Condensed azacycle as a sigma ligand compound and its use

Abstract

The present disclosure relates to compounds of formula (I) and their prodrugs, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful for modulating sigma receptors, have antiviral activity, and may be useful in the treatment and / or prevention of pain disorders, neurological disorders (e.g., Parkinson's disease and Alzheimer's disease), and cancer. JPEG2023537630000186.jpg3455

Description

Technical Field

[0001] Related Applications This application claims the priority and benefit of U.S. Provisional Patent Application No. 63 / 066,064, filed on August 14, 2020. The entire content thereof is incorporated herein by reference.

Background Art

[0002] Sigma receptors are involved in various diseases and disorders, including, for example, pain disorders, neuropathies (such as Parkinson's disease and Alzheimer's disease), and cancer. More recently, sigma receptor modulating compounds have been shown to have antiviral activity.

[0003] Coronaviruses are a group of related viruses that cause diseases in humans and animals. In humans, coronaviruses cause, among other things, typically mild respiratory infections, such as SARS, MERS, and COVID-19, although some forms can be lethal. Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of August 2020, there were over 20 million confirmed cases of COVID-19 worldwide, causing over 700,000 deaths (Johns Hopkins Coronavirus Resource Center). The economic impact of COVID-19 has also been staggering. For example, as of the week ending July 25, 2020, the advanced unadjusted insured unemployment rate in the United States was 10.7%, compared to only 1.2% the previous year (U.S. Department of Labor press release, August 6, 2020). Although vaccines have proven effective in reducing the incidence of COVID-19 and the severity of COVID-19 symptoms in breakthrough infections, more infectious variants are emerging that can pose further problems, even in vaccinated individuals. For this reason, among others (e.g., vaccine hesitancy, ineligible subjects for vaccination, and limited supply to meet global demand), additional measures in addition to vaccine access are urgently needed.

[0004] Thus, improved sigma receptor modulating compounds may be able to address unmet needs in the treatment of viruses, as well as pain disorders, neuropathies (e.g., Parkinson's disease and Alzheimer's disease), and cancer. SUMMARY OF THE INVENTION

[0005] In some embodiments, the disclosure relates, inter alia, to compounds of formula (I):

[0006]

Chemical formula

[0007] In one aspect, the disclosure provides, inter alia, a compound of formula (Ia):

[0008]

Chemical formula

[0009] In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0010] In some embodiments, the present disclosure provides a method of modulating a sigma receptor (e.g., sigma-1 or sigma-2) with a compound of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

[0011] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or symptom of a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein sigma receptor activity is involved or associated with the disease or disorder.

[0012] In one aspect, the present disclosure provides a method of treating or preventing an infectious disease or disorder, wherein the infectious disease or disorder is caused by bacteria, fungi, or viruses.

[0013] In one aspect, the present disclosure provides a method for treating or preventing a target viral infection or a disease resulting from a viral infection, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

[0014] In one embodiment, the viral infection is caused by a coronavirus, herpes simplex virus, human immunodeficiency virus, influenza, or human papillomavirus.

[0015] In one embodiment, the coronavirus is SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2).

[0016] In one embodiment, the disease resulting from the viral infection is COVID-19.

[0017] In one embodiment, the disease resulting from the viral infection is severe acute respiratory syndrome.

[0018] In some embodiments, the present disclosure provides a method for treating a disease or a symptom of a disease, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the disease or the symptom of the disease is anxiety, depression, mood disorder, schizophrenia, drug intoxication, drug addiction, sharp pain, dystonia, cerebrovascular disease, epilepsy, dementia, Parkinson's syndrome, attention deficit disorder, irritable bowel syndrome, irritable colon, spastic colon, mucous colitis, enteritis, diverticulitis, dysentery, hypertension, arrhythmia, angina pectoris, amyotrophic lateral sclerosis (ALS), Huntington's disease, stroke, retinal degeneration, or cognitive impairment in a neuropsychiatric disorder.

[0019] In some embodiments, the present disclosure provides a method of preventing a disease or a symptom of a disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the disease or the symptom of the disease is anxiety, depression, mood disorder, schizophrenia, drug intoxication, drug addiction, sharp pain, dyskinesia, cerebrovascular disease, epilepsy, dementia, Parkinson's syndrome, attention deficit disorder, irritable bowel syndrome, irritable colon, spastic colon, mucous colitis, enteritis, diverticulitis, dysentery, hypertension, arrhythmia, angina, amyotrophic lateral sclerosis (ALS), Huntington's disease, stroke, retinal degeneration, or cognitive impairment in a neuropsychiatric disorder.

[0020] In one aspect, the present disclosure provides a method of treating Alzheimer's disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

[0021] In one aspect, the present disclosure provides a method of treating a disease or a symptom of a disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the disease or the symptom of the disease is anxiety, depression, mood disorder, schizophrenia, drug intoxication, drug addiction, alcohol addiction, sharp pain, dyskinesia, cerebrovascular disease, epilepsy, dementia, Parkinson's syndrome, attention deficit disorder, irritable bowel syndrome, irritable colon, spastic colon, mucous colitis, enteritis, diverticulitis, dysentery, hypertension, arrhythmia, angina, amyotrophic lateral sclerosis (ALS), Huntington's disease, stroke, retinal degeneration, or cognitive impairment in a neuropsychiatric disorder.

[0022] In one aspect, the present disclosure provides a method of treating or preventing pain in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

[0023] In one embodiment, the pain is acute pain, chronic pain, nociceptive pain, neuropathic pain, nociceptive pain, inflammatory pain, postoperative pain, visceral pain, chemotherapy-induced pain, peripheral neuropathy, fibromyalgia, or a combination thereof.

[0024] In one aspect, the present disclosure provides a method for promoting an anti-hyperalgesic effect in a subject suffering from hyperalgesia, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

[0025] In one aspect, the present disclosure provides a method for reducing the sensitivity of a subject to pain, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

[0026] In one aspect, the present disclosure provides a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of any one compound of formula (I), or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

[0027] In one embodiment, the cancer is breast cancer, prostate cancer, colon cancer, rectal cancer, pancreatic cancer, liver cancer, bladder cancer, thyroid cancer, kidney cancer, skin cancer, non-Hodgkin lymphoma, or uterine cancer.

Brief Description of the Drawings

[0028]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Modes for Carrying Out the Invention

[0029] Definitions Unless otherwise specified, the following terms used in the specification and claims have the following meanings as set forth below.

[0030] As used herein, "alkyl", "C1, C2, C3, C4, C5 or C6 alkyl" or "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5 or C6 straight-chain (linear) saturated aliphatic hydrocarbon groups and C2, C3, C4, C5 or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5 and C6 alkyl groups. Examples of alkyl include moieties having 1 to 6 carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, the straight-chain or branched alkyl has 6 or fewer carbon atoms (e.g., C1-C6 for straight-chain and C3-C6 for branched-chain), and in other embodiments, the straight-chain or branched alkyl has 4 or fewer carbon atoms.

[0031] As used herein, "alkoxyl", "C1, C2, C3, C4, C5 or C6 alkoxyl" or "C1-C6 alkoxyl" is intended to include -O-C1, -O-C2, -O-C3, -O-C4, -O-C5 or -O-C6 straight-chain (linear) saturated aliphatic hydrocarbon groups and -O-C2, -O-C3, -O-C4, -O-C5 or -O-C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkoxyl is intended to include -O-C1, -O-C2, -O-C3, -O-C4, -O-C5 and -O-C6 alkyl groups. Examples of alkoxyl include moieties having 1 to 6 carbon atoms, such as, but not limited to, methoxyl, ethoxyl, n-propoxyl, i-propoxyl, n-butoxyl, s-butoxyl, t-butoxyl, n-pentoxyl, i-pentoxyl, or n-hexoxyl. In some embodiments, the straight-chain or branched alkoxyl has 6 or fewer carbon atoms (e.g., C1-C6 for straight-chain and C3-C6 for branched-chain), and in other embodiments, the straight-chain or branched alkoxyl has 4 or fewer carbon atoms.

[0032] As used herein, the term "alkenyl" includes an unsaturated aliphatic group having a length and possible substitutions similar to those of the above alkyl, but containing at least one double bond. For example, the term "alkenyl" includes linear alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, the linear or branched alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-C6 for linear and C3-C6 for branched). The term "C2-C6" includes alkenyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkenyl groups containing 3 to 6 carbon atoms.

[0033] As used herein, the term "alkynyl" includes an unsaturated aliphatic group having a length and possible substitutions similar to those of the above alkyl, but containing at least one triple bond. For example, "alkynyl" includes linear alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, the linear or branched alkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-C6 for linear and C3-C6 for branched). The term "C2-C6" includes alkynyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkynyl groups containing 3 to 6 carbon atoms. As used herein, the term "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to include C2, C3, C4, C5, or C6 chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, the C2-C6 alkenylene linker is intended to include C2, C3, C4, C5, and C6 alkenylene linker groups.

[0034] The term "alkylene" or "alkylenyl" refers to a divalent alkyl group. Any of the above monovalent alkyl groups can become alkylene by removing the second hydrogen atom from the alkyl. As defined herein, alkylene can also be C1-C6 alkylene. Alkylene can further be C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc.

[0035] Optionally substituted moieties (e.g., optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc.) include both unsubstituted moieties and moieties having one or more of the designated substituents. For example, substituted aryl moieties include those substituted with halogen and / or C1-C6 alkyl; substituted heteroaryl moieties include 2,6-dimethylpyridinyl; substituted heterocycloalkyls include those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl, and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0036] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) system having 3 to 30 carbon atoms (e.g., C3-C 12 、C3-C 10 、or C3-C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be non-aromatic.

[0037] As used herein, the term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic 3- to 8-membered, 7- to 12-membered bicyclic (fused, bridged, or spirocyclic), or 11- to 14-membered tricyclic ring system having one or more heteroatoms (e.g., O, N, S, P, or Se), e.g., one or from 1 to 2 or from 1 to 3 or from 1 to 4 or from 1 to 5 or from 1 to 6 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, unless otherwise specified.Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6 - tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4 - diazepanyl, 1,4 - oxazepanyl, 2 - oxa - 5 - azabicyclo[2.2.1]heptanyl, 2,5 - diazabicyclo[2.2.1]heptanyl, 2 - oxa - 6 - azaspiro[3.3]heptanyl, 2,6 - diazaspiro[3.3]heptanyl, 1,4 - dioxo - 8 - azaspiro[4.5]decanyl, 1,4 - dioxaspiro[4.5]decanyl, 1 - oxaspiro[4.5]decanyl, 1 - azaspiro[4.5]decanyl, 3’H - spiro[cyclohexane - 1,1’ - isobenzofuran] - yl, 7’H - spiro[cyclohexane - 1,5’ - furo[3,4 - b]pyridine] - yl, 3’H - spiro[cyclohexane - 1,1’ - furo[3,4 - c]pyridine] - yl, 3 - azabicyclo[3.1.0]hexanyl, 3 - azabicyclo[3.1.0]hexan - 3 - yl, 1,4,5,6 - tetrahydropyrrolo[3,4 - c]pyrazolyl, 3,4,5,6,7,8 - hexahydropyrido[4,3 - d]pyrimidinyl, 4,5,6,7 - tetrahydro - 1H - pyrazolo[3,4 - c]pyridinyl, 5,6,7,8 - tetrahydropyrido[4,3 - d]pyrimidinyl, 2 - azaspiro[3.3]heptanyl, 2 - methyl - 2 - azaspiro[3.3]heptanyl, 2 - azaspiro[3.5]nonanyl, 2 - methyl - 2 - azaspiro[3.5]nonanyl, 2 - azaspiro[4.5]decanyl, 2 - methyl - 2 - azaspiro[4.5]decanyl, 2 - oxa - azaspiro[3.4]octanyl, 2 - oxa - azaspiro[3.4]octan - 6 - yl, and the like. In the case of polycyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non - aromatic (for example, 4,5,6,7 - tetrahydrobenzo[c]isoxazolyl).

[0038] As used herein, the term "aryl" includes aromatic groups having one or more aromatic rings and including "conjugated" or polycyclic systems that do not contain heteroatoms in the ring structure. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. Conveniently, the aryl is phenyl.

[0039] As used herein, the term "heteroaryl" is intended to include carbon atoms and one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, such as 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or for example 1, 2, 3, 4, 5, or 6 heteroatoms, and includes stable 5-membered, 6-membered, or 7-membered monocyclic, or 7-membered, 8-membered, 9-membered, 10-membered, 11-membered or 12-membered bicyclic aromatic heterocyclic rings. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or another defined substituent). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O) p (where p = 1 or 2)). It should be noted that the total number of S and O atoms in the aromatic heterocycle is 1 or less. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. The heteroaryl group may also be fused or bridged to an alicyclic or heterocyclic ring that is not aromatic so as to form a polycyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0040] Furthermore, the terms "aryl" and "heteroaryl" include polycyclic aryl and heteroaryl groups, such as tricyclic, bicyclic, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

[0041] The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring may be substituted at one or more ring positions (e.g., ring-forming carbon or heteroatom, such as N) with substituents as described above, such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or may be substituted with an aromatic or heteroaromatic moiety. The aryl and heteroaryl groups may also be fused or bridged with an alicyclic or heterocyclic ring that is not aromatic so as to form a polycyclic system (e.g., tetralin, methylenedioxyphenyl, such as benzo[d][1,3]dioxol-5-yl).

[0042] As used herein, the term "substituted" means that one or more hydrogen atoms on the specified atom are replaced by a selection from the groups shown, without exceeding the normal valence of the specified atom and provided that a stable compound is obtained by the substitution. When the substituent is oxo or keto (i.e., =O), two hydrogen atoms on the atom are replaced. A keto substituent is not present on the aromatic moiety. A ring double bond as used herein is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). "Stable compound" and "stable structure" are intended to indicate compounds that are sufficiently robust to survive isolation to useful purity from a reaction mixture and formulation into an effective therapeutic agent.

[0043] When the bond to a substituent is shown to cross a bond connecting two atoms within the ring, the said substituent may be attached to any atom within the ring. When a substituent is listed without indicating the atom through which it is attached to the remainder of a compound of a given formula, the said substituent may be attached through any atom within the said formula. Combinations of substituents and / or variables are permitted only if such combinations result in a stable compound.

[0044] If any variable (e.g., R) occurs two or more times for any component of a compound or in the formula, its definition at each occurrence is independent of its definition at all other occurrences. Thus, for example, if a group is shown to be substituted with from 0 to 2 R moieties, the group may optionally be substituted with up to 2 R moieties, and each occurrence of R is selected independently from the definition of R. Also, combinations of substituents and / or variables are permitted only if such combinations result in a stable compound.

[0045] As used herein, the term "hydroxy" or "hydroxyl" includes a group having -OH or the corresponding anion -O - -.

[0046] As used herein, the terms "halo" or "halogen" refer to fluorine, chlorine, bromine and iodine.

[0047] As used herein, "haloalkyl" is intended to include an "alkyl" moiety substituted with one or more halogens. Non-limiting examples include -CH2F, -CHF2, -CF3, -CH2CF3, -CH2CHF2, -CH2Cl, -CClF2, -CCl3, -CClHCF3, -CCl2CHF2, -CClFCF3, and -CF2CCl3.

[0048] As used herein, "haloalkoxyl" is intended to include an "alkoxyl" moiety substituted with one or more halogens. Non-limiting examples include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCH2CHF2, -OCHFCF3, and -OCF2CF3.

[0049] As used herein, expressions such as "one or more of A, B, or C", "one or more of A, B, or C", "one or more of A, B, and C", "one or more of A, B, and C", "selected from the group consisting of A, B, and C", "selected from A, B, and C", etc. are used interchangeably, and unless otherwise indicated, all refer to a selection from the group consisting of A, B, and / or C, i.e., one or more of A, one or more of B, one or more of C, or any combination thereof.

[0050] The compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or intermediates that are readily prepared, by using standard synthetic methods and procedures known to those of skill in the art or that become apparent to those of skill in the art in light of the teachings herein. Standard synthetic methods and procedures for preparing organic molecules, as well as functional group transformations and manipulations, can be obtained from the relevant scientific literature or from standard texts in the art. Without limitation to any one or several sources, classical texts incorporated herein by reference, such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G.M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) are useful and recognized reference texts for organic synthesis known to those of skill in the art.

[0051] One of ordinary skill in the art will recognize that in the reaction sequences and synthetic schemes described herein, the order of certain steps, such as the introduction and removal of protecting groups, may be changed. One of ordinary skill in the art will recognize that certain groups may need to be protected from reaction conditions via the use of protecting groups. Protecting groups may also be used to distinguish similar functional groups within a molecule. A list of protecting groups and methods for introducing and removing these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999.

[0052] Unless otherwise specifically indicated, the terms “about” and “approximately” are synonymous. In some embodiments, “about” and “approximately” refer to the recited amount, value, dosage, or duration ±20%, ±15%, ±10%, ±8%, ±6%, ±5%, ±4%, ±2%, ±1%, or ±0.5%. In another embodiment, “about” and “approximately” refer to the recited amount or duration ±10%, ±8%, ±6%, ±5%, ±4%, or ±2%. In some embodiments, “about” and “approximately” refer to the recited amount, value, dosage, or duration ±5%. In some embodiments, “about” and “approximately” refer to the recited amount, value, dosage, or duration ±2%. In some embodiments, “about” and “approximately” refer to the recited amount, value, dosage, or duration ±1%.

[0053] The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., at least one) of the grammatical objects of the article. By way of example, “an element” means one element or more than one element.

[0054] The term “and / or” is used in this disclosure to mean either “and” or “or” unless specifically indicated otherwise.

[0055] As used herein, the term "unsubstituted" means that the specified group has no substituents.

[0056] The term "solvate" refers to a variable stoichiometric complex formed by a solute or a solvent. Such a solvent for the purposes of the present invention must not be able to interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. A solvate in which the solvent molecule is water is typically called a hydrate. Hydrates include compositions containing a stoichiometric amount of water, as well as compositions containing a variable amount of water.

[0057] The term "isomer" refers to compounds having the same composition and molecular weight, but different physical and / or chemical properties. The structural differences can be in the constitution (geometric isomers) or the ability to rotate the plane of polarization (stereoisomers). With respect to stereoisomers, the compounds of formula (I) can have one or more asymmetric carbon atoms and can exist as racemates, racemic mixtures and individual enantiomers or diastereomers.

[0058] The present invention also contemplates isotopically labeled compounds of formula I (e.g., 2 H and 14 C labeled compounds). Deuterium (i.e., 2 H or D) and carbon-14 (i.e., 14 C) isotopes are particularly preferred because of their ease of preparation and detectability. Further, substitution with heavier isotopes, such as deuterium, can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or decreased required dosage) and can thus be preferred in some situations. Isotopically labeled compounds of formula I can generally be prepared by replacing a non-isotopically labeled reagent with an appropriate isotopically labeled reagent and following procedures similar to those disclosed in the following schemes and / or examples herein.

[0059] As used herein, the term "pharmaceutically acceptable" refers to compounds, anions, cations, materials, compositions, carriers, and / or dosage forms that are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio.

[0060] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not otherwise undesirable for the preparation of pharmaceutical compositions, and includes excipients that are acceptable for veterinary and human pharmaceutical use. The term "pharmaceutically acceptable excipient" as used herein and in the claims includes both one such excipient and two or more such excipients.

[0061] The present disclosure also includes a pharmaceutical composition comprising an effective amount of the disclosed compound and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylic acid salt, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, basic acetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, theocurate, tosylate, triethiodide, and valerate.

[0062] As used herein, the term "carrier" encompasses carriers, excipients, and diluents and refers to a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting a pharmaceutical from one organ or body part to which it is administered to another organ or body part.

[0063] As used herein, the terms "pharmaceutically acceptable salt" and "pharmaceutically acceptable excipient" may be used interchangeably.

[0064] As used herein, the term "subject" is interchangeable with the term "subject in need thereof", and both refer to a subject having a disease or a subject at high risk of developing a disease. "Subject" includes mammals. Mammals can be, for example, humans or suitable non-human mammals such as primates, mice, rats, dogs, cats, cows, horses, goats, camels, sheep or pigs. A subject can also be a bird or poultry. In one embodiment, the mammal is a human. A subject in need thereof can be a subject previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be a subject suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be a subject at high risk of developing such a disease or disorder compared to the general population (i.e., a subject more likely to develop such a disorder compared to the general population). A subject in need thereof can have a refractory or resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). A subject can be resistant at the start of treatment or can become resistant during treatment. In some embodiments, a subject in need thereof has received and failed all known effective treatments for a disease or disorder disclosed herein. In some embodiments, a subject in need thereof has received at least one previous treatment.

