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WO2024181403A1 - Benzothiophènes à substitution pipérazine pour le traitement de troubles mentaux - Google Patents

Benzothiophènes à substitution pipérazine pour le traitement de troubles mentaux Download PDF

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Publication number
WO2024181403A1
WO2024181403A1 PCT/JP2024/006959 JP2024006959W WO2024181403A1 WO 2024181403 A1 WO2024181403 A1 WO 2024181403A1 JP 2024006959 W JP2024006959 W JP 2024006959W WO 2024181403 A1 WO2024181403 A1 WO 2024181403A1
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Prior art keywords
piperazin
butoxy
benzothiophen
dihydroquinolin
oxo
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PCT/JP2024/006959
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Inventor
Iain Lingard
Bernardo Pezzati
Giorgio Bonanomi
Giovanna BURGIO
Michela BELTRANI
Silvia CORBIOLI
Silvia LENZINI
Daniel Kim
Laura Barnes
Keisuke AIHARA
Toshio Shinohara
Naoji KIMURA
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Otsuka Pharmaceutical Co Ltd
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Otsuka Pharmaceutical Co Ltd
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Priority to AU2024230422A priority Critical patent/AU2024230422A1/en
Priority to KR1020257031216A priority patent/KR20250153813A/ko
Priority to CN202480006469.8A priority patent/CN120530108A/zh
Priority to IL322925A priority patent/IL322925A/en
Publication of WO2024181403A1 publication Critical patent/WO2024181403A1/fr
Priority to MX2025010076A priority patent/MX2025010076A/es
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present application relates to novel compounds which are prodrugs of brexpiprazole.
  • the novel compounds of the invention upon administration to a subject, undergo chemical conversion by one or more metabolic processes to release an active pharmacological agent in vivo.
  • Brexpiprazole sold under the Rexulti (registered trademark), is an atypical antipsychotic indicated for use as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adults and the treatment of schizophrenia in adults and pediatric patients ages 13 years and older.
  • MDD major depressive disorder
  • Brexpiprazole, 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one, or a salt thereof has dopamine D 2 receptor partial agonistic activity, serotonin 5-HT 2A receptor antagonistic activity, and adrenaline ⁇ 1 receptor antagonistic activity.
  • brexpiprazole or a salt thereof is known to have serotonin uptake or reuptake inhibitory activity as well and have a wide range of therapeutic possibilities against various nervous system disorders (PTL 1 and 2).
  • Drug designing in the medicinal field includes chemical conversion or modification of one or more functional groups of a known drug molecule to improve its pharmaceutical or pharmacokinetic properties, such as enhancing drug efficacy and delaying in-vivo metabolism.
  • Such a chemical conversion or modification includes formation of a conjugate of multiple API molecules with a carrier moiety (PTL 3).
  • PTL 3 carrier moiety
  • An object of the present invention is to provide novel compounds with antipsychotic activity, with acceptable pharmaceutical or pharmacokinetic properties, side effects, tolerability, and safety as compared with well-known typical and atypical antipsychotic drugs including brexpiprazole.
  • This invention describes compounds, or pharmaceutically acceptable salts thereof, which have antipsychotic activity.
  • the compounds, or pharmaceutically acceptable salts thereof, in accordance with the present invention are thus of use in medicine, for example in the treatment and/or prophylaxis of humans with diseases and conditions that are antipsychotic related.
  • the present invention provides a compound represented by Formula (I), its individual geometrical isomers, its individual enantiomers, its individual diastereoisomers, its individual tautomers, its individual zwitterions or pharmaceutically acceptable salts thereof: wherein: a is 2 or 3; R 1 is optionally substituted linear or branched 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 linear or branched C 1-20 alkylene); or optionally substituted divalent C 3-8 cycloalkenyl; R 2 is -C(O)-, -O-C(O)-, -C(O)-NR a -CH 2 -, -O-, -CH 2 -, -NR a -C(O)-, or a direct bond; R 3 is optionally
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof includes a structure wherein brexpiprazole is chemically modified, e.g., multiple brexpiprazole molecules are covalently linked with each other via a chemical linker.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof may undergo chemical conversion to an active pharmacological agent, brexpiprazole, upon administration to a subject under physiological conditions including one or more metabolic processes to release brexpiprazole in vivo.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof may have at least one pharmacological activity selected from the following: - stability in subcutaneous tissue, e.g., low conversion to the parent drug, brexpiprazole, in subcutaneous tissue; - rapid conversion to brexpiprazole in systemic circulation; - suitable PK profile as a long acting injection (LAI), e.g., a longer duration of action per dose than the parent drug; - low irritability at the injection site.
  • LAI long acting injection
  • Fig. 1 provides the XRPD pattern of Form A of a compound of Example 10.
  • Fig. 2 provides a DSC thermogram of Form A of a compound of Example 10.
  • Fig. 3 provides the XRPD pattern of Form B of a compound of Example 10.
  • Fig. 4 provides a DSC thermogram of Form B of a compound of Example 10.
  • Fig. 5 provides the XRPD pattern of Form 1 of a compound of Example 19.
  • Fig. 6 provides a TGA profile of Form 1 of a compound of Example 19.
  • Fig. 7 provides a DSC thermogram of Form 1 of a compound of Example 19.
  • Fig. 1 provides the XRPD pattern of Form A of a compound of Example 10.
  • Fig. 2 provides a DSC thermogram of Form A of a compound of Example 10.
  • Fig. 3 provides the XRPD pattern of Form B of a compound of Example 10.
  • Fig. 4 provides a DSC thermogram of Form B of a compound of Example 10.
  • the upper line shows a PK profile of Example 10 aqueous suspension (1.9 ⁇ m).
  • the lower line show a PK profile of Example 10 aqueous suspension (3.4 ⁇ m).
  • the upper line shows a PK profile of Example 19 aqueous suspension (0.8 ⁇ m).
  • the lower line show a PK profile of Example 19 aqueous suspension (1.5 ⁇ m).
  • Formula (I) can be represented by Formula (IA) or by Formula (IB).
  • Formula (IA) and Formula (IB) are represented below.
  • Formula (I) is represented by Formula (IA), as described below:
  • Formula (I) is represented by Formula (IB), as described below:
  • the present invention provides a compound represented by Formula (II) its individual geometrical isomers, its individual enantiomers, its individual diastereoisomers, its individual tautomers, its individual zwitterions or pharmaceutically acceptable salts thereof: wherein: b is 2 or 3; R 4 is optionally substituted linear or branched 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 linear or branched C 1-20 alkylene); or optionally substituted divalent C 3-8 cycloalkenyl; R 5 is -C(O)-, -O-C(O)-, -C(O)-NR b -CH 2 -, -O-, -CH 2 -, -NR b -C(O)-, or a direct bond; R 6 is
  • Formula (II) can be represented by Formula (IIA) or by Formula (IIB).
  • Formula (IIA) and Formula (IIB) are represented below.
  • Formula (IIA) is represented by Formula (IIA), as described below:
  • Formula (IIB) is represented by Formula (IIB), as described below:
  • the present invention provides a compound represented by the Formula (I), wherein: a is 2 or 3; R 1 is optionally substituted linear or branched C 2-16 alkylene, wherein one or more methylene groups can be replaced with a functional group selected from -O- or -NH-, or one or more methylene groups can be replaced with a spiro cyclopentane, or a divalent piperidine, or one or more methylene groups can be replaced with a divalent 1,3,5-triazole cycle; ethylene; optionally substituted divalent cyclohexyl; optionally substituted divalent azetidine; or optionally substituted divalent piperidine; R 2 is -C(O)-, -O-C(O)-, -C(O)-N(CH 3 )-CH 2 -, -C(O)-NH-CH 2 -, -O-, -NH-C(O)-, -CH 2 -, or a direct bond
  • the present invention provides a compound represented by the Formula (I), wherein: a is 2; R 1 is optionally substituted linear or branched C 2-16 alkylene, wherein one or more methylene groups can be replaced with an oxygen or amino group, or one or more methylene groups can be replaced with a spiro cyclopentane, or a divalent piperidine, or one or more methylene groups can be replaced with a divalent 1,3,5-triazole cycle; ethylene; optionally substituted divalent cyclohexyl; optionally substituted divalent azetidine; or optionally substituted divalent piperidine; R 2 is -C(O)-, -O-C(O)-, -C(O)-N(CH 3 )-CH 2 -, -C(O)-NH-CH 2 -, -CH 2 -, -NH-C(O)-, or a direct bond; and R 3 is optionally substituted divalent piperazine, optionally substituted
  • the present invention provides a compound represented by the Formula (I), wherein: a is 3; R 1 is optionally substituted linear or branched C 2-6 alkylene, wherein one or more methylene groups can be replaced with a divalent piperidine; R 2 is -C(O)-, -O-, or a direct bond; and R 3 is optionally substituted trivalent 1,4,7-triazonane, or optionally substituted trivalent 1,3,5-triazine.
