Piperazine substituted benzothiophenes for treatment of psychiatric disorders

Abstract

The present application relates to novel compounds that are prodrugs of brexpiprazole. The novel compounds of the present invention, upon administration to a subject, undergo chemical conversion by one or more metabolic processes to release the active agent in vivo. Brexpiprazole sold by Rexulti (registered trademark) is an atypical antipsychotic drug, is suitable for being used as an adjuvant therapy of an antidepressant drug, and is used for treating major depressive disorder (MDD) of adults and schizophrenia of adults and children patients over 13 years old. # imgabs0 #

Description

Technical Field

[0001] This application relates to novel compounds that serve as prodrugs of irinotecan. Upon administration to a subject, these compounds undergo chemical transformation through one or more metabolic processes to release the active agent in vivo. Iirinotecan, marketed as Rexulti (registered trademark), is an atypical antipsychotic indicated for use as an adjunct to antidepressants for the treatment of major depressive disorder (MDD) in adults and schizophrenia in adults and children aged 13 and older. Background Art

[0002] Eripiprazole (7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one) or its salt has dopamine D2 receptor partial agonist activity, serotonin 5-HT 2A In addition to the aforementioned activities, epriprazole or a salt thereof is known to have serotonin uptake or reuptake inhibitory activity and has a wide range of therapeutic potential for various nervous system disorders (PTLs 1 and 2).

[0003] Drug design in the pharmaceutical field involves chemically transforming or modifying one or more functional groups of known drug molecules to improve their pharmacokinetic or pharmacokinetic properties, such as enhancing drug efficacy and delaying in vivo metabolism. Such chemical transformations or modifications include the formation of conjugates of multiple API molecules with carrier moieties (PTL 3). There is a need for novel compounds that can be converted into ipiprazole in vivo and exhibit improved pharmacokinetic or pharmacokinetic properties, reduced side effects, and enhanced tolerability and safety.

[0004] [Citation List]

[0005] [Patent Document]

[0006] [PTL 1] WO2006 / 112464

[0007] [PTL 2] WO2013 / 035892

[0008] [PTL3] WO2012 / 088441 Summary of the Invention

[0009] [Technical Issues]

[0010] The object of the present invention is to provide novel compounds with antipsychotic properties that have acceptable pharmacokinetic properties, side effects, tolerability and safety compared to well-known typical and atypical antipsychotic drugs including epiliprazole.

[0011] [Solution to the problem]

[0012] The present invention describes compounds or pharmaceutically acceptable salts thereof having antipsychotic activity. Therefore, the compounds according to the present invention or pharmaceutically acceptable salts thereof can be used in medicine, for example to treat and / or prevent people suffering from diseases and conditions associated with antipsychotic drugs.

[0013] In one embodiment, the present invention provides a compound represented by formula (I), its individual geometric isomers, its individual enantiomers, its individual diastereomers, its individual tautomers, its individual zwitterions, or a pharmaceutically acceptable salt thereof:

[0014] [Chemical Formula 1]

[0015]

[0016] in:

[0017] a is 2 or 3;

[0018] R 1 is an optionally substituted straight or branched chain C 1-20 Alkylene, optionally substituted C 2-10 Alkenylene, optionally substituted divalent C 3-8 Cycloalkyl, optionally substituted divalent heterocycle, optionally substituted divalent C 6-10 Aryl, -NH (optionally substituted straight or branched C 1-20 Alkylene) or an optionally substituted divalent C 3-8 cycloalkenyl;

[0019] R 2 -C(O)-, -OC(O)-, -C(O)-NR a -CH2-, -O-, -CH2-, -NR a -C(O)- or direct bond;

[0020] R 3 is an optionally substituted non-aromatic divalent or trivalent heterocycle, an optionally substituted aromatic divalent or trivalent heterocycle, or an optionally substituted straight or branched chain C 1-20 alkylene;

[0021] R a is hydrogen or an optionally substituted straight or branched chain C 1-20 alkyl;

[0022] When a is 2, R 3 It is bivalent;

[0023] When a is 3, R 3 is trivalent; and

[0024] R 2 and R3 connected by covalent bonds;

[0025] The condition is that when R 1 is a straight chain alkylene group and R 2 When it is -CH2- or a direct bond, R 3 Not a straight chain alkylene group.

[0026] [Advantageous Effects of the Invention]

[0027] The compound of formula (I) or a pharmaceutically acceptable salt thereof includes structures in which epiliprazole is chemically modified, for example, multiple epiliprazole molecules are covalently linked to each other via a chemical linker. After administration to a subject, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be chemically converted to the active agent epiliprazole under physiological conditions, including one or more metabolic processes, to release epiliprazole in vivo.

[0028] The compound of formula (I) or a pharmaceutically acceptable salt thereof may have at least one pharmacological activity selected from the following:

[0029] - Stability in subcutaneous tissue, e.g., low conversion to the parent drug, epiriprazole, in subcutaneous tissue;

[0030] - Rapidly converted to ipiprazole in the systemic circulation;

[0031] - A PK profile suitable for use as a long-acting injectable (LAI), e.g., a longer duration of action per dose compared to the parent drug;

[0032] - Low irritation at the injection site. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] [ Figure 1 ] Figure 1 An XRPD pattern of Form A of the compound of Example 10 is provided.

[0034] [ Figure 2 ] Figure 2 A DSC thermogram of Form A of the compound of Example 10 is provided.

[0035] [ Figure 3 ] Figure 3 An XRPD pattern of Form B of the compound of Example 10 is provided.

[0036] [ Figure 4 ] Figure 4 A DSC thermogram of Form B of the compound of Example 10 is provided.

[0037] [ Figure 5 ] Figure 5 An XRPD pattern of Form 1 of the compound of Example 19 is provided.

[0038] [ Figure 6 ] Figure 6 The TGA curve of Form 1 of the compound of Example 19 is provided.

[0039] [ Figure 7 ] Figure 7 A DSC thermogram of Form 1 of the compound of Example 19 is provided.

[0040] [ Figure 8 ] Figure 8 Shown are the PK curves (plasma epiridol concentration-time) (mean ± SD; N = 3) when the compound of Example 10 was administered subcutaneously to rats according to Test 4. The upper curve shows the PK curve of the aqueous suspension of Example 10 (1.9 μM). The lower curve shows the PK curve of the aqueous suspension of Example 10 (3.4 μM).

[0041] [ Figure 9 ] Figure 9 Shown are the PK curves (plasma epiliprazole concentration-time) when the compound of Example 19 was administered subcutaneously to rats according to Test 4 (mean ± SD; N = 3). The upper curve shows the PK curve of the aqueous suspension of Example 19 (0.8 μM). The lower curve shows the PK curve of the aqueous suspension of Example 19 (1.5 μM). DETAILED DESCRIPTION

[0042] Depending on the value of "a", formula (I) can be represented by formula (IA) or formula (IB). For clarity, formula (IA) and formula (IB) are shown below.

[0043] When a=2, formula (I) is represented by formula (IA) as follows:

[0044] [Chemical Formula 2]

[0045]

[0046] When a=3, formula (I) is represented by formula (IB) as follows:

[0047] [Chemical Formula 3]

[0048] .

[0049] In another embodiment, the present invention provides a compound represented by formula (II), its individual geometric isomers, its individual enantiomers, its individual diastereomers, its individual tautomers, its individual zwitterions, or a pharmaceutically acceptable salt thereof:

[0050] [Chemical Formula 4]

[0051]

[0052] in:

[0053] b is 2 or 3;

[0054] R 4 is an optionally substituted straight or branched chain C 1-20 Alkylene, optionally substituted C 2-10 Alkenylene, optionally substituted divalent C 3-8 Cycloalkyl, optionally substituted divalent heterocycle, optionally substituted divalent C 6-10 Aryl, -NH (optionally substituted straight or branched C 1-20 Alkylene) or an optionally substituted divalent C 3-8 cycloalkenyl;

[0055] R 5 -C(O)-, -OC(O)-, -C(O)-NR b -CH2-, -O-, -CH2-, -NR b -C(O)- or direct bond;

[0056] R 6 is an optionally substituted non-aromatic divalent or trivalent heterocycle or an optionally substituted aromatic divalent or trivalent heterocycle or an optionally substituted straight or branched chain C 1-20 alkylene;

[0057] R b is hydrogen or an optionally substituted straight or branched chain C 1-20 alkyl;

[0058] When b is 2, R 6 It is bivalent;

[0059] When b is 3, R 6 is trivalent; and

[0060] R 5 and R 6 Connected by covalent bonds.

[0061] Depending on the value of "b", formula (II) can be represented by formula (IIA) or formula (IIB). For clarity, formula (IIA) and formula (IIB) are shown below.

[0062] When b = 2, formula (II) is represented by formula (IIA) as described below:

[0063] [Chemical Formula 5]

[0064]

[0065] When b = 3, formula (II) is represented by formula (IIB) as follows:

[0066] [Chemical Formula 6]

[0067] .

[0068] In one embodiment, the present invention provides a compound represented by formula (I), wherein:

[0069] a is 2 or 3;

[0070] R 1 is an optionally substituted straight or branched chain C 2-16 an alkylene group (wherein one or more methylene groups may be replaced by a functional group selected from -O- or -NH-, or one or more methylene groups may be replaced by a spirocyclopentane or a divalent piperidine, or one or more methylene groups may be replaced by a divalent 1,3,5-triazole ring), an ethylene group, an optionally substituted divalent cyclohexyl group, an optionally substituted divalent azetidine group, or an optionally substituted divalent piperidine group;

[0071] R 2 is -C(O)-, -OC(O)-, -C(O)-N(CH3)-CH2-, -C(O)-NH-CH2-, -O-, -NH-C(O)-, -CH2-, or a direct bond;

[0072] R 3 is an optionally substituted divalent or trivalent piperazine, an optionally substituted divalent or trivalent 2,5-diazabicyclo[2.2.2]octane, an optionally substituted divalent or trivalent 2,5-diazabicyclo[2.2.1]heptane, an optionally substituted divalent or trivalent octahydropyrrolo[3,4-c]pyrrole, an optionally substituted divalent or trivalent pyrazine, an optionally substituted divalent or trivalent 3,9-diazaspiro[5,5]undecane, an optionally substituted divalent or trivalent 1,4,7-triazacyclononane, an optionally substituted divalent or trivalent 2,6-diazaspiro[3.3]heptane, an optionally substituted divalent or trivalent 1,3,5-triazine, an optionally substituted divalent or trivalent 1,3-thiazole or an optionally substituted straight-chain or branched C 2-6 alkylene;

[0073] When a is 2, R 3 It is bivalent;

[0074] When a is 3, R 3 is trivalent; and

[0075] R 2 and R 3 Connected by covalent bonds.

[0076] In one embodiment, the present invention provides a compound represented by formula (I), wherein:

[0077] a is 2;

[0078] R 1 is an optionally substituted straight or branched chain C 2-16 an alkylene group (in which one or more methylene groups may be replaced by oxygen or amino groups, or one or more methylene groups may be replaced by spirocyclopentane or divalent piperidine, or one or more methylene groups may be replaced by a divalent 1,3,5-triazole ring), an ethylene group, an optionally substituted divalent cyclohexyl group, an optionally substituted divalent azetidine group, or an optionally substituted divalent piperidine group;

[0079] R 2 is -C(O)-, -OC(O)-, -C(O)-N(CH3)-CH2-, -C(O)-NH-CH2-, -CH2-, -NH-C(O)-, or a direct bond; and

[0080] R 3 is an optionally substituted divalent piperazine, an optionally substituted divalent 2,5-diazabicyclo[2.2.2]octane, an optionally substituted divalent 2,5-diazabicyclo[2.2.1]heptane, an optionally substituted divalent octahydropyrrolo[3,4-c]pyrrole, an optionally substituted divalent pyrazine, an optionally substituted divalent 3,9-diazaspiro[5,5]undecane, an optionally substituted divalent 2,6-diazaspiro[3.3]heptane, an optionally substituted divalent 1,3-thiazole or an optionally substituted straight-chain or branched C 2-6 Alkylene.

[0081] In one embodiment, the present invention provides a compound represented by formula (I), wherein:

[0082] a is 3;

[0083] R 1 is an optionally substituted straight or branched chain C 2-6 Alkylene, in which one or more methylene groups may be replaced by a divalent piperidine;

[0084] R 2 is -C(O)-, -O-, or a direct bond; and

[0085] R 3 is an optionally substituted trivalent 1,4,7-triazacyclononane or an optionally substituted trivalent 1,3,5-triazine.

[0086] In one embodiment, the present invention provides a compound represented by formula (I), wherein:

[0087] a is 2;

[0088] R 1 is -CH=CH-, -(CH2)2-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -NH-(CH2)7-, -(CH2)8-, -(CH2)9-, -(CH2) 12 -、-(CH2) 16 -、

[0089] [Chemical Formula 7]

[0090]

[0091] R 2 is -C(O)-, -OC(O)-, -C(O)-N(CH3)-CH2-, -C(O)-NH-CH2-, -CH2-, -NH-C(O)-, or a direct bond; and

[0092] R 3 It is -(CH2)4-,

[0093] [Chemical Formula 8]

[0094] .

[0095] In one embodiment, the present invention provides a compound represented by formula (I), wherein:

[0096] a is 3;

[0097] R 1 is -(CH2)2-, -(CH2)5- or

[0098] [Chemical Formula 9]

[0099] ;

[0100] R 2 is -C(O)-, -O-, or a direct bond; and

[0101] R 3 yes

[0102] [Chemical Formula 10]

[0103] .

[0104] In one embodiment, the present invention provides a compound represented by formula (I), wherein a is 2;

[0105] R 1 is an optionally substituted straight or branched chain C 1-20 alkylene;

[0106] R2 is -C(O)-; and

[0107] R 3 is an optionally substituted divalent piperazine.

[0108] In another embodiment, the present invention provides a compound represented by formula (I), wherein a is 2;

[0109] R 1 is an optionally substituted straight or branched chain C 1-20 alkylene;

[0110] R 2 is -C(O)-; and

[0111] R 3 yes

[0112] [Chemical Formula 11]

[0113] .

[0114] As used herein, the term "alkyl" refers to a saturated hydrocarbon moiety having straight or branched chain portions or combinations thereof and containing from 1 to 20 carbon atoms. One or more methylene groups (-CH2-) of the alkyl group may be replaced by oxygen, sulfur, sulfoxide, amino, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, divalent C 3-8 The alkyl group may be substituted by a cycloalkyl group, a divalent heterocyclic group or a divalent aryl group. The alkyl group may have one or more chiral centers. The alkyl group may be independently substituted by a halogen atom, a hydroxyl group, a cycloalkyl group, an amino group, a heterocyclic group, an aryl group, a carboxylic acid group, a phosphonic acid group, a sulfonic acid group, a phosphoric acid group, a nitro group, an amide group or a sulfonamide group. The monovalent alkyl group may be independently substituted by its chemical formula -C n H 2n+1 or its abbreviated conventional name.

[0115] As used herein, the term "alkylene" refers to a saturated divalent (bivalent) hydrocarbon moiety having straight or branched chain portions or combinations thereof and containing from 1 to 20 carbon atoms. The one or more methylene groups (-CH2-) of the alkylene group may be replaced by oxygen, sulfur, sulfoxide, amino, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, divalent C 3-8 The alkylene group may be substituted by a cycloalkyl group, a divalent heterocyclic group or a divalent aryl group. The alkylene group may have one or more chiral centers. The alkylene group may be independently substituted by a halogen atom, a hydroxyl group, a cycloalkyl group, an amino group, a heterocyclic group, an aryl group, a carboxylic acid group, a phosphonic acid group, a sulfonic acid group, a phosphoric acid group, a nitro group, an amide group or a sulfonamide group. The alkylene group may be independently substituted by its chemical formula -C n H 2n -express.

[0116] As used herein, the term "halogen" refers to chlorine, bromine, fluorine, or iodine atoms.

[0117] As used herein, the term "alkenyl" refers to a hydrocarbon group having 2 to 10 carbon atoms, derived from a saturated alkyl group, and having at least one double bond. The one or more methylene groups (-CH2-) of the alkenyl group may be replaced by oxygen, sulfur, sulfoxide, amino, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, divalent C 3-8 Cycloalkyl, divalent heterocyclic or divalent aromatic group. 2-10 The alkenyl group may adopt the configuration E or Z. The alkenyl group may be substituted by an alkyl group as defined above or a halogen atom.

[0118] As used herein, the term "alkenylene" refers to a divalent (divalent) hydrocarbon radical having 2 to 10 carbon atoms, derived from a saturated alkylene group, and having at least one double bond. The one or more methylene groups (-CH2-) of the alkenylene group may be replaced by oxygen, sulfur, sulfoxide, amino, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, divalent C 3-8 Cycloalkyl, divalent heterocyclic or divalent aromatic group. 2-10 The alkenylene group may take the configuration E or Z. The alkenylene group may be substituted by an alkyl group as defined above or a halogen atom.

[0119] The term "heterocycle" as used herein refers to a 3 to 12 membered ring which may be aromatic or non-aromatic, saturated or unsaturated, containing at least one heteroatom selected from oxygen, amino, sulfur, or a combination of at least two thereof, interrupting the carbocyclic structure. The heterocycle may be interrupted by C=O; the S and N heteroatoms may be oxidized. The heterocycle may be monocyclic or polycyclic, trivalent, divalent or monovalent, or spirocyclic. The heterocyclic moiety may be substituted by halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyano groups, -OC groups, or the like. 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-8 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, keto, alkylamino, amino, aryl, C 3-8 The heterocyclic group may be substituted with a cycloalkyl or hydroxyl group. Examples of heterocyclic groups are 1,3,5-triazole, azetidine, piperidine, piperazine, 2,5-diazabicyclo[2.2.2]octane, 2,5-diazabicyclo[3.2.1]heptane, octahydropyrrolo[3,4-c]pyrrole, pyrazine, 3,9-diazaspiro[5,5]undecane, 1,4,7-triazacyclononane, 2,6-diazaspiro[3.3]heptane, 1,3,5-triazine, and 1,3-thiazole. The heterocyclic group may be independently substituted with a halogen atom or a hydroxyl group.

[0120] The term "aryl" as used herein refers to an organic moiety derived from an aromatic hydrocarbon consisting of a ring containing 6 to 10 carbon atoms by removing one hydrogen atom. 1-6Alkyl, sulfoxide C 1-6 Alkyl, sulfonamide, carbocyclic acid, C 1-6 Alkyl carboxylate (ester) group, amide group, nitro group, cyano group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, keto, aldehyde, alkylamino, amino, aryl, C 3-8 The aryl group may be substituted with a cycloalkyl or hydroxyl group. The aryl group may be monocyclic or polycyclic. The aryl moiety may be divalent or monovalent.

[0121] The term "cycloalkyl" as used herein refers to a monovalent or divalent (bivalent) saturated carbocyclic group of 3 to 8 carbon atoms. Cycloalkyl groups may be spirocyclic, monocyclic or polycyclic. Cycloalkyl groups may be independently substituted with halogen atoms, sulfonyl groups, sulfoxide groups, sulfonyl C 1-8 Alkyl, sulfoxide C 1-8 Alkyl, sulfonamide, nitro, cyano, -OC 1-8 Alkyl, -SC 1-8 Alkyl, -C 1-8 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, keto, alkylamino, amino, aryl, C 3-8 cycloalkyl or hydroxy substituted.

[0122] The term "cycloalkenyl" as used herein refers to a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cycloalkyl group having at least one double bond. The cycloalkenyl group may be monocyclic or polycyclic. The cycloalkenyl group may be independently substituted with halogen atoms, sulfonyl groups, sulfoxide groups, sulfonyl C 1-8 Alkyl, sulfoxide C 1-8 Alkyl, sulfonamide, nitro, cyano, -OC 1-8 Alkyl, -SC 1-8 Alkyl, -C 1-8 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, keto, alkylamino, amino, aryl, C 3-8 cycloalkyl or hydroxy substituted.

[0123] As used herein, the term "hydroxy" refers to a group of formula "-OH".

[0124] As used herein, the term "carbonyl" refers to a group of the formula "-C(O)-".

[0125] The term "ketone" as used herein refers to an organic compound having a carbonyl group attached to a carbon atom, such as -(CO)R x , where R xIt may be an alkyl group, an aryl group, a cycloalkyl group, a cycloalkenyl group or a heterocycle as defined above.

[0126] As used herein, the term "amine" or "amino" refers to an amino group of the formula "-NR x R y " group, wherein R x and R y and R and R may be the same or independently be H, alkyl, aryl, cycloalkyl, cycloalkenyl or heterocycle as defined above.

[0127] As used herein, the term "carboxy" refers to a group of the formula "-C(O)O-".

[0128] The term "sulfonyl" as used herein refers to a group of formula "-SO2-".

[0129] As used herein, the term "sulfate" refers to a group of formula "-OS(O)2-O-".

[0130] As used herein, the term "sulfonate" refers to a group of formula "-S(O)2-O-".

[0131] As used herein, the term "carboxylic acid" refers to a group of formula "-C(O)OH".

[0132] As used herein, the term "nitro" refers to a group of formula "-NO2".

[0133] As used herein, the term "cyano" refers to a group of formula "-CN".

[0134] As used herein, the term "amide" refers to an amide of the formula "-C(O)NR x R y " group, wherein R x and R y and R and R may be the same or independently be H, alkyl, aryl, cycloalkyl, cycloalkenyl or heterocycle as defined above.

[0135] As used herein, the term "sulfonamide" refers to a sulfonamide of the formula "-S(O)2NR x R y " group, wherein R x and R y and R and R may be the same or independently be H, alkyl, aryl, cycloalkyl, cycloalkenyl or heterocycle as defined above.

[0136] As used herein, the term "azide" refers to a compound of the formula "-N=N + =N-" or "-N3" group.

[0137] As used herein, the term "sulfoxide" refers to a group of formula "-S(O)-".

[0138] As used herein, the term "phosphonic acid" refers to a group of formula "-P(O)(OH)2".

[0139] As used herein, the term "phosphoric acid" refers to a group of formula "-OP(O)(OH)2".

[0140] As used herein, the term "sulfonic acid" refers to a group of formula "-S(O)2OH".

[0141] As used herein, the formula "H" represents a hydrogen atom.

[0142] The formula "O" as used herein represents an oxygen atom.

[0143] As used herein, the formula "N" represents a nitrogen atom.

[0144] The formula "S" as used herein represents a sulfur atom.

[0145] As used herein, the term "1,3,5-triazole" refers to the following structure.

[0146] [Chemical Formula 12]

[0147] .

[0148] As used herein, the term "azetidine" refers to the following structure.

[0149] [Chemical Formula 13]

[0150] .

[0151] As used herein, the term "piperidine" refers to the following structure.

[0152] [Chemical Formula 14]

[0153] .

[0154] As used herein, the term "piperazine" refers to the following structure.

[0155] [Chemical Formula 15]

[0156] .

[0157] As used herein, the term "2,5-diazabicyclo[2.2.2]octane" refers to the following structure.

[0158] [Chemical Formula 16]

[0159] .

[0160] As used herein, the term "2,5-diazabicyclo[2.2.1]heptane" refers to the following structure.

[0161] [Chemical Formula 17]

[0162] .

[0163] As used herein, the term "octahydropyrrolo[3,4-c]pyrrole" refers to the following structure.

[0164] [Chemical Formula 18]

[0165] .

[0166] As used herein, the term "pyrazine" refers to the following structure.

[0167] [Chemical Formula 19]

[0168] .

[0169] As used herein, the term "3,9-diazaspiro[5,5]undecane" refers to the following structure.

[0170] [Chemical Formula 20]

[0171] .

[0172] As used herein, the term "1,4,7-triazacyclononane" refers to the following structure.

[0173] [Chemical Formula 21]

[0174] .