[0065] The term "disorder" is used in this disclosure to mean the term "disease", "condition", or "illness" unless otherwise indicated, and is used interchangeably with these terms.

[0066] As used herein, the terms "preventing," "prevent," or "protecting from" describe reducing or eliminating the onset of symptoms or complications of such diseases, conditions or disorders, or preventing the transmission or replication of a virus that causes such diseases, conditions or disorders.

[0067] It should be recognized that references to "treating" or "treatment" include reducing established symptoms of a condition. Thus, "treating" or "treatment" of a situation, infectious exposure, disorder or condition includes (1) delaying the appearance of clinical symptoms of a situation, infectious exposure, disorder or condition that afflicts or is likely to afflict a human who has not experienced and has not shown any clinical or subclinical symptoms of the situation, infectious exposure, disorder or condition, (2) inhibiting the situation, infectious exposure, disorder or condition, i.e., stopping, reducing or delaying the onset of a disease or its recurrence (in the case of maintenance treatment) or at least one of its clinical or subclinical symptoms, or (3) alleviating or attenuating the disease, i.e., causing at least one regression of the situation, infectious exposure, disorder or condition or its clinical or subclinical symptoms.

[0068] As used in this disclosure, the terms "administering," "administer," or "administration" refer to either directly administering the disclosed compound or a pharmaceutically acceptable salt or composition of the disclosed compound to a subject, or administering to the subject a prodrug derivative or analog of a compound or a pharmaceutically acceptable salt of a compound or composition that can form an equivalent active compound in the body of the subject.

[0069] In one embodiment, the term "therapeutically effective amount" as used herein refers to an amount of a compound disclosed herein, or a composition comprising said compound, administered to a patient already suffering from a disease, condition, or disorder that is sufficient to cure, or at least partially arrest, or to some extent alleviate one or more of the symptoms of the disease, disorder, or condition being treated. The effectiveness of such a composition depends on conditions including, but not limited to, the severity and course of the disease, disorder, or condition, previous treatment, the health status and response of the patient to the drug, and the judgment of the attending physician. The specific therapeutically effective dosage level for a particular patient depends on a variety of factors including the disorder being treated and the severity of the disorder; the specific composition being used; the age, weight, general health, gender and diet of the patient; the time of administration; the route of administration; the excretion rate of the specific compound being used; the duration of the treatment; drugs used in combination with or simultaneously with the specific compound being used as well as similar factors well known in the medical arts. Such an amount would be sufficient to induce a tissue-based, or biological or medical response in the patient as determined by a researcher or physician. Such a therapeutically effective amount can be determined by one of ordinary skill in the art in view of their own knowledge, the prior art, and the present disclosure. By way of mere example, a therapeutically effective amount can be determined by routine experimentation including, but not limited to, dose escalation clinical trials.

[0070] In one embodiment, the term "therapeutically effective amount" as used herein refers to an amount of a compound disclosed herein, or a composition comprising said compound, that is effective for the prevention of a disease, condition, or disorder.

[0071] As used herein, the term "prodrug" means a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis) to a compound disclosed herein.

[0072] As used herein, "MOI" is equivalent to "multiplicity of infection" and refers to the number of viral particles added per cell during infection.

[0073] As used herein, PB28 refers to 1-cyclohexyl-4-(3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl)piperazine dihydrochloride (i.e.,

[0074]

Chem.

[0075] As used herein, MIN-101, which may also be referred to as loperidone, has the following structure:

[0076]

Chem.

[0077] As used herein, MIN-S006 has the following structure:

[0078]

Chem.

[0079] The compounds of the present disclosure In some embodiments, the present disclosure provides, inter alia, compounds of formula (I):

[0080]

Chem.

[0081] In some embodiments, the present disclosure relates, inter alia, to a compound of formula (I):

[0082]

Chemical formula

[0083] In some embodiments, the disclosure relates, inter alia, to a compound of formula (Ia):

[0084]

Chemical formula

[0085] In some embodiments, X1 is absent, (CR3R4) q , -O-, -S(O)2-, -C(O)-, -C(S)-, -S(O)-, -NR3C(O)-, -C(O)NR3-, -C(O)O-, or -OC(O)-.

[0086] In some embodiments, X1 is -O-, -S(O)2-, -NR3C(O)-, or -C(O)NR3-.

[0087] In some embodiments, X1 is absent, -(CR3R4) q -, -C(O)-, -C(S)-, -S(O)-, -NR3C(O)-, or -C(O)O-.

[0088] In some embodiments, X1 is absent, -(CR3R4) q -, -C(O)-, or -C(O)O-.

[0089] In some embodiments, X1 is absent.

[0090] In some embodiments, X1 is -(CR3R4) q -.

[0091] In some embodiments, X1 is -C(O)- or -C(O)O-.

[0092] In some embodiments, X1 is -C(O)-.

[0093] In some embodiments, X1 is -C(O)O-.

[0094] In some embodiments, X1 is -NR3C(O)- or -C(O)NR3-.

[0095] In some embodiments, X1 is -O- or -S(O)2-. In some embodiments, X1 is -O-. In some embodiments, X1 is -S(O)2-. In some embodiments, X2 is absent, -(CR3R4) q -, -O-, -S(O)2-, -C(O)-, -C(S)-, -S(O)-, -NR3C(O)-, -C(O)NR3-, -C(O)O-, or -OC(O)-.

[0096] In some embodiments, X2 is -O-, -S(O)2-, -NR3C(O)-, or -C(O)NR3-.

[0097] In some embodiments, X2 is absent, -(CR3R4) q -, -C(O)-, -C(S)-, -S(O)-, -NR3C(O)-, or -C(O)O-.

[0098] In some embodiments, X2 is absent, -(CR3R4) q -, -C(O)-, or -C(O)O-.

[0099] In some embodiments, X2 is absent.

[0100] In some embodiments, X2 is -(CR3R4) q -.

[0101] In some embodiments, X2 is -C(O)- or -C(O)O-.

[0102] In some embodiments, X2 is -C(O)-.

[0103] In some embodiments, X2 is -C(O)O-.

[0104] In some embodiments, X2 is -NR3C(O)- or -C(O)NR3-.

[0105] In some embodiments, X2 is -O- or -S(O)2-. In some embodiments, X2 is -O-. In some embodiments, X2 is -S(O)2-.

[0106] In some embodiments, R1 is H, OH, halogen, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, C6-C 10 aryl, 5-12 membered heteroaryl containing 1-6 heteroatoms selected from N, O, and S, 5-14 membered saturated or unsaturated heterocycloalkyl containing 1-5 heteroatoms selected from N, O, and S; any of the foregoing alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl is optionally substituted with one or more R5s.

[0107] In some embodiments, R1 is H, OH, halogen, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl, and any of the foregoing alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, or cycloalkyl is optionally substituted with one or more R5s.

[0108] In some embodiments, R1 is H or OH. In some embodiments, R1 is H. In some embodiments, R1 is OH.

[0109] In some embodiments, R1 is halogen.

[0110] In some embodiments, R1 is NH2.

[0111] In some embodiments, R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl, and any of the foregoing alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, or cycloalkyl is optionally substituted with one or more R5s.

[0112] In some embodiments, R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl, and any of the foregoing alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, or cycloalkyl is substituted with one or more R5s.

[0113] In some embodiments, R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl, and any of the foregoing alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, or cycloalkyl is substituted with one R5.

[0114] In some embodiments, R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl, and any of the alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, or cycloalkyl is substituted with two R5s.

[0115] In some embodiments, R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl, and any of the alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, or cycloalkyl is substituted with three R5s.

[0116] In some embodiments, R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

[0117] In some embodiments, R1 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0118] In some embodiments, R1 is C1-C6 alkyl. In some embodiments, R1 is methyl. In some embodiments, R1 is ethyl. In some embodiments, R1 is propyl. In some embodiments, R1 is butyl. In some embodiments, R1 is isopropyl. In some embodiments, R1 is iso-butyl. In some embodiments, R1 is sec-butyl. In some embodiments, R1 is tert-butyl. In some embodiments, R1 is pentyl. In some embodiments, R1 is iso-pentyl. In some embodiments, R1 is hexyl. In some embodiments, R1 is iso-hexyl.

[0119] In some embodiments, R1 is C2-C6 alkenyl. In some embodiments, R1 is C2 alkenyl. In some embodiments, R1 is C3 alkenyl. In some embodiments, R1 is C4 alkenyl. In some embodiments, R1 is C5 alkenyl. In some embodiments, R1 is C6 alkenyl.

[0120] In some embodiments, R1 is C2-C6 alkynyl. In some embodiments, R1 is C2 alkynyl. In some embodiments, R1 is C3 alkynyl. In some embodiments, R1 is C4 alkynyl. In some embodiments, R1 is C5 alkynyl. In some embodiments, R1 is C6 alkynyl.

[0121] In some embodiments, R1 is C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

[0122] In some embodiments, R1 is C1-C6 haloalkyl. In some embodiments, R1 is halomethyl. In some embodiments, R1 is haloethyl. In some embodiments, R1 is halopropyl. In some embodiments, R1 is halobutyl. In some embodiments, R1 is halopentyl. In some embodiments, R1 is halohexyl.

[0123] In some embodiments, R1 is C1-C6 alkoxyl. In some embodiments, R1 is methoxyl. In some embodiments, R1 is ethoxyl. In some embodiments, R1 is propoxyl. In some embodiments, R1 is butoxyl. In some embodiments, R1 is pentoxyl. In some embodiments, R1 is hexoxyl.

[0124] In some embodiments, R1 is C1-C6 haloalkoxyl. In some embodiments, R1 is halomethoxyl. In some embodiments, R1 is haloethoxyl. In some embodiments, R1 is halopropoxyl. In some embodiments, R1 is halobutoxyl. In some embodiments, R1 is halopentoxyl. In some embodiments, R1 is halohexoxyl.

[0125] In some embodiments, R1 is C3-C6 cycloalkyl. In some embodiments, R1 is cyclopropyl. In some embodiments, R1 is cyclobutyl. In some embodiments, R1 is cyclopentyl. In some embodiments, R1 is cyclohexyl.

[0126] In some embodiments, R1 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and any of the alkyl, alkenyl, or alkynyl is optionally substituted with one or more R5s.

[0127] In some embodiments, R1 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and any of the alkyl, alkenyl, or alkynyl is substituted with one or more R5s.

[0128] In some embodiments, R1 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and any of the alkyl, alkenyl, or alkynyl is substituted with one R5.

[0129] In some embodiments, R1 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and any of the alkyl, alkenyl, or alkynyl is substituted with two R5s.

[0130] In some embodiments, R1 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and the alkyl, alkenyl, or alkynyl is substituted with three R5s.

[0131] In some embodiments, R1 is methyl substituted with one or more R5s. In some embodiments, R1 is ethyl substituted with one or more R5s. In some embodiments, R1 is propyl substituted with one or more R5s. In some embodiments, R1 is butyl substituted with one or more R5s. In some embodiments, R1 is pentyl substituted with one or more R5s. In some embodiments, R1 is hexyl substituted with one or more R5s.

[0132] In some embodiments, R1 is C6-C 10 aryl, 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, or 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S, and any of the foregoing aryl, heteroaryl, or heterocycloalkyl is optionally substituted with one or more R5s.

[0133] In some embodiments, R1 is C6-C 10 aryl, 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, or 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S.

[0134] In some embodiments, R1 is C6-C 10 aryl, 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, or 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S, and any of the foregoing aryl, heteroaryl, or heterocycloalkyl is optionally substituted with one or more R5s.

[0135] In some embodiments, R1 is C6-C 10 aryl, 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, or 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S, and any of said aryl, heteroaryl, or heterocycloalkyl is substituted with one R5.

[0136] In some embodiments, R1 is C6-C 10 aryl, 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, or 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S, and any of said aryl, heteroaryl, or heterocycloalkyl is substituted with two R5s.

[0137] In some embodiments, R1 is C6-C 10 aryl, 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, or 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S, and any of said aryl, heteroaryl, or heterocycloalkyl is substituted with three R5s.

[0138] In some embodiments, R1 is H, OH, methyl,

[0139]

Chemical formula

[0140] In some embodiments, R1 is H, OH, methyl,

[0141]

Chemical formula

[0142] In some embodiments, R1 is

[0143]

Chem.

[0144] In some embodiments, R1 is H, OH, methyl,

[0145]

Chem.

[0146] In some embodiments, R1 is

[0147]

Chem.

[0148] In some embodiments, R1 is

[0149]

Chem.

[0150] In some embodiments, R1 is

[0151]

Chem.

[0152] In some embodiments, R1 is

[0153]

Chem.

[0154] In some embodiments, R1 is

[0155] [Chem.] is.

[0156] In some embodiments, R2 is H, OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NHC1-C6 alkyl, -C(O)N(C1-C6 alkyl)2, C6-C 10 aryl, 5-12 membered heteroaryl containing 1-6 heteroatoms selected from N, O, and S, or 5-14 membered saturated or unsaturated heterocycloalkyl containing 1-5 heteroatoms selected from N, O, and S, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl is optionally substituted with one or more R6.

[0157] In some embodiments, R2 is OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NHC1-C6 alkyl, -C(O)N(C1-C6 alkyl)2, C6-C 10 aryl, 5-12 membered heteroaryl containing 1-6 heteroatoms selected from N, O, and S, or 5-14 membered saturated or unsaturated heterocycloalkyl containing 1-5 heteroatoms selected from N, O, and S; and any of the alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl is optionally substituted with one or more R6.

[0158] In some embodiments, R2 is H, OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NHC1-C6 alkyl, -C(O)N(C1-C6 alkyl)2, C6-C 10 aryl, 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, or 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any of the foregoing alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl is substituted with one or more R6s.

[0159] In some embodiments, R2 is H, OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NHC1-C6 alkyl, -C(O)N(C1-C6 alkyl)2, C6-C 10 aryl, 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, or 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any of the foregoing alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl is substituted with one R6.

[0160] In some embodiments, R2 is H, OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NHC1-C6 alkyl, -C(O)N(C1-C6 alkyl)2, C6-C 10 aryl, 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, or 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any of the foregoing alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl is substituted with two R6s.

[0161] In some embodiments, R2 is H, OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NHC1-C6 alkyl, -C(O)N(C1-C6 alkyl)2, C6-C 10 aryl, 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, or 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any of the foregoing alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl is substituted with three R6s.

[0162] In some embodiments, R2 is H, OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NHC1-C6 alkyl, -C(O)N(C1-C6 alkyl)2, C6-C 10 aryl, 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, or 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S.

[0163] In some embodiments, R2 is H, OH, or halogen. In some embodiments, R2 is H. In some embodiments, R2 is OH. In some embodiments, R2 is halogen. In some embodiments, R2 is fluorine. In some embodiments, R2 is chlorine. In some embodiments, R2 is bromine. In some embodiments, R2 is iodine.

[0164] In some embodiments, R2 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0165] In some embodiments, R2 is C1-C6 alkyl. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl. In some embodiments, R2 is propyl. In some embodiments, R2 is butyl. In some embodiments, R2 is isopropyl. In some embodiments, R2 is iso-butyl. In some embodiments, R2 is sec-butyl. In some embodiments, R2 is tert-butyl. In some embodiments, R2 is pentyl. In some embodiments, R2 is iso-pentyl. In some embodiments, R2 is hexyl. In some embodiments, R2 is iso-hexyl.

[0166] In some embodiments, R2 is C2-C6 alkenyl. In some embodiments, R2 is C2 alkenyl. In some embodiments, R2 is C3 alkenyl. In some embodiments, R2 is C4 alkenyl. In some embodiments, R2 is C5 alkenyl. In some embodiments, R2 is C6 alkenyl.

[0167] In some embodiments, R2 is C2-C6 alkynyl. In some embodiments, R2 is C2 alkynyl. In some embodiments, R2 is C3 alkynyl. In some embodiments, R2 is C4 alkynyl. In some embodiments, R2 is C5 alkynyl. In some embodiments, R2 is C6 alkynyl.

[0168] In some embodiments, R2 is C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

[0169] In some embodiments, R2 is C1-C6 haloalkyl. In some embodiments, R2 is halomethyl. In some embodiments, R2 is haloethyl. In some embodiments, R2 is halopropyl. In some embodiments, R2 is halobutyl. In some embodiments, R2 is halopentyl. In some embodiments, R2 is halohexyl.

[0170] In some embodiments, R2 is C1-C6 alkoxyl. In some embodiments, R2 is methoxyl. In some embodiments, R2 is ethoxyl. In some embodiments, R2 is propoxyl. In some embodiments, R2 is butoxyl. In some embodiments, R2 is pentoxyl. In some embodiments, R2 is hexoxyl.

[0171] In some embodiments, R2 is C1-C6 haloalkoxyl. In some embodiments, R2 is halomethoxyl. In some embodiments, R2 is haloethoxyl. In some embodiments, R2 is halopropoxyl. In some embodiments, R2 is halobutoxyl. In some embodiments, R2 is halopentoxyl. In some embodiments, R2 is halohexoxyl.

[0172] In some embodiments, R2 is C3-C6 cycloalkyl. In some embodiments, R2 is cyclopropyl. In some embodiments, R2 is cyclobutyl. In some embodiments, R2 is cyclopentyl. In some embodiments, R2 is cyclohexyl.

[0173] In some embodiments, R2 is -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NHC1-C6 alkyl, or -C(O)N(C1-C6 alkyl)2. In some embodiments, R2 is -C(O)OC1-C6 alkyl. In some embodiments, R2 is -C(O)NH2. In some embodiments, R2 is -C(O)NHC1-C6 alkyl. In some embodiments, R2 is -C(O)N(C1-C6 alkyl)2.

[0174] In some embodiments, R2 is, C6-C 10 aryl, 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, or 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; wherein the aryl, heteroaryl, or heterocycloalkyl is optionally substituted with one or more R6.

[0175] In some embodiments, R2 is, C6-C 10A 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from aryl, N, O, and S, or a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any of the foregoing aryl, heteroaryl, or heterocycloalkyl is substituted with one or more R6.

[0176] In some embodiments, R2 is C6-C 10 A 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from aryl, N, O, and S, or a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any of the foregoing aryl, heteroaryl, or heterocycloalkyl is substituted with one R6.

[0177] In some embodiments, R2 is C6-C 10 A 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from aryl, N, O, and S, or a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any of the foregoing aryl, heteroaryl, or heterocycloalkyl is substituted with two R6.

[0178] In some embodiments, R2 is C6-C 10 A 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from aryl, N, O, and S, or a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any of the foregoing aryl, heteroaryl, or heterocycloalkyl is substituted with three R6.

[0179] In some embodiments, R2 is C6-C 10It is a 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from aryl, N, O, and S, or a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S.

[0180] In some embodiments, R2 is C6-C 10 aryl. In some embodiments, R2 is C6 aryl. In some embodiments, R2 is C7 aryl. In some embodiments, R2 is C8 aryl. In some embodiments, R2 is C9 aryl. In some embodiments, R2 is C 10 aryl.

[0181] In some embodiments, R2 is C6-C 10 aryl, and the aryl is substituted with one or more R6s.

[0182] In some embodiments, R2 is C6-C 10 aryl, and the aryl is substituted with one R6.

[0183] In some embodiments, R2 is C6-C 10 aryl, and the aryl is substituted with two R6s.

[0184] In some embodiments, R2 is C6-C 10 aryl, and the aryl is substituted with three R6s.

[0185] In some embodiments, R2 is a 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S.

[0186] In some embodiments, R2 is a 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, and the heteroaryl is substituted with one or more R6s.

[0187] In some embodiments, R2 is a 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, and the heteroaryl is substituted with one R6.

[0188] In some embodiments, R2 is a 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, and the heteroaryl is substituted with two R6s.

[0189] In some embodiments, R2 is a 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, and the heteroaryl is substituted with three R6s.

[0190] In some embodiments, R2 is a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S.

[0191] In some embodiments, R2 is a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S, and the heterocycloalkyl is substituted with one or more R6s.

[0192] In some embodiments, R2 is a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S, and the heterocycloalkyl is substituted with one R6.

[0193] In some embodiments, R2 is a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S, and the heterocycloalkyl is substituted with two R6s.

