Negative allosteric modulator of metabotropic glutamate receptor 2

Abstract

Described are 6-arylisoindolin-1-ones as negative allosteric modulators of metabotropic glutamate receptor 2 (mGlu2), pharmaceutical compositions containing these compounds, and methods of using the compounds and compositions for treating depression, anxiety, obsessive-compulsive disorder, cognitive impairment, Alzheimer's disease, or autism spectrum disorder in a subject.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 407,484, filed September 16, 2022, which is incorporated herein by reference in its entirety.

[0002] Technical Field The present disclosure relates to compounds, compositions, and methods for treating metabotropic glutamate receptor 2-associated diseases and / or disorders, such as depression, anxiety, obsessive-compulsive disorder, cognitive disorders, Alzheimer's disease, and autism spectrum disorders. [Background technology]

[0003] Metabotropic glutamate (mGlu) receptors, a class of G protein-coupled receptors (GPCRs) family C, have recently emerged as targets of potential therapeutic value. They bind the amino acid glutamate, which is the most prominent excitatory neurotransmitter in the human central nervous system (CNS). mGlu is known to activate biochemical cascades, leading to the modification of other proteins. For example, this can result in changes in synaptic excitability by presynaptic inhibition of neurotransmission or modulation and even induction of postsynaptic responses.

[0004] Metabotropic glutamate receptor 2 (mGlu2) is one of eight mGlus that have been identified and, together with mGlu3, is classified as a group II mGlu. Group II mGlus play an important role in synaptic plasticity, which, among other things, directly influences cognitive function (including learning and memory). The effects of group II mGlus occur primarily presynaptically through their inhibition of glutamate release. These effects may also be due to inhibition of nonvesicular glutamate release from glia. However, group II receptors are also known to reduce postsynaptic activity, both excitatory and inhibitory, in the cortex.

[0005] Dysfunction of mGlu2 has been implicated in many diseases and / or disorders. Therefore, targeting mGlu2 activity has been the subject of much research. Several reports have highlighted its association with various diseases, such as depression, anxiety, obsessive-compulsive disorder, cognitive impairment, Alzheimer's disease, and autism spectrum disorder. Therefore, there is a need for selective modulators of mGlu2. Summary of the Invention

[0006] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony: R 1 is independently at each occurrence hydrogen, fluoro, or C 1~4 is alkyl; R 2 is hydrogen or C 1~6 is alkyl; R 3 is a 6- to 12-membered aryl or a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S, where R 3 is unsubstituted or C 1~4 Alkyl, halogen, cyano, C 1~2 Haloalkyl, OH, -OC 1~4 Alkyl and -OC 1~2 substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of haloalkyl; R 4 is G 4 , -C 1~4 Alkylene-G 4 , Cy, or -C 1~4 alkylene-Cy; G 4 is a 6- to 12-membered aryl or a 5- to 12-membered heteroaryl, wherein G 4 is unsubstituted or C 1~4 Alkyl, halogen, cyano, C 1~2Haloalkyl, oxo, -OR 4a , -N(R 4a )2, -N(R 4a )C(O)R 4a , -N(R 4a )SO2R 4b , -C(O)N(R 4a )2, -SO2N(R 4a )2, -SO2R 4b , -C 1~4 Alkylene-OH, G 4a , and -C 1~4 Alkylene-G 4a and C 1~4 Alkyl, halogen, cyano, C 1~2 Haloalkyl, -OC 1~4 Alkyl and -OC 1~2 optionally further substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl; R 4a Each occurrence independently represents hydrogen, C 1~4 Alkyl, C 1~2 Haloalkyl, G 4a , or -C 1~4 Alkylene-G 4a and; R 4b is C 1~4 Alkyl, C 1~2 Haloalkyl, G 4a , or -C 1~4 Alkylene-G 4a and; G 4a is phenyl, C 3~6 cycloalkyl, 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms, or 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms, wherein the heteroatoms in the heteroaryl and heterocyclyl are independently selected from the group consisting of O, N, and S; 4a is C 1~4 Alkyl, C 1~2 Fluoroalkyl, halogen, cyano, oxo, OH, and -OC 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; Cy is C 3~6 carbocyclyl or a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S, wherein Cy is C 1~4 Alkyl, C 1~2 Fluoroalkyl, halogen, oxo, OH, -OC 1~4 Alkyl, G 4a , and -C 1~4 Alkylene-G 4a and C 1~4 Alkyl, C 1~2 optionally further substituted with 1 to 3 substituents independently selected from the group consisting of fluoroalkyl, and halogen; R 5 and R 6 are each independently hydrogen, C 1~4 Alkyl, halogen, cyano, C 1~2 Haloalkyl, -OC 1~4 Alkyl or -OC 1~2 It is haloalkyl.

[0007] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0008] In another aspect, the present invention provides a method for treating a disease or disorder associated with dysfunction of metabotropic glutamate receptor 2 (mGlu2), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.

[0009] In another aspect, the present invention provides a method of inhibiting mGlu2 activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.

[0010] In another aspect, the present invention provides a method of treating a disease or disorder selected from at least one of depression, anxiety, obsessive-compulsive disorder, cognitive impairment, Alzheimer's disease, and autism spectrum disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.

[0011] In another aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of a disease or disorder selected from at least one of depression, anxiety, obsessive-compulsive disorder, cognitive impairment, Alzheimer's disease, and autism spectrum disorder.

[0012] In another aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, in the manufacture of a medicament for the treatment of a disease or disorder selected from at least one of depression, anxiety, obsessive-compulsive disorder, cognitive impairment, Alzheimer's disease, and autism spectrum disorder.

[0013] In another aspect, the present invention provides a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, and instructions for use. DETAILED DESCRIPTION OF THE INVENTION

[0014] Detailed Description Disclosed herein are negative allosteric modulators (NAMs) of mGlu2. The modulators can be compounds of formula (I). Compounds of formula (I) can exhibit selectivity for mGlu2 over other mGlu receptors. Compounds of formula (I) can be used to treat or prevent diseases and disorders associated with mGlu2 by modulating mGlu2 activity. mGlu2 has been implicated in several different diseases and disorders, including, but not limited to, depression, anxiety, obsessive-compulsive disorder, cognitive impairment, Alzheimer's disease, and autism spectrum disorder.

[0015] Because the orthosteric binding sites of mGlu isoforms are highly conserved, few selective modulators of mGlu that bind at the orthosteric site have been identified. One strategy to selectively bind and modulate mGlu involves identifying allosteric sites that are amenable to modulation by small molecules. In particular, negative allosteric modulation of mGlu2 could result in the inhibition of processes governed by mGlu2 and provide therapeutic benefits for disorders caused by mGlu2 dysfunction.

[0016] 1.Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present specification, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and are not intended to be limiting.

[0017] As used herein, the terms "comprise," "include," "having," "having," "can," "containing," and variations thereof are intended to be open-ended transitional phrases, terms, or words that do not exclude the possibility of additional acts or structures. The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments that "comprise," "consist," and "consist essentially of" the embodiments or elements provided herein, whether or not explicitly stated.

[0018] The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., it includes the smallest degree of error associated with measurement of the particular quantity). The modifier "about" should also be considered to reveal a range defined by the absolute values ​​of the two endpoints. For example, the expression "about 2 to about 4" also discloses the range "2 to 4." The term "about" can refer to plus or minus 10% of the indicated number. For example, "about 10%" can indicate a range of 9% to 11%, and "about 1" can mean 0.9 to 1.1. Other meanings of "about," such as rounding, may be apparent from the context; thus, for example, "about 1" can also mean 0.5 to 1.4.

[0019] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th (back cover), and specific functional groups are generally defined as described therein. Further, general principles of organic chemistry and specific functional groups and reactivity are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March's Advanced Organic Chemistry, 5 th Edition, John Wiley&Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987, the contents of each of which are incorporated herein by reference in their entirety.

[0020] The term "alkoxy" as used herein refers to the group -O-alkyl. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.

[0021] The term "alkyl," as used herein, means a straight or branched saturated hydrocarbon chain. The terms "lower alkyl" or "C 1-6 "Alkyl" means a straight or branched chain hydrocarbon containing 1 to 6 carbon atoms. 1-4 "Alkyl" means a straight or branched chain hydrocarbon containing from 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0022] The term "alkenyl," as used herein, means a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond.

[0023] The term "alkoxyalkyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.

[0024] The term "alkoxyfluoroalkyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.

[0025] The term "alkylene," as used herein, refers to a divalent group derived from a straight-chain or branched-chain saturated hydrocarbon. Representative examples of alkylene include, but are not limited to, -CH-, -CD-, -CHCH-, -C(CH)(H)-, -C(CH)(D)-, -CHCHCH-, -CHCHCHCHCH-, and -CHCHCHCHCHCH-.

[0026] The term "alkylamino," as used herein, means at least one alkyl group, as defined herein, appended to the parent molecular moiety through an amino group, as defined herein.

[0027] The term "amide," as used herein, means -C(O)NR- or -NRC(O)-, where R can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.

[0028] The term "aminoalkyl," as used herein, means at least one amino group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.

[0029] The term "amino" as used herein refers to -NR x R y (In the formula, R x and R y (which can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl). In the case of an aminoalkyl group or any other moiety where amino attaches two other moieties together, amino is represented by -NR x -(In the formula, R x can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl).

[0030] The term "aryl," as used herein, refers to phenyl or a phenyl attached to a parent molecular moiety and fused to a cycloalkane group (e.g., the aryl can be indan-4-yl), a 6-membered arene group (i.e., the aryl can be naphthyl), or a non-aromatic heterocycle (e.g., the aryl can be benzo[d][1,3]dioxol-5-yl). The term "phenyl" is used to refer to a substituent, and the term "6-membered arene" is used to refer to a fused ring. A 6-membered arene is monocyclic (e.g., benzene or benzo). An aryl can be monocyclic (phenyl) or bicyclic (e.g., a 9- to 12-membered fused bicyclic ring system).

[0031] The term "cyanoalkyl," as used herein, means at least one --CN group, appended to the parent molecular moiety through an alkylene group, as defined herein.

[0032] The term "cyanofluoroalkyl," as used herein, means at least one --CN group appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.

[0033] The term "cycloalkoxy," as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0034] The term "cycloalkyl" or "cycloalkane," as used herein, refers to a saturated ring system containing all carbon atoms as ring members and zero double bonds. The term "cycloalkyl" is used herein to refer to a cycloalkane when it is present as a substituent. A cycloalkyl can be a monocyclic cycloalkyl (e.g., cyclopropyl), a fused bicyclic cycloalkyl (e.g., decahydronaphthalenyl), or a bridged cycloalkyl (two non-adjacent atoms of a ring are connected by an alkylene bridge of 1, 2, 3, or 4 carbon atoms) (e.g., bicyclo[2.2.1]heptanyl). Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclo[1.1.1]pentanyl.

[0035] The term "cycloalkenyl" or "cycloalkene," as used herein, refers to a non-aromatic monocyclic or polycyclic ring system containing all carbon atoms as ring members and at least one carbon-carbon double bond, preferably having 5 to 10 carbon atoms per ring. The term "cycloalkenyl" is used herein to refer to cycloalkene when it is present as a substituent. A cycloalkenyl can be a monocyclic cycloalkenyl (e.g., cyclopentenyl), a fused bicyclic (e.g., octahydronaphthalenyl), or a bridged cycloalkenyl (two non-adjacent atoms of a ring are connected by an alkylene bridge of 1, 2, 3, or 4 carbon atoms) (e.g., bicyclo[2.2.1]heptenyl). Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, or cycloheptenyl. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, or cycloheptenyl.

[0036] The term "carbocyclyl" means "cycloalkyl" or "cycloalkenyl". The term "carbocycle" means "cycloalkane" or "cycloalkene". The term "carbocyclyl" refers to a "carbocycle" when present as a substituent.