[0175] As used herein, the term "2,6-diazaspiro[3.3]heptane" refers to a group of the formula:

[0176] [Chemical Formula 22]

[0177] .

[0178] As used herein, the term "1,3,5-triazine" refers to a group of the formula:

[0179] [Chemical Formula 23]

[0180] .

[0181] As used herein, the term "1,3-thiazole" refers to a group of the formula:

[0182] [Chemical Formula 24]

[0183] .

[0184] As used herein, the term "(2S)-2-ethylpiperazine" refers to a group of the formula:

[0185] [Chemical Formula 25]

[0186] .

[0187] As used herein, the term "1,4-diazidebutane" refers to a group of the formula:

[0188] [Chemical Formula 26]

[0189] .

[0190] As used herein, the term "pyrazine-2,5-dicarbonyl dichloride" refers to a group of the formula:

[0191] [Chemical Formula 27]

[0192] .

[0193] Throughout this specification, the above names, formulas, and structures are used interchangeably to refer to the same items. In the formulas (I, IA, IB, II, IIA, and IIB) described throughout this specification, it will be apparent to those skilled in the art that the "R" groups and their values ​​are consistent with the permissible valences such that the substitutions result in stable compounds represented by these formulas.

[0194] In another aspect, the present invention provides compounds of formula (I), wherein -R 1 -、-R 2 -、R 3 The values ​​of and "a" are shown in Table 1:

[0195] [Table 1]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205] In yet another aspect, the present invention also provides a compound having formula (X):

[0206] [Chemical Formula 28]

[0207]

[0208] where R 7 、R 8 、R 9 and R 10 Representative and illustrative values ​​are shown in Table 2:

[0209] [Table 2]

[0210]

[0211]

[0212] Some compounds of formula (I) and formula (II) and some intermediates thereof have at least one asymmetric center in their structure. This asymmetric center may exist in either R or S configuration, and the R and S symbols are used in accordance with the rules described in Pure Appli. Chem. (1976), 45, 11-13.

[0213] The term "pharmaceutically acceptable salt" refers to a salt or complex that retains the desired biological activity of the compounds identified above. "Pharmaceutically acceptable salts" according to the present invention include the therapeutically active base salts or acid salt forms that the compounds of formula (I) and formula (II) are able to form.

[0214] Acid addition salt forms of the compounds of formula (I) and formula (II) which occur in free form as a base can be obtained by treating the free base with an appropriate acid, for example, an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, or an organic acid such as acetic acid, glycolic acid, propionic acid, lactic acid, pyruvic acid, malonic acid, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, formic acid, or the like (Handbook of Pharmaceutical Salts, P. Heinrich Stahal and Camille G. Wermuth (eds.), Verlag Helvetica Chemica Acta- Zurich, 2002, 329-345).

[0215] Base addition salt forms of compounds of formula (I) and formula (II) that occur in acid form can be obtained by treating the acid with a suitable base, for example an inorganic base such as sodium hydroxide, magnesium hydroxide, potassium hydroxide, calcium hydroxide, ammonia, etc., or an organic base such as L-arginine, ethanolamine, betaine, benzathine, morpholine, etc. (Handbook of Pharmaceutical Salts, P. Heinrich Stahal and Camille G. Wermuth (eds.), Verlag Helvetica Chemica Acta- Zurich, 2002, 329-345).

[0216] The compounds of formula (I) and formula (II) and their salts may be in the form of solvates, which are included in the scope of the present invention. Such solvates include, for example, hydrates, alcoholates, and the like.

[0217] The compounds of formula (I) and (II) may be the compounds themselves or any form of crystalline polymorphs thereof.

[0218] The compounds provided herein can be synthesized according to the procedures described herein. The synthetic methods described herein are exemplary only, and the compounds disclosed herein can also be synthesized by alternative routes utilizing alternative synthetic strategies understood by those of ordinary skill in the art. At this stage, those skilled in the art will appreciate that many other compounds falling within the scope of the present invention can be prepared by performing a variety of common chemical reactions. Detailed information on certain specific chemical transformations is provided in the Examples. Those skilled in the art will be able to routinely modify and / or adapt the following reaction schemes to synthesize any compound of the present invention encompassed by Formula (I) (Formula (IA) or Formula (IB) respectively). Generally, compounds of Formula (I) (Formula (IA) or Formula (IB) respectively) can be synthesized according to the following reaction schemes. Unless otherwise indicated, any variables ("R" groups) used in the following reaction schemes are those defined for Formula (I). All starting materials are either commercially available or known in the art and can be synthesized using known methods using conventional techniques. Starting materials can also be synthesized by the procedures disclosed herein. Suitable reaction conditions, such as solvents, reaction temperatures, and reagents, for the reaction schemes discussed in this section can also be found in the Experimental Section.

[0219] Reaction Scheme 1: Reaction of compounds of formula (IA)

[0220] [Chemical Formula 29]

[0221]

[0222] where R 1 、R2 and R 3 As defined herein. Compounds of general formula (IA) can be prepared from intermediates of formula (IX) and formula (IY) by coupling reactions as shown in Scheme 1.

[0223] Examples of the reactive group "X" in formula (IX) that participates in the coupling reaction may be alkyl carboxylates, carboxylic acids, alkynes, alkyl ethers, amines, alkyl sulfonates, nitro groups or alcohols.

[0224] Examples of reactive groups "Y" in formula (IY) that participate in the coupling reaction can be azides, amines, acid chlorides, haloalkyl groups, or halogenated cyclic moieties. Intermediates where "Y" is an azide are Int78 and the intermediates described in Table 7. Other intermediates encompassed by formula (IY) are Int04, Int05, Int08, Int09, piperazine, (2R,5S)-2,5-dimethylpiperazine, 2,5-diazabicyclo[2.2.2]octane, octahydropyrrolo[3,4-c]pyrrole, 2,6-diazaspiro[3.3]heptane, 3,9-diazaspiro[5,5]undecane, 1-[5-(aminomethyl)-1-[1,2-dimethylpiperazine] ...

[00145] The intermediates encompassed by formula (IY) are methyl({5-[(methylamino)methyl]pyrazin-2-yl}methyl)amine, (2S)-2-ethylpiperazine, pyrazine-2,5-dicarbonyl dichloride, 2,4-dichloro-1,3,5-triazine, 2,5-bis(bromomethyl)pyrazine, 1,3-thiazole-2,5-dicarbonyl dichloride, 1,4-diazide butane, and (2S)-2-ethylpiperazine. Some intermediates encompassed by formula (IY) are commercially available.

[0225] The reaction in Reaction Scheme 1 can be an amide coupling reaction using an appropriate amide coupling reagent (e.g., TBTU) and an organic base (e.g., TEA), or an aromatic or non-aromatic nucleophilic substitution or copper-catalyzed Huisgen cycloaddition reaction according to methods described in the literature or known to those skilled in the art. The amount of the amide coupling reagent used can generally be at least equimolar, preferably equimolar to 1.5-fold molar, relative to the compound of Formula (IX).

[0226] The reaction in Reaction Scheme 1 can be carried out neat or in a suitable solvent. Examples of suitable solvents include water, ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, etc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), lower alcohols (e.g., methanol, ethanol, isopropanol, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), and polar solvents (e.g., N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric acid triamide, acetonitrile, etc.).

[0227] The ratio of the compound of formula (IX) to the compound of formula (IY) used in Reaction Scheme 1 is generally at least 1.5 times the molar ratio of the latter relative to the former, preferably about 1.5 to 3 times the molar ratio. The above reaction is generally carried out at room temperature to 200°C, preferably room temperature to 150°C, and is completed in about 1 to 72 hours.

[0228] In the case where the group "X" is a terminal alkyne as described in intermediate Int77, the compound of formula (IA) can be prepared by a copper-catalyzed Huisgen cycloaddition reaction. The group "Y" is an azide that participates in the reaction in the intermediate of formula (IY). The embodiments described in Example 58 and Table 11 were synthesized by this reaction.

[0229] Some intermediates of formula (IX) can be prepared according to the reactions described in reaction scheme 2. Such intermediates are Int02, Int03, Int39, Int42, Int47, Int48, Int49, Int50, Int52, Int57, Int59, Int60, Int68, Int69, Int70, Int73, Int74 and the intermediates described in Table 4, Table 5 and Table 6. Int26 is described by formula (IPG). Some intermediates of formula (ILG) are Int01 and the intermediates described in Table 3.

[0230] Reaction Scheme 2: Reaction of the intermediate for formula (IX)

[0231] [Chemical formula 30]

[0232]

[0233] a) Protection of the functional group "X", wherein suitable protecting groups may be tert-butyl (t-Bu), tert-butyloxycarbonyl (Boc), tert-butyldimethylsilyl (TBDMS),

[0234] b) alkylation in the presence of a quaternary ammonium salt (TBA-HSO4) in the presence of an alkylating agent such as chloromethyl chlorosulfate,

[0235] c) alkylation in the presence of a base such as NaH and in the presence of heat,

[0236] d) Deprotection of the functional group "X", wherein a suitable deprotection agent may be TFA, HCl or TBAF.

[0237] Some intermediates of formula (IY) can be prepared according to the reaction described in Reaction Scheme 3. Int05 is such an intermediate.

[0238] Reaction Scheme 3: Reaction of intermediates of formula (IY)

[0239] [Chemical Formula 31]

[0240]

[0241] a) Protection of the alcohol function; suitable protecting groups are Boc, phthalimide,

[0242] b) Deprotection in the presence of a known reagent (hydrazine).

[0243] Some intermediates of formula (IY) (wherein Y is an azide) can be prepared by amide coupling reactions, where the starting material is an alkyl carboxylic acid. Amide coupling reagents such as HATU or TBTU and organic bases such as TEA or DIPEA can be used according to methods described in the literature or known to those skilled in the art.

[0244] Compounds of formula (IB) can be prepared according to the general reaction described in Scheme 4.

[0245] Reaction Scheme 4: Reaction of compounds of formula (IB)

[0246] [Chemical Formula 32]

[0247]

[0248] Reactants of formula (IBY) are generally commercially available or they can be prepared by reactions known in the literature with which those skilled in the art will be familiar.

[0249] It should be understood that the general synthetic procedures and specific examples provided herein are illustrative only and are not to be construed as limiting the scope of the present disclosure in any way. Detailed Description of the Invention

[0251] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.As used herein, the use of the singular includes the plural unless specifically stated otherwise.

[0252] Those skilled in the art will readily appreciate that some of the compounds of the present invention may contain one or more asymmetric centers, such that the compounds may exist as enantiomers and diastereoisomers. Unless otherwise specifically stated, the scope of the present invention includes all enantiomers, diastereoisomers, and racemic mixtures. Some of the compounds of the present invention may form salts with pharmaceutically acceptable acids or bases, and such pharmaceutically acceptable salts of the compounds described herein are also within the scope of the present invention.

[0253] The present invention includes all pharmaceutically acceptable isotopically enriched compounds. Any compound and intermediate of the present invention may contain one or more isotopes of atoms that are enriched or different from the natural ratio, such as deuterium.2 H (or D) instead of hydrogen 1 H (or H) or use 13 C-enriched materials replaced 12 C, etc. Similar substitutions can be made for N, O, and S, etc. Examples of isotopic atoms include deuterium ( 2 H or D), tritium ( 3 H), 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 32 P. 35 S. 36 Cl, 37 Cl, 18 F. 123 I. 125 I, etc. The use of isotopes may facilitate analytical and therapeutic aspects of the present invention. For example, the use of deuterium may increase the in vivo half-life of the compounds of the present invention by altering their metabolism (rate). These compounds can be prepared using isotopically enriched reagents according to the described preparation methods.

[0254] In certain embodiments, the compounds of Formula (I) and (II) or pharmaceutically acceptable salts thereof may have an average particle size ranging from 0.05 to 10 μm, for example, 0.1 to 10 μm, for example, 0.1 to 5 μm, for example, 0.1 to 3.4 μm, for example, 0.2 to 1.9 μm, for example, 0.2 to 0.4 μm, as measured by laser diffraction, for example, using a laser diffraction particle size distribution measuring device. A suitable average particle size may be beneficial in providing desired absorption and / or acceptable irritation at the injection site. As used herein, the term "average particle size" refers to the volume average diameter measured by laser light scattering (LLS). The particle size distribution is measured by LLS, and the corresponding average particle size is calculated based on the particle size distribution.

[0255] Medical uses

[0256] The compounds of formula (I) and (II), or pharmaceutically acceptable salts thereof, can be converted to epiliprazole in the systemic circulation after administration to a subject. The polyvalent epiliprazole molecule can be biotransformed in vivo (e.g., in plasma) to intermediates, including N-hydroxymethyl epiliprazole, which is hydrolyzed to epiliprazole by enzyme-mediated hydrolysis. Eripiprazole is indicated for the treatment and / or prevention of central nervous system disorders associated with antipsychotic medications, such as schizophrenia; refractory, intractable, or chronic schizophrenia; mood disturbances; psychotic disorders; mood disorders; bipolar I disorder; bipolar II disorder; depression; endogenous depression; major depressive disorder (MDD); melancholic and refractory depression; dysthymic disorder; cyclothymic disorder; panic attacks; panic disorder; agoraphobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; generalized anxiety disorder; acute stress disorder; hysteria; somatization disorder; conversion disorder; pain disorder; hypochondriasis; factitious disorder; dissociative disorder; sexual dysfunction; sexual desire disorder; sexual arousal disorder; erectile dysfunction; anorexia nervosa; bulimia nervosa; sleep disorders; adjustment disorder; alcoholism; alcoholism; drug use disorder. Drug addiction; stimulant intoxication; anesthetic intoxication; anhedonia; iatrogenic anhedonia; anhedonia caused by psychiatric or psychological reasons; anhedonia associated with depression; anhedonia associated with schizophrenia; delirium; cognitive impairment; cognitive impairment associated with Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases; cognitive impairment caused by Alzheimer's disease, Parkinson's disease and related neurodegenerative diseases; cognitive impairment in schizophrenia; cognitive impairment caused by refractory, intractable or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain; mental retardation; autism; Tourette disorder; tic disorder; attention deficit / hyperactivity disorder; conduct disorder; Down syndrome; impulsive symptoms associated with dementia (such as agitation symptoms associated with Alzheimer's disease); and borderline personality disorder. Therefore, the compounds of formula (I) and (II) can also be used to treat and / or prevent central nervous system disorders.

[0257] The term "prevent" is used herein to mean providing in advance and thus may involve preventing the symptoms of a disease or disorder in a subject or preventing the recurrence of symptoms of a disease or disorder in a sick subject, and is not limited to complete prevention of the disease. The term "treat" as used herein includes controlling, alleviating, alleviating or regulating a disease state or its symptoms. The subject is typically a subject in need of treatment or prevention according to the present invention. The subject is typically a mammal. Suitably, the subject is a human.

[0258] Pharmaceutical composition

[0259] In one embodiment of the present invention, a pharmaceutical preparation (also referred to herein as a "pharmaceutical composition") is provided, comprising a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0260] Depending on the therapeutic purpose, the pharmaceutical preparations herein can be selected from various forms. Any route of administration of the pharmaceutical preparation can be selected according to the dosage form, the age and sex of the patient to be administered, the disease state and other conditions. As needed, the pharmaceutical preparation can be administered orally, intravenously, intramuscularly, intradermally, subcutaneously, intraperitoneally or rectally. Examples of the pharmaceutical preparations include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (liquids, suspensions, etc.). Tablets include coated tablets, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-layer tablets and multi-layer tablets.

[0261] The compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof can be combined with a pharmaceutically acceptable carrier to prepare any form of pharmaceutical preparation. Examples of the carrier include common substances used for pharmaceutical preparation components, including excipients such as lactose, binders such as polyvinyl pyrrolidone, disintegrants such as starch, absorption aids such as sodium lauryl sulfate, humectants such as glycerol and starch, adsorbents such as colloidal silicic acid, and lubricants such as magnesium stearate and polyethylene glycol, diluents, fillers, extenders and surfactants.

[0262] Pharmaceutically acceptable carriers for tablet formulation specifically include excipients such as lactose, binders such as polyvinyl pyrrolidone, disintegrants such as starch, absorption aids such as sodium lauryl sulfate, humectants such as glycerol and starch, adsorbents such as colloidal silicic acid and lubricants such as magnesium stearate and polyethylene glycol.

[0263] The pharmaceutically acceptable carrier used for preparing the pills specifically includes an excipient such as glucose, a binder such as gum arabic powder and a disintegrant such as laminarin.

[0264] Pharmaceutically acceptable diluents for preparing liquids, emulsions or suspensions specifically include water. Any common solubilizers and / or buffers as well as coloring agents, preservatives, spices, flavorings and sweeteners may also be included in the formulation, and other drugs may also be included if necessary.

[0265] Pharmaceutically acceptable carriers for formulation into suppositories specifically include cocoa butter.

[0266] In some embodiments, the compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof can be formulated into a liquid, emulsion, or suspension to prepare an injectable formulation. In one embodiment, the injectable formulation is preferably sterilized and is also preferably isotonic with blood. The injectable formulation can be formulated with commonly used diluents, including water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyethoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. The injectable formulation may also contain a stabilizer (e.g., polymer stabilizers, including poloxamer 188, 338; PEG 200, 1000, 4000; PPG 4000) and a surfactant (e.g., PS 20, 80; sodium deoxycholate, sodium cholate, sodium lauryl sulfate). The isotonic injectable formulation may contain a sufficient amount of sodium chloride and a soothing agent such as glucose, amino acids, and glycerol, and may optionally contain other agents, such as colorants, preservatives, flavorings, and sweeteners. Preferably, the injectable formulation is administered intramuscularly or subcutaneously.

[0267] The amount of the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof contained in the pharmaceutical preparation (also referred to herein as "effective amount") may be, but is not limited to, any amount conventionally used in the art, preferably including any amount from 1% to 70% of the pharmaceutical preparation. The dosage of the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof to be administered may be any dosage selected according to the route of administration, the age and sex of the patient to be administered, the severity of the disease, and other conditions, and includes 0.01 to 100 mg, preferably 0.1 to 50 mg, per kg of body weight per day. The dosage may be administered all at once or in divided doses, for example, two to four times.

[0268] The compound of formula (I) or (II) or its pharmaceutically acceptable salt can be used or administered in combination with at least one therapeutic or preventive drug or standard of care agent, which may be referred to herein as a combination drug and can be used for one of the above-mentioned diseases. When the compound of formula (I) or (II) or its pharmaceutically acceptable salt is used in combination with a combination drug, the compound of formula (I) or (II) or its pharmaceutically acceptable salt and the drug can be administered simultaneously or at the same time, or can be administered separately or sequentially at approximately the same time, or can be administered separately or sequentially at different times at appropriate intervals. The compound of formula (I) or (II) or its pharmaceutically acceptable salt and the combination drug can be formulated into separate preparations or mixed and formulated into a single preparation.

[0269] Implementation Method

[0270] Item 1: A compound having formula (I) or a pharmaceutically acceptable salt thereof:

[0271] [Chemical Formula 33]

[0272] ,

[0273] in:

[0274] a is 2 or 3;

[0275] R 1 is an optionally substituted straight or branched chain C 1-20 Alkylene, optionally substituted C 2-10 Alkenylene, optionally substituted divalent C 3-8 Cycloalkyl, optionally substituted divalent heterocycle, optionally substituted divalent C 6-10 Aryl, -NH (optionally substituted straight or branched C 1-20 Alkylene) or an optionally substituted divalent C 3-8 cycloalkenyl;

[0276] R 2 -C(O)-, -OC(O)-, -C(O)-NR a -CH2-, -O-, -CH2-, -NR a -C(O)- or direct bond;

[0277] R 3 is an optionally substituted non-aromatic divalent or trivalent heterocycle, an optionally substituted aromatic divalent or trivalent heterocycle, or an optionally substituted straight or branched chain C 1-20 alkylene;

[0278] R a is hydrogen or an optionally substituted straight or branched chain C 1-20 alkyl;

[0279] When a is 2, R 3 It is bivalent;

[0280] When a is 3, R 3 is trivalent; and

[0281] R 2 and R 3 connected by covalent bonds;

[0282] The condition is that when R 1 is a straight chain alkylene group and R 2 When it is -CH2- or a direct bond, R 3 Not a straight chain alkylene group.

[0283] Item 2: The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein:

[0284] a is 2 or 3;

[0285] R 1 is an optionally substituted straight or branched chain C2-16 Alkylene, wherein one or more methylene groups may be replaced by a functional group selected from -O- or -NH-, or one or more methylene groups may be replaced by a spirocyclopentane or a divalent piperidine, or one or more methylene groups may be replaced by a divalent 1,3,5-triazole ring; ethylene; an optionally substituted divalent cyclohexyl; an optionally substituted divalent azetidine or an optionally substituted divalent piperidine;

[0286] R 2 is -C(O)-, -OC(O)-, -C(O)-N(CH3)-CH2-, -C(O)-NH-CH2-, -O-, -NH-C(O)-, -CH2-, or a direct bond;

[0287] R 3 is an optionally substituted divalent or trivalent piperazine, an optionally substituted divalent or trivalent 2,5-diazabicyclo[2.2.2]octane, an optionally substituted divalent or trivalent 2,5-diazabicyclo[2.2.1]heptane, an optionally substituted divalent or trivalent octahydropyrrolo[3,4-c]pyrrole, an optionally substituted divalent or trivalent pyrazine, an optionally substituted divalent or trivalent 3,9-diazaspiro[5,5]undecane, an optionally substituted divalent or trivalent 1,4,7-triazacyclononane, an optionally substituted divalent or trivalent 2,6-diazaspiro[3.3]heptane, an optionally substituted divalent or trivalent 1,3,5-triazine, an optionally substituted divalent or trivalent 1,3-thiazole or an optionally substituted straight-chain or branched C 2-6 alkylene;

[0288] When a is 2, R 3 is bivalent; and

[0289] When a is 3, R 3 It is three-valent.

[0290] Item 3: The compound according to Item 1 or 2 or a pharmaceutically acceptable salt thereof, wherein:

[0291] a is 2;

[0292] R 1 is an optionally substituted straight or branched chain C 2-16 Alkylene, wherein one or more methylene groups may be replaced by oxygen or amino, or one or more methylene groups may be replaced by spirocyclopentane or divalent piperidine, or one or more methylene groups may be replaced by a divalent 1,3,5-triazole ring; ethylene; an optionally substituted divalent cyclohexyl; an optionally substituted divalent azetidine or an optionally substituted divalent piperidine;

[0293] R 2is -C(O)-, -OC(O)-, -C(O)-N(CH3)-CH2-, -C(O)-NH-CH2-, -CH2-, -NH-C(O)-, or a direct bond; and

[0294] R 3 is an optionally substituted divalent piperazine, an optionally substituted divalent 2,5-diazabicyclo[2.2.2]octane, an optionally substituted divalent 2,5-diazabicyclo[2.2.1]heptane, an optionally substituted divalent octahydropyrrolo[3,4-c]pyrrole, an optionally substituted divalent pyrazine, an optionally substituted divalent 3,9-diazaspiro[5,5]undecane, an optionally substituted divalent 2,6-diazaspiro[3.3]heptane, an optionally substituted divalent 1,3-thiazole or an optionally substituted straight-chain or branched C 2-6 Alkylene.

[0295] Item 4: The compound according to Item 1 or 2 or a pharmaceutically acceptable salt thereof, wherein:

[0296] a is 3;

[0297] R 1 is an optionally substituted straight or branched chain C 2-6 Alkylene, in which one or more methylene groups may be replaced by a divalent piperidine;

[0298] R 2 is -C(O)-, -O-, or a direct bond; and

[0299] R 3 is an optionally substituted trivalent 1,4,7-triazacyclononane or an optionally substituted trivalent 1,3,5-triazine.

