Sigma-1 receptor antagonist and application thereof

Abstract

The invention relates to a Sigma-1 receptor small molecule antagonist, and a pharmaceutical composition, a preparation method and an application of the Sigma-1 receptor small molecule antagonist. The Sigma-1 receptor small molecule antagonist is shown in a formula (I), wherein specific substituents and definitions are described in the specification. The small molecule antagonists of the Sigma-1 receptor show good binding and antagonistic activity aiming at the Sigma-1 receptor. The invention includes these compounds or pharmaceutical compositions thereof, and uses of the compounds or pharmaceutical compositions thereof for the treatment and / or prevention of pain disorders associated with the Sigma-1 receptor.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 452,034, filed March 14, 2023. The entire disclosure of the U.S. Provisional Application is hereby incorporated by reference. TECHNICAL FIELD

[0003] The present disclosure relates to novel small heterocyclic compounds designed as Sigma-1 receptor antagonists, aimed at managing pain and related conditions. BACKGROUND

[0004] Pain-relieving medications are critical to improving the quality of life for patients suffering from various conditions. With the global population aging and the rising incidence of chronic diseases such as diabetes, arthritis, joint or bone pain, epilepsy, depression, nerve injury, and various cancers, the demand for effective pain management solutions has grown significantly. Currently, the pain management therapy market is dominated by opioid drugs and non-steroidal anti-inflammatory drugs (NSAIDs). However, adverse reactions associated with opioid drugs, including respiratory depression, dependence, constipation, and social problems caused by opioid abuse highlight the urgent need to develop non-addictive analgesics to meet the urgent needs of most patients.

[0005] Sigma-1 (σ1) receptors, identified as chaperones, play a crucial role in modulating the activity of various proteins and ion channels, including N-methyl-D-aspartate (NMDA) and opioid receptors. Sigma-1 receptors are located in key areas of pain modulation within both the peripheral and central nervous systems, acting as unique ligand-activated chaperones. Sigma-1 antagonists interfere with the chaperone function of the receptor, amplifying opioid signaling and reducing NMDAR activity. This dual action not only facilitates opioid-induced pain relief but also reduces sensory hypersensitivity associated with chronic pain conditions. Significantly, targeting Sigma-1 receptors does not exacerbate opioid-related side effects, suggesting that Sigma-1 antagonists can enhance the safety and efficacy of opioid therapy. In addition, σ1 receptor antagonists show promise in treating psychiatric disorders, pain, substance abuse, and cancer, highlighting their potential as multifunctional therapeutic agents.

[0006] Sigma-1 receptors are known to be a single polypeptide of 223 amino acids with only two transmembrane domains compared to seven transmembrane domains of opioid receptors and have no homology with opioid receptors or any other known mammalian proteins. Sigma-1 (si) receptor protein is present in the mitochondria-associated endoplasmic reticulum (ER) membrane (Hayashi et al. Cell 131(3), 596-610, 2007). Sigma-1 (si) receptor is known to modulate Ca 2+ signaling through inositol triphosphate receptors (IP3R) (Su et al. Trends Pharmacol. Sci. 31(12), 557-566, 2010) and modulate hippocampal dendritic spine

[0007] 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. 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). Pharmaceutical companies have also filed patents to protect their inventions on Sigma-1 (σ1) receptor antagonists, including but not limited to US2016 / 0060275, US 7,696,199 B2, US2008 / 0125416 and US2016 / 0060275.

[0008] Disclosed herein are a series of novel Sigma-1 (σ1) receptor antagonists for the treatment of pain and related disorders. SUMMARY

[0009] The following is a summary of the detailed description of the application. This summary is not intended to limit the scope of the claims.

[0010] The present disclosure relates to a compound of Formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated derivative, a metabolite, or a prodrug thereof;

[0011]

[0012] wherein,

[0013] n = 0, 1, 2, or 3;

[0014] L is selected from -(CH2) m -, -(CH2)m (CR 5 R 6 )-or-(CH2) m Q-;

[0015]

[0016] Q is phenyl or heteroaryl, wherein said phenyl, said heteroaryl are optionally further substituted with 0-5 R 3 groups;

[0017] R 3 is halogen, C1-C6alkyl or C3-C6cycloalkyl;

[0018] wherein Y is C5-C14heteroaryl, and said heteroaryl is optionally further substituted with 0-5 R 4 groups; said heteroaryl contains 1-4 heteroatoms selected from N, O or S;

[0019] R 4 is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, substituted C3-C6cycloalkyl, aryl, substituted aryl, heterocycle and substituted heterocycle; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl, said substituted aryl and said substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C3alkyl, C1-C3alkoxy, halogenated C1-C3alkyl, heteroaryl and heterocycle; and

[0020] R 5 and R 6 are independently selected from the group consisting of hydrogen, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl and substituted C3-C6cycloalkyl; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl, said substituted phenyl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine and piperazine.

[0021] The present disclosure also relates to a pharmaceutical composition comprising a compound of Formula (I), or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated form, metabolite or prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

[0022] The present disclosure further relates to a method for inhibiting Sigma-1 receptor in a subject. The method comprises administering to the subject a compound of Formula (I).

[0023] The present disclosure further relates to a method for treating and / or preventing a disease or disorder associated with Sigma-1 receptor in a subject. The method comprises administering to the subject a compound of Formula (I).

[0024] Various aspects of the present disclosure relate to a method for treating and / or preventing one or more conditions in a subject. The one or more conditions include, but are not limited to, pain, psychosis, substance abuse, or cancer. The method comprises administering to the subject a compound of Formula (I). BRIEF DESCRIPTION OF DRAWINGS

[0025] The accompanying drawings are provided to help understand the technical solutions proposed in the present application, constitute a part of the present description, and are used together with the embodiments of the present application to explain the technical solutions of the present application, and do not limit the scope of the technical solutions of the present application.

[0026] Figure 1 The structures of reference compounds 1-3 related to the present application are shown.

[0027] Figure 2 The analgesic effect of the compounds of the present application in a spinal nerve ligation (SNL) model is shown. DETAILED DESCRIPTION

[0028] The present application provides a new type of Sigma-1 antagonist, as well as a preparation method and application thereof. The compound of the present application has good Sigma-1 antagonistic activity and can provide effective pain management to meet the needs of patients.

[0029] In a second aspect, the present application provides a pharmaceutical composition comprising a Sigma-1 antagonist, and stereoisomers, pharmaceutically acceptable salts, solvates, deuterated forms, metabolites, or prodrugs thereof, and at least one pharmaceutically acceptable excipient or carrier.

[0030] In a third aspect, the present application provides a method for synthesizing a Sigma-1 antagonist.

[0031] In a fourth aspect, the present application provides a method for treating a Sigma-1 related disease or disorder. The method involves administering to an individual in need a composition containing a compound of Formula (I).

[0032] I. Sigma-1 antagonist

[0033] In a first aspect, in embodiments of the present application, a compound as represented by Formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated form, a metabolite, or a prodrug thereof is provided.

[0034]

[0035] wherein,

[0036] n = 0, 1, 2, 3;

[0037] L is selected from -(CH2) m -, -(CH2) m (CR 5 R 6 )-, -(CH2) m Q-;

[0038] m = 0, 1, 2, 3;

[0039] X is selected from C, O, S;

[0040] R 1 and R 2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, substituted C3-C6cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl, said substituted aryl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C3alkyl, C1-C3alkoxy, halogenated C1-C3alkyl, heteroaryl, and heterocycle;

[0041] Alternatively, R 1 and R 2 together with the nitrogen atom to which they are attached can form a substituted or unsubstituted heterocyclic ring group, representative of which (but not limited to) are the following structures:

[0042]

[0043] Q is selected from aryl or heteroaryl, and said aryl, said heteroaryl are optionally further substituted with 0-5 R 3 groups;

[0044] R 3 is halogen, C1-C6alkyl, or C3-C6cycloalkyl;

[0045] wherein Y is selected from C5-C14heteroaryl, and said heteroaryl are optionally further substituted with 0-5 R 4 groups; said heteroaryl include 1-4 heteroatoms selected from N, O, S;

[0046] R 4selected from the group consisting of hydrogen, halogen, cyano, Ci-C6alkyl, substituted Ci-C6alkyl, C3-C6cycloalkyl, substituted C3-C6cycloalkyl, aryl, substituted aryl, heterocycle, and substituted heterocycle; said substituted Ci-C6alkyl, said substituted C3-C6cycloalkyl, said substituted aryl, said substituted heteroaryl, are substituted with 1-3 substituents independently selected from the group consisting of halogen, Ci-C3alkyl, Ci-C3alkoxy, halogenated Ci-C3alkyl, heteroaryl, heterocycle; and

[0047] R 5 and R 6 are each independently selected from the group consisting of hydrogen, Ci-C6alkyl, substituted Ci-C6alkyl, C3-C6cycloalkyl, and substituted C3-C6cycloalkyl; said substituted Ci-C6alkyl, said substituted C3-C6cycloalkyl, said substituted phenyl, said substituted heteroaryl, are substituted with 1-3 substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine.

[0048] In particular, in some embodiments, the present application provides a compound as represented by formula (I) and stereoisomers, pharmaceutically acceptable salts, solvates, deuterated forms, metabolites, or prodrugs thereof;

[0049]

[0050] wherein,

[0051] n = 0, 1, 2, or 3;

[0052] L is selected from -(CH2) m -, -(CH2) m (CR 5 R 6 )- or -(CH2) m Q-;

[0053] m = 0, 1, 2, or 3;

[0054] X is selected from C, O, or S;

[0055] R 1 and R 2each independently selected from the group consisting of hydrogen, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, substituted C3-C6cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl, said substituted aryl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C3alkyl, C1-C3alkoxy, halogenated C1-C3alkyl, heteroaryl, heterocycle;

[0056] alternatively, R 1 and R 2 may form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclic group, representative (but not limited to) structures are as follows:

[0057]

[0058] Q is aryl or heteroaryl, and said aryl, said heteroaryl are optionally further substituted with 0-5 R 3 groups;

[0059] R 3 is halogen, C1-C6alkyl, or C3-C6cycloalkyl;

[0060] wherein Y is C5-C14heteroaryl, and said heteroaryl are optionally further substituted with 0-5 R 4 groups; said heteroaryl comprises 1-4 heteroatoms selected from N, O, S;

[0061] R 4 is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, substituted C3-C6cycloalkyl, aryl, substituted aryl, heterocycle, and substituted heterocycle; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl, said substituted aryl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C3alkyl, C1-C3alkoxy, halogenated C1-C3alkyl, heteroaryl, heterocycle; and

[0062] R 5 and R 6each independently selected from the group consisting of hydrogen, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, and substituted C3-C6cycloalkyl; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl, said substituted phenyl, said substituted heteroaryl, are substituted with 1-3 substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine.

[0063] In particular, in some embodiments, the present disclosure provides a compound as represented by formula (II), or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated form, metabolite, or prodrug thereof.

[0064]

[0065] wherein,

[0066] n = 0, 1, 2, or 3;

[0067] L is selected from -(CH2) m -, -(CH2) m (CR 5 R 6 )- or -(CH2) m Q-;

[0068] m = 0, 1, 2, or 3;

[0069] X is selected from C, O, or S;

[0070] R 1 and R 2 each independently selected from the group consisting of hydrogen, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, substituted C3-C6cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl, said substituted aryl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C3alkyl, C1-C3alkoxy, halogenated C1-C3alkyl, heteroaryl, and heterocycle;

[0071] Alternatively, R 1 and R 2 may form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclic group, as indicated above;

[0072] Q is aryl, heteroaryl, or aryl, wherein heteroaryl is optionally further substituted with 0-5 R 3 groups;

[0073] R3 halogen, C1-C6alkyl or C3-C6cycloalkyl;

[0074] A, B, D, E, Z are each independently C, N or O;

[0075] wherein when any one of B, Z, E is selected from C, it can be attached to R 4 ;

[0076] R 4 is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, substituted C3-C6cycloalkyl, aryl, substituted aryl, heterocycle and substituted heterocycle; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl, said substituted aryl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C3alkyl, C1-C3alkoxy, halogenated C1-C3alkyl, heteroaryl and heterocycle; and

[0077] R 5 and R 6 are each independently selected from the group consisting of hydrogen, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl and substituted C3-C6cycloalkyl; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl, said substituted phenyl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine and piperazine.

[0078] In some specific embodiments, when A, D, E are carbon atoms, B is a nitrogen atom, Z is an oxygen atom, as shown in formula (IIa);

[0079]

[0080] wherein when X is an oxygen atom, n = 1, as shown in formula (IIa-1):

[0081] wherein L is -(CH2) m -, -(CH2) m (CR 5 R 6 )- or -(CH2) m Q-, as shown in formula (IIa-1a), (IIa-1b) and (IIa-1c):

[0082] when X is a carbon atom, n = 0, and L is -(CH2) m -, wherein m = 0, as shown in formula (IIa-2):

[0083]

[0084]

[0085] R 1 and R 2 each independently is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, and pyridine; said substituted Ci-C6alkyl, said substituted C3-C6cycloalkyl, said substituted phenyl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine;

[0086] alternatively, R 1 and R 2 may form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclic group, as indicated above;

[0087] Q is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridyl, quinolyl, and pyrazinyl, and is optionally further substituted with 0-5 R 3 groups;

[0088] R 3 is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0089] R 4 is 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; said substituted Ci-C6alkyl, said substituted C3-C6cycloalkyl, said substituted phenyl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine; and

[0090] R 5 and R 6each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; said substituted C1-C6 alkyl, said substituted C3-C6 cycloalkyl, said substituted phenyl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine.

[0091] In some embodiments, R 1 and R 2 each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, and t-butyl; or R 1 and R 2 may together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclic ring selected from the group consisting of:

[0092]

[0093] In some embodiments, Q is phenyl, naphthyl, or pyridyl, and is further substituted with 0-5 R 3 groups.

[0094] In some embodiments, R 3 is selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, and t-butyl.