[0037] The terms cycloalkylene and heterocyclylene refer to divalent radicals derived from a base ring, i.e., a cycloalkane, a heterocycle. For illustrative purposes, examples of cycloalkylene and heterocyclylene include, respectively: [ka] Cycloalkylene and heterocyclylene include geminal divalent groups, e.g., 1,1-C 3~6 Cycloalkylene (i.e., [ka] ) A further example includes 1,1-cyclopropylene (i.e., [ka] )

[0038] The term "fluoroalkyl," as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven, or eight hydrogen atoms have been replaced by fluorine. Representative examples of fluoroalkyl include, but are not limited to, 2-fluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trifluoropropyl, e.g., 3,3,3-trifluoropropyl.

[0039] The term "fluoroalkylene," as used herein, refers to an alkylene group, as defined herein, in which 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms have been replaced by fluorine. Representative examples of fluoroalkylene include, but are not limited to, -CF2-, -CH2CF2-, 1,2-difluoroethylene, 1,1,2,2-tetrafluoroethylene, 1,3,3,3-tetrafluoropropylene, 1,1,2,3,3-pentafluoropropylene, and perfluoropropylene, such as 1,1,2,2,3,3-hexafluoropropylene.

[0040] The term "halogen" or "halo" as used herein means Cl, Br, I, or F.

[0041] The term "haloalkyl," as used herein, means an alkyl group, as defined herein, in which 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms are replaced by halogen.

[0042] The term "haloalkoxy," as used herein, means at least one haloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0043] The term "halocycloalkyl," as used herein, means a cycloalkyl group, as defined herein, in which one or more hydrogen atoms has been replaced by halogen.

[0044] The term "heteroalkyl," as used herein, means an alkyl group, as defined herein, in which one or more carbon atoms is replaced by a heteroatom selected from S, O, P, and N. Representative examples of heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, amides, and alkyl sulfides.

[0045] The term "heteroaryl," as used herein, refers to an aromatic monocyclic heteroatom-containing ring (monocyclic heteroaryl) or a bicyclic ring system containing at least one monocyclic heteroaromatic ring (bicyclic heteroaryl). The term "heteroaryl" is used herein to refer to heteroarene when it is present as a substituent. A monocyclic heteroaryl is a 5- or 6-membered ring containing at least one heteroatom independently selected from the group consisting of N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, S, and N). A 5-membered aromatic monocyclic ring has two double bonds, and a 6-membered aromatic monocyclic ring has three double bonds. Bicyclic heteroaryl groups are 8- to 12-membered ring systems, including fused bicyclic heteroaromatic ring systems (i.e., 10π-electron systems), such as monocyclic heteroaryl rings fused to 6-membered arenes (e.g., quinolin-4-yl, indol-1-yl), monocyclic heteroaryl rings fused to monocyclic heteroarenes (e.g., naphthyridinyl), and phenyl rings fused to monocyclic heteroarenes (e.g., quinolin-5-yl, indol-4-yl). Bicyclic heteroaryl / heteroarene groups include 9-membered fused bicyclic heteroaromatic ring systems having four double bonds and at least one heteroatom contributing a lone pair of electrons to a fully aromatic 10π-electron system, such as ring systems with a nitrogen atom at the ring junction (e.g., imidazopyridine) and benzoxadiazolyl. Bicyclic heteroaryl also includes fused bicyclic systems consisting of one heteroaromatic ring and one non-aromatic ring, such as a monocyclic heteroaryl ring fused to a monocyclic carbocyclic ring (e.g., 6,7-dihydro-5H-cyclopenta[b]pyridinyl) or a monocyclic heteroaryl ring fused to a monocyclic heterocyclic ring (e.g., 2,3-dihydrofuro[3,2-b]pyridinyl). A bicyclic heteroaryl is attached to the parent molecular moiety at an aromatic ring atom.Other representative examples of heteroaryl include, but are not limited to, indolyl (e.g., indol-1-yl, indol-2-yl, indol-4-yl), pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl (e.g., pyrazol-4-yl), pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl (e.g., triazol-4-yl), 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl (e.g., thiazol-4-yl), isothiazolyl, thienyl, benzimidazolyl (e.g., For example, benzimidazol-5-yl), benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, furanyl, oxazolyl, isoxazolyl, purinyl, isoindolyl, quinoxalinyl, indazolyl (e.g., indazol-4-yl, indazol-5-yl), quinazolinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl, imidazo[1,2-a]pyridinyl (e.g., imidazo[1,2-a]pyridin-6-yl), naphthyridinyl, pyridoimidazolyl, thiazolo[5,4-b]pyridin-2-yl, and thiazolo[5,4-d]pyrimidin-2-yl.

[0046] The term "heterocycle" or "heterocyclic" as used herein means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle. The term "heterocyclyl" is used herein to refer to a heterocycle when it is present as a substituent. A monocyclic heterocycle is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. A 3- or 4-membered ring contains zero or one double bond and one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring contains zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 6-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The 7- and 8-membered rings contain 0, 1, 2, or 3 double bonds and 1, 2, or 3 heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxoazepan-3-yl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinyl, oxazolin ... Examples include cetyl, oxepanyl, oxocanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1,2-thiazinanyl, 1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholinesulfone), thiopyranyl, and trithianyl.A bicyclic heterocycle is a monocyclic heterocycle fused to a 6-membered arene, or a monocyclic heterocycle fused to a monocyclic cycloalkane, or a monocyclic heterocycle fused to a monocyclic cycloalkene, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a monocyclic heteroarene, or a spiroheterocyclic group, or a bridged monocyclic heterocycle system (wherein two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of 2, 3, or 4 carbon atoms). A bicyclic heterocyclyl is attached to the parent molecular moiety at a non-aromatic ring atom (e.g., indolin-1-yl). Representative examples of bicyclic heterocyclyl include, but are not limited to, chroman-4-yl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzotin-2-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 2-azaspiro[3.3]heptan-2-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), azabicyclo[3.1.0]hexanyl (including 3-azabicyclo[3.1.0]hexane), and the like. -3-yl), 2,3-dihydro-1H-indol-1-yl, isoindolin-2-yl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, tetrahydroisoquinolinyl, 7-oxabicyclo[2.2.1]heptanyl, hexahydro-2H-cyclopenta[b]furanyl, 2-oxaspiro[3.3]heptanyl, 3-oxaspiro[5.5]undecanyl, 6-oxaspiro[2.5]octan-1-yl, and 3-oxabicyclo[3.1.0]hexan-6-yl. Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a 6-membered arene, or a bicyclic heterocycle fused to a monocyclic cycloalkane, or a bicyclic heterocycle fused to a monocyclic cycloalkene, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non-adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of 2, 3, or 4 carbon atoms.Examples of tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[b]furan, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane (1-azatricyclo[3.3.1.13,7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13,7]decane). These monocyclic, bicyclic, and tricyclic heterocyclyls are linked to the parent molecular moiety at a non-aromatic ring atom.

[0047] The terms "hydroxyl" or "hydroxy," as used herein, refer to an --OH group.

[0048] The term "hydroxyalkyl," as used herein, means at least one --OH group, appended to the parent molecular moiety through an alkylene group, as defined herein.

[0049] The term "hydroxyfluoroalkyl," as used herein, means at least one --OH group, appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.

[0050] The terms "alkyl," "cycloalkyl," "alkylene," and the like, are used with a symbol indicating the number of atoms present in the group in a particular instance (e.g., "C 1~4 Alkyl," "C 3~6 cycloalkyl," "C 1~4 These symbols are used as commonly understood by those skilled in the art. For example, the designation "C" followed by a numeric subscript indicates the number of atoms present in the group that follows. Thus, a "C alkyl" is an alkyl group containing three carbon atoms (i.e., n-propyl, isopropyl). A "C 1~4 When a range is given, such as "C", subsequent group members can have any number of carbon atoms within the stated range. 1~4"Alkyl" refers, for example, to an alkyl group having from 1 to 4 carbon atoms of any configuration (ie, straight or branched).

[0051] The term "substituted" refers to a group that may be further substituted with one or more substituents that are not hydrogen. The substituents include, but are not limited to, halogen, ═O (oxo), ═S (thioxo), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketone, amide, carbamate, and acyl.

[0052] For the compounds described herein, groups and substituents can be selected according to the permitted valences of atoms and substituents, such that selection and substitution results in stable compounds (e.g., which do not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, etc.).

[0053] 2.Compound A. Compounds of Formula (I) In one aspect, the present invention provides a compound of formula (I), wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is as defined herein.

[0054] An unsubstituted or substituted ring (i.e., optionally substituted), such as an aryl or heteroaryl, is comprised of a ring system and any optional substituents of the ring system. Thus, a ring system can be defined independently of its substituents, so that any previous optional substituents remain present by redefining only the ring system. For example, a 5-12-membered heteroaryl having optional substituents can be further defined by specifying that the ring system of the 5-12-membered heteroaryl is a 5-6-membered heteroaryl (i.e., a 5-6-membered heteroaryl ring system), in which case, unless otherwise specified, any optional substituents of the 5-12-membered heteroaryl are still present on the 5-6-membered heteroaryl.

[0055] When heterocyclic rings and heteroaromatic ring systems are defined as "containing" specified heteroatoms (e.g., 1 to 3 heteroatoms independently selected from the group consisting of O, N, and S), any ring atom of the heterocyclic ring or heteroaromatic ring system that is not one of the specified heteroatoms is a carbon atom.

[0056] In the following, embodiments of the present invention are disclosed, a first embodiment is designated E1, further embodiments are designated E1.1, E2, etc.

[0057] E1. A compound of formula (I) or a pharmaceutically acceptable salt thereof [ka] (In the formula: R 1 is independently at each occurrence hydrogen, fluoro, or C 1~4 is alkyl; R 2 is hydrogen or C 1~6 is alkyl; R 3 is a 6- to 12-membered aryl or a 5- to 12-membered heteroaryl, where R 3 is unsubstituted or C 1~4 Alkyl, halogen, cyano, C 1~2 Haloalkyl, OH, -OC 1~4Alkyl and -OC 1~2 substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of haloalkyl; R 4 is G 4 , -C 1~4 Alkylene-G 4 , Cy, or -C 1~4 alkylene-Cy; G 4 is a 6- to 12-membered aryl or a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S, wherein G 4 is unsubstituted or C 1~4 Alkyl, halogen, cyano, C 1~2 Haloalkyl, oxo, -OR 4a , -N(R 4a )2, -N(R 4a )C(O)R 4a , -N(R 4a )SO2R 4b , -C(O)N(R 4a )2, -SO2N(R 4a )2, -SO2R 4b , -C 1~4 Alkylene-OH, G 4a , and -C 1~4 Alkylene-G 4a and C 1~4 Alkyl, halogen, cyano, C 1~2 Haloalkyl, -OC 1~4 Alkyl and -OC 1~2 optionally further substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl; R 4a Each occurrence independently represents hydrogen, C 1~4 Alkyl, C 1~2 Haloalkyl, G 4a , or -C 1~4 Alkylene-G 4a and; R 4b is C 1~4 Alkyl, C 1~2 Haloalkyl, G 4a , or -C1~4 Alkylene-G 4a and; G 4a is phenyl, C 3~6 cycloalkyl, 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms, or 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms, wherein the heteroatoms in the heteroaryl and heterocyclyl are independently selected from the group consisting of O, N, and S; 4a is C 1~4 Alkyl, C 1~2 Fluoroalkyl, halogen, cyano, oxo, OH, and -OC 1~4 optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; Cy is C 3~6 carbocyclyl or a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S, wherein Cy is C 1~4 Alkyl, C 1~2 Fluoroalkyl, halogen, oxo, OH, -OC 1~4 Alkyl, G 4a , and -C 1~4 Alkylene-G 4a and C 1~4 Alkyl, C 1~2 optionally further substituted with 1 to 3 substituents independently selected from the group consisting of fluoroalkyl, and halogen; R 5 and R 6 are each independently hydrogen, C 1~4 Alkyl, halogen, cyano, C 1~2 Haloalkyl, -OC 1~4 Alkyl or -OC 1~2 haloalkyl).