[0300] Clause 5: The compound according to any one of clauses 1 to 3 or a pharmaceutically acceptable salt thereof, wherein:

[0301] a is 2;

[0302] R 1 is -CH=CH-, -(CH2)2-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)9-, -(CH2) 12 -、-(CH2) 16 -、-NH-(CH2)7-、

[0303] [Chemical Formula 34]

[0304]

[0305] R 2is -C(O)-, -OC(O)-, -C(O)-N(CH3)-CH2-, -C(O)-NH-CH2-, -CH2-, -NH-C(O)-, or a direct bond; and

[0306] R 3 It is -(CH2)4-,

[0307] [Chemical Formula 35]

[0308] .

[0309] Item 6: The compound according to Item 1 or 2 or a pharmaceutically acceptable salt thereof, wherein:

[0310] a is 3;

[0311] R 1 is -(CH2)2-, -(CH2)5- or

[0312] [Chemical Formula 36]

[0313] ;

[0314] R 2 is -C(O)-, -O-, or a direct bond; and

[0315] R 3 yes

[0316] [Chemical Formula 37]

[0317] .

[0318] Clause 7: The compound according to Clause 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0319] 6-(4-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanoyl}piperazin-1-yl)-6-oxohexanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0320] 8-[(2R,5S)-4-{8-[(7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-2,5-dimethylpiperazin-1-yl]-8-oxooctanoic acid (7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0321] 8-(5-{8-[(7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-8-oxooctanoic acid (7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0322] 8-[(1S,4S)-5-{8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-2,5-diazabicyclo[2.2.1]hept-2-yl]-8-oxooctanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; tris(trifluoroacetic acid);

[0323] 8-(5-{8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-octahydropyrrolo[3,4-c]pyrrol-2-yl)-8-oxooctanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0324] 8-(6-{8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-2,6-diazaspiro[3.3]hept-2-yl)-8-oxooctanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0325] 8-(9-{8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-3,9-diazaspiro[5.5]undec-3-yl)-8-oxooctanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0326] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 7-({[5-({8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoylamido}methyl)pyrazin-2-yl]methyl}carbamoyl)heptanoate;

[0327] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 7-({[5-({8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-N-methyl-8-oxooctanamidyl}methyl)pyrazin-2-yl]methyl}(methyl)carbamoyl)heptanoate;

[0328] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl}piperazin-1-yl)-4-oxobutanoate;

[0329] 4-[(2S,5R)-4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl}-2,5-dimethylpiperazin-1-yl]-4-oxobutanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0330] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-(9-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl}-3,9-diazaspiro[5.5]undec-3-yl)-4-oxobutanoate;

[0331] 4-[(3ar,6ar)-5-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl}-octahydropyrrolo[3,4-c]pyrrol-2-yl]-4-oxobutanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0332] 4-[4,7-bis({4-[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl})-1,4,7-triazacyclononan-1-yl]-4-oxobutanoic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0333] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 10-(4-{10-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-10-oxodecanoyl}piperazin-1-yl)-10-oxodecanoate;

[0334] 10-[(2R,5S)-4-{10-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-10-oxodecanoyl}-2,5-dimethylpiperazin-1-yl]-10-oxodecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0335] 10-(5-{10-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-10-oxodecanoyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-10-oxodecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0336] 7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 9-({[5-({10-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-N-methyl-10-oxodecanamido}methyl)pyrazin-2-yl]methyl}(methyl)carbamoyl)nonanoate;

[0337] 8-(4-{8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}piperazin-1-yl)-8-oxooctanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0338] 6-[(2S,5R)-4-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanoyl}-2,5-dimethylpiperazin-1-yl]-6-oxohexanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0339] 6-(6-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanoyl}-2,6-diazaspiro[3.3]hept-2-yl)-6-oxohexanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0340] 6-[(3ar,6ar)-5-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanoyl}-octahydropyrrolo[3,4-c]pyrrol-2-yl]-6-oxohexanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0341] 6-(5-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanoyl}-octahydropyrrolo[3,4-c]pyrrol-2-yl)-6-oxohexanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0342] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 5-({[5-({6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-N-methyl-6-oxohexanamido}methyl)pyrazin-2-yl]methyl}(methyl)carbamoyl)pentanoate;

[0343] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 5-({[5-({6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanamido}methyl)pyrazin-2-yl]methyl}carbamoyl)pentanoate;

[0344] (2E)-4-{4-[(2E)-4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobut-2-enoyl]piperazin-1-yl}-4-oxobut-2-enoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0345] 14-(4-{14-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-14-oxotetradecanoyl}piperazin-1-yl)-14-oxotetradecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0346] 14-[(2S,5R)-4-{14-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-14-oxotetradecanoyl}-2,5-dimethylpiperazin-1-yl]-14-oxotetradecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0347] 18-(4-{18-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-18-oxooctadecanoyl}piperazin-1-yl)-18-oxooctadecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0348] 18-[(2S,5R)-4-{18-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-18-ooctadecanoyl}-2,5-dimethylpiperazin-1-yl]-18-oxooctadecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0349] (1r,4r)-4-{4-[(1r,4r)-4-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclohexanecarbonyl]piperazine-1-carbonyl}cyclohexane-1-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0350] (1r,4r)-4-[(2S,5R)-2,5-dimethyl-4-[(1r,4r)-4-{[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclohexanecarbonyl]piperazine-1-carbonyl]cyclohexane-1-carboxylic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0351] (1s,4s)-4-{4-[(1s,4s)-4-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclohexanecarbonyl]piperazine-1-carbonyl}cyclohexane-1-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0352] (1s,4s)-4-[(2S,5R)-2,5-dimethyl-4-[(1s,4s)-4-{[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclohexanecarbonyl]piperazine-1-carbonyl]cyclohexane-1-carboxylic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0353] 1-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclopentanecarbonyl)piperazine-1-carbonyl]cyclopentane-1-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0354] 1-[(3ar,6ar)-5-(1-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclopentanecarbonyl)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl]cyclopentane-1-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0355] 3-(4-{3-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-2,2-dimethyl-3-oxopropanoyl}piperazin-1-yl)-2,2-dimethyl-3-oxopropanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0356] 4-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-2,2-dimethyl-4-oxobutanoyl}piperazin-1-yl)-3,3-dimethyl-4-oxobutanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0357] 4-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3,3-dimethyl-4-oxobutanoyl}piperazin-1-yl)-2,2-dimethyl-4-oxobutanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0358] 5-(4-{5-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3,3-dimethyl-5-oxopentanoyl}piperazin-1-yl)-3,3-dimethyl-5-oxopentanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0359] 2-{2-[4-(2-{2-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-2-oxoethoxy}acetyl)piperazin-1-yl]-2-oxoethoxy}acetate (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0360] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl N-(8-{4-[8-({[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}amino)octanoyl]piperazin-1-yl}-8-oxooctyl)carbamate;

[0361] (7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl N-[(2S)-1-{4-[(2S)-2-({[(7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}amino)-3-methylbutanoyl]piperazin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate;

[0362] 4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}piperidine-4-carbonyl)piperazine-1-carbonyl]piperidine-1-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0363] 1-[5-(4-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}piperidine-1-carbonyl)pyrazine-2-carbonyl]piperidine-4-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0364] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 3-{1-[4-(4-{3-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3-oxopropyl}piperidin-1-yl)-1,3,5-triazin-2-yl]piperidin-4-yl}propanoate;

[0365] 7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 3-{1-[4,6-bis(4-{3-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3-oxopropyl}piperidin-1-yl)-1,3,5-triazin-2-yl]piperidin-4-yl}propanoate;

[0366] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 3-[1-({5-[(4-{3-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3-oxopropyl}piperidin-1-yl)methyl]pyrazin-2-yl}methyl)piperidin-4-yl]propanoate;

[0367] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 3-{1-[5-(4-{3-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3-oxopropyl}piperidine-1-carbonyl)pyrazine-2-carbonyl]piperidin-4-yl}propanoate;

[0368] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 1-[5-(3-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}azetidine-1-carbonyl)pyrazine-2-carbonyl]azetidine-3-carboxylate;

[0369] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 5-{[5-({5-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-5-oxopentyl}carbamoyl)-1,3-thiazol-2-yl]formamido}pentanoate;

[0370] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 5-{[5-({5-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-5-oxopentyl}carbamoyl)pyrazin-2-yl]formamido}pentanoate;

[0371] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 10-{[5-({10-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-10-oxodecanyl}carbamoyl)pyrazin-2-yl]formamido}decanoate;

[0372] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 6-(4-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexyl}piperazin-1-yl)hexanoate;

[0373] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 6-{4-[({6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexyl}oxy)carbonyl]piperazine-1-carbonyloxy}hexanoate;

[0374] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl (1r,4r)-4-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclohexyl]methyl}piperazin-1-yl)methyl]cyclohexane-1-carboxylate;

[0375] 6-{[4,6-bis({6-[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexyl}oxy)-1,3,5-triazin-2-yl]oxy}hexanoic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0376] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 5-{1-[4-(4-{5-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-5-oxopentyl}-1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3-triazol-4-yl}pentanoate;

[0377] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-{1-[4-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3-triazol-4-yl}butanoate;

[0378] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-[1-(5-{4-[5-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)pentanoyl]piperazin-1-yl}-5-oxopentyl)-1H-1,2,3-triazol-4-yl]butanoate;

[0379] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-(1-{5-[(2S,5R)-4-[5-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)pentanoyl]-2,5-dimethylpiperazin-1-yl]-5-oxopentyl}-1H-1,2,3-triazol-4-yl)butanoate;

[0380] 4-[1-(5-{5-[5-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)pentanoyl]-2,5-diazabicyclo[2.2.2]oct-2-yl}-5-oxopentyl)-1H-1,2,3-triazol-4-yl]butanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0381] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-[1-(6-{4-[6-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)hexanoyl]piperazin-1-yl}-6-oxohexyl)-1H-1,2,3-triazol-4-yl]butanoate; and

[0382] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-(1-{6-[(2S,5R)-4-[6-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)hexanoyl]-2,5-dimethylpiperazin-1-yl]-6-oxohexyl}-1H-1,2,3-triazol-4-yl)butanoate.

[0383] Clause 8: The compound according to Clause 6 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0384] 4-[4,7-bis({4-[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl})-1,4,7-triazacyclononan-1-yl]-4-oxobutanoic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0385] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 3-{1-[4,6-bis(4-{3-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3-oxopropyl}piperidin-1-yl)-1,3,5-triazin-2-yl]piperidin-4-yl}propanoate; and

[0386] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 6-{[4,6-bis({6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexyl}oxy)-1,3,5-triazin-2-yl]oxy}hexanoate.

[0387] Item 9: The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein:

[0388] a is 2;

[0389] R 1 are -(CH2)2-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)9-, -(CH2) 12 -or-(CH2) 16 -;

[0390] R 2 is -C(O)-, -CH2-, or a direct bond; and

[0391] R 3 yes

[0392] [Chemical Formula 38]

[0393] .

[0394] Clause 10: The compound according to Clause 9 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0395] 6-(4-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanoyl}piperazin-1-yl)-6-oxohexanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0396] 8-[(2R,5S)-4-{8-[(7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-2,5-dimethylpiperazin-1-yl]-8-oxooctanoic acid (7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0397] 8-(5-{8-[(7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-8-oxooctanoic acid (7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0398] 8-[(1S,4S)-5-{8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-2,5-diazabicyclo[2.2.1]hept-2-yl]-8-oxooctanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; tris(trifluoroacetic acid);

[0399] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl}piperazin-1-yl)-4-oxobutanoate;

[0400] 4-[(2S,5R)-4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl}-2,5-dimethylpiperazin-1-yl]-4-oxobutanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0401] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 10-(4-{10-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-10-oxodecanoyl}piperazin-1-yl)-10-oxodecanoate;

[0402] 10-[(2R,5S)-4-{10-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-10-oxodecanoyl}-2,5-dimethylpiperazin-1-yl]-10-oxodecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0403] 10-(5-{10-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-10-oxodecanoyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-10-oxodecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0404] 8-(4-{8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}piperazin-1-yl)-8-oxooctanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0405] 6-[(2S,5R)-4-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanoyl}-2,5-dimethylpiperazin-1-yl]-6-oxohexanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0406] 14-(4-{14-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-14-oxotetradecanoyl}piperazin-1-yl)-14-oxotetradecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0407] 14-[(2S,5R)-4-{14-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-14-oxotetradecanoyl}-2,5-dimethylpiperazin-1-yl]-14-oxotetradecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0408] 18-(4-{18-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-18-oxooctadecanoyl}piperazin-1-yl)-18-oxooctadecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0409] 18-[(2S,5R)-4-{18-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-18-ooctadecanoyl}-2,5-dimethylpiperazin-1-yl]-18-oxooctadecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0410] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl N-(8-{4-[8-({[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}amino)octanoyl]piperazin-1-yl}-8-oxooctyl)carbamate; and

[0411] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 6-(4-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexyl}piperazin-1-yl)hexanoate.

[0412] Item 11: The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein:

[0413] a is 2;

[0414] R 1 yes

[0415] [Chemical Formula 39]

[0416]

[0417] R 2 is -C(O)-, -CH2-, or a direct bond; and

[0418] R 3 It is -(CH2)4-,

[0419] [Chemical Formula 40]

[0420] .

[0421] Clause 12: The compound according to Clause 11 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0422] (1r,4r)-4-{4-[(1r,4r)-4-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclohexanecarbonyl]piperazine-1-carbonyl}cyclohexane-1-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0423] (1r,4r)-4-[(2S,5R)-2,5-dimethyl-4-[(1r,4r)-4-{[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclohexanecarbonyl]piperazine-1-carbonyl]cyclohexane-1-carboxylic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0424] (1s,4s)-4-{4-[(1s,4s)-4-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclohexanecarbonyl]piperazine-1-carbonyl}cyclohexane-1-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0425] (1s,4s)-4-[(2S,5R)-2,5-dimethyl-4-[(1s,4s)-4-{[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclohexanecarbonyl]piperazine-1-carbonyl]cyclohexane-1-carboxylic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0426] 1-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclopentanecarbonyl)piperazine-1-carbonyl]cyclopentane-1-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0427] 1-[(3ar,6ar)-5-(1-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclopentanecarbonyl)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl]cyclopentane-1-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0428] 3-(4-{3-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-2,2-dimethyl-3-oxopropanoyl}piperazin-1-yl)-2,2-dimethyl-3-oxopropanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0429] 4-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-2,2-dimethyl-4-oxobutanoyl}piperazin-1-yl)-3,3-dimethyl-4-oxobutanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0430] 4-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3,3-dimethyl-4-oxobutanoyl}piperazin-1-yl)-2,2-dimethyl-4-oxobutanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0431] 5-(4-{5-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3,3-dimethyl-5-oxopentanoyl}piperazin-1-yl)-3,3-dimethyl-5-oxopentanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0432] 2-{2-[4-(2-{2-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-2-oxoethoxy}acetyl)piperazin-1-yl]-2-oxoethoxy}acetate (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0433] (7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl N-[(2S)-1-{4-[(2S)-2-({[(7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}amino)-3-methylbutanoyl]piperazin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate;

[0434] 4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}piperidine-4-carbonyl)piperazine-1-carbonyl]piperidine-1-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0435] 1-[5-(4-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}piperidine-1-carbonyl)pyrazine-2-carbonyl]piperidine-4-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0436] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 3-{1-[4-(4-{3-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3-oxopropyl}piperidin-1-yl)-1,3,5-triazin-2-yl]piperidin-4-yl}propanoate;

[0437] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 3-[1-({5-[(4-{3-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3-oxopropyl}piperidin-1-yl)methyl]pyrazin-2-yl}methyl)piperidin-4-yl]propanoate;

[0438] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 3-{1-[5-(4-{3-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3-oxopropyl}piperidine-1-carbonyl)pyrazine-2-carbonyl]piperidin-4-yl}propanoate;

[0439] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 1-[5-(3-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}azetidine-1-carbonyl)pyrazine-2-carbonyl]azetidine-3-carboxylate;

[0440] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl (1r,4r)-4-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclohexyl]methyl}piperazin-1-yl)methyl]cyclohexane-1-carboxylate;

[0441] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 5-{1-[4-(4-{5-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-5-oxopentyl}-1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3-triazol-4-yl}pentanoate;

[0442] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-{1-[4-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3-triazol-4-yl}butanoate;

[0443] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-[1-(5-{4-[5-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)pentanoyl]piperazin-1-yl}-5-oxopentyl)-1H-1,2,3-triazol-4-yl]butanoate;

[0444] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-(1-{5-[(2S,5R)-4-[5-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)pentanoyl]-2,5-dimethylpiperazin-1-yl]-5-oxopentyl}-1H-1,2,3-triazol-4-yl)butanoate;

[0445] 4-[1-(5-{5-[5-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)pentanoyl]-2,5-diazabicyclo[2.2.2]oct-2-yl}-5-oxopentyl)-1H-1,2,3-triazol-4-yl]butanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0446] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-[1-(6-{4-[6-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)hexanoyl]piperazin-1-yl}-6-oxohexyl)-1H-1,2,3-triazol-4-yl]butanoate; and

[0447] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-(1-{6-[(2S,5R)-4-[6-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)hexanoyl]-2,5-dimethylpiperazin-1-yl]-6-oxohexyl}-1H-1,2,3-triazol-4-yl)butanoate.

[0448] Item 13: The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein:

[0449] a is 2;

[0450] R 1 is -(CH2)2-, -(CH2)4-, -(CH2)6- or -(CH2)9-;

[0451] R 2 is -C(O)-, -C(O)-N(CH3)-CH2-, -C(O)-NH-CH2-, or -NH-C(O)-; and

[0452] R 3 yes

[0453] [Chemical Formula 41]

[0454] .

[0455] Clause 14: The compound according to Clause 13 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0456] 8-(5-{8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-octahydropyrrolo[3,4-c]pyrrol-2-yl)-8-oxooctanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0457] 8-(6-{8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-2,6-diazaspiro[3.3]hept-2-yl)-8-oxooctanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0458] 8-(9-{8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-3,9-diazaspiro[5.5]undec-3-yl)-8-oxooctanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0459] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-(9-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl}-3,9-diazaspiro[5.5]undec-3-yl)-4-oxobutanoate;

[0460] 4-[(3ar,6ar)-5-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl}-octahydropyrrolo[3,4-c]pyrrol-2-yl]-4-oxobutanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0461] 6-(6-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanoyl}-2,6-diazaspiro[3.3]hept-2-yl)-6-oxohexanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0462] 6-[(3ar,6ar)-5-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanoyl}-octahydropyrrolo[3,4-c]pyrrol-2-yl]-6-oxohexanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0463] 6-(5-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanoyl}-octahydropyrrolo[3,4-c]pyrrol-2-yl)-6-oxohexanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester;

[0464] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 5-({[5-({6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-N-methyl-6-oxohexanamido}methyl)pyrazin-2-yl]methyl}(methyl)carbamoyl)pentanoate;

[0465] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 5-({[5-({6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanamido}methyl)pyrazin-2-yl]methyl}carbamoyl)pentanoate;

[0466] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 5-{[5-({5-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-5-oxopentyl}carbamoyl)-1,3-thiazol-2-yl]formamido}pentanoate;

[0467] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 5-{[5-({5-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-5-oxopentyl}carbamoyl)pyrazin-2-yl]formamido}pentanoate; and

[0468] (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 10-{[5-({10-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-10-oxodecanyl}carbamoyl)pyrazin-2-yl]formamido}decanoate.

[0469] Item 15: The compound according to any one of Items 1 to 14, or a pharmaceutically acceptable salt thereof, including any one of all Example compounds described herein, having an average particle size in the range of 0.05 μm to 10 μm as measured by laser diffraction.

[0470] Item 16: A pharmaceutical composition comprising the compound according to any one of Items 1 to 15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0471] Item 17: A medicament for treating and / or preventing central nervous system disorders, comprising the compound according to any one of Items 1 to 15 or a pharmaceutically acceptable salt thereof.

[0472] Clause 18: The drug according to Clause 17, wherein the central nervous system disorder is selected from the group consisting of schizophrenia; refractory, intractable or chronic schizophrenia; mood disturbance; psychotic disorder; mood disorder; bipolar I disorder; bipolar II disorder; depression; endogenous depression; major depressive disorder (MDD); melancholy and refractory depression; dysthymic disorder; cyclothymic disorder; panic attack; panic disorder; agoraphobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; generalized anxiety disorder; acute stress disorder; hysteria; somatization disorder; conversion disorder; pain disorder; hypochondriasis; factitious disorder; dissociative disorder; sexual dysfunction; sexual desire disorder; sexual arousal disorder; erectile dysfunction; anorexia nervosa; bulimia nervosa; sleep disorder; adjustment disorder; alcoholism; alcoholism; drugs Addiction; stimulant intoxication; narcotic intoxication; anhedonia; iatrogenic anhedonia; anhedonia of psychiatric or psychological origin; anhedonia associated with depression; anhedonia associated with schizophrenia; delirium; cognitive impairment; cognitive impairment associated with Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders; cognitive impairment due to Alzheimer's disease, Parkinson's disease, and related neurodegenerative disorders; cognitive impairment in schizophrenia; cognitive impairment due to refractory, intractable, or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain; mental retardation; autism; Tourette disorder; tic disorder; attention-deficit / hyperactivity disorder; conduct disorder; Down syndrome; impulsive symptoms associated with dementia (e.g., agitation associated with Alzheimer's disease); and borderline personality disorder.

[0473] Item 19: Use of the compound according to any one of Items 1 to 15 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing central nervous system disorders.

[0474] Item 20: The use according to Item 19, wherein the central nervous system disorder is selected from the group consisting of schizophrenia; refractory, intractable or chronic schizophrenia; mood disturbance; psychotic disorder; mood disorder; bipolar I disorder; bipolar II disorder; depression; endogenous depression; major depressive disorder (MDD); melancholy and refractory depression; dysthymic disorder; cyclothymic disorder; panic attack; panic disorder; agoraphobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; generalized anxiety disorder; acute stress disorder; hysteria; somatization disorder; conversion disorder; pain disorder; hypochondriasis; factitious disorder; dissociative disorder; sexual dysfunction; sexual desire disorder; sexual arousal disorder; erectile dysfunction; anorexia nervosa; bulimia nervosa; sleep disorder; adjustment disorder; alcoholism; alcoholism; drugs Addiction; stimulant intoxication; narcotic intoxication; anhedonia; iatrogenic anhedonia; anhedonia of psychiatric or psychological origin; anhedonia associated with depression; anhedonia associated with schizophrenia; delirium; cognitive impairment; cognitive impairment associated with Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders; cognitive impairment due to Alzheimer's disease, Parkinson's disease, and related neurodegenerative disorders; cognitive impairment in schizophrenia; cognitive impairment due to refractory, intractable, or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain; mental retardation; autism; Tourette disorder; tic disorder; attention-deficit / hyperactivity disorder; conduct disorder; Down syndrome; impulsive symptoms associated with dementia (e.g., agitation associated with Alzheimer's disease); and borderline personality disorder.

[0475] Clause 21: A method for treating and / or preventing a central nervous system disorder, comprising administering the compound according to any one of Clauses 1 to 15 or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0476] Clause 22: The method according to clause 21, wherein the central nervous system disorder is selected from the group consisting of schizophrenia; refractory, intractable or chronic schizophrenia; mood disturbance; psychotic disorder; mood disorder; bipolar I disorder; bipolar II disorder; depression; endogenous depression; major depressive disorder (MDD); melancholy and refractory depression; dysthymic disorder; cyclothymic disorder; panic attack; panic disorder; agoraphobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; generalized anxiety disorder; acute stress disorder; hysteria; somatization disorder; conversion disorder; pain disorder; hypochondriasis; factitious disorder; dissociative disorder; sexual dysfunction; sexual desire disorder; sexual arousal disorder; erectile dysfunction; anorexia nervosa; bulimia nervosa; sleep disorder; adjustment disorder; alcoholism; alcoholism; drug use disorder Addiction; stimulant intoxication; narcotic intoxication; anhedonia; iatrogenic anhedonia; anhedonia of psychiatric or psychological origin; anhedonia associated with depression; anhedonia associated with schizophrenia; delirium; cognitive impairment; cognitive impairment associated with Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders; cognitive impairment due to Alzheimer's disease, Parkinson's disease, and related neurodegenerative disorders; cognitive impairment in schizophrenia; cognitive impairment due to refractory, intractable, or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain; mental retardation; autism; Tourette disorder; tic disorder; attention-deficit / hyperactivity disorder; conduct disorder; Down syndrome; impulsive symptoms associated with dementia (e.g., agitation associated with Alzheimer's disease); and borderline personality disorder.

