experimental methods

[0377] Project Background

[0378] Forced swimming is a rodent behavioral test used to evaluate the antidepressant efficacy of antidepressants and novel compounds. Animals are placed in a transparent, inescapable tank filled with water, and their struggle to escape is measured. Due to rodents' innate aversion to water, they will struggle and swim desperately, attempting to escape the aquatic environment. When they are unable to escape after a period of time, they stop struggling and exhibit behavioral despair. The forced swimming test is simple, reliable, and requires minimal equipment. The cylindrical tank used for the forced swimming test (FST) is made of transparent plexiglass. A fixed water level should be marked on the tank to ensure consistent water volume for all animals. The tank size should be chosen so that the animal cannot touch the bottom with its feet or tail during the swimming test. The test animals are affected by water temperature; they tend to remain still in cold water, while struggling increases in high water temperatures. Therefore, the water temperature should be maintained at 23-25°C during the test, which can be ensured using a thermometer or thermometer. A white noise generator (or a computer playing white noise audio) should be used during testing, as sudden loud noises may frighten the animals. A quiet, stable experimental environment and white noise at 60-70 Hz are generally preferred. After the animal has completed the test, its fur should be gently dried with paper towels and pads, and a heating pad should be used to prevent hypothermia.

[0379] Animal grouping and administration frequency and method

[0380] Animal grouping

[0381] Table 6 Animal Grouping Information

[0382]

[0383] Dosage frequency and method

[0384] Route of administration: Gavage (ig)

[0385] Dosing frequency: single dose

[0386] Dosage volume: 5 mL / kg

[0387] Experimental steps

[0388] After purchasing C57 / BL6 mice, they were housed at 15-20 mice per cage, provided with ample water and feed, and allowed to acclimatize for 2 days. The housing was maintained with a 12-hour light-dark cycle (lighting was turned on at 8:00 AM). Before the forced swimming test, the animals were transferred to the laboratory and allowed to acclimatize for at least 1 hour. The solvent control group received 5 mL / kg physiological saline via tail vein injection (ip), while the drug treatment groups received the corresponding test drug via gavage (ig). Testing was conducted 1 hour after drug administration. Visutrack software recorded the time spent struggling, swimming, and floating (the plugin can also record underwater swimming) for each mouse. The immobility time of the animals needed to be calculated. In actual treatment, the immobility time was calculated by subtracting the "struggle time" from the time interval. In the forced swimming test, movement was defined as any movement other than those necessary to maintain body balance and keep the head above water. Each indicator is expressed as mean ± standard error. Data for each group were analyzed using GraphPad prim 8.0.1 software. The statistical method used was univariate analysis with additional Dunnett's multiple comparison test to compare whether there was a statistical difference between the groups. A p < 0.05 was considered statistically significant (** indicates p < 0.01, * indicates p < 0.05).

[0389] Experimental results

[0390] In a forced swimming model, mice administered compound 5 showed a significant reduction in activity levels after administration, demonstrating a significant antidepressant effect, which was superior to that of aticaprant. Specifically... Figure 1 As shown; in the dose-response study, compound 5 exhibited a clear dose-response relationship, specifically as follows: Figure 2 As shown.

[0391] While the embodiments disclosed in this application are as described above, the content is merely for the purpose of facilitating understanding of this application and is not intended to limit this application. Any person skilled in the art to which this application pertains may make any modifications and changes in the form and details of the implementation without departing from the spirit and scope disclosed in this application; however, the scope of protection of this application shall still be determined by the scope defined in the appended claims.