[0058] E1.1.R 3 is a 6- to 12-membered aryl or a 5- to 12-membered heteroaryl, where R 3 is unsubstituted, or C 1~4 Alkyl, halogen, cyano, C 1~2Haloalkyl, -OC 1~4 Alkyl and -OC 1~2 substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of haloalkyl; R 4 But, G 4 , -C 1~4 Alkylene-G 4 or Cy; R 4a Each occurrence of is independently hydrogen, C 1~4 Alkyl, C 1~2 Haloalkyl, C 3~4 Cycloalkyl, or -C 1~4 Alkylene-C 3~4 is cycloalkyl; R 4b But C 1~4 Alkyl, C 1~2 Haloalkyl, C 3~4 Cycloalkyl, or -C 1~4 Alkylene-C 3~4 A compound of E1, or a pharmaceutically acceptable salt thereof, wherein E1 is cycloalkyl.

[0059] E2.R 1 A compound of E1 or E1.1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0060] E3.R 2 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0061] E4.G 4 is unsubstituted or substituted 5- to 12-membered heteroaryl, or a pharmaceutically acceptable salt thereof.

[0062] E5.G 4 or a pharmaceutically acceptable salt thereof.

[0063] E5.1. The compound of E5, or a pharmaceutically acceptable salt thereof, wherein the 9-10 membered fully aromatic bicyclic heteroaryl ring system is indazolyl, indolyl, benzo[d]imidazolyl, benzo[d]thiazolyl, benzo[d]oxazolyl, quinolinyl, isoquinolinyl, pyrazolo[3,4-b]pyridinyl, imidazo[1,2-a]pyridinyl, or pyrrolo[2,3-b]pyridinyl.

[0064] E5.2. The compound of E5.1, or a pharmaceutically acceptable salt thereof, wherein the 9-10 membered fully aromatic bicyclic heteroaryl ring system is 1H-indazol-5-yl, 2H-indazol-4-yl, 2H-indazol-5-yl, 2H-indazol-6-yl, 2H-indazol-7-yl, 1H-indol-5-yl, 1H-benzo[d]imidazol-5-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]oxazol-5-yl, quinolin-6-yl, quinolin-7-yl, isoquinolin-6-yl, isoquinolin-7-yl, 2H-pyrazolo[3,4-b]pyridin-5-yl, imidazo[1,2-a]pyridin-6-yl, or 1H-pyrrolo[2,3-b]pyridin-5-yl.

[0065] E5.3.G 4 But C 1~4 A compound of any of E5-E5.2, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 2 substituents independently selected from the group consisting of alkyl and halogen (e.g., methyl and fluoro).

[0066] E5.4.G 4 but, [ka] or a pharmaceutically acceptable salt thereof.

[0067] E5.5.G 4 but, [ka] E5.4, or a pharmaceutically acceptable salt thereof.

[0068] E6.G 4 or a pharmaceutically acceptable salt thereof.

[0069] E6.1. The compound of E6, or a pharmaceutically acceptable salt thereof, wherein the 5-6 membered monocyclic heteroaryl ring system is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrrolyl, thiazolyl, pyridinyl, pyridazinyl, or pyrimidinyl.

[0070] E6.2. The compound of E6.1, or a pharmaceutically acceptable salt thereof, wherein the 5-6 membered monocyclic heteroaryl ring system is pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, thiazolyl, pyridinyl, pyridazinyl, or pyrimidinyl.

[0071] E6.3. The compound of E6.1, or a pharmaceutically acceptable salt thereof, wherein the 5- to 6-membered monocyclic heteroaryl ring system is 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-imidazol-4-yl, oxazol-5-yl, isoxazol-4-yl, 1H-pyrrol-3-yl, thiazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-4-yl, or pyrimidin-5-yl.

[0072] E6.4. A compound of any of E6.1 to E6.3, or a pharmaceutically acceptable salt thereof, wherein the 5- to 6-membered monocyclic heteroaryl ring system is 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, oxazol-5-yl, isoxazol-4-yl, 1H-pyrrol-3-yl, thiazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-4-yl, or pyrimidin-5-yl.

[0073] E6.5.G 4 But C 1~4 Alkyl, halogen, cyano, C 1~2 Haloalkyl, -OR 4a , -N(R 4a )2, -N(R 4a )C(O)R 4a , -N(R 4a )SO2R 4b , -C(O)N(R 4a )2, -SO2N(R 4a )2, -SO2R 4b , -C 1~4 Alkylene-OH, G 4a , and -C 1~4 Alkylene-G 4a and C 1~4 Alkyl, halogen, cyano, C 1~2 Haloalkyl, -OC 1~4 Alkyl and -OC 1~2 A compound of any of E6-E6.4, or a pharmaceutically acceptable salt thereof, optionally further substituted with 1-2 substituents independently selected from the group consisting of haloalkyl.

[0074] E6.6.G 4 But C 1~4 Alkyl, halogen, cyano, C 1~2 Haloalkyl, -OR 4a , -N(R 4a )2, -N(R 4a )C(O)R 4a , -SO2R 4b , -C 1~4 Alkylene-OH, G 4a , and -C1~4 Alkylene-G 4a and C 1~4 Alkyl, halogen, cyano, C 1~2 Haloalkyl, -OC 1~4 Alkyl and -OC 1~2 The compound of E6.5, or a pharmaceutically acceptable salt thereof, optionally further substituted with 1 to 2 substituents independently selected from the group consisting of haloalkyl.

[0075] E6.7.G 4 but, [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0076] E6.8.G 4 but, [ka] [ka] E6.7, or a pharmaceutically acceptable salt thereof.

[0077] E6.9.G 4a But C 1~4 Alkyl, C 1~2 Fluoroalkyl, halogen, cyano, oxo, OH, and -OC 1~4 The compound of any of E6-E6.8, or a pharmaceutically acceptable salt thereof, wherein the compound is phenyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of alkyl.

[0078] E6.10.G 4aA compound of any of E6 to E6.9, or a pharmaceutically acceptable salt thereof, wherein is phenyl optionally substituted with cyano.

[0079] E6.11.G 4a But C 1~4 C optionally substituted with 1 to 2 substituents independently selected from the group consisting of alkyl and halogen 3~6 Any of the compounds E6 to E6.8, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

[0080] E6.12.G 4a But unsubstituted C 3~6 A compound of any of E6 to E6.8 or E6.11, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

[0081] E6.13.G 4a is a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from the group consisting of O, N, and S, wherein the heterocyclyl is C 1~4 A compound of any of E6-E6.8, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 2 substituents independently selected from the group consisting of alkyl and halogen.

[0082] E6.14.G 4a is unsubstituted 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S, or a pharmaceutically acceptable salt thereof.

[0083] E6.15.G 4a The 4- to 6-membered heterocyclyl ring system in [ka] wherein X is O or S; or a pharmaceutically acceptable salt thereof.

[0084] E6.16.G 4a The 4- to 6-membered heterocyclyl ring system in [ka] E6.15, or a pharmaceutically acceptable salt thereof.

[0085] E6.17.R 4a is independently at each occurrence hydrogen or C 1~4 alkyl (e.g., methyl); R 4b But C 1~4 Any of compounds E6 to E6.16, or a pharmaceutically acceptable salt thereof, which is alkyl (eg, methyl).

[0086] E6.18.G 4 but, [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0087] E6.19.G 4 but, [ka] [ka] E6.18, or a pharmaceutically acceptable salt thereof.

[0088] E6.20.G 4 but, [ka] [ka] E6.18, or a pharmaceutically acceptable salt thereof.

[0089] E6.21.G 4 but, [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0090] E7.G 4 but, [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0091] E7.1.G 4 but, [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0092] E8.G 4is unsubstituted or substituted 6- to 12-membered aryl, or a pharmaceutically acceptable salt thereof.

[0093] E9.G 4 or a pharmaceutically acceptable salt thereof.

[0094] E9.1.G 4 But C 1~4 Alkyl, halogen, cyano, C 1~2 Haloalkyl, -OR 4a , -N(R 4a )2, -N(R 4a )C(O)R 4a , -N(R 4a )SO2R 4b , -C(O)N(R 4a )2, -SO2N(R 4a )2, -SO2R 4b , -C 1~4 Alkylene-OH, G 4a , and -C 1~4 Alkylene-G 4a and C 1~4 Alkyl, halogen, cyano, C 1~2 Haloalkyl, -OC 1~4 Alkyl and -OC 1~2 The compound of E9, or a pharmaceutically acceptable salt thereof, optionally further substituted with 1 to 2 substituents independently selected from the group consisting of haloalkyl.

[0095] E9.2.G 4 But C 1~4 Alkyl, halogen, cyano, C 1~2 Haloalkyl, -OR 4a , -N(R 4a )2, -N(R 4a )C(O)R 4a , -N(R 4a )SO2R 4b , -C(O)N(R 4a )2, -SO2N(R 4a)2, -SO2R 4b , -C 1~4 Alkylene-OH, and G 4a and C 1~4 Alkyl, halogen, cyano, C 1~2 Haloalkyl, -OC 1~4 Alkyl and -OC 1~2 A compound of E9 or E9.1, or a pharmaceutically acceptable salt thereof, optionally further substituted with 1 to 2 substituents independently selected from the group consisting of haloalkyl.

[0096] E9.3.G 4 but, [ka] or a pharmaceutically acceptable salt thereof.

[0097] E9.4.G 4 but, [ka] or a pharmaceutically acceptable salt thereof.

[0098] E9.5.G 4a is a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S, wherein G 4a But C 1~4 Alkyl, C 1~2 Fluoroalkyl, halogen, cyano, OH, and -OC 1~4 The compound of any of E9 to E9.4, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl.

[0099] E9.6.G 4a is a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S, wherein G4a But 1-2 C 1~4 Any of the compounds E9 to E9.5, or a pharmaceutically acceptable salt thereof, optionally substituted with alkyl (eg, methyl).

[0100] E9.7.G 4a or a pharmaceutically acceptable salt thereof.

[0101] E9.8.G 4a The compound of E9.7, wherein the 5-6 membered heteroaryl ring system is pyrazolyl (eg, pyrazol-1-yl) or oxadiazolyl (eg, 1,3,4-oxadiazol-2-yl), or a pharmaceutically acceptable salt thereof.

[0102] E9.9.G 4a is a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from the group consisting of O, N, and S, wherein G 4a But C 1~4 Alkyl, C 1~2 Fluoroalkyl, halogen, cyano, oxo, OH, and -OC 1~4 The compound of any of E9 to E9.4, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl.

[0103] E9.10.G 4a is a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from the group consisting of O, N, and S, wherein G 4a But 1-2 C 1~4 A compound of any of E9-E9.4 or E9.9, or a pharmaceutically acceptable salt thereof, optionally substituted with alkyl (eg, methyl).

[0104] E9.11.G 4a or a pharmaceutically acceptable salt thereof.

[0105] E9.12.R 4a is independently at each occurrence hydrogen or C 1~4 alkyl (e.g., methyl); R 4b But C 1~4 Any of the compounds E9 to E9.11, or a pharmaceutically acceptable salt thereof, wherein E9 is alkyl (eg, methyl).

[0106] E9.13.G 4 but, [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0107] E9.14.G 4 but, [ka] or a pharmaceutically acceptable salt thereof.