[0095] In some embodiments, R 4 is hydrogen, fluorine, chlorine, bromine, or thienyl.

[0096] In some embodiments, R 5 and R 6 each independently is hydrogen or methyl.

[0097] In some specific embodiments, when B, Z, D are carbon atoms and A and E are nitrogen atoms, as shown in formula (IIb):

[0098]

[0099] L is -(CH2) m -, -(CH2) m (CR 5 R 6 )- or -(CH2) m Q-;

[0100]

[0101] wherein when X is O, n = 2, L is -(CH2) m (CR5 R 6 )-, and m = 2, as shown in formula (IIb-1):

[0102] wherein when X is -CH2-, n = 0, and L is -(CH2) m - wherein m = 0, as shown in formula (IIb-2):

[0103]

[0104] R 1 and R 2 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, and pyridine; said substituted C1-C6 alkyl, said substituted C3-C6 cycloalkyl, said substituted phenyl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine;

[0105] Alternatively, R 1 and R 2 together with the nitrogen atom to which they are attached can form a substituted or unsubstituted heterocyclic group;

[0106] Q is phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridyl, quinolyl, or pyrazinyl, and is optionally further substituted with 0-5 R 3 groups;

[0107] R 3 is selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

[0108] R 4 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, and pyridine; said substituted C1-C6 alkyl, said substituted C3-C6 cycloalkyl, said substituted phenyl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine; and

[0109] R 5 and R 6each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl, said substituted phenyl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine.

[0110] In some embodiments, R 1 and R 2 may form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclic group selected from the group consisting of:

[0111]

[0112] In some embodiments, Q is phenyl or naphthyl, wherein Q is further substituted with 0-5 R 3 groups.

[0113] In some embodiments, R 3 is fluorine, chlorine, or bromine.

[0114] In some embodiments, R 4 is hydrogen;

[0115] In some embodiments, R 5 and R 6 are hydrogen.

[0116] In particular, a compound as represented by Formula (III), or a stereoisomer, a pharmaceutically acceptable salt, solvate, deuterated form, metabolite, or prodrug thereof;

[0117]

[0118] wherein,

[0119] L is selected from -(CH2) m -, -(CH2) m (CR 5 R 6 )-, -(CH2) m Q-;

[0120] m = 0, 1, or 2;

[0121] X is C, O, or S;

[0122] R 1 and R 2each independently selected from the group consisting of hydrogen, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, and substituted C3-C6cycloalkyl; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl, said substituted phenyl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine.

[0123] alternatively, R 1 and R 2 may form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclic group, as indicated above;

[0124] Q is aryl or heteroaryl, and said aryl, said heteroaryl are optionally further substituted with 0-5 R 3 groups;

[0125] R 3 is halogen, C1-C6alkyl, C3-C6cycloalkyl;

[0126] A, B, D, E, Z are each independently C, N, or O;

[0127] wherein when any one of B, Z, E is selected from C, it can be attached to R 4 ;

[0128] R 4 is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, and substituted C3-C6cycloalkyl; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl are substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C3alkyl, C1-C3alkoxy, halogenated C1-C3alkyl, heteroaryl, and heterocycle; and

[0129] R 5 and R 6 are each independently selected from the group consisting of hydrogen, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, and substituted C3-C6cycloalkyl; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl, said substituted phenyl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine.

[0130] In some specific embodiments, when Z, D, E are carbon atoms, and A and B are nitrogen atoms, as shown in formula (IIIa):

[0131] In some specific embodiments, when Z, D, E are carbon atoms, and A and B are nitrogen atoms, as shown in formula (IIIa):

[0132] In some specific embodiments, when A and D are carbon atoms, and B, Z, E are nitrogen atoms, as shown in formula (IIIb):

[0133]

[0134] In some specific embodiments, when A, D, E are carbon atoms, B is a nitrogen atom, and Z is an oxygen atom, as shown in formula (IIIc);

[0135]

[0136] In some specific embodiments, when A, Z, D are carbon atoms, and B and E are nitrogen atoms, as shown in formula (IIId):

[0137]

[0138] wherein,

[0139] m = 0, 1, 2 or 3;

[0140] X is C, O or S;

[0141] R 1 and R 2 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; said substituted Ci-C6alkyl, said substituted C3-C6cycloalkyl, said substituted phenyl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, piperazine;

[0142] Alternatively, R 1 and R 2 together with the nitrogen atom to which they are attached can form a substituted or unsubstituted heterocyclic group;

[0143] Q is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridyl, quinolyl, pyrazinyl, and is optionally further substituted with 0-5 R 3 groups;

[0144] R 3 is selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; and

[0145] R 4selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl, said substituted phenyl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, piperazine.

[0146] In some embodiments, m = 0, 1, or 2.

[0147] In some embodiments, X is a carbon atom or an oxygen atom.

[0148] In some embodiments, R 1 and R 2 may form, with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclic group selected from the group consisting of:

[0149]

[0150] In some embodiments, Q is phenyl or pyridyl, and is further substituted with 0-5 R 3 groups.

[0151] In some embodiments, R 3 is fluorine, chlorine, or bromine;

[0152] In some embodiments, R 4 is hydrogen, fluorine, chlorine, or bromine;

[0153] In addition, the compound of Formula (I) is selected from the group consisting of:

[0154]

[0155]

[0156]

[0157]

[0158]

[0159] II. Pharmaceutical Compositions

[0160] In some embodiments, the present application provides a pharmaceutical composition. The pharmaceutical composition includes a compound of Formula (I), and stereoisomers, pharmaceutically acceptable salts, solvates, deuterated forms, metabolites, or prodrugs thereof, and at least one pharmaceutically acceptable excipient.

[0161] The compounds are described above in Section I.

[0162] The disclosed pharmaceutical compositions contain at least one pharmaceutically acceptable excipient. Non-limiting examples of suitable excipients can include diluents, binders, fillers, buffering agents, pH adjusting agents, disintegrants, dispersing agents, stabilizing agents, preservatives, and coloring agents. The amount and type of excipient can be selected based on known pharmaceutical principles.

[0163] The pharmaceutical compositions can be mixed with one or more excipients to form a solid, liquid, or semi-solid dosage form. Methods of formulating solid, liquid, or semi-solid dosage forms are known in the art.

[0164] III. Methods of Making Sigma-1 Antagonists

[0165] In some embodiments, the present application provides a method for making the above-mentioned compound or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated form, a metabolite, or a prodrug thereof, the method comprising the steps of:

[0166]

[0167] The compound of formula (I-1) can be reacted with a compound of formula (I-2) under the conditions of sodium hydride and tetrahydrofuran in a nucleophilic substitution reaction to obtain a compound of formula (I-3), i.e., a compound of formula (II);

[0168] Alternatively, the compound of formula (I-1) can be reacted with a compound of formula (I-4) under the conditions of potassium / cesium carbonate in acetonitrile in a nucleophilic substitution reaction to obtain a compound of formula (I-5), i.e., a compound of formula (II);

[0169]

[0170] Alternatively, the compound of formula (I-6) can be reacted with a compound of formula (I-7) under the conditions of sodium fluoride in dichloromethane in a cyclization reaction to obtain a compound of formula (I-8), i.e., a compound of formula (II);

[0171]

[0172] Alternatively, the compound of formula (I-1) can be reacted with a compound of formula (I-9) under the conditions of potassium tert-butoxide in tetrahydrofuran to obtain a compound of formula (I-10), and then subjected to a heating reaction in acetic acid / tetrahydrofuran / water system to produce a compound of formula (I-11);

[0173]

[0174] The compound of formula (I-11) can be reacted with a compound of formula (I-4) under conditions of a reductive amination reaction with sodium triacetoxyborohydride in tetrahydrofuran / dichloromethane to obtain a compound of formula (I-12), i.e. a compound of formula (II);

[0175]

[0176] IV. Methods of use

[0177] In another aspect, the present application provides a method for treating a disease or disorder associated with Sigma-1 receptors, wherein the method comprises administering to a subject in need thereof a pharmaceutical composition comprising a compound of formula (I).

[0178] Without being bound by any theory, it is believed that the compounds of formula (I) act primarily as antagonists to mediate the activity of Sigma-1 receptors. Binding at this site is believed to treat conditions associated with pain, among others.

[0179] The compounds can be administered by a variety of routes. For example, the compounds of formula (I) can be administered orally, parenterally (i.e., subcutaneously, intradermally, intravenously (i.e., as a solution, suspension or emulsion in a carrier), intramuscularly, intracranially or intraperitoneally) by injection, or topically (i.e., transdermally or transmucosally, including but not limited to oral, rectal, vaginal and sublingual administration) in solid or liquid dosage forms (tablets, gel capsules, controlled-release capsules, powders, solutions or suspensions in aqueous or non-aqueous liquids).

[0180] In one embodiment, the compounds can be administered in saline or with the pharmaceutically acceptable excipients mentioned above. The compounds can be used as primary therapy or as adjuvant therapy, administered after local intervention (surgery, radiation therapy, local chemotherapy), or in combination with at least one other chemotherapeutic agent.

[0181] Suitable subjects can 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; farm animals such as cows, dairy cows, pigs, goats, sheep, horses, deer, chickens and other poultry; zoo animals; primates such as chimpanzees, monkeys and gorillas. The subjects are not limited by age. In a preferred embodiment, the subject can be a human.

[0182] In general, the compounds of Formula (I) will be administered in a therapeutically effective amount, which will include a prophylactic amount or a lower dosage, for example, when used in combination with another agent. As used herein, the term "effective amount" means the amount of a compound that is sufficient to provide a sufficiently high level of circulating concentration to produce a beneficial effect on the recipient. The skilled clinician can determine the precise dosages, taking into account the required dosage, side effects, and the patient's history.

[0183] In general, the compounds of Formula (I) will have an EC50for binding affinity to Sigma-1 receptors of less than about 100 nM. In various embodiments, the compounds consisting of Formula (I) have an EC50of less than about 100 nM, or less than 10 nM, or less than about 5 nM, or less than about 1 nM.

[0184] Beneficial effects

[0185] The compounds of the present application are capable of binding to Sigma-1 receptors, have good Sigma-1 receptor antagonistic activity, and thus are suitable for medical use and have clinical application value. In addition, the compounds in the present application have simple synthesis steps, thereby providing good economic value.

[0186] Definitions and descriptions of terms

[0187] Unless otherwise indicated, the definitions and descriptions of groups and terms used in the present application, including the groups and terms listed by way of example, exemplary groups and terms, preferred groups and terms, groups and terms listed in the tables, or groups and terms listed for specific compounds in the examples, can be combined and interchanged with each other. Subsequent group definitions and compound structures should be considered within the scope described in the present specification.

[0188] The compounds described herein can have asymmetric centers. The compounds of the present application containing asymmetrically substituted atoms can be isolated in optically active form or as racemates. Unless specifically indicated, all chiral, achiral, racemic forms and all geometric isomeric structures are intended to be within the scope of the present description.

[0189] As used herein, "sigma-1 receptor" and "σ1 receptor" are interchangeable or used interchangeably.

[0190] The term "alkyl" as used herein refers to lower alkyl groups having from 1 to 6 carbon atoms in the main chain, and up to 20 carbon atoms in total. It can be straight chain, branched or cyclic, including methyl, ethyl, propyl, isopropyl, butyl, hexyl, and the like.

[0191] The term "aryl," used alone or as part of another group, refers herein to any optionally substituted, conjugated planar ring or ring system containing delocalized electrons. These aryl groups are preferably monocyclic (e.g., furan or benzene), bicyclic, or tricyclic groups containing 5-14 atoms in the ring portions. The term "aromatic" includes "aryl" as defined.

[0192] The term "aryl" or "Ar," used alone or as part of another group, represents herein any optionally substituted aromatic group, preferably a monocyclic or bicyclic group having from 6 to 10 carbon atoms in the ring portions, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl, or substituted naphthyl.

[0193] The term "carbocycle" or "carbocyclic," used alone or as part of another group, represents herein any optionally substituted, aromatic or nonaromatic, monocyclic or polycyclic group in which all of the atoms in the ring are carbon atoms, preferably 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, amido, acetal, aminocarbonyl, carbocycle, cyano, ester, ether, halogen, heterocycle, hydroxyl, ketone, ketal, phosphate, nitro, and thio.

[0194] The term "heteroaryl," used alone or as part of another group, represents herein any optionally substituted aromatic group having at least one heteroatom in at least one ring, preferably 5 or 6 atoms in each ring. Heteroaryl groups preferably have 1 or 2 oxygen atoms and / or 1 to 4 nitrogen atoms in the ring and are bonded 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, isoindolynyl, indolizinyl, benzimidazolyl, indazolyl, benzotriazolyl, tetrazolopyrazinyl, carbazolyl, purinyl, quinolinyl, isoquinolinyl, imidazopyridinyl, and the like. Exemplary substituents include one or more of the following groups: alkyl, substituted alkyl, alkoxy, acyl, acyloxy, alkene, alkenoxy, aryl, aryloxy, amino, amido, acetal, aminocarbonyl, carbocycle, cyano, ester, ether, halogen, heterocycle, hydroxyl, ketone, ketal, phosphate, nitro, and thio.

[0195] The term "heterocycle" or "heterocyclic" used alone or as part of another group, means any optionally substituted, fully saturated or unsaturated, mono- or bicyclic, aromatic or non-aromatic group having at least one heteroatom in at least one ring, preferably having 5 or 6 atoms in each ring. Heterocyclic groups preferably have 1 or 2 oxygen atoms and / or 1 to 4 nitrogen atoms in the ring and are attached to the rest of the molecule by a carbon or heteroatom. Exemplary heterocyclic groups include the above-mentioned heteroaryl compounds. Exemplary substituents include one or more of the following groups: alkyl, substituted alkyl, alkoxy, acyl, acyloxy, alkene, alkenoxy, aryl, aryloxy, amino, acylamino, acetal, aminocarbonyl, carbocyclic, cyano, ester, ether, halogen, heterocyclic, hydroxyl, ketone, ketal, phosphate, nitro, and thio.

