SIGMA-1 receptor antagonists and their uses

Abstract

This disclosure relates to a class of Sigma-1 receptor small molecule antagonists, their pharmaceutically acceptable compositions, methods of preparation, and uses. Sigma-1 receptor small molecule antagonists are represented by formula (I) with the specific substituents and definitions described herein. These Sigma-1 receptor small molecule antagonists exhibit good binding and antagonist activity to the Sigma-1 receptor. The present invention includes these compounds or their pharmaceutically acceptable compositions, as well as their use in the treatment and / or prevention of pain disorders associated with the Sigma-1 receptor.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of U.S. Provisional Application No. 63 / 452,034, filed on 14 March 2023. Its entire disclosure is incorporated herein by reference.

[0002] This disclosure relates to a novel, small, heterocyclic compound designed as a Sigma-1 receptor antagonist for the management of pain and related conditions. [Background technology]

[0003] Pain relievers are essential for improving the quality of life for patients suffering from a variety of conditions. As the world's population ages and the prevalence of chronic diseases such as diabetes, arthritis, joint or bone pain, epilepsy, depression, nerve damage, and various forms of cancer rises, the demand for effective pain management solutions is increasing significantly. Currently, the market for pain management treatments is dominated primarily by opioids and non-steroidal anti-inflammatory drugs (NSAIDs). However, opioid-related side effects, including respiratory depression, addiction, and constipation, as well as the social problems arising from their abuse, highlight the urgent need for the development of non-addictive analgesics to address the urgent needs of the majority of patients.

[0004] Identified as a chaperone protein, the Sigma-1 (σ1) receptor plays a crucial role in regulating the activity of various proteins and ion channels, including N-methyl-D-aspartate (NMDA) and opioid receptors. Located in critical areas for pain modulation within both the peripheral and central nervous systems, the Sigma-1 receptor functions as a unique ligand-activated chaperone. Sigma-1 antagonists disrupt the receptor's chaperoning function, amplifying opioid signaling and reducing NMDAR activity. This dual action not only promotes opioid-induced pain relief but also reduces hypersensitivity associated with chronic pain states. Importantly, targeting the Sigma-1 receptor does not exacerbate opioid-related side effects, suggesting that Sigma-1 antagonists can enhance the safety and efficacy of opioid therapy. Furthermore, σ1 receptor antagonists show promise in addressing psychosis, pain, substance abuse, and cancer, highlighting their potential as versatile therapeutic agents.

[0005] In contrast to the seven transmembrane domains of opioid receptors, the Sigma-1 receptor is a single polypeptide composed of 223 amino acids, possessing only two transmembrane domains and known to have no homology to opioid receptors or any other known mammalian proteins. The Sigma-1 (σ1) receptor protein is located within the mitochondrial-associated endoplasmic reticulum (ER) membrane (Hayashi et al. Cell 131(3), 596-610, 2007). The Sigma-1 (σ1) receptor interacts with Ca via the inositol triphosphate receptor (IP3R). 2+It is known to regulate signal transduction (Su et al. Trends Pharmacol. Sci. 31(12), 557-566, 2010) and the dendritic structure of hippocampal dendritic spines by regulating reactive oxygen species (ROS) levels (Tsai et al. Proc. Natl. Acad. Sci. USA 106(52), 22468-22473, 2009). The crystal structure of the human σ1 receptor, which is complexed with two ligands, revealed a trimer structure with a single transmembrane domain in each protomer (Schmidt et al. Nature 532(7600), 527-530 (2016)). Several small Sigma-1 (σ1) receptor antagonists have been reported in the literature (Marrazzo et al. Life Sci. 78(21), 2449-2453, 2006; Moison et al. Neuropharmacology 45(7), 945-953, 2003; Marrazzo et al. J.Med.Chem. 54(10), 3669-3673, 2011; Parenti et al. Inflammation 37(1), 261-266, 2014; Guitart et al. CNS Drug Rev. 4(3), 201-224, 1998; Cobos et al. Curr. Neuropharmacol. 6(4), 344-366, 2008; Lan et al. (Al. J. Med. Chem. 57(24), 10404-10423, 2014; Lan et al. Bioorg. Med. Chem. Lett. 26(8), 2051-2056, 2016; Diaz et al. J. Med. Chem. 55(19), 8211-8224, 2012; Berardi et al. J. Med. Chem. 48(26), 8237-8244, 2005). Patents to protect these inventions in Sigma-1 (σ1) receptor antagonists have also been filed by pharmaceutical companies, including but not limited to US2016 / 0060275, US7,696,199 B2, US2008 / 0125416, and US2016 / 0060275. This specification discloses a series of novel Sigma-1 (σ1) receptor antagonists for the treatment of pain and related disorders. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] U.S. Patent Application Publication No. 2016 / 0060275 [Patent Document 2] US Patent No. 7,696,199 B2 [Patent Document 3] U.S. Patent Application Publication No. 2008 / 0125416 [Non-patent literature]

[0007] [Non-Patent Document 1] Hayashi et al.Cell 131(3),596-610,2007 [Non-Patent Document 2] Su et al.Trends Pharmacol.Sci.31(12),557-566,2010 [Non-Patent Document 3] Tsai et al.Proc.Natl.Acad.Sci.USA 106(52),22468-22473,2009 [Non-Patent Document 4] Schmidt et al.Nature 532(7600),527-530(2016) [Non-Patent Document 5] Marrazzo et al.Life Sci.78(21),2449-2453,2006 [Non-Patent Document 6] Moison et al.Neuropharmacology 45(7),945-953,2003 [Non-Patent Document 7] Marrazzo et al.J.Med.Chem.54(10),3669-3673,2011 [Non-Patent Document 8] Parenti et al.Inflammation 37(1),261-266,2014 [Non-Patent Document 9] Guitart et al.CNS Drug Rev.4(3),201-224,1998 [Non-Patent Document 10] Cobos et al.Curr.Neuropharmacol.6(4),344-366,2008 [Non-Patent Document 11] Lan et al.J.Med.Chem.57(24),10404-10423,2014 [Non-Patent Document 12] Lan et al.Bioorg.Med.Chem.Lett.26(8),2051-2056,2016 [Non-Patent Document 13] Diaz et al.J.Med.Chem.55(19),8211-8224,2012 [Non-Patent Document 14] Berardi et al.J.Med.Chem.48(26),8237-8244,2005 [Overview of the project]

[0008] The following is a summary of the detailed description of the present invention. This summary is not intended to limit the scope of the claims.

[0009] This disclosure relates to the compound represented by formula (I), its stereoisomers, pharmaceutically acceptable salts, solvates, deuterated derivatives, metabolites, or prodrugs. [ka] During the ceremony, n = 0, 1, 2, or 3, L is -(CH2) m -,-(CH2) m (CR 5 R 6 )-, or -(CH2) m Selected from Q-, m = 0, 1, 2, or 3, and X is C, O, or S, and R 1 and R 2 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, and substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted aryl, and substituted heteroaryl are each independently substituted by 1 to 3 substituents selected from the group: halogen, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, heteroaryl, and heterocyclic ring, or alternatively, R 1 and R 2 together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclic group having a representative structure as shown below (but not limited to):

Chemical formula

[0010] This disclosure also covers pharmaceutical compositions comprising a compound of formula (I), or its stereoisomers, pharmaceutically acceptable salts, solvates, deuterated forms, metabolites, or prodrugs, and a pharmaceutically acceptable carrier or excipient.

[0011] This disclosure further relates to a method for inhibiting the Sigma-1 receptor in a subject. This method includes administering a compound of formula (I) to the subject.

[0012] This disclosure further relates to methods for treating and / or preventing diseases or disorders related to the Sigma-1 receptor in subjects. These methods include administering a compound of formula (I) to a subject.

[0013] Aspects of this disclosure relate to methods for treating and / or preventing one or more conditions in a subject, including, but not limited to, pain, psychosis, substance abuse, or cancer. The method involves administering a compound of formula (I) to the subject.

[0014] The figures are provided to facilitate understanding of the technical solution proposed in this application and to form part of this specification, and are used in conjunction with the embodiments of this application to illustrate the technical solution of this application, and are not intended to limit the scope of the technical solution of this application. [Brief explanation of the drawing]

[0015] [Figure 1] The structures of reference compounds 1 to 3 involved in the present invention are shown.

[0016] [Figure 2] The present invention demonstrates the analgesic effect of the compound in a spinal nerve ligation (SNL) model. [Modes for carrying out the invention]

[0017] This invention provides a new class of Sigma-1 antagonists, along with methods for their preparation and applications. The compounds of this invention have good Sigma-1 antagonistic activity and can provide effective pain management to meet patient needs.

[0018] In a second aspect, the present invention provides a pharmaceutical composition comprising a Sigma-1 antagonist and its stereoisomers, pharmaceutically acceptable salts, solvates, deuterated forms, metabolites, or prodrugs, and at least one pharmaceutically acceptable excipient or carrier.

[0019] In a third aspect, the present invention provides a method for synthesizing a Sigma-1 antagonist.

[0020] In a fourth aspect, the present invention provides a method for treating a disease or disorder related to Sigma-1. This method comprises administering a composition containing a compound of formula (I) to an individual in need.

[0021] I. Sigma-1 Antagonist In a first embodiment of the present invention, compounds represented by formula (I), or stereoisomers, pharmaceutically acceptable salts, solvates, deuterated forms, metabolites, or prodrugs thereof are provided. [ka] During the ceremony, n = 0, 1, 2, 3, L is -(CH2) m -,-(CH2) m (CR 5 R 6 )-,-(CH2) m Selected from Q-, m = 0, 1, 2, 3, X is selected from C, O, and S. R 1 and R 2 Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, and each of the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted aryl, and substituted heteroaryl is independently substituted by 1 to 3 substituents selected from the group: halogen, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, heteroaryl, and heterocycle, Alternatively, R 1 and R 2 However, together with the nitrogen atoms to which they are bonded, they can form substituted or unsubstituted heterocyclic groups having representative (but not limited to) structures, as shown below. [ka] Q is selected from aryl and heteroaryl, and the aryl and heteroaryl can optionally have 0 to 5 R 3 Further substituted by the group, R 3 However, these are halogens, C1-C6 alkyls, or C3-C6 cycloalkyls. Y is a C5-C14 heteroaryl, and this heteroaryl has 0 to 5 R (R) at any choice. 4 Further substitution with a group, the heteroaryl contains 1 to 4 heteroatoms selected from N, O, and S. R 4 However, the group is selected from hydrogen, halogen, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, aryl, substituted aryl, heterocycle, and substituted heterocycle, and the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted aryl, and substituted heteroaryl groups are independently substituted with 1 to 3 substituents selected from the group: halogen, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, heteroaryl, and heterocycle. R 5 and R 6 Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, and substituted C3-C6 cycloalkyl, and the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted phenyl, and substituted heteroaryl are independently substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine.

[0022] Specifically, in some embodiments, the present invention provides a compound represented by formula (I), its stereoisomers, pharmaceutically acceptable salts, solvates, deuterated forms, metabolites, or prodrugs. [ka] During the ceremony, n = 0, 1, 2, or 3, L is -(CH2) m -,-(CH2) m (CR 5 R 6 )-, or -(CH2) m Selected from Q-, m = 0, 1, 2, or 3, X is selected from C, O, or S. R 1 and R 2 Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, and each of the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted aryl, and substituted heteroaryl is independently substituted by 1 to 3 substituents selected from the group: halogen, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, heteroaryl, and heterocycle, Alternatively, R 1 and R 2 However, together with the nitrogen atoms to which they are bonded, they can form substituted or unsubstituted heterocyclic groups having representative (but not limited to) structures, as shown below. [ka] Q is either aryl or heteroaryl, and aryl or heteroaryl can have 0 to 5 R values ​​of any choice. 3 Further substituted by the group, R 3 However, these are halogens, C1-C6 alkyls, or C3-C6 cycloalkyls. Y is a C5-C14 heteroaryl, and the heteroaryl has 0 to 5 R atoms of arbitrary choice. 4 Further substitution with a group, the heteroaryl contains 1 to 4 heteroatoms selected from N, O, and S. R 4However, the group is selected from hydrogen, halogen, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, aryl, substituted aryl, heterocycle, and substituted heterocycle, and the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted aryl, and substituted heteroaryl groups are independently substituted with 1 to 3 substituents selected from the group: halogen, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, heteroaryl, and heterocycle. R 5 and R 6 Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, and substituted C3-C6 cycloalkyl, and the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted phenyl, and substituted heteroaryl are independently substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine.

[0023] Specifically, in some embodiments, the present disclosure provides a compound represented by formula (II), or its stereoisomers, pharmaceutically acceptable salts, solvates, deuterated forms, metabolites, or prodrugs. [ka] During the ceremony, n = 0, 1, 2, or 3, L is -(CH2) m -,-(CH2) m (CR 5 R 6 )-, or -(CH2) m Selected from Q-, m = 0, 1, 2, or 3, X is selected from C, O, or S. R 1 and R 2Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, and each of the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted aryl, and substituted heteroaryl is independently substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, heteroaryl, and heterocycle, Alternatively, R 1 and R 2 However, together with the nitrogen atom to which they are bonded, they can form substituted or unsubstituted heterocyclic groups as shown above. Q is either aryl or heteroaryl, or aryl or heteroaryl, with 0 to 5 R of any choice. 3 Further substituted by the group, R 3 However, these are halogens, C1-C6 alkyls, or C3-C6 cycloalkyls. A, B, D, E, and Z are each independently C, N, or O. In the expression, when one of B, Z, or E is selected from C, R 4 It can connect to, R 4 However, the substituents are selected from the group consisting of hydrogen, halogen, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, aryl, substituted aryl, heterocycle, and substituted heterocycle, and the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted aryl, and substituted heteroaryl substituents are independently substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, heteroaryl, and heterocycle. R 5 and R 6Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, and substituted C3-C6 cycloalkyl, and the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted phenyl, and substituted heteroaryl are independently substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine.

[0024] In some specific embodiments, as shown in formula (IIa), when A, D, and E are carbon atoms, B is a nitrogen atom and Z is an oxygen atom, [ka] As shown in equation (IIa-1), when X is an oxygen atom, n=1, In the formula, as shown in formulas (IIa-1a), (IIa-1b), and (IIa-1c), L is -(CH2) m -,-(CH2) m (CR 5 R 6 )-, or -(CH2) m Q-, As shown in equation (IIa-2), when X is a carbon atom, n=0 and L is -(CH2) m - and m=0, [ka] R 1 and R 2Each of these is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, and pyridine, and the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted phenyl, and substituted heteroaryl are independently substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine, Alternatively, R 1 and R 2 However, together with the nitrogen atom to which they are bonded, they can form substituted or unsubstituted heterocyclic groups as shown above. Q is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridyl, quinolyl, and pyrazinyl, and R is optionally selected from 0 to 5. 3 Further substituted by the group, R 3 However, selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, R 4 However, the substituents are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, and pyridine, and the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted phenyl, and substituted heteroaryl substituents are independently substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine. R 5 and R 6Each of these is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted phenyl, and substituted heteroaryl are independently substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine.