[0477] Item 23: The compound according to any one of Items 1 to 15 or a pharmaceutically acceptable salt thereof, for use in treating and / or preventing a central nervous system disorder.

[0478] Item 24: The compound for use according to Item 23, wherein the central nervous system disorder is selected from the group consisting of schizophrenia; refractory, intractable or chronic schizophrenia; mood disturbances; psychotic disorders; mood disorders; bipolar I disorder; bipolar II disorder; depression; endogenous depression; major depressive disorder (MDD); melancholy and refractory depression; dysthymic disorder; cyclothymic disorder; panic attacks; panic disorder; agoraphobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; generalized anxiety disorder; acute stress disorder; hysteria; somatization disorder; conversion disorder; pain disorder; hypochondriasis; factitious disorder; dissociative disorder; sexual dysfunction; sexual desire disorder; sexual arousal disorder; erectile dysfunction; anorexia nervosa; bulimia nervosa; sleep disorders; adjustment disorders; alcoholism; alcoholism; Drug addiction; stimulant intoxication; narcotic intoxication; anhedonia; iatrogenic anhedonia; anhedonia of psychiatric or psychological origin; anhedonia associated with depression; anhedonia associated with schizophrenia; delirium; cognitive impairment; cognitive impairment associated with Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders; cognitive impairment due to Alzheimer's disease, Parkinson's disease, and related neurodegenerative disorders; cognitive impairment in schizophrenia; cognitive impairment due to refractory, intractable, or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain; mental retardation; autism; Tourette disorder; tic disorder; attention-deficit / hyperactivity disorder; conduct disorder; Down syndrome; impulsive symptoms associated with dementia (e.g., agitation associated with Alzheimer's disease); and borderline personality disorder.

[0479] Clause 25: A process for preparing a compound according to any one of Clauses 1 to 15 or a pharmaceutically acceptable salt thereof as described herein.

[0480] Clause 26: An intermediate compound for use in a process for preparing a compound according to any one of clauses 1 to 15 or a pharmaceutically acceptable salt thereof as described herein.

[0481] Item 27: A compound having formula (X) or a salt thereof:

[0482] [Chemical Formula 42]

[0483]

[0484] in:

[0485] R 7 is -CH=CH-, -(CH2)2-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)9-, -(CH2) 12-、-(CH2) 16 -、

[0486] [Chemical Formula 43]

[0487]

[0488] R 8 is -C(O)-, -C(O)-N(CH3)-CH2-, -C(O)-NH-CH2-, -CH2-, -NH-C(O)-, or a direct bond;

[0489] R 9 It is -(CH2)4-,

[0490] [Chemical Formula 44]

[0491]

[0492] and

[0493] R 10 -(CH2)2-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)9-, H, -COOH, -C(O)-(CH2) 2-10 -C(O)H, -C(O)-(CH2) 2-10 -C(O)(tBu) or -C(O)(tBu).

[0494] The following examples are for illustrative purposes only and are not intended to, and should not be construed as, limiting the present invention in any way. It will be appreciated by those skilled in the art that variations and modifications may be made to the following examples without departing from the spirit or scope of the present invention. As will be apparent to those skilled in the art, individual isomeric forms can be obtained by separating mixtures thereof in conventional manner. For example, in the case of diastereomers, chromatographic separation may be employed.

[0495] [Example]

[0496] General experimental details and methods

[0497] Analytical methods

[0498] Instruments, materials, and methods used for analysis

[0499] 1H-NMR spectra were performed on an Agilent INOVA 400, Agilent VNMRS 500, Agilent INOVA 600 spectrometer, or a Bruker Avance III 400 spectrometer operating at 400, 500, or 600 MHz (proton frequency). Chemical shifts are reported as δ values ​​in ppm using the residual solvent peak as an internal reference. Coupling constants (J values) are given in Hertz (Hz), and multiplicities are reported using the following abbreviations (s = singlet, d = doublet, t = triplet, q = quartet, p = quintet, h = septet, m = multiplet, br.s = broad singlet, nd = not determined, dd = doublet of doublet, ddd = doublet of doublet of doublet, quin = quintet, td = triplet of doublet, tt = triplet of triplet, qd = quadruplet of doublet).

[0500] LC / UV / MS analysis method

[0501] Estimated LC / MS retention times are subject to an experimental error of + 0.5 min. LCMS can be recorded under the following conditions: Diode array DAD chromatographic traces, mass chromatograms, and mass spectra can be acquired on a UPLC / PDA / MS Acquity™ system coupled to a Micromass ZQ™ or Waters SQD single quadrupole mass spectrometer operated in positive and / or negative electron spray ES ionization mode and / or a Fractionlynx system used in analytical mode coupled to a ZQ™ single quadrupole operated in positive and / or negative ES ionization mode. The quality control method used was run under the following low or high pH conditions:

[0502] Method 1, low pH conditions: Column: Acquity CSH C18 2.1 x 50 mm 1.7 μm, column temperature: 40°C; mobile phase solvent A: milliQ water + 0.1% HCOOH, mobile phase solvent B: MeCN + 0.1% HCOOH. Flow rate: 1 mL / min.

[0503] The gradient was t = 0 min 97% A 3% B, t = 1.5 min 0.1% A 99.9% B, t = 1.9 min 0.1% A 99.9% B, and t = 2 min 97% A 3% B. The UV detection range was 210–350 nm, and the ES+ / ES- range was 100 to 1900 AMU.

[0504] Method 2, high pH conditions: Column: Kinetex EVO C18 2.1 x 50 mm 1.7 μm, column temperature: 40°C; mobile phase solvent A: 10 mM NH4HCO3 in water, adjusted to pH = 10 with ammonia; mobile phase solvent B: MeCN. Flow rate: 1 mL / min. Gradient: t = 0 min: 97% A 3% B, t = 1.5 min: 0.1% A 99.9% B, t = 1.9 min: 0.1% A 99.9% B, and t = 2 min: 97% A 3% B. UV detection range: 210–350 nm, ES+ / ES- range: 100 to 1200 AMU.

[0505] Method 3, low pH conditions: Column: Acquity Peptide BEH C18 2.1 x 50 mm 1.7 μm, column temperature: 40°C; mobile phase solvent A: milliQ water + 0.05% TFA, mobile phase solvent B: MeCN + 0.05% TFA. Flow rate: 0.7 mL / min.

[0506] The gradient was t = 0 min 97% A 3% B, t = 3.0 min 20% A 80% B, t = 3.5 min 5% A 95% B, t = 3.9 min 5% A 95% B, and t = 4 min 97% A 3% B. The UV detection range was 210–350 nm, and the ES+ / ES- range was 100 to 1900 AMU.

[0507] Method 4, low pH conditions: Column: Acquity Peptide BEH C18 2.1 x 50 mm 1.7 μm, column temperature: 40°C; mobile phase solvent A: milliQ water + 0.05% TFA, mobile phase solvent B: MeCN + 0.05% TFA. Flow rate: 0.7 mL / min.

[0508] The gradient was t = 0 min 97% A 3% B, t = 0.5 min 97% A 3% B, t = 3.0 min 40% A 60% B, t = 3.5 min 5% A 95% B, t = 3.9 min 5% A 95% B, and t = 4 min 97% A 3% B. The UV detection range was 210–350 nm, and the ES+ / ES- range was 100 to 1900 AMU.

[0509] HPLC semi-preparative method

[0510] Semipreparative HPLC was performed using an MDAP Waters apparatus with mass spectrometry detection (MS: ZQ2000) and DAD detection 220, equipped with a CSH C18 (30 x 100 mm, 5 μm) column and a 1 mL injection loop. A gradient of MeCN in H2O + HCOOH decreasing from 50% to 70% over 10 minutes (flow rate = 40.00 mL / min.) was used as the mobile phase.

[0511] Compound Chemical name Generated using Structure To Name ChemAxon MarvinSketch software.

[0512] All reagents whose synthesis is not described in the experimental part are either commercially available, are known compounds or can be formed from known compounds by known methods by a person skilled in the art.

[0513] The following abbreviations are used in the examples:

[0514] 2-MeTHF = 2-methyltetrahydrofuran

[0515] atm = atmosphere

[0516] Boc = tert-Butoxycarbonyl

[0517] Boc2O = di-tert-butyl dicarbonate

[0518] cHex = cyclohexane

[0519] CuI = copper(I) iodide

[0520] DCM = dichloromethane

[0521] DIAD = diisopropyl azodicarboxylate

[0522] DIPEA = N,N-diisopropylethylamine

[0523] DMAP = 4-(dimethylamino)pyridine

[0524] DMF = dimethylformamide

[0525] DMSO = dimethyl sulfoxide

[0526] EtOAc = ethyl acetate

[0527] HCOOH = Formic acid

[0528] h = hours

[0529] HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate

[0530] HCl = hydrochloric acid

[0531] HBTU = [(1H-1,2,3-Benzotriazol-1-yloxy)(dimethylamino)methylene]dimethylammonium hexafluoro-λ5-phosphate

[0532] HCl = hydrochloric acid

[0533] H2O = water

[0534] IPA = propan-2-ol

[0535] K2CO3 = Potassium carbonate

[0536] LC-MS = liquid chromatography / mass spectrometry

[0537] MeCN = acetonitrile

[0538] MeOH = methanol

[0539] MsCl = methanesulfonyl chloride

[0540] N2 = Nitrogen

[0541] NaH = Sodium Hydride

[0542] NaOH = sodium hydroxide

[0543] Na2SO4 = Sodium sulfate

[0544] NaHCO3 = Sodium bicarbonate

[0545] Na2CO3 = Sodium carbonate

[0546] NH4Cl = ammonium chloride

[0547] nHex = n-hexane

[0548] Pd / C = Palladium on Carbon

[0549] Pd(OAc)2 = Palladium(II) acetate

[0550] PPh3 = triphenylphosphine

[0551] Py = pyridine

[0552] quant. = quantitative

[0553] Rt = retention time

[0554] RT = Room temperature

[0555] Sec. = Seconds

[0556] ss = saturated solution

[0557] TBA-HSO4 = Tetrabutylammonium hydrogen sulfate

[0558] TBTU = O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate

[0559] TEA = triethylamine

[0560] TFA = trifluoroacetic acid

[0561] THF = Tetrahydrofuran

[0562] Preparation of intermediates

[0563] Int01: 1-tert-Butyl Suberate 8-Chloromethyl Ester

[0564] [Chemical Formula 45]

[0565]

[0566] To a mixture of 8-[(2-methylpropan-2-yl)oxy]-8-oxooctanoic acid (3.7 g) in DCM (35 mL) and H2O (44 mL) were added NaHCO3 (5.4 g) and TBA-HSO4 (5.5 g). The mixture was cooled at 0°C, and a solution of chloromethyl chlorosulfate (1.6 mL) in 8 mL of DCM was added dropwise. The reaction was then allowed to stir at room temperature for 3 h. The mixture was diluted with DCM and washed with H2O. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting crude product was purified by chromatography on a silica gel column (eluent = 0% to 10% EtOAc in cHex) to provide Int01 (2.76 g).

[0567] 1 H NMR (400 MHz, CHLOROFORM-d) δ 5.70 (s, 2H), 2.38 (t, J = 7.45 Hz, 2H), 2.20 (t, J = 7.45 Hz, 2H), 1.72 - 1.55 (m, 4H), 1.44 (s, 9H), 1.40 - 1.26 (m,4H).

[0568] Int02: 8-tert-butyl 1-(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl suberate

[0569] [Chemical Formula 46]

[0570]

[0571] Under an N₂ atmosphere, NaH (60% in mineral oil, 0.14 g) was added to 1,4-dioxane (30 mL), followed by 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-1,2-dihydroquinolin-2-one (1.4 g), and the reaction was stirred at room temperature for 15 min. A solution of Int01 (1.35 g) in 1,4-dioxane (7 mL) was then added dropwise. The reaction mixture was stirred at 60°C (bath temperature) for 2.5 h. The reaction was cooled to room temperature, diluted with EtOAc, and quenched with NH₄Cl ss. The resulting mixture was extracted with EtOAc (2x). The combined organic layers were dried on a phase separator, and the solvent was concentrated under vacuum. The crude product was purified by chromatography on a silica gel column (eluent = 10% to 100% EtOAc in cHex) to give Int02 (2.9 g).

[0572] LC-MS (ESI): m / z (M+1): 676.4, Rt= 0.98 min. (Method 1).

[0573] Int03: 8-[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoic acid hydrochloride

[0574] [Chemical Formula 47]

[0575]

[0576] To a solution of Int02 (2.9 g) in DCM (91 mL) was added TFA (5.25 mL) dropwise at RT. The compound was stirred at RT for 48 h. The solvent was evaporated and the remaining TFA was partially co-evaporated with toluene. 1,4-dioxane (10 mL) and 1,4-dioxane containing 4N HCl (15 mL) were then added and the mixture was evaporated under high vacuum to give a yellow oil. This was dissolved in DCM and washed twice with NaHCO3 ss, the organic phase was filtered on a phase separator and acidified with 1.8 mL of 1M aqueous HCl solution (pH = 3-4). The organic phase was washed with H2O (2x), dried over Na2SO4, filtered and concentrated in vacuo to give Int03 (2.0 g).

[0577] LC-MS (ESI): m / z (M+1): 620.0, Rt= 0.68 min. (Method 1).

[0578] Int04: Methyl({5-[(methylamino)methyl]pyrazin-2-yl}methyl)amine

[0579] [Chemical Formula 48]

[0580]

[0581] A 2M solution of methylamine in THF (8 mL) was diluted with additional THF (10 mL) and cooled to 0°C. A solution of 2,5-bis(bromomethyl)pyrazine (0.28 g) in THF (3 mL) was added dropwise at 0°C. The reaction mixture was sealed in a vial and stirred at room temperature for 5 h. The solvent was then removed under high vacuum, and the residue was purified on an SCX column (eluent = MeOH, then 2M ammonia in MeOH) to give crude Int04 (174 mg).

[0582] 1 H NMR (400 MHz, chloroform-d) δ ppm 8.53 (s, 2H), 3.89 (d, J = 2.32 Hz, 4H), 2.49 (d, J = 1.63 Hz, 6H).

[0583] Int05: 1-[5-(Aminomethyl)pyrazin-2-yl]methanamine dihydrochloride

[0584] [Chemical Formula 49]

[0585]

[0586] Step A: To a solution of [5-(hydroxymethyl)pyrazin-2-yl]methanol (50 mg) in anhydrous THF (3.5 mL) was added PPh3 (206 mg) and phthalimide (105 mg) at room temperature. The mixture was cooled to 0°C, and DIAD (0.16 mL) was added dropwise. The mixture was allowed to stir at room temperature for 3 hours. The reaction mixture was filtered through a phase separator and washed with MeCN. The solid residue was dried under vacuum to give 2-({5-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]pyrazin-2-yl}methyl)-2,3-dihydro-1H-isoindole-1,3-dione (127 mg).

[0587] LC-MS (ESI): m / z (M+1): 399.1, Rt= 0.96 min. (Method 1).

[0588] Step B: To a suspension of 2-({5-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]pyrazin-2-yl}methyl)-2,3-dihydro-1H-isoindole-1,3-dione (127 mg) in DCM (4 mL) was added hydrazine (0.04 mL), and the mixture was refluxed for 3 h. The mixture was cooled to RT, TEA (0.2 mL) and Boc2O (0.21 g) were added, and the resulting mixture was stirred at 35°C for 24 h. The mixture was cooled to RT, and the solid was filtered off. The organic layer was washed with H2O, the organic phase was filtered on a phase separator, and evaporated under high vacuum. The crude product was purified by chromatography on a silica gel column (eluent = 0% to 40% EtOAc in cHex) to give tert-butyl N-{[5-({[(tert-butoxy)carbonyl]amino}methyl)pyrazin-2-yl]methyl}carbamate (48 mg).

[0589] LC-MS (ESI): m / z (M+1): 399.2, Rt= 0.90 min. (Method 1).

[0590] Step C: To a solution of tert-butyl N-[[5-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]pyrazin-2-yl]methyl]carbamate (48 mg) in 1,4-dioxane (2 mL) was added 4M HCl in 1,4-dioxane (0.57 mL), and the reaction mixture was stirred at RT overnight. More 4M HCl in 1,4-dioxane (0.2 mL) was then added, and the mixture was stirred at RT for an additional 6 h. The mixture was evaporated under high vacuum to give crude Int05 (31 mg).

[0591] 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 2H), 8.47 (s, 6H), 4.31 (s, 4H).

[0592] Int08: 2,6-diazaspiro[3.3]heptane bis(trifluoroacetate)

[0593] [Chemical Formula 50]

[0594]

[0595] To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (100 mg) in DCM (4 mL) was added TFA (0.6 mL) dropwise at 0° C. After stirring at RT for 3 h, the mixture was evaporated under high vacuum to give Int08 (197 mg).

[0596] 1 H NMR (400 MHz, chloroform-d) δ 4.07 (s, 8H), 2.25 (s, 2H).

[0597] Int09: 3,9-diazaspiro[5.5]undecane bis(trifluoroacetate)

[0598] [Chemical Formula 51]

[0599]

[0600] Int09 was prepared according to the procedure described for Int08 starting from tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (0.10 g) to give Int09 (0.197 g).

[0601] 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (brs, 4H), 3.05 (dq, J = 8.63, 4.88Hz, 8H), 1.63 (t, J = 5.92 Hz, 8H).

[0602] Intermediates Int10, Int13, Int18, Int21, Int27, Int30, Int33, Int36, Int39, Int41, Int44, Int55, Int58, Int61, Int63, Int66, Int71 and Int75 were synthesized according to the method used for the synthesis of Int01.

[0603] The starting materials used in the synthesis of each compound and their characterization are listed in Table 3.

[0604] [Table 3]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611] Intermediates Int06, Int11, Int14, Int16, Int19, Int22, Int24, Int28, Int31, Int32, Int34, Int37, Int45, Int53, Int72, Int76 and Int77 were synthesized according to the method used to synthesize Int02.

[0612] The starting materials used in the synthesis of each compound and their characterization are listed in Table 4.

[0613] [Table 4]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623] Intermediates Int07, Int12, Int15, Int17, Int20, Int23, Int25, Int29, Int35, Int38, Int40, Int43, Int46, Int54, and Int65 were synthesized following the method used for the synthesis of Int03.

[0624] The starting materials used in the synthesis of each compound and their characterization are listed in Table 5.

[0625] [Table 5]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633] Int26: (1s,4s)-4-[(tert-Butoxy)carbonyl]cyclohexane-1-carboxylic acid

[0634] [Chemical Formula 52]

[0635]

[0636] A suspension of (1s,4s)-cyclohexane-1,4-dicarboxylic acid (4.0 g) in toluene (30 mL) was refluxed for 10 minutes to give a clear solution; the mixture was then brought to 100°C, and N,N-dimethylformamide di-tert-butyl acetal (11.1 mL) was added dropwise over 5 minutes. The mixture was refluxed for 5 hours, then cooled to room temperature and the solvent evaporated under vacuum. The resulting crude product was purified by chromatography on a silica gel column (eluent = 20% to 50% EtOAc in cHex) to give Int26 (2.1 g).

[0637] 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.51 (tt, J = 7.5, 4.3 Hz, 1H), 2.36 (tt, J = 7.5, 4.2 Hz, 1H), 2.01 - 1.80 (m, 4H), 1.67 (dddd, J = 16.9, 12.5,7.8, 4.3 Hz, 5H), 1.44 (d, J = 2.7 Hz, 9H).

[0638] Int39: 4-tert-butyl 1-(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 2,2-dimethylsuccinate

[0639] [Chemical Formula 53]

[0640]

[0641] Step A: Int39 was prepared according to the procedure described for Int01 starting from a mixture of 4-(tert-butoxy)-2,2-dimethyl-4-oxobutanoic acid and 4-(tert-butoxy)-3,3-dimethyl-4-oxobutanoic acid (0.97 g) to give a mixture of 4-tert-butyl 1-chloromethyl 2,2-dimethylsuccinate and 1-tert-butyl 4-chloromethyl 2,2-dimethylsuccinate (0.45 g).

[0642] Step B: Following the procedure described for Int02, the resulting mixture was reacted with 7-{5-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-1,2-dihydroquinolin-2-one (0.45 g). The resulting mixture was further purified by chiral semi-preparative HPLC on a Chiralcel OJ-H column (eluent = nHex / EtOH: 80 / 20) to afford Int39 (120 mg).

[0643] 1H NMR (500 MHz, chloroform-d) δ ppm 7.62 (d, J=9.6 Hz, 1 H), 7.56 (d, J=7.9 Hz, 1 H), 7.37 - 7.46 (m, 3 H), 7.26 - 7.31 (m, 1 H), 6.94 (d, J=2.0 Hz,1 H), 6.90 (d, J=7.7 Hz, 1 H), 6.84 (dd, J=8.6, 2.0 Hz, 1 H), 6.52 (d, J=9.6Hz, 1 H), 6.35 (br s, 2 H), 4.14 (t, J=6.2 Hz, 2 H), 3.20 (br s, 4 H), 2.73(br s, 4 H), 2.52 - 2.57 (m, 2 H), 2.51 (s, 2 H), 1.85 - 1.98 (m, 2 H), 1.70- 1.83 (m, 2 H), 1.38 (s, 9 H), 1.26 (s, 6 H).

[0644] Int42: 5-tert-butyl 1-(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 3,3-dimethylglutarate

[0645] [Chemical Formula 54]

[0646]

[0647] To a suspension of 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-1,2-dihydroquinolin-2-one (1.67 g) in 2-MeTHF (20 mL) was added NaH (60% in mineral oil, 0.154 g) at room temperature under an N2 atmosphere. The reaction was stirred at 70°C (bath temperature) for 30 min, after which it was cooled to room temperature and a solution of Int41 (1.0 g) in 2-MeTHF (10 mL) was added dropwise. The reaction mixture was stirred at 70°C (bath temperature) for 3 h. The reaction was cooled to room temperature, diluted with EtOAc, and quenched with NH4Cl ss. The resulting mixture was extracted with EtOAc (2x). The combined organic layers were dried on a phase separator, and the solvent was evaporated under vacuum. The resulting crude product was purified by chromatography on a silica gel column (eluent = 10% to 100% EtOAc in cHex) to afford Int42 (610 mg).

[0648] LC-MS (ESI): m / z (M+1): 662.6, Rt= 2.91 min. (Method 4).