[0196] The term "protecting group" as used herein means a group that can protect a particular portion of a molecule, wherein the protecting group can be removed after the protected reaction without interfering with the rest of the molecule. When the portion is an oxygen atom (forming a protected hydroxyl group), exemplary protecting groups include ethers (e.g., allyl, trityl (tributyl or Tr), benzyl, p-methoxybenzyl (PMB), p-methylphenyl (PMP)), acetals (e.g., methoxymethyl (MOM), beta-methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), ethoxyethyl (EE), methylthiomethyl (MTM), 2-methoxy-2-propyl (MOP), 2-trimethylsilylethoxymethyl (SEM)), esters (e.g., benzoate, carbonic anhydride, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate), silyl ethers (e.g., trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), triphenylsilyl (TPS), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS)), and the like. When the portion is a nitrogen atom (forming a protected amine), exemplary protecting groups include benzyl groups (e.g., p-methoxyphenyl (PMP), 3,4-dimethoxybenzyloxy (PMB)), esters (e.g., benzoate), carbonyls (e.g., p-methoxybenzyl carbonyl (Moz), t-butoxy carbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC)), acetyl, carbamates, n-silyl groups, and the like. Various protecting groups and methods for their synthesis can be found in "Greene's Protective Groups in Organic Synthesis" (4th Ed.) by P. G. M. Wuts and T. W. Greene, eds., John Wiley & Sons, Inc.

[0197] The term "substituted hydrocarbon" moiety as used herein refers to a hydrocarbon moiety that is substituted with at least one non-carbon atom, including moieties in which a carbon chain atom is replaced with a heteroatom such as nitrogen, oxygen, silicon, phosphorus, boron, or halogen, as well as moieties in which the carbon chain includes additional substituents. These substituents include alkyl, alkoxy, acyl, acyloxy, alkene, alkenoxy, aryl, aryloxy, amino, acylamino, acetal, aminocarbonyl, carbocyclic, cyano, ester, ether, halogen, heterocyclic, hydroxyl, ketone, ketal, phosphate, nitro, and thio.

[0198] The terms "comprising," "including," and "having" are intended to be inclusive and allow for additional elements or steps, not excluding any possessed element. It will be apparent from the following description that modifications and variations can be made without departing from the scope of the claims.

[0199] Additional features and advantages of the present application will be set forth in the description that follows, and in part will be apparent from the description, or can be learned by practice of the present application. The objectives and other advantages of the present application will be realized and attained by the structure particularly pointed out in the written description and claims hereof.

[0200] Examples

[0201] The general compounds of the present application, methods of preparing and using the same will be described in more detail below with reference to specific examples. The following examples are provided for illustrative purposes and to explain the present application. These examples should not be construed as limiting the scope of protection of the present application. All techniques implemented by the present application are encompassed within the scope intended to be protected by the present application based on the above description.

[0202] Unless otherwise specified, the starting materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0203] The following abbreviations are used in the present application:

[0204] ACN: acetonitrile

[0205] AIBN: azobisisobutyronitrile

[0206] BBr3: boron tribromide

[0207] BPO: benzoyl peroxide

[0208] CCl4: carbon tetrachloride

[0209] Cs2CO3: cesium carbonate

[0210] DCM: dichloromethane

[0211] DCE: 1,2-dichloroethane

[0212] DIEA: N,N-diisopropylethylamine

[0213] DMF: N,N-dimethylformamide

[0214] EA: ethyl acetate

[0215] EtOH: ethanol

[0216] FA: formic acid

[0217] K2CO3: potassium carbonate

[0218] LAH: lithium aluminum hydride

[0219] NaH: sodium hydride

[0220] Na2SO4: sodium sulfate

[0221] NaBH4: sodium borohydride

[0222] NaBH(OAc)3: sodium triacetoxyborohydride

[0223] NaF: sodium fluoride

[0224] NBS: N-bromosuccinimide

[0225] NCS: N-chlorosuccinimide

[0226] PBr3: phosphorus tribromide

[0227] PE: petroleum ether

[0228] t-BuOK: potassium tert-butoxide

[0229] TBAB: tetra-n-butylammonium bromide

[0230] TCCA: trichloroisocyanuric acid

[0231] TEMED: N,N,N',N'-tetramethylethylenediamine

[0232] TEMPO: 2,2,6,6-tetramethylpiperidin-1-oxyl

[0233] THF: tetrahydrofuran

[0234] Compounds are named according to the conventional nomenclature rules of the art, and commercially available reagents are used with the vendor catalog name.

[0235] Bruker Avance Neo 400 MHz liquid superconducting nuclear magnetic resonance spectrometer was used to collect and record1H NMR spectra at 400 MHz 1HNMR data. Chemical shifts δ values (ppm) were reported using CDC13, MeOD, DMSO-d6 as solvents and TMS (δ = 0) as 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) column. Mobile phase A: 0.01% TFA / H20; 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 measured by Thermo UltiMate 3000 liquid chromatograph and ASB C18 (4.6*250 mm, 5 μm) column. Mobile phase A: aqueous phosphoric acid solution, pH = 1.5; 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 condition: eluted at a flow rate of 1.0 mL / min throughout the process, first eluted with 95% A and 5% B for 10 min, then with 20% A and 80% B for 5 min, and finally with 95% A and 5% B.5% B for 5 min. The percentage refers to the volume percentage of the mobile phase in the elution solution.

[0236] Example 1: Preparation of Intermediate I

[0237]

[0238] Hydroxylamine hydrochloride (366.91 g, 5.28 mol, 1.5 eq) was weighed and dissolved in 5 L of purified water. 3,4-Difluorobenzaldehyde (500.00 g, 3.52 mol, 1.0 eq) 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 filter cake was dissolved in DCM and separated. The organic phase was dried over anhydrous Na2S04, filtered, and saved as a reaction mixture.

[0239] N-chlorosuccinimide (466.54 g, 3.52 mol, 1.0 eq) 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 Na2S04 and concentrated under reduced pressure. Crystallization with petroleum ether yielded 330 g of I-2.

[0240] I-2 (300.00 g, 1.57 mol, 1.0 eq) was dissolved in 3 L of DCM. NaHC03(263.79 g, 3.14 mol, 2.0 eq) and propargyl bromide (196.28 g, 1.65 mol, 1.05 eq) were added. After 24 h, 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 light yellow solid of intermediate I. HPLC purity: 98.82%; MS m / z (ESI): 275.16 [M+H] + ; 1 HNMR (400 MHz, 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).

[0241] The preparation of the following compounds is described with reference to Example 1.

[0242]

[0243] Example 2: Preparation of intermediate VIII

[0244] Preparation of intermediate VIII-2

[0245]

[0246] Methyl 1H-pyrazole-3-carboxylate (924 mg, 7.33 mmol, 1.00 eq) and VIII-1 (2.00 g, 7.33 mmol, 1.00 eq) were dissolved in acetonitrile (20.0 mL), then Cs2C03(4.78 g, 14.7 mmol, 2.00 eq), CuI (279 mg, 1.47 mmol, 0.20 eq) and N,N,N',N'-tetramethylethylenediamine (170 mg, 1.47 mmol, 221 uL, 0.20 eq) were added. The reaction mixture was stirred at 80 °C for 2 h. LCMS showed the content of target product 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, then the organic phase was washed with 60.0 mL (20.0 mL x 3) of saturated brine. The organic phase was dried over Na2S04, filtered and concentrated. Purification by column chromatography (Si02, PE / EA = 3:1, R f= 0.45) to yield yellow solid intermediate VIII-2 (1.17 g, 4.04 mmol, 55.1% yield, 93.7% purity).

[0247] LCMS: m / z = 271.1, [M+H] + .

[0248] 1 H NMR (400 MHz, CDC13) 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).

[0249] Preparation of intermediate VIII-3

[0250]

[0251] Intermediate VIII-2 (1.17 g, 4.04 mmol, 93.7% purity, 1.00 equiv) was dissolved in THF (10.0 mL) and LAH (2.5 M, 2.10 mL, 1.30 equiv) was added at 0 °C. The mixture was stirred for 2 hours. TLC monitoring (petroleum ether / ethyl acetate = 3: 1) confirmed complete reaction of intermediate VIII-2 (Rf = 0.45) and formation of a new spot (Rf = 0.01). The reaction was quenched with 0.2 mL of water at 0 °C, NaOH (0.20 mL) was added dropwise, followed by H20 (0.60 mL). The reaction mixture was filtered and concentrated to yield yellow solid intermediate VIII-3 (0.99 g, 3.80 mmol, 94.0% yield, 93.4% purity). f

[0252] LCMS: m / z = 243.0, [M+H] + .

[0253] 1 H NMR: (400 MHz, CDC13) δ 7.85 (d, J = 2.4 Hz, 1H), 7.83 (s, 1H), 7.51 (s, 1H), 6.49 (d, J = 2.8 Hz, 1H), 4.78 (s, 2H).

[0254] Preparation of intermediate VIII

[0255]

[0256] ​Intermediate VIII-3 (200 mg, 768 pmol, 93.4% purity, 1.00 equiv) was dissolved in DCM (2.00 mL) and PBr3(208 mg, 768 pmol, 1.00 equiv) was added dropwise at 0 °C. The mixture was stirred at 20 °C for 16 h and LCMS showed 91.9% content of target product (m / z = 307.0, M+H+2). The reaction was quenched by adding NaHC03(2.00 mL) at 0 °C. The mixture was filtered and extracted with additional NaHC03(5.00 mL) and DCM (5.00 mL). The organic phase was washed with 5.00 mL of saturated brine, dried over Na2S04, filtered and concentrated under reduced pressure to obtain off-white solid intermediate VIII (230 mg, 720 pmol, 93.7% yield, 95.8% purity).

[0257] LCMS: m / z = 307.0, [M+H+2]

[0258] 1 H NMR: (400 MHz, CDC13) δ 7.84 (t, J = 1.6 Hz, 2H), 7.52 (d, J = 1.2 Hz, 2H), 6.56 (d, J = 2.8 Hz, 1H), 4.56 (s, 2H).

[0259] The following compounds were prepared according to Example 2.

[0260]

[0261] Example 3: Preparation of Compound 1

[0262]

[0263] Compound 1 (500 mg, 1.55 mmol, 1.0 equiv) was dissolved in 15 mL of THF. NaH (63 mg, 1.55 mmol, 1.0 equiv) was added and the mixture was stirred at 20 °C for 5 h. The reaction mixture was washed with saturated brine and extracted with ethyl acetate (EA). The organic phase was dried over anhydrous Na2S04, concentrated under reduced pressure and purified by column chromatography (PE:EA = 1:1) to yield 460 mg of Compound 1 as a white solid. HPLC purity: 98.77%; MS m / z (ESI): 325.26 [M+H] + ; 1H 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).

[0264] The preparation of the following compounds is carried out with reference to Example 3

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271] Example 4: Preparation of compound 74

[0272] Preparation of compound 74a

[0273]

[0274] Intermediate II (1.00 g, 3.26 mmol, 1.00 equiv) was dissolved in acetic acid and NBS (2.32 g, 13.0 mmol, 4.00 equiv) and H2SO4(1.92 g, 19.5 mmol, 1.04 mL, 6.00 equiv) were added. The mixture was stirred at 30 °C for 16 h. LCMS showed the target molecule content was 98.2% (m / z = 385.8, M+H + ). The reaction 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 x 3) of saturated brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification of the concentrate by column chromatography (SiO2, PE / EA = 10 / 1, R f = 0.46) gave compound 74a (1.12 g, 2.90 mmol, 79.5% yield, 100% purity) as a light yellow oil.

[0275] LCMS m / z = 385.8, M+H +

[0276] 1H NMR: 400 MHz, CDC13 δ 8.21 (d, J = 2.0 Hz, 1H), 7.98 (s, 1H), 7.94 (d, J = 12.4 Hz, 1H), 7.90 (t, J = 6.0 Hz, 3H), 7.54-7.56 (m, 2H), 7.07 (s, 1H), 4.00 (s, 3H).

[0277] Preparation of compound 74

[0278]

[0279] Compound 74a (50.0 mg, 129 pmol, 1.00 equiv) was added. The mixture was stirred at 20 °C for 1 h. LCMS showed 82.5% of the target product formed (m / z = 437.0, M+H + ). The reaction mixture was quenched by slow addition of NH4Cl (2.00 mL) at 10 °C, stirred for 0.5 h, diluted with 2.00 mL H2O and extracted with 2.00 mL of ethyl acetate. The organic phase was washed with 6.00 mL of saturated brine (2.00 mL x 3), dried over Na2S04, filtered and concentrated under reduced pressure to obtain a concentrate. Purification (FA condition, column: Phenomenex Luna C18 150 x 25 mm x 10 um; mobile phase: [water (FA)-ACN]; B%: 21%-51%, 10 min) yielded compound 74 as a yellow solid (22.0 mg, 50.2 pmol, 38.8% yield, 99.7% purity).

[0280] LCMS m / z = 437.0, M+H +

[0281] 1 H NMR: 400 MHz, CDC13 δ 7.99 (d, J = 2.4 Hz, 1H), 7.72-7.74 (m, 1H), 7.59 (d, J = 8.4 Hz, 1H), 4.71 (s, 2H), 3.79 (t, J = 4.8 Hz, 6H), 2.74 (t, J = 5.6 Hz, 2H), 2.65 (s, 4H).

[0282] Example 5: Preparation of compound 64

[0283]

[0284] Compound 74 (100 mg, 229 mΐol, 1.00 equiv), 3-thiopheneboronic acid (32.2 mg, 252 mΐol, 1.10 equiv), Sphos Pd G2 (16.5 mg, 22.9 mΐol, 0.10 equiv) and K2CO3(110 mg, 802 mΐol, 3.50 equiv) and toluene (1.00 mL) and water (0.20 mL) were added into a microwave reaction tube. The mixture was heated to 140 °C in a microwave oven for 1 hour. LCMS showed 29.0% of the target product formed (m / z = 439.1, M+H + ). The reaction mixture was filtered and concentrated under reduced pressure to obtain a concentrate. Purification (FA condition, column: Phenomenex Luna C18 150x25mmx10pm; mobile phase: [water(FA)-ACN]; B%: 26%-56%, 58 min) yielded compound 64 (14.3 mg, 31.5 mΐol, 13.7% yield, 96.8% purity) as a yellow oil.