  • Formula (I) wherein: a is 3; R 1 is optionally substituted linear or branched C 2-6 alkylene, wherein one or more methylene groups can be replaced with a divalent piperidine; R 2 is -C(O)-, -O-, or a direct bond; and R 3 is optionally substituted trivalent 1,4,7-triazonane, or optionally substituted trivalent 1,3,5-triazine.
  • the present invention provides a compound represented by the Formula (I), wherein: a is 3; R 1 is -(CH 2 ) 2 -, -(CH 2 ) 5 -, or R 2 is -C(O)-, -O-, or a direct bond; and R 3 is
  • the present invention provides a compound represented by the Formula (I), wherein a is 2; R 1 is optionally substituted linear or branched C 1-20 alkylene; R 2 is -C(O)-, and R 3 is optionally substituted divalent piperazine.
  • the present invention provides a compound represented by the Formula (I), wherein a is 2; R 1 is optionally substituted linear or branched C 1-20 alkylene; R 2 is -C(O)-, and R 3 is
  • alkyl refers to saturated hydrocarbon moieties having linear or branched moieties or combinations thereof and containing 1 to 20 carbon atoms.
  • One or more methylene (-CH 2 -) groups of the alkyl group can be replaced by oxygen, sulfur, sulfoxide, amino group, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C 3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group.
  • Alkyl groups can have one or more chiral centers.
  • Alkyl groups can be independently substituted by halogen atoms, hydroxyl groups, cycloalkyl groups, amino groups, heterocyclic groups, aryl groups, carboxylic acid groups, phosphonic acid groups, sulphonic acid groups, phosphoric acid groups, nitro groups, amide groups, or sulfonamide groups.
  • Monovalent alkyl groups can be independently represented by their formulae -C n H 2n+1 or by their abbreviated conventional names.
  • alkylene refers to saturated divalent (bivalent) hydrocarbon moieties having linear or branched moieties or combinations thereof and containing 1 to 20 carbon atoms.
  • One or more methylene (-CH 2 -) groups of the alkylene group can be replaced by oxygen, sulfur, sulfoxide, amino group, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C 3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group.
  • Alkylene groups can have one or more chiral centers.
  • Alkylene groups can be independently substituted by halogen atoms, hydroxyl groups, cycloalkyl groups, amino groups, heterocyclic groups, aryl groups, carboxylic acid groups, phosphonic acid groups, sulphonic acid groups, phosphoric acid groups, nitro groups, amide groups, or sulfonamide groups.
  • Alkylene groups can be independently represented by their formulae -C n H 2n -.
  • halogen refers to an atom of chlorine, bromine, fluorine, iodine.
  • alkenyl refers to a hydrocarbon radical having 2 to 10 carbon atoms, derived from a saturated alkyl, having at least one double bond.
  • One or more methylene (-CH 2 -) groups of the alkenyl can be replaced by oxygen, sulfur, sulfoxide, amino group, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C 3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group.
  • C 2-10 alkenyl can be in the E or Z configuration.
  • Alkenyl groups can be substituted by alkyl groups, as defined above, or by halogen atoms.
  • alkenylene refers to a divalent (bivalent) hydrocarbon radical having 2 to 10 carbon atoms, derived from a saturated alkylene, having at least one double bond.
  • One or more methylene (-CH 2 -) groups of the alkenylene can be replaced by oxygen, sulfur, sulfoxide, amino group, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C 3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group.
  • C 2-10 alkenylene can be in the E or Z configuration.
  • Alkenylene groups can be substituted by alkyl groups, as defined above, or by halogen atoms.
  • heterocycle refers to a 3 to 12 membered ring, which can be aromatic or non-aromatic, saturated or unsaturated, containing at least one heteroatom selected form oxygen, amino group, sulfur, or combinations of at least two thereof, interrupting the carbocyclic ring structure.
  • Heterocycles can be monocyclic or polycyclic, trivalent, divalent or monovalent or spiro.
  • Heterocyclic ring moieties can be substituted by halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyano groups, -OC 1-6 alkyl groups, -SC 1-6 alkyl groups, -C 1-8 alkyl groups, -C 2-6 alkenyl groups, -C 2-6 alkynyl groups, ketone groups, alkylamino groups, amino groups, aryl groups, C 3-8 cycloalkyl groups or hydroxyl groups.
  • heterocycles are: 1,3,5-triazole, azetidine, piperidine, piperazine, 2,5-diazabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2.1]heptane, octahydropyrrolo[3,4-c]pyrrole, pyrazine, 3,9-diazaspiro[5,5]undecane, 1,4,7-triazonane, 2,6-diazaspiro[3.3]heptane, 1,3,5-triazine, and 1,3-thiazol.
  • Heterocycle groups can be independently substituted by halogen atoms, or hydroxyl groups.
  • aryl refers to an organic moiety derived from an aromatic hydrocarbon consisting of a ring containing 6 to 10 carbon atoms, by removal of one hydrogen atom.
  • Aryl can be substituted by halogen atoms, sulfonyl C 1-6 alkyl groups, sulfoxide C 1-6 alkyl groups, sulfonamide groups, carboxcyclic acid groups, C 1-6 alkyl carboxylates (ester) groups, amide groups, nitro groups, cyano groups, -OC 1-6 alkyl groups, -SC 1-6 alkyl groups, -C 1-6 alkyl groups, -C 2-6 alkenyl groups, -C 2-6 alkynyl groups, ketone groups, aldehydes, alkylamino groups, amino groups, aryl groups, C 3-8 cycloalkyl groups or hydroxyl groups.
  • Aryls can be monocyclic or polycyclic.
  • Aryl moieties can be divalent or mono
  • cycloalkyl refers to a monovalent or divalent (bivalent) saturated carbocycle group of 3 to 8 carbon atoms. Cycloalkyl groups can be spiro, monocyclic or polycyclic.
  • Cycloalkyl groups can be independently substituted by halogen atoms, sulfonyl groups, sulfoxide groups, sulfonyl C 1-8 alkyl groups, sulfoxide C 1-8 alkyl groups, sulfonamide groups, nitro groups, cyano groups, -OC 1-8 alkyl groups, -SC 1-8 alkyl groups, -C 1-8 alkyl groups, -C 2-6 alkenyl groups, -C 2-6 alkynyl groups, ketone groups, alkylamino groups, amino groups, aryl groups, C 3-8 cycloalkyl groups or hydroxyl groups.
  • cycloalkenyl refers to a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cycloalkyl having at least one double bond. Cycloalkenyl groups can be monocyclic or polycyclic.
  • Cycloalkenyl groups can be independently substituted by halogen atoms, sulfonyl groups, sulfoxide groups, sulfonyl C 1-8 alkyl groups, sulfoxide C 1-8 alkyl groups, sulfonamide groups, nitro groups, cyano groups, -OC 1-8 alkyl groups, -SC 1-8 alkyl groups, -C 1-8 alkyl groups, -C 2-6 alkenyl groups, -C 2-6 alkynyl groups, ketone groups, alkylamino groups, amino groups, aryl groups, C 3-8 cycloalkyl groups or hydroxyl groups.
  • hydroxyl as used herein, represents a group of formula “-OH”.
  • carbonyl as used herein, represents a group of formula “-C(O)-”.
  • ketone represents an organic compound having a carbonyl group linked to a carbon atom such as -(CO)R x , wherein R x can be alkyl, aryl, cycloalkyl, cycloalkenyl, or heterocycle as defined above.
  • amine or “amino” as used herein, represents a group of formula “-NR x R y ”, wherein R x and R y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, or heterocycle as defined above.
  • sulfonyl as used herein, represents a group of formula “-SO 2 -”.
  • sulfonate represents a group of the formula “-S(O) 2 -O-”.
  • carboxylic acid as used herein, represents a group of formula “-C(O)OH”.
  • nitro as used herein, represents a group of formula “-NO 2 ”.
  • cyano as used herein, represents a group of formula “-CN”.
  • amide as used herein, represents a group of formula “-C(O)NR x R y ” wherein R x and R y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, or heterocycle as defined above.