[0649] Int47: tert-Butyl 8-({[(7-{5-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}amino)octanoate

[0650] [Chemical Formula 55]

[0651]

[0652] Under an N₂ atmosphere, NaH (60% in mineral oil, 24 mg) was added to DMF (2 mL) and 2-MeTHF (2 mL) at room temperature, followed by 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-1,2-dihydroquinolin-2-one (220 mg). The reaction was stirred at 60°C for 5 minutes and then cooled to -18°C. A solution of chloromethyl 4-nitrophenyl carbonate (153 mg) in DMF (2 mL) was added dropwise. The reaction mixture was stirred at -18°C for 18 hours. Cold NH₄Cl₂ was added, and the mixture was extracted with DCM (2x). The combined organic layers were dried on a phase separator, and the solvent was evaporated under vacuum to provide a solution of [7-[4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy]-2-oxoquinolin-1-yl]methyl(4-nitrophenyl)carbonate in DMF. A solution of tert-butyl 8-aminooctanoate (109 mg) in DCM (5 mL) and TEA (0.35 mL) was added at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. Volatiles were removed under vacuum, and the resulting crude product was purified by chromatography on a C-18 column (eluent = 0% to 100% MeCN in H2O containing 0.1% TFA) to afford Int47 (98 mg).

[0653] LC-MS (ESI): m / z (M+1): 705,7, Rt = 3.0 min (Method 3).

[0654] Int48: 8-({[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}amino)octanoic acid trifluoroacetate

[0655] [Chemical Formula 56]

[0656]

[0657] To a solution of tert-butyl Int47 (98 mg) in DCM (4 mL) was added TFA (0.24 mL) dropwise at RT. The reaction was stirred at RT for 16 h. Toluene (10 mL) was added and the volatiles were removed under vacuum to afford Int48 (100 mg).

[0658] LC-MS (ESI): m / z (M+1): 649.6, Rt= 2.52 min. (Method 3).

[0659] Int49: tert-Butyl (2S)-2-({[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}amino)-3-methylbutanoate

[0660] [Chemical Formula 57]

[0661]

[0662] Int49 was prepared according to the procedure described for Int47 starting from 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-1,2-dihydroquinolin-2-one (500 mg), tert-butyl (2S)-2-amino-3-methylbutanoate hydrochloride (360 mg) and chloromethyl 4-nitrophenyl carbonate (350 mg) to give Int49 (570 mg).

[0663] LC-MS (ESI): m / z (M+1): 663.3, Rt= 0.88 min. (Method 1).

[0664] Int50: (2S)-2-({[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}amino)-3-methylbutanoic acid trifluoroacetate

[0665] [Chemical Formula 58]

[0666]

[0667] Int50 was prepared following the procedure described for Int48 starting from Int49 (570 mg) to give Int50 (370 mg).

[0668] LC-MS (ESI): m / z (M+1): 607.2, Rt= 0.75 min. (Method 1).

[0669] Intermediates Int51, Int56, Int62, Int64, and Int67 were synthesized following the method used to synthesize Int49. The starting materials used in the synthesis of each compound and their characterization are listed in Table 6.

[0670] [Table 6]

[0671]

[0672]

[0673]

[0674] Int52: 1-{[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}piperidine-4-carboxylic acid trifluoroacetate

[0675] [Chemical Formula 59]

[0676]

[0677] Int52 was prepared starting from Int51 (800 mg) following the procedure described for Int48 to give Int52 (545 mg, 63% yield).

[0678] LC-MS (ESI): m / z (M+1): 619.5, Rt= 2.35 min. (Method 3).

[0679] Int57: 3-(piperidin-4-yl)propanoic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester

[0680] [Chemical Formula 60]

[0681]

[0682] Int57 was prepared following the procedure described for Int54 starting from Int56 (1.28 g) to give Int57 (1.24 g).

[0683] LC-MS (ESI): m / z (M+1): 603.3, Rt= 0.55 min. (Method 1).

[0684] Int59: 1-tert-butyl 3-(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl azetidine-1,3-dicarboxylate

[0685] [Chemical Formula 61]

[0686]

[0687] Int59 was prepared according to the procedure described for Int49 starting from 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-1,2-dihydroquinolin-2-one (1.6 g) and Int58 (1.4 g) to give Int59 (1.9 g).

[0688] LC-MS (ESI): m / z (M+1): 647.5, Rt= 0.83 min. (Method 1).

[0689] Int60: Azetidine-3-carboxylic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester

[0690] [Chemical Formula 62]

[0691]

[0692] Int60 was prepared following the procedure described for Int54 starting from Int59 (1.9 g) to give Int60 (1.6 g).

[0693] LC-MS (ESI): m / z (M+1): 547.3, Rt= 0.53 min. (Method 1).

[0694] Int68: 4-(1-Benzothiophen-4-yl)-1-{4-[(1-{[(6-hydroxyhexanoyl)oxy]methyl}-2-oxo-1,2-dihydroquinolin-7-yl)oxy]butyl}piperazin-1-ium fluoride

[0695] [Chemical Formula 63]

[0696]

[0697] To a solution of Int67 (1 g) in THF (8 mL) at 0°C was added N-ethyldiisopropylamine trihydrofluoride (1.5 mL). The reaction was stirred at room temperature for 7 h. NaHCO₃ ss was added, and the mixture was extracted with EtOAc (2 x). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and evaporated under vacuum. The resulting crude product was triturated with ether:EtOAc 90:10 to afford Int68 (775 mg).

[0698] LC-MS (ESI): m / z (M+1): 578.2, Rt= 0.73 min. (Method 1)

[0699] Int69: 6-(methylsulfonyloxy)hexanoic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester

[0700] [Chemical Formula 64]

[0701]

[0702] To a mixture of Int68 (250 mg), TEA (0.16 mL) and DMAP (4.8 mg) in DCM (4.3 mL) was added MsCl (0.06 mL) at 0°C. The reaction was stirred at RT for 3 h. The reaction mixture was diluted with DCM and washed with H2O (x2) and brine. The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated under vacuum. The resulting crude product was purified by chromatography on a silica gel column (eluent = 0% to 10% MeOH in DCM) to give Int69 (223 mg).

[0703] LC-MS (ESI): m / z (M+1): 656.4, Rt= 0.8 min. (Method 1).

[0704] Int70: 6-{[(4-nitrophenoxy)carbonyl]oxy}hexanoic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester

[0705] [Chemical Formula 65]

[0706]

[0707] To a solution of Int68 (32.0 mg) in DCM (1 mL) was added Py (0.01 mL) at 0°C, followed by 4-nitrophenyl chloroformate (11 mg). The reaction was stirred at RT overnight. The reaction mixture was diluted with DCM and washed with NaHCO s.s. (5x). The organic phase was dried on a phase separator and evaporated under vacuum. The resulting crude product was purified by chromatography on a silica gel column (eluent = 0% to 100% MeOH in MeCN) to give Int70 (20 mg).

[0708] LC-MS (ESI): m / z (M+1): 743.4, Rt= 0.96 min. (Method 1).

[0709] Int73: 4-(1-Benzothiophen-4-yl)-1-{4-[(2-oxo-1-{[(1r,4r)-4-(hydroxymethyl)cyclohexanecarbonyloxy]methyl}-1,2-dihydroquinolin-7-yl)oxy]butyl}piperazin-1-ium fluoride

[0710] [Chemical Formula 66]

[0711]

[0712] Int73 was prepared following the procedure described for Int68 starting from Int72 (970 mg) to give Int73 (744 mg).

[0713] LC-MS (ESI): m / z (M+1): 604.2, Rt= 0.75 min. (Method 1).

[0714] Int74: (1r,4r)-4-[(methylsulfonyloxy)methyl]cyclohexane-1-carboxylic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester

[0715] [Chemical Formula 67]

[0716]

[0717] Int74 was prepared following the procedure described for Int69 starting from Int73 (250 mg) to give Int74 (237 mg, 87% yield).

[0718] LC-MS (ESI): m / z (M+1): 682.1, Rt= 0.82 min. (Method 1).

[0719] Int78: 5-Azido-1-[4-(5-azidopentanoyl)piperazin-1-yl]pentan-1-one

[0720] [Chemical Formula 68]

[0721]

[0722] To a solution of 5-azidopentanoic acid (0.350 mL) and piperazine (60 mg) in THF (5 mL) was added DIPEA (0.36 mL) and HBTU (660 mg), and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with NaHCO s.s. (x2). The organic phase was dried on a phase separator, and the solvent was evaporated at 37°C under vacuum. The resulting crude product was purified by chromatography on a C18 column (eluent = 5% to 50% MeCN in H 2 O) to give Int78 (170 mg).

[0723] LC-MS (ESI): m / z (M+1): 337.2, Rt= 0.82 min. (Method 1).

[0724] Intermediates Int79, Int80, Int81 and Int82 were synthesized following the method used for the synthesis of Int78.

[0725] The starting materials used in the synthesis of each compound and their characterization are listed in Table 7.

[0726] [Table 7]

[0727]

[0728]

[0729] Int83 :4-[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoic acid trifluoroacetate

[0730] [Chemical Formula 69]

[0731]

[0732] To a solution of Int06 (6.2 g, 10 mmol) in DCM (85 mL) was added TFA (6.1 mL, 80 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 20 hours. Additional TFA (6.1 mL, 80 mmol) was then added, and the mixture was stirred at room temperature for an additional 8 hours. The solvent was evaporated, and the remaining TFA was partially co-evaporated with toluene. The residue was concentrated under vacuum to afford 4-[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoic acid trifluoroacetate (6.9 g, 10.2 mmol, quantitative yield).

[0733] LC-MS (ESI): m / z (M+1): 564.5, Rt = 2.28 min. (Method 4).

[0734] Int84 : tert-butyl 4-{4-[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl}piperazine-1-carboxylate

[0735] [Chemical Formula 70]

[0736]

[0737] To a solution of Int83 (710 mg, 1.05 mmol) in anhydrous DMF (5 mL) was added TBTU (405 mg, 1.26 mmol). After 5 minutes, TEA (0.58 mL, 4.2 mmol) and a solution of tert-butyl piperazine-1-carboxylate (215 mg, 1.16 mmol) in DMF (10 mL) were added, and the reaction was stirred at room temperature for 3 hours. HO and DCM were added to the reaction mixture, the phases were separated, and the aqueous phase was extracted with DCM (3 times). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under vacuum. The crude product was purified by chromatography on a silica gel column (eluent = neat DCM to 6% MeOH in DCM) to give tert-butyl 4-{4-[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl}piperazine-1-carboxylate (0.50 g, 0.68 mmol, 64% yield).

[0738] LC-MS (ESI): m / z (M+1): 732.6, Rt = 2.05 min. (Method 4).

[0739] Int85: 4-Oxo-4-(piperazin-1-yl)butanoic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester

[0740] [Chemical Formula 71]

[0741]

[0742] Int85 was prepared according to the procedure described for Int03 starting from Int84 (150 mg, 0.156 mmol) to give (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-oxo-4-(piperazin-1-yl)butanoate (93 mg, 0.147 mmol, 95% yield).

[0743] LC-MS (ESI): m / z (M+1): 632.4, Rt = 1.40-1.50 min. (Method 4).

[0744] Int86: 4-{4-[4-(tert-Butoxy)-4-oxobutanoyl]piperazin-1-yl}-4-oxobutanoic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester trifluoroacetate

[0745] [Chemical Formula 72]

[0746]

[0747] Int86 was prepared according to the procedure described for Int6 starting from Int85 (90 mg, 0.142 mmol) and 4-tert-butoxy-4-oxo-butanoic acid (30 mg, 0.17 mmol) to give 4-{4-[4-(tert-butoxy)-4-oxobutanoyl]piperazin-1-yl}-4-oxobutanoic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester trifluoroacetate (70 mg, 55% yield).

[0748] LC-MS (ESI): m / z (M+1): m / z (M+1): 788.6, Rt = 2.02 min. (Method 4).

[0749] Int87: 4-(4-{4-[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl}piperazin-1-yl)-4-oxobutanoic acid

[0750] [Chemical Formula 73]

[0751]

[0752] Int87 was prepared according to the procedure described for Int03 starting from Int86 (70 mg, 0.089 mmol) to give 4-(4-{4-[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl}piperazin-1-yl)-4-oxobutanoic acid (12 mg, 0.016 mmol, 17% yield).

[0753] LC-MS (ESI): m / z (M+1): 732.5, Rt = 1.66 min. (Method 4).

[0754] 1 H NMR (500 MHz, DMSO-d6) δ ppm 10.44 - 13.97 (m, 2 H), 8.13 (s, 1H), 7.89 (d, J=9.5 Hz, 1 H), 7.69 (d, J=5.5 Hz, 1 H), 7.66 (d, J=9.1 Hz, 1H), 7.61 (d, J=8.1 Hz, 1 H), 7.40 (d, J=5.4 Hz, 1 H), 7.27 (t, J=7.8 Hz, 1H), 6.92 - 6.97 (m, 2 H), 6.89 (br d, J=7.5 Hz, 1 H), 6.43 (d, J=9.5 Hz, 1H), 6.16 - 6.29 (m, 2 H), 4.16 (t, J=6.4 Hz, 2 H), 3.23 - 3.53 (m, 8 H), 3.07 (br s, 4 H), 2.59 - 2.74 (m, 4 H), 2.47 - 2.53 (m, 2 H), 2.31 - 2.81 (m, 8H), 1.76 - 1.87 (m, 2H), 1.62 - 1.72 (m, 2 H).

[0755] Int88: 4-[4-(3-carboxypropionyl)piperazin-1-yl]-4-oxobutanoic acid

[0756] [Chemical Formula 74]

[0757]

[0758] A suspension of piperazine (1.0 g, 11.6 mmol) and oxolane-2,5-dione (2.3 g, 23.2 mmol) in toluene (15 mL) was stirred at 110°C for 1 hour. DMF (5 mL) was then added, and the suspension was further stirred at 110°C for 4 hours. The solvent was evaporated under reduced pressure. The solid residue was dissolved in EtOH, filtered, and washed with EtOH. The solid residue was dried under vacuum to provide 4-[4-(3-carboxypropanoyl)piperazin-1-yl]-4-oxobutanoic acid (2.51 g, 8.8 mmol, 76% yield).

[0759] LC-MS (ESI): m / z (M+1): 287.2, Rt = 0.39 min. (Method 1).

[0760] 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.05 (s, 2H), 3.52 - 3.39 (m, 8H), 2.56 (t, J = 6.6 Hz, 4H), 2.44 (dd, J = 7.3, 5.6 Hz, 4H).

[0761] Int89: 8,8'-(piperazine-1,4-diyl)bis(8-oxooctanoic acid)

[0762] [Chemical Formula 75]

[0763]

[0764] Int89 was prepared in a similar manner to the methods described herein.

[0765] Preparation of final compounds

[0766] Example 01: 6-(4-{6-[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanoyl}piperazin-1-yl)-6-oxohexanoic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester

[0767] [Chemical Formula 76]

[0768]

[0769] To a solution of Int15 (0.19 g) in anhydrous DMF (13 mL) was added TBTU (543 mg). After 5 minutes, TEA (0.54 mL) and piperazine (50 mg) were added, and the reaction was stirred at room temperature overnight. More piperazine (17 mg) and TEA (0.15 mL) were added, and the reaction was stirred at room temperature for another 1 hour. HO and DCM were added to the reaction mixture, the phases were separated, and the aqueous phase was extracted with DCM (3 times). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under vacuum. The resulting crude product was purified by chromatography on a silica gel column (eluent: neat DCM to 3% MeOH in DCM) to give Example 01 (660 mg).

[0770] LC-MS (ESI): m / z (M+1): 1233.7, Rt= 2.72 min. (Method 4).

[0771] 1 H NMR (400 MHz, chloroform-d) δ ppm 8.49 (s, 2 H), 7.63 (d, J=9.6 Hz, 2H), 7.55 (d, J=8.1 Hz, 2 H), 7.46 (d, J=8.6 Hz, 2 H), 7.37 - 7.43 (m, 4 H),7.18 - 7.34 (m, 2 H), 6.82 - 6.94 (m, 6 H), 6.68 (br t, J=5.0 Hz, 2 H), 6.50 (d, J=9.4 Hz, 2 H), 6.32 (br s, 4 H), 4.56 (d, J=5.5 Hz, 4 H), 4.09 (t, J=6.1Hz, 4 H), 3.21 (br s, 8 H), 2.75 (br s, 8 H), 2.56 (br t, J=7.3 Hz, 4 H), 2.36 (t, J=7.3 Hz, 4 H), 2.22 (t, J=7.6 Hz, 4 H), 1.87 - 1.98 (m, 4 H), 1.78(quin, J=7.3 Hz, 4 H), 1.51 - 1.69 (m, 8 H), 1.28 - 1.43 (m, 8 H).

[0772] Examples 02, 03, 05, 06, 07, 09, 11, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 and 44 were synthesized according to the method used to synthesize Example 01.

[0773] The reactants used in the synthesis of each compound and their characterizations are listed in Table 8.

[0774] [Table 8]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814] Example 04: 8-[(1S,4S)-5-{8-[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-2,5-diazabicyclo[2.2.1]hept-2-yl]-8-oxooctanoic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; tris(trifluoroacetic acid) salt

[0815] [Chemical Formula 77]

[0816]

[0817] To a solution of Int03 (90 mg) and (2S)-2-ethylpiperazine dihydrochloride (12 mg) in anhydrous DMF (13 mL) was added TBTU (543 mg). The final compound was purified by chromatography on a C18 column (eluent = 5% to 50% MeCN in H2O containing 0.1% TFA) to afford Example 04 (12 mg).

[0818] LC-MS (ESI): m / z (M+1): 1302.8, Rt= 2.91 min. (Method 4).

[0819] 1 H NMR (400 MHz, chloroform-d) δ ppm 11.83 - 12.91 (m, 2 H), 7.65 (d, J=7.9Hz, 4 H), 7.43 - 7.51 (m, 4 H), 7.28 - 7.34 (m, 4 H), 6.96 (d, J=7.5 Hz, 2H), 6.90 (d, J=0.9 Hz, 2 H), 6.78 - 6.87 (m, 2 H), 6.55 (d, J=9.4 Hz, 2 H), 6.33 (br s, 4 H), 4.42 - 5.01 (m, 2 H), 4.09 (t, J=5.4 Hz, 4 H), 3.77 - 3.93(m, 4 H), 3.35 - 3.65 (m, 12 H), 3.25 - 3.34 (m, 4 H), 3.10 - 3.24 (m, 4 H), 2.33 - 2.42 (m, 4 H), 2.03 - 2.31 (m, 8 H), 1.74 - 2.03 (m, 6 H), 1.46 - 1.70 (m, 8 H), 1.18 - 1.42 (m, 8 H).

[0820] Example 08: 7-({[5-({8-[(7-{4-[4-(1-Benzothiophene-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoylamido}methyl)pyrazin-2-yl]methyl}carbamoyl)heptanoic acid (7-{4-[4-(1-Benzothiophene-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester

[0821] [Chemical Formula 78]

[0822]

[0823] To a solution of Int03 (110 mg) and Int05 (16 mg) in anhydrous DMF (13 mL) was added TBTU (543 mg). After 5 minutes, TEA (0.54 mL) and piperazine (50 mg) were added, and the reaction was stirred at room temperature overnight. More piperazine (17 mg) and TEA (0.15 mL) were added, and the reaction was stirred at room temperature for another 1 h. HO and DCM were added to the reaction mixture, the mixture phases were separated, and the aqueous phase was extracted with DCM (3 times). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under vacuum. The resulting crude product was purified by chromatography on a silica gel column (eluent = neat DCM to 3% MeOH in DCM) to give Example 08 (30 mg).

[0824] LC-MS (ESI): m / z (M+1): 1342.9, Rt= 2.09 min. (Method 3).

[0825] 1 H NMR (400 MHz, chloroform-d) δ ppm 8.49 (s, 2 H), 7.63 (d, J=9.6 Hz, 2H), 7.55 (d, J=8.1 Hz, 2 H), 7.46 (d, J=8.6 Hz, 2 H), 7.37 - 7.43 (m, 4 H),7.18 - 7.34 (m, 2 H), 6.82 - 6.94 (m, 6 H), 6.68 (br t, J=5.0 Hz, 2 H), 6.50 (d, J=9.4 Hz, 2 H), 6.32 (br s, 4 H), 4.56 (d, J=5.5 Hz, 4 H), 4.09 (t, J=6.1Hz, 4 H), 3.21 (br s, 8 H), 2.75 (br s, 8 H), 2.56 (br t, J=7.3 Hz, 4 H), 2.36 (t, J=7.3 Hz, 4 H), 2.22 (t, J=7.6 Hz, 4 H), 1.87 - 1.98 (m, 4 H), 1.78(quin, J=7.3 Hz, 4 H), 1.51 - 1.69 (m, 8 H), 1.28 - 1.43 (m, 8 H).

[0826] Example 10: 4-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl}piperazin-1-yl)-4-oxobutanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester

[0827] [Chemical Formula 79]

[0828]

[0829] To a solution of Int07 (568 mg) in anhydrous DMF (7.73 mL) was added TBTU (395 mg). After 5 minutes, piperazine (37 mg) and TEA (0.26 mL) were added. The mixture was stirred at room temperature for 16 hours. Water and DCM were added to the reaction mixture, and the mixture was extracted with DCM (3 times). The collected organic layer was dried over Na2SO4, filtered, and concentrated under high vacuum. The resulting crude product was purified by chromatography on a silica gel column (eluent = 0 to 6% MeOH in DCM) to give Example 10 (250 mg).

[0830] LC-MS (ESI): m / z (M+1): 1177.9, Rt= 1.99 min. (Method 3). 1 H NMR (600MHz, chloroform-d) δ ppm 7.63 (d, J=9.6 Hz, 2 H), 7.55 (d, J=7.9 Hz, 2 H), 7.45 (d,J=8.6 Hz, 2 H), 7.40 (q, J=5.6 Hz, 4 H), 7.21 - 7.31 (m, 2 H), 6.87 - 6.92(m, 4 H), 6.85 (dd, J=8.6, 2.3 Hz, 2 H), 6.51 (d, J=9.6 Hz, 2 H), 6.34 (br s,4 H), 4.14 (t, J=6.1 Hz, 4 H), 3.28 - 3.62 (m, 8 H), 3.22 (br s, 8 H), 2.67 -2.89 (m, 12 H), 2.51 - 2.66 (m, 8 H), 1.88 - 1.96 (m, 4 H), 1.80 (br d, J=6.6Hz, 4 H).

[0831] Example 12: 4-(9-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl}-3,9-diazaspiro[5.5]undec-3-yl)-4-oxobutanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester

[0832] [Chemical formula 80]

[0833]

[0834] To a solution of Int07 (200 mg) and Int09 (57 mg) in anhydrous DMF (13 mL) was added TBTU (543 mg). After 5 minutes, TEA (0.54 mL) and piperazine (50 mg) were added, and the reaction was stirred at room temperature overnight. More piperazine (17 mg) and TEA (0.15 mL) were added, and the reaction was further stirred at room temperature for 1 h. HO and DCM were added to the reaction mixture, the mixture phases were separated, and the aqueous phase was extracted with DCM (3 times). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under vacuum. The resulting crude product was purified by chromatography on a silica gel column (eluent = neat DCM to 3% MeOH in DCM) to give Example 12 (41 mg).

[0835] LC-MS (ESI): m / z (M+1): 1245.7, Rt= 2.03 min. (Method 3).

[0836] 1H NMR (500 MHz, chloroform-d) δ ppm 7.63 (d, J=9.5 Hz, 2 H), 7.56 (d, J=8.1 Hz, 2 H), 7.44 (d, J=8.6 Hz, 2 H), 7.36 - 7.42 (m, 4 H), 7.23 - 7.31 (m,2 H), 6.87 - 6.94 (m, 4 H), 6.85 (dd, J=8.6, 2.2 Hz, 2 H), 6.52 (d, J=9.5 Hz, 2 H), 6.34 (br s, 4 H), 4.16 (t, J=5.9 Hz, 4 H), 3.31 - 3.63 (m, 8 H), 3.16 -3.31 (m, 8 H), 2.78 - 3.10 (m, 8 H), 2.59 - 2.77 (m, 12 H), 1.82 - 1.96 (m, 8H), 1.29 - 1.51 (m, 8 H).