[0108] E9.15.G 4 but, [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0109] E9.16.G 4 but, [ka] or a pharmaceutically acceptable salt thereof.

[0110] E10.G 4 or a pharmaceutically acceptable salt thereof.

[0111] E10.1. The compound of E10, or a pharmaceutically acceptable salt thereof, wherein the 5- to 6-membered heterocycle fused to the phenyl is optionally substituted with oxo.

[0112] E10.2.G 4 but, [ka] E10.1, or a pharmaceutically acceptable salt thereof.

[0113] E10.3.G 4 but, [ka] The compound of E10.2, wherein:

[0114] E11.G 4 but, [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0115] E11.1.G 4 but, [ka] or a pharmaceutically acceptable salt thereof.

[0116] E12.R 4 But, G 4 or a pharmaceutically acceptable salt thereof.

[0117] E13.R 4 But -C 1~4 Alkylene-G 4 or a pharmaceutically acceptable salt thereof.

[0118] E14.R 4 is Cy, or a pharmaceutically acceptable salt thereof.

[0119] E15.R 4 But -C 1~4 A compound of any one of E1 to E11.1, or a pharmaceutically acceptable salt thereof, which is alkylene-Cy.

[0120] E15.1.R 4 is -CH2-Cy, or a pharmaceutically acceptable salt thereof.

[0121] E16. Cy is optionally substituted C 3~6 A compound of any of E1 to E11.1 or E14 to E15.1, or a pharmaceutically acceptable salt thereof, which is carbocyclyl.

[0122] Optionally substituted C in E16.1.Cy3~6 Carbocyclyl is -OC 1~4 A compound of any of E1 to E11.1 or E14 to E16, or a pharmaceutically acceptable salt thereof, optionally substituted with alkyl.

[0123] E16.2.Cy [ka] The compound of E16.1, wherein:

[0124] E16.3.Cy [ka] The compound of E16.2, wherein:

[0125] E17. A compound of any of E1 to E11.1 or E14 to E15.1, or a pharmaceutically acceptable salt thereof, wherein Cy is optionally substituted 4-6 membered heterocyclyl.

[0126] E17.1. A compound of any of E1-E11.1, E14-E15.1, or E17, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4-6 membered heterocyclyl in Cy contains 1-2 heteroatoms independently selected from the group consisting of O, N, and S.

[0127] E17.2. The compound of E17.1, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4- to 6-membered heterocyclyl in Cy contains one heteroatom selected from the group consisting of O, N, and S.

[0128] E17.3. The optionally substituted 4- to 6-membered heterocyclyl in Cy is C 1~4 Alkyl (e.g., methyl), C 1~2 Fluoroalkyl, halogen, OH, oxo, and -C 1~4Alkylene-G 4a (e.g., benzyl), and C 1~4 Alkyl (e.g., methyl), halogen, and C 1~2 A compound of any of E1-E11.1, E14-E15.1, or E17-E17.2, or a pharmaceutically acceptable salt thereof, optionally further substituted with 1 to 3 substituents independently selected from the group consisting of fluoroalkyl (e.g., CHF2).

[0129] E17.4. The optionally substituted 4- to 6-membered heterocyclyl in Cy is C 1~4 Alkyl (e.g., methyl), C 1~2 Fluoroalkyl, halogen, oxo, and -C 1~4 Alkylene-G 4a (e.g., benzyl), and C 1~4 Alkyl (e.g., methyl), halogen, and C 1~2 The compound of E17.3, or a pharmaceutically acceptable salt thereof, optionally further substituted with 1 to 3 substituents independently selected from the group consisting of fluoroalkyl (eg, CHF2).

[0130] E17.5.Cy [ka] The compound of E17.3, wherein:

[0131] E17.6.Cy [ka] or a pharmaceutically acceptable salt thereof.

[0132] E17.7.Cy [ka] or a pharmaceutically acceptable salt thereof.

[0133] E17.8.Cy [ka] or a pharmaceutically acceptable salt thereof.

[0134] E18.Cy is [ka] or a pharmaceutically acceptable salt thereof.

[0135] E18.1.Cy [ka] or a pharmaceutically acceptable salt thereof.

[0136] E19.R 3 The compound of any one of E1 to E18.1, or a pharmaceutically acceptable salt thereof, wherein is unsubstituted or substituted 6- to 12-membered aryl.

[0137] E20.R 3 or a pharmaceutically acceptable salt thereof.

[0138] E20.1.R 3 is unsubstituted, or C 1~4 Alkyl, halogen, cyano, C 1~2 Haloalkyl, OH, -OC 1~4 Alkyl and -OC 1~2The compound of E20, or a pharmaceutically acceptable salt thereof, substituted with 1, 2, or 3 substituents independently selected from the group consisting of haloalkyl.

[0139] E20.2.R 3 is unsubstituted, or C 1~4 Alkyl, halogen, cyano, and C 1~2 The compound of E20.1, or a pharmaceutically acceptable salt thereof, substituted with one, two, or three substituents independently selected from the group consisting of haloalkyl.

[0140] E21.R 3 but, [ka] or a pharmaceutically acceptable salt thereof.

[0141] E21.1.R 3 but, [ka] or a pharmaceutically acceptable salt thereof.

[0142] E22.R 5 and R 6 But hydrogen, C 1~4 A compound of any one of E1 to E21.1, or a pharmaceutically acceptable salt thereof, each independently selected from the group consisting of alkyl, and halogen.

[0143] E23.R 5 and R 6 and R are each hydrogen, or a pharmaceutically acceptable salt thereof.

[0144] E24. 6-(4-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(oxazol-5-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(pyridin-4-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-methylthiazol-5-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(6-methylpyridin-3-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-methyl-2H-indazol-5-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-methyl-2H-indazol-6-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(4-methyl-1H-indazol-5-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-methyl-1H-benzo[d]imidazol-5-yl)isoindolin-1-one; 5-(benzo[d]thiazol-6-yl)-6-(4-fluorophenyl)isoindolin-1-one; 5-(benzo[d]oxazol-5-yl)-6-(4-fluorophenyl)isoindolin-1-one; 5-(benzo[d]thiazol-5-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(isoquinolin-6-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(isoquinolin-7-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-methyl-2H-indazol-7-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(quinolin-7-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(quinolin-6-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(imidazo[1,2-a]pyridin-6-yl)isoindolin-1-one; 5-(5,8-difluoroquinolin-6-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(pyridazin-4-yl)isoindolin-1-one; 5-(benzo[d]thiazol-5-yl)-6-(2,4-difluorophenyl)isoindolin-1-one; 5-(benzo[d]oxazol-5-yl)-6-(2,4-difluorophenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2-methyl-2H-indazol-6-yl)isoindolin-1-one; 5-(6-cyclopropylpyridin-3-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(6-(trifluoromethyl)pyridin-3-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-methyl-2H-indazol-4-yl)isoindolin-1-one; 5-(2,6-dimethylpyridin-3-yl)-6-(4-fluorophenyl)isoindolin-1-one; 5-(6-fluoro-2-methylpyridin-3-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)isoindolin-1-one; 5-(2,6-difluoropyridin-3-yl)-6-(4-fluorophenyl)isoindolin-1-one; 5-(6-(4-fluorophenyl)-1-oxoisoindolin-5-yl)picolinonitrile; 5-(6-(dimethylamino)pyridin-3-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(1-methyl-1H-pyrazol-3-yl)isoindolin-1-one; N-(5-(6-(4-fluorophenyl)-1-oxoisoindolin-5-yl)pyridin-2-yl)acetamide; 5-(6-fluoro-4-methylpyridin-3-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)isoindolin-1-one; 5-(2-(dimethylamino)pyridin-3-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-fluoropyridin-3-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-methylpyridin-3-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-isopropylpyridin-3-yl)isoindolin-1-one; 5-(2-cyclopropylpyridin-3-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(pyridin-3-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(pyridin-2-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(6-methylpyridazin-4-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(3-methyl-1H-indazol-5-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(4-methylpyridin-3-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(1H-indol-5-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(p-tolyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(5-methylpyridin-2-yl)isoindolin-1-one; 4-(6-(4-fluorophenyl)-1-oxoisoindolin-5-yl)-1,5-dimethyl-1H-pyrrole-2-carbonitrile; 6-(4-fluorophenyl)-5-(4-methoxycyclohex-1-en-1-yl)isoindolin-1-one; 5-(3,6-dihydro-2H-pyran-4-yl)-6-(4-fluorophenyl)isoindolin-1-one; 5-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(1,2,5,6-tetrahydropyridin-3-yl)isoindolin-1-one; 5-(2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(4-fluorophenyl)isoindolin-1-one; 5-Cyclohexyl-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(tetrahydro-2H-pyran-4-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(1-methylpiperidin-3-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(1-methylpiperidin-4-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(piperidin-4-yl)isoindolin-1-one; 5-(2,6-dimethylpiperidin-4-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(6-methylpyridin-3-yl)isoindolin-1-one; 5-(6-cyclopropylpyridin-3-yl)-6-(2,4-difluorophenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2-(dimethylamino)pyridin-3-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2-fluoropyridin-3-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2-methylpyridin-3-yl)isoindolin-1-one; 5-(2-cyclopropylpyridin-3-yl)-6-(2,4-difluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2,2,6,6-tetramethylpiperidin-4-yl)isoindolin-1-one; 5-(3,3-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(3-methylpiperidin-4-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(piperidin-3-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(6-(trifluoromethyl)pyridin-3-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1-methyl-1H-pyrazol-3-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(6-fluoro-4-methylpyridin-3-yl)isoindolin-1-one; 5-(2,5-dihydro-1H-pyrrol-3-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(pyrrolidin-3-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-methylpiperidin-4-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(pyridin-3-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1H-indol-5-yl)isoindolin-1-one; 4-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-1,5-dimethyl-1H-pyrrole-2-carbonitrile; 3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-5-methylbenzonitrile; 5-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-2-methoxybenzonitrile; 5-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-2-fluorobenzonitrile; 3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-2-fluorobenzonitrile; 3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-5-methoxybenzonitrile; 3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-4-methylbenzonitrile; 6-(2,4-difluorophenyl)-5-(1,2,5-trimethyl-1H-pyrrol-3-yl)isoindolin-1-one; 3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-1,5-dimethyl-1H-pyrrole-2-carbonitrile; 3-(4-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-1H-pyrazol-1-yl)benzonitrile; 6-(2,4-difluorophenyl)-5-(2-methoxypyridin-3-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(5-methoxypyridin-3-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2-(pyrrolidin-1-yl)pyridin-3-yl)isoindolin-1-one; 4-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-3-fluorobenzonitrile; 4-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)picolinonitrile; 6-(2,4-difluorophenyl)-5-(4-fluoro-2-methoxyphenyl)isoindolin-1-one; 3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-5-fluorobenzonitrile; 3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)benzonitrile; 5-(1-cyclopropyl-1H-pyrazol-3-yl)-6-(2,4-difluorophenyl)isoindolin-1-one; 3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-2-methylbenzonitrile; 6-(2,4-difluorophenyl)-5-(2-(trifluoromethyl)pyridin-3-yl)isoindolin-1-one; 4-(4-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-1H-pyrazol-1-yl)benzonitrile; 6-(2,4-difluorophenyl)-5-(3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(4-(4-methylpiperazin-1-yl)phenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)isoindolin-1-one; 4-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-1-methyl-1H-pyrazole-5-carbonitrile; N-(3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)phenyl)methanesulfonamide; 3-chloro-5-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-N-methylbenzamide; 3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-N-isopropylbenzamide; 3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-N-methylbenzenesulfonamide; N-(2-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)phenyl)acetamide; 3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-4-fluoro-N-methylbenzamide; 6-(2,4-difluorophenyl)-5-(3-(methylsulfonyl)phenyl)isoindolin-1-one; 2-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-5-fluorobenzonitrile; 2-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)benzonitrile; 4-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 6-(2,4-difluorophenyl)-5-(3,5-dimethylisoxazol-4-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1-(methylsulfonyl)-1H-pyrazol-4-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2-(methylsulfonyl)phenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)isoindolin-1-one; 5-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-6-(2,4-difluorophenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1-ethyl-1H-pyrazol-4-yl)isoindolin-1-one; 5-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridin-3-yl)-6-(2,4-difluorophenyl)isoindolin-1-one; 6'-(2,4-difluorophenyl)-[4,5'-bisisoindoline]-1,1'-dione; 5-(2-aminophenyl)-6-(2,4-difluorophenyl)isoindolin-1-one; 4-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-3-fluorobenzonitrile; 3-(1-oxo-6-(2,3,4-trifluorophenyl)isoindolin-5-yl)benzonitrile; 3-(1-oxo-6-(2,4,5-trifluorophenyl)isoindolin-5-yl)benzonitrile; 2-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-5-fluorobenzonitrile; 3-(6-(2-fluoro-4-methylphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(4-fluoro-2-methylphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(2-fluoro-4-(trifluoromethyl)phenyl)-1-oxoisoindolin-5-yl)benzonitrile; 6-(2,4-difluorophenyl)-5-(3-(2-hydroxypropan-2-yl)phenyl)isoindolin-1-one; 5-(3-(1H-pyrazol-1-yl)phenyl)-6-(2,4-difluorophenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)isoindolin-1-one; 5-(2-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-5-yl)-6-(2,4-difluorophenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2,3-dihydrobenzofuran-7-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2-(4-methylpiperazin-1-yl)phenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(3-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(3-(1-(methyl-d3)-1H-1,2,3-triazol-5-yl)phenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(3-(1-(ethyl-1,1-d2)-1H-1,2,3-triazol-5-yl)phenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)isoindolin-1-one; 3-(6-(4-fluoro-2-methoxyphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(2-fluoro-4-methoxyphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(3,4-difluorophenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(2-fluorophenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(1-oxo-6-(2,4,6-trifluorophenyl)isoindolin-5-yl)benzonitrile; 3-(6-(2,4-dimethylphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(4-(difluoromethoxy)-2-fluorophenyl)-1-oxoisoindolin-5-yl)benzonitrile; N-(2-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)phenyl)-1-methyl-1H-1,2,3-triazole-4-sulfonamide; N-(2-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)phenyl)-2-methylthiazole-5-sulfonamide; N-(2-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide; 4-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-3-methoxybenzonitrile; 4-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-2-fluorobenzonitrile; 3-(6-(2-fluoro-4-hydroxyphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(2-chloro-4-fluorophenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(2-fluoro-5-methoxyphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(3-fluoro-4-methoxyphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 5-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-2-methoxybenzonitrile; 3-(6-(2-chloro-4-methoxyphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(2,5-difluoro-4-methoxyphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(4-methoxy-2-methylphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-4-fluorobenzonitrile; 3-(6-(2,4-difluoro-5-methylphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 5-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-2-fluorobenzonitrile; 4-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-2-(trifluoromethyl)benzonitrile; 3-(6-(2-fluoro-5-(trifluoromethyl)phenyl)-1-oxoisoindolin-5-yl)benzonitrile; 4-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-5-fluoro-2-methylbenzonitrile; 3-(6-(3,5-difluoro-4-methoxyphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-2-fluorobenzonitrile; 3-(6-(2,3-difluoro-4-methoxyphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(2,5-difluorophenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(5-fluoro-2-methoxyphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 2-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-4-fluorobenzonitrile; 3-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-4-methylbenzonitrile; 3-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-5-fluorobenzonitrile; 6-(2,4-difluorophenyl)-5-(2-(1-methyl-1H-pyrazol-3-yl)ethyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2-(pyrimidin-5-yl)ethyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2-(1-methyl-1H-pyrazol-3-yl)ethyl-1,1,2,2-d4)isoindolin-1-one; 3-(2-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)ethyl)benzonitrile; 6-(2,4-difluorophenyl)-5-(2-(1-methyl-1H-pyrazol-3-yl)ethyl-1,1,2,2-d4)isoindolin-1-one-3,3-d2; 6-(2,4-difluorophenyl)-5-(2-(1-methyl-1H-pyrazol-5-yl)ethyl-1,1,2,2-d4)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2-(1-methyl-1H-pyrazol-5-yl)ethyl)isoindolin-1-one; 5-(2-(1-cyclopropyl-1H-pyrazol-3-yl)ethyl)-6-(2,4-difluorophenyl)isoindolin-1-one; 3-(2-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)ethyl)-1-methyl-1H-pyrazole-5-carbonitrile; 6-(2,4-difluorophenyl)-5-(thiomorpholinomethyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(morpholinomethyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-((3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)methyl)isoindolin-1-one or a pharmaceutically acceptable salt thereof.