Claims

1. A compound having the general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof; in, R 1 Selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-7 membered heterocycloalkyl, -C 1-3 Alkylene-C 3-8 cycloalkyl and -C 1-3 alkylene-4-7-membered heterocyclic alkyl, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-7 membered heterocycloalkyl, -C 1-3 Alkylene-C 3-8 cycloalkyl and -C 1-3 Each of the alkylene-4-7-membered heterocyclic alkyl groups is independently and optionally surrounded by one or more R a Substitution, the 4-7 membered heterocyclic alkyl and -C 1-3 Each alkylene-4-7-membered heterocyclic alkyl group independently contains one to two heteroatoms selected from N, O, and S; R 2 Each is independently selected from H, halogen, -OH, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-3 alkyl), -N(C) 1-3 Alkyl)2, C 3-8 Cycloalkyl, 4-7 membered heterocycloalkyl, -C 1-3 Alkylene-C 3-8 cycloalkyl and -C 1-3 alkylene-4-7-membered heterocyclic alkyl; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-7 membered heterocycloalkyl, -C 1-3 Alkylene-C 3-8 cycloalkyl and -C 1-3 Each alkylene-4-7-membered heterocyclic alkyl group is independently and optionally surrounded by one or more R b Substitution; the 4-7 membered heterocyclic alkyl group and -C 1-3 Each alkylene-4-7-membered heterocyclic alkyl group independently contains one to two heteroatoms selected from N, O, and S; R 3 Each is independently selected from H, halogen, -OH, C 1-3 Alkyl, C 1-3 Alkyl groups and oxo groups (C=O); R 4 Each is independently selected from H, halogen, -OH, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkyl groups; R 5 Each is independently selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Halogenated alkoxy groups; m is 0, 1, or 2; n is 0, 1, or 2; p is 1, 2, or 3; q can be 0, 1, 2, or 3; r can be 0, 1, 2, or 3; X is selected from CR 6 R 7 and O; Y 1 Y 2 Y 3 and Y 4 Each is independently selected from CH and N; and Y is specified. 1 Y 2 Y 3 and Y 4 Only two of them can be N at the same time; R 6 and R 7 Each is independently selected from H, halogen, -OH, C 1-3 Alkyl and C 1-3 Alkoxy; R a and R b Each is independently selected from halogens, -OH, -NH2, and -NH(C). 1-3 alkyl), -N(C) 1-3 Alkyl)2 and C 1-3 alkyl; The configuration of the carbon atom at position * is R configuration, S configuration, or a mixture of R and S configurations.

2. The compound of formula (I) as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, The compounds represented by general formula (I) satisfy one or more of the following conditions: (1) The C 1-6 The alkyl group is independently selected from methyl, ethyl, n-propyl or isopropyl, preferably from methyl and ethyl; (2) The C 1-3 The alkylene group is independently selected from methylene, ethylene, n-propylene, or isopropylene, preferably from methylene; (3) The C 1-3 The alkyl group is independently selected from methyl, ethyl, n-propyl or isopropyl, preferably from methyl and ethyl; (4) The C 1-3 The alkoxy group is independently selected from methoxy, ethoxy, n-propoxy or isopropoxy, preferably from methoxy and ethoxy; (5) The C 1-6 A haloalkyl group is independently a C-shaped alkyl group substituted with one or more halogens. 1-3 Alkyl groups, such as -CH2F, -CH2Cl, -CHF2, -CHCl2, -CCl3, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 or -CF2CF3; (6) The C 1-6 The alkoxy group is independently selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy, preferably methoxy; (7) The C 1-6 A haloalkoxy group is independently a C- group substituted with one or more halogens. 1-3 Alkyl groups, such as -OCH2F, -OCH2Cl, -OCHF2, -OCHCl2, -OCCl3, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3 or -OCF2CF3; (8) The halogen is independently selected from fluorine, chlorine, bromine or iodine; (9) The C 3-8 Cycloalkyl group is C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (10) The -C 1-3 Alkylene-C 3-8 The cycloalkyl group is -CH2-C 3-6 cycloalkyl, for example (11) The 4-7 membered heterocyclic alkyl group is a 4-6 membered heterocyclic alkyl group, such as oxocyclic butyl or tetrahydropyranyl; (12) The heteroatom of the 4-7 member heterocyclic group is selected from N or O, preferably O, and the number of heteroatoms is 1 or 2; And (13) as described -C 1-3 Alkylene-4-7-membered heterocyclic alkyl groups are -CH2-4-6-membered heterocyclic alkyl groups, for example...