[0285] LCMS: m / z = 439.1, M+H +

[0286] 1 H NMR: 400 MHz, CDC13 δ 7.65 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 8.4 Hz, 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).

[0287] Example 6: Preparation of compound 73

[0288]

[0289] 2-selenomorpholinoethanol (71.0 mg, 366 mΐol, 1.00 equiv) was dissolved in THF (1.00 mL), followed by the addition of t-BuOK (1 M, 549 mΐL, 1.50 equiv), and then intermediate X (100 mg, 366 mΐol, 1.00 equiv). The reaction was stirred at 20 °C for 2 hours. LC-MS showed 58.4% of the target product formed (m / z = 388.0, M+H +). The mixture was diluted with 2.00 mL of H2O, extracted with 2.00 mL of EtOAc, and the organic phase was washed with 6.00 mL of saturated brine (2.00 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a concentrate. Purification (FA conditions, column: Phenomenex Luna C18 150 x 25 mm x 10 pm; mobile phase: [water (FA)-ACN]; B%: 7%-37%, 10 min) yielded compound 73 (87.7 mg, 207 pmol, 28.3% yield, 91.4% purity) as a yellow gel.

[0290] LCMS: m / z = 388.0, M+H +

[0291] 1 H NMR: 400 MHz, CDC13 δ 7.81 (d, J = 2.0 Hz, 1H), 7.55-7.60 (m, 1H), 7.36-7.37 (m, 1H), 7.23-7.25 (m, 1H), 6.50 (d, J = 2.4 Hz, 1H), 4.61 (s, 2H), 3.66 (t, J = 6.4 Hz, 2Hz), 2.96 (t, J = 5.2 Hz, 4H), 2.69-2.75 (m, 6H).

[0292] Example 7: Preparation of compound 37

[0293]

[0294] Intermediate I (500 mg, 1.82 mmol, 1.2 eq) was 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] + ;

[0295] 1H NMR (400 MHz, 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 = 4.0 Hz, 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).

[0296] The preparation of the following compounds is carried out with reference to Example 7

[0297]

[0298]

[0299]

[0300]

[0301]

[0302] Example 8: Preparation of compound 65

[0303] Preparation of compound 65a

[0304]

[0305] Intermediate II-2 (1.00 g, 4.45 mmol, 1.00 equiv) was dissolved in DCM (10.0 mL) and triethylamine (TEA, 676 mg, 6.68 mmol, 930 μL, 1.50 equiv) was added. At 20 °C, 2-propyn-1-ol (299 mg, 5.35 mmol, 315 μL, 1.20 equiv) was added. The reaction was stirred at 50 °C for 2 h and the target molecular weight was detected by LCMS. NaOH (aq., 2.00 mL) was added to the reaction mixture at 10 °C and stirred for 0.5 h. 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 of saturated brine (2.00 mL x 3). The mixture was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a concentrate. Purification by column chromatography (SiO2, PE / EA = 1 / 1, Rf = 0.45) yielded off-white solid compound 65a (170 mg, 615 μmol, 13.8% yield, 88.3% purity). f = 0.45) yielded off-white solid compound 65a (170 mg, 615 μmol, 13.8% yield, 88.3% purity).

[0306] LCMS: m / z = 244.0, M+H +

[0307] Preparation of compound 65b

[0308]

[0309] Compound 65a (170 mg, 696 pmol, 1.00 equiv) was dissolved in THF (2.00 mL) and NaH (30.6 mg, 766 pmol, 60.0% purity, 1.10 equiv) was added at 0 °C. The mixture was stirred for 0.5 h, then ethyl bromoacetate (127 mg, 766 pmol, 84.7 pL, 1.10 equiv) was added. The reaction was stirred at 20 °C for 1 h, and LCMS showed 72.6% of the desired product formed (m / z = 330.1, M+H + ). The reaction was quenched with NH4CI (2.00 mL) at 10 °C. The mixture was stirred at 10 °C for 0.5 h, diluted with 2 mL of water, and extracted with 2 mL of ethyl acetate. The organic phase was washed with 6.00 mL of saturated brine (2.00 mL x 3), dried over Na2S04, filtered, and concentrated under reduced pressure to obtain a concentrate. Purification by preparative thin-layer chromatography (S1O2, PE / EA = 2 / 1, R f = 0.45) yielded compound 65b (170 mg, 511 pmol, 73.4% yield, 99.3% purity) as a yellow solid.

[0310] LCMS: m / z = 330.1, M+H +

[0311] Preparation of compound 65c

[0312]

[0313] Compound 65b (100 mg, 302 pmol, 1.00 equiv) was dissolved in THF (1.00 mL) and lithium aluminum hydride (LAH, 2.5 M, 157 pL, 1.30 equiv) was added at 0 °C. The reaction was stirred at 20 °C for 1 h, and LCMS showed 93.7% of the desired product formed (m / z = 288.3, M+H + ). The reaction was quenched with H20 (0.05 mL) at 0 °C, followed by dropwise addition of NaOH (0.05 mL), and then H20 (0.15 mL). The reaction mixture was filtered and concentrated under reduced pressure to obtain compound 65c (94.0 mg, 286 pmol, 94.4% yield, 87.7% purity) as a yellow oil.

[0314] LCMS: m / z = 288.3, M+H +

[0315] Preparation of compound 65d

[0316]

[0317] Compound 65c (50.0 mg, 173 pmol, 1.00 equiv) was dissolved in DCM (0.50 mL), and triethylamine (TEA, 52.6 mg, 520 pmol, 72.4 pL, 3.00 equiv) and p-toluenesulfonyl chloride (TosCl, 36.3 mg, 190 pmol, 1.10 equiv) were added. The reaction was stirred at 20 °C for 16 h, and LCMS showed the formation of the target product (m / z = 442.0, M+H + ). The reaction mixture was diluted with 3.00 mL water and extracted with 3.00 mL DCM. The organic phase was washed with 6.00 mL of saturated brine (2.00 mL x 3), dried over Na2S04, filtered and concentrated under reduced pressure to obtain a concentrate. Purification by preparative thin-layer chromatography (S1O2, PE / EA = 1 / 1, R f = 0.58) yielded compound 65d (40.0 mg, 77.9 pmol, 44.9% yield, 86.2% purity) as a yellow oil.

[0318] LCMS: m / z = 442.0, M+H +

[0319] Preparation of compound 65

[0320]

[0321] Compound 65d (10.0 mg, 22.6 pmol, 1.00 equiv) was dissolved in ACN (0.50 mL), and K2C03(9.37 mg, 67.8 pmol, 3.00 equiv) and 4-hydroxypiperidine (2.52 mg, 24.8 pmol, 1.10 equiv) were added. The mixture was stirred at 40 °C for 16 h. LC-MS showed the formation of 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 condition, column: Phenomenex Luna C18 150 x 25 mm x 10 pm; mobile phase: [water (FA)-ACN]; B%: 18%-48%, 10 min) yielded compound 65 (2.26 mg, 5.75 pmol, 25.4% yield, 94.5% purity) as a yellow gel.

[0322] LCMS: m / z = 371.1, M+H +

[0323] 1 H NMR: 400 MHz, CDC13 δ 7.91 (d, J = 2.0 Hz, 1H), 7.64-7.67 (m, 1H), 7.54 (d, J = 8.4 Hz, 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 = 5.2 Hz, 2H), 2.24 (s, 2H), 2.03-2.06 (m, 2H), 1.73-1.76 (m, 2H).

[0324] Example 9: Preparation of compound 81

[0325]

[0326] Intermediate I (200 mg, 444 pmol, 1.00 equiv) was dissolved in ACN (3.00 mL), and 4-fluoropiperidine (75.2 mg, 729 pmol, 1.00 equiv) and Cs2CO3 (475 mg, 1.46 mmol, 2.00 equiv) were added. The mixture was stirred at 25 °C for 1 h, and LCMS showed that Intermediate I was completely reacted and a new main peak was detected. The mixture was filtered through celite, 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 x 25 mm x 5 pm; mobile phase: [water (FA)-ACN]; gradient: 8% - 38% B in 12 min) yielded compound 81 (203 mg, 592 pmol, 81.1% yield, 99.9% purity, FA) as a white solid.

[0327] LCMS: m / z = 297.4, M+H +

[0328] 1 H NMR: (400 MHz, CDC13) δ 7.65-7.66 (m, 1H), 7.52-7.55 (m, 1H), 7.24-7.27 (m, 1H), 6.47 (s, 1H), 4.64-4.80 (m, 1H), 3.76 (s, 2H), 2.68-2.71 (m, 2H), 2.55-2.59 (m, 2H), 1.89-1.97 (m, 4H).

[0329] The following compounds were prepared according to Example 9

[0330]

[0331]

[0332] Example 10: Preparation of compound 91 Preparation of compound 91a

[0333]

[0334] Intermediate I (400 mg, 1.46 mmol, 1.00 equiv) was dissolved in ACN (4.00 mL), and Cs2CO3 (951 mg, 2.92 mmol, 2.00 equiv) and methyl 4-piperidinecarboxylate (251 mg, 1.75 mmol, 1.20 equiv) were added. The mixture was stirred at 25 °C for 1 h, and LCMS showed that Intermediate I was completely reacted (m / z = 337.3, M+H + ) and the main peak of the target product was formed. The reaction was quenched by adding 4.00 mL of water at 20 °C, extracted with dichloromethane (DCM, 4.00 mL x 3), and the combined organic phase was washed with saturated brine (4.00 mL x 2), dried over Na2SO4, filtered and concentrated to obtain a concentrate. The crude white solid compound 91a (500 mg, crude product) was used directly in the next step without further purification.

[0335] LCMS: m / z = 337.3, M+H +

[0336] Preparation of compound 91

[0337]

[0338] Compound 91a (409 mg, 1.22 mmol, 1.00 equiv) was dissolved in methanol (5.00 mL) and water (2.50 mL), and sodium hydroxide (146 mg, 3.65 mmol, 3.00 equiv) was added. The mixture was stirred at 25 °C for 2 h. LCMS showed that compound 91a (m / z = 323.3, M+H + ) was completely reacted and the main peak of the target product was formed. The reaction was quenched by adding 3.00 mL of water at 20 °C, then extracted with DCM (3.00 mL x 3), and the combined organic phase was washed with saturated brine (3.00 mL x 2), dried over Na2SO4, filtered and concentrated to obtain a concentrate. Purification (column: Phenomenex Luna C18 150 25 mm 10 μm; mobile phase: [water (FA)-ACN]; B%: 7%-37%, 2 min) yielded white solid compound 91 (136 mg, 406 μmol, 33.4% yield, 96.3% purity).

[0339] LCMS: m / z = 323.3, M+H +

[0340] 1 H NMR: (400 MHz, CDC13) 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 = 10.4 Hz, 2H), 2.15-2.20 (m, 3H), 1.79-1.82 (m, 2H), 1.56-1.59 (m, 2H).

[0341] Example 11: Preparation of compound 87

[0342] Preparation of compound 87a

[0343]

[0344] Compound I (300 mg, 1.09 mmol, 1.00 equiv) and compound 87a-1 (283 mg, 1.09 mmol, 1.00 equiv) were dissolved in ACN (3.00 mL) and Cs2C03(713 mg, 2.19 mmol, 2.00 equiv) was added. The mixture was stirred at 80 °C for 3 h and LCMS showed compound I was completely reacted and a new peak m / z (MS = 452.7, M+H + ) was formed. The reaction mixture was filtered and concentrated under reduced pressure to obtain yellow gummy material compound 87a (500 mg, crude).

[0345] LCMS: MS = 452.7, M+H +

[0346] Preparation of compound 87b

[0347]

[0348] Compound 87a (500 mg, 1.11 mmol, 1.00 equiv) was dissolved in EtOAc (5.00 mL) and HC1 in EtOAc (4 M, 3.32 mL, 12.0 equiv) was added. The mixture was stirred at 20 °C for 16 h. LCMS showed compound 87a was completely reacted and a new peak m / z (MS = 352.4, M+H+) of the target product was formed. The reaction mixture was concentrated under reduced pressure to yield white solid compound 87b (450 mg, crude, HC1).

[0349] LCMS: MS = 352.4, M+H +

[0350] Preparation of compound 87

[0351]

[0352] Compound 87b (450 mg, 1.28 mmol, 1.00 equiv) was dissolved in MeOH (3.60 mL) and H2O (0.90 mL), and LiOH H2O (107 mg, 2.56 mmol, 2.00 equiv) was added. The mixture was stirred at 20 °C for 2 h, and LCMS showed compound 87b was completely reacted, and a new target product peak m / z (MS = 338.3, M+H + ) was formed. The reaction mixture was filtered and concentrated under reduced pressure to obtain a concentrate. Purification (column: Phenomenex Luna C18 200*40mm*10um; mobile phase: [water(HCl)-ACN]; B%: 3%-33%, 10 min) yielded compound 87 (200 mg, 584 pmol, 45.6% yield, 98.5% purity) as a white solid.

[0353] LCMS: MS = 338.3, M+H +

[0354] 1 H NMR: (400 MHz, DMSO-d6) d 7.94-7.99 (m, 1H), 7.77 (t, J = 4.8 Hz, 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).

[0355] Example 12: Preparation of compound 51

[0356] Preparation of compound 51a

[0357]

[0358] Intermediate II (0.10 g, 322 pmol, 98.8% purity, 1.00 equiv) was dissolved in THF (2.00 mL), and 2,2-dimethoxyethanol (68.3 mg, 644 pmol, 2.00 equiv) and t-BuOK (1.00 M, 966 pL, 3.00 equiv) were added. The mixture was stirred at 0 °C for 3 h, and TLC (PE:EA = 3:1) showed compound II was completely reacted Rf = 0.65), and many new spots (R f= 0.35). The reaction solution was quenched by adding 4.00 mL of H2O at 20 °C, extracted with EtOAc (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 a concentrate. Purification (SiO2, PE:EA = 3:1) yielded compound 51a (56.0 mg, 164 µmol, 50.9% yield, 97.2% purity) as a light yellow liquid.