[0025] In some embodiments, R 1 and R 2 Each of these is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl, or R 1 and R 2 These, together with the nitrogen atom to which they are bonded, can form substituted or unsubstituted heterocyclic groups selected from the group shown below. [ka]

[0026] In some embodiments, Q is phenyl, naphthyl, or pyridyl, and R is 0 to 5. 3 It is further substituted by the element.

[0027] In some embodiments, R 3 The compound is selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl.

[0028] In some embodiments, R 4 These are hydrogen, fluorine, chlorine, bromine, or thiophenyl.

[0029] In some embodiments, R 5 and R 6 Each of these is independently either hydrogen or methyl.

[0030] In some specific embodiments, when B, Z, and D are carbon atoms as shown in formula (IIb), A and E are nitrogen atoms,

Chemical formula

Chemical formula

Chemical formula

[0031] In some embodiments, R 1 and R 2 These, together with the nitrogen atom to which they are bonded, can form substituted or unsubstituted heterocyclic groups selected from the following group: [ka]

[0032] In some embodiments, Q is phenyl or naphthyl, where Q is 0 to 5 R 3It is further substituted by the element.

[0033] In some embodiments, R 3 These are fluorine, chlorine, or bromine.

[0034] In some embodiments, R 4 It is hydrogen.

[0035] In some embodiments, R 5 and R 6 It is hydrogen.

[0036] Specifically, the compound represented by formula (III), or its stereoisomer, pharmaceutically acceptable salt, solvate, deuterated form, metabolite, or prodrug, [ka] During the ceremony, L is -(CH2) m -,-(CH2) m (CR 5 R 6 )-,-(CH2) m Selected from Q-, m = 0, 1, or 2, X is C, O, or S, R 1 and R 2 Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, and substituted C3-C6 cycloalkyl, and the substituted C1-C6 alkyl and substituted C3-C6 cycloalkyl are independently substituted with 1 to 3 substituents selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, heteroaryl, and heterocycle, Alternatively, R 1 and R 2 However, together with the nitrogen atom to which they are bonded, they can form substituted or unsubstituted heterocyclic groups as shown above. Q is either aryl or heteroaryl, and aryl or heteroaryl can have 0 to 5 R values ​​of any choice. 3 Further substituted by the group, R 3 However, these are halogens, C1-C6 alkyls, and C3-C6 cycloalkyls. A, B, D, E, and Z are each independently C, N, or O. In the expression, when one of B, Z, or E is selected from C, R 4 It can connect to, R 4 However, the substituents are selected from the group consisting of hydrogen, halogen, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, and substituted C3-C6 cycloalkyl, and the substituted C1-C6 alkyl and substituted C3-C6 cycloalkyl are independently substituted with 1 to 3 substituents selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, heteroaryl, and heterocycle. R 5 and R 6 Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, and substituted C3-C6 cycloalkyl, and the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted phenyl, and substituted heteroaryl are independently substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine.

[0037] In some specific embodiments, as shown in formula (IIIa), when Z, D, and E are carbon atoms, A and B are nitrogen atoms. [ka]

[0038] In some specific embodiments, as shown in formula (IIIb), when A and D are carbon atoms, B, Z, and E are nitrogen atoms. [ka]

[0039] In some specific embodiments, as shown in formula (IIIc), when A, D, and E are carbon atoms, B is a nitrogen atom and Z is an oxygen atom. [ka]

[0040] In some specific embodiments, as shown in formula (IIId), when A, Z, and D are carbon atoms, B and E are nitrogen atoms. [ka] During the ceremony, m = 0, 1, 2, or 3, X is C, O, or S, R 1 and R 2 Each of these is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted phenyl, and substituted heteroaryl groups are independently substituted with 1 to 3 substituents selected from the group: fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine. Alternatively, R 1 and R 2 However, together with the nitrogen atom to which they are bonded, they can form substituted or unsubstituted heterocyclic groups. Q is selected from phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridyl, quinolyl, and pyrazinyl, and 0 to 5 R are optionally selected. 3 Further substituted by the group, R 3However, selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, R 4 The groups are independently substituted with 1 to 3 substituents selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted phenyl, and substituted heteroaryl groups are independently substituted with 1 to 3 substituents selected from the groups: fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine.

[0041] In some embodiments, m = 0, 1, or 2.

[0042] In some embodiments, X is a carbon atom or an oxygen atom.

[0043] In some embodiments, R 1 and R 2 These, together with the nitrogen atom to which they are bonded, can form substituted or unsubstituted heterocyclic groups selected from the groups shown below. [ka]

[0044] In some embodiments, Q is phenyl or pyridyl, and R is 0 to 5. 3 It is further substituted by the element.

[0045] In some embodiments, R 3 These are fluorine, chlorine, or bromine.

[0046] In some embodiments, R 4 These are hydrogen, fluorine, chlorine, or bromine.

[0047] Furthermore, the compound of formula (I) is selected from the following compounds and their stereoisomers, pharmaceutically acceptable salts, solvates, deuterated forms, metabolites, or prodrugs. [ka] [ka] [ka] [ka] [ka]

[0048] II. Pharmaceutical Compositions In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, deuterated forms, metabolites, or prodrugs, and at least one pharmaceutically acceptable excipient.

[0049] The compounds are described in Section I above.

[0050] The disclosed pharmaceutical compositions comprise at least one pharmaceutically acceptable excipient. Non-limiting examples of suitable excipients may include diluents, binders, fillers, buffers, pH adjusters, disintegrants, dispersants, stabilizers, preservatives, and colorants. The amount and type of excipient may be selected based on known pharmaceutical principles.

[0051] Pharmaceutical compositions can be mixed with one or more excipients to form solid, liquid, or semi-solid dosage forms. Methods for formulating solid, liquid, or semi-solid dosage forms are known in the art.

[0052] III. Method for fabricating a Sigma-1 antagonist In some embodiments, the present application provides a method for preparing the above-mentioned compounds or their stereoisomers, pharmaceutically acceptable salts, solvates, deuterated forms, metabolites, or prodrugs, comprising the following steps: [ka]

[0053] The compound of formula (I-1) can react with the compound of formula (I-2) in a nucleophilic substitution reaction under the conditions of sodium hydride and tetrahydrofuran to obtain the compound of formula (I-3), i.e., the compound of formula (II).

[0054] Alternatively, the compound of formula (I-1) can react with the compound of formula (I-4) in a nucleophilic substitution reaction under potassium carbonate / cesium carbonate conditions in acetonitrile to obtain the compound of formula (I-5), i.e., the compound of formula (II). [ka]

[0055] Alternatively, the compound of formula (I-6) can react with the compound of formula (I-7) in a cyclization reaction under the conditions of sodium fluoride in dichloromethane to obtain the compound of formula (I-8), i.e., the compound of formula (II). [ka]

[0056] Alternatively, the compound of formula (I-1) can react with the compound of formula (I-9) under potassium tert-butoxide in tetrahydrofuran to obtain the compound of formula (I-10), which is then heated in an acetic acid / tetrahydrofuran / water system to obtain the compound of formula (I-11). [ka]

[0057] The compound of formula (I-11) can be reacted with the compound of formula (I-4) in a reductive amination reaction under the conditions of sodium triacetoxyborohydride in tetrahydrofuran / dichloromethane to obtain the compound of formula (I-12), i.e., the compound of formula (II). [ka]

[0058] IV.How to use In another embodiment, the present invention provides a method for treating a disease or disorder related to the Sigma-1 receptor, the method comprising administering a pharmaceutical composition to a subject in need thereof, the pharmaceutical composition comprising a compound of formula (I).

[0059] Without being constrained by any particular theory, the compound of formula (I) is thought to act primarily as an antagonist that mediates the activity of the Sigma-1 receptor. Binding at this site is considered to be particularly beneficial for the treatment of pain-related conditions.

[0060] These compounds can be administered via a variety of routes. For example, the compound of formula (I) may be administered orally in solid or liquid dosage forms (tablets, gel caps, controlled-release capsules, powders, solutions, or suspensions in aqueous or non-aqueous liquids), parenterally (i.e., subcutaneous, intradermal, intravenous (i.e., as a solution, suspension, or emulsion in a carrier), intramuscular, intracranial, or intraperitoneal injection), or topically (i.e., transdermal or transmucosal administration, including but not limited to oral, rectal, vaginal, and sublingual).

[0061] In one embodiment, the compound may be administered in physiological saline or together with the aforementioned pharmaceutically acceptable excipients. The compound may be administered as primary therapy or adjunctive therapy after local intervention (surgery, radiation, local chemotherapy) or in combination with at least one other chemotherapeutic agent.

[0062] Preferred subjects include, but are not limited to, humans and companion animals such as cats, dogs, rodents, and horses; research animals such as rabbits, sheep, pigs, dogs, primates, mice, rats, and other rodents; livestock such as cattle, cows, pigs, goats, sheep, horses, deer, chickens, and other poultry; zoo animals; and primates such as chimpanzees, monkeys, and gorillas. There are no age restrictions on the subjects. In preferred embodiments, the subjects may be humans.

[0063] Generally, compounds of formula (I) are administered in therapeutically effective doses, including prophylactic doses or lower doses, for example, when used in combination with another formulation. As used herein, the term “effective dose” refers to a dose of the compound sufficient to provide a circulating concentration high enough to have a beneficial effect on the receptor. Those skilled in the art can determine the exact dose based on the required dose, side effects, and the patient’s medical history.

[0064] Generally, compounds of formula (I) have an EC50 of binding affinity to the Sigma-1 receptor of less than about 100 nM. In various embodiments, the EC50 of compounds comprising formula (I) is less than about 100 nM, or less than 10 nM, or less than about 5 nM, or less than about 1 nM.

[0065] Beneficial effects The compounds of the present invention can bind to the Sigma-1 receptor, possess good Sigma-1 receptor antagonistic activity, and are suitable for clinically applicable pharmaceutical applications. Furthermore, the synthesis steps of the compounds in this application are simple, thereby providing good economic value.

[0066] Terminology definitions and explanations Unless otherwise specified, the definitions of groups and terms used in this application, including those listed as examples, exemplary, preferred, in tables, or specific compounds in embodiments, may be combined and interchangeable with each other. Such subsequent definitions of groups and compound structures should be considered within the scope described herein.

[0067] The compounds described herein may have a chiral center. Compounds of the present invention containing a chiral substituted atom may be isolated in an optically active or racemic form. Unless a specific stereochemical or isomeric form is explicitly mentioned, all chiral, achiral, racemic, and geometric isomers of the structure are applicable.

[0068] As used herein, the terms "sigma-1 receptor" and "σ1 receptor" are interchangeable and should be used interchangeably.

[0069] As used herein, the term "alkyl" refers to lower alkyl groups having 1 to 6 carbon atoms in the main chain and up to 20 carbon atoms in total. These may be linear, branched, or cyclic, and include methyl, ethyl, propyl, isopropyl, butyl, and hexyl.

[0070] As used herein, either alone or as part of another group, the term “aryl” refers to a conjugated planar ring or ring system that is optionally substituted and contains delocalized electrons. These aryl groups are preferably monocyclic (e.g., furan or benzene), bicyclic, or tricyclic rings containing 5 to 14 atoms in the ring portion. The term “aromatic” includes the defined “aryl.”

[0071] The terms “aryl” or “Ar” as used herein, either alone or as part of another group, refer to a substituted aromatic group of any choice, preferably a single or bicyclic group having 6 to 10 carbon atoms in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl, or substituted naphthyl.

[0072] The terms “carbocyclic” or “carbocyclic formula,” used alone or as part of another group, refer to any optionally substituted aromatic or non-aromatic monocyclic or polycyclic group in which all atoms in the ring are carbon, preferably having 5 or 6 carbon atoms in each ring. Exemplary substituents include one or more of the following groups: alkyl, substituted alkyl, alkoxy, acyl, acyloxy, alkene, alkenoxy, aryl, aryloxy, amino, amide, acetal, aminocarbonyl, carbocyclic, cyano, ester, ether, halogen, heterocyclic, hydroxyl, ketone, ketal, phosphate, nitro, and thio.

[0073] The term “heteroaryl,” used alone or as part of another group, refers to any optionally substituted aromatic group having at least one heteroatom in at least one ring, preferably five or six atoms in each ring. Heteroaryl groups preferably have one or two oxygen atoms and / or one to four nitrogen atoms in the ring, connected to the rest of the molecule through carbon. Exemplary groups include furanyl, benzofuranyl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, quinolyl, pyrazinyl, quinoxalinyl, indolyl, isoindolyl, indolidinyl, benzimidazolyl, indazolyl, benzotriazolyl, tetrazolopyrazinyl, carbazolyl, prynyl, quinolinyl, isoquinolinyl, and imidazopyridinyl. Examples of substituents include one or more of the following groups: alkyl, substituted alkyl, alkoxy, acyl, acyloxy, alkene, alkenoxy, aryl, aryloxy, amino, amide, acetal, aminocarbonyl, carbocyclic, cyano, ester, ether, halogen, heterocyclic, hydroxyl, ketone, ketal, phosphate, nitro, and thio.

[0074] The terms “heterocyclic” or “heterocyclic” used alone or as part of another group refer to fully saturated or unsaturated monocyclic or bicyclic aromatic or non-aromatic groups that are substituted at any discretion, having at least one heteroatom in at least one ring, preferably five or six atoms in each ring. Heterocyclic groups preferably have one or two oxygen atoms and / or one to four nitrogen atoms in the ring, connected to the rest of the molecule through carbon or heteroatoms. Examples of heterocyclic groups include the heteroaryl compounds described above. Examples of substituents include one or more groups: alkyl, substituted alkyl, alkoxy, acyl, acyloxy, alkene, alkenoxy, aryl, aryloxy, amino, amide, acetal, aminocarbonyl, carbocyclic, cyano, ester, ether, halogen, heterocyclic, hydroxyl, ketone, ketal, phosphate, nitro, and thio.

[0075] As used herein, the term “protecting group” refers to a group that can protect a particular portion of a molecule, and the protecting group can be removed after the protection reaction without interfering with the rest of the molecule. When this portion is an oxygen atom (forming a protected hydroxyl group), exemplary protecting groups include ethers (e.g., allyl, triphenylmethyl (tributyl or Tr), benzyl, p-methoxybenzyl (PMB), p-methylphenyl (PMP)), acetals (e.g., methoxymethyl (MOM), β-methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), ethoxyethyl (EE), methylthiomethyl (MTM), 2-methoxy-2-propyl (MOP), 2-methyl-2-propyl (MOP)), 2-methyl-2-propyl (MOP), 2-methyl-2-propyl (2-methyl-2-propyl) Examples include trimethylsilylethoxymethyl (SEM), esters (e.g., benzoates, anhydride carbonates, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate), and silyl ethers (e.g., trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), triphenylsilyl (TPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS)). When this part is a nitrogen atom (and thus forms a protected amine), exemplary protecting groups include benzyl (e.g., p-methoxyphenyl (PMP), 3,4-dimethoxybenzyloxy (PMB)), ester (e.g., benzoates), carbonyl (e.g., p-methoxybenzylcarbonyl (Moz), tert-butoxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (FMOC)), acetyl, carbamate, and n-silyl. Various protecting groups and their synthesis methods can be found in "Greene's Protective Groups in Organic Synthesis" (4th edition) by PGMWuts and TW Greene, John Wiley & Sons, Inc.