[0194] In some embodiments, R2 is a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S, and the heterocycloalkyl is substituted with three R6s.

[0195] In some embodiments, R2 is a 5- to 14-membered saturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S.

[0196] In some embodiments, R2 is a 6-membered saturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S.

[0197] In some embodiments, R2 is a 6-membered saturated heterocycloalkyl containing 2 heteroatoms selected from N, O, and S.

[0198] In some embodiments, R2 is a 6-membered saturated heterocycloalkyl containing 2 N atoms.

[0199] In some embodiments, R2 is

[0200]

Chemical formula

[0201] In some embodiments, R2 is

[0202]

Chemical formula

[0203] In some embodiments, R2 is

[0204]

Chemical formula

[0205] In some embodiments, R2 is

[0206]

Chemical formula

[0207] In some embodiments, R2 is

[0208] [Chemical formula] .

[0209] In some embodiments, R3 is H or halogen. In some embodiments, R3 is H. In some embodiments, R3 is halogen.

[0210] In some embodiments, R4 is H or halogen. In some embodiments, R4 is H. In some embodiments, R4 is halogen.

[0211] In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0212] In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0213] In some embodiments, m is 1 and n is 1.

[0214] In some embodiments, m is 1 and n is 2.

[0215] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0216] In some embodiments, q is 1, 2, 3, or 4. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.

[0217] In some embodiments, R5 is OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, C6-C 10 aryl, or 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, or aryl being optionally substituted with -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NHC1-C6 alkyl, or -C(O)N(C1-C6 alkyl)2.

[0218] In some embodiments, R5 is OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, C6-C 10 aryl, or 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, or aryl being substituted with -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NHC1-C6 alkyl, or -C(O)N(C1-C6 alkyl)2.

[0219] In some embodiments, R5 is OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, or C6-C 10Aryl, and any of the alkyl, alkenyl, alkynyl, cycloalkyl, or aryl is optionally substituted with one or more -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NHC1-C6 alkyl, or -C(O)N(C1-C6 alkyl)2.

[0220] In some embodiments, R5 is OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, or C6-C 10 Aryl, and any of the alkyl, alkenyl, alkynyl, cycloalkyl, or aryl is substituted with one or more -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NHC1-C6 alkyl, or -C(O)N(C1-C6 alkyl)2.

[0221] In some embodiments, R5 is OH or halogen. In some embodiments, R5 is OH. In some embodiments, R5 is halogen. In some embodiments, R5 is fluorine. In some embodiments, R5 is chlorine. In some embodiments, R5 is bromine. In some embodiments, R5 is iodine.

[0222] In some embodiments, R5 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0223] In some embodiments, R5 is C1-C6 alkyl. In some embodiments, R5 is methyl. In some embodiments, R5 is ethyl. In some embodiments, R5 is propyl. In some embodiments, R5 is butyl. In some embodiments, R5 is isopropyl. In some embodiments, R5 is iso-butyl. In some embodiments, R5 is sec-butyl. In some embodiments, R5 is tert-butyl. In some embodiments, R5 is pentyl. In some embodiments, R5 is iso-pentyl. In some embodiments, R5 is hexyl. In some embodiments, R5 is iso-hexyl.

[0224] In some embodiments, R5 is C2-C6 alkenyl. In some embodiments, R5 is C2 alkenyl. In some embodiments, R5 is C3 alkenyl. In some embodiments, R5 is C4 alkenyl. In some embodiments, R5 is C5 alkenyl. In some embodiments, R5 is C6 alkenyl.

[0225] In some embodiments, R5 is C2-C6 alkynyl. In some embodiments, R5 is C2 alkynyl. In some embodiments, R5 is C3 alkynyl. In some embodiments, R5 is C4 alkynyl. In some embodiments, R5 is C5 alkynyl. In some embodiments, R5 is C6 alkynyl.

[0226] In some embodiments, R5 is C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

[0227] In some embodiments, R5 is C1-C6 haloalkyl. In some embodiments, R5 is halomethyl. In some embodiments, R5 is haloethyl. In some embodiments, R5 is halopropyl. In some embodiments, R5 is halobutyl. In some embodiments, R5 is halopentyl. In some embodiments, R5 is halohexyl.

[0228] In some embodiments, R5 is C1-C6 alkoxyl. In some embodiments, R5 is methoxyl. In some embodiments, R5 is ethoxyl. In some embodiments, R5 is propoxyl. In some embodiments, R5 is butoxyl. In some embodiments, R5 is pentoxyl. In some embodiments, R5 is hexoxyl.

[0229] In some embodiments, R5 is C1-C6 haloalkoxyl. In some embodiments, R5 is halomethoxyl. In some embodiments, R5 is haloethoxyl. In some embodiments, R5 is halopropoxyl. In some embodiments, R5 is halobutoxyl. In some embodiments, R5 is halopentoxyl. In some embodiments, R5 is halohexoxyl.

[0230] In some embodiments, R5 is C3-C6 cycloalkyl. In some embodiments, R5 is cyclopropyl. In some embodiments, R5 is cyclobutyl. In some embodiments, R5 is cyclopentyl. In some embodiments, R5 is cyclohexyl.

[0231] In some embodiments, R5 is -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NHC1-C6 alkyl, or -C(O)N(C1-C6 alkyl)2. In some embodiments, R5 is -C(O)OC1-C6 alkyl. In some embodiments, R5 is -C(O)NH2. In some embodiments, R5 is -C(O)NHC1-C6 alkyl. In some embodiments, R5 is -C(O)N(C1-C6 alkyl)2.

[0232] In some embodiments, R5 is alkyl substituted with -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NHC1-C6 alkyl, or -C(O)N(C1-C6 alkyl)2.

[0233] In some embodiments, R5 is alkyl substituted with -C(O)OC1-C6 alkyl. In some embodiments, R5 is alkyl substituted with -C(O)O methyl. In some embodiments, R5 is alkyl substituted with -C(O)O ethyl. In some embodiments, R5 is alkyl substituted with -C(O)O propyl. In some embodiments, R5 is alkyl substituted with -C(O)O isopropyl. In some embodiments, R5 is alkyl substituted with -C(O)O butyl. In some embodiments, R5 is alkyl substituted with -C(O)O pentyl. In some embodiments, R5 is alkyl substituted with -C(O)O hexyl.

[0234] In some embodiments, R6 is OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, C6-C 10 aryl, or 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heterocycloalkyl being optionally substituted with one or more -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NHC1-C6 alkyl, or -C(O)N(C1-C6 alkyl)2.

[0235] In some embodiments, R6 is OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, C6-C 10Aryl, or a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any of the above alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heterocycloalkyl is substituted with one or more -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NHC1-C6 alkyl, or -C(O)N(C1-C6 alkyl)2.

[0236] In some embodiments, R6 is OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, or C6-C 10 Aryl, and any of the above alkyl, alkenyl, alkynyl, cycloalkyl, or aryl is optionally substituted with one or more -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NHC1-C6 alkyl, or -C(O)N(C1-C6 alkyl)2.

[0237] In some embodiments, R6 is OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, or C6-C 10 Aryl, and any of the above alkyl, alkenyl, alkynyl, cycloalkyl, or aryl is substituted with one or more -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NHC1-C6 alkyl, or -C(O)N(C1-C6 alkyl)2.

[0238] In some embodiments, R6 is OH or a halogen. In some embodiments, R6 is OH. In some embodiments, R6 is a halogen. In some embodiments, R6 is fluorine. In some embodiments, R6 is chlorine. In some embodiments, R6 is bromine. In some embodiments, R6 is iodine.

[0239] In some embodiments, R6 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0240] In some embodiments, R6 is C1-C6 alkyl. In some embodiments, R6 is methyl. In some embodiments, R6 is ethyl. In some embodiments, R6 is propyl. In some embodiments, R6 is butyl. In some embodiments, R6 is isopropyl. In some embodiments, R6 is iso-butyl. In some embodiments, R6 is sec-butyl. In some embodiments, R6 is tert-butyl. In some embodiments, R6 is pentyl. In some embodiments, R6 is iso-pentyl. In some embodiments, R6 is hexyl. In some embodiments, R6 is iso-hexyl.

[0241] In some embodiments, R6 is C2-C6 alkenyl. In some embodiments, R6 is C2 alkenyl. In some embodiments, R6 is C3 alkenyl. In some embodiments, R6 is C4 alkenyl. In some embodiments, R6 is C5 alkenyl. In some embodiments, R6 is C6 alkenyl.

[0242] In some embodiments, R6 is C2-C6 alkynyl. In some embodiments, R6 is C2 alkynyl. In some embodiments, R6 is C3 alkynyl. In some embodiments, R6 is C4 alkynyl. In some embodiments, R6 is C5 alkynyl. In some embodiments, R6 is C6 alkynyl.

[0243] In some embodiments, R6 is C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

[0244] In some embodiments, R6 is C1-C6 haloalkyl. In some embodiments, R6 is halomethyl. In some embodiments, R6 is haloethyl. In some embodiments, R6 is halopropyl. In some embodiments, R6 is halobutyl. In some embodiments, R6 is halopentyl. In some embodiments, R6 is halohexyl.

[0245] In some embodiments, R6 is C1-C6 alkoxyl. In some embodiments, R6 is methoxyl. In some embodiments, R6 is ethoxyl. In some embodiments, R6 is propoxyl. In some embodiments, R6 is butoxyl. In some embodiments, R6 is pentoxyl. In some embodiments, R6 is hexoxyl.

[0246] In some embodiments, R6 is C1-C6 haloalkoxyl. In some embodiments, R6 is halomethoxyl. In some embodiments, R6 is haloethoxyl. In some embodiments, R6 is halopropoxyl. In some embodiments, R6 is halobutoxyl. In some embodiments, R6 is halopentoxyl. In some embodiments, R6 is halohexoxyl.

[0247] In some embodiments, R6 is C3-C6 cycloalkyl. In some embodiments, R6 is cyclopropyl. In some embodiments, R6 is cyclobutyl. In some embodiments, R6 is cyclopentyl. In some embodiments, R6 is cyclohexyl.

[0248] In some embodiments, R6 is -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NHC1-C6 alkyl, or -C(O)N(C1-C6 alkyl)2. In some embodiments, R6 is -C(O)OC1-C6 alkyl. In some embodiments, R6 is -C(O)NH2. In some embodiments, R6 is -C(O)NHC1-C6 alkyl. In some embodiments, R6 is -C(O)N(C1-C6 alkyl)2.

[0249] In some embodiments, R6 is alkyl substituted with -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NHC1-C6 alkyl, or -C(O)N(C1-C6 alkyl)2.

[0250] In some embodiments, R6 is alkyl substituted with -C(O)OC1-C6 alkyl. In some embodiments, R6 is alkyl substituted with -C(O)O methyl. In some embodiments, R6 is alkyl substituted with -C(O)O ethyl. In some embodiments, R6 is alkyl substituted with -C(O)O propyl. In some embodiments, R6 is alkyl substituted with -C(O)O isopropyl. In some embodiments, R6 is alkyl substituted with -C(O)O butyl. In some embodiments, R6 is alkyl substituted with -C(O)O pentyl. In some embodiments, R6 is alkyl substituted with -C(O)O hexyl.

[0251] In some embodiments, R6 is a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S, and the heterocycloalkyl is optionally substituted with one or more -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NHC1-C6 alkyl, or -C(O)N(C1-C6 alkyl)2.

[0252] In some embodiments, R6 is a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S, and the heterocycloalkyl is substituted with one or more -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)NH2, -C(O)NHC1-C6 alkyl, or -C(O)N(C1-C6 alkyl)2.

[0253] In some embodiments, R6 is a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 heteroatom selected from N, O, and S.

[0254] In some embodiments, R6 is a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 2 heteroatoms selected from N, O, and S.

[0255] In some embodiments, R6 is a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 3 heteroatoms selected from N, O, and S.

[0256] In some embodiments, R6 is a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 4 heteroatoms selected from N, O, and S.

[0257] In some embodiments, R6 is a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 5 heteroatoms selected from N, O, and S.

[0258] In some embodiments, R6 is a 5-membered saturated or unsaturated heterocycloalkyl containing 2 heteroatoms selected from N, O, and S.

[0259] In some embodiments, R6 is a 6-membered saturated or unsaturated heterocycloalkyl containing 2 heteroatoms selected from N, O, and S.

[0260] In some embodiments, R6 is a 7-membered saturated or unsaturated heterocycloalkyl containing two heteroatoms selected from N, O, and S.

[0261] In some embodiments, R6 is an 8-membered saturated or unsaturated heterocycloalkyl containing two heteroatoms selected from N, O, and S.

[0262] In some embodiments, R6 is a 9-membered saturated or unsaturated heterocycloalkyl containing two heteroatoms selected from N, O, and S.

[0263] In some embodiments, R6 is a 10-membered saturated or unsaturated heterocycloalkyl containing two heteroatoms selected from N, O, and S.

[0264] In some embodiments, R6 is an 11-membered saturated or unsaturated heterocycloalkyl containing two heteroatoms selected from N, O, and S.

[0265] In some embodiments, R6 is a 12-membered saturated or unsaturated heterocycloalkyl containing two heteroatoms selected from N, O, and S.

[0266] In some embodiments, R6 is a 13-membered saturated or unsaturated heterocycloalkyl containing two heteroatoms selected from N, O, and S.

[0267] In some embodiments, R6 is a 14-membered saturated or unsaturated heterocycloalkyl containing two heteroatoms selected from N, O, and S.

[0268] In some embodiments, R6 is

[0269]

Chemical formula

[0270] In some embodiments, R7 is C1-C6 alkyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl. In some embodiments, R7 is methyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl. In some embodiments, R7 is ethyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl. In some embodiments, R7 is propyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl. In some embodiments, R7 is butyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl. In some embodiments, R7 is pentyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl. In some embodiments, R7 is hexyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl.

[0271] In some embodiments, R8 is C1-C6 alkyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl. In some embodiments, R8 is methyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl. In some embodiments, R8 is ethyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl. In some embodiments, R8 is propyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl. In some embodiments, R8 is butyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl. In some embodiments, R8 is pentyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl. In some embodiments, R8 is hexyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl.

[0272] In some embodiments, R7 is C1-C6 alkyl. In some embodiments, R7 is methyl. In some embodiments, R7 is ethyl. In some embodiments, R7 is propyl. In some embodiments, R7 is butyl. In some embodiments, R7 is pentyl. In some embodiments, R7 is hexyl.

[0273] In some embodiments, R8 is C1-C6 alkyl. In some embodiments, R8 is methyl. In some embodiments, R8 is ethyl. In some embodiments, R8 is propyl. In some embodiments, R8 is butyl. In some embodiments, R8 is pentyl. In some embodiments, R8 is hexyl.

[0274] In some embodiments, R7 and R8 are different.

[0275] In some embodiments, R7 and R8 are the same.

[0276] In some embodiments, R7 and R8 are each methyl.

[0277] In some embodiments, R7 and R8, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl. In some embodiments, R7 and R8, together with the carbon atom to which they are attached, form a cyclopropyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl. In some embodiments, R7 and R8, together with the carbon atom to which they are attached, form a cyclobutyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl. In some embodiments, R7 and R8, together with the carbon atom to which they are attached, form a cyclopentyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl. In some embodiments, R7 and R8, together with the carbon atom to which they are attached, form a cyclohexyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl.

[0278] In some embodiments, R7 and R8, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl. In some embodiments, R7 and R8, together with the carbon atom to which they are attached, form a cyclopropyl. In some embodiments, R7 and R8, together with the carbon atom to which they are attached, form a cyclobutyl. In some embodiments, R7 and R8, together with the carbon atom to which they are attached, form a cyclopentyl. In some embodiments, R7 and R8, together with the carbon atom to which they are attached, form a cyclohexyl.

[0279] In some embodiments, m is 1, n is 1, and p is 1.

[0280] In some embodiments, m is 1, n is 1, p is 1, and R2 is C6-C 10 aryl.

[0281] In some embodiments, m is 1, n is 1, p is 1, and R2 is phenyl.

[0282] In some embodiments, m is 1, n is 1, p is 1, and R2 is a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S.

[0283] In some embodiments, m is 1, n is 2, p is 1.

[0284] In some embodiments, m is 1, n is 2, p is 1, and R2 is C6-C 10 aryl.

[0285] In some embodiments, m is 1, n is 2, p is 1, and R2 is phenyl.

[0286] In some embodiments, m is 1, n is 2, p is 1, and R2 is a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S.

[0287] In some embodiments, m is 1, n is 1, p is 1, X1 is -C(O)O-, and X2 is absent.

[0288] In some embodiments, m is 1, n is 1, p is 1, X1 is absent, and X2 is absent.

[0289] In some embodiments, m is 1, n is 1, p is 1, X1 is -O-, and X2 is absent.

[0290] In some embodiments, m is 1, n is 1, p is 1, X1 is -S(O)2-, and X2 is absent.

[0291] In some embodiments, m is 1, n is 1, p is 1, X1 is -C(O)NR3-, and X2 is absent.

[0292] In some embodiments, m is 1, n is 2, p is 1, X1 is absent, and X2 is -O-.

[0293] In some embodiments, m is 1, n is 2, p is 1, X1 is absent, and X2 is S(O)2.

[0294] In some embodiments, m is 1, n is 2, p is 1, X1 is absent, and X2 is -C(O)NR3-.

[0295] In some aspects, the present disclosure provides, inter alia, a compound of formula (I’):

[0296]

Chemical formula

[0297] In some embodiments, the compound of formula (I’) is X1 is absent; X2 is -S(O)2- or -C(O)O-; R1 is C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 Aryl; any of the foregoing alkyl, cycloalkyl, or aryl is optionally substituted with one or two R5; Each R2 is a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S, optionally substituted with one or two R6; Each R5 is independently halogen; Each R6 is independently C3-C6 cycloalkyl; R7 is C1-C6 alkyl; R8 is C1-C6 alkyl; m is 1; n is 1; p is 1, a compound of formula (I’’), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0298] In some embodiments, the compound of formula (I’) is X1 is absent or -(CR3R4) q -; X2 is absent, -S(O)2-, -C(O)-, or -C(O)O-; R1 is C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, or a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any of the foregoing alkyl, cycloalkyl, aryl, or heterocycloalkyl being optionally substituted with one or two R5; each R2 is C6-C 10 aryl, a 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, or a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any of the foregoing aryl, heteroaryl, or heterocycloalkyl being optionally substituted with one or two R6; each R3 is H; each R4 is H; each R5 is, independently, halogen or C1-C6 alkyl; each R6 is, independently, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C6-C 10 aryl, or a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; R7 is C1-C6 alkyl; R8 is C1-C6 alkyl; m is 1; n is 2; p is 1; q is 2, which is a compound of formula (I’’’), or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0299] In some embodiments, the compound of formula (I) is a compound of formula (II):

[0300]

Chem.

[0301] In some embodiments, the compound of formula (I) is a compound of formula (IIa):

[0302]

Chem.

[0303] In some embodiments, the compound of formula (I) is a compound of formula (IIb):

[0304]

Chem.

[0305] In some embodiments, the compound of formula (I) is a compound of formula (IIc):

[0306]

Chem.