[0837] Example 19: 8-(4-{8-[(7-{4-[4-(1-Benzothiophene-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}piperazin-1-yl)-8-oxooctanoic acid (7-{4-[4-(1-Benzothiophene-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester

[0838] [Chemical Formula 81]

[0839]

[0840] To a solution of Int03 (890 mg) in anhydrous DMF (13 mL) was added TBTU (543 mg). After 5 minutes, TEA (0.54 mL) and piperazine (50 mg) were added, and the reaction was stirred at room temperature overnight. More piperazine (17 mg) and TEA (0.15 mL) were added, and the reaction was stirred at room temperature for another 1 h. HO and DCM were added to the reaction mixture, the mixture phases were separated, and the aqueous phase was extracted with DCM (3 times). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under vacuum. The resulting crude product was purified by chromatography on a silica gel column (eluent = neat DCM to 3% MeOH in DCM) to give Example 19 (660 mg).

[0841] LC-MS (ESI): m / z (M+1): 1290.0, Rt= 2.17 min. (Method 3). 1 H NMR (400MHz, DMSO-d6) δ ppm 7.88 (d, J=9.6 Hz, 2 H), 7.63 - 7.72 (m, 4 H), 7.59 (d, J=8.1 Hz, 2 H), 7.38 (d, J=5.7 Hz, 2 H), 7.25 (t, J=7.8 Hz, 2 H), 6.91 - 7.00(m, 4 H), 6.86 (d, J=7.7 Hz, 2 H), 6.42 (d, J=9.4 Hz, 2 H), 6.27 (br s, 4 H), 4.13 (t, J=6.2 Hz, 4 H), 3.23 - 3.48 (m, 8 H), 3.04 (br s, 8 H), 2.60 (br s,8 H), 2.43 (br t, J=7.0 Hz, 4 H), 2.28 - 2.37 (m, 4 H), 2.21 (t, J=7.3 Hz, 4H), 1.75 - 1.86 (m, 4 H), 1.58 - 1.71 (m, 4 H), 1.50 (quin, J=7.2 Hz, 4 H),1.34 - 1.44 (m, 4 H), 1.16 - 1.29 (m, 8 H).

[0842] Example 45: 1-[5-(4-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}piperidine-1-carbonyl)pyrazine-2-carbonyl]piperidine-4-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester

[0843] [Chemical Formula 82]

[0844]

[0845] To a solution of Int54 (200 mg) and TEA (0.24 mL) in DCM (6 mL) was added pyrazine-2,5-dicarbonyl dichloride (36 mg) at 0°C. The reaction was allowed to stir at room temperature for 1 h. The mixture was diluted with DCM and washed with H2O and brine. The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting crude product was purified by chromatography on a silica gel column (eluent = 0% to 10% MeOH in DCM) to provide Example 45 (6 mg).

[0846] LC-MS (ESI): m / z (M+1): 1282.0, Rt= 2.72 min. (Method 3). 1 H NMR (600 MHz, DMSO-d6 ) δ ppm 9.59 (br s, 2 H), 8.78 (s, 2 H), 7.91 (d, J=9.6 Hz, 2 H), 7.75 (d, J=5.6 Hz, 2 H), 7.64 - 7.73 (m, 4 H), 7.49 (d, J=5.6 Hz, 2 H), 7.31(t, J=7.9 Hz, 2 H), 6.90 - 7.06 (m, 6 H), 6.45 (d, J=9.6 Hz, 2 H), 6.09 -6.42 (m, 4 H), 4.16 (br t, J=5.4 Hz, 4 H), 3.64 - 4.40 (m, 4 H), 3.33 - 3.71(m, 8 H), 3.30 (br d, J=3.0 Hz, 4 H), 3.04 - 3.60 (m, 8 H), 2.94 - 3.18 (m, 4H), 2.77 (td, J=10.5, 4.1 Hz, 2 H), 1.70 - 2.02 (m, 12 H), 1.46 - 1.67 (m, 4H).

[0847] Example 46: 3-{1-[4-(4-{3-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3-oxopropyl}piperidin-1-yl)-1,3,5-triazin-2-yl]piperidin-4-yl}propanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester

[0848] [Chemical Formula 83]

[0849]

[0850] To a solution of 2,4-dichloro-1,3,5-triazine (6.2 mg) and Int57 (49 mg) in DMF (1.2 mL) was added DIPEA (32 mg). The reaction was stirred at room temperature for 16 h. The mixture was diluted with EtOAc and washed with H₂O (2x) and brine (2x). The organic phase was dried over Na₂SO₄, filtered, and evaporated under vacuum. The crude product was purified by chromatography on a silica gel column (eluent: 0% to 10% MeOH in DCM) followed by chromatography on a C-18 column (eluent: 5% to 50% MeCN in H₂O containing 0.1% HCOOH). The product was diluted with DCM and desalted with excess K₂CO₃. After stirring for 10 minutes, the solid was filtered off, and the solution was concentrated in vacuo to afford Example 46 (17 mg).

[0851] LC-MS (ESI): m / z (M+1): 1293.0, Rt= 1.98 min. (Method 3). 1 H NMR (400 MHz, chloroform-d) δ ppm 8.13 (s, 1 H), 7.63 (d, J=9.5 Hz, 2 H), 7.55 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.7 Hz, 2 H), 7.36 - 7.43 (m, 4 H), 7.23 - 7.32 (m, 2 H), 6.82- 6.92 (m, 6 H), 6.53 (d, J=9.4 Hz, 2 H), 6.35 (br s, 4 H), 4.67 (br d, J=13.4 Hz, 4 H), 4.09 (t, J=6.1 Hz, 4 H), 3.20 (br s, 8 H), 2.72 (br s, 8 H), 2.61 - 2.70 (m, 4 H), 2.54 (t, J=7.4 Hz, 4 H), 2.41 (t, J=7.6 Hz, 4 H), 1.86- 1.96 (m, 4 H), 1.72 - 1.82 (m, 4 H), 1.63 - 1.71 (m, 4 H), 1.42 - 1.64 (m, 6 H), 1.00 - 1.15 (m, 4 H).

[0852] Example 47: 3-{1-[4,6-bis(4-{3-[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3-oxopropyl}piperidin-1-yl)-1,3,5-triazin-2-yl]piperidin-4-yl}propanoic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester hexa(trifluoroacetate)

[0853] [Chemical Formula 84]

[0854]

[0855] To a solution of Int57 (199 mg) and 2,4,6-trichloro-1,3,5-triazine (20 mg) in DMF (4 mL) was added DIPEA (0.12 mL), and the reaction was stirred at 60°C for 16 h. The mixture was cooled to room temperature, diluted with EtOAc, and washed with H₂O (2x) and brine (2x). The organic phase was dried over Na₂SO₄, filtered, and concentrated under vacuum. The resulting crude product was purified by chromatography on a silica gel column (eluent = 0% to 10% MeOH in DCM). The product was further purified by chromatography on a C-18 column (eluent = 5% to 50% MeCN in H₂O containing 0.1% HCOOH) to afford Example 47 (51 mg).

[0856] LC-MS (ESI): m / z (M+1): 1885, Rt= 2.22 min. (Method 3). 1H NMR (400 MHz, chloroform-d) δ ppm 10.92 - 13.62 (m, 3 H), 7.64 (dd, J=8.9, 5.4 Hz, 6 H), 7.42 -7.51 (m, 6 H), 7.28 - 7.34 (m, 6 H), 6.94 (d, J=7.5 Hz, 3 H), 6.90 (s, 3 H), 6.84 (br d, J=8.6 Hz, 3 H), 6.54 (d, J=9.6 Hz, 3 H), 6.35 (br s, 6 H), 4.46 (br d, J=12.7 Hz, 6 H), 4.08 (br t, J=5.6 Hz, 6 H), 3.79 (br d, J=11.0 Hz, 6H), 3.47 - 3.61 (m, 6 H), 3.34 - 3.45 (m, 6 H), 3.07 - 3.30 (m, 12 H), 2.75(br t, J=12.5 Hz, 6 H), 2.38 (br t, J=7.3 Hz, 6 H), 2.01 - 2.18 (m, 6 H), 1.64 - 1.99 (m, 12 H), 1.35 - 1.63 (m, 9 H), 1.09 (q, J=11.0 Hz, 6 H).

[0857] Example 48: (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 3-[1-({5-[(4-{3-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3-oxopropyl}piperidin-1-yl)methyl]pyrazin-2-yl}methyl)piperidin-4-yl]propanoate

[0858] [Chemical Formula 85]

[0859]

[0860] Example 48 was prepared starting from Int57 (150 mg) and 2,5-bis(bromomethyl)pyrazine (33 mg) according to the procedure described for Example 46. The crude product was purified by chromatography on a silica gel column (eluent = 0% to 4% MeOH in DCM) to afford Example 48 (15 mg).

[0861] LC-MS (ESI): m / z (M+1): 1309, Rt= 1.77 min. (Method 3). 1 H NMR (500 MHz, chloroform-d) δ ppm 8.54 (s, 2 H), 7.63 (d, J=9.5 Hz, 2 H), 7.55 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.6 Hz, 2 H), 7.37 - 7.43 (m, 4 H), 7.23 - 7.31 (m, 2 H), 6.87- 6.92 (m, 4 H), 6.85 (dd, J=8.5, 2.1 Hz, 2 H), 6.52 (d, J=9.5 Hz, 2 H), 6.34(br s, 4 H), 4.09 (t, J=6.2 Hz, 4 H), 3.59 (s, 4 H), 3.01 - 3.36 (m, 8 H), 2.79 - 2.87 (m, 4 H), 2.62 - 2.79 (m, 8 H), 2.54 (br t, J=7.2 Hz, 4 H), 2.38 (t, J=7.8 Hz, 4 H), 1.87 - 2.01 (m, 8 H), 1.73 - 1.83 (m, 4 H), 1.46 - 1.64 (m, 8 H), 1.17 - 1.29 (m, 6 H).

[0862] Example 49: 3-{1-[5-(4-{3-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3-oxopropyl}piperidine-1-carbonyl)pyrazine-2-carbonyl]piperidin-4-yl}propanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester

[0863] [Chemical Formula 86]

[0864]

[0865] To a solution of Int57 (250 mg) and TEA (0.58 mL) in DMF (8 mL) at 0°C was added pyrazine-2,5-dicarbonyl dichloride (43 mg). The reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc and washed with H₂O and brine (2 x). The organic phase was dried over Na₂SO₄, filtered, and concentrated under vacuum. The resulting crude product was purified by chromatography on a silica gel column (eluent = 0% to 10% MeOH in DCM) to afford Example 49 (35 mg).

[0866] LC-MS (ESI): m / z (M+1): 1338, Rt= 2.11 min. (Method 3). 1 H NMR (400 MHz, chloroform-d) δ ppm 8.79 (s, 2 H), 7.64 (d, J=9.4 Hz, 2 H), 7.55 (d, J=7.9 Hz, 2H), 7.47 (d, J=8.6 Hz, 2 H), 7.37 - 7.44 (m, 4 H), 7.20 - 7.31 (m, 2 H), 6.82- 6.93 (m, 6 H), 6.53 (d, J=9.4 Hz, 2 H), 6.35 (br s, 4 H), 4.10 (t, J=6.2Hz, 4 H), 3.73 - 4.80 (m, 4 H), 3.20 (br s, 8 H), 2.74 (br s, 8 H), 2.64 -3.05 (m, 4 H), 2.55 (t, J=7.5 Hz, 4 H), 2.42 (t, J=7.5 Hz, 4 H), 1.86 - 1.98 (m, 4 H), 1.11 - 1.85 (m, 18 H).

[0867] Example 50: 1-[5-(3-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}azetidine-1-carbonyl)pyrazine-2-carbonyl]azetidine-3-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester bis(trifluoroacetate)

[0868] [Chemical Formula 87]

[0869]

[0870] Example 50 was prepared according to the procedure described for Example 49 starting from Int60 (350 mg) and pyrazine-2,5-dicarbonyl dichloride (66 mg) to give Example 50 (8.2 mg).

[0871] LC-MS (ESI): m / z (M+1): 1225.9, Rt= 2.64 min. (Method 3). 1 H NMR (400 MHz, chloroform-d) δ ppm 11.32 - 13.18 (m, 3 H), 9.13 - 9.17 (m, 2 H), 7.59 - 7.73 (m, 4H), 7.41 - 7.52 (m, 4 H), 7.27 - 7.36 (m, 4 H), 6.95 (dd, J=7.6, 3.0 Hz, 2H), 6.89 (br d, J=4.6 Hz, 2 H), 6.85 (br d, J=8.6 Hz, 2 H), 6.56 (d, J=9.4Hz, 2 H), 6.34 - 6.51 (m, 4 H), 4.85 (br d, J=7.0 Hz, 4 H), 4.33 - 4.46 (m, 4H), 4.09 (br t, J=5.5 Hz, 4 H), 3.83 (br d, J=10.7 Hz, 4 H), 3.48 - 3.68 (m,6 H), 3.40 (br t, J=12.3 Hz, 4 H), 3.09 - 3.32 (m, 8H), 1.80 - 2.11 (m, 8H).

[0872] Example 51: 5-{[5-({5-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-5-oxopentyl}carbamoyl)-1,3-thiazol-2-yl]formamido}pentanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester

[0873] [Chemical Formula 88]

[0874]

[0875] Step A: To a solution of Int62 (0.68 g) in DCM (10 mL) was added TFA (1.12 mL) dropwise at room temperature. The reaction was stirred at room temperature for 4 h. Toluene (20 mL) was added, and the volatiles were evaporated under vacuum. The residue was dissolved in THF (10 mL) and toluene (20 mL) at room temperature, and 4M HCl in 1,4-dioxane (1.2 mL) was added dropwise. After stirring for 10 minutes, the mixture was concentrated under vacuum to provide Example 51-Step A: 5-aminopentanoic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester dihydrochloride (658 mg, quantitative yield).

[0876] Step B: To a solution of crude 5-aminopentanoic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester dihydrochloride (0.20 g) in DMF (6 mL) was added 1,3-thiazole-2,5-dicarbonyl dichloride (33 mg) followed by TEA (0.6 mL) at room temperature. The reaction was stirred at 100°C for 3 h. The reaction was cooled to room temperature, diluted with cold NH4Cl ss, and extracted with DCM (2 x). The combined organic layers were dried on a phase separator and concentrated under vacuum. The crude product was purified by chromatography on a C-18 column (eluent = 0% to 100% MeCN in H2O containing 0.1% TFA) followed by chromatography on a silica gel column (eluent = 0% to 10% MeOH in DCM) to afford Example 51 (3.3 mg).

[0877] LC-MS (ESI): m / z (M+1): 1257.7, Rt= 2.09 min. (Method 3).

[0878] 1H NMR (500 MHz, chloroform-d) δ ppm 8.23 ​​(s, 1 H), 7.61 - 7.69 (m, 2 H), 7.52 - 7.58 (m, 2 H), 7.44 - 7.50 (m, 2 H), 7.36 - 7.43 (m, 4 H), 7.32 (t, J=6.0 Hz, 1 H), 7.23 - 7.29 (m, 2 H), 6.83 - 6.93 (m, 6 H), 6.61 (br s, 1 H), 6.47 - 6.55 (m, 2 H), 6.23 - 6.39 (m, 4 H), 4.04 - 4.15 (m, 4 H), 3.37 - 3.49(m, 4 H), 3.19 (br s, 8 H), 2.73 (br s, 8 H), 2.49 - 2.59 (m, 4 H), 2.40 -2.48 (m, 4 H), 1.86 - 1.95 (m, 4 H), 1.71 - 1.81 (m, 8 H), 1.63 - 1.70 (m, 4H)

[0879] Examples 52 and 53 were prepared following the procedure described for Example 51. The reactants used in the synthesis of each compound and their characterizations are listed in Table 9.

[0880] [Table 9]

[0881]

[0882]

[0883] Example 54: (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 6-(4-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexyl}piperazin-1-yl)hexanoate

[0884] [Chemical Formula 89]

[0885]

[0886] To a suspension of Int69 (140 mg) in DMF (1 mL) was added TEA (0.04 mL) and piperazine (9 mg). The mixture was stirred at 100°C for 5 h. The solution was cooled to RT, diluted with EtOAc, and washed with H2O (x2) and brine. The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting crude product was purified by chromatography on a silica gel column (eluent = 0% to 10% MeOH in DCM) to afford Example 54 (40 mg).

[0887] LC-MS (ESI): m / z (M+1): 1207.0, Rt= 1.78 min. (Method 3). 1 H NMR (400 MHz, chloroform-d) δ ppm 7.63 (d, J=9.5 Hz, 2 H), 7.55 (d, J=7.9 Hz, 2 H), 7.45 (d, J=8.4 Hz, 2 H), 7.37 - 7.43 (m, 4 H), 7.23 - 7.32 (m, 2 H), 6.80 - 6.93 (m, 6H), 6.52 (d, J=9.5 Hz, 2 H), 6.34 (s, 4 H), 4.09 (t, J=6.2 Hz, 4 H), 3.20 (brs, 8 H), 2.65 - 2.91 (m, 8 H), 2.51 - 2.59 (m, 4H), 2.34 - 2.40 (m, 4 H), 2.20 - 2.29 (m, 4 H), 2.16 - 2.64 (m, 8 H), 1.85 - 1.96 (m, 4 H), 1.73 - 1.82 (m, 4 H), 1.55 - 1.71 (m, 4 H), 1.40 - 1.50 (m, 4 H), 1.27 - 1.35 (m, 4 H).

[0888] Example 55: 6-{4-[({6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexyl}oxy)carbonyl]piperazine-1-carbonyloxy}hexanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester

[0889] [Chemical formula 90]

[0890]

[0891] To a solution of Int70 (20 mg) in DCM (1 mL) at 0°C was added DIPEA (0.02 mL) followed by piperazine (0.9 mg). The reaction was stirred at room temperature for 6 h. The reaction mixture was diluted with DCM and washed with Na2CO3 (2x). The organic phase was filtered through a phase separator and concentrated under vacuum. The resulting crude product was purified by chromatography on a silica gel column (eluent = 0% to 10% MeOH in DCM) to afford Example 55 (7 mg).

[0892] LC-MS (ESI): m / z (M+1): 1293.7, Rt= 2.23 min. (Method 3). 1 H NMR (600 MHz, chloroform-d) δ ppm 7.61 (d, J=9.6 Hz, 2 H), 7.54 (d, J=8.1 Hz, 2 H), 7.44 (d, J=8.6 Hz, 2 H), 7.39 - 7.41 (m, 2 H), 7.36 - 7.38 (m, 2 H), 7.25 - 7.28 (m, 2H), 6.88 (d, J=7.6 Hz, 2 H), 6.86 (d, J=2.0 Hz, 2 H), 6.83 (dd, J=8.6, 2.1Hz, 2 H), 6.50 (d, J=9.6 Hz, 2 H), 6.31 (br s, 4 H), 4.07 (t, J=6.3 Hz, 4 H), 4.03 (t, J=6.7 Hz, 4 H), 3.40 (br s, 8 H), 3.18 (br s, 8 H), 2.71 (br s, 8H), 2.53 (br t, J=7.3 Hz, 4 H), 2.36 (t, J=7.5 Hz, 4 H), 1.85 - 1.94 (m, 4H), 1.72 - 1.79 (m, 4 H), 1.66 (quin, J=7.7 Hz, 4 H), 1.58 - 1.64 (m, 4 H), 1.32 - 1.40 (m, 4 H).

[0893] Example 56 was prepared according to the procedure described for Example 54. The reactants used in the synthesis of Example 56 and their characterizations are listed in Table 10.

[0894] [Table 10]

[0895]

[0896] Example 57: 6-{[4,6-bis({6-[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexyl}oxy)-1,3,5-triazin-2-yl]oxy}hexanoic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester tetra(trifluoroacetate)

[0897] To a solution of 2,4,6-trichloro-1,3,5-triazine (16 mg) and Int68 (150 mg) in MeCN (1 mL) was added DIPEA (0.11 mL) dropwise at 0°C. The reaction was stirred at room temperature for 5 days. The reaction mixture was diluted with DCM (10 mL) and washed with H₂O (3 mL). The organic phase was dried on a phase separator and concentrated under vacuum. The resulting crude product was purified on a silica gel column (eluent = 0% to 7% in DCM) and then chromatographed on a C-18 column (eluent = 5% to 95% in H₂O containing 0.1% TFA) to afford Example 57 (7 mg).

[0898] [Chemical Formula 91]

[0899]

[0900] LC-MS (ESI): m / z (M+1): 1808.3, Rt= 2.32 min. (Method 3). 1H NMR (500 MHz, chloroform-d) δ ppm 7.61 - 7.65 (m, 6 H), 7.41 - 7.49 (m, 6 H), 7.28 - 7.35 (m, 6H), 6.94 (d, J=7.5 Hz, 3 H), 6.90 (d, J=1.8 Hz, 3 H), 6.83 (dd, J=8.6, 2.1Hz, 3 H), 6.54 (d, J=9.5 Hz, 3 H), 6.32 (br s, 6 H), 4.30 (br t, J=6.6 Hz, 6H), 4.06 - 4.13 (m, 6 H), 3.83 (br d, J=11.4 Hz, 6 H), 3.55 (br d, J=12.5 Hz, 6 H), 3.40 (br t, J=12.3 Hz, 6 H), 3.24 - 3.33 (m, 6 H), 3.19 (br t, J=10.4Hz, 6 H), 2.37 (br t, J=7.5 Hz, 6 H), 2.06 - 2.13 (m, 6 H), 1.95 (br dd, J=13.0, 6.2 Hz, 6 H), 1.70 - 1.77 (m, 6 H), 1.67 (dt, J=15.3, 7.7 Hz, 6 H), 1.36 - 1.50 (m, 6 H).

[0901] Example 58: 5-{1-[4-(4-{5-[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-5-oxopentyl}-1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3-triazol-4-yl}pentanoic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester formate

[0902] [Chemical Formula 92]

[0903]

[0904] DIPEA (0.04 mL) and CuI (48 mg) were dissolved in degassed DMF (1.5 mL). Int76 (357 mg) and 1,4-diazide butane (35.0 mg) were then added at RT, and the reaction was stirred at 40°C overnight. The reaction mixture was cooled to RT and directly purified by chromatography on a C18 column (eluent = 3% to 40% MeCN in H2O containing 0.1% HCOOH) to give Example 58 (24 mg).

[0905] LC-MS (ESI): m / z (M / 2+H): 642.6, Rt= 1.93 min. (Method 4). 1 H NMR (500MHz, DMSO-d6) δ ppm 7.88 (d, J=9.6 Hz, 2 H), 7.71 (s, 2 H), 7.67 (d, J=5.5Hz, 2 H), 7.65 (d, J=8.6 Hz, 2 H), 7.59 (d, J=8.0 Hz, 2 H), 7.37 (d, J=5.4Hz, 2 H), 7.25 (t, J=7.9 Hz, 2 H), 6.96 (d, J=1.8 Hz, 2 H), 6.94 (dd, J=8.6,2.1 Hz, 2 H), 6.85 (d, J=7.5 Hz, 2 H), 6.42 (d, J=9.5 Hz, 2 H), 6.26 (br s, 4H), 4.26 (br s, 4 H), 4.11 (t, J=6.4 Hz, 4 H), 3.03 (br s, 8 H), 2.59 (br s,8 H), 2.55 (br t, J=6.9 Hz, 4 H), 2.42 (br t, J=7.1 Hz, 4 H), 2.33 - 2.37 (m,4 H), 1.74 - 1.83 (m, 4 H), 1.69 (br s, 4 H), 1.62 (dt, J=14.5, 7.2 Hz, 4 H), 1.51 - 1.58 (m, 8 H).

[0906] Examples 59, 60, 61, 62, 63, and 64 were prepared following the procedure described for Example 58. The reactants used in the synthesis of each compound and their characterizations are listed in Table 11.