[0076] As used herein, the term “substituted hydrocarbon” moiety refers to hydrocarbon moieties substituted by at least one non-carbon atom, including moieties in which carbon chain atoms are replaced by heteroatoms such as nitrogen, oxygen, silicon, phosphorus, boron, or halogens, and moieties in which carbon chains contain additional substituents. Examples of these substituents include alkyl, alkoxy, acyl, acyloxy, alkene, alkenoxy, aryl, aryloxy, amino, amide, acetal, aminocarbonyl, carbocyclic, cyano, ester, ether, halogen, heterocyclic, hydroxyl, ketone, ketal, phosphate, nitro, and thio.

[0077] The terms “includes,” “equip,” and “possess” are comprehensive and imply that additional elements beyond those described may exist. Following the detailed description of the invention, it will be apparent that modifications and variations can be made without departing from the scope defined in the claims.

[0078] Other features and advantages of the present invention are described below, some of which are obvious from the description or can be learned through the practice of the invention. The objectives and other advantages of the present invention can be realized and achieved by the structures specifically pointed out in the specification, claims, and drawings. [Examples]

[0079] The following provides a further detailed description of the general formula compounds of the present invention, methods for their preparation, and their uses in conjunction with specific embodiments. The following examples are provided for illustrative purposes and to illustrate the present invention. They should not be construed as limiting the scope of protection of the present invention. All techniques realized based on the foregoing aspects of the present invention are encompassed to the extent intended to be protected by the present invention.

[0080] Unless otherwise specified, the raw materials and reagents used in the following examples are either commercially available products or can be prepared by known methods.

[0081] This application uses the following abbreviations: ACN: Acetonitrile AIBN: Azobisisobutyronitrile BBr3: Boron tribromide BPO: Benzoyl peroxide CCl4: Carbon tetrachloride Cs2CO3: Cesium Carbonate DCM: Dichloromethane DCE: 1,2-Dichloroethane DIEA: N,N-diisopropylethylamine DMF: N,N-dimethylformamide EA: Ethyl acetate EtOH: Ethanol FA: Formic acid K2CO3: Potassium carbonate LAH: Lithium aluminum hydride NaH: Sodium hydride Na2SO4: Sodium sulfate NaBH4: Sodium borohydride NaBH(OAc)3: Sodium triacetoxyborohydride NaF: Sodium fluoride NBS: N-bromosuccinimide NCS: N-chlorosuccinimide PBr3: Phosphorus tribromide PE: Petroleum ether t-BuOK:tert-butoxide potassium TBAB: Tetra-n-butylammonium bromide TCCA: Trichloroisocyanuric acid TEMED:N,N,N',N'-tetramethylethylenediamine TEMPO:2,2,6,6-tetramethylpiperidine 1-oxyl THF: Tetrahydrofuran

[0082] Compounds are named according to conventional naming conventions in the field, and commercially available reagents use the supplier catalog name.

[0083] 1 ¹H NMR data were collected and recorded using a Bruker Avance NEO 400 MHz liquid superconducting nuclear magnetic resonance spectrometer at 400 MHz. Chemical shift δ values ​​(ppm) were reported using CDCl3, MeOD, and DMSO-d6 as solvents and TMS (δ=0) as an internal standard. Mass spectra were collected and recorded using a Waters ACQUITY UPLC and detected using an ACQUITY UPLC BEH C8, 50 mm × 2.1 mm, 1.7 μm (20180306-C8-08) chromatography column. Mobile phase A: 0.01% TFA / H2O, Mobile phase B: CH3CN, Flow rate: 0.2 mL / min, Column temperature: 30°C, Detection wavelength: UV-210 nm. High-performance liquid chromatography (HPLC) was performed using a Thermo UltiMate 3000 liquid chromatograph, with a Venusil ASB C18 (4.6 × 250 mm, 5 μm) column for detection. Mobile phase A: pH=1.5 aqueous phosphoric acid solution, Mobile phase B: CH3CN, Flow rate: 1.0 mL / min, Column temperature: 35°C, Detection wavelength: UV-215 nm, Injection volume: 2 μL, Gradient elution conditions: The entire process was eluted at a flow rate of 1.0 mL / min, first eluting with 95% A and 5% B for 10 minutes, then eluting with 20% A and 80% B for 5 minutes, and finally eluting with 95% A and 5% B for 5 minutes. Percentages represent the volume percentage of the mobile phase in the elution solution.

[0084] Example 1: Preparation of Intermediate I [ka] Hydroxylamine hydrochloride (366.91 g, 5.28 mol, 1.5 equivalents) was weighed and dissolved in 5 L of purified water. 3,4-difluorobenzaldehyde (500.00 g, 3.52 mol, 1.0 equivalent) was added, and after 5 hours, the molecular weight of I-1 was detected by LC-MS. The reaction mixture was filtered under vacuum and washed with purified water. The filtration cake was dissolved in DCM and separated. The organic phase was dried over anhydrous Na2SO4, filtered, and retained as a reaction mixture.

[0085] N-chlorosuccinimide (466.54 g, 3.52 mol, 1.0 equivalent) was added to the reaction mixture. After 8 hours, TLC showed no residual I-1. The reaction mixture was washed with purified water, separated, and the organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Crystallization with petroleum ether yielded 330 g of I-2.

[0086] I-2 (300.00 g, 1.57 mol, 1.0 equivalent) was dissolved in 3 L of DCM. NaHCO3 (263.79 g, 3.14 mol, 2.0 equivalent) and propargyl bromide (196.28 g, 1.65 mol, 1.05 equivalent) were added. After 24 hours, the molecular weight of intermediate I was detected by LC-MS. The reaction mixture was filtered and concentrated under reduced pressure. Column chromatography (PE:EA=20:1) was used for elution to obtain 360 g of intermediate I, a pale yellow solid. HPLC purity was 98.82%; MS m / z (ESI): 275.16 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ 7.65-7.56(m,1H),7.56-7.47(m,1H),7.44-7.33(m,1H),7.27(s,1H),4.69(s,2H).

[0087] The preparation of the compounds listed below will be carried out with reference to Example 1. [Table 3]

[0088] Example 2: Preparation of Intermediate VIII Preparation of intermediate VIII-2 [ka]

[0089] Methyl 1H-pyrazole-3-carboxylate (924 mg, 7.33 mmol, 1.00 equivalent) and VIII-1 (2.00 g, 7.33 mmol, 1.00 equivalent) were dissolved in acetonitrile (20.0 mL), followed by the addition of Cs2CO3 (4.78 g, 14.7 mmol, 2.00 equivalents), CuI (279 mg, 1.47 mmol, 0.20 equivalent), and N,N,N’,N’-tetramethylethylenediamine (170 mg, 1.47 mmol, 221 uL, 0.20 equivalent). The reaction mixture was stirred at 80 °C for 2 h. LCMS indicated that the target product content was 79.2% (m / z = 271.1, M+H + ). The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was diluted with 20.0 mL of water and extracted with 20.0 mL of ethyl acetate, followed by washing the organic phase with 60.0 mL (20.0 mL×3) of saturated brine. The organic phase was dried over Na2SO4, filtered, and concentrated. Purification by column chromatography (SiO2, PE / EA = 3:1, R f = 0.45) afforded the intermediate VIII-2 as a pale yellow solid (1.17 g, 4.04 mmol, yield 55.1%, purity 93.7%).

[0090] LCMS: m / z = 271.1, [M+H] + .

[0091] 1 H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.54 - 7.62 (m, 2H), 7.03 (d, J = 2.4 Hz, 1H), 3.98 (s, 3H).

[0092] Preparation of Intermediate VIII-3

Chemical Structure

[0093] Intermediate VIII-2 (1.17 g, 4.04 mmol, purity 93.7%, 1.00 equivalent) was dissolved in THF (10.0 mL), and LAH (2.5 M, 2.10 mL, 1.30 equivalent) was added at 0°C. The mixture was stirred for 2 hours. TLC monitoring (petroleum ether / ethyl acetate = 3:1) confirmed the complete reaction of intermediate VIII-2 (R f Rf = 0.45) and the formation of new spots (Rf = 0.01) were confirmed. At 0°C, the reactants were quenched with 0.2 mL of water, NaOH (0.20 mL) was added dropwise, followed by H2O (0.60 mL). The reaction mixture was filtered and concentrated to obtain a pale yellow solid intermediate VIII-3 (0.99 g, 3.80 mmol, yield 94.0%, purity 93.4%).

[0094] LCMS: m / z = 243.0, [M + H] + .

[0095] 1 H NMR:(400MHz,CDCl3) δ 7.85(d,J=2.4Hz,1H),7.83(s,1H),7.51(s,1H),6.49(d,J=2.8Hz,1H),4.78(s,2H).

[0096] Preparation of intermediate VIII [ka]

[0097] Intermediate VIII-3 (200 mg, 768 μmol, 93.4% purity, 1.00 equivalent) was dissolved in DCM (2.00 mL), and PBr3 (208 mg, 768 μmol, 1.00 equivalent) was added dropwise at 0°C. The mixture was stirred at 20°C for 16 hours, and LC-MS showed a target product content of 91.9% (m / z = 307.0, M + H + 2). The reaction was quenched at 0°C by adding NaHCO3 (2.00 mL). The mixture was filtered, and additional NaHCO3 (5.00 mL) and DCM (5.00 mL) were used for extraction. The organic phase was washed with 5.00 mL of saturated brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain intermediate VIII (230 mg, 720 μmol, yield 93.7%, purity 95.8%), a grayish-white solid.

[0098] LCMS: m / z = 307.0, [M + H + 2]

[0099] 1 H NMR:(400MHz,CDCl3) δ 7.84(t,J=1.6Hz,2H),7.52(d,J=1.2Hz,2H),6.56(d,J=2.8Hz,1H),4.56(s,2H).

[0100] The preparation of the compounds listed below is carried out with reference to Example 2. [Table 4]

[0101] Example 3: Preparation of Compound 1 [ka] 2-Morpholinoethanol (286 mg, 2.18 mmol, 1.2 eq) was weighed and dissolved in 15 mL of THF. NaH (146 mg, 3.64 mmol, 2.0 eq) and Intermediate I (500 mg, 1.82 mmol, 1.0 eq) were added. After 5 hours, the molecular weight of Compound 1 was detected by LC-MS. The reaction mixture was washed with saturated brine and extracted with ethyl acetate (EA). The organic phase was dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 1:1) to obtain 460 mg of Compound 1 as a white solid. HPLC purity: 98.77%; MS m / z (ESI): 325.26 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.66 - 7.48 (m, 2H), 7.42 - 7.34 (m, 1H), 6.80 (s, 1H), 4.67 (s, 2H), 3.95 - 3.35 (m, 7H), 2.77 - 2.23 (m, 7H).

[0102] The preparation of the compounds listed below is carried out by referring to Example 3.

Table 5-1

Table 5-2

Table 5-3

Table 5-4

Table 5-5

Table 5-6

Table 5-7

[0103] Example 4: Preparation of Compound 74 Preparation of Compound 74a [ka] Intermediate II (1.00 g, 3.26 mmol, 1.00 equivalent) was dissolved in acetic acid, and NBS (2.32 g, 13.0 mmol, 4.00 equivalent) and H2SO4 (1.92 g, 19.5 mmol, 1.04 mL, 6.00 equivalent) were added. The mixture was stirred at 30°C for 16 hours. LC-MS showed a target molecule content of 98.2% (m / z=385.8, M+H). + This demonstrated that the reaction was as follows: The reaction product was quenched with NaHCO3 (20.0 mL) at 10°C, diluted with 20.0 mL of water, and extracted with 20.0 mL of ethyl acetate. The organic phase was washed with 60.0 mL (20.0 mL × 3) of saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, PE / EA = 10 / 1, R f Compound 74a (1.12 g, 2.90 mmol, yield 79.5%, purity 100%), a pale yellow oil, was obtained using a ratio of 0.46.

[0104] LCMS m / z=385.8,M+H +

[0105] 1 H NMR:400MHz, CDCl3δ 8.21(d,J=2.0Hz,1H),7.98(s,1H),7.94(d,J=12.4Hz,1H),7.90(t,J=6.0Hz,3H),7.54-7.56(m,2H),7.07(s,1H),4.00(s,3H).

[0106] Preparation of Compound 74 [ka] 2-Morpholinoethanol (20.4 mg, 155 μmol, 19.0 μL, 1.20 equivalents) was dissolved in THF (0.50 mL), and NaH (5.70 mg, 142 μmol, 60.0% content, 1.00 equivalent) was added at 0°C. The reaction mixture was stirred for 0.5 hours. Then, compound 74a (50.0 mg, 129 μmol, 1.00 equivalent) was added. The mixture was stirred at 20°C for 1 hour. LC-MS yielded 82.5% of the target product (m / z = 437.0, M + H + The reaction mixture was quenched by slowly adding NH4Cl (2.00 mL) at 10°C, stirred for 0.5 hours, diluted with 2.00 mL of H2O, and extracted with 2.00 mL of ethyl acetate. The organic phase was washed with 6.00 mL (2.00 mL × 3) of saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the concentrate. Purification (FA conditions, column: Phenomenex Luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; B%: 21%~51%, 10 min) yielded compound 74 (22.0 mg, 50.2 μmol, yield 38.8%, purity 99.7%) as a yellow solid.

[0107] LCMS m / z=437.0,M+H +

[0108] 1 H NMR:400MHz, CDCl3δ 7.99(d,J=2.4Hz,1H),7.72-7.74(m,1H),7.59(d,J=8.4Hz,1H),4.71(s,2H),3.79(t,J=4.8Hz,6H),2.74(t,J=5.6Hz,2H),2.65(s,4H).

[0109] Example 5: Preparation of Compound 64 [ka] Compound 74 (100 mg, 229 μmol, 1.00 equivalent), 3-thiopheneboronic acid (32.2 mg, 252 μmol, 1.10 equivalent), Sphos Pd G2 (16.5 mg, 22.9 μmol, 0.10 equivalent), and K2CO3 (110 mg, 802 μmol, 3.50 equivalent) were added to a microwave reaction tube along with toluene (1.00 mL) and water (0.20 mL). The mixture was heated in a microwave oven at 140°C for 1 hour. LC-MS was performed on 29.0% of the target product (m / z=439.1, M+H). + The reaction mixture was filtered and concentrated under reduced pressure to obtain a concentrate. Purification (FA conditions, column: Phenomenex Luna C18 150×25mm×10μm; mobile phase: [water(FA)-ACN]; B%: 26%~56%, 58 min) yielded compound 64 (14.3 mg, 31.5 μmol, yield 13.7%, purity 96.8%), a yellow oil.