[0359] 1 H NMR: 400 MHz, CDCI3 δ 7.91 (d, J = 2.0 Hz, 1H), 7.64-7.67 (m, 1H), 7.55 d, J = 8.4 Hz, 1H), 6.58 (s, 1H), 4.73 (s, 2H), 4.54-4.57 (m, 1H), 3.64 (d, J = 5.2 Hz, 1H), 3.41-3.45 (m, 6H).

[0360] Preparation of compound 51b

[0361]

[0362] Compound 51a (0.05 g, 151 µmol, 1.00 equiv) 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 LCMS showed compound 51a was completely reacted to produce a new target peak (m / z = 286.1, M+H + ). The reaction mixture was concentrated under pressure to obtain compound 51b (0.05 g, crude) as a yellow oil.

[0363] LCMS: m / z = 286.1, M+H +

[0364] Preparation of compound 51

[0365]

[0366] Compound 51b (0.04 g, 139 µmol, 1.00 equiv) was dissolved in THF (0.50 mL) and DCM (0.50 mL), and compound 51c (32.2 mg, 167 µmol, 1.20 equiv) and NaBH(OAc)3 (59.3 mg, 279 µmol, 2.00 equiv) were added. The mixture was stirred at 20 °C for 16 hours. LCMS showed that compound 51b was completely reacted, and a new target peak (m / z = 462.2, M+H +). The crude product was purified (Column: Phenomenex Luna C18 150 x 25 mm x 10 pm; mobile phase: [water (FA)-ACN]; B%: 57-87%, 10 min) to obtain compound 51 (24.0 mg, 50.8 pmol, 36.4% yield, 97.9% purity) as yellow oil.

[0367] LCMS: m / z = 462.2, M+H +

[0368] 1 H NMR: 400 MHz, CDC13 δ 7.91 (t, J = 2.0 Hz, 1H), 7.64-7.66 (m, 1H), 7.55 (d, J = 8.4 Hz, 1H), 6.56 (s, 1H), 4.69 (s, 2H), 4.28 (t, J = 5.6 Hz, 2H), 3.96 (s, 2H), 3.81 (t, J = 5.2 Hz, 2H), 3.16-3.15 (m, 2H), 2.94-2.96 (m, 2H).

[0369] The following compounds were prepared according to Example 12

[0370]

[0371]

[0372] Example 13: Preparation of compound 78

[0373] Preparation of compound 78b

[0374]

[0375] Compound 78a (1.00 g, 9.34 mmol, 877 pL, 1.00 equiv) was dissolved in MeOH (5.00 mL) and H20 (5.00 mL), and NH2OH HCI (778 mg, 11.2 mmol, 1.20 equiv) was added. The mixture was stirred at 25 °C for 5 h, and TLC (PE:EA = 1 : 1, Rf = 0.45) monitored that compound 78a was completely reacted and a new spot was formed. The reaction mixture was filtered and concentrated under reduced pressure to obtain white solid 78b (1.20 g, crude). f

[0376] 1 H NMR: (400 MHz, DMSO-d6) d 10.3 (s, 1H), 8.87 (d, J = 6.8 Hz, 2H), 8.41 (s, 1H), 8.12 (d, J = 6.4 Hz, 2H). ​

[0377] Preparation of compound 78c

[0378]

[0379] Compound 78b (500 mg, 4.09 mmol, 1.00 equiv) was dissolved in DMF (5.00 mL), and NCS (546 mg, 4.09 mmol, 1.00 equiv) was added. The mixture was stirred at 20 °C for 12 hours, and TLC (PE:EA = 1:1, Rf= 0.55) showed that compound 78b was completely reacted and a new spot was formed. The reaction mixture was filtered and concentrated under reduced pressure to obtain compound 78c (700 mg, crude) as a white solid. f

[0380] 1 H NMR: (400 MHz, DMSO-d6) d 11.0 (s, 1H), 8.85 (d, J = 6.4 Hz, 2H), 8.11 (d, J = 6.4 Hz, 2H).

[0381] Preparation of compound 78d

[0382]

[0383] 2-Morpholinoethanol (2.12 g, 16.1 mmol, 1.97 mL, 1.20 equiv) was dissolved in THF (20.0 mL), and NaH (645 mg, 16.1 mmol, 60.0% content, 1.20 equiv) was added dropwise at 0 °C, stirred for 0.5 hours. At 20 °C, 3-bromopropyne (2.00 g, 13.4 mmol, 1.45 mL, 1.00 equiv) was added dropwise, stirred for 11.5 hours. LCMS showed that 2-morpholinoethanol was completely reacted and a new target product peak (m / z = 170.1, M+H + ) was formed. At 0 °C, 10.0 mL of H2O was added to quench the reaction, and the mixture was extracted with EtOAc (10.0 mL x 3), washed with saturated brine (10.0 mL x 3), and 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%) as a yellow liquid.

[0384] LCMS: m / z = 170.1, M+H +

[0385] Preparation of compound 78

[0386]

[0387] ​Compound 78d (300 mg, 1.77 mmol, 1.00 equiv) was dissolved in DCM (3.00 mL), and NaF (245 mg, 5.85 mmol, 245 μL, 3.30 equiv) and compound 78b (333 mg, 2.13 mmol, 1.20 equiv) were added. The mixture was stirred at 50 °C for 6 h, and LCMS showed compound 78d was completely reacted and the main peak of the target product was formed (m / z = 290.1, M+H + ). The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified (column: Phenomenex C18 250 x 50 mm x 10 um; mobile phase: [water (ammonium hydroxide v / v) - ACN]; B%: 8% - 38%, 8 min) to yield compound 78 as a yellow solid (110 mg, 374 μmol, yield 21.1%, purity 98.4%).

[0388] LCMS: m / z = 290.1, M+H +1 H NMR: (400 MHz, CDC13) δ 8.75 (d, J = 5.6 Hz, 2H), 7.69 (d, J = 6.0 Hz, 2H), 6.64 (s, 1H), 4.71 (s, 2H), 3.73-3.76 (m, 6H), 2.54-2.68 (m, 6H).

[0389] The following compounds were prepared according to Example 13

[0390]

[0391] Example 14: Preparation of compound 98

[0392] Preparation of compound 98b

[0393]

[0394] Compound 98a (500 mg, 3.23 mmol, 1.00 equiv) was dissolved in MeOH (5.00 mL), and NaBH4(244 mg, 6.45 mmol, 2.00 equiv) was added. The reaction was stirred at 0 °C for 2 h, and TLC (PE:EA = 2:1, R f = 0.50) showed compound 98a was completely reacted and a new spot was formed. 5.00 mL H2O was added to quench the reaction, and the mixture was extracted with ethyl acetate (5.00 mL x 3), washed with saturated brine (5.00 mL x 3), and dried over Na2S04, filtered, and concentrated under reduced pressure to obtain compound 98b as a yellow oil (450 mg, 2.87 mmol, yield 88.8%).

[0395] 1 H NMR: (400 MHz, CDC13) δ 4.13-4.18 (m, 1H), 3.68-3.78 (m, 4H), 1.89-1.99 (m, 4H).

[0396] Preparation of compound 98c

[0397]

[0398] Intermediate I (2.00 g, 7.30 mmol, 1.00 equiv) and tert-butyl (2-hydroxyethyl)carbamate (1.41 g, 8.76 mmol, 1.36 mL, 1.20 equiv) were dissolved in DCM (20.0 mL), and TBAB (1.65 g, 5.11 mmol, 0.70 equiv) and NaOH (10.0 M, 1.46 mL, 2.00 equiv) were added. The reaction was stirred at 20 °C for 12 h, and LCMS showed that Intermediate I was completely reacted and a new target molecule was formed (m / z = 377.3, M+Na + ). The reaction mixture was extracted with 30.0 mL DCM, washed with saturated brine (30.0 mL), and the combined organic phase was dried over Na2S04, filtered and concentrated under reduced pressure to obtain a concentrate which was purified by column chromatography (Si02, PE / EA = 10 / 1 to 3 / 1, R f = 0.50) to give compound 98c (1.00 g, 2.82 mmol, 38.7% yield) as a light yellow oil.

[0399] LCMS: m / z = 377.3, M+Na +

[0400] 1 H NMR: (400 MHz, CDC13) 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 = 4.8 Hz, 2H), 3.37-3.38 (m, 2H), 1.45 (s, 9H).

[0401] Preparation of compound 98d

[0402]

[0403] Compound 98c (800 mg, 2.26 mmol, 1.00 equiv) was dissolved in EtOAc (8.00 mL), and HCl / EtOAc (4.00 M, 5.64 mL, 10.0 equiv) was added. The reaction was stirred at 20 °C for 2 h, and LCMS showed compound 98c was completely reacted, and a new target main peak (m / z = 255.5, M+H + ) was generated. The reaction mixture was concentrated under reduced pressure to obtain compound 98d (750 mg, crude, HC1) as a white solid.

[0404] LCMS: m / z = 255.5, M+H +

[0405] Preparation of compound 98

[0406]

[0407] Compound 98d (200 mg, 688 µmol, 1.00 equiv, HC1) was dissolved in DMF (2.00 mL), and DIEA (444 mg, 3.44 mmol, 599 µL, 5.00 equiv) and compound 98b (130 mg, 825 µmol, 1.20 equiv) were added. The mixture was stirred at 85 °C for 12 h. LCMS showed compound 98d was completely reacted, and a target main peak (m / z = 339.3, M+H + ) was generated. The reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product, which was then purified by preparative separation method (column: Phenomenex Luna C18 150×30 mm×5 µm; mobile phase: [water (HC1)-ACN]; gradient: 15%-45% B in 10 min) to yield compound 98 (100 mg, 281 µmol, 40.8% yield, 95.0% purity) as a yellow oil.

[0408] LCMS: m / z = 339.3, M+H +

[0409] 1H NMR: (400 MHz, 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).

[0410] Example 15: Preparation of compound 99

[0411] Preparation of compound 99b

[0412]

[0413] Compound 99a (1.15 g, 4.79 mmol, 1.00 equiv), 4-methoxy-lH-indole (710 mg, 4.79 mmol, 1.00 equiv), CuI (274 mg, 1.44 mmol, 0.30 equiv), TEMED (111 mg, 958 μmol, 145 μL, 0.20 equiv) and Cs2CO3(3.12 g, 9.58 mmol, 2.00 equiv) were dissolved in ACN (15.0 mL), and the mixture was purged with N2three times. The reaction was stirred at 85 °C for 2 h under nitrogen protection. LCMS showed that compound 99a was completely reacted, and a new target main peak (m / z = 261.1, M+H + ) was generated. The reaction mixture was added to 50.0 mL H2O for phase separation, and the organic phase was separated. The aqueous phase was washed with 60.0 mL (30.0 mL x 2) dichloromethane, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (SiO2, PE:EA = 10: 1, R f = 0.46) to produce compound 99b (400 mg, 1.53 mmol, 31.9% yield, 99.3% purity) as a yellow solid.

[0414] LCMS: m / z = 261.1, M+H +

[0415] 1H NMR: 400 MHz, CDC13δ 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 = 8.0 Hz, 1H), 4.01 (s, 3H).

[0416] Preparation of compound 99c

[0417]

[0418] Compound 99b (100 mg, 384 μmol, 1.00 equiv) was dissolved in DCM (1.00 mL), and BBr3(289 mg, 1.15 mmol, 111 μL, 3.00 equiv) was added at 0 °C. The reaction was stirred at 20 °C for 4 h. LCMS showed compound 99b was completely reacted, and a new target main peak (m / z = 247.3, M+H + ) was generated. H2O (3.00 mL) was added to the reaction mixture at 0 °C, followed by extraction, filtration, and concentration under reduced pressure to obtain compound 99c (90.0 mg, 362 μmol, 94.2% yield, 99.1% purity) as a white solid.

[0419] LCMS: m / z = 247.3, M+H +

[0420] Preparation of compound 99

[0421]

[0422] Compound 99c (100 mg, 406 μmol, 1.00 equiv), N-(2-chloroethyl)morpholine hydrochloride (90.7 mg, 487 μmol, 1.20 equiv), and Cs2CO3(397 mg, 1.22 mmol, 3.00 equiv) were dissolved in DMF (2.00 mL), and the atmosphere was replaced with nitrogen three times. The mixture was stirred at 60 °C for 3 h under nitrogen protection. LCMS showed compound 99c was completely reacted, and a new target main peak (m / z = 360.4, M+H + ) was generated. The DMF (2.00 mL) was removed under reduced pressure, and the concentrate was purified (column: Phenomenex Luna C18 150 x 25 mm x 10 μm; mobile phase: [water (FA)-ACN]; B%: 11%-41%, 10 min) to obtain compound 99 (28.3 mg, 267 μmol, 65.6% yield, 95.8% purity) as a white solid.

[0423] LCMS: m / z = 360.4, M+H+

[0424] 1 H NMR: 400 MHz, CDC13 δ 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 = 7.6 Hz, 1H), 4.36 (d, J = 5.6 Hz, 2H), 3.774-3.78 (m, 4H), 2.96 (d, J = 3.78 Hz, 2H), 2.69-2.72 (m, 4H).

[0425] Example 16: Preparation of compound 100

[0426] Preparation of compound 100b

[0427]

[0428] Compound 100a (5.00 g, 39.2 mmol, 4.27 mL, 1.00 equiv) was dissolved in CCl4(50.0 mL), and BPO (94.9 mg, 392 µmol, 0.01 equiv) and NBS (6.28 g, 35.3 mmol, 0.90 equiv) were added. The mixture was stirred at 80 °C for 16 hours, and LCMS showed that the target compound was formed (m / z = 207.9, M+H + ). The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by column chromatography (column: SiO2, PE:EA = 10:1, R f = 0.56) to obtain compound 100b (3.30 g, 11.7 mmol, yield 29.9%, purity 73.2%) as yellow oil.