[0145] E25. A pharmaceutical composition comprising any one of the compounds of E1 to E24, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0146] E26. A method for treating a disease or disorder associated with dysfunction of metabotropic glutamate receptor 2 (mGlu2), comprising administering to a subject in need thereof a therapeutically effective amount of any one of the compounds E1 to E24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of E25.

[0147] E27. The method of E26, wherein the disease or disorder is selected from at least one of depression, anxiety, obsessive-compulsive disorder, cognitive impairment, Alzheimer's disease, and autism spectrum disorder.

[0148] E28. Any one of the compounds of E1 to E24, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E25, for use in treating a disease or disorder selected from at least one of depression, anxiety, obsessive-compulsive disorder, cognitive impairment, Alzheimer's disease, and autism spectrum disorder.

[0149] E29. Use of any one of the compounds E1 to E24, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E25 in the manufacture of a medicament for the treatment of a disease or disorder selected from at least one of depression, anxiety, obsessive-compulsive disorder, cognitive impairment, Alzheimer's disease, and autism spectrum disorder.

[0150] Compound names can be assigned by using the Struct=Name naming algorithm as part of CHEMDRAW® ULTRA.

[0151] Compounds may exist as stereoisomers where asymmetric or chiral centers exist. Stereoisomers are "R" or "S" depending on the configuration of substituents around the chiral carbon atom. As used herein, the terms "R" and "S" refer to the configurations as defined in the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45:13-30. The present disclosure contemplates various stereoisomers and mixtures thereof, which are specifically included within the scope of the present invention. Stereoisomers include enantiomers and diastereomers, as well as mixtures of enantiomers or diastereomers. In the compounds disclosed herein, chiral atoms depicted or described without a specific stereochemical configuration (e.g., straight bond, non-wedge or dashed bond, HC(OH)(CH3)(CH2CH3)) encompass any stereochemical configuration at the chiral atom.

[0152] Individual stereoisomers of this compound can be prepared from commercially available starting materials containing asymmetric or chiral centers by synthesis or by preparation of a racemic mixture followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and optional liberation of the optically pure product from the auxiliary (as described in Furniss, Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical Organic Chemistry," 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England), or (2) direct separation of a mixture of optical enantiomers on a chiral chromatography column, or (3) fractional recrystallization methods.

[0153] It is to be understood that the compounds may have tautomeric forms as well as geometric isomers which also form an aspect of the present disclosure.

[0154] In the compounds of formula (I) and any subformula, any "hydrogen" or "H", whether explicitly stated or implicit in the structure, is a hydrogen isotope. 1 H (protium) and 2 Includes H (deuterium).

[0155] The present disclosure also includes isotopically labeled compounds (e.g., deuterium labeled), where an atom in an isotopically labeled compound is identified as a particular isotope of the atom. Examples of isotopes suitable for inclusion in compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, including, but not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively. 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 Examples include Cl.

[0156] Isotopically enriched forms of compounds of formula (I), or any subformula, may generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the accompanying Examples, substituting an appropriate isotopically enriched reagent for a non-isotopically enriched reagent. The degree of isotopic enrichment may be characterized as the percent incorporation of a particular isotope at an isotopically labeled atom (e.g., % deuterium incorporation in a deuterium-labeled atom).

[0157] B. Allosteric regulation of mGlu2 The disclosed compounds may act or function as non-competitive antagonists, allosteric inhibitors, allosteric antagonists, or negative allosteric modulators (NAMs) of mGlu2. The compounds may be cognitive-promoting and neuroprotective even in the presence of mGlu2 dysfunction.

[0158] Compounds of formula (I) have an IC in the range of about 1 nM to about 30 μM. 50 The compounds can inhibit mGlu2 with concentrations of about 30 μM, about 29 μM, about 28 μM, about 27 μM, about 26 μM, about 25 μM, about 24 μM, about 23 μM, about 22 μM, about 21 μM, about 20 μM, about 19 μM, about 18 μM, about 17 μM, about 16 μM, about 15 μM, about 14 μM, about 13 μM, about 12 μM, about 11 μM, about 10 μM, about 9 μM, about 8 μM, about 7 μM, about 6 μM, about 5 μM, about 4 μM, about 3 μM, about 2 μM, IC of about 1 μM, about 950 nM, about 900 nM, about 850 nM, about 800 nM, about 850 nM, about 800 nM, about 750 nM, about 700 nM, about 650 nM, about 600 nM, about 550 nM, about 500 nM, about 450 nM, about 400 nM, about 350 nM, about 300 nM, about 250 nM, about 200 nM, about 150 nM, about 100 nM, about 50 nM, about 10 nM, about 5 nM, or about 1 nM 50The compound of formula (I) may have a concentration of less than 30 μM, less than 29 μM, less than 28 μM, less than 27 μM, less than 26 μM, less than 25 μM, less than 24 μM, less than 23 μM, less than 22 μM, less than 21 μM, less than 20 μM, less than 19 μM, less than 18 μM, less than 17 μM, less than 16 μM, less than 15 μM, less than 14 μM, less than 13 μM, less than 12 μM, less than 11 μM, less than 10 μM, less than 9 μM, less than 8 μM, less than 7 μM, less than 6 μM, less than 5 μM, less than 4 μM, less than 3 μM, less than 2 μM, less than 1 μM, less than 9 μM It can inhibit mGlu2 with an IC50 of less than 50 nM, less than 900 nM, less than 850 nM, less than 800 nM, less than 850 nM, less than 800 nM, less than 750 nM, less than 700 nM, less than 650 nM, less than 600 nM, less than 550 nM, less than 500 nM, less than 450 nM, less than 400 nM, less than 350 nM, less than 300 nM, less than 250 nM, less than 200 nM, less than 150 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 5 nM, or less than 1 nM.