[0110] LCMS: m / z = 439.1, M+H +

[0111] 1 H NMR:400MHz, CDCl3δ 7.65(d,J=2.0Hz,1H),7.44(d,J=8.4Hz,1H),7.39-7.41(m,1H),7.35-7.36(m,1H),7.28- 7.30(m,1H),6.91-6.92(m,1H),4.62(s,2H),3.72-3.76(m,6H),2.65(s,2H),2.54(s,4H).

[0112] Example 6: Preparation of Compound 73 [ka] 2-Selenomorpholinoethanol (71.0 mg, 366 μmol, 1.00 equivalent) was dissolved in THF (1.00 mL), followed by the addition of t-BuOK (1 M, 549 μL, 1.50 equivalent), and then intermediate X (100 mg, 366 μmol, 1.00 equivalent). The reaction mixture was stirred at 20°C for 2 hours. LC-MS revealed 58.4% of the target product (m / z = 388.0, M + H).+ The mixture was shown to form ). The mixture was diluted with 2.00 mL of H2O and extracted with 2.00 mL of siRNA. The organic phase was washed with 6.00 mL (2.00 mL × 3) of saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a concentrate. Purification (FA conditions, column: Phenomenex Luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; B%: 7%~37%, 10 min) yielded compound 73 (87.7 mg, 207 μmol, yield 28.3%, purity 91.4%) as a yellow gel.

[0113] LCMS: m / z = 388.0, M+H +

[0114] 1 H NMR:400MHz, CDCl3δ 7.81(d,J=2.0Hz,1H),7.55-7.60(m,1H),7.36-7.37(m,1H),7.23-7.25(m,1H),6.50(d,J= 2.4Hz,1H),4.61(s,2H),3.66(t,J=6.4Hz,2Hz),2.96(t,J=5.2Hz,4H),2.69-2.75(m,6H).

[0115] Example 7: Preparation of Compound 37 [ka] 4-hydroxypiperidine (221 mg, 2.18 mmol, 1.2 equivalents) was weighed and dissolved in 30 mL of ACN. Potassium carbonate (K2CO3, 503 mg, 3.64 mmol, 2.0 equivalents) and intermediate I (500 mg, 1.82 mmol, 1.2 equivalents) were added. After 5 hours, the molecular weight of compound 37 was detected by LC-MS. The reaction mixture was washed with saturated brine and extracted with ethyl acetate (EA). The organic phase was dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 1:1) to obtain 400 mg of compound 37 as a yellow solid. HPLC purity: 96.86%; MS m / z (ESI): 295.23 [M+H] + ;

[0116] 1 H NMR(400MHz,DMSO-d6) δ 8.02-7.90(m,1H),7.82-7.67(m,1H),7.64-7.52(m,1H),4.58(d,J=4.0Hz,1H),3.69(s,2H),3 .52-3.40(m,1H),2.85-2.61(m,1H),2.25-2.10(m,2H),1.86-1.58(m,2H),1.52-1.31(m,2H).

[0117] The preparation of the compounds listed below will be carried out with reference to Example 7. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7]

[0118] Example 8: Preparation of Compound 65 Preparation of compound 65a [ka] Intermediate II-2 (1.00 g, 4.45 mmol, 1.00 equivalent) was dissolved in DCM (10.0 mL), and triethylamine (TEA, 676 mg, 6.68 mmol, 930 μL, 1.50 equivalent) was added. At 20°C, 2-propyne-1-ol (299 mg, 5.35 mmol, 315 μL, 1.20 equivalent) was added. The reaction mixture was stirred at 50°C for 2 hours, and the target molecular weight was detected by LC-MS. At 10°C, NaOH (aqueous solution, 2.00 mL) was added to the reaction mixture, and the mixture was stirred for 0.5 hours. The reaction mixture was diluted with 3.00 mL of water, extracted with 3.00 mL of DCM, and the organic phase was washed with 6.00 mL (2.00 mL × 3) of saturated brine. The mixture was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a concentrate. Column chromatography purification (SiO2, PE / EA = 1 / 1, R f Compound 65a (170 mg, 615 μmol, yield 13.8%, purity 88.3%) was obtained as a grayish-white solid using a ratio of 0.45. LCMS: m / z = 244.0, M+H +

[0119] Preparation of compound 65b [ka] Compound 65a (170 mg, 696 μmol, 1.00 equivalent) was dissolved in THF (2.00 mL), and NaH (30.6 mg, 766 μmol, purity 60.0%, 1.10 equivalent) was added at 0°C. The mixture was stirred for 0.5 hours, and then ethyl bromo (127 mg, 766 μmol, 84.7 μL, 1.10 equivalent) was added. The reaction mixture was stirred at 20°C for 1 hour, and LC-MS was performed to obtain 72.6% of the target product (m / z = 330.1, M + H). + The formation of ) was observed. At 10°C, the reaction product was quenched with NH4Cl (2.00 mL). The mixture was stirred at 10°C for 0.5 hours, diluted with 2 mL of water, and extracted with 2 mL of ethyl acetate. The organic phase was washed with 6.00 mL (2.00 mL × 3) of saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a concentrate. Preparative thin-layer chromatography (SiO2, PE / EA = 2 / 1, R fPurification with (0.45) yielded compound 65b (170 mg, 511 μmol, yield 73.4%, purity 99.3%), which was a yellow solid.

[0120] LCMS: m / z = 330.1, M+H +

[0121] Preparation of compound 65c [ka] Compound 65b (100 mg, 302 μmol, 1.00 equivalent) was dissolved in THF (1.00 mL), and lithium aluminum hydride (LAH, 2.5 M, 157 μL, 1.30 equivalents) was added at 0°C. The reaction mixture was stirred at 20°C for 1 hour, and LC-MS was performed to obtain 93.7% of the target product (m / z = 288.3, ​​M + H). + The reaction showed the formation of ). At 0°C, the reaction product was quenched with H2O (0.05 mL), then NaOH (0.05 mL) was added dropwise, followed by the addition of H2O (0.15 mL). The reaction mixture was filtered and concentrated under reduced pressure to obtain a yellow oily compound 65c (94.0 mg, 286 μmol, yield 94.4%, purity 87.7%).

[0122] LCMS: m / z = 288.3, ​​M+H +

[0123] Preparation of compound 65d [ka] Compound 65c (50.0 mg, 173 μmol, 1.00 equivalent) was dissolved in DCM (0.50 mL), and triethylamine (TEA, 52.6 mg, 520 μmol, 72.4 μL, 3.00 equivalent) and tosyl chloride (TosCl, 36.3 mg, 190 μmol, 1.10 equivalent) were added. The reaction mixture was stirred at 20°C for 16 hours, and LC-MS was performed to obtain the target product (m / z = 442.0, M + H). +The reaction mixture was diluted with 3.00 mL of water and extracted with 3.00 mL of DCM. The organic phase was washed with 6.00 mL (2.00 mL × 3) of saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a concentrate. Preparative thin-layer chromatography (SiO2, PE / EA=1 / 1, R f Purification using (0.58) yielded a yellow, oily compound 65d (40.0 mg, 77.9 μmol, yield 44.9%, purity 86.2%).

[0124] LCMS: m / z = 442.0, M+H +

[0125] Preparation of compound 65 [ka] Compound 65d (10.0 mg, 22.6 μmol, 1.00 equivalent) was dissolved in ACN (0.50 mL), and K2CO3 (9.37 mg, 67.8 μmol, 3.00 equivalent) and 4-hydroxypiperidine (2.52 mg, 24.8 μmol, 1.10 equivalent) were added. The mixture was stirred at 40°C for 16 hours. LC-MS revealed 67.0% of the target product (m / z=371.1, M+H). + The reaction mixture was filtered and concentrated under reduced pressure to obtain a concentrate. Purification (FA conditions, column: Phenomenex Luna C18 150×25mm×10μm; mobile phase: [water(FA)-ACN]; B%: 18%~48%, 10 min) yielded compound 65 (2.26 mg, 5.75 μmol, yield 25.4%, purity 94.5%), which was a yellow gel.

[0126] LCMS: m / z = 371.1, M+H +

[0127] 1H NMR:400MHz, CDCl3δ 7.91(d,J=2.0Hz,1H),7.64-7.67(m,1H),7.54(d,J=8.4Hz,1H),6.59(s,1H),4.69(s,2H),3.82-3.85 (m,3H),3.02-3.04(m,2H),2.88(t,J=5.2Hz,2H),2.24(s,2H),2.03-2.06(m,2H),1.73-1.76(m,2H).

[0128] Example 9: Preparation of Compound 81 [ka] Intermediate I (200 mg, 444 μmol, 1.00 equivalent) was dissolved in ACN (3.00 mL), and 4-fluoropiperidine (75.2 mg, 729 μmol, 1.00 equivalent) and Cs2CO3 (475 mg, 1.46 mmol, 2.00 equivalent) were added. The mixture was stirred at 25°C for 1 hour, and LC-MS showed complete reaction of intermediate I, with a new major peak detected. The mixture was filtered through diatomaceous earth, the filter cake was washed with ACN, and the combined organic phase was concentrated under reduced pressure to obtain a concentrate. Purification (column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (FA)-ACN]; gradient: 8%~38% B, over 12 minutes) yielded compound 81 (203 mg, 592 μmol, yield 81.1%, purity 99.9%, FA) as a white solid.

[0129] LCMS: m / z = 297.4, M+H +

[0130] 1 H NMR:(400MHz,CDCl3)δ 7.65-7.66(m,1H),7.52-7.55(m,1H),7.24-7.27(m,1H),6.47(s,1H),4.64-4.8 0(m,1H),3.76(s,2H),2.68-2.71(m,2H),2.55-2.59(m,2H),1.89-1.97(m,4H).

[0131] The preparation of the compounds listed below will be carried out with reference to Example 9. [Table 7-1] [Table 7-2]

[0132] Example 10: Preparation of Compound 91 Preparation of compound 91a [ka] Intermediate I (400 mg, 1.46 mmol, 1.00 equivalent) was dissolved in ACN (4.00 mL), and Cs2CO3 (951 mg, 2.92 mmol, 2.00 equivalent) and 4-piperidine carboxylate methyl ester (251 mg, 1.75 mmol, 1.20 equivalent) were added. The mixture was stirred at 25°C for 1 hour, and LCMS was performed on intermediate I (m / z = 337.3, M + H). + The reaction was shown to be complete and the formation of the main peak of the target product. The reaction was quenched by adding 4.00 mL of water at 20°C, extracted with dichloromethane (DCM, 4.00 mL x 3), the combined organic phase was washed with saturated brine (4.00 mL x 2), dried over Na2SO4, filtered, and concentrated to obtain a concentrate. Compound 91a (500 mg, crude product), a crude white solid, was used directly in the next step without further purification.

[0133] LCMS: m / z = 337.3, M+H +

[0134] Preparation of compound 91 [ka] Compound 91a (409 mg, 1.22 mmol, 1.00 equivalent) was dissolved in methanol (5.00 mL) and water (2.50 mL), and sodium hydroxide (146 mg, 3.65 mmol, 3.00 equivalent) was added. The mixture was stirred at 25°C for 2 hours. LC-MS analysis revealed that compound 91a (m / z=323.3, M+H) was analyzed. +The reaction was complete, and the formation of the main peak of the target product was observed. At 20°C, the reactants were quenched by adding 3.00 mL of water, then extracted with DCM (3.00 mL x 3), the combined organic phase was washed with saturated brine (3.00 mL x 2), dried over Na2SO4, filtered, and concentrated to obtain the concentrate. Purification (column: Phenomenex Luna C18 150 25 mm 10 μm; mobile phase: [water (FA)-ACN]; B%: 7%~37%, 2 min) yielded compound 91 (136 mg, 406 μmol, yield 33.4%, purity 96.3%) as a white solid.

[0135] LCMS: m / z = 23.3, M+H +

[0136] 1 H NMR:(400MHz,CDCl3)δ 11.7(s,1H),7.94-8.13(m,1H),7.75-7.75(m,1H),7.58-7.63(m,1H),7.04(s,1H),3.74 (s,2H),2.82(d,J=10.4Hz,2H),2.15-2.20(m,3H),1.79-1.82(m,2H),1.56-1.59(m,2H).

[0137] Example 11: Preparation of Compound 87 Preparation of compound 87a [ka] Compound I (300 mg, 1.09 mmol, 1.00 equivalent) and Compound 87a-1 (283 mg, 1.09 mmol, 1.00 equivalent) were dissolved in ACN (3.00 mL), and Cs2CO3 (713 mg, 2.19 mmol, 2.00 equivalent) was added. The mixture was stirred at 80°C for 3 hours, and LCMS showed that Compound I had completely reacted, with a new peak at m / z (MS=452.7, M+H). + This indicated that compound 87a (500 mg, crude product) was formed. The reaction mixture was filtered and concentrated under reduced pressure to obtain compound 87a (500 mg, crude product), a yellow gel-like substance.

[0138] LCMS: MS=452.7, M+H +

[0139] Preparation of compound 87b [ka] Compound 87a (500 mg, 1.11 mmol, 1.00 equivalent) was dissolved in RINKAN (5.00 mL) and HCl (4 M, 3.32 mL, 12.0 equivalents) in RINKAN was added. The mixture was stirred at 20°C for 16 hours. LC-MS showed that compound 87a had reacted completely and a new target product peak m / z (MS=352.4, M+H+) had been formed. The reaction mixture was concentrated under reduced pressure to obtain compound 87b (450 mg, crude product, HCl) as a white solid.

[0140] LCMS: MS=352.4, M+H +

[0141] Preparation of compound 87 [ka] Compound 87b (450 mg, 1.28 mmol, 1.00 equivalent) was dissolved in MeOH (3.60 mL) and H2O (0.90 mL), and LiOH·H2O (107 mg, 2.56 mmol, 2.00 equivalent) was added. The mixture was stirred at 20°C for 2 hours, and LC-MS showed that compound 87b had reacted completely, and a new target product peaked at m / z (MS=338.3, M+H). + This indicated the formation of compound 87. The reaction mixture was filtered and concentrated under reduced pressure to obtain a concentrate. Purification (column: Phenomenex Luna C18 200×40mm×10μm; mobile phase: [water(HCl)-ACN]; B%: 3%~33%, 10 min) yielded compound 87 as a white solid (200 mg, 584 μmol, yield 45.6%, purity 98.5%).