[0307] In some embodiments, a compound of formula (I) is a compound of formula (IId):

[0308]

Chemical formula

[0309] In some embodiments, a compound of formula (I) is a compound of formula (IIe):

[0310]

Chemical formula

[0311] In some embodiments, a compound of formula (I) is a compound of formula (IIf):

[0312]

Chemical formula

[0313] In some embodiments, a compound of formula (I) is a compound of formula (IIg):

[0314]

Chemical formula

[0315] In some embodiments, the compound of formula (I) is a compound of formula (IIh):

[0316]

Chemical formula

[0317] In some embodiments, the compound of formula (I) is a compound of formula (IIi):

[0318]

Chemical formula

[0319] In some embodiments, the compound of formula (I) is a compound of formula (IIj):

[0320]

Chemical formula

[0321] In some embodiments, the compound of formula (I) is a compound of formula (IIk):

[0322]

Chemical formula

[0323] In some embodiments, the compound of formula (I) is a compound of formula (III):

[0324]

Chemical formula

[0325] In some embodiments, the compound of formula (I) is a compound of formula (III):

[0326]

Chemical formula

[0327] In some embodiments, the compound of formula (I) is a compound of formula (IIIa):

[0328]

Chemical formula

[0329] In some embodiments, the compound of formula (I) is a compound of formula (IIIb):

[0330]

Chemical formula

[0331] In some embodiments, the compound of formula (I) is a compound of formula (IIIc):

[0332]

Chemical formula

[0333] In some embodiments, the compound of formula (I) is a compound of formula (IIId):

[0334]

Chemical formula

[0335] In some embodiments, the compound of formula (I) is a compound of formula (IIIe):

[0336]

Chemical formula

[0337] In some embodiments, the compound of formula (I) is a compound of formula (IIIf):

[0338]

Chemical formula

[0339] In some embodiments, the compound of formula (I) is a compound of formula (IIIg):

[0340]

Chemical formula

[0341] In some embodiments, the compound of formula (I) is a compound of formula (IIIh):

[0342]

Chemical formula

[0343] In some embodiments, the compound of formula (I) is a compound of formula (IIIi):

[0344]

Chemical formula

[0345] In some embodiments, the compound of formula (I) is a compound of formula (IIIj):

[0346]

Chemical formula

[0347] In some embodiments, the compound of formula (I) is a compound of formula (IIIk):

[0348]

Chemical formula

[0349] In some embodiments, the compound of formula (I) is a compound of formula (IIIl):

[0350]

Chemical formula

[0351] In some aspects, the present disclosure provides a compound, 2-(2-(1-(2-(4-fluorophenyl)-2-oxoethyl)pyrrolidin-3-yl)ethyl)isoindolin-1-one, i.e., MIN-101-B:

[0352]

Chemical formula

[0353] In one embodiment, MIN-101-B is (S)-2-(2-(1-(2-(4-fluorophenyl)-2-oxoethyl)pyrrolidin-3-yl)ethyl)isoindolin-1-one,

[0354] [Chemical formula] or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0355] In one embodiment, MIN-101-B is (R)-2-(2-(1-(2-(4-fluorophenyl)-2-oxoethyl)pyrrolidin-3-yl)ethyl)isoindoline-1-one,

[0356] [Chemical formula] or a prodrug, solvate, or pharmaceutically acceptable salt thereof.

[0357] In some embodiments, the compound is selected from the compounds described in Table 1.

[0358] [Table 1-1]

[0359] [Table 1-2]

[0360] [Table 1-3]

[0361] [Table 1-4]

[0362] [Table 1-5]

[0363] [Table 1-6]

[0364]

Table 1-7

[0365]

Table 1-8

[0366]

Table 1-9

[0367]

Table 1-10

[0368]

Table 1-11

[0369]

Table 1-12

[0370]

Table 1-13

[0371]

Table 1-14

[0372]

Table 1-15

[0373]

Table 1-16

[0374]

Table 1-17

[0375]

Table 1-18

[0376]

Table 1-19

[0377]

Table 1-20

[0378]

Table 1-21

[0379]

Table 1-22

[0380]

Table 1-23

[0381]

Table 1-24

[0382]

Table 1-25

[0383]

Table 1-26

[0384]

Table 1-27

[0385]

Table 1-28

[0386]

Table 1-29

[0387]

Table 1-30

[0388]

Table 1-31

[0389]

Table 1-32

[0390]

Table 1-33

[0391]

Table 1-34

[0392]

Table 1-35

[0393]

Table 1-36

[0394]

Table 1-37

[0395]

Table 1-38

[0396]

Table 1-39

[0397]

Table 1-40

[0398]

Table 1-41

[0399]

Table 1-42

[0400]

Table 1-43

[0401]

Table 1-44

[0402]

Table 1-45

[0403]

Table 1-46

[0404]

Table 1-47

[0405]

Table 1-48

[0406]

Table 1-49

[0407]

Table 1-50

[0408]

Table 1-51

[0409]

Table 1-52

[0410] The general routes for preparing the compounds of the present application are described in Scheme I and Scheme II:

[0411]

Chemical

[0412] Methods for treating viral infections, pain, cancer, and other diseases or disorders In some embodiments, the present disclosure provides a method of modulating a sigma receptor (e.g., sigma-1 or sigma-2, e.g., in vitro or in vivo), the method comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

[0413] In some embodiments, modulation of a sigma receptor (e.g., sigma-1 or sigma-2, e.g., in vitro or in vivo) treats or prevents a disease or disorder associated with the sigma receptor.

[0414] In some embodiments, modulation of a sigma receptor (e.g., sigma-1 or sigma-2, e.g., in vitro or in vivo) treats or prevents a disease or disorder associated with a viral infection.

[0415] In some embodiments, modulation of a sigma receptor (e.g., sigma-1 or sigma-2, e.g., in vitro or in vivo) prevents replication or spread of a viral infection.

[0416] In one aspect, the present disclosure provides a method of treating or preventing an infectious disease or disorder, wherein the infectious disease or disorder is caused by bacteria, fungi, or viruses.

[0417] In one aspect, the present disclosure provides a method of treating a viral infection in a subject or a disease resulting from a viral infection, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

[0418] In one aspect, the present disclosure provides a compound of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof for use in treating a viral infection in a subject or a disease resulting from a viral infection.

[0419] In one aspect, the present disclosure provides the use of a compound of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof in the manufacture of a medicament for treating a viral infection in a subject or a disease resulting from a viral infection.

[0420] In one aspect, the present disclosure provides a method for preventing a target viral infection, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

[0421] In one aspect, the present disclosure provides a method for preventing viral transmission, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

[0422] In some embodiments, the present disclosure provides a method of binding a sigma receptor (e.g., sigma-1 or sigma-2) to a compound of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

[0423] In one embodiment, the viral infection is caused by a coronavirus, herpes simplex virus, human immunodeficiency virus, influenza virus, or human papillomavirus.

[0424] In one embodiment, the coronavirus is Middle East respiratory syndrome-related coronavirus, severe acute respiratory syndrome coronavirus, or severe acute respiratory syndrome coronavirus 2 (i.e., SARS-CoV-2 or COVID-19).

[0425] In one embodiment, the disease resulting from the viral infection is severe acute respiratory syndrome, Middle East respiratory syndrome, acquired immunodeficiency syndrome, influenza, or viral hepatitis.

[0426] In some embodiments, the present disclosure provides a method of treating a target viral infection or a disease resulting from a viral infection, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the subject is at risk of viral infection. Examples of subjects at risk of viral infection include subjects who work or have visited a high-risk environment (e.g., college students and university staff, cruise line participants, healthcare workers, first responders, physicians, nurses, residents of a nursing home, or residents of an elderly care facility). Examples of subjects at risk of viral infection include subjects known to be at high risk of infection (e.g., healthcare workers, first responders, physicians, nurses, the elderly, subjects previously tested positive for SARS-CoV-2, or subjects living with a subject known to be at high risk of infection).

[0427] In one aspect, the present disclosure provides a method of treating Alzheimer's disease, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

[0428] In one aspect, the present disclosure provides a compound of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof for use in the treatment of Alzheimer's disease.

[0429] In one aspect, the present disclosure provides the use of a compound of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof in the manufacture of a medicament for treating Alzheimer's disease.

[0430] In one aspect, the present disclosure provides a method for preventing Alzheimer's disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

[0431] In one aspect, the present disclosure provides a method for treating a disease or a symptom of a disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the disease or the symptom of the disease is anxiety, depression, mood disorder, schizophrenia, drug intoxication, drug addiction, sharp pain, dyskinesia, cerebrovascular disease, epilepsy, dementia, Parkinson's syndrome, attention deficit disorder, irritable bowel syndrome, irritable colon, spastic colon, mucous colitis, enteritis, diverticulitis, dysentery, hypertension, arrhythmia, angina pectoris, amyotrophic lateral sclerosis (ALS), Huntington's disease, stroke, retinal degeneration, or cognitive impairment in a neuropsychiatric disorder.

[0432] In one aspect, the present disclosure provides a compound of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof for use in treating a disease or a symptom of a disease, wherein the disease or the symptom of the disease is anxiety, depression, mood disorder, schizophrenia, drug intoxication, drug addiction, sharp pain, dyskinesia, cerebrovascular disease, epilepsy, dementia, Parkinson's syndrome, attention deficit disorder, irritable bowel syndrome, irritable colon, spastic colon, mucous colitis, enteritis, diverticulitis, dysentery, hypertension, arrhythmia, angina pectoris, amyotrophic lateral sclerosis (ALS), Huntington's disease, stroke, retinal degeneration, or cognitive impairment in a neuropsychiatric disorder.

[0433] In one aspect, the present disclosure provides for the use of a compound of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, in the manufacture of a medicament for treating a disease or a symptom of a disease, wherein the disease or the symptom of the disease is anxiety, depression, mood disorder, schizophrenia, drug intoxication, drug addiction, sharp pain, dyskinesia, cerebrovascular disease, epilepsy, dementia, Parkinson's syndrome, attention deficit disorder, irritable bowel syndrome, irritable colon, spastic colon, mucous colitis, enteritis, diverticulitis, dysentery, hypertension, arrhythmia, angina pectoris, amyotrophic lateral sclerosis (ALS), Huntington's disease, stroke, retinal degeneration, or cognitive impairment in a neuropsychiatric disorder.

[0434] In one aspect, the present disclosure provides a method for preventing a disease or a symptom of a disease, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein the disease or the symptom of the disease is anxiety, depression, mood disorder, schizophrenia, drug intoxication, drug addiction, sharp pain, dyskinesia, cerebrovascular disease, epilepsy, dementia, Parkinson's syndrome, attention deficit disorder, irritable bowel syndrome, irritable colon, spastic colon, mucous colitis, enteritis, diverticulitis, dysentery, hypertension, arrhythmia, angina pectoris, amyotrophic lateral sclerosis (ALS), Huntington's disease, stroke, retinal degeneration, or cognitive impairment in a neuropsychiatric disorder.

[0435] In one aspect, the present disclosure provides a method for treating and / or preventing pain in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

[0436] In one embodiment, the pain is acute pain, chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, postoperative pain, visceral pain, chemotherapy-induced pain, peripheral neuropathy, fibromyalgia, or a combination thereof.

[0437] In one aspect, the present disclosure provides a method for promoting an anti-hyperalgesic effect in a subject suffering from hyperalgesia, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

[0438] In one aspect, the present disclosure provides a method for reducing a subject's sensitivity to pain, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

[0439] In one aspect, the present application relates to a method for treating and preventing pain, the method comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

[0440] In one embodiment, the pain treated and / or prevented by the method of the present application is acute pain.

[0441] Acute pain includes, but is not limited to, nociceptive or inflammatory pain resulting from thermal, mechanical, or chemical stimulation of sensory nerve fibers that respond to stimuli approaching or exceeding a noxious intensity caused by injury and / or visceral pain, including, but not limited to, irritable bowel syndrome (IBS) with or without chronic fatigue syndrome (CFS), inflammatory bowel disease (IBD), Crohn's disease, food poisoning, food allergy, gas-related pain, hernia, pain associated with gallstones and / or kidney stones, endometriosis, gastroesophageal reflux disease (GERD), appendicitis, interstitial cystitis, deep somatic pain (e.g., contusion, fracture), neuropathic pain caused by injury or disease affecting the somatosensory nervous system, and superficial somatic pain (e.g., burns).

[0442] In one embodiment, the pain treated and / or prevented by the method of the present application is nociceptive pain.

[0443] Nociceptive pain includes, but is not limited to, pain resulting from physical damage to the body from heat, cold, pressure, pinching, torsion, friction, chemicals, etc. Specific examples of nociceptive pain include contusions, fractures, burns, abrasions, bruises, inflammation, obstruction, and myofascial pain.

[0444] In one embodiment, the pain treated and / or prevented by the method of the present application is inflammatory pain.

[0445] Inflammatory pain includes, but is not limited to, pain resulting from inflammation, including arthritis.

[0446] In one embodiment, the pain treated and / or prevented by the method of the present application is visceral pain.

[0447] Visceral pain includes, but is not limited to, pain resulting from distension, ischemia, and inflammation of nociceptors in the thoracic, pelvic, or abdominal organs.

[0448] In one embodiment, the pain treated and / or prevented by the method of the present application is chronic, i.e., persistent pain.

[0449] Chronic pain includes, but is not limited to, postoperative pain, cancer pain (e.g., chemotherapy-induced pain), pain from degenerative major joint diseases (e.g., osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, Reiter's syndrome, psoriatic arthritis, gout, pseudogout, infectious arthritis, tendinitis, bursitis, bone lesions, and joint soft tissue inflammation), headache (e.g., cluster headache, migraine, tension headache), vascular pain (e.g., atherosclerotic obliterans, thromboangiitis obliterans, acute arterial occlusion, embolism, congenital arteriovenous aneurysm, vasospastic disease, Raynaud's disease, acrocyanosis, acute venous occlusion, thrombophlebitis, varicose veins, and lymphedema), myofascial or muscle pain (e.g., temporomandibular joint (TMJ) disorder / syndrome, chronic musculoskeletal pain, fibromyalgia with or without chronic fatigue syndrome, myofascial pain syndrome or related pain), neuralgia (trigeminal, postherpetic, glossopharyngeal), herpes zoster, neuropathy, central pain syndrome, complex regional pain syndrome, hyperalgesia, allodynia, central sensitization, peripheral sensitization, disinhibition, and facilitation enhancement.

[0450] In one embodiment, the pain treated and / or prevented by the method of the present application is chemotherapy-induced pain.

[0451] In one embodiment, the pain treated and / or prevented by the method of the present application is postoperative pain.

[0452] Postoperative pain includes, but is not limited to, tissue injury optionally combined with postoperative muscle spasm.

[0453] In one embodiment, the pain treated and / or prevented by the method of the present application is fibromyalgia and / or symptoms of fibromyalgia. Fibromyalgia is a disorder characterized by widespread musculoskeletal pain often accompanied by fatigue and / or sleep disturbances.

[0454] In one embodiment, the pain treated and / or prevented by the method of the present application is fibromyalgia with chronic fatigue syndrome and / or symptoms of fibromyalgia with chronic fatigue syndrome.

[0455] In one embodiment, the pain treated and / or prevented by the method of the present application is neuropathic pain, i.e., neuropathy. In one embodiment, neuropathic pain can be caused by damage or disease to any part of the nervous system or somatosensory system. Types of neuropathic pain include, but are not limited to, diabetic neuropathy, peripheral neuropathy, and diabetic peripheral neuropathy, i.e., diabetic peripheral neuropathic pain.

[0456] Neuropathic pain caused by damage or disease to any part of the somatosensory system includes, but is not limited to, phantom limb pain, multiple chemical sensitivity, sick building syndrome, repetitive stress injury, chronic whiplash, chronic Lyme disease, side effects of silicone breast implants, candida hypersensitivity, Gulf War syndrome, food allergies, mitral valve prolapse, and hypoglycemia.

[0457] In one embodiment, the pain treated and / or prevented by the method of the present application is diabetic neuropathy, i.e., nerve damage caused by diabetes.

[0458] In one embodiment, the pain treated and / or prevented by the method of the present application is peripheral neuropathy, i.e., peripheral neuropathic pain, which is damage or disease that develops in the sensory, motor, and / or autonomic nerves of the peripheral nervous system.

[0459] Peripheral neuropathic pain occurs when the peripheral nerves are unable to carry information to and from the brain and spinal cord, resulting in pain, loss of sensation, or muscle weakness. In some cases, dysfunction of the nerves that control blood vessels, the intestines, and other organs can lead to abnormal blood pressure, indigestion, and loss of other basic body processes. The symptoms also depend on whether the condition is systemic or affects only one nerve. Risk factors for neuropathy include diabetes, heavy alcohol consumption, exposure to certain chemicals and drugs, and prolonged pressure on the nerves. Some people have a genetic predisposition to peripheral neuropathy.

[0460] In one embodiment, the target peripheral neuropathy results from exposure to toxins, alcohol abuse, nutritional disorders, diabetes, Guillain-Barré syndrome, or complications from renal failure, complications from cancer, infectious diseases (e.g., AIDS, herpes zoster, Lyme disease), kidney diseases, thyroid diseases, parathyroid diseases, and / or carpal tunnel syndrome.

[0461] Causes of peripheral neuropathic pain include, but are not limited to, neuropathies associated with systemic diseases such as diabetic neuropathy, neuropathies associated with metabolic conditions such as alcoholic neuropathy and erythromelalgia syndrome, neuropathies associated with viral infections such as herpes zoster and HIV, neuropathies associated with nutritional disorders, neuropathies associated with toxins, neuropathies associated with compression by tumors, neuropathies associated with remote symptoms of malignant tumors, neuropathies associated with drugs such as chemotherapy, neuropathies associated with radiation, neuropathies associated with immune-mediated disorders, and neuropathies associated with physical trauma to nerve trunks.

[0462] The four basic patterns of peripheral neuropathic pain are mononeuropathy, multiple mononeuropathy, polyneuropathy, and autonomic neuropathy.

[0463] In one embodiment, the pain treated and / or prevented by the method of the present application is a peripheral neuropathy that is a peripheral mononeuropathy. Mononeuropathy is a peripheral neuropathy accompanied by loss of function or pathological changes that occur in a single nerve or nerve group. Mononeuropathy is most often caused by injury to a local area resulting from injury or trauma, but sometimes a systemic disorder may cause isolated nerve injury. Common causes are direct trauma, prolonged compression of the nerve, and compression of the nerve by swelling or injury to nearby body structures.

[0464] In one embodiment, damage from mononeuropathy involves destruction of the myelin sheath (covering) of a nerve or a part of the nerve cell (axon). This damage delays or prevents the conduction of impulses through the nerve. Mononeuropathy can affect any part of the body. Mononeuropathy pain is associated with, for example, sciatic nerve dysfunction, common peroneal nerve dysfunction, radial nerve dysfunction, ulnar nerve dysfunction, cranial mononeuropathy VI, cranial mononeuropathy VII, cranial mononeuropathy III (compressive), cranial mononeuropathy III (diabetic), axillary nerve dysfunction, carpal tunnel syndrome, femoral nerve dysfunction, tibial nerve dysfunction, Bell's palsy, thoracic outlet syndrome, carpal tunnel syndrome or other focal entrapment neuropathies, and cranial (abducens) nerve palsy VI. For example, mononeuropathy is ulnar nerve palsy, radial nerve palsy, or peroneal nerve palsy.

[0465] In one embodiment, the pain treated and / or prevented by the method of the present application is a peripheral neuropathy that is multiple mononeuropathy. Multiple mononeuropathy is a peripheral neuropathy with loss of function or pathological changes that occur sequentially or simultaneously in several discontinuous nerves asymmetrically. Neuropathic pain based on multiple mononeuropathy can develop over several days to years and typically presents with an acute or subacute loss of sensory and motor function of individual nerves. The pattern of involvement is asymmetric, but as the disease progresses, the deficits become more dense and symmetric, making it difficult to distinguish from polyneuropathy. Multiple mononeuropathy can also cause pain that worsens at night and is characterized by deep aching pain that is frequently present in the lower back, buttocks, or legs. Multiple mononeuropathy can also cause pain characterized by acute, unilateral, severe lower limb pain followed by weakness of the anterior muscles and loss of the knee reflex. Multiple mononeuropathy pain is associated with, for example, diabetes, infections such as leprosy, Lyme disease, HIV, and toxicity.

[0466] In one embodiment, the pain treated and / or prevented by the method of the present application is a peripheral neuropathy, which is a peripheral polyneuropathy that is a peripheral neuropathy with loss of function or pathological changes occurring symmetrically in multiple nerves throughout the body. Polyneuropathy can be acute and can appear without any warning, or it can be chronic and develop gradually over a long period of time. Many polyneuropathies have both motor and sensory impairments, and some are also accompanied by autonomic nervous system dysfunction. These impairments are often symmetrical and are usually due to various systemic diseases and disease processes that affect the peripheral nervous system as a whole. Polyneuropathy often develops in the hands and feet, causing weakness, loss of sensation, pins-and-needle sensations or burning pain. Polyneuropathy can be classified in various ways, for example, by cause, rate of progression, or part of the body involved. The classes of polyneuropathy are also distinguished by which part of the nerve cell is mainly affected: axon, myelin sheath, or cell body.

[0467] Causes of polyneuropathy pain include, but are not limited to, post-polio syndrome, post-mastectomy syndrome, diabetic neuropathy, alcoholic neuropathy, amyloid, toxins, AIDS, hypothyroidism, uremia, vitamin deficiency, chemotherapy-induced pain, 2′,3′-dideoxycytidine (ddC) treatment, Guillain-Barré syndrome, and Fabry disease.