[0159] The compounds of formula (I) can be selective modulators of mGlu2 over mGlu3. The compounds have an mGlu2IC of at least 100, at least 95, at least 90, at least 85, at least 80, at least 75, at least 70, at least 64, at least 60, at least 55, at least 50, at least 45, at least 40, at least 35, at least 33, at least 31, at least 30, at least 29, at least 28, at least 27, at least 26, at least 25, at least 24, at least 23, at least 22, at least 21, at least 20, at least 19, at least 18, at least 17, at least 16, at least 15, at least 14, at least 13, at least 12, at least 11, at least 10, at least 9, at least 8, at least 7, at least 6, at least 5, at least 4, at least 3, or at least 2. 50 and mGlu3EC 50The compound of formula (I) may have an mGlu2IC ratio of about 100, about 95, about 90, about 85, about 80, about 75, about 70, about 64, about 60, about 55, about 50, about 45, about 40, about 35, about 33, about 31, about 30, about 29, about 28, about 27, about 26, about 25, about 24, about 23, about 22, about 21, about 20, about 19, about 18, about 17, about 16, about 15, about 14, about 13, about 12, about 11, about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, or about 2. 50 and mGlu3EC 50 The ratio may be:

[0160] The compounds of formula (I) can be selective modulators of mGlu2 over mGlu5. The compounds have an mGlu2IC of at least 100, at least 95, at least 90, at least 85, at least 80, at least 75, at least 70, at least 64, at least 60, at least 55, at least 50, at least 45, at least 40, at least 35, at least 33, at least 31, at least 30, at least 29, at least 28, at least 27, at least 26, at least 25, at least 24, at least 23, at least 22, at least 21, at least 20, at least 19, at least 18, at least 17, at least 16, at least 15, at least 14, at least 13, at least 12, at least 11, at least 10, at least 9, at least 8, at least 7, at least 6, at least 5, at least 4, at least 3, or at least 2. 50 and mGlu5EC 50 The compound of formula (I) may have an mGlu2IC ratio of about 100, about 95, about 90, about 85, about 80, about 75, about 70, about 64, about 60, about 55, about 50, about 45, about 40, about 35, about 33, about 31, about 30, about 29, about 28, about 27, about 26, about 25, about 24, about 23, about 22, about 21, about 20, about 19, about 18, about 17, about 16, about 15, about 14, about 13, about 12, about 11, about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, or about 2. 50 and mGlu5EC 50 The ratio may be:

[0161] C. Pharmaceutical Salts The disclosed compounds can exist as pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a water- or oil-soluble or dispersible salt or zwitterion of the compound suitable for treating disorders without undue toxicity, irritation, or allergic reactions, at a reasonable benefit / risk ratio and effective for its intended use. These salts can be prepared during the final isolation and purification of the compound or separately by reacting the amino group of the compound with a suitable acid. For example, the compound can be dissolved in a suitable solvent, such as, but not limited to, methanol and water, and treated with at least one acid equivalent, such as hydrochloric acid. The resulting salt can be precipitated, isolated by filtration, and dried under reduced pressure. Alternatively, the solvent and excess acid can be removed under reduced pressure to provide the salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloride, hydrobromide, sulfate, phosphate, and the like. The amino groups of the compounds can also be quaternized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like.

[0162] Base addition salts can be prepared during the final isolation and purification of the disclosed compounds by reaction of the carboxyl group with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a metal cation, such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or a primary, secondary, or tertiary organic amine. Quaternary amine salts can also be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0163] D. General synthesis The compounds of formula (I) may be prepared by synthetic processes or by metabolic processes, including those that occur within the human or animal body (in vivo) or in vitro.

[0164] Abbreviations in the following schemes are as follows: DMF is dimethylformamide; EtN is triethylamine; MeOH is methanol; min or min. is minute(s); mw or μW is microwave irradiation; PhNTf is N-phenyl-bis(trifluoromethanesulfonimide); Pd(dppf)Cl is [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(PPh)Cl is bis(triphenylphosphine)palladium(II) dichloride; PPh is triphenylphosphine; and TBAI is tetrabutylammonium iodide.

[0165] Compounds of formula (I) or any of its subformulas may be synthesized as shown in the scheme below.

[0166] General Scheme 1 [ka] As shown in General Scheme 1, 6-bromo-5-hydroxyisoindolin-1-one compounds of formula A can be subjected to Suzuki reaction conditions, where compound A is reacted with an appropriate R 3 -substituted boronic acid or ester reagent to form R 3 An intermediate compound BI is formed which displays the substituents.

[0167] General Scheme 2 [ka] As shown in General Scheme 2, intermediate BI can be converted to intermediate B-Ia with N-phenyl-bis(trifluoromethanesulfonimide) and a base (e.g., EtN). Intermediate B-Ia can be subjected to standard Sonogashira coupling conditions with an alkyne, a palladium catalyst (e.g., Pd(PPh)Cl), a base (e.g., EtN), copper(I) iodide, and a solvent (e.g., DMF) to give compound DI.

[0168] General Scheme 3 [ka] As shown in General Scheme 3, compound EI is formed by subjecting compound DI to hydrogenation conditions with a palladium catalyst (e.g., palladium on carbon) in a solvent (e.g., methanol) under a hydrogen atmosphere. 2 The reaction can be carried out in the presence of H2 to provide the deuterium-enriched compound EI.

[0169] General Scheme 4 [ka] As shown in General Scheme 4, compound B-Ia may be subjected to standard Suzuki reaction conditions with a boronic acid or ester, a palladium catalyst (e.g., Pd(dppf)Cl·DCM), a base (e.g., NaCO), a solvent (e.g., 1,4-dioxane / water), and heat to give compound FI. [ka] A similar reaction with (wherein the boronic acid or ester is substituted on the unsaturated carbon of Cy) can be carried out to form R 4 The product of the Suzuki reaction can be converted to further compounds of the invention, such as by hydrogenation of the double bond in Cy, to provide compounds with saturated Cy (e.g., Example 15).

[0170] Suzuki coupling conditions suitable for use in the synthetic processes described herein are well known in the art. Suitable Suzuki conditions include those generally outlined in the general schemes and examples.

[0171] The boronic acid and ester reagents can be purchased from commercial sources or prepared from the corresponding halides (eg, bromides) using known procedures.

[0172] The compounds and intermediates can be isolated and purified by methods well known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups by recrystallization at high or low temperatures, with optional pretreatment with activated carbon, as described in, for example, "Vogel's Textbook of Practical Organic Chemistry," 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England; thin-layer chromatography; distillation at various pressures; sublimation and trituration in vacuo.

[0173] The disclosed compounds may have at least one basic nitrogen, which allows the compound to be treated with an acid to form a desired salt. For example, the compound can be reacted with an acid at room temperature or above room temperature to provide the desired salt, which precipitates and is collected by filtration after cooling. Examples of acids suitable for this reaction include, but are not limited to, tartaric acid, lactic acid, succinic acid, mandelic acid, atrolactic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, carbonic acid, fumaric acid, maleic acid, gluconic acid, acetic acid, propionic acid, salicylic acid, hydrochloric acid, phosphoric acid of hydrobromic acid, sulfuric acid, citric acid, hydroxybutyric acid, camphorsulfonic acid, malic acid, phenylacetic acid, aspartic acid, or glutamic acid.

[0174] Optimum reaction conditions and reaction times for each individual step may vary depending on the particular reactants employed and substituents present in the reactants. Specific procedures are provided in the Examples section. The reactions can be worked up in a conventional manner, for example, by removing the solvent from the residue, and further purified according to methodologies commonly known in the art, including, but not limited to, crystallization, distillation, extraction, trituration, and chromatography. Unless otherwise noted, starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. When not commercially available, starting materials can be prepared by procedures selected from standard organic chemistry techniques, techniques analogous to the synthesis of known structurally similar compounds, or procedures similar to those described in the schemes or synthetic examples section above.

[0175] Routine experimentation, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that may not be compatible with the reaction conditions and deprotection at appropriate points in the reaction sequence of the method, is within the scope of the present invention. Suitable protecting groups and methods for protecting and deprotecting various substituents using such suitable protecting groups are well known to those skilled in the art, examples of which can be found in "Protective Groups in Organic Synthesis" (4), the entire contents of which are incorporated herein by reference. th ed.), PGM Wuts and TW Greene, John Wiley & Sons, NY (2006). Synthesis of the compounds of the present invention can be achieved by methods similar to those described in the synthetic schemes described above and in the specific examples.

[0176] When an optically active form of a disclosed compound is required, this can be obtained by carrying out one of the procedures described herein using optically active starting materials (prepared, for example, by asymmetric induction in an appropriate reaction step), or by resolution of a stereoisomeric mixture of the compound or intermediate using standard procedures (such as chromatographic separation, recrystallization, or enzymatic resolution).

[0177] Similarly, if a pure geometric isomer of this compound is required, this can be obtained by performing one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of geometric isomers of the compound or intermediate using standard procedures such as chromatographic separation.

[0178] It will be understood that the synthetic schemes and specific examples described are illustrative and should not be construed as limiting the scope of the invention, which is defined in the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims.

[0179] 3. Pharmaceutical Compositions The disclosed compounds can be incorporated into pharmaceutical compositions suitable for administration to a subject (eg, a patient, which can be human or non-human).

[0180] These pharmaceutical compositions may contain a "therapeutically effective amount" or a "prophylactically effective amount" of the agent. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. The therapeutically effective amount of the composition can be determined by one of ordinary skill in the art and may vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also an amount in which the therapeutically beneficial effects of any of the compounds of the present invention [e.g., compounds of Formula (I)] outweigh any toxic or harmful effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Generally, since a prophylactic dose is used in subjects prior to or at an early stage of disease, the prophylactically effective amount will be lower than the therapeutically effective amount.

[0181] For example, a therapeutically effective amount of a compound of a subformula of Formula (I) may be from about 1 mg / kg to about 1000 mg / kg, from about 5 mg / kg to about 950 mg / kg, from about 10 mg / kg to about 900 mg / kg, from about 15 mg / kg to about 850 mg / kg, from about 20 mg / kg to about 800 mg / kg, from about 25 mg / kg to about 750 mg / kg, from about 30 mg / kg to about 700 mg / kg, from about 35 mg / kg to about 650 mg / kg, from about 40 mg / kg to about 600 mg / kg, or from about It may be 45 mg / kg to about 550 mg / kg, about 50 mg / kg to about 500 mg / kg, about 55 mg / kg to about 450 mg / kg, about 60 mg / kg to about 400 mg / kg, about 65 mg / kg to about 350 mg / kg, about 70 mg / kg to about 300 mg / kg, about 75 mg / kg to about 250 mg / kg, about 80 mg / kg to about 200 mg / kg, about 85 mg / kg to about 150 mg / kg, and about 90 mg / kg to about 100 mg / kg.

[0182] The pharmaceutical composition may include a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" refers to any type of non-toxic, inert solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation auxiliary. Some examples of materials that can serve as pharmaceutically acceptable carriers include sugars, such as, but not limited to, lactose, glucose, and sucrose; starches, such as, but not limited to, corn starch and potato starch; cellulose and its derivatives, such as, but not limited to, sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as, but not limited to, cocoa butter and suppository wax; oils, such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols; for example, propylene glycol; esters, for example, but not limited to, ethyl oleate and ethyl laurate; agar; buffers, for example, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol and phosphate buffer; and other non-toxic compatible lubricants, for example, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0183] Thus, the compounds and their physiologically acceptable salts and solvents can be formulated, for example, in solid dosages, eye drops, oil-based topical preparations, by injection, inhalation (through the mouth or nose), administration by implant, or for oral, buccal, parenteral, or rectal administration. Techniques and formulations can generally be found in "Remington's Pharmaceutical Sciences" (Meade Publishing Co., Easton, Pa.). Therapeutic compositions generally must be sterile and stable under the conditions of manufacture and storage.

[0184] The route by which the disclosed compounds are administered and the form of the composition will determine the type of carrier used, which may be in a variety of forms suitable for, for example, systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implanted, or parenteral) or topical administration (e.g., skin, lung, nose, ear, eye, liposome delivery system, or iontophoresis).

[0185] Carriers for systemic administration generally include at least one diluent, lubricant, binder, disintegrant, colorant, flavor, sweetener, antioxidant, preservative, flow agent, solvent, suspending agent, wetting agent, surfactant, combinations thereof, etc. All carriers are optional within the composition.

[0186] Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols such as glycerin; mannitol; and sorbitol. The amount of diluent in a systemic or topical composition is generally about 50 to about 90%.

[0187] Suitable lubricants include silica, talc, stearic acid and its magnesium and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa oil. The amount of lubricant in a systemic or topical composition is generally about 5 to about 10%.

[0188] Suitable binders include polyvinylpyrrolidone, magnesium aluminum silicate, starches such as corn starch and potato starch, gelatin, tragacanth, and cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder in a systemic composition is generally about 5 to about 50%.