[0429] LCMS: m / z = 207.9, M+H +

[0430] Preparation of compound 100c

[0431]

[0432] Compound 100b (3.30 g, 11.7 mmol, 1.00 equiv) was dissolved in ACN (20.0 mL), and morpholine (2.04 g, 23.4 mmol, 2.06 mL, 2.00 equiv) was added. The mixture was stirred at 20 °C for 2 hours, and LCMS showed that the target compound was formed (m / z = 213.1, M+H +). The reaction mixture was diluted with 20 mL of water and extracted with 20.0 mL of ethyl acetate, washed with saturated brine (30.0 mL), dried over Na2S04, filtered and concentrated under reduced pressure to get crude product 100c (1.70 g, 7.40 mmol, 63.3% yield, 92.6% purity) as yellow oil, which was taken to the next step without purification.

[0433] LCMS: m / z = 213.1, M+H +

[0434] Preparation of compound 100d

[0435]

[0436] Compound 100c (500 mg, 2.18 mmol, 1.00 eq) was dissolved in hydrazine hydrate (1.22 g, 24.0 mmol, 1.19 mL, 98.0% purity, 11.0 eq) at 20 °C. The mixture was stirred at 110 °C for 24 h and LCMS showed formation of the desired 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 yield compound 100d (500 mg, crude) as yellow oil.

[0437] LCMS: m / z = 209.1, M+H +

[0438] Preparation of compound 100e

[0439]

[0440] Compound 100d (200 mg, 960 pmol, 1.00 eq) was dissolved in DCM (2.00 mL) and TEA (97.2 mg, 960 pmol, 134 pL, 1.00 eq) and chloroisocyanuric acid chloride (154 mg, 864 pmol, 0.90 eq, HC1) were added. The mixture was stirred at 20 °C for 2 h and LCMS showed formation of the desired 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 yield compound 100e (300 mg, crude) as yellow oil.

[0441] LCMS: m / z = 314.1, M+H +

[0442] Preparation of compound 100

[0443]

[0444] Compound 100e (300 mg, 777 pmol, 1.00 equiv) was placed in a microwave reaction tube and AcOH (3.00 mL) was added. The tube was sealed and heated to 160 °C in the microwave for 3 h. LCMS showed the formation of the target compound (m / z = 296.2, M+H + ). The reaction mixture was concentrated under reduced pressure and the crude product was purified using a basic condition column (Phenomenex C18 250 x 50 mm x 10 pm; mobile phase: [water (NH 3· H2O) - ACN]; B%: 1-25%, 10 min) to yield compound 100 as a white solid (150 mg, 508 pmol, 50.0% yield, 100% purity).

[0445] LCMS: m / z = 296.2, M+H +

[0446] 1 H NMR: (400 MHz, CDC13) δ 8.87 (d, J = 6.0 Hz, 2H), 8.29 (d, J = 6.8 Hz, 1H), 7.81-7.82 (m, 2H), 7.47 s 1H), 7.00 (t, J = 6.8 Hz, 1H), 4.11 (s, 2H), 3.80 (s, 4H), 2.68 (s, 4H).

[0447] Example 17: Preparation of Compound 101

[0448] Preparation of Compound 101b

[0449]

[0450] Compound 100d (250 mg, 1.20 mmol, 1.00 equiv) was dissolved in DCM (2.00 mL) and compound 101a (191 mg, 1.08 mmol, 135 pL, 0.90 equiv) was added. The reaction mixture was stirred at 20 °C for 16 h. LCMS showed the formation of the target compound (m / z = 349.1, M+H + ). The reaction mixture was concentrated under reduced pressure to yield 101b as a yellow solid (250 mg, crude).

[0451] LCMS: MS = 349.1, M+H +

[0452] Preparation of Compound 101

[0453]

[0454] Compound 101b (157 mg, 452 pmol, 1.00 equiv) was placed in a microwave reaction tube and dissolved in AcOH (2.50 mL). The tube was sealed and heated to 160 °C in the microwave for 2 hours. LCMS 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 NH3H2O (3.00 mL) and filtered. The filter cake was dried under reduced pressure to yield yellow solid compound 101 (140 mg, 415 pmol, 91.8% yield, 97.9% purity).

[0455] LCMS: m / z: 331.1, M+H +

[0456] 1 HNMR (400 MHz, CDC13) δ 8.14-8.16 (d, J = 6.8 Hz, 1H), 7.61-7.70 (m, 1H), 7.58-7.59 (m, 1H), 7.44-7.58 (m, 2H), 6.96 (t, J = 6.8 Hz, 1H), 4.08 (s, 2H), 3.79 (s, 4H), 2.63 (s, 4H).

[0457] Example 18: Preparation of compound 103

[0458] Preparation of compound 103b

[0459]

[0460] Compound 103a (1.00 g, 4.52 mmol, 1.00 equiv) was dissolved in THF (10.0 mL). At 0 °C, i-PrMgCl LiCl (1.3 M, 5.21 mL, 1.50 equiv) was added and the reaction was stirred for 1 hour. Then 4-pyridinecarboxaldehyde (713 mg, 6.66 mmol, 627 pL, 1.47 equiv) was added while keeping the temperature at 0 °C and the reaction continued for 3 hours. LCMS showed complete consumption of 4-pyridinecarboxaldehyde and formation of a new target peak (MS = 250.3, M+H + ) was observed. The reaction mixture was quenched with NH4CI (10.0 mL), extracted with EtOAc (10.0 mL x 3), washed with saturated brine (10.0 mL x 3), dried over Na2S04, filtered and concentrated under reduced pressure to obtain a concentrate. Preparative thin layer chromatography (PE / EA = 2 / 1, R f= 0.26) to yield compound 103b (860 mg, 3.07 mmol, 68.0% yield, 89.1% purity) as a brown oil.

[0461] LCMS: MS = 250.3, M+H +

[0462] Preparation of compound 103c

[0463]

[0464] Compound 103b (860 mg, 3.07 mmol, 1.00 equiv) was dissolved in DCM (9.00 mL). At 0 °C, TEMPO (19.3 mg, 123 pmol, 0.04 equiv) and KOAc (376 mg, 3.84 mmol, 1.25 equiv) were added, followed by dropwise addition of TCCA (321 mg, 1.38 mmol, 0.45 equiv). The reaction was maintained at 0 °C and stirred for 2 h. LCMS showed complete reaction of compound 103b and formation of a new target compound (MS = 248.4, M+H + ). The reaction mixture was filtered through celite, and the filter cake was washed with DCM. Preparative thin layer chromatography (PE / EA = 2 / 1, R f = 0.48) to yield compound 103c (570 mg, 1.99 mmol, 64.9% yield, 86.5% purity) as a brown oil.

[0465] LCMS: MS = 248.3, M+H +

[0466] Preparation of compound 103d

[0467]

[0468] Compound 103c (570 mg, 1.99 mmol, 1.00 equiv) was dissolved in pyridine (5.00 mL) and NH2OH HCI (346 mg, 4.98 mmol, 2.50 equiv) was added. The mixture was stirred at 50 °C for 12 h. LCMS showed complete reaction of compound 103c and formation of a new target compound (MS = 263.4, M+H + ). The pyridine was removed under reduced pressure, and the residue was diluted with 5.00 mL H2O and extracted with EtOAc (5.00 mL x 3). The combined organic layers were washed with saturated brine (5.00 mL x 2), dried over Na2S04, filtered, and concentrated under reduced pressure to yield compound 103d (500 mg, 1.85 mmol, 93.0% yield, 97.3% purity) as a yellow solid.

[0469] LCMS: MS = 263.4, M+H +

[0470] Preparation of compound 103e

[0471]

[0472] Compound 103d (200 mg, 741 pmol, 1.00 equiv) and t-BuOK (1 M, 1.48 mL, 2.00 equiv) were added into a microwave reaction tube, dissolved in THF (2.00 mL), and then the tube was sealed and heated to 100 °C in the microwave for 2 hours. LCMS showed that compound 103d was partially reacted and formed a new target compound (MS = 227.3, M+H + ). 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 compound 103e (90.0 mg, 306 pmol, yield 41.3%, purity 77.0%) as a light yellow solid.

[0473] LCMS: MS = 227.3, M+H +

[0474] Preparation of compound 103f

[0475]

[0476] Compound 103e (90.0 mg, 398 pmol, 1.00 equiv) was dissolved in DCM (1.00 mL), cooled to 0 °C, and BBr3(109 mg, 437 pmol, 42.2 pL, 1.10 equiv) was added. The mixture was stirred at 20 °C for 10 hours. LCMS showed that compound 103e was completely reacted to produce a new target product peak (MS = 213.3, M+H + ). The reaction 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) as a yellow solid.

[0477] LCMS: MS = 213.3, M+H +

[0478] Preparation of compound 103

[0479]

[0480] Compound 103f (130 mg, 613 µmol, 1.00 equiv) was dissolved in ACN (1.30 mL), and compound 103g (137 mg, 919 µmol, 1.50 equiv) and Cs2CO3 (399 mg, 1.23 mmol, 2.00 equiv) were added. The mixture was stirred at 20 °C for 1 h. LCMS showed compound 103f was completely reacted, a new target peak (MS = 326.3, M+H + ) was generated. The reaction mixture was filtered, concentrated under reduced pressure and purified (column: Waters xbridge 150 x 25 mm x 10 µm; mobile phase: [water (NH3·H2O)-ACN]; B%: 25%-45%, 10 min) to obtain compound 103 (60.0 mg, 182 µmol, 29.7% yield, 98.6% purity) as off-white solid.

[0481] LCMS: MS = 326.3, M+H +

[0482] 1 H NMR: (400 MHz, CDCl3) δ 8.85 (t, J = 4.8 Hz, 2H), 7.88 (t, J = 4.4 Hz, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.35 (t, J = 8 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 4.46 (s, 2H), 3.77 (s, 4H), 2.97 (s, 2H), 2.69 (s, 4H).

[0483] Example 19: Preparation of compound 106

[0484] Preparation of compound 106b

[0485]

[0486] Compound 106a (1.00 g, 5.18 mmol, 1.00 equiv) was dissolved in THF (10.0 mL), and i-PrMgCl-LiCl (1.50 M, 5.18 mL, 1.50 equiv) was added at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. HPLC showed the starting material was completely reacted. The reaction mixture was used in the next step without purification.

[0487] Preparation of compound 106c

[0488]

[0489] Compound 106b (1.13 g, 5.20 mmol, 1.17 mL, 1.00 equiv) was dissolved in THF (10.0 mL) and 2-fluoro-3-methoxybenzaldehyde (961 mg, 6.24 mmol, 1.20 equiv) was added. The reaction mixture was stirred at 25 ° C for 12 hours. LCMS showed that compound 106b was completely reacted and a new target peak was generated. The reaction mixture was quenched with NH4Cl (10.0 mL), extracted with EtOAc (10.0 mL × 3), washed with saturated brine (10.0 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain yellow oily compound 106c (900 mg, 3.36 mmol, 64.5% yield).

[0490] Preparation of compound 106d

[0491]

[0492] Compound 106c (500 mg, 1.86 mmol, 1.00 equiv) was dissolved in DCM (8.00 mL), and MnO2 (1.62 g, 18.6 mmol, 10.0 equiv) was added. The reaction mixture was stirred at 25°C for 2 hours, indicating that compound 106c was completely reacted and a new target peak was generated by LCMS (m / z=267.4, M+H + The reaction mixture was concentrated under reduced pressure to obtain compound 106d (500 mg, crude product) as a yellow oil.

[0493] LCMS: m / z=267.4, M+H +

[0494] Preparation of compound 106e

[0495]

[0496] Compound 106d (500 mg, 1.88 mmol, 1.00 equiv) was dissolved in pyridine (5.00 mL) and hydroxylamine hydrochloride (NH2OH·HCl, 326 mg, 4.70 mmol, 2.50 equiv) was added. The reaction mixture was stirred at 50°C for 12 hours. LC-MS showed that compound 106d was completely reacted and a new target peak (m / z = 282.3, M+H) was generated. + The reaction mixture was concentrated under reduced pressure to obtain yellow solid Compound 106e (326 mg, 1.15 mmol, yield 61.2%, purity 99.2%).

[0497] LCMS: m / z=282.3, M+H +

[0498] 1 H NMR: (400 MHz, CDCI3) δ 7.47-7.53 (m, 1 H), 7.38-7.43 (m, 1 H), 7.18-7.22 (m, 2 H), 6.95-6.99 (m, 1 H), 6.77-6.81 (m, 1 H), 3.95 (s, 3 H).

[0499] Preparation of compound 106f

[0500]

[0501] Compound 106e (230 mg, 817 μmol, 1.00 equiv) was dissolved in DMSO (2.50 mL) and K2CO3 (169 mg, 1.23 mmol, 1.50 equiv) was added. The reaction was stirred at 80 °C for 12 h. LC-MS showed compound 106e was completely reacted and a new target peak (m / z = 262.3, M+H + ) was generated. The reaction was quenched with 5.00 mL water at 25 °C and extracted with ethyl acetate (EtOAc, 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 give compound 106f (170 mg, 633 μmol, 77.5% yield, 97.4% purity) as a brown solid.

[0502] LCMS: m / z = 262.3, M+H +

[0503] 1 H NMR: (400 MHz, CDCI3) δ 7.72-7.85 (m, 2 H), 7.31-7.45 (m, 3 H), 7.05 (d, J = 7.6, 1 H), 4.09 (s, 3 H).

[0504] Preparation of compound 106g

[0505]

[0506] Compound 106f (170 mg, 650 μmol, 1.00 equiv) was dissolved in dichloromethane (DCM, 2.00 mL) and boron tribromide (BBr3, 489 mg, 1.95 mmol, 188 μL, 3.00 equiv) was added at 0 °C. The reaction was stirred at 20 °C for 12 h. LC-MS showed compound 106f was completely reacted and a new target peak (m / z = 248.3, M+H +) at 0 °C, then extracted, filtered and concentrated to obtain compound 106g (172 mg, crude) as a yellow solid.