  • sulfonamide represents a group of formula “-S(O) 2 NR x R y ” wherein R x and R y can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, or heterocycle as defined above.
  • sulfoxide as used herein, represents a group of formula “-S(O)-”.
  • phosphonic acid as used herein, represents a group of formula “-P(O)(OH) 2 ”.
  • phosphoric acid as used herein, represents a group of formula “-OP(O)(OH) 2 ”.
  • sulphonic acid as used herein, represents a group of formula “-S(O) 2 OH”.
  • N represents a nitrogen atom
  • azetidine as used herein, represents structure.
  • pyrazine as used herein, represents structure.
  • 1,3-thiazol represents a group of formula.
  • 1,4-diazidobutane represents a group of formula.
  • pyrazine-2,5-dicarbonyl dichloride represents a group of formula.
  • the invention provides compounds having Formula (I), wherein the values of -R 1 -, -R 2 -, R 3 and “a” are represented in Table 1:
  • the invention also provides compounds having Formula (X): wherein representative and illustrative values of R 7 , R 8 , R 9 , and R 10 are shown in Table 2:
  • Some compounds of Formula (I) and of Formula (II) and some of their intermediates have at least one asymmetric center in their structure.
  • This asymmetric center may be present in an R or S configuration, and said R and S notations are used in correspondence with the rules described in Pure Appli. Chem. (1976), 45, 11-13.
  • pharmaceutically acceptable salts refers to salts or complexes that retain the desired biological activity of the above identified compounds.
  • pharmaceutically acceptable salts include therapeutically active base or acid salt forms, which the compounds of Formula (I) and of Formula (II) are able to form.
  • the acid addition salt form of a compound of Formula (I) and of Formula (II) that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; or an organic acid such as for example, acetic acid, hydroxyacetic acid, propanoic 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, methylsulfonic acid, ethanesulfonic acid, benzenesulfonic acid, formic acid and the like (Handbook of Pharmaceutical Salts, P. Heinrich Stahal & Camille G. Wermuth (Eds), Verlag Helvetica Chemica Acta- Zur
  • the base addition salt form of a compound of Formula (I) and of Formula (II) that occurs in its acid form can be obtained by treating the acid with an appropriate base such as an inorganic base, for example, sodium hydroxide, magnesium hydroxide, potassium hydroxide, calcium hydroxide, ammonia and the like; or an organic base such as for example, L-arginine, ethanolamine, betaine, benzathine, morpholine and the like.
  • an appropriate base such as an inorganic base, for example, sodium hydroxide, magnesium hydroxide, potassium hydroxide, calcium hydroxide, ammonia and the like
  • an organic base such as for example, L-arginine, ethanolamine, betaine, benzathine, morpholine and the like.
  • solvates include for example hydrates, alcoholates and the like.
  • Compounds of Formulae (I) and (II) may be the compound itself or any forms of its crystal polymorphs.
  • the compounds provided herein can be synthesized according to procedures described herein.
  • the synthetic methods described herein are merely exemplary, and the compounds disclosed herein may also be synthesized by alternate routes utilizing alternative synthetic strategies, appreciated by those of ordinary skill in the art.
  • those skilled in the art will appreciate that many additional compounds that fall under the scope of the invention may be prepared by performing various common chemical reactions. Details of certain specific chemical transformations are provided in the examples.
  • Those skilled in the art will be able to routinely modify and/or adapt the following schemes to synthesize any compounds of the invention covered by Formula (I), respectively Formula (IA) or Formula (IB).
  • the compounds of Formula (I), Formula (IA) or Formula (IB) respectively can be synthesized according to the following schemes.
  • Scheme 1 Reaction for compounds of Formula (IA) wherein R 1 , R 2 and R 3 are as defined herein.
  • Compounds of general Formula (IA) can be prepared from intermediates of Formula (IX) and Formula (IY) through a coupling reaction as shown in Scheme 1.
  • Examples of the reactive group “X” in Formula (IX) participating in a coupling reaction can be an alkyl carboxylate, a carboxylic acid, an alkyne, an alkyl ether, an amine, an alkyl sulfonate, a nitro group, or an alcohol.
  • Examples of the reactive group “Y” in Formula (IY) participating in a coupling reaction can be an azide, an amine, an acyl chloride, a halogenated alkyl, or a halogenated cyclic moiety.
  • Intermediates wherein “Y” is an azide are Int78 and the intermediates described in Table 7.
  • the reaction in 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 a copper catalysed 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 to be used can be generally at least an equimolar amount, preferably equimolar to 1.5-fold molar amount, relative to the compound of Formula (IX).
  • the reaction in Scheme 1 can be performed neat or in a suitable solvent.
  • suitable solvents include water, ethers such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethylether, ethylene glycol dimethylether and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; lower alcohols such as methanol, ethanol, isopropanol and the like; ketones such as acetone, methylethyl ketone and the like; polar solvents such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric acid triamide, acetonitrile and the like.
  • DMF N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • hexamethylphosphoric acid triamide acetonitrile and the like.
  • the proportion of the compound of Formula (IX) and the compound of Formula (IY) to be used in the Scheme 1, is generally at least 1.5-fold mol, preferably about 1.5- to 3-fold mol, of the latter relative to the former.
  • the above-mentioned reaction is performed generally at room temperature to 200°C, preferably room temperature to 150°C, and completes in about 1 to 72 hr.
  • the compounds of general Formula (IA) can be prepared via a copper catalyzed Huisgen cycloaddition reaction.
  • Group “Y” is an azide in the intermediates of Formula (IY) participating in this reaction.
  • Example 58 and the examples described in Table 11 have been synthesized via this reaction.
  • Some intermediates of Formula (IX) can be prepared according to the reaction described in 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.
  • Scheme 2 Reaction for intermediates of Formula (IX) a) Protection of functional group “X” wherein suitable protecting groups can be tert-butyl (t-Bu), tert-butyloxycarbonyl (Boc), tert-butyldimethylsilyl (TBDMS), b) Alkylation in the presence of alkylating agents such as chloromethyl chlorosulfate, in the presence of a quaternary ammonium salt (TBA-HSO 4 ) c) Alkylation in the presence of a base such as NaH and in the presence of heat d) Deprotection of functional group “X” wherein suitable deprotecting reagents can be TFA, HCl or TBAF.
  • suitable protecting groups can be tert-butyl (t-Bu), tert-butyloxycarbonyl (Boc), tert-butyldimethylsilyl (TBDMS), b) Alkylation in the presence of alkylating agents such
  • Some intermediates of Formula (IY), wherein Y is an azide, can be prepared via an amide coupling reaction, wherein 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.
  • the compounds of Formula (IB) can be prepared according to the general reaction described in Scheme 4.
  • Scheme 4 Reaction for compounds of Formula (IB)
  • the reactants of Formula (IBY) were generally commercially available, otherwise they can be prepared by reactions known in the literature with which on of skill in the art will be familiar with.
  • the compounds of the invention may contain one or more asymmetric centers, such that the compounds may exist in enantiomeric as well as in diastereomeric forms. Unless it is specifically noted otherwise, the scope of the present invention includes all enantiomers, diastereomers and racemic mixtures. Some of the compounds of the 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 invention.
  • the present invention includes all pharmaceutically acceptable isotopically enriched compounds.
  • Any compounds of the invention and intermediates may contain one or more isotopic atoms enriched or different than the natural ratio such as deuterium 2 H (or D) in place of hydrogen 1 H (or H) or use of 13 C enriched material in place of 12 C and the like. Similar substitutions can be employed for N, O and S, etc.
  • isotope 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, and the like.
  • the use of isotopes may assist in analytical as well as therapeutic aspects of the invention. For example, use of deuterium may increase the in vivo half-life by altering the metabolism (rate) of the compounds of the invention.
  • These compounds can be prepared in accord with the preparations described by use of isotopically enriched reagent
  • compounds of Formulae (I) and (II), or pharmaceutically acceptable salts thereof may have the mean particle size measured by laser diffractometry, e.g., using a laser diffraction particle size distribution measuring device, ranging from 0.05 to 10 ⁇ m, for example, 0.1 to 10 ⁇ m, for example, 0.1 to 5 ⁇ m, for example, 0.1 to 3.4 ⁇ m, for example, 0.2 to 1.9 ⁇ m, for example, 0.2 to 0.4 ⁇ m.
  • Suitable mean particle sizes may be beneficial to provide a desired absorption rate and/or acceptable irritability at the injection site.