[0189] Suitable disintegrants include agar, alginic acid and its sodium salt, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant in a systemic or topical composition is generally about 0.1 to about 10%.

[0190] Suitable coloring agents include coloring agents such as the FD&C dyes. If used, the amount of coloring agent in a systemic or topical composition is generally about 0.005 to about 0.1%.

[0191] Suitable flavors include menthol, peppermint, and fruit flavors. If used, the amount of flavor in a systemic or topical composition is generally about 0.1 to about 1.0%.

[0192] Suitable sweeteners include aspartame and saccharin. The amount of sweetener in a systemic or topical composition is generally from about 0.001 to about 1%.

[0193] Suitable antioxidants include butylhydroxyanisole ("BHA"), butylhydroxytoluene ("BHT"), and vitamin E. The amount of antioxidant in a systemic or topical composition is generally from about 0.1 to about 5%.

[0194] Suitable preservatives include benzalkonium chloride, methylparaben, and sodium benzoate. The amount of preservative in a systemic or topical composition is generally from about 0.01 to about 5%.

[0195] Suitable glidants include silicon dioxide. The amount of glidant in a systemic or topical composition is generally about 1 to about 5%.

[0196] Suitable solvents include water, isotonic saline, ethyl oleate, glycerin, castor oil hydroxide, alcohols such as ethanol, and phosphate buffers. The amount of solvent in a systemic or topical composition is generally from about 0 to about 100%.

[0197] Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, PA) and sodium alginate. The amount of suspending agent in a systemic or topical composition is generally about 1 to about 8%.

[0198] Suitable surfactants include lecithin, polysorbate 80, and sodium lauryl sulfate, and TWEENS (from Atlas Powder Company of Wilmington, Delaware). Suitable surfactants include those disclosed in CTFA Cosmetic Ingredient Handbook, 1992, pp. 587-592; Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant in a systemic or topical composition is generally about 0.1% to about 5%.

[0199] The amounts of components in a systemic composition may vary depending on the type of systemic composition being prepared, but generally, a systemic composition will contain 0.01% to 50% of an active compound (e.g., a compound of a subformula of Formula (I)) and 50% to 99.99% of one or more carriers. Compositions for parenteral administration generally contain 0.1% to 10% of an active substance and 90% to 99.9% of a carrier (including diluents and solvents).

[0200] Compositions for oral administration can be in various dosage forms. For example, solid dosage forms include tablets, capsules, granules, and bulk powders. These oral dosage forms contain a safe and effective amount of an active ingredient, typically at least about 5%, more specifically about 25% to about 50%. These oral dosage compositions contain about 50% to about 95%, more specifically about 50% to about 75%, of a carrier.

[0201] Tablets can be compressed, tablet triturated, enteric coated, sugar coated, film coated, or multiple compressed. Tablets generally contain an active ingredient and a carrier containing components selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, flow agents, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific coloring agents are FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, and fruit flavors, or combinations thereof.

[0202] Capsules (including implants, sustained-release, and sustained release formulations) generally contain an active compound (e.g., a compound of a subformula of Formula (I)) and a carrier comprising one or more of the diluents disclosed above in a gelatin-containing capsule. Granules generally contain a disclosed compound and preferably a glidant, such as silicon dioxide, to improve flow properties. Implants can be biodegradable or non-biodegradable.

[0203] The selection of ingredients in a carrier for an oral composition depends on secondary considerations such as taste, cost, and shelf stability, which are not critical for purposes of this invention.

[0204] The solid compositions can be coated by conventional methods, typically with pH or time-dependent coatings, so that the disclosed compounds are released in the gastrointestinal tract or near the desired application site, or at various locations and times to maintain the desired effect. The coating typically comprises one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, ethylcellulose, EUDRAGIT coatings (available from Rohm & Haas GmbH, Darmstadt, Germany), waxes, and shellac.

[0205] The composition for oral administration can be in liquid form. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, etc. The liquid composition for oral administration generally comprises the disclosed compound and a carrier, i.e., a carrier selected from diluents, colorants, flavorants, sweeteners, preservatives, solvents, suspending agents, and surfactants. The oral liquid composition preferably comprises one or more components selected from colorants, flavorants, and sweeteners.

[0206] Other compositions useful for achieving systemic delivery of target compounds include sublingual, buccal and nasal dosage forms.These compositions generally comprise one or more soluble fillers, such as diluents including sucrose, sorbitol and mannitol; and binders such as gum arabic, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose.These compositions can also comprise lubricants, colorants, flavors, sweeteners, antioxidants and flow agents.

[0207] The disclosed compounds can be administered topically. Topical compositions that can be applied topically to the skin can be in any form, including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-in and rinse-off hair conditioners, emulsions, cleansers, moisturizers, sprays, skin patches, etc. The topical composition comprises the disclosed compounds (e.g., compounds of the subformula of Formula (I)) and a carrier. The carrier of the topical composition preferably facilitates the penetration of the compound into the skin. The carrier may further comprise one or more optional components.

[0208] The amount of carrier used with the disclosed compound is sufficient to provide a useful amount of the composition for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of the present invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

[0209] The carrier may comprise a single component or a combination of two or more components. In topical compositions, the carrier comprises a topical carrier. Suitable topical carriers include one or more components selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, and combinations thereof. More specifically, carriers for skin application include propylene glycol, dimethyl isosorbide, and water, more specifically phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.

[0210] The carrier of the topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, dyes, and preservatives, all of which are optional.

[0211] Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecane-2-ol, isocetyl alcohol, cetyl palmitate, sebacillus acidophilus, sorbitan ol ... Examples of emollients for topical use include di-n-butyl phosphate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohol, petroleum oil, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient in topical compositions for skin applications is generally about 5% to about 95%.

[0212] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant in a topical composition is generally from about 0% to about 95%.

[0213] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent in a topical composition is generally about 0% to about 95%.

[0214] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant in a topical composition is generally 0% to 95%.

[0215] The amount of thickener in a topical composition is generally from about 0% to about 95%.

[0216] Suitable powders include beta-cyclodextrin, hydroxypropyl cyclodextrin, chalk, talc, Fuller's earth, kaolin, starch, gum, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder in a topical composition is generally 0% to 95%.

[0217] The amount of fragrance in the topical composition is generally from about 0% to about 0.5%, particularly from about 0.001% to about 0.1%.

[0218] Suitable pH-adjusting additives include HCl or NaOH in an amount sufficient to adjust the pH of the topical pharmaceutical composition.

[0219] 4. Treatment Method The disclosed compounds and compositions can be used in methods for the treatment of mGlu2-related medical disorders and / or diseases. The methods of treatment can include administering to a subject in need of such treatment a therapeutically effective amount of a composition comprising a compound of Formula (I).

[0220] The compositions can be administered to a subject in need thereof to modulate mGlu2 for a variety of diverse biological processes. The present disclosure is directed to methods for administering the compositions to inhibit mGlu2, a GPCR that plays a role in synaptic plasticity and directly impacts, for example, cognitive function and memory.

[0221] The compositions may be useful for treating and preventing certain diseases and disorders in humans and animals associated with dysfunction of mGlu2. Treatment or prevention of such diseases and disorders can be brought about by modulating mGlu2 in a subject by administering a compound or composition of the invention to a subject in need thereof, either alone or in combination with another active agent as part of a therapeutic regimen.

[0222] A. Depression mGlu 2 / 3 The antidepressant-like effects of receptor antagonists MGS0039 and LY341495 were first demonstrated in normal animals in the rat forced swim test (FST) and mouse tail suspension test (TST) (Chaki et al. Neuropharmacology, 2004, 46, 457-467). More recently, studies have attempted to evaluate the effects of these drugs in paradigms implicated in the etiology of human depression. MGS0039 demonstrated antidepressant effects in the learned helplessness test, in which 7-day treatment with MGS0039 significantly reduced the number of escape failures (Yoshimizu et al. Psychopharmacology, 2006, 186, 587-593).

[0223] Psychopharmacology, 2010, 212, 523-535 evaluated the potential antidepressant-like effects of MGS0039 in the olfactory bulbectomy (OB) model of depression in rats. Surgical lesions of the olfactory bulb in animals are known to induce substantial behavioral, physiological, endocrine, and immune changes, many of which are qualitatively similar to those observed in depressed patients. Repeated administration of MGS0039 for 14 days attenuated hyperactivity in olfactory bulbectomized rats in the open field test and attenuated learning impairment in the passive avoidance test.

[0224] Kawasaki et al. Neuropharmacology, 2011, 60, 397-404 also examined the effect of MGS0039 on the behavior of socially isolated mice in the FST. It is known that rearing rodents in isolation after weaning causes changes in brain neurochemistry that disrupt behavior. Chronic social isolation after weaning for more than 6 weeks increased immobility in the FST, suggesting that isolation rearing caused depression-like behavior. MGS0039 reversed the increased immobility of socially isolated mice in the test.

[0225] Campo, B. et al. J. Neurogenetics 2011, 25, 152-166 showed that a selective group II (mGlu2 and mGlu3) negative allosteric modulator (RO4491533) is effective in several in vitro biochemical assays and in vivo models of depression. 2 / 3 It was shown to bind central mGlu2 and mGlu3 receptors, as it reversed the locomotor-suppressing effects of an agonist (LY379268) in a target-specific manner. 2 / 3The antagonist LY341495 achieved the same results. RO4491533 and LY341495 dose-dependently reduced immobility time in C57B16 / J mice in the FST. RO4491533 and LY341495 were also active in the tail suspension test in the helpless (H) mouse strain, a putative genetic model of depression.

[0226] mGlu 2 / 3 Blockade of mGlu receptors and ketamine may converge on the same neural circuitry involving activation of AMPA receptors and mTOR signaling. Both AMPA receptor stimulation and subsequent mTOR signaling activation are presumed to be involved in the rapid effects of ketamine on patients with treatment-resistant depression (TRD). 2 / 3 Receptor antagonists could exert the same effect in humans. This assumption is supported by several animal studies. First, mGlu receptor antagonists 2 / 3 The mGlu receptor antagonist MGS0039 showed antidepressant effects in an animal model (learned helplessness paradigm) in which currently prescribed antidepressants are ineffective (Yoshimizu et al. Psychopharmacology, 2006, 186, 587-593). 2 / 3 There is no evidence of a rapid onset of action by receptor antagonists, but AMPA receptor potentiators (AMPA receptor potentiation is mGlu 2 / 3 LY341495 (which mediates the antidepressant effects of mGlu receptor antagonists) showed a faster effect (during the first week of treatment) compared to fluoxetine (after two weeks) in the dominance-dependence test (Knapp et al. Eur. J. Pharmacol. 2002, 440, 121-125). Furthermore, LY341495 showed a potent antidepressant effect in helpless mice following acute administration, whereas fluoxetine exerted a full antidepressant effect following chronic (21 days) treatment (Campo, B. et al. J. Neurogenetics 2011, 25, 152-166; El Yacoubi et al. PNAS, 2003, 100, 6227-6232). Thus, mGlu receptor antagonists are involved in the regulation of mGlu receptor activity. 2 / 3Blockade of the receptor can have rapid and potent antidepressant effects in humans.

[0227] B. Cognitive impairment Woltering et al. Bioorg. Med. Chem. Lett. 2010, 20, 6969-74 mGlu 2 / 3 Negative allosteric modulators of mGluR1 inhibit the activity of mGluR1 in the delayed match to position (DMTP) task, a measure of working memory, in rodents. 2 / 3 Woltering showed that low doses of mGluR1 reversed working memory deficits induced by agonists or scopolamine. 2 / 3 When a negative allosteric modulator of mGlu2 was combined with a tolerable dose of the acetylcholinesterase inhibitor donezepil, it showed synergistic reversal of scopolamine-induced deficits in DMTP. Given the effectiveness of donepezil and other acetylcholinesterase inhibitors in treating cognitive decline in Alzheimer's disease, negative allosteric modulators of mGlu2 may have efficacy as cognitive improvers.