[0507] LCMS: m / z = 248.3, M+H +

[0508] 1 H NMR: EC6663-444-P1A (400 MHz, CDC13) δ 7.72-7.85 (m, 2H), 7.29-7.45 (m, 3H), 7.12-7.14 (m, 1H).

[0509] Preparation of compound 106

[0510]

[0511] Compound 106g (170 mg, 687 pmol, 1.00 equiv) was dissolved in acetonitrile (ACN, 2.00 mL) and K2CO3 (142 mg, 1.03 mmol, 1.50 equiv) and 4-(2-chloroethyl)morpholine (123 mg, 825 pmol, 1.20 equiv) were added. The reaction mixture was stirred at 20 °C for 5 hours. LC-MS showed that compound 106g was completely reacted and a new target peak (m / z = 361.4, M+H + ) was generated. The reaction was quenched with 10 mL of water at 25 °C, filtered and concentrated under reduced pressure to obtain compound 106 (165 mg, 452 pmol, yield 65.7%, purity 98.2%) as a brown solid.

[0512] LCMS: m / z = 361.4, M+H +

[0513] 1 H NMR: (400 MHz, DMSO-d6) δ 8.75 (d, J = 5.6 Hz, 2H), 7.69 (d, J = 6.0 Hz, 2H), 6.64 (s, 1H), 4.71 (s, 2H), 3.73-3.76 (m, 6H), 2.54-2.68 (m, 6H).

[0514] Example 20: Preparation of compound 107

[0515] Preparation of compound 107b

[0516]

[0517] Compound 107a (500 mg, 1.51 mmol, 1.00 equiv) was dissolved in DMSO (5.00 mL) and added dropwise to K2CO3 (314 mg, 2.27 mmol, 1.50 equiv). The mixture was heated to 80 °C and stirred for 2 hours. TLC monitoring revealed the formation of a new spot, which prompted a preparative 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 yield a yellow solid crude product 107b (500 mg, crude), which was used directly in the next reaction step without further purification.

[0518] Preparation of compound 107c

[0519]

[0520] Compound 107b (200 mg, 645 pmol, 1.00 equiv) was dissolved in THF (2.00 mL) and cooled to 0 °C. Then i-PrMgCl LiCl (1.30 M, 744 pL, 1.50 equiv) was added, and the mixture was maintained at 0 °C and stirred for 2 hours. HPLC analysis showed complete reaction of the starting material. The crude product, colorless liquid 107c (215.0 mg, crude), was used directly in the next step without purification.

[0521] Preparation of compound 107d

[0522]

[0523] Compound 107c (215 mg, 642 pmol, 1.00 equiv) was dissolved in THF (2.00 mL), and DMF (93.9 mg, 1.29 mmol, 98.9 pL, 2.00 equiv) was added. The mixture was stirred at 20 °C for 12 hours. LC-MS analysis showed complete reaction of compound 107c and the generation of a new peak of interest (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.

[0524] LCMS: m / z = 260.3, M+H +

[0525] Preparation of compound 107

[0526]

[0527] Compound 107d (100 mg, 385 pmol, 1.00 equiv) was dissolved in methanol (MeOH, 0.20 mL), and NaBH3CN (72.7 mg, 1.16 mmol, 3.00 equiv) and morpholine (40.3 mg, 462 pmol, 40.7 pL, 1.20 equiv) were added. The reaction mixture was stirred at 20 °C for 16 h. LC-MS analysis showed that compound 107d was completely reacted and a new target peak was generated. After filtration and concentration under reduced pressure, the concentrate was purified using a column (Phenomenex Luna C18, 150 x 25 mm x 10 pm; mobile phase: [water (FA)-ACN]; gradient: 8%-38% B in 10 min) to obtain compound 107 (50.0 mg, 145 pmol, 18.9% yield, 96.4% purity) as a white solid.

[0528] LCMS: m / z = 331.4, M+H +

[0529] 1 H NMR: (400 MHz, DMSO-d6) d 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).

[0530] Example 21: Preparation of compound 102

[0531] Preparation of compound 102b

[0532]

[0533] Compound 102a (5.00 g, 42.3 mmol, 1.00 equiv), NBS (11.3 g, 63.5 mmol, 1.50 equiv) and AIBN (6.95 g, 42.3 mmol, 1.00 equiv) were dissolved in DCE (50.0 mL). The mixture was purged with nitrogen three times and stirred at 80 °C for 16 h without light. LC-MS analysis showed that the target compound (m / z = 196.0, M+H + ) was formed. The reaction mixture was filtered and concentrated under reduced pressure to obtain crude material 102b (5.20 g, 26.4 mmol, 62.4% yield) as a yellow oil.

[0534] LCMS: m / z = 197.2, M+H +

[0535] Preparation of compound 102c

[0536]

[0537] Compound 102b (5.00 g, 25.3 mmol, 1.00 equiv) and morpholine (4.42 g, 50.7 mmol, 4.47 mL, 2.00 equiv) were dissolved in CH3CN (50.0 mL). The mixture was purged with nitrogen three times and stirred at 20 °C for 6 h. LC-MS analysis indicated the formation of the target compound (m / z = 204.1, M+H + ). The reaction mixture was quenched with water (60.0 mL) and extracted with ethyl acetate (60.0 mL) three times. The combined organic layer was washed with brine (60.0 mL) three times, dried over sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure to obtain material 102c (4.90 g, 24.1 mmol) as a yellow oil.

[0538] LCMS: m / z = 204.1, M+H +

[0539] Preparation of compound 102d

[0540]

[0541] Compound 102c (4.90 g, 24.1 mmol, 1.00 equiv) was dissolved in methanol (MeOH, 50.0 mL) under argon atmosphere and Raney-Ni (980 mg, 11.4 mmol, 0.10 equiv) was added. The mixture was purged with hydrogen three times and stirred at 25 °C under hydrogen (50 Psi) for 16 h. LC-MS analysis indicated the formation of the target compound (m / z = 208.2, M+H + ). The reaction mixture was filtered and washed with methanol (50.0 mL) three times, then concentrated to obtain material 102d (4.50 g, 21.7 mmol) as a brown oil.

[0542] LCMS: m / z = 208.2, M+H +

[0543] Preparation of compound 102e

[0544]

[0545] Compound 102d (600 mg, 2.89 mmol, 1.00 equiv) was dissolved in DCM (6.00 mL) and TEA (585 mg, 5.79 mmol, 805 μL, 2.00 equiv) and isonicotinyl chloride (368 mg, 2.61 mmol, 0.90 equiv) were added. The mixture was stirred at 25 °C for 12 h. LC-MS analysis indicated the formation of the target compound (m / z = 313.2, M+H + ). The reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product 102e (1.00 g) as a brown oil.

[0546] LCMS: m / z = 313.2, M+H +

[0547] Preparation of compound 102

[0548]

[0549] Compound 102e (500 mg, 1.60 mmol, 1.00 equiv) and phosphorus oxychloride (POCl3, 3.00 mL) were placed in a microwave sealed tube and heated at 155 °C for 2 h under microwave conditions. LC-MS analysis indicated the formation of the target compound (m / z = 295.2, M+H + ). After the reaction mixture was cooled to room temperature, water (4.00 mL) was added to quench the reaction. 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 x 50 mm x 10 μm; mobile phase: [water (NH4HCO3) - ACN]; B%: 10% - 40%, 8 min). Compound 102 (205 mg, 685 μmol) was obtained as a white solid in 42.8% yield with 98.4% purity.

[0550] LCMS: m / z = 295.2, M+H +

[0551] 1 H NMR: (400 MHz, CDC13) δ 8.77 (d, J = 5.6 Hz, 1H), 8.32 (d, J = 6.8 Hz, 1H), 7.83-7.86 (m, 1H), 7.77 (d, J = 6.0 Hz, 1H), 6.86 (d, J = 6.4 Hz, 1H), 6.69 (t, J = 7.2 Hz, 1H), 3.71-3.76 (m, 6H), 2.55 (s, 4H).

[0552] Example 22: Preparation of compound 104

[0553] Preparation of compound 104b

[0554]

[0555] Compound 102d (500 mg, 2.41 mmol, 1.00 equiv) was dissolved in DCM (5.00 mL) and compound 104a (383 mg, 2.17 mmol, 271 pL, 0.90 equiv) was added. The reaction mixture was stirred at 20 °C for 2 h. LC-MS analysis indicated the formation of the target compound (m / z = 348.1, M+H + ). The reaction mixture was filtered and concentrated under reduced pressure to obtain crude yellow solid 104b (800 mg, 2.16 mmol) in 89.6% yield, 93.9% purity.

[0556] LCMS: m / z = 348.1, M+H +

[0557] Preparation of compound 104

[0558]

[0559] Compound 104b (500 mg, 1.44 mmol, 1.00 equiv) and POCl3(3.00 mL) were added to a microwave sealed tube and heated at 155 °C for 2 h under microwave conditions. LC-MS analysis indicated the formation of the target compound (m / z = 330.1, M+H + ). After the reaction mixture was cooled to room temperature, water (5.00 mL) was added to quench the reaction. The mixture was filtered and concentrated under reduced pressure to obtain crude product which was purified by reverse phase HPLC (column: Phenomenex C18 250x50mmx10pm; mobile phase: [water(NH4HCO3)-ACN]; B%: 29%-59%, 8 min). This resulted in compound 104 (265 mg, 803 pmol) as a yellow solid in 55.8% yield, 99.9% purity.

[0560] LCMS: m / z = 330.1, M+H +

[0561] 1H NMR: (400 MHz, CDC13) δ 8.14 (d, J = 7.2 Hz, 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 = 6.4 Hz, 1H), 6.61 (t, J = 6.4 Hz, 1H), 3.69-3.75 (m, 6H), 2.54 (s, 4H).

[0562] Example 23: Preparation of compound 105

[0563]

[0564] Compound 104 (200 mg, 607 pmol, 1.00 equiv) was dissolved in DMF (0.50 mL) and a selective fluorination reagent (430 mg, 1.21 mmol, 2.00 equiv) was added. The mixture was stirred at 80 °C for 12 h. LC-MS analysis indicated the formation of 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 x 25 mm x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 35% - 65% B in 18 min). This resulted in compound 105 (4.36 mg, 28.2 pmol) as a yellow solid in 4.65% yield with 98.1% purity.

[0565] LCMS: m / z = 348.4, M+H +

[0566] 1 H NMR: (400 MHz, CDC13) δ 8.14 (d, J = 7.2 Hz, 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 = 6.4 Hz, 1H), 6.61 (t, J = 6.4 Hz, 1H), 3.69-3.75 (m, 6H), 2.54 (s, 4H).

[0567] Biological activity data

[0568] Example 24: Binding affinity test

[0569] (1) Preparation of Sigma-1 receptor membrane

[0570] Guinea pigs (provided by Beijing Vital River Laboratory Animal Technology Co., Ltd.) were decapitated and the procedure was performed on ice. The cerebral cortex was rapidly collected and pooled into a centrifuge tube. An appropriate amount of buffer (0.05 M Tris-HCl plus 0.32 M sucrose) was added in the tube and homogenized with a homogenizer (IKA, Ultra Turrax T25 Digital) at 4 for 3-4 seconds, repeated 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 then it was centrifuged at 1000 g for 10 minutes using a high-speed refrigerated centrifuge. The supernatant was collected and adjusted to 2 mL / g with solution B, followed by centrifugation at 1000 g for 10 minutes at 4°C. The supernatant was then centrifuged at 18000 rpm for 25 minutes at 4°C. The precipitate was resuspended in solution B to a final volume of 3 mL / g and incubated at 25°C in a water bath for 15 minutes. After incubation, the suspension was centrifuged at 18000 rpm for 45 minutes at 4°C. The precipitate was stored at -80°C for future use.

[0571] (2) Experimental procedure for binding affinity test

[0572] An appropriate amount of homogenate buffer was added to the prepared membrane and dispersed into a suspension with a homogenizer; the measured protein concentration was 4 mg / ml. 100 micrograms of protein was added in each well of a 96-well plate, with a volume of 90 μΐ. 1 μΐ of compound was added to the test well (highest final concentration 10 μΜ, diluted four times, across 10 concentrations), followed by 1 μΐ of buffer to the HPE well, and 1 μΐ of haloperidol (MedChemExpress, Catalog No. HY-14538) to the HPE well (final concentration 1 μΜ). [3H]-(+) Prazosin (Perkin-Elmer, Catalog No. NET1056250UC) was added to each well (final concentration 10 nM). The 96-well plate was incubated in a constant temperature water bath (25°C, 180 minutes). After incubation, the suspension was quickly filtered through a GF / C plate prepared in advance with a 0.25% PEI solution using vacuum filtration in a 96-well, followed by washing the GF / C plate three times with assay buffer. After washing, the samples were dried in a 37°C oven. 50 μΐ / 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 the experimental values.

[0573] (3) Experimental results

[0574] Table 1. Affinity of compounds to Sigma-1 receptor.

[0575] Compounds Sigma 1R Ki (nM) 1 80.33 19 171.6 20 48.93 37 308.2 38 378.50 40 190.00 41 34.02 43 7.97 44 18.99 47 0.74 65 39.57 74 84.44 77 14.86 88 958.89 Reference Compound 1 6.17 Reference Compound 2 313.3 Flupentixol 5.037

[0576] Note: The structure of reference compound 1-2 is shown in Figure 1 .

[0577] Example 25: SNL model

[0578] Neuropathic pain is pain directly caused by injury or disease of the somatosensory nervous system. It is a chronic pain characterized by spontaneous pain, hyperalgesia, allodynia, and sensory disorder. After nerve injury, neuropathic pain can persist, and its characteristics include hypersensitivity to stimuli (hyperalgesia), presence of abnormal sensations (allodynia), and painful response to non-noxious stimuli (hyperalgesia). The spinal nerve ligation (SNL) model involves tight ligation of L5 and L6 spinal nerves using a suture. After modeling of the surgical procedure, animals exhibit clear signs of neuropathic pain such as mechanical allodynia in the ipsilateral hind paw, which occurs 7-14 days after the surgical procedure.