  • the term "mean particle size" as used herein refers to the volume mean diameter as measured by laser-light scattering (LLS). A particle size distribution is measured by LLS, and a corresponding mean particle size is calculated from the particle size distribution.
  • Multivalent brexpiprazole molecules may undergo bioconversion into intermediates including N-hydroxymethyl brexpiprazole in vivo, such as in the plasma, which will be hydrolyzed to brexpiprazole via enzyme-mediated hydrolysis.
  • Brexpiprazole is useful for treating and/or preventing central nervous system disorders, which are antipsychotic related, such as schizophrenia; refractory, intractable or chronic schizophrenia; emotional disturbance; psychotic disorder; mood disorder; bipolar I type disorder; bipolar II type 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; alcohol abuse; alcohol intoxication; drug addiction; stimulant intoxication; narcotism
  • prophylaxis is used herein to mean the provision in advance, and as such may involve preventing symptoms of a disease or disorder in a subject or preventing recurrence of symptoms of a disease or disorder in an afflicted subject and is not limited to complete prevention of an affliction.
  • treatment or “treating” as used herein includes the control, mitigation, reduction, or modulation of the disease state or its symptoms.
  • a subject will typically be a subject in need of treatment or prophylaxis according to the invention.
  • a subject is typically a mammal.
  • the subject is a human.
  • compositions comprising a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, as an active ingredient is provided.
  • a medical preparation herein may be selected from various forms depending on therapeutic objectives. Any administration routes of a medical preparation may be chosen depending on dosage forms, the age and sex of a patient to be administered, disease status, and other conditions.
  • a medical preparation may be administered orally, intravenously, intramuscularly, intradermally, subcutaneously, intraperitoneally, or rectally as necessary.
  • Examples of the medical preparation 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 tablets, and multilayered tablets.
  • a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof may be combined with a pharmaceutically acceptable carrier to be formulated into any forms of a medical preparation.
  • a pharmaceutically acceptable carrier include commonly used substances for a component of a medical preparation, including excipients such as lactose; binders such as polyvinylpyrrolidone; disintegrants such as starch; absorption aids such as sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as colloidal silicic acid; and lubricants such as magnesium stearate and polyethylene glycol; diluents; fillers; bulking agents; and surfactants.
  • Pharmaceutically acceptable carriers to be used in formulating into a tablet specifically include excipients such as lactose; binders such as polyvinylpyrrolidone; disintegrants such as starch; absorption aids such as sodium lauryl sulfate; humectants such as glycerin and starch; adsorbants such as colloidal silicic acid; and lubricants such as magnesium stearate and polyethylene glycol.
  • excipients such as lactose
  • binders such as polyvinylpyrrolidone
  • disintegrants such as starch
  • absorption aids such as sodium lauryl sulfate
  • humectants such as glycerin and starch
  • adsorbants such as colloidal silicic acid
  • lubricants such as magnesium stearate and polyethylene glycol.
  • Pharmaceutically acceptable carriers to be used in formulating into a pill specifically include excipients such as glucose; binders such as gum arabic powder; and disintegrants such as laminaran.
  • compositions to be used in formulating into a liquid, emulsion, or suspension specifically include water. Any ordinary solubilizing agents and/or buffers as well as colorants, preservatives, aromatics, flavorings, and sweeteners may also be comprised in the preparation, and other drugs may also be comprised as necessary.
  • Pharmaceutically acceptable carriers to be used in formulating into a suppository specifically include cocoa butter.
  • a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof may be formulated into the form of a liquid, emulsion, or suspension to prepare an injection.
  • the injection is preferably sterilized, and is also preferably isotonic with blood.
  • the injection may be formulated with diluents which are conventionally used and include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters.
  • the injection may also comprise stabilizers such as polymeric stabilizers including Poloxamer 188, 338; PEG200, 1000, 4000; PPG 4000, and surfactants such as PS20, 80; sodium deoxycholate, sodium cholate, sodium dodecyl sulfate.
  • the isotonic injection may comprise a sufficient amount of sodium chloride and soothing agents, such as glucose, amino acids, and glycerin, and may also optionally comprise other agents, such as coloring agents, preserving agents, perfumes, and sweetening agents.
  • the injection is an intramuscular injection or subcutaneous injection.
  • the amount (herein also referred to as "effective amount") of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, comprised in a medical preparation may be, but is not limited thereto, any amounts conventionally used in the art, and preferably includes any amounts of 1% to 70% of the medical preparation.
  • the dose of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, to be administered may be any doses selected depending on administration routes, the age and sex of a patient to be administered, the severity of diseases, and other conditions, and includes 0.01 to 100 mg, preferably 0.1 to 50 mg, per 1 kg of body weight per day.
  • the dose may be administered once or separately in several times, such as two to four times.
  • a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof may be used or administered in combination with at least one therapeutic or preventive drug or standard-of-care agent, which may be referred to as a combined drug herein, useful for one of the above-mentioned diseases.
  • a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof is used in combination with a combined drug, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, and the drug may be administered simultaneously or at the same time, separately or sequentially at about the same time, or separately or sequentially at different times with a suitable interval in between.
  • a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, and the combined drug may be formulated into separate preparations or mixed and formulated into a single preparation.
  • Embodiments Clause 1 A compound having Formula (I), or a pharmaceutically acceptable salt thereof: wherein: a is 2 or 3; R 1 is optionally substituted linear or branched 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 linear or branched C 1-20 alkylene); or optionally substituted divalent C 3-8 cycloalkenyl; R 2 is -C(O)-, -O-C(O)-, -C(O)-NR a -CH 2 -, -O-, -CH 2 -, -NR a -C(O)-, or a direct bond; R 3 is optionally substituted non-aromatic divalent or trivalent heterocycle, optionally substituted aromatic divalent or trivalent heterocycle, or optionally substituted linear or branched C 1
  • Clause 2 A compound according to clause 1, or a pharmaceutically acceptable salt thereof, wherein: a is 2 or 3; R 1 is optionally substituted linear or branched C 2-16 alkylene, wherein one or more methylene groups can be replaced with a functional group selected from -O- or -NH-, or one or more methylene groups can be replaced with a spiro cyclopentane, or a divalent piperidine, or one or more methylene groups can be replaced with a divalent 1,3,5-triazole cycle; ethylene; optionally substituted divalent cyclohexyl; optionally substituted divalent azetidine; or optionally substituted divalent piperidine; R 2 is -C(O)-, -O-C(O)-, -C(O)-N(CH 3 )-CH 2 -, -C(O)-NH-CH 2 -, -O-, -NH-C(O)-, -CH 2 -, or a
  • Clause 3 A compound according to clause 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: a is 2; R 1 is optionally substituted linear or branched C 2-16 alkylene, wherein one or more methylene groups can be replaced with an oxygen or amino group, or one or more methylene groups can be replaced with a spiro cyclopentane, or a divalent piperidine, or one or more methylene groups can be replaced with a divalent 1,3,5-triazole cycle; ethylene; optionally substituted divalent cyclohexyl; optionally substituted divalent azetidine; or optionally substituted divalent piperidine; R 2 is -C(O)-, -O-C(O)-, -C(O)-N(CH 3 )-CH 2 -, -C(O)-NH-CH 2 -, -CH 2 -, -NH-C(O)-, or a direct bond; and R 3 is optionally substituted divalent piperaz
  • Clause 4 A compound according to clause 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: a is 3; R 1 is optionally substituted linear or branched C 2-6 alkylene, wherein one or more methylene groups can be replaced with a divalent piperidine; R 2 is -C(O)-, -O-, or a direct bond; and R 3 is optionally substituted trivalent 1,4,7-triazonane, or optionally substituted trivalent 1,3,5-triazine.