[0907] [Table 11]

[0908]

[0909]

[0910]

[0911]

[0912]

[0913]

[0914]

[0915]

[0916] Preparation of crystal forms

[0917] The instruments used in this article are as follows:

[0918] XRPD: Empyrean, Malvern Panalytical

[0919] DSC: DSC Q2000 V24.11 Build 124, TA Instruments

[0920] TGA: TGA Q5000 V3.17 Build 265, TA Instruments

[0921] (1) The reference material of Form A of the compound of Example 10 was prepared according to the following procedure:

[0922] The compound from Example 10 (48.0 mg, 0.040 mmol) was suspended in 2-propanol (2 mL). The suspension was warmed to 50°C, and DCM was added at the same temperature. The suspension turned from a pale pink wax to a white solid. The solvent was concentrated in vacuo. A portion of the white solid was recovered.

[0923] The solid was suspended in 2-propanol (2 mL). The suspension was warmed to 50°C, and DCM (0.9 mL) was added at the same temperature. The suspension changed from a pale pink wax to a white solid, and then to a clear solution. At the end of the DCM addition, an opaque solution was observed, and the heat was turned off; the suspension was allowed to stand over the weekend to reach room temperature (in a heating mantle, without stirring). The compound of Example 10 (48.0 mg, 0.040 mmol) was recovered by filtration and washed with cold IPA.

[0924] The characteristic XRPD peaks of Form A of the compound of Example 10 are shown below.

[0925] [Table 12]

[0926]

[0927] The XRPD pattern of Form A is shown in Figure 1 Form A is characterized by at least one, two, three, four, five, or six XRPD peaks selected from the group consisting of about 5.4±0.2, 9.7±0.2, 11.8±0.2, 12.1±0.2, 12.6±0.2, 13.7±0.2, 14.3±0.2, 15.0±0.2, 16.2±0.2, 16.7±0.2, 20.5±0.2, 21.2±0.2, 21.7±0.2, 23.7±0.2, and 27.6±0.2 (°2θ).

[0928] like Figure 2 As shown in , the DSC trace shows an endothermic event at 176°C, which can be attributed to the melting of Form A. Form A has a DSC thermogram characterized by an endothermic peak at about 176±3°C.

[0929] (2) The compound of Example 10 (50 mg) was suspended in DMSO (20 vol). The system was heated to 75°C (hot plate temperature); dissolution was achieved at around 70-71°C. The solution was cooled to 50°C and seeded with crystals of Form B (approximately 4-5 mg); the crystals appeared persistent, and the system was aged for approximately 10 minutes. The heat was turned off, and the suspension was allowed to cool to room temperature and aged overnight with stirring. The next day, the solid was isolated by filtration, evaporated in vacuo, and then dried in a vacuum oven at 50°C under reduced pressure overnight.

[0930] Output material: 44.1 mg (uncorrected recovery 88% w / w)

[0931] The characteristic XRPD peaks of Form B are shown below.

[0932] [Table 13]

[0933]

[0934] The XRPD pattern of Form B is shown in Figure 3 Form B is characterized by at least one, two, three, four, five, or six XRPD peaks selected from the group consisting of about 7.5±0.2, 8.8±0.2, 10.1±0.2, 11.1±0.2, 11.5±0.2, 11.9±0.2, 12.5±0.2, 15.5±0.2, 15.7±0.2, 16.4±0.2, 17.4±0.2, 18.4±0.2, 19.9±0.2, 21.0±0.2, and 22.0±0.2 (°2θ).

[0935] like Figure 4 As shown in , the DSC trace shows an initial small desolvation event followed by a major endotherm with an onset at 159°C (enthalpy 83 J / g). Form B has a DSC thermogram characterized by an endotherm at approximately 159±3°C.

[0936] (3) The reference material of Form 1 of the compound of Example 19 was prepared according to the following procedure:

[0937] The compound of Example 19 (55.4 g, 42.96 mmol) was suspended in ethanol (664.8 mL) and stirred at 47°C (external) for 2 days. The suspension was then cooled to room temperature and stirred at this temperature for another 2 days. The product was collected by filtration and dried at room temperature for 2 days.

[0938] Output material: 45.3 g, 35.13 mmol, (81.7% yield) as a white solid.

[0939] The characteristic XRPD peaks of Form 1 are shown below.

[0940] [Table 14]

[0941]

[0942] The XRPD pattern of Form 1 is shown in Figure 5 Form 1 is characterized by at least one, two, three, four, five, or six XRPD peaks selected from the group consisting of about 7.6±0.2, 8.3±0.2, 12.4±0.2, 12.7±0.2, 13.9±0.2, 15.4±0.2, 15.8±0.2, 19.6±0.2, 20.3±0.2, and 22.9±0.2 (°2θ).

[0943] like Figure 6 As shown in , the TGA curve shows a weight loss of 2.7% w / w from ambient temperature to 150°C; the weight loss data is consistent with the theoretical amount required for the dihydrate (i.e., 2.7% w / w).

[0944] like Figure 7 As shown in , the DSC trace shows an endothermic event at 81°C, which is associated with the melting of the crystalline material. Form 1 has a DSC thermogram characterized by an endothermic peak at about 81±3°C.

[0945] Test 1: Stability of S9 on human skin

[0946] Skin S9 from human donors (male and female) were stored at -80°C until use. On the day of the experiment, skin S9 were quickly thawed in a 37°C water bath and diluted to a protein concentration of 3.165 mg / mL with 50 mM potassium phosphate buffer, pH 7.4. Test compounds were dissolved in DMSO to obtain a 10 mM stock solution. 5 μL of the 10 mM stock solution in DMSO was diluted with 995 μL of methanol to obtain a 50 μM dosing solution. The positive control (clopidogrel) was dissolved in DMSO to obtain a 10 mM stock solution. A 50 μM dosing solution was prepared by diluting 5 μL of the 10 mM stock solution in DMSO with 995 μL of methanol. The general procedure involved incubating the test compound at 0.5 μM (final concentration) with pooled skin S9 (final concentration) plus a 2.5 mg / mL solution of NADPH regeneration system and UDPGA. Negative controls were performed using pooled skin S9 without all cofactors. To 395 μL of a 3.165 mg / mL skin S9 solution in a 96-well plate (incubation plate), 5 μL of test compound or positive control dosing solution was added for 5 minutes at 37°C. The incubation reaction was initiated by adding 50 μL of prewarmed NADPH regeneration system and 50 μL of UDPGA or 100 μL of buffer (for negative controls) to the incubation mixture. Test compounds were incubated in duplicate with and without cofactors, while positive controls were incubated in duplicate with and without cofactors. Incubations were performed in a shaking water bath at 37°C for 1 hour. At each time point (after 0, 5, 15, 30, 45, and 60 minutes), 25 μL of the spiked skin S9 suspension was collected and added to 25 μL of milliQ water and 150 μL of stop solution (1% formic acid and 0.2 μM epiprazole-D8 in acetonitrile) to precipitate proteins. The sample was mixed thoroughly and centrifuged at 3000 rpm for 10 minutes at 4°C. The supernatant (100 μL) was collected, diluted with 18% acetonitrile in Milli-Q water (200 μL), and then injected into the LC MS / MS system. The peak area ratio of the test compound to the internal standard was monitored as a representative of the compound concentration. Each time point was referenced to the zero time point sample (taken as 100%) to determine the percentage of test compound remaining. The half-life was calculated according to the relationship T1 / 2 = -0.693 / k, where k is the slope of the concentration vs. time curve. In addition, in each sample, the active parent compound (epirazole) was quantified based on the MS response of epiriprazole-D8 in the same sample. Table 15 lists the stability results of the exemplary compounds in human skin S9. When multiple values ​​were measured, the average half-life was calculated.

[0947] [Table 15]

[0948]

[0949] Experiment 2: Stability of human hepatocytes

[0950] Cryopreserved hepatocytes from human donors were stored in the vapor phase of a liquid nitrogen freezer until use. Cell viability was assessed using a trypan blue dye exclusion assay after thawing and before use. 0.5 x 10 6 Incubate the test compounds and positive controls (testosterone and 7-OH coumarin) at a cell concentration of 10 cells / mL. Dispense 0.495 mL of the cell suspension into a 48-well plate and pre-incubate at 37°C for at least 10 minutes.

[0951] The test compound and positive control were dissolved in DMSO to obtain 10 mM, 50 mM, and 5 mM stock solutions of the test compound, testosterone, and 7-OH coumarin, respectively. The stock solutions were further diluted in methanol to obtain 50 μM, 1 mM, and 500 μM final dosing solutions of the test compound, testosterone, and 7-OH coumarin, respectively. All solutions were prepared immediately before the assay. 0.495 mL of 0.5 x 10 6 The cell suspension was supplemented with 5 μL of 50 μM test compound, 1000 μM testosterone, and 500 μM 7-OH-coumarin to final concentrations of 0.5 μM (test compound), 10 μM (testosterone), and 5 μM (7-OH-coumarin). Incubations were performed at 37°C with gentle orbital shaking at 350 rpm. Test compounds were performed in duplicate, while positive controls were performed in single replicates. At each time point (0, 5, 10, 15, 20, 30, 45, 60, 90, 120, and 180 min), 30 μL of the incubation mixture from each well was added to 30 μL of milliQ water and 180 μL of a reservoir solution (1% formic acid and 0.2 μM epiprazole-D8 in acetonitrile) to precipitate proteins. The sample was mixed thoroughly and centrifuged at 3000 rpm for 10 min at 4°C. The supernatant (100 μL) was collected, diluted with 18% acetonitrile in Milli-Q water (200 μL), and injected onto the LC MS / MS system to monitor the peak area ratio of the test compound to the internal standard as a representative of the compound concentration.

[0952] Metabolic stability was calculated from the change in the peak area ratio of the remaining test compound or positive control to the internal standard over time. The first-order elimination constant k (min) was obtained from the log-linear plot of XLFit or Morphit software by plotting the change in the peak area ratio of the remaining test compound to the internal standard over time. -1The half-life is obtained from the relationship T1 / 2 = -0.693 / k. The value of CLi is calculated from the first-order elimination constant k (min) using the actual incubation volume (mL), the number of hepatocytes in the incubation (millions of cells), and a scaling factor per gram of liver for all species. -1 )Sure.

[0953] In addition, in each sample, the active parent compound (epiprazole) was quantified based on the MS response of epiriprazole-D8 in the same sample.

[0954] The stability results of exemplary compounds in human plasma and human hepatocytes are listed in Table 16. When multiple values ​​were determined, the mean half-life was calculated.

[0955] [Table 16]

[0956]

[0957]

[0958] "Yes" means that the parent compound was detected at at least one time point; a difference in the level of the parent compound was observed between the test compound incubations.

[0959] Study 3: Short-term rat PK study

[0960] The study protocol was designed to evaluate the pharmacokinetic (PK) characteristics of the test compound following intravenous (IV) and subcutaneous (SC) administration in rats.

[0961] Male Sprague Dawley rats obtained from Charles River were acclimated for at least 5 days in groups of 3 or 4 in cages in a humidity- and temperature-controlled fume hood (relative humidity 45-65%, temperature 20-22°C, light on from approximately 06:00 to 18:00 daily). During the study, the animals had free access to a standard rodent diet (Altromin 1324) and water.

[0962] Animals were randomly assigned to receive either IV or SC administration of the test compound (n=3 per group). For IV administration, the test compound was dissolved in 50 mM acetate buffer (pH 5.5) containing 5% N-methylpyrrolidone and 10% Solutol HS15 and administered at a dose of 1 mg / kg. Blood samples were collected at nine time points up to 24 hours post-dose: 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose. For SC administration, the test compound was suspended in a solution of 1% hydroxymethylpropylcellulose and 0.2% Tween 80 in water and administered at a dose of 30 mg / kg, with the exception of Example 24, which was administered at a dose of 45 mg / kg. Blood samples were collected at up to 20 time points over a period of time up to 120 hours after dosing: 3, 6, 10, 24, 27, 30, 34, 48, 51, 54, 58, 72, 75, 78, 82, 96, 99, 102, 106, and 120 hours after dosing. From both groups, blood sample aliquots were obtained from the lateral tail vein and collected into K3EDTA tubes. After gentle mixing after collection, the aliquots were immediately transferred to microtubes and protein precipitation was performed online using acetonitrile containing 1% formic acid and rolipram as an internal standard. The samples were then stored at -80°C until analysis. Skin samples were also collected from the injection site at the last time point after SC administration. Approximately 2 cm from the injection site were excised. 2 Hairless skin samples were collected into vials and stored frozen at -80°C until analysis. On the day of analysis, the skin was thawed, weighed, and diluted to allow homogenization.

[0963] On the day of dosing, calibration standards (CS) and quality control samples (QC) were prepared by spiking standard solutions (test compound and epiliprazole, respectively) into blank matrices (blood and skin homogenate) and stored under the same conditions as the study samples. The study samples, along with the CS, QC, and blank samples, were analyzed on an LC-MS / MS system. The test compound and epiliprazole were quantified in each sample. Non-compartmental pharmacokinetic analysis of the test compound and epiliprazole results in blood was performed, and the area under the curve (AUC) was calculated using Phoenix WinNonlin 6.3. The percentage of epiliprazole converted to epiliprazole in the blood after IV administration was calculated as the ratio of the epiliprazole AUC during test compound administration to the epiliprazole AUC during subcutaneous administration. The percentage of epiliprazole in the skin after subcutaneous administration was calculated as the ratio of the skin tissue epiliprazole concentration to the test compound concentration.

[0964] The results of Test 3 are shown in the table below.

[0965] [Table 17]

[0966]

[0967] The test compound dose administered IV was 1 mg / kg. The test compound dose administered SC was 30 mg / kg, except for Example 24, which was administered SC at 45 mg / kg.

[0968] Study 4: Long-term rat PK study

[0969] Preparation of 16.3% aqueous suspension of Example 10

[0970] A medium containing 1% sodium carboxymethylcellulose, 3.4% D(-)-mannitol, and 0.14% sodium dihydrogen phosphate monohydrate was prepared, and the pH was adjusted to 6 with sodium hydroxide. This medium was sterilized by filtration through a 0.22 μm polyethersulfone (PES) membrane. 3348 mg of this medium and 652 mg of Example 10 were added to two glass vials and suspended. Zirconia beads (1.5 mm diameter) and a stirring bar were then added, and the suspension was milled by stirring with a magnetic stirrer for several minutes or 3 hours. The average particle size of Example 10 after milling was measured using a laser diffraction particle size distribution analyzer SALD-3100 (Shimadzu Corporation) under ultrasonic irradiation and a refractive index of 2.00-0.20 μm, and was found to be 3.4 μm and 1.9 μm. The suspension was separated from the zirconia beads using a pipette, placed in a separate vial, sterilized by irradiation with 25 kGy of gamma rays, and used as a test preparation.

[0971] Preparation of 17.8% aqueous suspension of Example 19

[0972] A medium containing 2% D-α-tocopheryl polyethylene glycol succinate, 3.4% D(-)-mannitol, and 0.14% sodium dihydrogen phosphate monohydrate was prepared, and the pH was adjusted to 6 with sodium hydroxide. This medium was sterilized by filtration through a 0.22 μm polyvinylidene fluoride (PVDF) membrane. 4150 mg of this medium and 890 mg of Example 19 were added to two glass vials and suspended. Zirconia beads (1 mm diameter) and a stir bar were then added, and the suspension was milled by stirring with a magnetic stirrer at 5°C for 17 or 65 hours. After milling, the suspension was separated from the zirconia beads using a pipette and transferred to a separate vial, which was then sterilized by irradiation with 25 kGy of gamma rays to prepare test formulations. The average particle size of Example 19 in the test formulations was measured using a SALD-3100 under ultrasonic irradiation and a refractive index of 1.70-0.20i and found to be 1.5 μm and 0.8 μm, respectively.

[0973] method

[0974] The test formulations were administered subcutaneously to male rats, and the plasma concentrations of the prodrug compound and epiriprazole were measured.

[0975] Rats were purchased from SLC, Inc., Japan, at 7 weeks of age and used in the experiments after acclimation. The housing conditions were as follows: free access to food and water, three rats per cage, temperature: 21-25°C, humidity: 50-70%, and light cycle: 7:00 AM to 7:00 PM. Under isoflurane anesthesia, the formulations of Examples 10 and 19 were subcutaneously administered to the rats using a plastic syringe at doses of 34 mg / kg and 37 mg / kg (equivalent to 25 mg / kg of irinotecan), respectively. Approximately 0.5 mL of blood was collected from the jugular vein of the rats using a heparinized syringe 2 hours after administration and on days 1, 3, 6, 9, 14, 21, and 28. To prevent hydrolysis of the prodrug compound, the blood samples were mixed with 2-thenoyltrifluoroacetone to a final concentration of 10 mM and rapidly cooled. Plasma was separated by centrifugation, and the concentrations of the prodrug compound and irinotecan were measured by LC-MS / MS. Based on the obtained plasma epiriprazole concentration-time curve, the cumulative absorbance at each blood collection point was calculated by deconvolution method.

[0976] Results and discussion

[0977] When the suspension of Example 10 or 19 was administered subcutaneously to rats, epiliprazole was detected in the blood for 28 consecutive days after administration. Based on these results, it is believed that these compounds have suitable characteristics as active pharmaceutical ingredients of epiliprazole long-acting injection formulations. The PK curves of Examples 10 and 19 are shown in Figure 2. Figure 8 and Figure 9 middle.

[0978] Experiment 5: Dog Stimulation Study

[0979] As test preparations, the aqueous suspensions of Examples 10 and 19 prepared for Test 4 were used. Each test preparation was subcutaneously administered to male and female beagle dogs, and after observation for 7 or 28 days, the injection site was subjected to histopathological examination after autopsy.

[0980] Beagle dogs were purchased from Kitayama Labes Co., Ltd. at 6-8 months of age and used in the experiments after acclimation. The housing conditions were as follows: 300 g of solid feed once daily, water ad libitum, one animal per cage, temperature: 20-26°C, humidity: 30-70%, and photoperiod: 7:00 AM to 7:00 PM. Each test formulation was administered subcutaneously using a plastic syringe at a dose of 10 mg / kg of each formulation to different sites in the dorsal lumbar region of the dogs anesthetized with 1 mg / kg of xylazine hydrochloride and 15 mg / kg of ketamine hydrochloride. Following administration, the dogs were observed for 7 or 28 days and then sacrificed by exsanguination under anesthesia with 0.08 mg / kg of medetomidine hydrochloride, 0.5 mg / kg of butorphanol tartrate, and 20 mg / kg of thiopental sodium. Tissues from the injection sites were collected. The collected tissues were fixed in 10% neutral buffered formalin, and hematoxylin and eosin-stained specimens were prepared for histopathological examination.

[0981] Results and discussion

[0982] During the observation period, edema and induration were observed at the injection site of each test formulation. On histopathological examination, the main finding at the injection site was granulomatous inflammation, characterized by infiltration of macrophages and foreign body giant cells. These histological changes are physiological responses to foreign matter and are not considered to be signs of irritation. From these results, it can be concluded that Examples 10 and 19 do not have limited irritation.

[0983] [Industrial Applicability]