[0579] In this experiment, pregabalin at a dose of 100 mg / kg was used as a positive control to compare the analgesic effect of the test compounds. After administration, the mechanical pain threshold of the ipsilateral hind paw of the rats was tested using a Von Frey filament. The change in mechanical pain threshold before and after administration was used to determine whether 100 mg / kg of the test compound had a neuropathic pain relief 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, while oral administration of 10 mg / kg of reference compound 3 did not show analgesic activity in the SNL model.

[0580] Table 2. Analgesic effect of compounds in the SNL model.

[0581] Grouping Drug Dose (mg / kg) Method of administration Solvent group 0.9% sodium chloride injection - - 1 Compound 37 100 Gavage 2 Reference Compound 3 100 Gavage 3 Pregabalin 100 Gavage

[0582] Note: The structure of reference compound 3 is shown in Figure 1 .

[0583] Example 26: Rotarod test in rats

[0584] Rats placed on a continuously rotating rod immediately move in the opposite direction of the rod movement. Based on this characteristic, rats were initially placed on a stably rotating rotating rod for acclimation training, and then rats exhibiting satisfactory motor balance ability were selected for actual testing. During the formal experiment, the time spent by rats on the rotating rod was used as an indicator of their motor balance ability. This experiment aimed to explore the effects of compound 37 at doses ranging from 10 mg / kg to 300 mg / kg on the motor balance ability of rats in the rotating rod test.

[0585] After administering the test substance to the rats, they were placed on a rotating rod fatigue tester, and the average time spent by the rats on the rod after three tests was recorded and analyzed.

[0586] The maximum possible effect on motor balance ability was calculated as a percentage:

[0587] Maximum possible effect on motor balance ability = (1 - test group / vehicle) x 100%

[0588] Note: The motor balance ability of the vehicle group was considered 0%, and the maximum possible effect on motor balance ability for each group was calculated based on this standard.

[0589] In the rat rotating rod test, the time spent by rats on the rod at a rotation speed of 15 rpm increased with training time, indicating that the experimental system was functioning properly. Subcutaneous injection of dexmedetomidine hydrochloride injection 30 μg / kg 15 minutes before resulted in a maximum possible effect on motor balance ability of 62% compared to the vehicle (P < 0.001), which was consistent with historical results, indicating the reliability and effectiveness of this experimental procedure. In contrast, when compound 37 was orally administered at doses of 10-300 mg / kg 15 minutes before, there was no significant change in the time spent on the rotating rod compared to the vehicle, and the maximum possible effect on motor balance ability was -6%, 11%, -6%, and -6%, respectively, indicating that compound 37 (gavage) at doses of 10-300 mg / kg had no effect on the motor balance ability of rats.

Claims

1. A compound as represented by Formula (I) or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated derivative, metabolite, or prodrug thereof; wherein, n = 0, 1, 2, or 3; m = 0, 1, 2, or 3; X is C, O, or S; wherein the substituted C1-C6 alkyl, the substituted C3-C6 cycloalkyl, the substituted aryl, the substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, heteroaryl, heterocycle; Q is phenyl or heteroaryl, wherein the substituted C1-C6 alkyl, the substituted C3-C6 cycloalkyl, the substituted aryl, and the substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl, heteroaryl, heterocycle; and R1is selected from the group consisting of: C1-C6 alkyl, C3-C6 cycloalkyl, and substituted C3-C6 cycloalkyl; wherein the substituted C1-C6 alkyl, the substituted C3-C6 cycloalkyl, the substituted phenyl, the substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of: fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine.

2. The compound of claim 1, wherein the compound is represented by Formula (II) or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated form, metabolite, or prodrug thereof; wherein, X is selected from C, O, S; A, B, D, E, Z are each independently C, N, or O; R1is selected from the group consisting of: C1-C6 alkyl, C3-C6 cycloalkyl, and substituted C3-C6 cycloalkyl; wherein the substituted C1-C6 alkyl, the substituted C3-C6 cycloalkyl, the substituted phenyl, the substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of: fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine.

3. The compound of claim 2, wherein the compound is represented by Formula (IIa) or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated form, metabolite, or prodrug thereof; wherein n = 0 or 1; m = 0, 1, or 2; X is C, O, or S; R1is selected from the group consisting of: C1-C6 alkyl, C3-C6 cycloalkyl, and substituted C3-C6 cycloalkyl; wherein the substituted C1-C6 alkyl, the substituted C3-C6 cycloalkyl, the substituted phenyl, the substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of: fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine. L is selected from the group consisting of -(CH2) m - -(CH2) m (CR 5 R 6 )- and -(CH2) m Q-; 4. The compound of claim 3, wherein the compound is represented by Formula (IIa-1), (IIa-2), (IIa-1a), (IIa-1b), and (IIa-1c) or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated form, metabolite, or prodrug thereof; when X is O, n = 1, as shown in Formula (IIa-1): shown in Formula (IIa-2): shown in Formula (IIa-1a): shown in Formula (IIa-1b): shown in Formula (IIa-1c):

5. The compound of claim 2, as represented by Formula (IIb) or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated form, metabolite, or prodrug thereof; wherein, n = 0 or 1; m = 0, 1, or 2; X is C, O, or S; R1is selected from the group consisting of: C1-C6 alkyl, C3-C6 cycloalkyl, and substituted C3-C6 cycloalkyl; wherein the substituted C1-C6 alkyl, the substituted C3-C6 cycloalkyl, the substituted phenyl, the substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of: fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine. R 1 and R 2 each independently is selected from the group consisting of hydrogen, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, substituted C3-C6cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 6. The compound of claim 4, wherein the compound is represented by Formula (IIb-1) and (IIb-2) or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated form, metabolite, or prodrug thereof; Alternatively, R 1 and R 2 together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclic group, representative structures of which include: ​ wherein said phenyl or said heteroaryl is optionally further substituted with 0-5 R 3 groups; R 3 selected from the group consisting of halogen, Ci-C6-alkyl and C3-C6-cycloalkyl; wherein Y is C5-C14heteroaryl, and said C5-C14heteroaryl is optionally further substituted with 0-5 R 4 groups; said C5-C14heteroaryl contains 1-4 heteroatoms selected from N, O, or S; R 4 is selected from the group consisting of hydrogen, halogen, cyano, Ci-C6alkyl, substituted Ci-C6alkyl, C3-C6cycloalkyl, substituted C3-C6cycloalkyl, aryl, substituted aryl, heterocycle, and substituted heterocycle; ​ R 5 and R 6 are independently selected from the group consisting of hydrogen, Ci-C6alkyl, substituted Ci-C6alkyl, ​ ​ ​ ​ n＝0、1、2、3； L is selected from -(CH2) m - -(CH2) m (CR 5 R 6 )- -(CH2) m Q-; m＝0、1、2、3； ​ R 1 and R 2 each independently is selected from the group consisting of hydrogen, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, substituted C3-C6cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; wherein said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl, said substituted aryl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from halogen, C1-C3alkyl, C1-C3alkoxy, halogenated C1-C3alkyl, heteroaryl, heterocycle; Alternatively, R 1 and R 2 may form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclic group as indicated in claim 1 ; Q is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally further substituted with 0-5 R 3 groups; R 3 is halogen, Ci-C6alkyl or C3-C6cycloalkyl; ​ wherein when any of B, Z, E is selected from C, it can be attached to R 4 ; R 4 selected from hydrogen, halogen, cyano, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, substituted C3-C6cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl, said substituted aryl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from halogen, C1-C3alkyl, C1-C3alkoxy, halogenated C1-C3alkyl, heteroaryl, heterocycle; and R 5 and R 6 each independently is selected from the group consisting of hydrogen, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, and substituted C3-C6cycloalkyl; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl, said substituted phenyl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, piperazine. ​ ​ ​ L is -(CH2) m - or -(CH2) m (CR 5 R 6 )- or -(CH2) m Q-; ​ ​ R 1 and R 2 each independently is selected from the group consisting of hydrogen, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, substituted C3-C6cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl, said substituted aryl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from halogen, C1-C3alkyl, C1-C3alkoxy, halogenated C1-C3alkyl, heteroaryl, heterocycle; Alternatively, R 1 and R 2 may form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclic group as indicated in claim 1 ; Q is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally further substituted with 0-5 R 3 groups; R 3 is halogen, Ci-C6alkyl or C3-C6cycloalkyl; R 4 is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, substituted C3-C6cycloalkyl, aryl, substituted aryl, heterocycle, and substituted heterocycle; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl, said substituted aryl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from halogen, C1-C3alkyl, C1-C3alkoxy, halogenated C1-C3alkyl, heteroaryl, heterocycle; and R 5 and R 6 each independently is selected from the group consisting of hydrogen, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, and substituted C3-C6cycloalkyl; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl, said substituted phenyl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, piperazine. ​ wherein L is -(CH2) m - -(CH2) m (CR 5 R 6 )- -(CH2) m Q- as in formula (IIa-1a), (IIa-1b) and (IIa-1c) ​ when X is C, n = 0, and L is -(CH2) m - wherein m = 0, as shown in formula (IIa-2): R 1 and R 2 each independently is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, and pyridine, said substituted Ci-C6alkyl, said substituted C3-C6cycloalkyl, said substituted phenyl, said substituted heteroaryl being substituted with 1-3 substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, piperazine; Alternatively, R 1 and R 2 may form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclic group as indicated in claim 1 ; Q is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridyl, quinolinyl, pyrazinyl, and is optionally further substituted with 0-5 R 3 groups; R 3 is selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; R 4 is 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; said substituted Ci-C6alkyl, said substituted C3-C6cycloalkyl, said substituted phenyl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine; and R 5 and R 6 each independently is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; said substituted Ci-C6alkyl, said substituted C3-C6cycloalkyl, said substituted phenyl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine. ​ ​ ​ L is -(CH2) m - or -(CH2) m (CR 5 R 6 )- or -(CH2) m Q-; ​ ​ R 1 and R 2 each independently is selected from the group consisting of hydrogen, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, and substituted C3-C6cycloalkyl; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl being substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C3alkyl, C1-C3alkoxy, halogenated C1-C3alkyl, heteroaryl, heterocycle; Alternatively, R 1 and R 2 may form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclic group as indicated in claim 1 ; Q is aryl or heteroaryl, wherein said aryl, said heteroaryl are optionally further substituted with 0-5 R 3 groups; R 3 selected from halogen, Ci-C6alkyl, C3-C6cycloalkyl; R 4 selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, substituted C3-C6cycloalkyl; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl being substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C3alkyl, C1-C3alkoxy, halogenated C1-C3alkyl, heteroaryl, heterocycle; and R 5 and R 6 each independently is selected from the group consisting of hydrogen, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, substituted C3-C6cycloalkyl; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl, said substituted phenyl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of ​ ​ R 1 and R 2 each independently is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; said substituted Ci-C6alkyl, said substituted C3-C6cycloalkyl, said substituted phenyl, said substituted heteroaryl are substituted with 1-3 substituents independently 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 may form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclic group as indicated in claim 1 ; Q is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridyl, quinolinyl, pyrazinyl, and is optionally further substituted with 0-5 R 3 groups; R 3 is selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; R 4 selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl is substituted with 1-3 substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, piperazine; and R 5 and R 6 each independently is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl is substituted with 1-3 substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, and piperazine.

7. The compound of claim 1, wherein the compound is represented by Formula (III) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated form, a metabolite, or a prodrug thereof; wherein, L is -(CH2) m - or -(CH2) m (CR 5 R 6 )- or -(CH2) m Q-; m = 0, 1, or 2; X is C, O, or S; R 1 and R 2 each independently is selected from the group consisting of hydrogen, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, and substituted C3-C6cycloalkyl; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl being substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C3alkyl, C1-C3alkoxy, halogenated C1-C3alkyl, heteroaryl, and heterocycle; Alternatively, R 1 and R 2 may form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclic group as indicated in claim 1 ; Q is aryl or heteroaryl, and said aryl or said heteroaryl is optionally further substituted by 0-5 R 3 groups; R 3 is halogen, Ci-C6alkyl or C3-C6cycloalkyl; A, B, D, E, Z are each independently C, N, or O; wherein when any of B, Z, E is selected from C, it can be attached to R 4 ; R 4 is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, and substituted C3-C6cycloalkyl; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl being substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C3alkyl, C1-C3alkoxy, halogenated C1-C3alkyl, heteroaryl, heterocycle; and R 5 and R 6 each independently is selected from the group consisting of hydrogen, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, and substituted C3-C6cycloalkyl; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl, said substituted phenyl, said substituted heteroaryl are substituted with 1-3 substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, piperazine.

8. The compound of claim 7, wherein the compound is represented by Formula (Ilia), (Illb), (IIIc), (IIId) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated form, a metabolite, or a prodrug thereof; wherein 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, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; said substituted Ci-C6alkyl, said substituted C3-C6cycloalkyl is substituted with 1-3 substituents independently 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 may form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclic group as indicated in claim 1 ; Q is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridyl, quinolinyl, and pyrazinyl, and is optionally further substituted with 0-5 R 3 groups; R 3 selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; and R 4 selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; said substituted C1-C6alkyl, said substituted C3-C6cycloalkyl is substituted with 1-3 substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, pyridine, piperidine, piperazine.

9. The compound of claim 2, wherein the compound of Formula (II) comprises the following compounds or any pharmaceutically acceptable salt thereof:

10. The compound of claim 7, wherein the compound of Formula (III) is selected from the group consisting of the following compounds or any pharmaceutically acceptable salt thereof:

11. A pharmaceutical composition comprising a compound according to claim 1 or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated form, a metabolite, or a prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

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

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

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

15. A method for treating and / or preventing one or more conditions associated with Sigma-1 receptors in a subject, the method comprising administering to the subject a compound according to claim 1, wherein the one or more conditions comprise pain, psychosis, substance abuse, or cancer.

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