  • Clause 6 A compound according to clause 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: a is 3; R 1 is -(CH 2 ) 2 -, -(CH 2 ) 5 -, or R 2 is -C(O)-, -O-, or a direct bond; and R 3 is
  • Clause 7 A compound according to clause 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: (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-oxohexanoyl ⁇ piperazin-1-yl)-6-oxohexanoate; (7- ⁇ 5-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy ⁇ -2-oxo-1,2-dihydroquinolin-1-yl)methyl-8-[(2R,5S)-4- ⁇ 8-[(7- ⁇
  • Clause 8 A compound according to clause 6, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: (7- ⁇ 4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy ⁇ -2-oxo-1,2-dihydroquinolin-1-yl)methyl-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-triazonan-1-yl]-4-oxobutanoate; (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
  • Clause 9 A compound according to clause 1, or a pharmaceutically acceptable salt thereof, wherein: a is 2; R 1 is -(CH 2 ) 2 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 -, -(CH 2 ) 7 -, -(CH 2 ) 8 -, -(CH 2 ) 9 -, -(CH 2 ) 12 -, or -(CH 2 ) 16 -; R 2 is -C(O)-, -CH 2 -, or a direct bond; and R 3 is
  • Clause 10 A compound according to clause 9, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: (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-oxohexanoyl ⁇ piperazin-1-yl)-6-oxohexanoate; (7- ⁇ 5-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy ⁇ -2-oxo-1,2-dihydroquinolin-1-yl)methyl-8-[(2R,5S)-4- ⁇ 8-[(7- ⁇
  • Clause 11 A compound according to clause 1, or a pharmaceutically acceptable salt thereof, wherein: a is 2; R 1 is R 2 is -C(O)-, -CH 2 -, or a direct bond; and R 3 is -(CH 2 ) 4 -,
  • Clause 12 A compound according to clause 11, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: (7- ⁇ 4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy ⁇ -2-oxo-1,2-dihydroquinolin-1-yl)methyl-(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-carboxylate; (7- ⁇ 4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy ⁇ -2-oxo-1,2-dihydroquinolin-1-yl)
  • Clause 13 A compound according to clause 1, or a pharmaceutically acceptable salt thereof, wherein: a is 2; R 1 is -(CH 2 ) 2 -, -(CH 2 ) 4 -, -(CH 2 ) 6 -, or -(CH 2 ) 9 -; R 2 is -C(O)-, -C(O)-N(CH 3 )-CH 2 -, -C(O)-NH-CH 2 -, or -NH-C(O)-; and R 3 is
  • Clause 14 A compound according to clause 13, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: (7- ⁇ 4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy ⁇ -2-oxo-1,2-dihydroquinolin-1-yl)methyl-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-oxooctanoate; (7- ⁇ 4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy ⁇ -2-oxo-1,2-dihydroquinolin-1-yl)methyl-8-(6- ⁇ 8-
  • Clause 15 A compound according to any one of clauses 1 to 14, or a pharmaceutically acceptable salt thereof, including any of all the example compounds described herein, having the mean particle size measured by laser diffractometry ranging from 0.05 to 10 ⁇ m.
  • Clause 16 A pharmaceutical composition comprising a compound according to any one of clauses 1 to 15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Clause 17 A medicament for treating and/or preventing a central nervous system disorder, comprising a compound according to any one of clauses 1 to 15, or a pharmaceutically acceptable salt thereof.
  • Clause 18 The medicament according to clause 17, wherein the central nervous system disorder is selected from the group consisting of schizophrenia; refractory, intractable or chronic schizophrenia; emotional disturbance; psychotic disorder; mood disorder; bipolar I type disorder; bipolar II type 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; alcohol abuse; alcohol intoxication; drug addiction; stimulant intoxication; narcotism; anhedonia;
  • Clause 19 Use of a compound according to any one of clauses 1 to 15, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating and/or preventing a central nervous system disorder.
  • the central nervous system disorder is selected from the group consisting of schizophrenia; refractory, intractable or chronic schizophrenia; emotional disturbance; psychotic disorder; mood disorder; bipolar I type disorder; bipolar II type 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; alcohol abuse; alcohol intoxication; drug addiction; stimulant intoxication; narcotism; anhedonia;
  • Clause 21 A method for treating and/or preventing a central nervous system disorder, comprising administering a compound according to any one of clauses 1 to 15, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the central nervous system disorder is selected from the group consisting of schizophrenia; refractory, intractable or chronic schizophrenia; emotional disturbance; psychotic disorder; mood disorder; bipolar I type disorder; bipolar II type 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; alcohol abuse; alcohol intoxication; drug addiction; stimulant intoxication; narcotism; anhedonia;
  • Clause 23 A compound according to any one of clauses 1 to 15, or a pharmaceutically acceptable salt thereof, for use in treating and/or preventing a central nervous system disorder.
  • the central nervous system disorder is selected from the group consisting of schizophrenia; refractory, intractable or chronic schizophrenia; emotional disturbance; psychotic disorder; mood disorder; bipolar I type disorder; bipolar II type 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; alcohol abuse; alcohol intoxication; drug addiction; stimulant intoxication; narcotism; anhed
  • Clause 25 A process of preparing a compound according to any one of clauses 1 to 15, or a pharmaceutically acceptable salt thereof, as described herein.
  • Clause 26 An intermediate compound in the process of preparing a compound according to any one of clauses 1 to 15, or a pharmaceutically acceptable salt thereof, as described herein.
  • a compound having Formula (X), or a salt thereof: wherein: R 7 is -CH CH-, -(CH 2 ) 2 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 -, -(CH 2 ) 7 -, -(CH 2 ) 8 -, -(CH 2 ) 9 -, -(CH 2 ) 12 -, -(CH 2 ) 16 -, R 8 is -C(O)-, -C(O)-N(CH 3 )-CH 2 -, -C(O)-NH-CH 2 -, -CH 2 -, -NH-C(O)-, or a direct bond; R 9 is -(CH 2 ) 4 -, and R 10 is -(CH 2 ) 2 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6
  • LC/UV/MS Analytical Methods LC/MS retention times are estimated to be affected by an experimental error of + 0.5 min.
  • LCMS may be recorded under the following conditions: diode array DAD chromatographic traces, mass chromatograms and mass spectra may be taken on UPLC/PDA/MS AcquityTM system coupled with Micromass ZQTM or Waters SQD single quadrupole mass spectrometer operated in positive and/or negative electron spray ES ionization mode and/or Fractionlynx system used in analytical mode coupled with ZQTM single quadrupole operated in positive and/or negative ES ionisation mode.
  • Step A To a solution of [5-(hydroxymethyl)pyrazin-2-yl]methanol (50 mg) in dry THF (3.5 mL), PPh 3 (206 mg) and Phthalimide (105 mg) were added at RT. The mixture was cooled down to 0°C and DIAD (0.16 mL) was added dropwise. The mixture was allowed to stir at RT for 3 hours. The reaction mixture was filtered over a phase separator and washed with MeCN.
  • 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), hydrazine (0.04 mL) was added and the mixture was refluxed for 3 h. The mixture was cooled to RT and TEA (0.2 mL) and Boc 2 O (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.
  • 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), HCl 4M in 1,4-dioxane (0.57 mL) was added and the reaction mixture was stirred at RT overnight. Then more HCl 4M in 1,4-dioxane (0.2 mL) was added and the mixture was stirred at RT for further 6 h. The mixture was evaporated with high vacuum to yield crude Int05 (31 mg). 1 H NMR (400 MHz, DMSO-d6) ⁇ 8.81 (s, 2H), 8.47 (s, 6H), 4.31 (s, 4H).
  • Int09 was prepared following the procedure described for Int08, starting from tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (0.10 g), to afford Int09 (0.197 g).
  • Int39 1-(7- ⁇ 4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy ⁇ -2-oxo-1,2-dihydroquinolin-1-yl)methyl 4-tert-butyl 2,2-dimethylbutanedioate
  • Step A Int39 was prepared following 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 afford a mixture of 4-tert-butyl 1-chloromethyl 2,2-dimethylbutanedioate and 1-tert-butyl 4-chloromethyl 2,2-dimethylbutanedioate (0.45 g).
  • Step B The mixture obtained was reacted with 7- ⁇ 5-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy ⁇ -1,2-dihydroquinolin-2-one (0.45 g), following the procedure described for Int02.
  • 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 trifluoroacetic acid salt
  • TFA 0.24 mL
  • LC-MS (ESI): m/z (M+1): 649.6, Rt 2.52 min. (Method 3).
  • 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 trifluoroacetic acid salt
  • Int50 was prepared following the procedure described for Int48, starting from Int49 (570 mg), to afford Int50 (370 mg).
  • LC-MS (ESI): m/z (M+1): 607.2, Rt 0.75 min. (Method 1).
  • 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 trifluoroacetic acid salt
  • Int52 was prepared following the procedure described for Int48, starting from Int51 (800 mg), to afford Int52 (545 mg, 63% yield).
  • LC-MS (ESI): m/z (M+1): 619.5, Rt 2.35 min. (Method 3).
  • Int57 (7- ⁇ 4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy ⁇ -2-oxo-1,2-dihydroquinolin-1-yl)methyl 3-(piperidin-4-yl)propanoate Int57 was prepared following the procedure described for Int54, starting from Int56 (1.28 g), to afford Int57 (1.24 g).