[0468] In one embodiment, the pain treated and / or prevented by the method of the present application is a peripheral neuropathy that is an autonomic neuropathy. Autonomic neuropathy is a peripheral neuropathy with loss of function or pathological changes occurring in the involuntary sensory nervous system (i.e., the autonomic nervous system). Autonomic neuropathy is mostly in the form of polyneuropathy that develops in internal organs such as the bladder, muscles, cardiovascular system, digestive tract, and reproductive organs.

[0469] In one embodiment, the treatment and / or prevention of pain in a subject having peripheral and / or diabetic neuropathy comprises reducing one or more symptoms of the subject selected from the group consisting of stabbing pain, numbness, loss of sensation (e.g., in the arms and / or legs), and burning sensation (e.g., in the feet and / or hands).

[0470] In one embodiment, the pain treated by the method of the present application is neuropathy induced by chemotherapy.

[0471] In one embodiment, the pain prevented by the method of the present application is neuropathy induced by chemotherapy.

[0472] In one aspect, the present disclosure provides a method for treating and / or preventing cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of any one of the compounds of formula (I), MIN-101, MIN-101-B, MIN-S006, or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

[0473] In one embodiment, the cancer is breast cancer, prostate cancer, colon cancer, rectal cancer, pancreatic cancer, liver cancer, bladder cancer, thyroid cancer, kidney cancer, skin cancer, non-Hodgkin lymphoma, or uterine cancer.

[0474] In one aspect, treatment of the cancer results in a decrease in tumor size. The decrease in tumor size may also be referred to as "tumor regression". Preferably, after treatment, the tumor size is reduced by 5% or more compared to the size before treatment; more preferably, the tumor size is reduced by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; most preferably, by 75% or more. The tumor size can be measured by any reproducible means of measurement. In a preferred aspect, the tumor size can be measured as the diameter of the tumor.

[0475] In another aspect, treatment of cancer results in a reduction in tumor volume. Preferably, after treatment, the tumor volume is reduced by at least 5% compared to its size prior to treatment; more preferably, the tumor volume is reduced by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; even more preferably, by at least 50%; most preferably, by at least 75%. Tumor volume can be measured by any reproducible measuring means.

[0476] In another aspect, treatment of cancer results in a reduction in the number of tumors. Preferably, after treatment, the number of tumors is reduced by at least 5% compared to its number prior to treatment; more preferably, the number of tumors is reduced by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; even more preferably, by at least 50%; most preferably, by more than 75%. The number of tumors can be measured by any reproducible measuring means. In a preferred aspect, the number of tumors can be measured by counting tumors visible to the naked eye or at a specified magnification. In a preferred aspect, the specified magnification is 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or 50-fold.

[0477] In another aspect, treatment of cancer results in a reduction in the number of metastatic lesions in other tissues or organs distant from the primary tumor site. Preferably, after treatment, the number of metastatic lesions is reduced by at least 5% compared to its number prior to treatment; more preferably, the number of metastatic lesions is reduced by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; even more preferably, by at least 50%; most preferably, by more than 75%. The number of metastatic lesions can be measured by any reproducible measuring means. In a preferred aspect, the number of metastatic lesions can be measured by counting metastatic lesions visible to the naked eye or at a specified magnification. In a preferred aspect, the specified magnification is 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or 50-fold.

[0478] In another aspect, treatment of cancer results in an increase in the average survival time of the treated population compared to a population that received only the carrier. Preferably, the average survival time increases by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; most preferably, by more than 120 days. The increase in the average survival time of the population can be measured by any reproducible means. In a preferred aspect, the increase in the average survival time of the population can be measured, for example, by calculating the average length of survival for the population after the start of treatment with a compound of formula (I). In another preferred aspect, the increase in the average survival time of the population can also be measured, for example, by calculating the average length of survival for the population after completion of the first treatment with a compound of formula (I).

[0479] In another aspect, treatment of cancer results in an increase in the average survival time of the treated population compared to an untreated population. Preferably, the average survival time increases by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; most preferably, by more than 120 days. The increase in the average survival time of the population can be measured by any reproducible means. In a preferred aspect, the increase in the average survival time of the population can be measured, for example, by calculating the average length of survival for the population after the start of treatment with a compound of formula (I). In another preferred aspect, the increase in the average survival time of the population can also be measured, for example, by calculating the average length of survival for the population after completion of the first treatment with a compound of formula (I).

[0480] In another aspect, treatment of cancer results in a decrease in tumor growth rate. Preferably, after treatment, the tumor growth rate decreases by at least 5% compared to the pre-treatment value; more preferably, the tumor growth rate decreases by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 50%; most preferably, by at least 75%. The tumor growth rate can be measured by any reproducible measurement means. In a preferred aspect, the tumor growth rate is measured by the change in tumor diameter per unit time.

[0481] In another aspect, treatment of cancer results in a reduction in tumor regrowth. Preferably, after treatment, tumor regrowth is less than 5%; more preferably, tumor regrowth is less than 10%; more preferably, less than 20%; more preferably, less than 30%; more preferably, less than 40%; more preferably, less than 50%; even more preferably, less than 50%; most preferably, less than 75%. Tumor regrowth can be measured by any reproducible means of measurement. In a preferred aspect, tumor regrowth is measured, for example, by measuring the increase in tumor diameter after tumor shrinkage prior to treatment following treatment. In another preferred aspect, a reduction in tumor regrowth is indicated by the inability of the tumor to recur after treatment has been stopped.

[0482] Once generated, the compounds designed, selected, and / or optimized by the methods described above can be characterized using a variety of assays known to those of skill in the art to determine whether the compound has biological activity. For example, the molecule can be characterized by conventional assays including, but not limited to, the assays described below to determine whether the molecule has predicted activity, binding activity, and / or binding specificity.

[0483] Furthermore, high-throughput screening can be used to accelerate the analysis using such assays. As a result, it may be possible to rapidly screen the molecules described herein for activity using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay technologies including, but not limited to, those described below.

[0484] A variety of in vitro or in vivo biological assays can be suitable for detecting the effects of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, receptor gene assays, in vitro cell viability assays, and the assays described herein.

[0485] The biological activity of the compounds of the present disclosure can be determined using a binding assay or a patch clamp assay. The binding assay can be for Sigma-1, Sigma-2, or 5-HT 2A and the patch clamp assay can be for hERG.

[0486] Results showing inhibition (or stimulation for assays run under basal conditions) of more than 50% are considered to represent a significant effect of the test compound. 50% is the most common cut-off value for further investigation (determination of IC 50 or EC 50 values from a concentration-response curve) recommended by the inventors. Results showing inhibition (or stimulation) between 25% and 50% indicate a weak to moderate effect (in most assays, these are within the range where more experimental variability can occur and should be confirmed by further testing). Results showing inhibition (or stimulation) of less than 25% are not considered significant and are mainly due to fluctuations in the signal around the control level. Low to moderate negative values have no real meaning and are due to fluctuations in the signal around the control level. High negative values (≥50%) sometimes obtained with high concentrations of the test compound are generally due to non-specific effects of the test compound in the assay. Very rarely, these values can suggest an allosteric effect of the test compound.

[0487] The toxicity of the compounds of the present disclosure can be determined using a toxicity assessment assay. The toxicity assessment assay can be performed on the vero-E6 cell line.

[0488] The toxicity assessment assay can be performed according to the following procedure. On day 1, cells can be seeded in a 96-well plate at 10,000 cells / well of Vero E6, P40. The growth conditions can include DMEM high glucose medium. On day 2, the compound can be diluted in a mixture of 50% DMSO and 50% growth medium. A 10 mM concentration can be used for PB28 (10 mg vial from Tocris, 1-cyclohexyl-4-(3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl)piperazine dihydrochloride, see Gordon et al. Nature 2020, 583, 4459-468). Other compounds can be prepared as 2 mM stock solutions. Cells can be treated in triplicate at 50 μM to 0.39 μM by two-fold serial dilution. The control can be designed to contain the same concentration of DMSO as each test article. On day 5, the cells can be fixed with formalin and stained with Hoetsch33342 72 hours after treatment. The cells can be imaged using a Cell Insight CX7 high content screening microscope. The cell count and nuclear parameters can be evaluated using an internal cytotoxicity test protocol.

[0489] The biological activity of the compounds of the present disclosure against SARS-CoV-2 can be determined using an antiviral evaluation assay. The antiviral evaluation assay can be performed on SARS-CoV-2-infected cells.

[0490] The antiviral evaluation assay can be performed according to the following procedure. On day 1, cells can be seeded in a 96-well plate. The growth conditions can include DMEM high glucose medium (Dutscher L0104-500, lot MS008A). On day 2, the compound can be diluted in a mixture of 50% DMSO and 50% growth medium. The compound can first be diluted in pure DMSO and then diluted with the medium. The stock compound was prepared at 10 mM for PB28 (10 mg vial from Tocris). Other compounds can be prepared as 2 mM stock solutions.

Example

[0491] For illustrative purposes, the neutral compounds of formula (I) are synthesized and tested in the examples. It is understood that the neutral compounds of formula (I) can be converted to the corresponding pharmaceutically acceptable salts of the compounds using routine techniques in the art (e.g., by saponification of an ester to the carboxylate salt, or by hydrolyzing an amide to form the corresponding carboxylic acid and then converting the carboxylic acid to a carboxylate salt).

[0492] Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz as indicated; chemical shifts (δ) are reported in parts per million (ppm). Spectra were recorded using a Bruker or Varian instrument with 8, 16, or 32 scans.

[0493] UPLC-MS chromatograms and spectra were recorded using a Waters Acquity instrument with a C-18 column such as Xtimate C18 100×2.1 mm, 1.7 μm for 2 minutes of chromatography, unless otherwise indicated. Detection methods were diode array (DAD), photodiode array (PDA), or evaporative light scattering (ELSD) and positive ion electrospray ionization. The MS range was 100 - 1000 Da. The solvents were a gradient of water and acetonitrile both containing a modifier (typically 0.01 - 0.1%), e.g., formic acid or ammonium carbonate.

[0494] Abbreviations:

[0495]

Table 2-1

[0496]

Table 2-2

[0497] General synthetic route 1:

[0498]

Chemical formula

[0499] Step 1: Synthesis of 3-hydroxy-3-methylbutanenitrile 1-Chloro-2-methyl-2-propanol (16.42 mL, 160 mmol) was added to a mixture of EtOH (320 mL) and water (55 mL). Next, sodium cyanide (9.41 g, 192 mmol) was added and the reaction mixture was stirred under reflux (110 °C) for 3 h. Next, the reaction mixture was cooled to room temperature and evaporated in vacuo. The crude product was dissolved in 300 mL of water and 300 mL of EtOAc. The aqueous layer was washed with EtOAc (2 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated in vacuo. 3-Hydroxy-3-methylbutanenitrile was obtained in 84% yield.

[0500] Step 2: Synthesis of 4-amino-2-methylbutan-2-ol 3-Hydroxy-3-methylbutanenitrile (13.3 g, 134 mmol) was dissolved in anhydrous THF (200 mL) and stirred at 0 °C. Next, borane dimethyl sulfide complex (38.2 mL, 402 mmol) was added slowly (over about 15 min) and the reaction mixture was stirred at room temperature for about 30 min. Next, the reaction mixture was stirred under reflux conditions (87 °C). The peak related to the starting material could not be detected by 1 1H NMR after about 2 h. The reaction mixture was cooled to 0 °C and quenched with MeOH (added slowly, gas evolution, about 60 mL). Next, the reaction mixture was evaporated in vacuo. The reaction mixture was purified by normal phase chromatography, starting with 1% MeOH in DCM, changing to 10% MeOH in DCM in 5 min, staying at 10% MeOH in DCM for 5 min, and finally switching to DCM / MeOH / 7N NH3 (5:4:1, v / v / v) in MeOH in about 20 min. The fractions corresponding to the product were combined and pooled and evaporated in vacuo. 4-Amino-2-methylbutan-2-ol was obtained in 88% yield.

[0501] Step 3: Synthesis of 4-((3-bromobenzyl)amino)-2-methylbutan-2-ol 4-Amino-2-methylbutan-2-ol (51.3 mg, 0.497 mmol) was dissolved in MeOH (2.5 mL). Next, 3-bromobenzaldehyde (58.3 μL, 0.498 mmol) was added and the reaction mixture was stirred at room temperature. After 1 hour, sodium triacetoxyborohydride (STAB, 211 mg, 0.995 mmol) was added and the resulting mixture was stirred at room temperature. After 20 minutes, LCMS. Therefore, glacial acetic acid (28.7 μL, 0.497 mmol) and additional STAB (52.7 mg, 0.249 mmol) were added. After about 30 minutes, additional STAB (52.7 mg, 0.249 mmol) was added. After about 10 minutes, the reaction mixture was directly subjected to reverse-phase chromatography. The fractions corresponding to the product were combined and pooled, and evaporated in vacuo. 4-((3-Bromobenzyl)amino)-2-methylbutan-2-ol was obtained in 76% yield.

[0502] Step 4: Synthesis of benzyl 8-bromo-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate 4-((3-Bromobenzyl)amino)-2-methylbutan-2-ol formate (49.0 mg, 0.154 mmol) was cooled to 0 °C. Next, cold (0 °C) sulfuric acid (85%, v / v) (2 mL, 37.5 mmol) was added and the reaction mixture was stirred at 0 °C. The reaction mixture was stirred at room temperature until completion as determined by LCMS. Next, about 10 mL of crushed ice was added to the reaction mixture and the resulting mixture was slowly basified with 4N NaOH until the pH became basic (a white precipitate formed). The mixture was washed with DCM (3 × 25 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated in vacuo. LCMS indicated good purity.

[0503] Step 5: Synthesis of benzyl 8-bromo-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate 8-Bromo-5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine (22.9 mg, 0.090 mmol) was dissolved in dichloromethane (1 mL) at room temperature. Next, benzyl chloroformate (0.017 ml, 0.117 mmol) and DIPEA (0.022 mL, 0.126 mmol) were added, and the reaction mixture was stirred at room temperature until completion as determined by LCMS. The reaction mixture was diluted with DCM (9 mL), and the resulting solution was washed with saturated aqueous NaHCO3 (10 mL) and 10% aqueous KHSO4 (10 mL), dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified by reverse-phase chromatography. The fractions corresponding to the product were combined and pooled and evaporated in vacuo.

[0504] Step 6: Coupling Reaction General Procedure for Suzuki Coupling To an 8 mL vial were added aryl bromide (1 equiv), boronic acid (1.4 equiv), potassium carbonate (2.0 equiv), and Pd(dppf)Cl2 (5 mol%, 0.027 mmol). Next, toluene (0.5 mL), ethanol (0.250 mL), and water (0.250 mL) were added, the vial was flushed with argon (for 30 seconds), capped, and the reaction was stirred at 120 °C. The reaction was carried out until completion as determined by LCMS. The reaction mixture was cooled to room temperature, the reaction mixture was diluted with EtOAc (10 mL), and the resulting solution was washed with water (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified by normal-phase flash chromatography (0 - 30% EtOAc in heptane). The fractions corresponding to the product were combined and pooled and evaporated in vacuo to give the product.

[0505] General Procedure for Backward Coupling Argon was flowed through a 40 mL vial containing sodium tert-butoxide (1.2 equiv), Pd2(dba)3 (20 mol%), 2-dicyclohexylphosphino-2’,6’-diisopropoxybiphenyl (RuPhos) (5 mol%) and 1-cyclopentylpiperazine (1.2 equiv) for about 5 minutes. Next, toluene (22.11 ml) was added to aryl bromide (1 equiv), and the resulting solution was first degassed with argon for about 30 seconds and then added to the vial. Argon was flowed through the vial for about 1 minute, capped, and the reaction mixture was stirred at 120 °C. The reaction was carried out until completion as determined by LCMS. The reaction mixture was cooled to room temperature, diluted with DCM (200 mL), and the resulting solution was washed with saturated aqueous NaHCO3 (200 mL). The aqueous layer was washed with DCM (150 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified by normal phase chromatography (0 - 50% EtOAc in heptane). The fractions corresponding to the product were combined and pooled, and evaporation in vacuo gave the product.

[0506] Step 7: Deprotection of the protecting group To the protected building block, anisole (3 equiv) and HBr (33 wt% in acetic acid) (about 20 equiv) were added. The reaction was swirled and the viscous mixture was allowed to stand at room temperature for 1 hour - 3 hours with occasional swirling. The reaction was carried out until completion as determined by LCMS. Et2O (about 10 volume equiv) was added and mixed vigorously. The mixture was filtered off and the residue was washed with Et2O (2 x about 5 volume equiv). The residue was partitioned between EtOAc (about 10 volume equiv) and 1 M aqueous NaOH (about 10 volume equiv). The phases were separated and the aqueous phase was extracted with EtOAc (about 10 volume equiv). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo to give the product.

[0507] Step 8: N-atom functionalization The N-atom of the compound from Step 7 (referred to herein as "amine") was functionalized by one of the procedures described below.

[0508] General procedure for coupling of amines to acids: To the acid (0.125 mmol, 1.25 equiv), HATU (0.044 g, 0.115 mmol, 1.15 equiv; stock solution in DMAc (0.5 mL)) and DIPEA (0.040 mL, 0.230 mmol, ca. 2.3 equiv) were added and the reaction mixture was shaken for 30 min. Then, the amine (0.1 mmol, 1 equiv; stock solution / suspension in DMAc (0.5 mL)) was added and the reaction mixture was shaken overnight at room temperature.

[0509] General procedure for coupling of amines to sulfonyl chlorides, acid chlorides, isocyanates and chloroformates (referred to herein as "electrophiles"): To the electrophile (0.125 mmol, 1.25 equiv), DMAc (0.5 mL) * , DIPEA (0.040 mL, 0.230 mmol * , ca. 2.3 equiv) and the amine (0.1 mmol, 1 equiv; stock solution in DMAc (0.5 mL)) were added and the reaction mixture was shaken overnight at room temperature. (For aliphatic sulfonyl chlorides, pyridine (0.5 mL, 6.18 mmol) was added instead of DMAc and DIPEA.)

[0510] General procedure for coupling of amines to alcohols: Bis(p-nitrophenyl) carbonate (0.033 g, 0.110 mmol) (1.1 equiv), the alcohol (0.125 mmol, 1.25 equiv) and NaH (60% dispersion, 8.00 mg, 0.200 mmol, 2 equiv) were dissolved in DMAc (0.5 mL) and the reaction mixture was shaken for 30 min. Then, the amine (0.1 mmol, 1 equiv, stock solution in DMAc (0.5 mL)) was added and the reaction mixture was shaken overnight at room temperature.

[0511] General procedure for coupling of amines to aldehydes or ketones: To aldehyde / ketone (0.150 mmol, 1.5 equiv) and amine (0.1 mmol, 1 equiv, stock solution / suspension in 0.5 mL of DMAc), zinc chloride (0.027 g, 0.200 mmol, 2 equiv) and STAB (0.064 g, 0.300 mmol, 3 equiv, both in one stock suspension in 0.5 mL of DMAc) were added, and the reaction mixture was shaken overnight at room temperature.

[0512] General procedure for the coupling of an amine with an alkyl halide: To alkyl halide (0.110 mmol, 1.1 equiv) and amine (0.1 mmol, 1 equiv, stock solution / suspension in 0.5 mL of DMAc), K2CO3 (0.035 g, 0.250 mmol, ca. 2.5 equiv) and DMAc (0.5 mL) were added, and the reaction mixture was shaken overnight at 50 °C.

[0513] General procedure for purification: The reaction mixture was analyzed by LCMS. For reductive amination, 35% aqueous NH3 (0.2 mL, ca. 1.75 mmol) was added. All reaction mixtures were filtered (0.45 μm) and purified by basic preparative HPLC-MS. The product fractions were concentrated, combined with acetonitrile in a vial, water was added, and the product was lyophilized. General synthetic route 2:

[0514]

Chemical formula

[0515] Step 1: Synthesis of benzyl 7-bromo-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate 7-Bromo-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (2 g, 7.23 mmol; product ID: ADVH0430AD62 from Millipore Sigma) was dissolved in dichloromethane (26 mL) and cooled to 0 °C. DIPEA (2.78 mL, 15.91 mmol) was added followed by benzyl chloroformate (1.135 mL, 7.95 mmol), and the reaction mixture was stirred at room temperature. The reaction was stopped after about 4 hours. The reaction mixture was evaporated in vacuo. The crude residue was dissolved in EtOAc (50 mL), and the resulting solution was washed with 0.5 N KHSO4 (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (30 mL), dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified by normal-phase flash chromatography (0 - 35% EtOAc in heptane). The fractions corresponding to the product were pooled and evaporated in vacuo to give a colorless oil.