[0142] LCMS: MS=338.3, M+H +

[0143] 1H NMR:(400MHz,DMSO-d6)δ 7.94-7.99(m,1H),7.77(t,J=4.8Hz,1H),7.59-7.61(m,1H),7.06(s,1H),3.79(s,2H),2.65(s,4H),2.06-2.12(m,2H),1.80-1.83(m,2H).

[0144] Example 12: Preparation of Compound 51 Preparation of compound 51a [ka] Intermediate II (0.10 g, 322 μmol, 98.8% purity, 1.00 equivalent) was dissolved in THF (2.00 mL), and 2,2-dimethoxyethanol (68.3 mg, 644 μmol, 2.00 equivalent) and t-BuOK (1.00 M, 966 μL, 3.00 equivalent) were added. The mixture was stirred at 0°C for 3 hours, and TLC (PE:EA = 3:1) showed that compound II had completely reacted (R f =0.65) and the formation of many new spots (R f The reaction was monitored (=0.35). The reaction was quenched at 20°C by adding 4.00 mL of H2O, extracted with Depositphotos (8.00 mL x 3), and washed with saturated brine (10.0 mL x 2). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the concentrate. Purification (SiO2, PE:EA = 3:1) yielded compound 51a (56.0 mg, 164 μmol, yield 50.9%, purity 97.2%) as a pale yellow liquid.

[0145] 1 H NMR:400MHz, CDCl3δ 7.91(d,J=2.0Hz,1H),7.64-7.67(m,1H),7.55d,J=8.4Hz,1H),6.58(s,1H) ,4.73(s,2H),4.54-4.57(m,1H),3.64(d,J=5.2Hz,1H),3.41-3.45(m,6H).

[0146] Preparation of compound 51b [ka] Compound 51a (0.05 g, 151 μmol, 1.00 equivalent) was dissolved in AcOH (0.40 mL), THF (0.10 mL), and water (0.10 mL). The mixture was stirred at 70°C for 10 hours, and LC-MS showed that compound 51a had completely reacted, and a new target peak (m / z = 286.1, M+H) was observed. + This indicated that ) was produced. The reaction mixture was concentrated under pressure to obtain a yellow, oily compound 51b (0.05 g, crude product).

[0147] LCMS: m / z = 286.1, M+H +

[0148] Preparation of compound 51 [ka] Compound 51b (0.04 g, 139 μmol, 1.00 equivalent) was dissolved in THF (0.50 mL) and DCM (0.50 mL), and compound 51c (32.2 mg, 167 μmol, 1.20 equivalent) and NaBH(OAc)3 (59.3 mg, 279 μmol, 2.00 equivalent) were added. The mixture was stirred at 20°C for 16 hours. LC-MS showed that compound 51b had reacted completely, and a new target peak (m / z = 462.2, M+H) was observed. + This demonstrated the formation of ). The crude product was purified (column: Phenomenex Luna C18 150×25mm×10μm; mobile phase: [water(FA)-ACN]; B%: 57%~87%, 10 min) to obtain a yellow oily compound 51 (24.0 mg, 50.8 μmol, yield 36.4%, purity 97.9%).

[0149] LCMS: m / z = 462.2, M+H +

[0150] 1H NMR:400MHz, CDCl3δ 7.91(t,J=2.0Hz,1H),7.64-7.66(m,1H),7.55(d,J=8.4Hz,1H),6.56(s,1H),4.69(s,2H),4. 28(t,J=5.6Hz,2H),3.96(s,2H),3.81(t,J=5.2Hz,2H),3.16-3.15(m,2H),2.94-2.96(m,2H).

[0151] The preparation of the compounds listed below will be carried out with reference to Example 12. [Table 8]

[0152] Example 13: Preparation of Compound 78 Preparation of compound 78b [ka] Compound 78a (1.00 g, 9.34 mmol, 877 μL, 1.00 equivalent) was dissolved in MeOH (5.00 mL) and H2O (5.00 mL), and NH2OH·HCl (778 mg, 11.2 mmol, 1.20 equivalent) was added. The mixture was stirred at 25°C for 5 hours and then subjected to TLC (PE:EA = 1:1, R f The reaction was monitored for complete reaction of compound 78a and formation of new spots (0.45). The reaction mixture was filtered and concentrated under reduced pressure to obtain a white solid 78b (1.20 g, crude product).

[0153] 1 H NMR:(400MHz,DMSO-d6) δ 10.3(s,1H),8.87(d,J=6.8Hz,2H),8.41(s,1H),8.12(d,J=6.4Hz,2H).

[0154] Preparation of compound 78c [ka] Compound 78b (500 mg, 4.09 mmol, 1.00 equivalent) was dissolved in DMF (5.00 mL), and NCS (546 mg, 4.09 mmol, 1.00 equivalent) was added. The mixture was stirred at 20°C for 12 hours, and TLC (PE:EA = 1:1, R) was performed. f The reaction was monitored for complete reaction of compound 78b and formation of new spots (0.55). The reaction mixture was filtered and concentrated under reduced pressure to obtain compound 78c (700 mg, crude product), a white solid.

[0155] 1 H NMR:(400MHz,DMSO-d6) δ 11.0(s,1H),8.85(d,J=6.4Hz,2H),8.11(d,J=6.4Hz,2H).

[0156] Preparation of compound 78d [ka] 2-Morpholinoethanol (2.12 g, 16.1 mmol, 1.97 mL, 1.20 equivalents) was dissolved in THF (20.0 mL), and NaH (645 mg, 16.1 mmol, 60.0% content, 1.20 equivalents) was added dropwise at 0°C and the mixture was stirred for 0.5 hours. At 20°C, 3-bromopropine (2.00 g, 13.4 mmol, 1.45 mL, 1.00 equivalent) was added dropwise and the mixture was stirred for 11.5 hours. LC-MS showed the complete reaction of 2-morpholinoethanol and a new target product peak (m / z = 170.1, M+H). + The reaction showed the formation of compound 78d. At 0°C, the reaction was quenched by adding 10.0 mL of H2O, the mixture was extracted with siRNA (10.0 mL x 3), washed with saturated brine (10.0 mL x 3), the combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 78d (2.20 g, 13.0 mmol, yield 96.7%), a yellow liquid.

[0157] LCMS: m / z = 170.1, M+H +

[0158] Preparation of compound 78 [ka] Compound 78d (300 mg, 1.77 mmol, 1.00 equivalent) was dissolved in DCM (3.00 mL), and NaF (245 mg, 5.85 mmol, 245 μL, 3.30 equivalents) and compound 78b (333 mg, 2.13 mmol, 1.20 equivalents) were added. The mixture was stirred at 50°C for 6 hours, and LC-MS showed a complete reaction of compound 78d, with the main peak of the target product (m / z = 290.1, M+H) being present. + This indicated that compound 78 was formed. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified (column: Phenomenex C18 250×50mm×10um; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 8%~38%, 8 min) to obtain compound 78 (110 mg, 374 μmol, yield 21.1%, purity 98.4%), a yellow solid.

[0159] LCMS: m / z = 290.1, M+H +

[0160] 1 H NMR:(400MHz,CDCl3) δ 8.75(d,J=5.6Hz,2H),7.69(d,J=6.0Hz,2H),6.64(s,1H),4.71(s,2H),3.73-3.76(m,6H),2.54-2.68(m,6H).

[0161] The preparation of the compounds listed below will be carried out with reference to Example 13. [Table 9]

[0162] Example 14: Preparation of Compound 98 Preparation of compound 98b [ka] Compound 98a (500 mg, 3.23 mmol, 1.00 equivalent) was dissolved in MeOH (5.00 mL), and NaBH4 (244 mg, 6.45 mmol, 2.00 equivalent) was added. The reaction mixture was stirred at 0°C for 2 hours, and TLC (PE:EA = 2:1, R) was performed. f The complete reaction of compound 98a and the formation of new spots were monitored at a dilution of 0.50. The reaction product was quenched with 5.00 mL of H2O, the mixture was extracted with ethyl acetate (5.00 mL x 3), washed with saturated brine (5.00 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a yellow, oily compound 98b (450 mg, 2.87 mmol, yield 88.8%).

[0163] 1 H NMR:(400MHz,CDCl3) δ 4.13-4.18(m,1H),3.68-3.78(m,4H),1.89-1.99(m,4H).

[0164] Preparation of compound 98c [ka] Intermediate I (2.00 g, 7.30 mmol, 1.00 equivalent) and tert-butyl(2-hydroxyethyl) carbamate (1.41 g, 8.76 mmol, 1.36 mL, 1.20 equivalents) were dissolved in DCM (20.0 mL), and TBAB (1.65 g, 5.11 mmol, 0.70 equivalents) and NaOH (10.0 M, 1.46 mL, 2.00 equivalents) were added. The reaction mixture was stirred at 20°C for 12 hours, and LC-MS showed a complete reaction of intermediate I, resulting in a new target molecule (m / z=377.3, M+Na). + The reaction mixture was extracted with 30.0 mL of DCM, washed with saturated brine (30.0 mL), the combined organic phase was dried with Na2SO4, filtered, and concentrated under reduced pressure to obtain a concentrate, which was then subjected to column chromatography (SiO2, PE / EA = 10 / 1~3 / 1, R f The compound was purified using a solution of 0.50 to obtain a pale yellow, oily compound 98c (1.00 g, 2.82 mmol, yield 38.7%).

[0165] LCMS: m / z = 377.3, M + Na +

[0166] 1 H NMR:(400MHz,CDCl3)δ 7.63-7.69(m,1H),7.52-7.56(m,1H),7.23-7.29(m,1H),6.53(s,1H),4.89 (s,1H),4.66(s,1H),3.64(t,J=4.8Hz,2H),3.37-3.38(m,2H),1.45(s,9H).

[0167] Preparation of compound 98d [ka] Compound 98c (800 mg, 2.26 mmol, 1.00 equivalent) was dissolved in Depositphotos (8.00 mL), and HCl / Depositphotos (4.00 M, 5.64 mL, 10.0 equivalents) was added. The reaction mixture was stirred at 20°C for 2 hours, and LC-MS showed a complete reaction of compound 98c, with a new target major peak (m / z = 255.5, M + H). + This indicated that compound 98d was produced. The reaction mixture was concentrated under reduced pressure to obtain compound 98d (750 mg, crude, HCl), a white solid.

[0168] LCMS: m / z = 255.5, M + H +

[0169] Preparation of compound 98 [ka] Compound 98d (200 mg, 688 μmol, 1.00 equivalent, HCl) was dissolved in DMF (2.00 mL), and DIEA (444 mg, 3.44 mmol, 599 μL, 5.00 equivalent) and compound 98b (130 mg, 825 μmol, 1.20 equivalent) were added. The mixture was stirred at 85°C for 12 hours. LC-MS showed a complete reaction of compound 98d, with the target major peak (m / z = 339.3, M+H) +This indicated that compound 98 was produced. The reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product, which was then purified by preparative separation (column: Phenomenex Luna C18 150×30mm×5μm; mobile phase: [water(HCl)-ACN]; gradient: 15%~45% B over 10 minutes) to obtain a yellow oily compound 98 (100 mg, 281 μmol, yield 40.8%, purity 95.0%).

[0170] LCMS: m / z = 339.3, M+H +

[0171] 1 H NMR:(400MHz,MeOD) δ 7.78-7.83(m,1H),7.68-7.71(m,1H),7.38-7.45(m,1H),6.96(s,1H),4.78-4.80(m,2H),4.07-4.10(m,0.5H),3. 91-3.96(m,2H),3.81-3.86(m,0.5H),3.61-3.64(m,1H),3.35-3.43(m,4H),3.06-3.13(m,1H),1.74-2.15(m,4H).

[0172] Example 15: Preparation of Compound 99 Preparation of compound 99b [ka] Compound 99a (1.15 g, 4.79 mmol, 1.00 equivalent), 4-methoxy-1H-indole (710 mg, 4.79 mmol, 1.00 equivalent), CuI (274 mg, 1.44 mmol, 0.30 equivalent), TEMED (111 mg, 958 μmol, 145 μL, 0.20 equivalent), and Cs2CO3 (3.12 g, 9.58 mmol, 2.00 equivalent) were dissolved in ACN (15.0 mL), and the mixture was purged three times with N2. Under nitrogen protection, the reaction was stirred at 85°C for 2 hours. LCMS showed a complete reaction of compound 99a, with a new target major peak (m / z = 261.1, M+H). +This indicated that the following was produced. The reaction mixture was added to 50.0 mL of H2O for phase separation, and the organic phase was separated. The aqueous phase was washed with 60.0 mL (30.0 mL × 2) of dichloromethane, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was then subjected to column chromatography (SiO2, PE:EA = 10:1, R f The compound was purified using a solution of 0.46 to obtain a yellow solid compound 99b (400 mg, 1.53 mmol, yield 31.9%, purity 99.3%).

[0173] LCMS: m / z = 261.1, M+H +

[0174] 1 H NMR:400MHz, CDCl3δ 8.27(s,1H),7.50-7.51(m,1H),7.47-7.50(m,1H),7.27-7.40(m,3H),6.59(d,J=8.0Hz,1H),4.01(s,3H).

[0175] Preparation of compound 99c [ka] Compound 99b (100 mg, 384 μmol, 1.00 equivalent) was dissolved in DCM (1.00 mL), and BBr3 (289 mg, 1.15 mmol, 111 μL, 3.00 equivalent) was added at 0°C. The reaction mixture was stirred at 20°C for 4 hours. LC-MS showed a complete reaction of compound 99b, with a new target major peak (m / z = 247.3, M+H). + This indicated that compound 99c was produced. At 0°C, H2O (3.00 mL) was added to the reaction mixture, then extracted, filtered, and concentrated under reduced pressure to obtain a white solid compound 99c (90.0 mg, 362 μmol, yield 94.2%, purity 99.1%).

[0176] LCMS: m / z = 247.3, M+H +

[0177] Preparation of compound 99 [ka] Compound 99c (100 mg, 406 μmol, 1.00 equivalent), N-(2-chloroethyl)morpholine hydrochloride (90.7 mg, 487 μmol, 1.20 equivalent), and Cs2CO3 (397 mg, 1.22 mmol, 3.00 equivalent) were dissolved in DMF (2.00 mL), and the atmosphere was changed to nitrogen three times. The mixture was stirred at 60°C for 3 hours under nitrogen protection. LC-MS showed a complete reaction of compound 99c, with a new target major peak (m / z = 360.4, M+H). + This indicated that compound 99 was produced. The DMF (2.00 mL) was removed under reduced pressure, and the concentrate was purified (column: Phenomenex Luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; B%: 11%~41%, 10 min) to obtain compound 99 (28.3 mg, 267 μmol, yield 65.6%, purity 95.8%) as a white solid.

[0178] LCMS: m / z = 360.4, M+H +

[0179] 1 H NMR:400MHz, CDCl3δ 8.24(s,1H),7.36-7.59(m,1H),7.34-7.34(m,1H),7.27-7.34(m,3H),6.58(d,J=7.6Hz,1 H),4.36(d,J=5.6Hz,2H),3.774-3.78(m,4H),2.96(d,J=3.78Hz,2H),2.69-2.72(m,4H).