  • LC-MS (ESI): m/z (M+1): 603.3, Rt 0.55 min. (Method 1).
  • Int59 3-(7- ⁇ 4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy ⁇ -2-oxo-1,2-dihydroquinolin-1-yl)methyl 1-tert-butyl azetidine-1,3-dicarboxylate Int59 was prepared following 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 afford Int59 (1.9 g).
  • LC-MS (ESI): m/z (M+1): 647.5, Rt 0.83 min. (Method 1).
  • Int60 (7- ⁇ 4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy ⁇ -2-oxo-1,2-dihydroquinolin-1-yl)methyl azetidine-3-carboxylate Int60 was prepared following the procedure described for Int54, starting from Int59 (1.9 g) to afford Int60 (1.6 g).
  • LC-MS (ESI): m/z (M+1): 547.3, Rt 0.53 min. (Method 1).
  • 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
  • N-ethyldiisopropylamine tris(hydrofluoride (1.5 mL) was added to a solution of Int67 (1 g) in THF (8 mL) at 0°C. The reaction was stirred at RT for 7 h. NaHCO 3 s.s. was added and the mixture was extracted with EtOAc (2 x).
  • Int69 (7- ⁇ 4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy ⁇ -2-oxo-1,2-dihydroquinolin-1-yl)methyl 6-(methanesulfonyloxy)hexanoate MsCl (0.06 mL) was added to a mixture of Int68 (250 mg), TEA (0.16 mL) and DMAP (4.8 mg) in DCM (4.3 mL) at 0°C. The reaction was stirred at RT for 3 h. The reaction mixture was diluted with DCM and washed with H 2 O (x2) and brine. The organic phase was dried over Na 2 SO 4 , filtered and the solvent was evaporated under vacuum.
  • Int70 (7- ⁇ 4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy ⁇ -2-oxo-1,2-dihydroquinolin-1-yl)methyl 6- ⁇ [(4-nitrophenoxy)carbonyl]oxy ⁇ hexanoate Py (0.01 mL) was added to a solution of Int68 (32.0 mg) in DCM (1 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 3 s.s. (5x). The organic phase was dried over a phase separator and evaporated under vacuum.
  • 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
  • Int73 was prepared following the procedure described for Int68, starting from Int72 (970 mg), to afford Int73 (744 mg).
  • LC-MS (ESI): m/z (M+1): 604.2, Rt 0.75 min. (Method 1).
  • Int74 (7- ⁇ 4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy ⁇ -2-oxo-1,2-dihydroquinolin-1-yl)methyl (1r,4r)-4-[(methanesulfonyloxy)methyl]cyclohexane-1-carboxylate
  • Int74 was prepared following the procedure described for Int69, starting from Int73 (250 mg), to afford Int74 (237 mg, 87% yield).
  • LC-MS (ESI): m/z (M+1): 682.1, Rt 0.82 min. (Method 1).
  • 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
  • TBTU 405 mg, 1.26 mmol
  • Int86 (7 ⁇ 4 ⁇ [4 ⁇ (1 ⁇ benzothiophen ⁇ 4 ⁇ yl)piperazin ⁇ 1 ⁇ yl]butoxy ⁇ 2 ⁇ oxo ⁇ 1,2 ⁇ dihydroquinolin ⁇ 1 ⁇ yl)methyl 4 ⁇ 4 ⁇ [4 ⁇ (tert ⁇ butoxy) ⁇ 4 ⁇ oxobutanoyl]piperazin ⁇ 1 ⁇ yl ⁇ 4 ⁇ oxobutanoate trifluoroacetic acid Int86 was prepared following 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 afford (7 ⁇ 4 ⁇ [4 ⁇ (1 ⁇ benzothiophen ⁇ 4 ⁇ yl)piperazin ⁇ 1 ⁇ yl]butoxy ⁇ 2 ⁇ oxo ⁇ 1,2 ⁇ dihydroquinolin ⁇ 1 ⁇ yl)methyl 4 ⁇ 4 ⁇ [4 ⁇ (tert ⁇ butoxy) ⁇ 4 ⁇ oxobutanoyl]piperazin ⁇ 1
  • 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
  • Int87 was prepared following the procedure described for Int03, starting from Int86 (70 mg, 0.089 mmol) to afford 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).
  • Int89 8,8'-(piperazine-1,4-diyl)bis(8-oxooctanoic acid) Int89 is prepared in a similar way to methods described herein.
  • 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.
  • Example 04 (7- ⁇ 4-[4-(1-benzothiophen-4-yl)piperazin-1- yl]butoxy ⁇ -2-oxo-1,2-dihydroquinolin-1-yl)methyl 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]heptan-2-yl]-8-oxooctanoate; tris(trifluoroacetic acid) To a solution of Int03 (90 mg) and (2S)-2-ethylpiperazine dihydrochloride (12 mg) in dry DMF (13 mL) was added TBTU (543 mg).
  • Example 08 (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-oxooctanamido ⁇ methyl)pyrazin-2-yl]methyl ⁇ carbamoyl)heptanoate To a solution of Int03 (110 mg) and Int05 (16 mg), in dry DMF (13 mL) was added TBTU (543 mg).
  • Example 10 (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
  • TBTU (395 mg).
  • Example 12 (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]undecan-3-yl)-4-oxobutanoate To a solution of Int07 (200 mg) and Int09 (57 mg), in dry DMF (13 mL) was added TBTU (543 mg).
  • Example 19 (7- ⁇ 4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy ⁇ -2-oxo-1,2-dihydroquinolin-1-yl)methyl 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 oxooctanoate
  • Int03 890 mg
  • dry DMF 13 mL
  • TBTU 543 mg
  • Example 45 (7- ⁇ 4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy ⁇ -2-oxo-1,2-dihydroquinolin-1-yl)methyl-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-carboxylate Pyrazine-2,5-dicarbonyl dichloride (36 mg) was added to a solution of Int54 (200 mg) and TEA (0.24 mL) in DCM (6 mL) at 0°C.
  • Example 46 (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 DIPEA (32 mg) was added to a solution of 2,4-dichloro-1,3,5-triazine (6.2 mg) and Int57 (49 mg) in DMF (1.2 mL).
  • Example 47 (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 hexakis(trifluoroacetic acid) salt DIPEA (0.12 mL) was added to a solution of Int57 (199 mg) and 2,4,6-trichloro-1,3,5-triazine (20 mg) in DMF (4 mL) and the reaction was stirred at 60°C for 16 h.
  • 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
  • Example 48 was prepared following the procedure described for Example 46, starting from Int57 (150 mg) and 2,5-bis(bromomethyl)pyrazine (33 mg).
  • Example 49 (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 Pyrazine-2,5-dicarbonyl dichloride (43 mg) was added to a solution of Int57 (250 mg) and TEA (0.58 mL) in DMF (8 mL) at 0°C.
  • Example 50 (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 bis(trifluoroacetic acid) salt
  • Example 50 was prepared following the procedure described for Example 49, starting from Int60 (350 mg) and pyrazine-2,5-dicarbonyl dichloride (66 mg), to afford Example 50 (8.2 mg).
  • Example 51 (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
  • Step A TFA (1.12 mL) was added dropwise to a solution of Int62 (0.68 g) in DCM (10 mL) at RT.
  • Example 51-Step A (7- ⁇ 4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy ⁇ -2-oxo-1,2-dihydroquinolin-1-yl)methyl 5-aminopentanoate dihydrochloride salt (658 mg, quant. yield).
  • Step B 1,3-thiazole-2,5-dicarbonyl dichloride (33 mg) was added to a solution of crude (7- ⁇ 4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy ⁇ -2-oxo-1,2-dihydroquinolin-1-yl)methyl 5-aminopentanoate dihydrochloride salt (0.20 g) in DMF (6 mL) at RT, followed by TEA (0.6 mL). The reaction was stirred at 100 °C for 3 h. The reaction was cooled down to RT, diluted with cold NH 4 Cl s.s. and extracted with DCM (2 x).
  • Examples 52 and 53 were prepared following the procedure described for Example 51.
  • the reactants used in the synthesis of each compound as well as their characterization are tabulated in Table 9.
  • 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 TEA (0.04 mL) and piperazine (9 mg) were added to a suspension of Int69 (140 mg) in DMF (1 mL).
  • Example 55 (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 DIPEA (0.02 mL) was added to a solution of Int70 (20 mg) in DCM (1 mL) at 0°C, followed by piperazine (0.9 mg).