3. The compound of formula (I) as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, The compounds represented by general formula (I) satisfy one or more of the following conditions: (1)R 1 Selected from H, C 1-3 Alkyl, C 3-6 cycloalkyl, -C 1-3 Alkylene-C 3-6 cycloalkyl and -C 1-3 alkylene-4-6-membered heterocyclic alkyl, wherein the C 1-3 Alkyl, C 3-6 cycloalkyl, -C 1-3 Alkylene-C 3-6 cycloalkyl and -C 1-3 Each alkylene-4-6-membered heterocyclic alkyl group is independently and optionally surrounded by one or more R a Instead, the -C 1-3 Alkylene-4-6-membered heterocyclic alkyl groups independently contain one to two heteroatoms selected from N, O, and S; Better, R 1 Selected from H, C 1-3 Alkyl, -CH2-C 3-6 Cycloalkyl and -CH2-4-6-membered heterocycloalkyl, wherein the C 1-3 Alkyl groups are formed by one or more R groups a The -CH2-4-6-membered heterocyclic alkyl group independently comprises one to two heteroatoms selected from N, O, and S; Further, better, R 1 Selected from H, methyl, ethyl, n-propyl, isopropyl, Better yet, R 1 Selected from H, methyl, ethyl, and isopropyl; (2)R 2 Each is independently selected from H, halogen, C 1-3 Alkyl and C 1-3 Alkoxy; wherein the C 1-3 Alkyl and C 1-3 Each alkoxy group is independently and optionally influenced by one or more R groups. b replace; Better, R 2 Each is independently selected from H, halogens, and C. 1-3 Alkyl; wherein the C 1-3 Alkyl groups are optionally surrounded by one or more R b replace; Further, better, R 2 Each is independently selected from H, fluorine, chlorine, bromine, methyl, ethyl and Better yet, R 2 Each is independently selected from H and methyl; (3)R 3 Each is independently selected from H, halogens, and C. 1-3 alkyl; Better, R 3 Each is independently selected from H and halogens; (4)R 4 Each is independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkyl groups; Better, R 4 Each is independently selected from H and halogens; (5)R 5 Each is independently selected from H, halogens, and C. 1-3 Alkyl group, preferably H; (6) X is CR 6 R 7 For example, CH2; (7) n is 0 or 1; (8) p is 1 or 2; (9) q is 0 or 1; (10) r is 0 or 1; (11)R 6 and R 7 Each is independently selected from H, halogens, and C. 1-3 Alkyl group, preferably H; (12)R a and R b Each is independently selected from halogens, -OH, and C. 1-3 alkyl; The carbon atom at position (13)* has an S configuration.