[0180] Example 16: Preparation of Compound 100 Preparation of compound 100b [ka] Compound 100a (5.00 g, 39.2 mmol, 4.27 mL, 1.00 equivalent) was dissolved in CCl4 (50.0 mL), and BPO (94.9 mg, 392 μmol, 0.01 equivalent) and NBS (6.28 g, 35.3 mmol, 0.90 equivalent) were added. The mixture was stirred at 80°C for 16 hours, and LCMS was performed to obtain the target compound m / z (m / z = 207.9, M + H). + The reaction mixture was concentrated under reduced pressure, and the concentrate was subjected to column chromatography (SiO2, PE:EA=10:1, R f The compound was purified using a solution of 0.56 to obtain a yellow, oily compound 100b (3.30 g, 11.7 mmol, yield 29.9%, purity 73.2%).

[0181] LCMS: m / z = 207.9, M+H +

[0182] Preparation of compound 100c [ka] Compound 100b (3.30 g, 11.7 mmol, 1.00 equivalent) was dissolved in ACN (20.0 mL), and morpholine (2.04 g, 23.4 mmol, 2.06 mL, 2.00 equivalent) was added. The mixture was stirred at 20°C for 2 hours, and LC-MS showed the formation of the target compound (m / z = 213.1, M + H). + The reaction mixture was diluted with 20 mL of water, extracted with 20.0 mL of ethyl acetate, washed with saturated saline (30.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a yellow, oily crude product 100c (1.70 g, 7.40 mmol, yield 63.3%, purity 92.6%) without purification, and proceeded directly to the next step.

[0183] LCMS: m / z = 213.1, M+H +

[0184] Preparation of compound 100d [ka] At 20°C, compound 100c (500 mg, 2.18 mmol, 1.00 equivalent) was dissolved in hydrated hydrazine (1.22 g, 24.0 mmol, 1.19 mL, purity 98.0%, 11.0 equivalent). The mixture was stirred at 110°C for 24 hours, and LC-MS was performed to obtain the target compound (m / z=209.1, M+H). + The reaction mixture was concentrated under reduced pressure, and the crude product was used in the next step without purification to obtain 100d (500 mg, crude product), a yellow, oily compound.

[0185] LCMS: m / z = 209.1, M+H +

[0186] Preparation of compound 100e [ka] Compound 100d (200 mg, 960 μmol, 1.00 equivalent) was dissolved in DCM (2.00 mL), and TEA (97.2 mg, 960 μmol, 134 μL, 1.00 equivalent) and chloroisocyanurate (154 mg, 864 μmol, 0.90 equivalent, HCl) were added. The mixture was stirred at 20°C for 2 hours, and LCMS was performed on the target compound (m / z = 314.1, M + H). + The reaction mixture was concentrated under reduced pressure, and the crude product was used in the next step without purification to obtain 100e (300 mg, crude product), a yellow, oily compound.

[0187] LCMS: m / z = 314.1, M+H +

[0188] Preparation of compound 100 [ka] Compound 100e (300 mg, 777 μmol, 1.00 equivalent) was placed in a microwave reaction tube, and AcOH (3.00 mL) was added. The tube was sealed and heated in a microwave oven at 160°C for 3 hours. LC-MS was performed on the target compound (m / z = 296.2, M+H). +The reaction mixture was concentrated under reduced pressure, and the crude product was collected in a basic column (Phenomenex C18 250×50mm×10μm; mobile phase: [water(NH4)]). 3· The compound was purified using [H2O)-ACN]; B%: 1%~25%, 10 min) to obtain compound 100 (150 mg, 508 μmol, yield 50.0%, purity 100%) as a white solid.

[0189] LCMS: m / z = 296.2, M+H +

[0190] 1 H NMR:(400MHz,CDCl3) δ 8.87(d,J=6.0Hz,2H),8.29(d,J=6.8Hz,1H),7.81-7.82(m,2H),7.47(s 1H),7.00(t,J=6.8Hz,1H),4.11(s,2H),3.80(s,4H),2.68(s,4H).

[0191] Example 17: Preparation of Compound 101 Preparation of compound 101b [ka] Compound 100d (250 mg, 1.20 mmol, 1.00 equivalent) was dissolved in DCM (2.00 mL), and compound 101a (191 mg, 1.08 mmol, 135 μL, 0.90 equivalent) was added. The reaction mixture was stirred at 20°C for 16 hours. LC-MS analysis was performed on the target compound (m / z = 349.1, M+H). + The reaction mixture was concentrated under reduced pressure to obtain a yellow solid 101b (250 mg, crude product).

[0192] LCMS: MS=349.1, M+H +

[0193] Preparation of compound 101 [ka] Compound 101b (157 mg, 452 μmol, 1.00 equivalent) was placed in a microwave reaction tube and dissolved in AcOH (2.50 mL). The tube was sealed and heated in a microwave oven at 160°C for 2 hours. LC-MS showed the formation of the target compound (m / z = 331.1, M + H +). The reaction mixture was concentrated under reduced pressure to obtain a concentrate, which was then treated with NH3·H2O (3.00 mL) and filtered. The filtered cake was dried under reduced pressure to obtain a yellow solid compound 101 (140 mg, 415 μmol, yield 91.8%, purity 97.9%).

[0194] LCMS:m / z:331.1,M+H +

[0195] 1 HNMR(400MHz,CDCl3) δ 8.14-8.16(d,J=6.8Hz,1H),7.61-7.70(m,1H),7.58-7.59(m,1H),7.44-7 .58(m,2H),6.96(t,J=6.8Hz,1H),4.08(s,2H),3.79(s,4H),2.63(s,4H).

[0196] Example 18: Preparation of Compound 103 Preparation of compound 103b [ka] Compound 103a (1.00 g, 4.52 mmol, 1.00 equivalent) was dissolved in THF (10.0 mL). At 0°C, i-PrMgCl·LiCl (1.3 M, 5.21 mL, 1.50 equivalent) was added, and the reaction mixture was stirred for 1 hour. Then, while maintaining the temperature at 0°C, 4-pyridinecarbaldehyde (713 mg, 6.66 mmol, 627 μL, 1.47 equivalent) was added, and the reaction was continued for 3 hours. LC-MS revealed complete consumption of 4-pyridinecarbaldehyde and a new target peak (MS=250.3, M+H). +The reaction mixture was quenched with NH4Cl (10.0 mL), extracted with dimethyl (10.0 mL x 3), washed with saturated brine (10.0 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a concentrate. Preparative thin-layer chromatography (PE / EA = 2 / 1, R f Using a ratio of 0.26, a brownish oily compound 103b (860 mg, 3.07 mmol, yield 68.0%, purity 89.1%) was obtained.

[0197] LCMS: MS=250.3, M+H +

[0198] Preparation of compound 103c [ka] Compound 103b (860 mg, 3.07 mmol, 1.00 equivalent) was dissolved in DCM (9.00 mL). At 0°C, TEMPO (19.3 mg, 123 μmol, 0.04 equivalent) and KOAc (376 mg, 3.84 mmol, 1.25 equivalent) were added, followed by the dropwise addition of TCCA (321 mg, 1.38 mmol, 0.45 equivalent). The reaction mixture was maintained at 0°C and stirred for 2 hours. LC-MS was performed to confirm the complete reaction of compound 103b and the new target compound (MS=248.4, M+H). + The reaction mixture was filtered through diatomaceous earth, and the filtered cake was washed with DCM. Preparative thin-layer chromatography (PE / EA=2 / 1, R f Using a ratio of 0.48, a brownish oily compound 103c (570 mg, 1.99 mmol, yield 64.9%, purity 86.5%) was obtained.

[0199] LCMS: MS=248.3, M+H +

[0200] Preparation of compound 103d [ka] Compound 103c (570 mg, 1.99 mmol, 1.00 equivalent) was dissolved in pyridine (5.00 mL), and NH2OH·HCl (346 mg, 4.98 mmol, 2.50 equivalents) was added. The mixture was stirred at 50°C for 12 hours. LC-MS was performed to confirm the complete reaction of compound 103c and the new target compound (MS=263.4, M+H). + The formation of compound 103d was observed. Pyridine was removed under reduced pressure, the residue was diluted with 5.00 mL of H2O, and then extracted with ÃA (5.00 mL × 3). The combined organic layers were washed with saturated brine (5.00 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the yellow solid compound 103d (500 mg, 1.85 mmol, yield 93.0%, purity 97.3%).

[0201] LCMS: MS=263.4, M+H +

[0202] Preparation of compound 103e [ka] Compound 103d (200 mg, 741 μmol, 1.00 equivalent) and t-BuOK (1 M, 1.48 mL, 2.00 equivalent) were added to a microwave reaction tube, dissolved in THF (2.00 mL), the tube was sealed, and heated in a microwave at 100°C for 2 hours. LC-MS showed that compound 103d partially reacted, and a new target compound was formed (MS = 227.3, M + H + This indicated the formation of compound 103e. The reaction mixture was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (PE:EA=1 / 1, Rf=0.18) to obtain a pale yellow solid compound 103e (90.0 mg, 306 μmol, yield 41.3%, purity 77.0%).

[0203] LCMS: MS=227.3, M+H +

[0204] Preparation of compound 103f [ka] Compound 103e (90.0 mg, 398 μmol, 1.00 equivalent) was dissolved in DCM (1.00 mL), cooled to 0°C, and BBr3 (109 mg, 437 μmol, 42.2 μL, 1.10 equivalent) was added. The mixture was stirred at 20°C for 10 hours. LC-MS showed that compound 103e had reacted completely, and a new target product peak (MS=213.3, M+H) was observed. + This indicated that compound 103f was produced. The reaction mixture was quenched with 1 mL of water, stirred at 20°C for 0.5 hours, and the mixture was concentrated under reduced pressure to obtain compound 103f (130 mg, crude), a yellow solid.

[0205] LCMS: MS=213.3, M+H +

[0206] Preparation of compound 103 [ka] Compound 103f (130 mg, 613 μmol, 1.00 equivalent) was dissolved in ACN (1.30 mL), and compound 103g (137 mg, 919 μmol, 1.50 equivalent) and Cs2CO3 (399 mg, 1.23 mmol, 2.00 equivalent) were added. The mixture was stirred at 20°C for 1 hour. LC-MS showed that compound 103f had reacted completely, and a new target peak was observed (MS=326.3, M+H). + This indicated that compound 103 was produced. The reaction mixture was filtered, concentrated under reduced pressure, and purified (column: Waters xbridge 150×25mm×10μm; mobile phase: [water(NH3·H2O)-ACN]; B%: 25%~45%, 10 min) to obtain compound 103 (60.0 mg, 182 μmol, yield 29.7%, purity 98.6%) as a grayish-white solid.

[0207] LCMS: MS=326.3, M+H +

[0208] 1H NMR:(400MHz,CDCl3)δ 8.85(t,J=4.8Hz,2H),7.88(t,J=4.4Hz,2H),7.51(d,J=8.0Hz,1H),7.35(t,J=8H z,1H),7.10(d,J=7.6Hz,1H),4.46(s,2H),3.77(s,4H),2.97(s,2H),2.69(s,4H).

[0209] Example 19: Preparation of Compound 106 Preparation of compound 106b [ka] Compound 106a (1.00 g, 5.18 mmol, 1.00 equivalent) was dissolved in THF (10.0 mL), and i-PrMgCl-LiCl (1.50 M, 5.18 mL, 1.50 equivalent) was added at 0°C. The reaction mixture was stirred at 20°C for 2 hours. HPLC showed that the starting materials had reacted completely. The reaction mixture was used in the next step without purification.

[0210] Preparation of compound 106c [ka] Compound 106b (1.13 g, 5.20 mmol, 1.17 mL, 1.00 equivalent) was dissolved in THF (10.0 mL), and 2-fluoro-3-methoxybenzaldehyde (961 mg, 6.24 mmol, 1.20 equivalent) was added. The reaction mixture was stirred at 25°C for 12 hours. LC-MS showed that compound 106b had reacted completely and a new target peak had been generated. The reaction mixture was quenched with NH4Cl (10.0 mL), extracted with Âx (10.0 mL × 3), washed with saturated brine (10.0 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a yellow, oily compound 106c (900 mg, 3.36 mmol, 64.5% yield).

[0211] Preparation of compound 106d [ka] Compound 106c (500 mg, 1.86 mmol, 1.00 equivalent) was dissolved in DCM (8.00 mL), and MnO2 (1.62 g, 18.6 mmol, 10.0 equivalent) was added. The reaction mixture was stirred at 25°C for 2 hours, showing complete reaction of compound 106c, and a new target peak was observed in LCMS (m / z = 267.4, M+H). + This indicated that ) was produced. The reaction mixture was concentrated under reduced pressure to obtain a yellow, oily compound 106d (500 mg, crude product).

[0212] LCMS: m / z = 267.4, M+H +

[0213] Preparation of compound 106e [ka] Compound 106d (500 mg, 1.88 mmol, 1.00 equivalent) was dissolved in pyridine (5.00 mL), and hydroxylamine hydrochloride (NH2OH·HCl, 326 mg, 4.70 mmol, 2.50 equivalents) was added. The reaction mixture was stirred at 50°C for 12 hours. LC-MS showed complete reaction of compound 106d and a new target peak (m / z=282.3, M+H). + The reaction mixture was concentrated under reduced pressure to obtain compound 106e (326 mg, 1.15 mmol, yield 61.2%, purity 99.2%), a yellow solid.

[0214] LCMS: m / z = 282.3, M+H +

[0215] 1 H NMR:(400MHz,CDCl3) δ 7.47-7.53(m,1H),7.38-7.43(m,1H),7.18-7.22(m,2H),6.95-6.99(m,1H),6.77-6.81(m,1H),3.95(s,3H).

[0216] Preparation of compound 106f [ka] Compound 106e (230 mg, 817 μmol, 1.00 equivalent) was dissolved in DMSO (2.50 mL), and K2CO3 (169 mg, 1.23 mmol, 1.50 equivalent) was added. The reaction mixture was stirred at 80°C for 12 hours. LC-MS confirmed the complete reaction of compound 106e and revealed a new target peak (m / z = 262.3, M+H). + The reaction was shown to produce compound 106f (106f). The reaction was quenched with 5.00 mL of water at 25°C and extracted with ethyl acetate (ÃO, 5.00 mL x 3). The organic phase was washed with saturated brine (5.00 mL x 3), dried over sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure to obtain the brown solid compound 106f (170 mg, 633 μmol, yield 77.5%, purity 97.4%).

[0217] LCMS: m / z = 262.3, M+H +

[0218] 1 H NMR:(400MHz,CDCl3) δ 7.72-7.85(m,2H),7.31-7.45(m,3H),7.05(d,J=7.6,1H),4.09(s,3H).