[0516] Step 2: Coupling reaction General procedure for Suzuki coupling To an 8 mL vial were added aryl bromide (1 equiv), boronic acid (1.4 equiv), potassium carbonate (2.0 equiv), and Pd(dppf)Cl2 (5 mol%, 0.027 mmol). Next, toluene (0.5 mL), ethanol (0.250 mL), and water (0.250 mL) were added, the vial was flushed with argon (for 30 seconds), capped, and the reaction was stirred at 120 °C. The reaction was carried out until completion as determined by LCMS. The reaction mixture was cooled to room temperature, the reaction mixture was diluted with EtOAc (10 mL), and the resulting solution was washed with water (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified by normal-phase flash chromatography (0 - 30% EtOAc in heptane). The fractions corresponding to the product were pooled and evaporated in vacuo to give the product.

[0517] General procedure for backward coupling Argon was flowed through a 40 mL vial containing sodium tert-butoxide (1.2 equiv), Pd2(dba)3 (20 mol%), 2-dicyclohexylphosphino-2’,6’-diisopropoxybiphenyl (RuPhos) (5 mol%), and 1-cyclopentylpiperazine (1.2 equiv) for about 5 minutes. Next, toluene (22.11 ml) was added to the aryl bromide (1 equiv), and the resulting solution was first degassed with argon for about 30 seconds and then added to the vial. Argon was flowed through the vial for about 1 minute, capped, and the reaction mixture was stirred at 120 °C. The reaction was carried out until completion as determined by LCMS. The reaction mixture was cooled to room temperature, diluted with DCM (200 mL), and the resulting solution was washed with saturated aqueous NaHCO3 (200 mL). The aqueous layer was washed with DCM (150 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified by normal phase chromatography (0 - 50% EtOAc in heptane). The fractions corresponding to the product were combined and pooled, and evaporation in vacuo gave the product.

[0518] Step 3: Deprotection of the protecting group To the protected building block, anisole (3 equiv) and HBr (33 wt% in acetic acid) (about 20 equiv) were added. The reaction was swirled and the viscous mixture was allowed to stand at room temperature for 1 hour - 3 hours with occasional swirling. The reaction was carried out until completion as determined by LCMS. Et2O (about 10 volume equiv) was added and mixed vigorously. The mixture was filtered off and the residue was washed with Et2O (2 × about 5 volume equiv). The residue was partitioned between EtOAc (about 10 volume equiv) and 1 M aqueous NaOH (about 10 volume equiv). The phases were separated and the aqueous phase was extracted with EtOAc (about 10 volume equiv). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo to give the product.

[0519] Step 4: N-atom functionalization The N-atom of the compound from Step 3 (referred to herein as “amine”) was functionalized by one of the procedures described below.

[0520] General procedure for the coupling of amines to acids: To the acid (0.125 mmol, 1.25 eq), HATU (0.044 g, 0.115 mmol, 1.15 eq; stock solution in DMAc (0.5 mL)) and DIPEA (0.040 mL, 0.230 mmol, ca. 2.3 eq) were added and the reaction was shaken for 30 min. Then, the amine (0.1 mmol, 1 eq; stock solution / suspension in DMAc (0.5 mL)) was added and the reaction was shaken overnight at room temperature.

[0521] General procedure for the coupling of amines to sulfonyl chlorides, acid chlorides, isocyanates and chloroformates (referred to herein as "electrophiles"): To the electrophile (0.125 mmol, 1.25 eq), DMAc (0.5 mL) * , DIPEA (0.040 mL, 0.230 mmol * , ca. 2.3 eq) and the amine (0.1 mmol, 1 eq; stock solution in DMAc (0.5 mL)) were added and the reaction was shaken overnight at room temperature. (For aliphatic sulfonyl chlorides, pyridine (0.5 mL, 6.18 mmol) was added instead of DMAc and DIPEA).

[0522] General procedure for the coupling of amines to alcohols: Bis(p-nitrophenyl) carbonate (0.033 g, 0.110 mmol) (1.1 eq), the alcohol (0.125 mmol, 1.25 eq) and NaH (60% dispersion, 8.00 mg, 0.200 mmol, 2 eq) were dissolved in DMAc (0.5 mL) and the reaction was shaken for 30 min. Then, the amine (0.1 mmol, 1 eq, stock solution in DMAc (0.5 mL)) was added and the reaction was shaken overnight at room temperature.

[0523] General procedure for the coupling of amines to aldehydes or ketones: To aldehyde / ketone (0.150 mmol, 1.5 equiv) and amine (0.1 mmol, 1 equiv, stock solution / suspension in 0.5 mL of DMAc), zinc chloride (0.027 g, 0.200 mmol, 2 equiv) and STAB (0.064 g, 0.300 mmol, 3 equiv, both in one stock suspension in 0.5 mL of DMAc) were added, and the reaction mixture was shaken overnight at room temperature.

[0524] General procedure for the coupling of an amine with an alkyl halide: To alkyl halide (0.110 mmol, 1.1 equiv) and amine (0.1 mmol, 1 equiv, stock solution / suspension in 0.5 mL of DMAc), K2CO3 (0.035 g, 0.250 mmol, ca. 2.5 equiv) and DMAc (0.5 mL) were added, and the reaction mixture was shaken overnight at 50 °C.

[0525] General procedure for purification: The reaction mixture was analyzed by LCMS. For reductive amination, 35% aqueous NH3 (0.2 mL, ca. 1.75 mmol) was added. All reaction mixtures were filtered (0.45 μm) and purified by basic preparative HPLC-MS. The product fractions were concentrated, combined with acetonitrile in a vial, water was added, and the product was lyophilized.

[0526] [Example 1] Synthesis of benzyl 4,4-dimethyl-7-(4-propylpiperazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Compound 2)

[0527] [Chemical formula] Step 1: Synthesis of benzyl 7-bromo-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0528] [Chemical formula]

[0529] Benzyl 7-bromo-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate was prepared according to Step 1 of General Procedure 2. Benzyl 7-bromo-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate was isolated in 95% yield.

[0530] Step 2: Synthesis of benzyl 4,4-dimethyl-7-(4-propylpiperazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate Benzyl 7-bromo-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate was reacted with 1-propylpiperazine dihydrobromide in toluene in the presence of Pd(OAc)2, JohnPhos, and t-BuONa at 80 °C. Benzyl 4,4-dimethyl-7-(4-propylpiperazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate was produced in 30% yield. M / Z+1 = 422.32

[0531] [Example 2] Synthesis of benzyl 7-(4-(3-methoxy-3-oxopropyl)piperazin-1-yl)-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (Compound 3)

[0532] [Chemical formula]

[0533] Compound 3 was synthesized by General Synthetic Route 2 using the general procedure for backward coupling and the general procedures for sulfonyl chloride, acid chloride, isocyanate, and chloroformate. UPLC-MS: M / Z+1 = 466.09.

[0534] [Example 3] Synthesis of benzyl 5,5-dimethyl-8-(4-propylpiperazin-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (Compound 8)

[0535]

Chem.

[0536] Compound 8 was synthesized according to General Synthetic Route 1 using the general procedures for backward coupling and the general procedures for sulfonyl chloride, acid chloride, isocyanate, and chloroformate. UPLC-MS: M / Z+1 = 436.4.

[0537] [Example 4] Synthesis of Benzyl 8-(4-(3-methoxy-3-oxopropyl)piperazin-1-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (Compound 9)

[0538]

Chem.

[0539] Compound 9 was synthesized according to General Synthetic Route 1 using the general procedures for backward coupling and the general procedures for sulfonyl chloride, acid chloride, isocyanate, and chloroformate. UPLC-MS: M / Z+1 = 480.4.

[0540] [Example 5] Synthesis of 2-Cyclopentyl-5,5-dimethyl-8-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine (Compound 10)

[0541]

Chem.

[0542] Compound 10 was synthesized according to General Synthetic Route 1 using the general procedures for backward coupling and the general procedures for aldehyde / ketone. UPLC-MS: M / Z+1 = 388.4.

[0543] [Example 6] Synthesis of 5,5-dimethyl-2-propyl-8-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine (Compound 12)

[0544] [Chemical formula]

[0545] Compound 12 was synthesized by General Synthetic Route 1 using the general procedures for Suzuki coupling and aldehyde / ketone. UPLC-MS: M / Z+1 = 362.4.

[0546] [Example 7] Synthesis of 2-cyclohexyl-5,5-dimethyl-8-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine (Compound 32)

[0547] [Chemical formula]

[0548] Compound 32 was synthesized by General Synthetic Route 1 using the general procedures for Suzuki coupling and aldehyde / ketone.

[0549] [Example 8] Synthesis of 2-((3-chlorophenyl)sulfonyl)-7-(4-cyclopentylpiperazin-1-yl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline (Compound 33)

[0550] [Chemical formula]

[0551] Compound 33 was synthesized according to General Synthetic Route 2 using the general procedures for backward coupling and the general procedures for sulfonyl chloride, acid chloride, isocyanate, and chloroformate.

[0552] [Example 9] (3-Chloro-5-fluorophenyl)(7-(4-cyclopentylpiperazin-1-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (Compound 38) Synthesis

[0553] [Chemical Structure]

[0554] Compound 38 was synthesized according to General Synthetic Route 2 using the general procedures for backward coupling and the general procedures for sulfonyl chloride, acid chloride, isocyanate, and chloroformate.

[0555] [Example 10] Cyclohexyl 7-(4-cyclopentylpiperazin-1-yl)-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (Compound 43) Synthesis

[0556] [Chemical Structure]

[0557] Compound 43 was synthesized according to General Synthetic Route 2 using the general procedures for backward coupling and the general procedures for sulfonyl chloride, acid chloride, isocyanate, and chloroformate.

[0558] [Example 11] Isopropyl 7-(4-cyclopentylpiperazin-1-yl)-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (Compound 45) Synthesis

[0559] [Chemical formula]

[0560] Compound 45 was synthesized according to General Synthetic Route 2 using the general procedures for backward coupling and the general procedures for sulfonyl chloride, acid chloride, isocyanate, and chloroformate.

[0561] [Example 12] Synthesis of cyclopentyl(8-(4-cyclopentylpiperazin-1-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)methanone (Compound 73)

[0562] [Chemical formula]

[0563] Compound 73 was synthesized according to General Synthetic Route 1 using the general procedures for backward coupling and the general procedures for sulfonyl chloride, acid chloride, isocyanate, and chloroformate.

[0564] [Example 13] Synthesis of isopropyl 8-(4-cyclopentylpiperazin-1-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (Compound 79)

[0565] [Chemical formula]

[0566] Compound 79 was synthesized according to General Synthetic Route 1 using the general procedures for backward coupling and the general procedures for sulfonyl chloride, acid chloride, isocyanate, and chloroformate.

[0567] [Example 14] Synthesis of 4-(1-(2-((3-chlorophenyl)sulfonyl)-5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)piperidin-4-yl)morpholine (Compound 80)

[0568] [Chemical formula]

[0569] Compound 80 was synthesized according to General Synthetic Route 1 using the general procedure for backward coupling and the general procedures for sulfonyl chloride, acid chloride, isocyanate, and chloroformate.

[0570] [Example 15] Synthesis of benzod[1,3]dioxol-4-yl(5,5-dimethyl-8-(4-morpholinopiperidin-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)methanone (Compound 84)

[0571] [Chemical formula]

[0572] Compound 84 was synthesized according to General Synthetic Route 1 using the general procedure for backward coupling and the general procedure for acid.

[0573] [Example 16] Synthesis of cyclopentyl(5,5-dimethyl-8-(4-morpholinopiperidin-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)methanone (Compound 85)

[0574] [Chemical formula]

[0575] Compound 85 was synthesized according to the general synthetic route 1 using the general procedures for backward coupling and the general procedures for sulfonyl chloride, acid chloride, isocyanate, and chloroformate.

[0576] [Example 17] Synthesis of cyclohexyl(5,5-dimethyl-8-(4-morpholinopiperidin-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)methanone (Compound 86)

[0577] [Chemical formula]

[0578] Compound 86 was synthesized according to the general synthetic route 1 using the general procedures for backward coupling and the general procedures for sulfonyl chloride, acid chloride, isocyanate, and chloroformate.

[0579] [Example 18] Synthesis of 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(8-(2,6-dimethylpyridin-4-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)propan-1-one (Compound 111)

[0580] [Chemical formula]

[0581] Compound 111 was synthesized according to the general synthetic route 1 using the general procedures for Suzuki coupling and the general procedures for alkyl halide.

[0582] [Example 19] Synthesis of 3-(8-(2,6-dimethylpyridin-4-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-1(4-methylpiperidin-1-yl)propan-1-one (Compound 131)

[0583] [Chemical]

[0584] Compound 131 was synthesized according to General Synthetic Route 1 using the general procedures for Suzuki coupling and alkyl halides.

[0585] [Example 20] Binding assay for Sigma-1 and Sigma-2 An assay for determining Sigma-1 and Sigma-2 binding values was performed according to Ganapathy, M.E. et al. (1999), J. Pharmacol. Exp. Ther., 289 : 251-260.

[0586] [Table 3]

[0587] Results showing inhibition (or stimulation for assays run under basal conditions) greater than 50% are considered to represent a significant effect of the test compound. 50% is the most common cut-off value for further investigation (determination of IC 50 or EC 50 values from concentration-response curves) recommended by the inventors. Results showing inhibition (or stimulation) between 25% and 50% indicate weak to moderate effects (in most assays these are within the range where more experimental variability can occur and should be confirmed by further testing). Results showing inhibition (or stimulation) less than 25% are not considered significant and are mainly due to fluctuations in the signal around the control level. Low to moderate negative values have no true meaning and are due to fluctuations in the signal around the control level. High negative values (≥50%) sometimes obtained with high concentrations of the test compound are generally due to non-specific effects of the test compound in the assay. Very rarely, these values may suggest an allosteric effect of the test compound.

[0588] The measured K of the compounds of the present disclosure i values are shown in Table A below (A means greater than 0.1 nM and less than or equal to 5 nM; B means greater than 5 and less than or equal to 50; C means greater than 50 and less than or equal to 100 nM; D means greater than 100 nM and less than or equal to 500 nM; E means greater than 500 nM).

[0589] [Table 4]

[0590] [Example 21] 5-HT 2A assay to determine binding 5-HT 2A The assay to determine the 5-HT binding value was performed according to Bonhaus, D.W. et al. (1995), Brit. J. Pharmacol., 115: 622-628; Schwinn, D.A. et al. (1995), J. Pharmacol. Exp. Ther., 272: 134-142; and Vicentic, A. et al. (2002), J. Pharmacol. Exp. Ther., 302: 58-65; Bylund DB et al. (1994), Pharmacol.Rev. 46: 121-136. Each of these is incorporated herein by reference in its entirety.

[0591] [Table 5]

[0592] [Table 6]

[0593] Results showing more than 50% inhibition (or stimulation for assays run under basal conditions) are considered to represent a significant effect of the test compound. 50% is the IC 50 or EC 50It is the most common cut-off value for (determination of values). Results showing inhibition (or stimulation) between 25% and 50% indicate weak to moderate effects (in most assays, these are within the range where more experimental variation can occur and should be confirmed by further tests). Results showing inhibition (or stimulation) less than 25% are not considered significant and are mainly due to fluctuations in the signal around the control level. Low to moderate negative values have no real meaning and are due to fluctuations in the signal around the control level. High negative values (≥50%) sometimes obtained with high concentrations of the test compound are generally due to non-specific effects of the test compound in the assay. Very rarely, these values may suggest an allosteric effect of the test compound.

[0594] The measured IC of the compounds of the present disclosure 50 values are shown in Table B below.

[0595] [Table 7]

[0596] [Example 22] D2S human dopamine An assay for determining dopamine D2S receptor binding values was carried out according to Eurofins Cerep protocol item 1322, and the results are presented in Table C below. The parameters used in the assay are described below. The compounds in Table C do not bind to the dopamine D2S receptor. In contrast, typical antipsychotics block dopamine receptors (Keefe, et al., J Clin Psychiatry. 2018;79(3):17m11753).

[0597] [Table 8]

[0598] [Table 9]

[0599] [Example 23] α1A(h) (agonist effect) of the compound An assay for determining the agonist effect on α1A(h) was carried out according to the procedure described in Example 21, and the results are shown in Table D below. The compounds in Table D do not have an agonist effect on α1A(h).

[0600] [Table 10]

[0601] [Example 24] α1A(h) (antagonist effect) An assay for determining the antagonist effect on α1A(h) was carried out according to the procedure described in Example 21, and the results are shown in Table E below. Compounds 38 and 111 show a small antagonist effect. For other compounds, no antagonist effect was observed.

[0602] [Table 11]

[0603] [Example 25] 5HT 2A (agonist effect) 5HT 2A An assay for determining the agonist effect on 5HT was carried out according to the procedure described in Example 21, and the results are shown in Table F below. The compounds in Table F do not have an agonist effect on 5HT 2A at 1 μM and 100 nM.

[0604] [Table 12]

[0605] [Example 26] 5HT 2A (antagonist effect) 5HT 2AAn assay for determining the antagonist effect against [substance] was carried out according to the procedure described in Example 21, and the results are shown in Table G below. The compounds in Table G do not have an agonist effect on 5HT 2A at 1 μM and 100 nM.

[0606] [Table 13]

[0607] [Example 27] An assay for determining hERG inhibition The measured K i values of the compounds of the present disclosure are shown in Table H below. These compounds do not significantly inhibit hERG. Therefore, these compounds are not expected to cause QT interval prolongation when administered to humans.

[0608] [Table 14]

[0609] [Example 28] Toxicity evaluation of the compound against the vero-E6 cell line The test protocol is described below.

[0610] Day 1: Cells were seeded into 96-well plates at 10,000 cells / well of Vero E6, P40. The growth conditions included DMEM high-glucose medium.

[0611] Day 2: The compound was diluted in a mixture of 50% DMSO and 50% growth medium. A 10 mM concentration was used for PB28 (1-cyclohexyl-4-(3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl)piperazine dihydrochloride, from a 10 mg vial from Tocris, see Gordon et al. Nature 2020, 583, 4459-468). Other compounds were prepared as 2 mM concentration stock solutions. Cells were treated in triplicate at 50 μM to 0.37 μM by two-fold serial dilution. Controls were designed to contain DMSO at the same concentration as each test article.

[0612] Day 5: 72 hours after treatment, cells were fixed with formalin and stained with Hoetsch33342. Cells were imaged using a Cell Insight CX7 high-content screening microscope. Cell counts and nuclear parameters were evaluated using an in-house cytotoxicity test protocol.

[0613] Figure 1 shows the cell counts after exposing cells to the above conditions, indicating that Compound 2 and Compound 10 are not cytotoxic to the cells.

[0614] [Example 29] Antiviral evaluation of compounds against Vero-E6 cell line infected with SARS-CoV-2 The test protocol is described below and illustrated in Figure 3. The replication kinetics of untreated SARS-CoV-2 over time are shown in Figure 2.

[0615] Day 1: Cells were seeded in 96-well plates with Vero E6, P38. The growth conditions included DMEM high glucose medium (Dutscher L0104-500, lot MS008A).

[0616] Day 2: The compound was diluted in a mixture of 50% DMSO and 50% growth medium. The compound was first diluted in pure DMSO and then diluted with the medium. Stock compounds were prepared at 10 mM for PB28 (10 mg vial from Tocris), and the other compounds were prepared as 2 mM stock solutions.

[0617] Figure 4 shows virus production in SARS-CoV-2-infected cells with a multiplicity of infection (MOI) of 10 -1 treated with PB28, MIN-S006, Compound 2, Compound 10, MIN101, and DMSO control.

[0618] Figure 5 shows virus production in SARS-CoV-2-infected cells with a multiplicity of infection (MOI) of 10 -3 treated with PB28, MIN-S006, Compound 2, Compound 10, MIN101, and DMSO control.

[0619] Equivalents Details of one or more embodiments of the present disclosure are set forth in the accompanying description above. Any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, but the preferred methods and materials are described herein. Other features, objects, and advantages of the present disclosure will be apparent from the description and claims. In the specification and the appended claims, the singular forms include the plural unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference.