[0984] The compounds of formula (I) and (II) or pharmaceutically acceptable salts thereof may possess antipsychotic activity and may be used in medicine, for example, for treating and / or preventing subjects suffering from diseases and conditions associated with antipsychotic drugs.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] ， in: a is 2 or 3; R 1 is an optionally substituted straight or branched chain C 1-20 Alkylene, optionally substituted C 2-10 Alkenylene, optionally substituted divalent C 3-8 Cycloalkyl, optionally substituted divalent heterocycle, optionally substituted divalent C 6-10 Aryl, -NH (optionally substituted straight or branched C 1-20 Alkylene) or an optionally substituted divalent C 3-8 cycloalkenyl; R 2 -C(O)-, -OC(O)-, -C(O)-NR a -CH2-, -O-, -CH2-, -NR a -C(O)- or direct bond; R 3 is an optionally substituted non-aromatic divalent or trivalent heterocycle, an optionally substituted aromatic divalent or trivalent heterocycle, or an optionally substituted straight or branched chain C 1-20 alkylene; R a is hydrogen or an optionally substituted straight or branched chain C 1-20 alkyl; When a is 2, R 3 It is bivalent; When a is 3, R 3 is trivalent; and R 2 and R 3 connected by covalent bonds; The condition is that when R 1 is a straight chain alkylene group and R 2 When it is -CH2- or a direct bond, R 3 Not a straight chain alkylene group.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: a is 2 or 3; R 1 is an optionally substituted straight or branched chain C 2-16 Alkylene, wherein one or more methylene groups may be replaced by a functional group selected from -O- or -NH-, or one or more methylene groups may be replaced by a spirocyclopentane or a divalent piperidine, or one or more methylene groups may be replaced by a divalent 1,3,5-triazole ring; ethylene; an optionally substituted divalent cyclohexyl; an optionally substituted divalent azetidine or an optionally substituted divalent piperidine; R 2 is -C(O)-, -OC(O)-, -C(O)-N(CH3)-CH2-, -C(O)-NH-CH2-, -O-, -NH-C(O)-, -CH2-, or a direct bond; R 3 is an optionally substituted divalent or trivalent piperazine, an optionally substituted divalent or trivalent 2,5-diazabicyclo[2.2.2]octane, an optionally substituted divalent or trivalent 2,5-diazabicyclo[2.2.1]heptane, an optionally substituted divalent or trivalent octahydropyrrolo[3,4-c]pyrrole, an optionally substituted divalent or trivalent pyrazine, an optionally substituted divalent or trivalent 3,9-diazaspiro[5,5]undecane, an optionally substituted divalent or trivalent 1,4,7-triazacyclononane, an optionally substituted divalent or trivalent 2,6-diazaspiro[3.3]heptane, an optionally substituted divalent or trivalent 1,3,5-triazine, an optionally substituted divalent or trivalent 1,3-thiazole or an optionally substituted straight-chain or branched C 2-6 alkylene; When a is 2, R 3 is bivalent; and When a is 3, R 3 It is three-valent.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: a is 2; R 1 is an optionally substituted straight or branched chain C 2-16 Alkylene, wherein one or more methylene groups may be replaced by oxygen or amino, or one or more methylene groups may be replaced by spirocyclopentane or divalent piperidine, or one or more methylene groups may be replaced by a divalent 1,3,5-triazole ring; ethylene, an optionally substituted divalent cyclohexyl; an optionally substituted divalent azetidine or an optionally substituted divalent piperidine; R 2 is -C(O)-, -OC(O)-, -C(O)-N(CH3)-CH2-, -C(O)-NH-CH2-, -CH2-, -NH-C(O)-, or a direct bond; and R 3 is an optionally substituted divalent piperazine, an optionally substituted divalent 2,5-diazabicyclo[2.2.2]octane, an optionally substituted divalent 2,5-diazabicyclo[2.2.1]heptane, an optionally substituted divalent octahydropyrrolo[3,4-c]pyrrole, an optionally substituted divalent pyrazine, an optionally substituted divalent 3,9-diazaspiro[5,5]undecane, an optionally substituted divalent 2,6-diazaspiro[3.3]heptane, an optionally substituted divalent 1,3-thiazole or an optionally substituted straight-chain or branched C 2-6 Alkylene.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: a is 3; R 1 is an optionally substituted straight or branched chain C 2-6 Alkylene, in which one or more methylene groups may be replaced by a divalent piperidine; R 2 is -C(O)-, -O-, or a direct bond; and R 3 is an optionally substituted trivalent 1,4,7-triazacyclononane or an optionally substituted trivalent 1,3,5-triazine.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: a is 2; R 1 is -CH=CH-, -(CH2)2-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)9-, -(CH2) 12 -, -(CH2) 16 -, -NH-(CH2)7-, [Chemical Formula 2] R 2 is -C(O)-, -OC(O)-, -C(O)-N(CH3)-CH2-, -C(O)-NH-CH2-, -CH2-, -NH-C(O)-, or a direct bond; and R 3 It is -(CH2)4-, [Chemical Formula 3] 。 6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: a is 3; R 1 is -(CH2)2-, -(CH2)5- or [Chemical Formula 4] ； R 2 is -C(O)-, -O-, or a direct bond; and R 3 yes [Chemical Formula 5] 。 7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 6-(4-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanoyl}piperazin-1-yl)-6-oxohexanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 8-[(2R,5S)-4-{8-[(7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-2,5-dimethylpiperazin-1-yl]-8-oxooctanoic acid (7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 8-(5-{8-[(7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-8-oxooctanoic acid (7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 8-[(1S,4S)-5-{8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-2,5-diazabicyclo[2.2.1]hept-2-yl]-8-oxooctanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; tris(trifluoroacetic acid); 8-(5-{8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-octahydropyrrolo[3,4-c]pyrrol-2-yl)-8-oxooctanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 8-(6-{8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-2,6-diazaspiro[3.3]hept-2-yl)-8-oxooctanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 8-(9-{8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-3,9-diazaspiro[5.5]undec-3-yl)-8-oxooctanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 7-({[5-({8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoylamido}methyl)pyrazin-2-yl]methyl}carbamoyl)heptanoate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 7-({[5-({8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-N-methyl-8-oxooctanamidyl}methyl)pyrazin-2-yl]methyl}(methyl)carbamoyl)heptanoate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl}piperazin-1-yl)-4-oxobutanoate; 4-[(2S,5R)-4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl}-2,5-dimethylpiperazin-1-yl]-4-oxobutanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-(9-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl}-3,9-diazaspiro[5.5]undec-3-yl)-4-oxobutanoate; 4-[(3ar,6ar)-5-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl}-octahydropyrrolo[3,4-c]pyrrol-2-yl]-4-oxobutanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 4-[4,7-bis({4-[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl})-1,4,7-triazacyclononan-1-yl]-4-oxobutanoic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 10-(4-{10-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-10-oxodecanoyl}piperazin-1-yl)-10-oxodecanoate; 10-[(2R,5S)-4-{10-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-10-oxodecanoyl}-2,5-dimethylpiperazin-1-yl]-10-oxodecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 10-(5-{10-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-10-oxodecanoyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-10-oxodecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 9-({[5-({10-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-N-methyl-10-oxodecanamido}methyl)pyrazin-2-yl]methyl}(methyl)carbamoyl)nonanoate; 8-(4-{8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}piperazin-1-yl)-8-oxooctanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 6-[(2S,5R)-4-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanoyl}-2,5-dimethylpiperazin-1-yl]-6-oxohexanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 6-(6-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanoyl}-2,6-diazaspiro[3.3]hept-2-yl)-6-oxohexanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 6-[(3ar,6ar)-5-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanoyl}-octahydropyrrolo[3,4-c]pyrrol-2-yl]-6-oxohexanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 6-(5-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanoyl}-octahydropyrrolo[3,4-c]pyrrol-2-yl)-6-oxohexanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 5-({[5-({6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-N-methyl-6-oxohexanamido}methyl)pyrazin-2-yl]methyl}(methyl)carbamoyl)pentanoate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 5-({[5-({6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanamido}methyl)pyrazin-2-yl]methyl}carbamoyl)pentanoate; (2E)-4-{4-[(2E)-4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobut-2-enoyl]piperazin-1-yl}-4-oxobut-2-enoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 14-(4-{14-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-14-oxotetradecanoyl}piperazin-1-yl)-14-oxotetradecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 14-[(2S,5R)-4-{14-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-14-oxotetradecanoyl}-2,5-dimethylpiperazin-1-yl]-14-oxotetradecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 18-(4-{18-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-18-oxooctadecanoyl}piperazin-1-yl)-18-oxooctadecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 18-[(2S,5R)-4-{18-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-18-octadecanoyl}-2,5-dimethylpiperazin-1-yl]-18-oxooctadecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; (1r,4r)-4-{4-[(1r,4r)-4-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclohexanecarbonyl]piperazine-1-carbonyl}cyclohexane-1-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; (1r,4r)-4-[(2S,5R)-2,5-dimethyl-4-[(1r,4r)-4-{[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclohexanecarbonyl]piperazine-1-carbonyl]cyclohexane-1-carboxylic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; (1s,4s)-4-{4-[(1s,4s)-4-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclohexanecarbonyl]piperazine-1-carbonyl}cyclohexane-1-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; (1s,4s)-4-[(2S,5R)-2,5-dimethyl-4-[(1s,4s)-4-{[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclohexanecarbonyl]piperazine-1-carbonyl]cyclohexane-1-carboxylic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 1-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclopentanecarbonyl)piperazine-1-carbonyl]cyclopentane-1-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 1-[(3ar,6ar)-5-(1-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclopentanecarbonyl)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl]cyclopentane-1-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 3-(4-{3-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-2,2-dimethyl-3-oxopropanoyl}piperazin-1-yl)-2,2-dimethyl-3-oxopropanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 4-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-2,2-dimethyl-4-oxobutanoyl}piperazin-1-yl)-3,3-dimethyl-4-oxobutanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 4-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3,3-dimethyl-4-oxobutanoyl}piperazin-1-yl)-2,2-dimethyl-4-oxobutanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 5-(4-{5-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3,3-dimethyl-5-oxopentanoyl}piperazin-1-yl)-3,3-dimethyl-5-oxopentanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 2-{2-[4-(2-{2-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-2-oxoethoxy}acetyl)piperazin-1-yl]-2-oxoethoxy}acetate (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl N-(8-{4-[8-({[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}amino)octanoyl]piperazin-1-yl}-8-oxooctyl)carbamate; (7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl N-[(2S)-1-{4-[(2S)-2-({[(7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}amino)-3-methylbutanoyl]piperazin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate; 4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}piperidine-4-carbonyl)piperazine-1-carbonyl]piperidine-1-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 1-[5-(4-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}piperidine-1-carbonyl)pyrazine-2-carbonyl]piperidine-4-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 3-{1-[4-(4-{3-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3-oxopropyl}piperidin-1-yl)-1,3,5-triazin-2-yl]piperidin-4-yl}propanoate; 7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 3-{1-[4,6-bis(4-{3-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3-oxopropyl}piperidin-1-yl)-1,3,5-triazin-2-yl]piperidin-4-yl}propanoate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 3-[1-({5-[(4-{3-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3-oxopropyl}piperidin-1-yl)methyl]pyrazin-2-yl}methyl)piperidin-4-yl]propanoate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 3-{1-[5-(4-{3-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3-oxopropyl}piperidine-1-carbonyl)pyrazine-2-carbonyl]piperidin-4-yl}propanoate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 1-[5-(3-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}azetidine-1-carbonyl)pyrazine-2-carbonyl]azetidine-3-carboxylate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 5-{[5-({5-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-5-oxopentyl}carbamoyl)-1,3-thiazol-2-yl]formamido}pentanoate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 5-{[5-({5-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-5-oxopentyl}carbamoyl)pyrazin-2-yl]formamido}pentanoate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 10-{[5-({10-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-10-oxodecanyl}carbamoyl)pyrazin-2-yl]formamido}decanoate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 6-(4-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexyl}piperazin-1-yl)hexanoate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 6-{4-[({6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexyl}oxy)carbonyl]piperazine-1-carbonyloxy}hexanoate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl (1r,4r)-4-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclohexyl]methyl}piperazin-1-yl)methyl]cyclohexane-1-carboxylate; 6-{[4,6-bis({6-[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexyl}oxy)-1,3,5-triazin-2-yl]oxy}hexanoic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 5-{1-[4-(4-{5-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-5-oxopentyl}-1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3-triazol-4-yl}pentanoate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-{1-[4-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3-triazol-4-yl}butanoate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-[1-(5-{4-[5-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)pentanoyl]piperazin-1-yl}-5-oxopentyl)-1H-1,2,3-triazol-4-yl]butanoate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-(1-{5-[(2S,5R)-4-[5-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)pentanoyl]-2,5-dimethylpiperazin-1-yl]-5-oxopentyl}-1H-1,2,3-triazol-4-yl)butanoate; 4-[1-(5-{5-[5-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)pentanoyl]-2,5-diazabicyclo[2.2.2]oct-2-yl}-5-oxopentyl)-1H-1,2,3-triazol-4-yl]butanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-[1-(6-{4-[6-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)hexanoyl]piperazin-1-yl}-6-oxohexyl)-1H-1,2,3-triazol-4-yl]butanoate; and (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-(1-{6-[(2S,5R)-4-[6-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)hexanoyl]-2,5-dimethylpiperazin-1-yl]-6-oxohexyl}-1H-1,2,3-triazol-4-yl)butanoate.

8. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 4-[4,7-bis({4-[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl})-1,4,7-triazacyclononan-1-yl]-4-oxobutanoic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 3-{1-[4,6-bis(4-{3-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3-oxopropyl}piperidin-1-yl)-1,3,5-triazin-2-yl]piperidin-4-yl}propanoate; and (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 6-{[4,6-bis({6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexyl}oxy)-1,3,5-triazin-2-yl]oxy}hexanoate.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: a is 2; R 1 are -(CH2)2-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)9-, -(CH2) 12 -or-(CH2) 16 -; R 2 is -C(O)-, -CH2-, or a direct bond; and R 3 yes [Chemical Formula 6] 。 10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 6-(4-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanoyl}piperazin-1-yl)-6-oxohexanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 8-[(2R,5S)-4-{8-[(7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-2,5-dimethylpiperazin-1-yl]-8-oxooctanoic acid (7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 8-(5-{8-[(7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-8-oxooctanoic acid (7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 8-[(1S,4S)-5-{8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-2,5-diazabicyclo[2.2.1]hept-2-yl]-8-oxooctanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; tris(trifluoroacetic acid); (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl}piperazin-1-yl)-4-oxobutanoate; 4-[(2S,5R)-4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl}-2,5-dimethylpiperazin-1-yl]-4-oxobutanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 10-(4-{10-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-10-oxodecanoyl}piperazin-1-yl)-10-oxodecanoate; 10-[(2R,5S)-4-{10-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-10-oxodecanoyl}-2,5-dimethylpiperazin-1-yl]-10-oxodecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 10-(5-{10-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-10-oxodecanoyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)-10-oxodecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 8-(4-{8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}piperazin-1-yl)-8-oxooctanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 6-[(2S,5R)-4-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanoyl}-2,5-dimethylpiperazin-1-yl]-6-oxohexanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 14-(4-{14-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-14-oxotetradecanoyl}piperazin-1-yl)-14-oxotetradecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 14-[(2S,5R)-4-{14-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-14-oxotetradecanoyl}-2,5-dimethylpiperazin-1-yl]-14-oxotetradecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 18-(4-{18-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-18-oxooctadecanoyl}piperazin-1-yl)-18-oxooctadecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 18-[(2S,5R)-4-{18-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-18-octadecanoyl}-2,5-dimethylpiperazin-1-yl]-18-oxooctadecanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl N-(8-{4-[8-({[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}amino)octanoyl]piperazin-1-yl}-8-oxooctyl)carbamate; and (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 6-(4-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexyl}piperazin-1-yl)hexanoate.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: a is 2; R 1 yes [Chemical Formula 7] R 2 is -C(O)-, -CH2-, or a direct bond; and R 3 It is -(CH2)4-, [Chemical Formula 8] 。 12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: (1r,4r)-4-{4-[(1r,4r)-4-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclohexanecarbonyl]piperazine-1-carbonyl}cyclohexane-1-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; (1r,4r)-4-[(2S,5R)-2,5-dimethyl-4-[(1r,4r)-4-{[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclohexanecarbonyl]piperazine-1-carbonyl]cyclohexane-1-carboxylic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; (1s,4s)-4-{4-[(1s,4s)-4-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclohexanecarbonyl]piperazine-1-carbonyl}cyclohexane-1-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; (1s,4s)-4-[(2S,5R)-2,5-dimethyl-4-[(1s,4s)-4-{[(7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclohexanecarbonyl]piperazine-1-carbonyl]cyclohexane-1-carboxylic acid (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 1-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclopentanecarbonyl)piperazine-1-carbonyl]cyclopentane-1-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 1-[(3ar,6ar)-5-(1-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclopentanecarbonyl)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl]cyclopentane-1-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 3-(4-{3-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-2,2-dimethyl-3-oxopropanoyl}piperazin-1-yl)-2,2-dimethyl-3-oxopropanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 4-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-2,2-dimethyl-4-oxobutanoyl}piperazin-1-yl)-3,3-dimethyl-4-oxobutanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 4-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3,3-dimethyl-4-oxobutanoyl}piperazin-1-yl)-2,2-dimethyl-4-oxobutanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 5-(4-{5-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3,3-dimethyl-5-oxopentanoyl}piperazin-1-yl)-3,3-dimethyl-5-oxopentanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 2-{2-[4-(2-{2-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-2-oxoethoxy}acetyl)piperazin-1-yl]-2-oxoethoxy}acetate (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; (7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl N-[(2S)-1-{4-[(2S)-2-({[(7-{5-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}amino)-3-methylbutanoyl]piperazin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate; 4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}piperidine-4-carbonyl)piperazine-1-carbonyl]piperidine-1-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 1-[5-(4-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}piperidine-1-carbonyl)pyrazine-2-carbonyl]piperidine-4-carboxylic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 3-{1-[4-(4-{3-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3-oxopropyl}piperidin-1-yl)-1,3,5-triazin-2-yl]piperidin-4-yl}propanoate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 3-[1-({5-[(4-{3-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3-oxopropyl}piperidin-1-yl)methyl]pyrazin-2-yl}methyl)piperidin-4-yl]propanoate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 3-{1-[5-(4-{3-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-3-oxopropyl}piperidine-1-carbonyl)pyrazine-2-carbonyl]piperidin-4-yl}propanoate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 1-[5-(3-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}azetidine-1-carbonyl)pyrazine-2-carbonyl]azetidine-3-carboxylate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl (1r,4r)-4-{[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]carbonyl}cyclohexyl]methyl}piperazin-1-yl)methyl]cyclohexane-1-carboxylate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 5-{1-[4-(4-{5-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-5-oxopentyl}-1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3-triazol-4-yl}pentanoate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-{1-[4-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)butyl]-1H-1,2,3-triazol-4-yl}butanoate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-[1-(5-{4-[5-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)pentanoyl]piperazin-1-yl}-5-oxopentyl)-1H-1,2,3-triazol-4-yl]butanoate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-(1-{5-[(2S,5R)-4-[5-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)pentanoyl]-2,5-dimethylpiperazin-1-yl]-5-oxopentyl}-1H-1,2,3-triazol-4-yl)butanoate; 4-[1-(5-{5-[5-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)pentanoyl]-2,5-diazabicyclo[2.2.2]oct-2-yl}-5-oxopentyl)-1H-1,2,3-triazol-4-yl]butanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-[1-(6-{4-[6-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)hexanoyl]piperazin-1-yl}-6-oxohexyl)-1H-1,2,3-triazol-4-yl]butanoate; and (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-(1-{6-[(2S,5R)-4-[6-(4-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutyl}-1H-1,2,3-triazol-1-yl)hexanoyl]-2,5-dimethylpiperazin-1-yl]-6-oxohexyl}-1H-1,2,3-triazol-4-yl)butanoate.

13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: a is 2; R 1 is -(CH2)2-, -(CH2)4-, -(CH2)6- or -(CH2)9-; R 2 is -C(O)-, -C(O)-N(CH3)-CH2-, -C(O)-NH-CH2-, or -NH-C(O)-; and R 3 yes [Chemical Formula 9] 。 14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 8-(5-{8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-octahydropyrrolo[3,4-c]pyrrol-2-yl)-8-oxooctanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 8-(6-{8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-2,6-diazaspiro[3.3]hept-2-yl)-8-oxooctanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 8-(9-{8-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-8-oxooctanoyl}-3,9-diazaspiro[5.5]undec-3-yl)-8-oxooctanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-(9-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl}-3,9-diazaspiro[5.5]undec-3-yl)-4-oxobutanoate; 4-[(3ar,6ar)-5-{4-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-4-oxobutanoyl}-octahydropyrrolo[3,4-c]pyrrol-2-yl]-4-oxobutanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 6-(6-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanoyl}-2,6-diazaspiro[3.3]hept-2-yl)-6-oxohexanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 6-[(3ar,6ar)-5-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanoyl}-octahydropyrrolo[3,4-c]pyrrol-2-yl]-6-oxohexanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; 6-(5-{6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanoyl}-octahydropyrrolo[3,4-c]pyrrol-2-yl)-6-oxohexanoic acid (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl ester; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 5-({[5-({6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-N-methyl-6-oxohexanamido}methyl)pyrazin-2-yl]methyl}(methyl)carbamoyl)pentanoate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 5-({[5-({6-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-6-oxohexanamido}methyl)pyrazin-2-yl]methyl}carbamoyl)pentanoate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 5-{[5-({5-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-5-oxopentyl}carbamoyl)-1,3-thiazol-2-yl]formamido}pentanoate; (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 5-{[5-({5-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-5-oxopentyl}carbamoyl)pyrazin-2-yl]formamido}pentanoate; and (7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methyl 10-{[5-({10-[(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}-2-oxo-1,2-dihydroquinolin-1-yl)methoxy]-10-oxodecanyl}carbamoyl)pyrazin-2-yl]formamido}decanoate. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which has an average particle size within a range of 0.05 μm to 10 μm as measured by laser diffraction. 16 . A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. A medicament for treating and / or preventing central nervous system disorders, comprising the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

18. The drug according to claim 17, wherein the central nervous system disorder is selected from the group consisting of schizophrenia; refractory, intractable or chronic schizophrenia; emotional distress; psychotic disorder; mood disorder; bipolar I disorder; bipolar II disorder; depression; endogenous depression; Major depressive disorder (MDD); melancholy and refractory depression; dysthymic disorder; cyclothymic disorder; panic attacks; panic disorder; agoraphobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; generalized anxiety disorder; acute stress disorder; hysteria; somatization disorder; conversion disorder; pain disorder; hypochondriasis; factitious disorder; dissociative disorder; sexual dysfunction; sexual desire disorder; sexual arousal disorder; erectile dysfunction; anorexia nervosa; bulimia nervosa; sleep disorders; adjustment disorder; alcoholism; alcoholism; drug addiction; stimulant intoxication; narcotic intoxication; anhedonia anhedonia; iatrogenic anhedonia; anhedonia of psychiatric or psychological origin; anhedonia associated with depression; anhedonia associated with schizophrenia; delirium; cognitive impairment; cognitive impairment associated with Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders; cognitive impairment due to Alzheimer's disease, Parkinson's disease, and related neurodegenerative disorders; cognitive impairment in schizophrenia; cognitive impairment due to refractory, intractable, or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain; mental retardation; autism; Tourette disorder; tic disorders; Attention-deficit / hyperactivity disorder; conduct disorder; Down syndrome; impulsive symptoms associated with dementia (such as agitation associated with Alzheimer's disease); and borderline personality disorder.

19. Use of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing central nervous system disorders.

20. The method of claim 19, wherein the central nervous system disorder is selected from the group consisting of schizophrenia; refractory, intractable or chronic schizophrenia; emotional distress; psychotic disorder; mood disorder; bipolar I disorder; bipolar II disorder; depression; endogenous depression; Major depressive disorder (MDD); melancholy and refractory depression; dysthymic disorder; cyclothymic disorder; panic attacks; panic disorder; agoraphobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; generalized anxiety disorder; acute stress disorder; hysteria; somatization disorder; conversion disorder; pain disorder; hypochondriasis; factitious disorder; dissociative disorder; sexual dysfunction; sexual desire disorder; sexual arousal disorder; erectile dysfunction; anorexia nervosa; bulimia nervosa; sleep disorders; adjustment disorder; alcoholism; alcoholism; drug addiction; stimulant intoxication; narcotic intoxication; anhedonia anhedonia; iatrogenic anhedonia; anhedonia of psychiatric or psychological origin; anhedonia associated with depression; anhedonia associated with schizophrenia; delirium; cognitive impairment; cognitive impairment associated with Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders; cognitive impairment due to Alzheimer's disease, Parkinson's disease, and related neurodegenerative disorders; cognitive impairment in schizophrenia; cognitive impairment due to refractory, intractable, or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain; mental retardation; autism; Tourette disorder; tic disorders; Attention-deficit / hyperactivity disorder; conduct disorder; Down syndrome; impulsive symptoms associated with dementia (such as agitation associated with Alzheimer's disease); and borderline personality disorder.

21. A method for treating and / or preventing central nervous system disorders, comprising administering to a subject in need thereof a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

22. The method of claim 21, wherein the central nervous system disorder is selected from the group consisting of schizophrenia; refractory, intractable, or chronic schizophrenia; mood disturbances; psychotic disorders; mood disorders; bipolar I disorder; bipolar II disorder; depression; endogenous depression; Major depressive disorder (MDD); melancholy and refractory depression; dysthymic disorder; cyclothymic disorder; panic attacks; panic disorder; agoraphobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; generalized anxiety disorder; acute stress disorder; hysteria; somatization disorder; conversion disorder; pain disorder; hypochondriasis; factitious disorder; dissociative disorder; sexual dysfunction; sexual desire disorder; sexual arousal disorder; erectile dysfunction; anorexia nervosa; bulimia nervosa; sleep disorders; adjustment disorder; alcoholism; alcoholism; drug addiction; stimulant intoxication; narcotic intoxication; anhedonia anhedonia; iatrogenic anhedonia; anhedonia of psychiatric or psychological origin; anhedonia associated with depression; anhedonia associated with schizophrenia; delirium; cognitive impairment; cognitive impairment associated with Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders; cognitive impairment due to Alzheimer's disease, Parkinson's disease, and related neurodegenerative disorders; cognitive impairment in schizophrenia; cognitive impairment due to refractory, intractable, or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain; mental retardation; autism; Tourette disorder; tic disorders; Attention-deficit / hyperactivity disorder; conduct disorder; Down syndrome; impulsive symptoms associated with dementia (such as agitation associated with Alzheimer's disease); and borderline personality disorder.

23. A compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof for use in treating and / or preventing central nervous system disorders.

24. The compound for use according to claim 23, wherein the central nervous system disorder is selected from the group consisting of schizophrenia; refractory, intractable or chronic schizophrenia; mood disturbances; psychotic disorders; mood disorders; bipolar I disorder; bipolar II disorder; depression; endogenous depression; Major depressive disorder (MDD); melancholy and refractory depression; dysthymic disorder; cyclothymic disorder; panic attacks; panic disorder; agoraphobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; generalized anxiety disorder; acute stress disorder; hysteria; somatization disorder; conversion disorder; pain disorder; hypochondriasis; factitious disorder; dissociative disorder; sexual dysfunction; sexual desire disorder; sexual arousal disorder; erectile dysfunction; anorexia nervosa; bulimia nervosa; sleep disorders; adjustment disorder; alcoholism; alcoholism; drug addiction; stimulant intoxication; narcotic intoxication; anhedonia anhedonia; iatrogenic anhedonia; anhedonia of psychiatric or psychological origin; anhedonia associated with depression; anhedonia associated with schizophrenia; delirium; cognitive impairment; cognitive impairment associated with Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders; cognitive impairment due to Alzheimer's disease, Parkinson's disease, and related neurodegenerative disorders; cognitive impairment in schizophrenia; cognitive impairment due to refractory, intractable, or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain; mental retardation; autism; Tourette disorder; tic disorders; Attention-deficit / hyperactivity disorder; conduct disorder; Down syndrome; impulsive symptoms associated with dementia (such as agitation associated with Alzheimer's disease); and borderline personality disorder.

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