4. The compound of formula (I) as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, The compounds represented by general formula (I) satisfy one or more of the following conditions: (1) Structural Unit Selected from Preferably, structural unit for (2) Structural Unit Selected from Preferably, structural unit Selected from and (3) structural unit for Preferred For example 5. The compound of general formula (I) as described in any one of claims 1-4, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, The compound represented by general formula (I) satisfies one of the following schemes: Option 1: The compound represented by formula (I) has the structural features of formula (II): Among them, R 1 R 2 R 3 R 4 R 5 m, n, p, q, r, X, Y 1 Y 2 Y 3 and Y 4 The definition is as described in any one of claims 1-4; Option 2: The compound represented by formula (I) has the structural features of formula (III-1): Among them, R 1 R 2 R 3 R 4 The definitions of m, n, * and q are as described in any one of claims 1-4; Option 3: The compound represented by formula (I) has the structural features of formula (III-2): Where R 1 Selected from H, C 1-3 Alkyl, -C 1-3 Alkylene-C 3-6 cycloalkyl and -C 1-3 alkylene-4-6-membered heterocyclic alkyl, wherein the C1-3 alkyl group, -C 1-3 Alkylene-C 3-6 cycloalkyl and -C 1-3 Each alkylene-4-6-membered heterocyclic alkyl group is independently and optionally surrounded by one or more R a Instead, the -C 1-3 The alkylene-4-6-membered heterocyclic alkyl group independently comprises one to two heteroatoms selected from N, O, and S; preferably, R 1 Selected from H, methyl, ethyl, n-propyl, isopropyl, More preferably, R 1 Selected from H, methyl, and ethyl; R 2 Each is independently selected from H, halogens, and C. 1-3 Alkyl; wherein the C 1-3 Alkyl groups are optionally surrounded by one or more R b Replacement; preferably, R 2 Each is independently selected from H, fluorine, chlorine, bromine, methyl, ethyl and More preferably, the above-mentioned R 2 Each is independently selected from H and methyl; R 3 Selected from H; R 4 Selected from H and halogens; preferably, R 4 Selected from H and fluorine; m is 0, 1, or 2; n is 0; q is 0 or 1; R a and R b Each is independently selected from fluorine, chlorine, bromine, and iodine; preferably, R a and R b Each is independently selected from fluorine; Option 4: The compound represented by formula (I) has the structural features of formula (III-2): Where R 1 Selected from H, C 1-3 Alkyl, C 3-6 cycloalkyl, -C 1-3 Alkylene-C 3-6 cycloalkyl and -C 1-3 alkylene-4-6-membered heterocyclic alkyl, wherein the -C 1-3 Alkylene-4-6-membered heterocyclic alkyl groups independently contain one to two heteroatoms selected from N, O, and S; R 2 Each is independently selected from H, halogens, and C. 1-3 Alkyl; wherein the C 1-3 Alkyl groups are optionally surrounded by one or more R b replace; R 3 Selected from H; R 4 Selected from H and halogens; m is 0, 1, or 2; n is 0; q is 0 or 1; R a and R b Each is independently selected from fluorine, chlorine, bromine, and iodine; Option 5: The compound represented by formula (I) has the structural features of formula (IV-1): Among them, R 1 Selected from H, C 1-3 Alkyl, -CH2-C 3-6 Cycloalkyl and -CH2-4-6-membered heterocycloalkyl, wherein the C 1-3 Alkyl groups are formed by one or more R groups a The -CH2-4-6-membered heterocyclic alkyl group independently comprises one to two heteroatoms selected from N, O, and S; R 2 Each is independently selected from H, halogens, and C. 1-3 Alkyl; wherein the C 1-3 Alkyl groups are optionally surrounded by one or more R b replace; m is 0, 1, or 2; p is 1 or 2; q is 0 or 1; R 4 Selected from H and halogens; R a and R b Each is independently selected from fluorine, chlorine, bromine, and iodine; Y 1 Y 2 Y 3 and Y 4 Each is independently selected from CH and N; and Y is specified. 1 Y 2 Y 3 and Y 4 Only two of them can be N at the same time; The configuration of the carbon atom at position * is R configuration, S configuration, or a mixture of R and S configurations; Option Six: The compound represented by formula (I) has the structural features of formula (IV-2): Among them, structural units Selected from Preferably, structural unit Selected from p is 1 or 2; q is 0 or 1; R 4 Selected from H and halogens; Y 1 Y 2 Y 3 and Y 4 Each is independently selected from CH and N; and Y is specified. 1 Y 2 Y 3 and Y 4 Only two of them can be N at the same time; Option Seven: The compound represented by formula (I) has the structural features of formula (V): Among them, R 1 Selected from H, C 1-3 Alkyl and -CH2-C 3-6 cycloalkyl; R 2 Selected from H, methyl, and trifluoromethyl; m is selected from 0, 1, and 2.

6. The compound of formula (I) as claimed in claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, The compound represented by general formula (I) is any of the following compounds: Preferably, the compound represented by general formula (I) is any of the following compounds:

7. A method for preparing a compound of general formula (I) as described in any one of claims 1-6, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein the method for preparing the compound of general formula (I) comprises the following steps: Compound (IA) and compound (IB) undergo a reductive amination reaction in an acidic system in the presence of borohydrides (e.g., sodium borohydride, sodium cyanoborohydride, or sodium borohydride acetate) to yield compound (I). in, R 1 R 2 R 3 R 4 R 5 m, n, p, q, r, X, Y 1 Y 2 Y 3 Y 4 The definitions of * and are as described in any one of claims 1-6.

8. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1-6, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.

9. Use of a compound of formula (I) as claimed in any one of claims 1-6, its stereoisomers or pharmaceutically acceptable salts thereof, or a pharmaceutical composition as claimed in claim 8, wherein the use is selected from any of the following: (1) Application in the preparation of κ opioid receptor inhibitors; (2) Use in the preparation of medicines for the prevention and / or treatment of diseases associated with κ opioid receptors; (3) Use in the preparation of medicines for the prevention and / or treatment of diseases; said diseases are selected from depression, anxiety disorders, addictive disorders, epilepsy, schizophrenia, cognitive impairment, Alzheimer's disease and pain.

10. The application as described in claim 9, characterized in that, The diseases associated with the κ opioid receptor are selected from depression, anxiety disorders, addictive disorders, epilepsy, schizophrenia, cognitive impairment, Alzheimer's disease, and pain.

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