[0620] The foregoing description is presented for purposes of illustration only and is not intended to limit the present disclosure to the precise form disclosed, but rather is limited by the appended claims.

[0621] The present invention is further described with reference to the following clauses: A compound of formula (I) as defined above, or a prodrug, solvate or pharmaceutically acceptable salt thereof, for use in a method of treating or preventing a viral infection of interest or a disease resulting from a viral infection. B. A compound for use as defined in clause A, wherein the viral infection is caused by a coronavirus, herpes simplex virus, human immunodeficiency virus, influenza, or human papillomavirus. C. A compound for use as defined in clause B, wherein the coronavirus is SARS-CoV-2. D. A compound for use as defined in any one of clauses A to C, wherein the disease resulting from the viral infection is severe acute respiratory syndrome or COVID-19. E. A compound of formula (I) as defined above, or a prodrug, solvate or pharmaceutically acceptable salt thereof, for use in a method of treating Alzheimer's disease. F. A compound of formula (I) as defined above, or a prodrug, solvate or pharmaceutically acceptable salt thereof, for use in a method of treating a disease or a symptom of a disease that is a disease or cognitive impairment in anxiety, depression, mood disorder, schizophrenia, drug intoxication, drug addiction, sharp pain, dystonia, cerebrovascular disease, epilepsy, dementia, Parkinson's syndrome, attention deficit disorder, irritable bowel syndrome, irritable colon, spastic colon, mucous colitis, enteritis, diverticulitis, dysentery, hypertension, arrhythmia, angina, amyotrophic lateral sclerosis (ALS), Huntington's disease, stroke, retinal degeneration, or a neuropsychiatric disorder. G. A compound of formula (I) as defined above, or a prodrug, solvate or pharmaceutically acceptable salt thereof, for use in a method of treating or preventing pain in a subject in need of treatment. H. A compound for use as defined in clause G, wherein the pain is acute pain, chronic pain, nociceptive pain, neuropathic pain, nociceptive pain, inflammatory pain, postoperative pain, visceral pain, chemotherapy-induced pain, peripheral neuropathy, fibromyalgia, or a combination thereof. The compound of formula (I) as defined above, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, for use in a method of promoting an anti-hyperalgesic effect in a subject suffering from hyperalgesia. J. The compound of formula (I) as defined above, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, for use in a method of reducing the sensitivity of a subject to pain. K. The compound of formula (I) as defined above, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject in need thereof. L. The compound for use according to clause K, wherein the cancer is breast cancer, prostate cancer, colon cancer, rectal cancer, pancreatic cancer, liver cancer, bladder cancer, thyroid cancer, kidney cancer, skin cancer, non-Hodgkin lymphoma, or uterine cancer. M. Use of the compound of formula (I) as defined above, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a viral infection or a disease resulting from a viral infection in a subject. N. Use according to clause M, wherein the viral infection is caused by a coronavirus, herpes simplex virus, human immunodeficiency virus, influenza, or human papillomavirus. O. Use according to clause N, wherein the coronavirus is SARS-CoV-2. P. Use according to any one of clauses M to O, wherein the disease resulting from the viral infection is severe acute respiratory syndrome or COVID-19. Q. Use of the compound of formula (I) as defined above, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating Alzheimer's disease. Use of a compound of formula (I), or a prodrug, solvate or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease which is R. anxiety, depression, mood disorder, schizophrenia, drug intoxication, drug addiction, sharp pain, dyskinesia, cerebrovascular disease, epilepsy, dementia, Parkinson's syndrome, attention deficit disorder, irritable bowel syndrome, irritable colon, spastic colon, mucous colitis, enteritis, diverticulitis, dysentery, hypertension, arrhythmia or angina pectoris, or a symptom of a disease. Use of a compound of formula (I), or a prodrug, solvate or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing pain in a subject in need of treatment. T. The use according to clause S, wherein the pain is acute pain, chronic pain, toxic pain, neuropathic pain, nociceptive pain, inflammatory pain, postoperative pain, visceral pain, chemotherapy-induced pain, peripheral neuropathy, fibromyalgia, or a combination thereof. Use of a compound of formula (I), or a prodrug, solvate or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for promoting an anti-hyperalgesic effect in a subject suffering from hyperalgesia. Use of a compound of formula (I), or a prodrug, solvate or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for reducing the sensitivity of a subject to pain. Use of a compound of formula (I), or a prodrug, solvate or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject in need thereof. X. The use according to clause W, wherein the cancer is breast cancer, prostate cancer, colon cancer, rectal cancer, pancreatic cancer, liver cancer, bladder cancer, thyroid cancer, kidney cancer, skin cancer, non-Hodgkin lymphoma, or uterine cancer. Use of a compound of formula (I), or a prodrug, solvate or pharmaceutically acceptable salt thereof, in a method for treating or preventing a viral infection or a disease resulting from a viral infection in a subject. Use according to clause Y, wherein the viral infection is caused by a coronavirus, herpes simplex virus, human immunodeficiency virus, influenza virus, or human papillomavirus. Use according to clause Z, wherein the coronavirus is SARS-CoV-2. Use according to any one of clauses Y to AA, wherein the disease resulting from the viral infection is severe acute respiratory syndrome or COVID-19. Use of a compound of formula (I) as defined above, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, in a method for treating Alzheimer's disease. Use of a compound of formula (I) as defined above, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, in a method for treating a disease, or a symptom of a disease, which is a cognitive impairment in anxiety, depression, mood disorder, schizophrenia, drug intoxication, drug addiction, sharp pain, dystonia, cerebrovascular disease, epilepsy, dementia, Parkinson's syndrome, attention deficit disorder, irritable bowel syndrome, irritable colon, spastic colon, mucous colitis, enteritis, diverticulitis, dysentery, hypertension, arrhythmia, angina, amyotrophic lateral sclerosis (ALS), Huntington's disease, stroke, retinal degeneration, or a neuropsychiatric disorder. Use of a compound of formula (I) as defined above, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, in a method for treating or preventing pain in a subject in need of treatment. Use according to clause EE, wherein the pain is acute pain, chronic pain, nociceptive pain, neuropathic pain, nociceptive inflammatory pain, postoperative pain, visceral pain, chemotherapy-induced pain, peripheral neuropathy, fibromyalgia, or a combination thereof. Use of a compound of formula (I) as defined above, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, in a method for promoting an anti-hyperalgesic effect in a subject suffering from hyperalgesia. Use of a compound of formula (I) as defined above, or a prodrug, solvate, or pharmaceutically acceptable salt thereof, in a method for reducing the sensitivity of a subject to pain. II. Use of a compound of formula (I), or a prodrug, solvate, or pharmaceutically acceptable salt thereof, in a method of treating cancer in a subject in need thereof.

[0622] JJ. Use according to clause II, wherein the cancer is breast cancer, prostate cancer, colon cancer, rectal cancer, pancreatic cancer, liver cancer, bladder cancer, thyroid cancer, kidney cancer, skin cancer, non-Hodgkin lymphoma, or uterine cancer. The inventions described in the original claims of this application are listed below. [Invention 1] Compound of formula (I): [Chemical formula] or its prodrug, solvate, or pharmaceutically acceptable salt (wherein, X 1 is absent, -(CR 3 R 4 ) q -, -O-, -S(O) 2 -, -C(O)-, -C(S)-, -S(O)-, -NR 3 C(O)-, -C(O)NR 3 -, -C(O)O-, or -OC(O)-; X 2 is absent, -(CR 3 R 4 ) q -, -O-, -S(O 2 )-, -C(O)-, -C(S)-, -S(O)-, -NR 3 C(O)-, -C(O)NR 3 -, -C(O)O-, or -OC(O)-; R 1 is H, OH, halogen, NH 2 、C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkoxyl, C 3 ~C 6 cycloalkyl, C 6 ~C 10 aryl, 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any of the above alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl is optionally substituted with one or more R 5 ; each R2 is independently H, OH, halogen, C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkoxyl, C 3 ~C 6 cycloalkyl, -C(O)C 1 ~C 6 alkyl, -C(O)OC 1 ~C 6 alkyl, -C(O)NH 2 , -C(O)NHC 1 ~C 6 alkyl, -C(O)N(C 1 ~C 6 alkyl) 2 、C 6 ~C 10 aryl, 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, or 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any of the above alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl is optionally substituted with one or more R 6 ; each R 3 is independently H, halogen, or C 1 ~C 6 alkyl; each R 4 is independently H, halogen, or C 1 ~C 6 alkyl; each R 5 is independently OH, halogen, C 1 ~C 6 alkyl, C 2 ~C 6 alkenyl, C 2 ~C 6 alkynyl, C 1 ~C 6 haloalkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 Haloalkoxyl, C 3 ~C 6 Cycloalkyl, C 6 ~C 10 Aryl, or a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any of the alkyl, alkenyl, alkynyl, cycloalkyl, or aryl is optionally substituted with one or more -C(O)C 1 ~C 6 Alkyl, -C(O)OC 1 ~C 6 Alkyl, -C(O)NH 2 , -C(O)NHC 1 ~C 6 Alkyl, or -C(O)N(C 1 ~C 6 Alkyl) 2 ; Each R 6 is independently OH, halogen, C 1~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkoxyl, C 3 ~C 6 Cycloalkyl, C 6 ~C 10 Aryl, or a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any of the alkyl, alkenyl, alkynyl, cycloalkyl, or aryl is optionally substituted with one or more -C(O)C 1 ~C 6 Alkyl, -C(O)OC 1 ~C 6 Alkyl, -C(O)NH 2 , -C(O)NHC 1 ~C 6 Alkyl, or -C(O)N(C 1 ~C 6 Alkyl) 2 ; R 7 is C 1 ~C 6 Alkyl optionally substituted with one or more OH, halogen, or C 1 ~C 6 Alkoxyl; R 8 is C 1 ~C 6 Alkyl optionally substituted with one or more OH, halogen, or C 1 ~C 6 Alkoxyl; Or R 7 And R 8 together with the carbon atom to which they are attached form one or more C 1 ~C 6 Cycloalkyl optionally substituted with OH, halogen, or C 3 ~C 6 Alkoxyl; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; each q is independently 1, 2, 3, or 4). [Invention 2] A compound of formula (Ia):

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Claims

1. A compound of formula (I): 【Chemical 1】 or a solvate or pharmaceutically acceptable salt thereof (wherein X １ is absent, -(CR ３ R ４ ) ｑ -, -S(O) ２ -, -C(O)-, -C(S)-, -S(O)-, -C(O)NR ３ -, -C(O)O-, or -OC(O)-; X ２ is absent, -(CR ３ R ４ ) ｑ -, -O-, -S(O ２ )-, -C(O)-, -C(S)-, -S(O)-, -NR ３ C(O)-, -C(O)NR ３ -, -C(O)O-, or -OC(O)-; R １ is OH, C １ ~ C ６ alkyl, C ２ ~ C ６ alkenyl, C ２ ~ C ６ alkynyl, C １ ~ C ６ haloalkyl, C １ ~ C ６ alkoxyl, C １ ~ C ６ haloalkoxyl, C ３ ~ C ６ cycloalkyl, C ６ ~ C １０ aryl, a 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any of the foregoing alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl may be substituted with one or more R ５and is optionally substituted; R ２ is C ６ -C １０ a 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from C, N, O, and S, or a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any of said aryl, heteroaryl, or heterocycloalkyl is optionally substituted with one or more R ６ and is optionally substituted; Each R ３ is independently H or methyl; Each R ４ is independently H or methyl; Each R ５ is independently OH, halogen, C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ haloalkyl, C １ -C ６ alkoxyl, C １ -C ６ haloalkoxyl, C ３ -C ６ cycloalkyl, C ６ -C １０ aryl, or a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any of said alkyl, alkenyl, alkynyl, cycloalkyl, or aryl is optionally substituted with one or more -C(O)C １ -C ６ alkyl, -C(O)OC １ -C ６ alkyl, -C(O)NH ２ , -C(O)NHC １ -C ６ alkyl, or -C(O)N(C １ -C ６ alkyl); ２ and is optionally substituted; Each R ６ is, independently, OH, halogen, C １ ~ C ６ alkyl, C ２ ~ C ６ alkenyl, C ２ ~ C ６ alkynyl, C １ ~ C ６ haloalkyl, C １ ~ C ６ alkoxyl, C １ ~ C ６ haloalkoxyl, C ３ ~ C ６ cycloalkyl, C ６ ~ C １０ aryl, or a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heterocycloalkyl is optionally substituted with one or more -C(O)C １ ~ C ６ alkyl, -C(O)OC １ ~ C ６ alkyl, -C(O)NH ２ , -C(O)NHC １ ~ C ６ alkyl, or -C(O)N(C １ ~ C ６ alkyl); ２ and is optionally substituted; R ７ is C １ ~ C3 alkyl; R ８ is C １ ~ C3 alkyl; m is 1; n is 2; p is 1; each q is, independently, 1, 2, 3, or 4).

2. A compound of formula (Ia): [Chemical Formula 2] or a solvate or pharmaceutically acceptable salt thereof (wherein, X １ is non-existent, (CR ３ R ４ ) ｑ , -C(O)-, -C(S)-, -S(O)-, or -C(O)O-; R １ is OH, C １ - C ６ alkyl, C ２ - C ６ alkenyl, C ２ - C ６ alkynyl, C １ - C ６ haloalkyl, C １ - C ６ alkoxyl, C １ - C ６ haloalkoxyl, or C ３ - C ６ cycloalkyl, and any of the above alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, or cycloalkyl may be optionally substituted with one or more R ５ ; R ２ is C ６ - C １０ aryl, 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, or 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; and any of the above aryl, heteroaryl, or heterocycloalkyl may be optionally substituted with one or more R ６ ; Each R ３ is independently H; Each R ４ is independently H; Each R ５ is independently OH, halogen, C １ - C ６ alkyl, C ２ - C ６ alkenyl, C ２ - C ６ alkynyl, C １ - C ６ Haloalkyl, C １ ~C ６ Alkoxyl, C １ ~C ６ Haloalkoxyl, C ３ ~C ６ Cycloalkyl, or C ６ ~C １０ Aryl, and any of the alkyl, alkenyl, alkynyl, cycloalkyl, or aryl may be optionally substituted with one or more -C(O)C １ ~C ６ Alkyl, -C(O)OC １ ~C ６ Alkyl, -C(O)NH ２ , -C(O)NHC １ ~C ６ Alkyl, or -C(O)N(C １ ~C ６ Alkyl); ２ optionally substituted; Each R ６ is independently OH, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxyl, C １ ~C ６ Haloalkoxyl, C ３ ~C ６ Cycloalkyl, C ６ ~C １０ Aryl, or a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; and any of the alkyl, alkenyl, alkynyl, cycloalkyl, or aryl may be optionally substituted with one or more -C(O)C １ ~C ６ Alkyl, -C(O)OC １ ~C ６ Alkyl, -C(O)NH ２ , -C(O)NHC １ ~C ６ alkyl, or -C(O)N(C １ ~C ６ alkyl) ２ optionally substituted with) The compound according to claim 1, which is

3. X １ is (CR ３ R ４ ) ｑ , -C(O)-, or -C(O)O-, the compound according to claim 1, or a solvate or pharmaceutically acceptable salt thereof.

4. X １ is absent, the compound according to claim 1, or a solvate or pharmaceutically acceptable salt thereof.

5. X ２ is (CR ３ R ４ ) ｑ , -C(O)-, -C(S)-, -S(O)-, -NR ３ C(O)-, or -C(O)O-, the compound according to claim 1, or a solvate or pharmaceutically acceptable salt thereof.

6. X ２ is absent, the compound according to claim 1, or a solvate or pharmaceutically acceptable salt thereof.

7. R １ is OH, the compound according to claim 1, or a solvate or pharmaceutically acceptable salt thereof.

8. R １ is C １ ~C ６ alkyl, C ２ ~C ６ alkenyl, C ２ ~C ６ alkynyl, C １ ~C ６ haloalkyl, C １ ~C ６ alkoxyl, C １ ~C ６ haloalkoxyl, or C ３ -C ６ is cycloalkyl, and any one of the alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, or cycloalkyl is optionally substituted with one or more R ５ The compound according to claim 1, or a solvate or pharmaceutically acceptable salt thereof.

9. R １ is C ６ -C １０ aryl, 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, or 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any one of the aryl, heteroaryl, or heterocycloalkyl is optionally substituted with one or more R ５ The compound according to claim 1, or a solvate or pharmaceutically acceptable salt thereof.

10. R １ is OH, methyl, 【Formula 3】 The compound according to claim 1, or a solvate or pharmaceutically acceptable salt thereof.

11. R ２ is 【Formula 4】 The compound according to claim 1, or a solvate or pharmaceutically acceptable salt thereof.

12. R ５ is OH or halogen, the compound according to claim 1, or a solvate or pharmaceutically acceptable salt thereof.

13. R ５ is C １ -C ６ alkyl, the compound according to claim 1, or a solvate or pharmaceutically acceptable salt thereof.

14. R ５ is C １ to C ６ haloalkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, the compound according to claim 1, or a solvate or pharmaceutically acceptable salt thereof.

15. R ６ is C １ to C ６ alkyl, the compound according to claim 1, or a solvate or pharmaceutically acceptable salt thereof.

16. R ６ is C １ to C ６ haloalkyl, or C ３ to C ６ cycloalkyl, the compound according to claim 1, or a solvate or pharmaceutically acceptable salt thereof.

17. R ６ is a 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; the heterocycloalkyl is optionally substituted with one or more -C(O)OC １ to C ６ alkyl, the compound according to claim 1, or a solvate or pharmaceutically acceptable salt thereof.

18. R ６ is 【Chemical Formula 5】 , the compound according to claim 1, or a solvate or pharmaceutically acceptable salt thereof.

19. R ７ and R ８ are each methyl, the compound according to claim 1, or a solvate or pharmaceutically acceptable salt thereof.

20. The compound is a compound of formula (III): 【Chemical Formula 6】 The compound according to claim 1, or a solvate or pharmaceutically acceptable salt thereof.