[0219] Preparation of 106 g of compound [ka] Compound 106f (170 mg, 650 μmol, 1.00 equivalent) was dissolved in dichloromethane (DCM, 2.00 mL), and boron tribromide (BBr3, 489 mg, 1.95 mmol, 188 μL, 3.00 equivalent) was added at 0°C. The reaction mixture was stirred at 20°C for 12 hours. LC-MS confirmed the complete reaction of compound 106f and a new target peak (m / z = 248.3, M+H). + The reaction was shown to produce ). The reaction was quenched with H2O (3.00 mL) at 0°C, then extracted, filtered, and concentrated to obtain 106 g (172 mg, crude) of the yellow solid compound.

[0220] LCMS: m / z = 248.3, M+H +

[0221] 1 H NMR:EC6663-444-P1A(400MHz,CDCl3) δ 7.72-7.85(m,2H),7.29-7.45(m,3H),7.12-7.14(m,1H).

[0222] Preparation of compound 106 [ka] 106 g (170 mg, 687 μmol, 1.00 equivalent) of the compound was dissolved in acetonitrile (ACN, 2.00 mL), and K2CO3 (142 mg, 1.03 mmol, 1.50 equivalent) and 4-(2-chloroethyl)morpholine (123 mg, 825 μmol, 1.20 equivalent) were added. The reaction mixture was stirred at 20°C for 5 hours. LC-MS showed complete reaction of 106 g of the compound and a new target peak (m / z = 361.4, M+H). + The reaction was shown to produce compound 106 (165 mg, 452 μmol, yield 65.7%, purity 98.2%) as a brown solid. The reaction was quenched with 10 mL of water at 25°C, filtered, and concentrated under reduced pressure.

[0223] LCMS: m / z = 361.4, M+H +

[0224] 1 H NMR:(400MHz,DMSO-d6) δ 8.75(d,J=5.6Hz,2H),7.69(d,J=6.0Hz,2H),6.64(s,1H),4.71(s,2H),3.73-3.76(m,6H),2.54-2.68(m,6H). Example 20: Preparation of Compound 107 Preparation of compound 107b [ka] Compound 107a (500 mg, 1.51 mmol, 1.00 equivalent) was dissolved in DMSO (5.00 mL) and added dropwise to K2CO3 (314 mg, 2.27 mmol, 1.50 equivalent). The mixture was heated to 80°C and stirred for 2 hours. TLC monitoring revealed the formation of new spots, which prompted preliminary purification (PE:EA = 2:1, Rf(P1) = 0.28, Rf(R1) = 0.73). The reaction mixture was diluted with 10.0 mL of water and extracted with ethyl acetate (10.0 mL x 3). The organic phase was washed with saturated brine (10.0 mL), dried over sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure to obtain a yellow solid crude product 107b (500 mg, crude), which was used directly in the next reaction step without further purification. Preparation of compound 107c [ka] Compound 107b (200 mg, 645 μmol, 1.00 equivalent) was dissolved in THF (2.00 mL) and cooled to 0°C. Then, i-PrMgCl.LiCl (1.30 M, 744 μL, 1.50 equivalents) was added, and the mixture was maintained at 0°C and stirred for 2 hours. HPLC analysis showed complete reaction of the starting materials. The crude product, a colorless liquid 107c (215.0 mg, crude), was used directly in the next step without purification.

[0225] Preparation of compound 107d [ka] Compound 107c (215 mg, 642 μmol, 1.00 equivalent) was dissolved in THF (2.00 mL), and DMF (93.9 mg, 1.29 mmol, 98.9 μL, 2.00 equivalent) was added. The mixture was stirred at 20°C for 12 hours. LC-MS analysis confirmed the complete reaction of compound 107c and revealed a new target peak (m / z = 260.3, M+H). + The reaction mixture was concentrated under reduced pressure to obtain a brown solid crude product 107d (200 mg, crude), which was used directly in the next step without purification.

[0226] LCMS: m / z = 260.3, M+H +

[0227] Preparation of compound 107 [ka] Compound 107d (100 mg, 385 μmol, 1.00 equivalent) was dissolved in methanol (MeOH, 0.20 mL), and NaBH3CN (72.7 mg, 1.16 mmol, 3.00 equivalent) and morpholine (40.3 mg, 462 μmol, 40.7 μL, 1.20 equivalent) were added. The reaction mixture was stirred at 20°C for 16 hours. LC-MS analysis showed complete reaction of compound 107d and the generation of a new target peak. After filtration and concentration under reduced pressure, the concentrate was purified using a column (Phenomenex Luna C18, 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; gradient: 8%~38% B, over 10 minutes) to obtain compound 107 (50.0 mg, 145 μmol, yield 18.9%, purity 96.4%) as a white solid.

[0228] LCMS: m / z = 331.4, M+H +

[0229] 1 H NMR:(400MHz,DMSO-d6)δ 8.05-8.13(m,2H),7.81-7.85(m,1H),7.67-7.74(m,2H),7.46-7.50(m,1H),3.81(s,2H),3.52-3.65(m,4H),2.35-2.41(m,4H).

[0230] Example 21: Preparation of Compound 102 Preparation of compound 102b [ka] Compound 102a (5.00 g, 42.3 mmol, 1.00 equivalent), NBS (11.3 g, 63.5 mmol, 1.50 equivalent), and AIBN (6.95 g, 42.3 mmol, 1.00 equivalent) were dissolved in DCE (50.0 mL). The mixture was purged three times with nitrogen and stirred at 80°C for 16 hours under light exclusion. LC-MS analysis was performed on the target compound (m / z=196.0, M+H). + The reaction mixture was filtered and concentrated under reduced pressure to obtain a crude yellow oily substance 102b (5.20 g, 26.4 mmol, yield 62.4%).

[0231] LCMS: m / z = 197.2, M+H +

[0232] Preparation of compound 102c [ka] Compound 102b (5.00 g, 25.3 mmol, 1.00 equivalent) and morpholine (4.42 g, 50.7 mmol, 4.47 mL, 2.00 equivalent) were dissolved in CH3CN (50.0 mL). The mixture was purged three times with nitrogen and stirred at 20°C for 6 hours. LC-MS analysis was performed on the target compound (m / z = 204.1, M+H). + The reaction mixture was quenched with water (60.0 mL) and extracted three times with ethyl acetate (60.0 mL). The combined organic layers were washed three times with brine (60.0 mL), dried over sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure to obtain a yellow oily substance, 102c (4.90 g, 24.1 mmol).

[0233] LCMS: m / z = 204.1, M+H +

[0234] Preparation of compound 102d [ka] Compound 102c (4.90 g, 24.1 mmol, 1.00 equivalent) was dissolved in methanol (MeOH, 50.0 mL) under an argon atmosphere, and Raney Ni (980 mg, 11.4 mmol, 0.10 equivalent) was added. The mixture was purged three times with hydrogen and stirred at 25°C for 16 hours under hydrogen gas (50 Psi). LC-MS analysis was performed on the target compound (m / z = 208.2, M+H). + The reaction mixture was filtered, washed three times with methanol (50.0 mL), and then concentrated to obtain a brownish oily substance 102d (4.50 g, 21.7 mmol).

[0235] LCMS: m / z = 208.2, M+H +

[0236] Preparation of compound 102e [ka] Compound 102d (600 mg, 2.89 mmol, 1.00 equivalent) was dissolved in DCM (6.00 mL), and TEA (585 mg, 5.79 mmol, 805 μL, 2.00 equivalent) and isonicotinyl chloride (368 mg, 2.61 mmol, 0.90 equivalent) were added. The mixture was stirred at 25°C for 12 hours. LC-MS analysis was performed on the target compound (m / z=313.2, M+H). + The reaction mixture was filtered and concentrated under reduced pressure to obtain a brown, oily crude product 102e (1.00 g).

[0237] LCMS: m / z = 313.2, M + H +

[0238] Preparation of compound 102 [ka] Compound 102e (500 mg, 1.60 mmol, 1.00 equivalent) and phosphorus oxychloride (POCl3, 3.00 mL) were placed in microwave-sealed tubes and heated at 155°C under microwave conditions for 2 hours. LC-MS analysis was performed on the target compound (m / z=295.2, M+H). +The reaction mixture was shown to form compound 102 (205 mg, 685 μmol), and 42.8% was obtained with a purity of 98.4%.

[0239] LCMS: m / z = 295.2, M + H +

[0240] 1 H NMR:(400MHz,CDCl3)δ 8.77(d,J=5.6Hz,1H),8.32(d,J=6.8Hz,1H),7.83-7.86(m,1H),7.77(d,J=6.0Hz, 1H),6.86(d,J=6.4Hz,1H),6.69(t,J=7.2Hz,1H),3.71-3.76(m,6H),2.55(s,4H).

[0241] Example 22: Preparation of Compound 104 Preparation of compound 104b [ka] Compound 102d (500 mg, 2.41 mmol, 1.00 equivalent) was dissolved in DCM (5.00 mL), and compound 104a (383 mg, 2.17 mmol, 271 μL, 0.90 equivalent) was added. The reaction mixture was stirred at 20°C for 2 hours. LC-MS analysis was performed on the target compound (m / z=348.1, M+H). + The reaction mixture was filtered and concentrated under reduced pressure to obtain a crude yellow solid 104b (800 mg, 2.16 mmol), with a purity of 93.9% and a concentration of 89.6%.

[0242] LCMS: m / z = 348.1, M+H +

[0243] Preparation of compound 104 [ka] Compound 104b (500 mg, 1.44 mmol, 1.00 equivalent) and POCl3 (3.00 mL) were added to a microwave-sealed tube and heated at 155°C for 2 hours under microwave conditions. LC-MS analysis was performed on the target compound (m / z=330.1, M+H). + The reaction mixture was shown to form compound 104. After cooling the reaction mixture to room temperature, water (5.00 mL) was added to quench the reaction product. The mixture was filtered and concentrated under reduced pressure to obtain the crude product, which was purified by reverse-phase HPLC (column: Phenomenex C18 250 × 50 mm × 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 29%~59%, 8 min). This yielded compound 104 (265 mg, 803 μmol) as a yellow solid, with a purity of 99.9% and yielding 55.8%.

[0244] LCMS: m / z = 330.1, M+H +

[0245] 1 H NMR:(400MHz,CDCl3)δ 8.14(d,J=7.2Hz,1H),7.77(s,1H),7.54-7.64(m,1H),7.53-7.54(m,1H),7.31-7.34 (m,1H),6.78(d,J=6.4Hz,1H),6.61(t,J=6.4Hz,1H),3.69-3.75(m,6H),2.54(s,4H).

[0246] Example 23: Preparation of Compound 105 [ka] Compound 104 (200 mg, 607 μmol, 1.00 equivalent) was dissolved in DMF (0.50 mL), and a selective fluorinating reagent (430 mg, 1.21 mmol, 2.00 equivalent) was added. The mixture was stirred at 80°C for 12 hours. LC-MS analysis was performed on the target compound (m / z = 348.4, M+H). +The reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product, which was purified by reverse-phase HPLC (column: Waters xbridge 150×25mm×10μm; mobile phase: [water(NH4HCO3)-ACN]; gradient: 35%~65% over 18 minutes). This yielded compound 105 (4.36 mg, 28.2 μmol) as a yellow solid, with a purity of 98.1% and yielding 4.65%.

[0247] LCMS: m / z = 348.4, M+H +

[0248] 1 H NMR:(400MHz,MeOD) δ 8.21(d,J=7.6Hz,1H),7.66-7.72(m,1H),7.57-7.61(m,1H),7.42-7.49(m,1H),6 .76(d,J=6.4Hz,1H),6.69(t,J=7.2Hz,1H),3.69-3.71(m,6H),2.56-2.58(m,4H).

[0249] Biological activity data Example 24: Binding affinity test (1) Preparation of Sigma-1 receptor membrane Guinea pigs (provided by Beijing Vital River Laboratory Animal Technology Co., Ltd.) were decapitated and manipulated on ice. The cerebral cortex was immediately collected and pooled in a centrifuge tube. An appropriate amount of buffer (0.05 M Tris-HCl containing 0.32 M sucrose) was added to the tube, and the tissue was homogenized using a homogenizer (IKA, Ultra Turrax T25 Digital) at setting 4 for 3-4 seconds, repeating four times. After homogenization, solution B was added to adjust the volume to 10 mL / g. The weight of the centrifuge tube was balanced, and the tube was centrifuged at 1000 g for 10 minutes using a high-speed cryogenic centrifuge. The supernatant was collected, adjusted to 2 mL / g with solution B, and then centrifuged at 1000 g and 4°C for 10 minutes. The supernatant was then centrifuged at 18000 rpm and 4°C for 25 minutes. The pellets were resuspended in solution B to a final volume of 3 mL / g and incubated in a 25°C water bath for 15 minutes. After incubation, the suspension was centrifuged at 18000 rpm and 4°C for 45 minutes. The pellets were stored at -80°C for future use. (2) Experimental process of binding affinity test

[0250] An appropriate amount of homogenization buffer was added to the prepared membrane, and the mixture was dispersed into a suspension using a homogenizer. The protein concentration was measured at 4 mg / ml. 100 micrograms of protein were added to each well of a 96-well plate in a volume of 90 μl. 1 μl of the compound was added to the test wells (maximum final concentration was 10 μM, diluted 4-fold over 10 concentrations), followed by 1 μl of buffer to the HPE wells, and then 1 μL of haloperidol (MedChemExpress, catalog no. HY-14538) to the HPE wells (final concentration 1 μM). [3H]-(+)-pentazocine (Perkin-Elmer, catalog no. NET1056250UC) was added to each well (final concentration 10 nM). The 96-well plates were incubated in a constant temperature water bath (25°C, 180 minutes). After incubation, the suspension was rapidly filtered through a 96-well GF / C plate pre-prepared with 0.25% PEI solution using vacuum filtration, followed by washing the GF / C three times with assay buffer. After washing, the sample was dried in an oven at 37°C. 50 μl / well of scintillation fluid (Perkin Elmer, catalog no. 6013621) was added to the GF / C plate. The GF / C plate was placed in a liquid scintillation counter (Perkin Elmer 1450 MicroBeta TriLux) and operated according to the program to read experimental values. (3) Experimental results [Table 1]

[0251] Example 25: SNL Model Neuropathic pain is pain directly caused by injury or disease of the somatosensory nervous system. It is a type of chronic pain characterized by features such as spontaneous pain, hyperalgesia, paresthesia, and sensory disturbances. After nerve injury, neuropathic pain can persist, and its features include hypersensitivity to stimuli (hyperalgesia), the presence of paresthesia (allodynia), and painful reactions to harmless stimuli (hyperalgesia). The spinal nerve ligation (SNL) model involves tight ligation of the L5 and L6 spinal nerves using sutures. Following surgical modeling, animals show clear signs of neuropathic pain, such as mechanical allodynia, in the ipsilateral hind leg that appear 7–14 days postoperatively.