  • Example 56 was prepared following the procedure described for Example 54. The reactants used in the synthesis of Example 56 as well as its characterization are tabulated in Table 10.
  • Example 57 (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 tetrakis(trifluoroacetic acid) salt DIPEA (0.11 mL) was added dropwise solution of 2,4,6-trichloro-1,3,5-triazine (16 mg) and Int68 (150 mg) in MeCN (1 mL) at 0°C.
  • DIPEA tetrakis(trifluoroacetic acid) salt
  • Example 58 (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 formic acid salt DIPEA (0.04 mL) and CuI (48 mg) were dissolved in degassed DMF (1.5 mL).
  • 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 as well as their characterization are tabulated in Table 11.
  • Example 10 (48.0 mg, 0.040 mmol) was recovered by filtration and washed with cold IPA.
  • the characteristic XRPD peaks of Form A of a compound of Example 10 are shown as follows.
  • the XRPD pattern of Form A is shown in Figure 1.
  • Form A features at least one, two, three, four, five, or six XRPD peaks (°2 ⁇ ) selected from 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.
  • DSC trace showed one endothermic event at 176°C attributable to the melt of Form A as shown in Figure 2.
  • Form A has a DSC thermogram characterized by an endothermic peak at about 176 ⁇ 3°C.
  • Example 10 A compound of Example 10 (50 mg) was suspended in DMSO (20 vol). The system was heated to 75°C (temperature of the heating plate); dissolution was reached around 70-71°C. The solution was cooled to 50°C, then seeded with a seed crystal of Form B (ca. 4-5 mg); the seed appeared persistent and the system was aged for ca. 10 minutes. Heating was turned off and the suspension was allowed to cool down to room temperature and left aging under stirring for the night. The following day the solid was isolated by filtration, deliquored in vacuum, then dried in vacuum oven at reduced pressure at 50°C for the night. Output material: 44.1 mg (88%w/w uncorrected recovery) The characteristic XRPD peaks of Form B are shown as follows.
  • Form B features at least one, two, three, four, five, or six XRPD peaks (°2 ⁇ ) selected from 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.
  • DSC trace showed an initial small event of desolvation, followed by a main endothermic peak with onset at 159°C (enthalpy 83 J/g) as shown in Figure 4.
  • Form B has a DSC thermogram characterized by an endothermic peak at about 159 ⁇ 3°C.
  • Form 1 features at least one, two, three, four, five, or six XRPD peaks (°2 ⁇ ) selected from 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.
  • the TGA profile showed a weight loss of 2.7%w/w from ambient to 150°C; the weight loss data is consistent with the theoretical amount required for a dihydrate (i.e. 2.7%w/w) as shown in Figure 6.
  • DSC trace showed one endothermic event at 81°C associated with the melt of the crystalline material as shown in Figure 7.
  • Form 1 has a DSC thermogram characterized by an endothermic peak at about 81 ⁇ 3°C.
  • Test 1 Human Skin S9 Stability Skin S9 from human donors (male and female) were stored at -80°C until use. On the day of the experiment, skin S9 were thawed rapidly in a waterbath at 37°C and diluted with 50 mM potassium phosphate buffer pH 7.4 to a protein concentration of 3.165 mg/mL. Test compounds were dissolved in DMSO to obtain 10 mM stock solutions. 5 ⁇ L of 10 mM stock solution in DMSO were diluted with 995 ⁇ L methanol to obtain 50 ⁇ M dosing solution. Positive control (clopidogrel) was dissolved in DMSO to 10 mM stock solution.
  • 50 ⁇ M dosing solution was prepared by diluting 5 ⁇ L of 10mM stock solution in DMSO with 995 ⁇ L methanol.
  • the general procedure consisted of incubation of test compound at 0.5 ⁇ M (final concentration) with 2.5 mg/ml of pooled Skin S9 (final concentration) plus NADPH regenerating system and UDPGA solution. Negative control was performed with pooled skin S9 without all cofactors. 5 ⁇ L of test compounds or positive control dosing solution were added to 395 ⁇ L of 3.165 mg/ml skin S9 solution in a 96 well plate (incubation plate) at 37°C for 5 minutes.
  • the incubation reactions was initiated by adding 50 ⁇ L of pre-warmed NADPH regenerating system and 50 ⁇ L UDPGA or 100 ⁇ L buffer (for negative control) to the incubation mixtures. Test compounds were incubated in two replicates with and without cofactor while positive control was incubated in single with and without cofactor. The incubation was performed in shacking water bath at 37°C for 1 hours. At each time point (after 0, 5, 15, 30, 45 and 60 min), 25 ⁇ L of spiked skin S9 suspension were collected, added to 25 ⁇ L of milliQ water and 150 ⁇ L of stop solution (acetonitrile containing 1% formic acid and Brexpiprazole-D8 0.2 ⁇ M) to precipitate proteins.
  • stop solution acetonitrile containing 1% formic acid and Brexpiprazole-D8 0.2 ⁇ M
  • the active parent compound (brexpiprazole) was quantified based on the MS response of brexpiprazole-D8 in the same sample.
  • the stability results of exemplary compounds in human skin S9 are listed in Table 15. When multiple values were determined, mean half-life was calculated.
  • Test 2 Human Hepatocytes Stability Cryopreserved hepatocytes from human donors were stored in vapour phase of liquid nitrogen freezer until use. After thawing and prior to use, cell viability check was performed using Trypan Blue dye exclusion test. Incubations of test compounds and positive controls (testosterone and 7-OH coumarin) were carried out at the cell concentration of 0.5 x 10 6 cells/mL in William's medium E added with Glutamine 200 mM and HEPES 1M. 0.495 mL of cells suspension were dispensed to 48-well plate and pre incubate at 37°C for at least 10 minutes.
  • Test compounds and positive controls were dissolved in DMSO to obtain a 10 mM, 50 mM and 5 mM stock solution for test compounds, testosterone and 7OH-coumarin respectively. Stock solutions were further diluted in methanol to achieve a final dosing solution of 50 ⁇ M, 1 mM and 500 ⁇ M solution for test compounds, testosterone and 7OH-coumarin respectively. All solutions were prepared immediately before the assay. 5 ⁇ L of 50 ⁇ M test compounds, 1000 ⁇ M testosterone and 500 ⁇ M 7-OH-coumarin were added to 0.495 mL of 0.5 x 10 6 cell suspensions to give final concentrations of 0.5 ⁇ M for test compounds, 10 ⁇ M for testosterone and 5 ⁇ M for 7-OH-coumarin.
  • the incubations were conducted at 37°C with gentle orbital shaking at 350 rpm in duplicate for test compounds and in single for positive controls. At each time point (0, 5, 10, 15, 20, 30, 45, 60, 90, 120 and 180 min) 30 ⁇ L of incubation mixture from each well were added to 30 ⁇ L of milliQ water and 180 ⁇ L of stock solution (acetonitrile containing 1% formic acid and Brexpiprazole-D8 0.2 ⁇ M) to precipitate protein. Samples were mixed thoroughly and centrifuged at 3000 rpm at 4°C for 10 min.
  • Test 3 Short Term Rat PK Study The study protocol was designed to assess the pharmacokinetic (PK) profile after intravenous (IV) and subcutaneous (SC) administration of the test compounds in rats.
  • IV intravenous
  • SC subcutaneous
  • the animals had free access to a standard rodent diet (Altromin 1324) and water ad libitum during the study.
  • test compound For IV administration, a test compound was dissolved in 5% N-methyl pyrrolidone and 10% Solutol HS15 in 50 mM acetate buffer (pH 5.5) and administered at a dose of 1 mg/kg. Blood samples were collected at 9 timepoints over a time period up to 24 hours post dose: 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post dose.
  • SC administration a test compound was suspended in 1% hydroxymethyl propyl cellulose and 0.2% Tween 80 in water and administered at a dose of 30 mg/kg except for Example 24, which was administered at a dose of 45 mg/kg.
  • Blood samples were collected at up to 20 timepoints over a time period up to 120 hours post dose: 3, 6, 10, 24, 27, 30, 34, 48, 51, 54, 58, 72, 75, 78, 82, 96, 99, 102, 106, and 120 hours post dose. From both groups, blood samples aliquots were obtained from lateral tail vein and collected into K3EDTA tubes. After gentle mix following collection, aliquots were immediately transferred into micronic tubes to perform protein precipitation online using acetonitrile containing 1% formic acid and rolipram as internal standard. Samples were then stored at -80°C until analysis. After SC administration, a skin sample was also collected at the last time point from the site of injection.