21. The compound is 【Chemical Formula 7】 The compound according to claim 1, or a solvate or pharmaceutically acceptable salt thereof, which is any of

22. 【Chemical Formula 8】 Benzyl 4,4-dimethyl-7-(4-methylpiperazin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate; 【Chemical Formula 9】 Benzyl 4,4-dimethyl-7-(4-methylpiperazin-1-yl)-3,4-dihydroisoquinoline-2(1H)carboxylate; 【Chemical Formula 10】 Benzyl 7-(4-(3-methoxy-3-oxopropyl)piperazin-1-yl)-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate; 【Chemical Formula 11】 2-Cyclopentyl-4,4-dimethyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline; 【Chemical Formula 12】 3-(4,4-Dimethyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-yl)propan-1-ol; 【Chemical Formula 13】 4,4-Dimethyl-2-propyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline; 【Chemical Formula 14】 Benzyl 5,5-dimethyl-8-(4-methylpiperazin-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate; 【Chemical Formula 15】 Benzyl 5,5-dimethyl-8-(4-propylpiperazin-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate; 【Chemical Formula 16】 Benzyl 8-(4-(3-methoxy-3-oxopropyl)piperazin-1-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate; 【Chemical 17】 2-Cyclopentyl-5,5-dimethyl-8-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine; 【Chemical 18】 3-(5,5-Dimethyl-8-(4-(trifluoromethyl)phenyl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)propan-1-ol; 【Chemical 19】 5,5-Dimethyl-2-propyl-8-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine; 【Chemical 20】 4,4-Dimethyl-2-((tetrahydro-2H-pyran-4-yl)methyl)-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline; 【Chemical 21】 3-(5,5-Dimethyl-8-(4-(trifluoromethyl)phenyl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-1-(indolin-1-yl)propan-1-one; 【Chemical 22】 7-(4-Cyclopentylpiperazin-1-yl)-2-((4-fluorobenzyl)sulfonyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline; 【Chemical 23】 (7-(4-Cyclopentylpiperazin-1-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)(4-(pyrrolidin-1-yl)phenyl)methanone; 【Chemical 24】 (7-(4-Cyclopentylpiperazin-1-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)(1,3-dimethyl-1H-pyrazol-5-yl)methanone; 【Chemical 25】 N-Cyclopentyl-7-(4-cyclopentylpiperazin-1-yl)-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxamide; 【Chemical 26】 p-Tolyl 7-(4-cyclopentylpiperazin-1-yl)-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate; 【Chemical 27】 5,5-Dimethyl-2-((tetrahydro-2H-pyran-4-yl)methyl)-8-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine; 【Chemical 28】 2-(5,5-Dimethyl-8-(4-(trifluoromethyl)phenyl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-N,N-dimethylacetamide; 【Chemical Formula 29】 2-(4-Fluorobenzyl)-5,5-dimethyl-8-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine; 【Chemical 30】 4-(2-(5,5-Dimethyl-8-(4-(trifluoromethyl)phenyl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)ethyl)-2-methylthiazole; 【Chemical 31】 2-(2-(2,6-Dimethoxyphenoxy)ethyl)-5,5-dimethyl-8-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine; 【Chemical 32】 Cyclohexyl(7-(4-cyclopentylpiperazin-1-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 【Chemical 33】 N-(3-Chloro-4-fluorophenyl)-7-(4-cyclopentylpiperazin-1-yl)-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxamide; 【Chemical 34】 Cyclopentyl 7-(4-cyclopentylpiperazin-1-yl)-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate; 【Chemical 35】 2-((1H-Imidazol-4-yl)sulfonyl)-7-(4-cyclopentylpiperazin-1-yl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline; 【Chemical 36】 2-(Cyclohexylsulfonyl)-7-(4-cyclopentylpiperazin-1-yl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline; 【Chemical 37】 5,5-Dimethyl-2-((1-methyl-1H-pyrazol-5-yl)methyl)-8-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine; 【Chemical Formula 38】 2,5,5-Trimethyl-8-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine; 【Chemical Formula 39】 2-Cyclohexyl-5,5-dimethyl-8-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine; 【Chemical 40】 2-((3-chlorophenyl)sulfonyl)-7-(4-cyclopentylpiperazin-1-yl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline; 【Chemical 41】 7-(4-cyclopentylpiperazin-1-yl)-2-((3,5-dichlorophenyl)sulfonyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline; 【Chemical 42】 Benzo[d][1,3]dioxol-4-yl (7-(4-cyclopentylpiperazin-1-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 【Chemical 43】 Cyclopentyl (7-(4-cyclopentylpiperazin-1-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 【Chemical 44】 (7-(4-cyclopentylpiperazin-1-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)(2-methoxyphenyl)methanone; 【Chemical 45】 (3-chloro-5-fluorophenyl)(7-(4-cyclopentylpiperazin-1-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 【Chemical 46】 (7-(4-cyclopentylpiperazin-1-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)(3,5-dichlorophenyl)methanone; 【Chemical 47】 7-(4-cyclopentylpiperazin-1-yl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxamide; 【Chemical 48】 7-(4-cyclopentylpiperazin-1-yl)-4,4-dimethyl-N-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; 【Chemical 49】 4-methoxyphenyl 7-(4-cyclopentylpiperazin-1-yl)-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate; 【Chemical Formula 50】 Cyclohexyl 7-(4-cyclopentylpiperazin-1-yl)-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate; 【Chemical 51】 4-fluorophenyl 7-(4-cyclopentylpiperazin-1-yl)-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate; 【Chemical 52】 Isopropyl 7-(4-cyclopentylpiperazin-1-yl)-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate; 【Chemical Formula 53】 5,5-Dimethyl-2-((6-methylpyridin-2-yl)methyl)-8-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine; 【Chemical 54】 5,5-Dimethyl-2-((6-methylpyridin-3-yl)methyl)-8-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine; 【Chemical Formula 55】 N-(Cyclohexylmethyl)-2-(5,5-dimethyl-8-(4-(trifluoromethyl)phenyl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)acetamide; 【Chemical Formula 56】 Cyclohexyl 8-(4-cyclopentylpiperazin-1-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate; 【Chemical 57】 Cyclohexyl 5,5-dimethyl-8-(4-morpholinopiperidin-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate; 【Chemical Formula 58】 4-(1-(2-((1H-Imidazol-4-yl)sulfonyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)piperidin-4-yl)morpholine; 【Chemical Formula 59】 4-(1-(2-((3-Chlorophenyl)sulfonyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)piperidin-4-yl)morpholine; 【Chemical Formula 60】 4-(1-(2-((3,5-Dichlorophenyl)sulfonyl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)piperidin-4-yl)morpholine; 【Chemical Formula 61】 Benzod][1,3]dioxol-4-yl(4,4-dimethyl-7-(4-morpholinopiperidin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 【Chemical Formula 62】 Cyclopentyl(4,4-dimethyl-7-(4-morpholinopiperidin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 【Chemical Formula 63】 Cyclohexyl(4,4-dimethyl-7-(4-morpholinopiperidin-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 【Chemical Formula 64】 (1,3-Dimethyl-1H-pyrazol-5-yl)(4,4-dimethyl-7-(4-morpholinopiperidin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 【Chemical Formula 65】 (4,4-Dimethyl-7-(4-morpholinopiperidin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(2-methoxyphenyl)methanone; 【Chemical Formula 66】 (4,4-Dimethyl-7-(4-morpholinopiperidin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(pyrazin-2-yl)methanone; 【Chemical 67】 (3-Chloro-5-fluorophenyl)(4,4-dimethyl-7-(4-morpholinopiperidin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 【Chemical Formula 68】 (4,4-Dimethyl-7-(4-morpholinopiperidin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)cyclopentylcarboxamide; 【Chemical Formula 69】 (4,4-Dimethyl-7-(4-morpholinopiperidin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(3-chloro-4-fluorophenyl)carboxamide; 【Chemical 70】 (4,4-Dimethyl-7-(4-morpholinopiperidin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)carboxamide; 【Chemical Formula 71】 (4,4-Dimethyl-7-(4-morpholinopiperidin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(3,5-dichlorophenyl)carboxamide; 【Chemical Formula 72】 (4,4-Dimethyl-7-(4-morpholinopiperidin-1-yl)-N-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)carboxamide; 【Chemical Formula 73】 (4,4-Dimethyl-7-(4-morpholinopiperidin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)p-tolylcarboxylate; 【Chemical 74】 (4,4-Dimethyl-7-(4-morpholinopiperidin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)cyclopentylcarboxylate; 【Chemical 75】 (4,4-Dimethyl-7-(4-morpholinopiperidin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)isopropylcarboxylate; 【Chemical 76】 (4,4-Dimethyl-7-(4-morpholinopiperidin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(3-chlorophenyl)sulfonyl)-8-(4-cyclopentylpiperazin-1-yl)-5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine; 【Chemical 77】 8-(4-Cyclopentylpiperazin-1-yl)-2-((3,5-dichlorophenyl)sulfonyl)-5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine; 【Chemical 78】 (8-(4-Cyclopentylpiperazin-1-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-(pyrrolidin-1-yl)phenyl)methanone; 【Chemical 79】 Benzod][1,3]dioxol-4-yl(8-(4-cyclopentylpiperazin-1-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)methanone; 【Chemical 80】 Cyclopentyl(8-(4-cyclopentylpiperazin-1-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)methanone; 【Chemical 81】 Cyclohexyl(8-(4-cyclopentylpiperazin-1-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)methanone; 【Chemical 82】 (8-(4-Cyclopentylpiperazin-1-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)(1,3-dimethyl-1H-pyrazol-5-yl)methanone; 【Chemical 83】 (3-Chloro-5-fluorophenyl(8-(4-cyclopentylpiperazin-1-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)methanone; 【Chemical 84】 (8-(4-Cyclopentylpiperazin-1-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)(3,5-dichlorophenyl)methanone; 【Chemical 85】 4-Fluorophenyl(8-(4-cyclopentylpiperazin-1-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate; 【Chemical 86】 Isopropyl 8-(4-cyclopentylpiperazin-1-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate; 【Chemical 87】 4-(1-(2-((3-chlorophenyl)sulfonyl)-5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)piperidin-4-yl)morpholine; 【Chemical 88】 4-(1-(2-(Cyclohexylsulfonyl)-5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)piperidin-4-yl)morpholine; 【Chemical 89】 4-(1-(2-((4-Fluorobenzyl)sulfonyl)-5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)piperidin-4-yl)morpholine; 【Chemical Formula 90】 4-(1-(2-((3,5-Dichlorophenyl)sulfonyl)-5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)piperidin-4-yl)morpholine; 【Chemical Formula 91】 Benzod][1,3]dioxol-4-yl(5,5-dimethyl-8-(4-morpholinopiperidin-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)methanone; 【Chemical Formula 92】 Cyclopentyl(5,5-dimethyl-8-(4-morpholinopiperidin-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)methanone; 【Chemical Formula 93】 Cyclohexyl(5,5-dimethyl-8-(4-morpholinopiperidin-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)methanone; 【Chemical 94】 (1,3-Dimethyl-1H-pyrazol-5-yl)(5,5-dimethyl-8-(4-morpholinopiperidin-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)methanone; 【Chemical Formula 95】 (3-Chloro-5-fluorophenyl)(5,5-dimethyl-8-(4-morpholinopiperidin-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)methanone; 【Chemical Formula 96】 (3,5-Dichlorophenyl)(5,5-dimethyl-8-(4-morpholinopiperidin-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)methanone; 【Chemical 97】 N-Cyclopentyl-5,5-dimethyl-8-(4-morpholinopiperidin-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-carboxamide; 【Chemical Formula 98】 N-(3-Chloro-4-fluorophenyl)-5,5-dimethyl-8-(4-morpholinopiperidin-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-carboxamide; 【Chemical Formula 99】 N-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-5,5-dimethyl-8-(4-morpholinopiperidin-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxamide; 【Chemical 100】 N-(3,5-Dichlorophenyl)-5,5-dimethyl-8-(4-morpholinopiperidin-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxamide; 【Chemical 101】 5,5-Dimethyl-8-(4-morpholinopiperidin-1-yl)-N-(4-(trifluoromethyl)phenyl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxamide; 【Chemical 102】 p-Tolyl 5,5-dimethyl-8-(4-morpholinopiperidin-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate; 【Chemical 103】 Cyclopentyl 5,5-dimethyl-8-(4-morpholinopiperidin-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate; 【Chemical 104】 4-Methoxyphenyl 5,5-dimethyl-8-(4-morpholinopiperidin-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate; 【Chemical 105】 4-Fluorophenyl 5,5-dimethyl-8-(4-morpholinopiperidin-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate; 【Chemical 106】 Isopropyl 5,5-dimethyl-8-(4-morpholinopiperidin-1-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate; 【Chemical 107】 7-(2,6-Dimethylpyridin-4-yl)-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinoline; 【Chemical 108】 2-(2-Methoxyethyl)-4,4-dimethyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline; 【Chemical 109】 2-(4-Fluorobenzyl)-4,4-dimethyl-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline; 【Chemical 110】 4,4-Dimethyl-2-((6-methylpyridin-3-yl)methyl)-7-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline; 【Chemical 111】 N-(Cyclohexylmethyl)-2-(4,4-dimethyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetamide; 【Chemical 112】 2-(4,4-Dimethyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)-N-isopropylacetamide; 【Chemical 113】 2-(7-(2,6-Dimethylpyridin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)-N-isopropylacetamide; 【Chemical 114】 2-(8-(2,6-Dimethylpyridin-4-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-N,N-dimethylacetamide; 【Chemical 115】 8-(2,6-Dimethylpyridin-4-yl)-2-(4-fluorobenzyl)-5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine; 【Chemical 116】 3-(8-(2,6-Dimethylpyridin-4-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-1-(indolin-1-yl)propan-1-one; 【Chemical 117】 4-(2-(8-(2,6-Dimethylpyridin-4-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)ethyl)-2-methylthiazole; 【Chemical 118】 1-(3,4-Dihydroisoquinolin-2(1H)-yl-3-(8-(2,6-Dimethylpyridin-4-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-1-propan-1-one; 【Chemical 119】 2-(2-(2,6-Dimethoxyphenoxy)ethyl)-8-(2,6-Dimethylpyridin-4-yl)-5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine; 【Chemical 120】 N-(Cyclohexylmethyl)-2-(8-(2,6-Dimethylpyridin-4-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)acetamide; 【Chemical 121】 2-(8-(2,6-Dimethylpyridin-4-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-N-isopropylacetamide; 【Chemical 122】 3-(7-(2,6-Dimethylpyridin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)-1-(indolin-1-yl)propan-1-one; 【Chemical 123】 2-(2-(2,6-Dimethoxyphenoxy)ethyl)-7-(2,6-dimethylpyridin-4-yl)-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline; 【Chemical 124】 2-Cyclopentyl-8-(2,6-dimethylpyridin-4-yl)-5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine; 【Chemical 125】 8-(2,6-Dimethylpyridin-4-yl)-5,5-dimethyl-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine; 【Chemical 126】 7-(4-Cyclopentylpiperazin-1-yl)-N-(3,5-dichlorophenyl)-4,4-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxamide; 【Chemical 127】 N-Cyclopentyl-8-(4-cyclopentylpiperazin-1-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxamide; 【Chemical 128】 2-(2-Methoxyethyl)-5,5-dimethyl-8-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine; 【Chemical 129】 2-(5,5-Dimethyl-8-(4-(trifluoromethyl)phenyl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)ethyl acetate; 【Chemical 130】 2-(5,5-Dimethyl-8-(4-(trifluoromethyl)phenyl)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-1-morpholinoethan-1-one; 【Chemical Formula 131】 (3,5-Dichlorophenyl)(4,4-dimethyl-7-(4-morpholinopiperidin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; 【Chemical 132】 8-(4-Cyclopentylpiperazin-1-yl)-N-(3,5-dichlorophenyl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxamide; 【Chemical 133】 5,5-Dimethyl-2-(tetrahydro-2H-pyran-4-yl)-8-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-2H-benzo[c]azepine; 【Chemical 134】 2-(4,4-Dimethyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)-N,N-dimethylacetamide; 【Chemical 135】 2-(4,4-Dimethyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)-1-(pyrrolidin-1-yl)ethan-1-one; 【Chemical 136】 2-(7-(2,6-Dimethylpyridin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)-1-(pyrrolidin-1-yl)ethan-1-one; 【Chemical 137】 N-(Cyclohexylmethyl)-2-(7-(2,6-dimethylpyridin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)acetamide; 【Chemical 138】 3-(8-(2,6-Dimethylpyridin-4-yl)-5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-1-(4-methylpiperidin-1-yl)propan-1-one; 【Chemical 139】 8-(2,6-Dimethylpyridin-4-yl)-5,5-dimethyl-2-((6-methylpyridin-2-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine; 【Chemical 140】 8-(2,6-Dimethylpyridin-4-yl)-5,5-dimethyl-2-((tetrahydro-2H-pyran-4-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine; 【Chemical 141】 8-(2,6-Dimethylpyridin-4-yl)-2,5,5-trimethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine; 【Chemical 142】 7-(2,6-Dimethylpyridin-4-yl)-4,4-dimethyl-2-((6-methylpyridin-3-yl)methyl)-1,2,3,4-tetrahydroisoquinoline; 【Chemical 143】 8-(2,6-Dimethylpyridin-4-yl)-2-(2-methoxyethyl)-5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine; or 【Chemical 144】 2-(8-(2,6-Dimethylpyridin-4-yl)5,5-dimethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-1-morpholinoethan-1-one A compound which is, or a solvate or pharmaceutically acceptable salt thereof. Claim 23 A pharmaceutical composition comprising the compound according to claim 1, or a solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent and / or carrier.

24. R ２ is 【Chemical Formula 145】 The compound according to claim 1, or a solvate or pharmaceutically acceptable salt thereof, wherein R is as defined above.

25. The compound is 【Chemical Formula 146】 The compound according to claim 1, or a solvate or pharmaceutically acceptable salt thereof.

26. A compound of formula (I): 【Chemical Formula 147】 or a solvate or pharmaceutically acceptable salt thereof (wherein X １ is absent, -(CR ３ R ４ ) ｑ -, -S(O) ２ -, -C(O)-, -C(S)-, -S(O)-, -C(O)NR ３ -, -C(O)O-, or -OC(O)-; X ２ is absent, -(CR ３ R ４ ) ｑ -, -O-, -S(O ２ )-, -C(O)-, -C(S)-, -S(O)-, -NR ３ C(O)-, -C(O)NR ３ -, -C(O)O-, or -OC(O)-; R １ is OH, C １ ~C ６ alkyl, C ２ ~C ６ alkenyl, C ２ ~C ６ alkynyl, C １ ~C ６ haloalkyl, C １~C ６ alkoxyl, C １ ~C ６ haloalkoxyl, C ３ ~C ６ cycloalkyl, C ６ ~C １０ aryl, N, O, and S selected from 1 to 6 heteroatoms containing 5 to 12 membered heteroaryl, N, O, and S selected from 1 to 5 heteroatoms containing 5 to 14 membered saturated or unsaturated heterocycloalkyl; any of the alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl is optionally substituted with one or more R ５ ; R ２ is 【Chemical 148】 ; each R ３ is independently H, or methyl; each R ４ is independently H, or methyl; each R ５ is independently OH, halogen, C １ ~C ６ alkyl, C ２ ~C ６ alkenyl, C ２ ~C ６ alkynyl, C １ ~C ６ haloalkyl, C １ ~C ６ alkoxyl, C １ ~C ６ haloalkoxyl, C ３ ~C ６ cycloalkyl, C ６ ~C １０ aryl, or 5 to 14 membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; any of the alkyl, alkenyl, alkynyl, cycloalkyl, or aryl is one or more -C(O)C １ ~C ６Alkyl, -C(O)OC １ ~C ６ Alkyl, -C(O)NH ２ , -C(O)NHC １ ~C ６ Alkyl, or -C(O)N(C １ ~C ６ Alkyl) ２ and is optionally substituted therewith; R ７ is C １ ~C3 alkyl; R ８ is C １ ~C3 alkyl; each q is independently 1, 2, 3, or 4).

27. R ５ is OH or halogen, the compound according to claim 26, or a solvate or pharmaceutically acceptable salt thereof.

28. X １ is (CR ３ R ４ ), -S(O)2, -C(O)-, or -C(O)O-, the compound according to claim 26, or a solvate or pharmaceutically acceptable salt thereof. ｑ

29. X １ is absent, the compound according to claim 26, or a solvate or pharmaceutically acceptable salt thereof.

30. X ２ is (CR ３ R ４ ), -C(O)-, -C(S)-, -S(O)-, -NR ｑ C(O)-, or -C(O)O-, the compound according to claim 26, or a solvate or pharmaceutically acceptable salt thereof. ３

31. X ２ is absent, the compound according to claim 26, or a solvate or pharmaceutically acceptable salt thereof.

32. R １ The compound according to claim 26, or a solvate or pharmaceutically acceptable salt thereof, wherein R is OH.

33. R １ is C １ to C ６ alkyl, C ２ to C ６ alkenyl, C ２ to C ６ alkynyl, C １ to C ６ haloalkyl, C １ to C ６ alkoxyl, C １ to C ６ haloalkoxyl, or C ３ to C ６ cycloalkyl, and any of the foregoing alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, or cycloalkyl is optionally substituted with one or more R ５ The compound according to claim 26, or a solvate or pharmaceutically acceptable salt thereof.

34. R １ is C ６ to C １０ aryl, 5- to 12-membered heteroaryl containing 1 to 6 heteroatoms selected from N, O, and S, or 5- to 14-membered saturated or unsaturated heterocycloalkyl containing 1 to 5 heteroatoms selected from N, O, and S; and any of the foregoing aryl, heteroaryl, or heterocycloalkyl is optionally substituted with one or more R ５ The compound according to claim 26, or a solvate or pharmaceutically acceptable salt thereof.

35. R ７ and R ８ are each methyl, The compound according to claim 26, or a solvate or pharmaceutically acceptable salt thereof.

36. The compound is a compound of formula (II): 【Chemical 149】 The compound according to claim 26, or a solvate or pharmaceutically acceptable salt thereof.

37. The compound is 【Chemical Formula 150】 The compound according to claim 26, or a solvate or pharmaceutically acceptable salt thereof.

38. The compound is 【Chemical Formula 151】 The compound according to claim 26, or a solvate or pharmaceutically acceptable salt thereof.

39. A pharmaceutical composition comprising the compound according to claim 26, or a solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent and / or carrier.

40. A pharmaceutical composition comprising the compound according to claim 22, or a solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent and / or carrier.

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