[0252] In this experiment, the analgesic effects of the test compounds were compared using a 100 mg / kg dose of pregabalin as a positive control. After administration, the mechanical pain threshold of the ipsilateral hind leg of rats was tested using a Von Frey filament. The change in mechanical pain threshold before and after administration was used to determine whether the 100 mg / kg test compound had an analgesic effect in the SNL model. The experimental results are shown in Figure 2. In the rat SNL model, oral administration of 100 mg / kg of compound 37 and pregabalin showed some analgesic activity, but oral administration of 10 mg / kg of reference compound 3 showed no analgesic activity in the SNL model. [Table 2]

[0253] Example 26: Rat Rotarot Test When a rat is placed on a continuously rotating rod, it immediately moves in the opposite direction to the rod's movement. Based on this characteristic, rats are initially placed on a steadily rotating rotor rod for adaptive training, and those that demonstrate sufficient motor balance ability are selected for the actual test. During the formal experiment, the time a rat remains on the rotor rod is used as an indicator to measure motor balance ability. This experiment aims to explore the effects of compound 37 on the motor balance ability of rats in the rotor rod test at doses ranging from 10 to 300 mg / kg.

[0254] After administering the test substance to rats, they are placed in a rotary rod fatigue tester. The average time spent on the rod is recorded and analyzed after three tests.

[0255] Calculate the maximum possible effect % on motor balance ability. Maximum possible effect on motor balance ability % = (1 - test group / vehicle) × 100%

[0256] Note: The motor balance ability of the vehicle group is set to 0%, and the maximum possible effect % on the motor balance ability of each group is calculated based on this criterion.

[0257] In the rat rotorod test, the time rats spent on the rod at a rotation speed of 15 rpm increased with training time, indicating that the experimental system was functioning correctly. Compared to the vehicle, subcutaneous injection of 30 μg / kg dexmedetomidine hydrochloride 15 minutes prior resulted in a 62% maximum possible effect on motor balance ability (P<0.001), which is consistent with historical results and suggests the reliability and effectiveness of the experimental procedure. In contrast, when compound 37 was orally administered at doses of 10–300 mg / kg 15 minutes prior, there was no significant change in the time spent on the rotorod compared to the vehicle, and the maximum possible effects on motor balance ability were -6%, 11%, -6%, and -6%, respectively, indicating that compound 37 at doses of 10–300 mg / kg (intragastric administration) does not affect the motor balance ability of rats.

Claims

1. A compound represented by formula (I), or its stereoisomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite, or prodrug, 【Chemical 94】 During the ceremony, n = 0, 1, 2, or 3, L is - (CH ２ ) ｍ -, - (CH ２ ) ｍ (CR ５ R ６ ) - and - (CH ２ ) ｍ Selected from the group consisting of Q-, m = 0, 1, 2, or 3, X is C, O, or S, R １ and R ２ each independently is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl The substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted aryl, and substituted heteroaryl groups are independently substituted with 1 to 3 substituents selected from the group: halogen, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, heteroaryl, and heterocycle. Alternatively, R １ and R ２ However, together with the nitrogen atoms to which they are bonded, they form substituted or unsubstituted heterocyclic groups having representative structures including the following: 【Chemical 95】 Q is a phenyl group or a heteroaryl group, In the formula, the phenyl group or heteroaryl group may optionally contain 0 to 5 R ３ Further substituted by the group, R ３ However, it is selected from the group consisting of halogens, C1-C6 alkyl groups, and C3-C6 cycloalkyl groups. In the formula, Y is a C5-C14 heteroaryl, and the C5-C14 heteroaryl is optionally composed of 0 to 5 R ４ Further substitution with a group, the C5-C14 heteroaryl contains 1 to 4 heteroatoms selected from N, O, or S, R ４ However, it is selected from the group consisting of hydrogen, halogen, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, aryl group, substituted aryl group, heterocycle, and substituted heterocycle. The substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted aryl, and substituted heteroaryl groups are independently substituted with 1 to 3 substituents selected from the group: halogen, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, heteroaryl, and heterocycle. R ５ and R ６ However, independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, and substituted C3-C6 cycloalkyl, Compounds, stereoisomers thereof, pharmaceutically acceptable salts, solvates, deuterated derivatives, metabolites, or prodrugs, wherein the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted phenyl, or substituted heteroaryl is independently substituted with one to three substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine.

2. The compound is represented by formula (II), or is a stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, a deuterated form, a metabolite, or a prodrug. 【Chemistry 96】 During the ceremony, n = 0, 1, 2, 3, L is - (CH ２ ) ｍ -, - (CH ２ ) ｍ (CR ５ R ６ )-,-(CH ２ ) ｍ Selected from Q-, m = 0, 1, 2, 3, X is selected from C, O, and S. R １ and R ２ However, each is independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, and the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted aryl, and substituted heteroaryl are independently substituted by 1 to 3 substituents selected from the group: halogen, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, heteroaryl, and heterocycle, Alternatively, R １ and R ２ However, together with the nitrogen atoms to which they are bonded, they may form substituted or unsubstituted heterocyclic groups as shown in claim 1. Q is an aryl or heteroaryl, and the aryl or heteroaryl may optionally contain 0 to 5 R ３ Further substituted by the group, R ３ However, these are halogens, C1-C6 alkyls, or C3-C6 cycloalkyls. A, B, D, E, and Z are each independently C, N, or O. In the formula, when one of B, Z, or E is selected from C, R ４ It can connect to, R ４ However, the substituents are selected from hydrogen, halogen, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, aryl, substituted aryl, heterocycle, and substituted heterocycle, and the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted aryl, and substituted heteroaryl groups are independently substituted with 1 to 3 substituents selected from the group: halogen, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, heteroaryl, and heterocycle. R ５ and R ６ The compound according to claim 1, wherein each of the members is independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, and substituted C3-C6 cycloalkyl, and the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted phenyl, and substituted heteroaryl are independently substituted with 1 to 3 substituents selected from the group: fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine.

3. The compound is represented by formula (IIa), or is a stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, a deuterated form, a metabolite, or a prodrug. 【Chemistry 97】 During the ceremony, n = 0 or 1, L is - (CH ２ ) ｍ -, - (CH ２ ) ｍ (CR ５ R ６ ) - or - (CH ２ ) ｍ Q-, m = 0, 1, or 2, X is C, O, or S, R １ and R ２ Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, and the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted aryl, and substituted heteroaryl are independently substituted by 1 to 3 substituents selected from the group: halogen, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, heteroaryl, and heterocycle, Alternatively, R １ and R ２ However, together with the nitrogen atoms to which they are bonded, they may form substituted or unsubstituted heterocyclic groups as shown in claim 1. Q is an aryl or heteroaryl, and the aryl or heteroaryl may optionally contain 0 to 5 R ３ Further substituted by the group, R ３ However, these are halogens, C1-C6 alkyls, or C3-C6 cycloalkyls. R ４ However, selected from the group consisting of hydrogen, halogen, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, aryl, substituted aryl, heterocycle, and substituted heterocycle, the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted aryl, and substituted heteroaryl are independently substituted by 1 to 3 substituents selected from the group: halogen, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, heteroaryl, and heterocycle. R ５ and R ６ The compound according to claim 2, wherein each of the members is independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, and substituted C3-C6 cycloalkyl, and the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted phenyl, and substituted heteroaryl are independently substituted with 1 to 3 substituents selected from the group: fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine.

4. The compound is represented by formulas (IIa-1), (IIa-2), (IIa-1a), (IIa-1b), and (IIa-1c), or is a stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, a deuterated form, a metabolite, or a prodrug, and as shown in formula (IIa-1), when X is O and n=1, 【Chem.98】 In the formulas, as shown in formulas (IIa-1a), (IIa-1b), and (IIa-1c), L is -(CH ２ ) ｍ -, - (CH ２ ) ｍ (CR ５ R ６ )-,-(CH ２ ) ｍ Q-, 【Chem.99】 As shown in equation (IIa-2), when X is C and n=0, L is -(CH2) ｍ - and in the equation m = 0, 【Chemistry 100】 R １ and R ２ Each of these is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, and pyridine, and the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted phenyl, and substituted heteroaryl are independently substituted with 1 to 3 substituents selected from the group: fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine. Alternatively, R １ and R ２ However, together with the nitrogen atoms to which they are bonded, they may form substituted or unsubstituted heterocyclic groups as shown in claim 1. Q is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridyl, quinolyl, and pyrazinyl, and 0 to 5 R are selected at will. ３ Further substituted by the group, R ３ However, it is selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. R ４ However, the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted phenyl, and substituted heteroaryl are independently substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine. R ５ and R ６ The compound according to claim 3, wherein each of is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted phenyl, and substituted heteroaryl are independently substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine.

5. A compound represented by formula (IIb), or its stereoisomer, pharmaceutically acceptable salt, solvate, deuterated form, metabolite, or prodrug, 【Chemistry 101】 During the ceremony, n = 0 or 1, L is - (CH ２ ) ｍ -, - (CH ２ ) ｍ (CR ５ R ６ ) - or - (CH ２ ) ｍ Q-, m = 0, 1, or 2, X is C, O, or S, R １ and R ２ However, each is independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, and substituted C3-C6 cycloalkyl, and the substituted C1-C6 alkyl and substituted C3-C6 cycloalkyl are independently substituted with 1 to 3 substituents selected from the group: halogen, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, heteroaryl, and heterocycle, Alternatively, R １ and R ２ However, together with the nitrogen atoms to which they are bonded, they may form substituted or unsubstituted heterocyclic groups as shown in claim 1. Q is an aryl or heteroaryl, and the aryl or heteroaryl may have 0 to 5 R components. ３ Further substituted by the group, R ３ However, it is selected from halogens, C1-C6 alkyls, and C3-C6 cycloalkyls. R ４ However, the substituted C1-C6 alkyl group is selected from hydrogen, halogen, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, and the substituted C1-C6 alkyl and substituted C3-C6 cycloalkyl groups are independently substituted with 1 to 3 substituents selected from the group: halogen, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, heteroaryl, and heterocyclic. R ５ and R ６ The compound according to claim 2, wherein each of the groups is independently selected from hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, and substituted C3-C6 cycloalkyl, and the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted phenyl, and substituted heteroaryl groups are independently substituted with 1 to 3 substituents selected from the groups: fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine.

6. The compound is represented by formulas (IIb-1) and (IIb-2), or is a stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, a deuterated form, a metabolite, or a prodrug. 【Chemical Engineering 102】 R １ and R ２ each independently is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted phenyl, and substituted heteroaryl are each independently substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine, or Alternatively, R １ and R ２ However, together with the nitrogen atoms to which they are bonded, they may form substituted or unsubstituted heterocyclic groups as shown in claim 1. Q is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridyl, quinolyl, and pyrazinyl, and 0 to 5 R are selected at will. ３ Further substituted by the group, R ３ However, it is selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. R ４ The group is selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and the substituted C1-C6 alkyl and substituted C3-C6 cycloalkyl groups are independently substituted with 1 to 3 substituents selected from the group: fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine. R ５ and R ６ each independently is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and the substituted C1-C6 alkyl and the substituted C3-C6 cycloalkyl are each independently substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine, the compound according to claim 4.

7. The compound is represented by formula (III), or is a stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, a deuterated form, a metabolite, or a prodrug. 【Chemistry 103】 During the ceremony, L is - (CH ２ ) ｍ -, - (CH ２ ) ｍ (CR ５ R ６ ) - or - (CH ２ ) ｍ Q-, m = 0, 1, or 2, X is C, O, or S, R １ and R ２ Each of these is independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, and substituted C3-C6 cycloalkyl, and the substituted C1-C6 alkyl and substituted C3-C6 cycloalkyl are independently substituted with 1 to 3 substituents selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, heteroaryl, and heterocycle, Alternatively, R １ and R ２ However, together with the nitrogen atoms to which they are bonded, they may form substituted or unsubstituted heterocyclic groups as shown in claim 1. Q is an aryl or heteroaryl, and the aryl or heteroaryl may optionally contain 0 to 5 R ３ Further substituted by the group, R ３ However, these are halogens, C1-C6 alkyls, or C3-C6 cycloalkyls. A, B, D, E, and Z are each independently C, N, or O. In the formula, when one of B, Z, or E is selected from C, R ４ It can connect to, R ４ However, the group is selected from hydrogen, halogen, cyano, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, and substituted C3-C6 cycloalkyl, and the substituted C1-C6 alkyl and substituted C3-C6 cycloalkyl are independently substituted with 1 to 3 substituents selected from the group: halogen, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, heteroaryl, and heterocycle. R ５ and R ６ The compound according to claim 1, wherein each of the members is independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, and substituted C3-C6 cycloalkyl, and the substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted phenyl, and substituted heteroaryl are independently substituted with 1 to 3 substituents selected from the group: fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine.

8. The compound is represented by formula (IIIa), (IIIb), (IIIc), (IIId), or is a stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, a deuterated form, a metabolite, or a prodrug. 【Chemical 104】 During the ceremony, m = 0, 1, 2, or 3, X is C, O, or S, R １ and R ２ Each of these is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and the substituted C1-C6 alkyl and substituted C3-C6 cycloalkyl are independently substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine, Alternatively, R １ and R ２ However, together with the nitrogen atoms to which they are bonded, they may form substituted or unsubstituted heterocyclic groups as shown in claim 1. Q is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridyl, quinolyl, and pyrazinyl, and R is optionally selected from 0 to 5. ３ Further substituted by the group, R ３ However, it is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. R ４ The compound according to claim 7, wherein the substituent is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and the substituted C1-C6 alkyl and substituted C3-C6 cycloalkyl groups are independently substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine.

9. The compound according to claim 2, wherein the compound of formula (II) comprises the following compounds or any pharmaceutically acceptable salt thereof. 【Chemistry 105-1】 【Chemistry 105-2】 【Chemistry 105-3】

10. The compound according to claim 7, wherein the compound of formula (III) is selected from the group consisting of the following compounds or any pharmaceutically acceptable salt thereof. 【Chemistry 106】

11. A pharmaceutical composition comprising the compound described in claim 1, or its stereoisomer, pharmaceutically acceptable salt, solvate, deuterated form, metabolite, or prodrug, and a pharmaceutically acceptable carrier or excipient.

12. A method for inhibiting the Sigma-1 receptor in a subject, comprising administering the compound described in claim 1 to the subject.

13. A method for treating and / or preventing a disease or disorder related to the Sigma-1 receptor in a subject, comprising administering the compound according to claim 1 to the subject.

14. A method for treating and / or preventing a condition such as pain, comprising administering the compound described in claim 1 to the target.

15. A method for treating and / or preventing one or more conditions related to the Sigma-1 receptor in a subject, wherein the method comprises administering to the subject a compound according to claim 1, and the one or more conditions include pain, psychosis, drug abuse, or cancer.

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