  • test compounds and brexpiprazole in blood were subjected to non-compartmental pharmacokinetic analysis and area under the curve (AUC) was calculated using Phoenix WinNonlin 6.3.
  • AUC area under the curve
  • % Blood conversion to brexpiprazole after IV administration was calculated as the ratio of AUC of brexpiprazole when the test compound was administered to the value when brexpiprazole was administered.
  • % Brexpiprazole in the skin after SC administration was calculated as the ratio of brexpiprazole concentration to the concentration of a test compound in the skin tissue.
  • Test 3 The results of Test 3 are shown in the following table.
  • the dose of test compounds by IV administration was 1 mg/kg.
  • the dose of test compounds by SC administration other than Example 24 was 30 mg/kg.
  • Example 24 was administered 45 mg/kg by SC administration.
  • Test 4 Long Term Rat PK Study Preparation of 16.3% Example 10 aqueous suspension A medium was prepared containing 1% sodium carboxymethyl cellulose, 3.4% D(-)-mannitol, 0.14% sodium dihydrogen phosphate monohydrate, and adjusting the pH to 6 with sodium hydroxide was prepared. This medium was sterilized by filtration through a 0.22 ⁇ m poly ether sulfone (PES) membrane. 3348 mg of the medium and 652 mg of Example 10 were added to two glass vials and suspended. Then, zirconia beads (1.5 mm in diameter) and a stir bar were added, and the suspension was milled by stirring for a few minutes or 3 hours with a magnetic stirrer.
  • PES poly ether sulfone
  • Example 10 The mean particle sizes of Example 10 after milling were measured using a laser diffraction particle size distribution measuring device SALD-3100 (Shimadzu Corporation) under condition of ultrasonic irradiation and a refractive index of 2.00-0.20i, and they were found to be 3.4 ⁇ m and 1.9 ⁇ m.
  • SALD-3100 Laser diffraction particle size distribution measuring device
  • the suspensions were separated from the zirconia beads using a pipette and placed in separate vials, sterilized by irradiating with 25 kGy of gamma ray, and used as test formulations.
  • Example 19 aqueous suspension A medium was prepared containing 2% D- ⁇ -tocopherol polyethylene glycol succinate, 3.4% D(-)-mannitol, 0.14% sodium dihydrogen phosphate monohydrate, and adjusted to a pH of 6 with sodium hydroxide. This medium was sterilized by filtration through a 0.22 ⁇ m polyvinylidene fluoride (PVDF) membrane. 4150 mg of medium and 890 mg of Example 19 were added to two glass vials and suspended. Then, zirconia beads (1 mm in diameter) and a stir bar were added, and the suspension was milled by stirring for 17 or 65 hours with a magnetic stirrer at 5°C.
  • PVDF polyvinylidene fluoride
  • Example 19 in the test formulations were measured under condition of ultrasonic irradiation and a refractive index of 1.70-0.20i using SALD-3100, and they were found to be 1.5 ⁇ m and 0.8 ⁇ m.
  • test formulations were subcutaneously administered to male rats, and the plasma concentrations of the prodrug compounds and brexpiprazole were measured. Rats were purchased at 7 weeks of age from Japan SLC, Inc. and used in the experiment after acclimatization. The breeding environment was as follows: feeding/watering: unlimited, number of rats per cage: 3, temperature: 21-25°C, humidity: 50-70%, lighting time: 7:00-19:00. Under isoflurane anesthesia, Example 10 and 19 formulations were subcutaneously administered to the rats at doses of 34 mg/kg and 37 mg/kg (equivalent to 25 mg/kg brexpiprazole), respectively, using a plastic syringe.
  • Blood was collected approximately 0.5 mL from the rats' jugular vein using heparinized syringes at 2 hours, and 1, 3, 6, 9, 14, 21, 28 days after administration.
  • blood samples were mixed with 2-thenoyltrifluoroacetone at a final concentration of 10 mM and were quickly chilled.
  • the plasma was separated by centrifugation, and the concentrations of the prodrug compounds and brexpiprazole were measured by LC-MS/MS. Based on the obtained plasma brexpiprazole concentration - time profile, the cumulative absorption rate at each blood collection point was calculated by the deconvolution method.
  • Example 10 or 19 were subcutaneously administered to rats, brexpiprazole was detected in the blood continuously for 28 days after administration. From these results, it was considered that these compounds have suitable characteristics as the active pharmaceutical ingredient for brexpiprazole long-acting injectable preparation. PK profiles of Examples 10 and 19 are shown in Figures 8 and 9, respectively.
  • Test 5 Dog irritation study Aqueous suspensions of Example 10 and Example 19 prepared for Test 4 were used as the test formulations. Each of the test formulations was subcutaneously administered to male and female beagle dogs, and after observation for 7 or 28 days, histopathological examination was performed on the injection site after dissection. Beagle dogs were purchased at the age of 6-8 months from Kitayama Labes Co., Ltd. and used in the experiment after acclimatization. The breeding environment was as follows: feeding: 300 g of solid feed once a day, water intake: unlimited, number of animals per cage: 1, temperature: 20-26°C, humidity: 30-70%, lighting time: 7:00-19:00.
  • Each test formulation was subcutaneously administered to dogs anesthetized with 1 mg/kg xylazine hydrochloride and 15 mg/kg ketamine hydrochloride, using a plastic syringe at a dose of 10 mg/kg per formulation at different sites in the dorso-lumbar area.
  • dogs were observed for 7 or 28 days, then sacrificed by bleeding under anesthesia with 0.08 mg/kg medetomidine hydrochloride, 0.5 mg/kg butorphanol tartrate, and 20 mg/kg thiopental sodium, and tissues of 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.
  • Compounds of Formulas (I) and (II), or pharmaceutically acceptable salts thereof, may have antipsychotic activity and may be of use in medicine, for example in the treatment and/or prophylaxis of subjects with diseases and conditions that are antipsychotic related.

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Abstract

La présente invention concerne de nouveaux composés de formule (I) qui sont des promédicaments de brexpiprazole. Les nouveaux composés de l'invention, lors de l'administration à un sujet, subissent une conversion chimique par un ou plusieurs processus métaboliques pour libérer un agent pharmacologique actif in vivo. Le brexpiprazole, vendu sous le nom de Rexulti (marque déposée), est un antipsychotique atypique indiqué pour une utilisation en tant que traitement d'appoint à des antidépresseurs pour le traitement d'un trouble dépressif majeur (TDM) chez des adultes et le traitement de la schizophrénie chez des adultes et des patients pédiatriques âgés de 13 ans et plus.
PCT/JP2024/006959 2023-02-27 2024-02-27 Benzothiophènes à substitution pipérazine pour le traitement de troubles mentaux Ceased WO2024181403A1 (fr)

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AU2024230422A AU2024230422A1 (en) 2023-02-27 2024-02-27 Piperazine-substituted benzothiophenes for treatment of mental disorders
KR1020257031216A KR20250153813A (ko) 2023-02-27 2024-02-27 정신 장애의 치료를 위한 피페라진-치환된 벤조티오펜
CN202480006469.8A CN120530108A (zh) 2023-02-27 2024-02-27 用于治疗精神障碍的哌嗪取代的苯并噻吩
IL322925A IL322925A (en) 2023-02-27 2024-02-27 Piperazine-substituted benzothiophenes for the treatment of mental disorders
MX2025010076A MX2025010076A (es) 2023-02-27 2025-08-26 Benzotiofenos sustituidos con piperazina para el tratamiento de trastornos mentales

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013035892A1 (fr) * 2011-09-08 2013-03-14 Otsuka Pharmaceutical Co., Ltd. Dérivés de benzothiophène substitué par pipérazine en tant qu'agents antipsychotiques
US20160024011A1 (en) * 2010-12-23 2016-01-28 Alkermes Pharma Ireland Limited Multi-API Loading Prodrugs

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160024011A1 (en) * 2010-12-23 2016-01-28 Alkermes Pharma Ireland Limited Multi-API Loading Prodrugs
WO2013035892A1 (fr) * 2011-09-08 2013-03-14 Otsuka Pharmaceutical Co., Ltd. Dérivés de benzothiophène substitué par pipérazine en tant qu'agents antipsychotiques

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical", 2002, VERLAG HELVETICA CHEMICA ACTA, pages: 329 - 345
PURE APPLI. CHEM., vol. 45, 1976, pages 11 - 13

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