[0228] C. Obsessive-compulsive disorder Shimazaki, T. et al. Eur. J. Pharmacol. 2004, 501, 121-125 showed that MGS0039 induced glutamatergic changes in mice, resulting in anti-obsessive-compulsive disorder effects. In these studies, the marble-burying behavior test was used as a model for obsessive-compulsive disorder. The marble-burying behavior test is recognized as a useful model for evaluating the clinical potential of anti-obsessive-compulsive disorder drugs. Specifically, mice treated with MGS0039 showed a significant and dose-dependent reduction in marble-burying behavior, while no significant changes in locomotor activity were observed. Furthermore, LY341495, another potent antagonist of group II mGlu receptors, was also shown to significantly reduce marble-burying behavior in treated mice.

[0229] D. Alzheimer's disease Kim, SH et al. (Molecular Psychiatry 2014, pp. 1–8) assessed the therapeutic potential of chronic pharmacological inhibition of group II mGlu receptors (mGlu2 and mGlu3) with a group II mGlu receptor antagonist in an APP transgenic mouse model, which develops learning and behavioral deficits associated with the accumulation of mutant Aβ oligomers that do not form amyloid plaques. Once-daily administration of the orally bioavailable prodrug BCI-838 delivered sufficient brain concentrations of its active metabolite BCI-632 to inhibit group II mGlu receptors for 22 hours. Three-month treatment with BCI-838 achieved anxiolytic effects, reversed the learning and memory decline associated with the Dutch APP transgene, and reduced levels of monomeric and oAβ peptides in the hippocampus and cortex of two different AD mouse models. Notably, BCI-838 administration stimulated hippocampal progenitor cell proliferation for 3 months in both wild-type and Alzheimer's disease mice, resulting in significantly increased numbers of newborn neurons in the hippocampus of Dutch APP transgenic mice. In addition to its therapeutic properties, the proneurogenic properties make the compound attractive for potential use in reversing some of the early symptoms of Alzheimer's disease (AD), likely through the restorative effects of newborn neurons. These findings suggest that chronic pharmacological inhibition of group II mGlu receptors may have the potential to be a disease-modifying treatment for AD that targets cognitive / emotional deficits and modulates neurogenesis.

[0230] Further research by Caraci, F. et al. Mol. Pharmacol. 2011, 79, 618-626 showed that a positive allosteric modulator of mGlu2 (LY566332) amplified Aβ-induced neurodegeneration, but this effect was not mediated by mGlu 2 / 3 This was prevented by the receptor antagonist LY341495.

[0231] E. Anxiety Yoshimizu et al., Psychopharmacology, 2006, 186, 587-593, also demonstrated the anxiolytic effects of MGS0039, a potent antagonist of group II mGlu receptors (mGlu2 and mGlu3), using a conditioned fear stress (CFS) model, which represents emotional disorders including anxiety. The CFS model reflects mental stress without physical stimulation and is useful for predicting the clinical efficacy of anxiolytic drugs. In these studies, MGS0039 significantly reduced freezing behavior, similar to diazepam and fluvoxamine, indicating the anxiolytic potential of MGS0039. mGlu 2 / 3 The receptor acts as an autoreceptor located on glutamatergic terminals and inhibits neurotransmitter release, inhibiting mGluR1 receptors in vivo. 2 / 3 Treatment with antagonists such as MGS0039 leads to an increase in extracellular glutamate. Therefore, the moderate increase in glutamate levels in specific brain regions by MGS0039 may lead to the anxiolytic effects seen in CFS models. These results suggest that MGS0039 may be involved in the upregulation of mGlu 2 / 3 This suggests that blockade of ATP may be effective in treating anxiety disorders.

[0232] F. Mode of Administration Therapeutic methods can include any number of modes of administering the disclosed compositions. Modes of administration can include tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily, or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions, or dispersible powders. To prepare pharmaceutical compositions for oral administration, the agent can be mixed with commonly known and used adjuvants and excipients, such as gum arabic, talc, starch, sugars (e.g., mannitol, methylcellulose, lactose, etc.), gelatin, surfactants, magnesium stearate, aqueous or non-aqueous solvents, paraffin derivatives, crosslinking agents, dispersants, emulsifiers, lubricants, preservatives, flavorings (e.g., ethereal oils), solubility enhancers (e.g., benzyl benzoate or benzyl alcohol), or bioavailability enhancers (e.g., Gelucire™). In pharmaceutical compositions, the drug may also be dispersed in microparticles, such as nanoparticle compositions.

[0233] For parenteral administration, the drug may be dissolved or suspended in a physiologically acceptable diluent, such as water, a buffer, an oil with or without a solubilizer, a surfactant, a dispersant, or an emulsifier. Oils that can be used include, but are not limited to, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil, and sesame oil. More generally, for parenteral administration, the drug may be in the form of an aqueous, lipid, oily, or other type of solution or suspension, or may even be administered in the form of a liposome or nanosuspension.

[0234] The term "parenteral," as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

[0235] G. Combination Therapy The additional therapeutic agent may be administered simultaneously or sequentially with the disclosed compounds and compositions. Sequential administration includes administration before or after the disclosed compounds and compositions. In some embodiments, the additional therapeutic agent or agent may be administered in the same composition as the disclosed compound. In other embodiments, there may be a time interval between the administration of the additional therapeutic agent and the disclosed compound. In some embodiments, administration of the additional therapeutic agent with the disclosed compound may allow for a lower dose of the other therapeutic agent and / or administration at less frequent intervals. When used in combination with one or more other active ingredients, the compound of the present invention and the other active ingredients may be used in lower doses than when each is used alone. Thus, pharmaceutical compositions of the present invention include those containing one or more other active ingredients in addition to the compound of formula (I). The above combinations include combinations of the compound of the present invention not only with one other active compound, but also with two or more other active compounds. For example, the compound of formula (I) can be combined with various antidepressants, Alzheimer's drugs, and anti-anxiety drugs.

[0236] The compounds of formula (I) may be combined with the following antidepressants, but are not limited to: selective serotonin reuptake inhibitors (SSRIs), such as citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, indalpine, paroxetine, sertraline, and zimelidine; serotonin-norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, desvenlafaxine, duloxetine, milnacipran, levomilnacipran, and sibutramine; noradrenergic and specific serotonergic antidepressants (NaSSAs) or tetracyclic antidepressants (TeCAs), such as aptazapine, esmirtazapine, mianserin, mirtazapine, and setiptiline; serotonin antagonists and reuptake inhibitors (SARIs), such as etoperidone, lorpiprazole, mepiprazole, nefazodone, trazodone, vilazodone, and niaprazine; norepinephrine-dopamine reuptake inhibitors (NDRIs), such as armodafinil, bupropion, desoxypipradrol, dexmethylphenidate, ... Luphenidate, modafinil, prolintane, and tametraline; Serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs) such as nefopam, amitifadine, tesofensine, and tedatioxetine; Tricyclic antidepressants (TCAs) such as clomipramine, desipramine, imipramine, dibenzepin, lofepramine, nortriptyline, protriptyline, amitriptyline, amitriptylinoxide, amoxapine, butriptyline, demexiptyline, dimetacrine, dosulepin, doxepin , imipraminooxide, melitracen, metapramine, nitroxazepine, noxiptiline, pipofezin, propizepine, quinupramine, amineptine, iprindole, opipramol, tianeptine, and trimipramine; and negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu5), such as mavoglurant, basimuglurant, dipraglurant, STX107, and N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide.

[0237] The compounds of formula (I) may be combined with the following Alzheimer's medications, but are not limited to: acetylcholinesterase inhibitors, such as tacrine, rivastigmine, galantamine, donepezil, edrophonium, physostigmine, pyridostigmine, ambenonium, rivastigmine, ladostigil, and ungeremine; and NMDA receptor antagonists, such as memantine, amantadine, delsemin, and ketamine.

[0238] The compounds of formula (I) may be combined with the following anti-anxiety agents, including, but not limited to, buspirone, tandosprione, gepirone, adaptol, afobazole, hyroxyzine, validol, melatonin, and benzodiazepines such as alprazolam, chlordiazepoxide, clonazepam, diazepam, etizolam, lorazepam, oxazepam, and tofisopam.

[0239] The disclosed compounds can be included in a kit that includes a compound (e.g., one or more compounds of Formula (I)), a systemic or topical composition as described above, or both; and information, instructions, or both, that use of the kit provides treatment for a medical condition in a mammal (e.g., a human). The information and instructions can be in the form of words, pictures, or both. Additionally or alternatively, the kit can include a drug, composition, or both, preferably with the benefit of treating or preventing a medical condition in a mammal (e.g., a human); and information, instructions, or both, regarding a method of application of the drug, or composition.

[0240] The compounds and processes of the present invention will be better understood by reference to the following examples, which are intended to illustrate, but not limit, the scope of the invention. [Example]

[0241] 5. Working Example All NMR spectra were recorded on a 400 MHz AMX Bruker NMR spectrometer.1 H chemical shifts are reported as δ values ​​in ppm (downfield) using deuterated solvent as internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet, ABq = AB quartet), coupling constant, and integration. Reversed-phase LCMS analysis was performed using an Agilent 1200 system consisting of a binary pump equipped with a degasser, a high-performance autosampler, a thermostated column compartment, a C18 column, a diode array detector (DAD), and an Agilent 6150 MSD, with the following parameters: gradient conditions: 5% to 95% acetonitrile (aqueous phase: 0.1% TFA in water) over 1.4 min. Samples were separated on a Waters Acquity UPLC BEH C18 column (1.7 μm, 1.0 × 50 mm) at 0.5 mL / min, with column and solvent temperatures maintained at 55 °C. The DAD was set to scan from 190 to 300 nm, with signals at 220 nm and 254 nm (both with 4 nm bands). The MS detector was set with an electrospray ionization source, and low-resolution mass spectra were acquired by scanning from 140 to 700 AMU with a step size of 0.2 AMU and a peak width of 0.008 min at 0.13 cycles / sec. The drying gas flow was set to 13 liters / min at 300 °C, and the nebulizer pressure was set to 30 psi. The capillary needle voltage was set to 3000 V, and the fragmentor voltage was set to 100 V. Data acquisition was performed using Agilent Chemstation and Analytical Studio Reviewer software.

[0242] Abbreviations that may be used in the examples below are: AIBN is 2,2'-azobis(2-methylpropionitrile); atm is atmospheric pressure; Celite® is diatomaceous earth; DCM is dichloromethane; DIAD is diisopropyl azodicarboxylate; DMF is N,N-dimethylformamide; DMAP is 4-dimethylaminopyridine; DMSO is dimethyl sulfoxide; eq, eq., or equiv is equivalent; Et3N is triethylamine; EtOAc is ethyl acetate; h is the time; LCMS is liquid chromatography mass spectrometry; MeCN is acetonitrile; MeOH is methanol; MeOD is CH3OD; min or min. is minutes; mw or μW is microwave radiation; NBS is N-bromosuccinimide; PhNTf2 is N-phenyl-bis(trifluoromethanesulfonimide); Pd(dppf)Cl2 is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); PPh3 is triphenylphosphine; rt, RT, or rt is room temperature; sat. is saturated; Tf is triflate; TFA is trifluoroacetic acid; THF is tetrahydrofuran.

[0243] Preparation of intermediates Intermediate Example 1. 6-Bromo-5-methoxyisoindolin-1-one (B). [ka] Methyl 5-bromo-2-(bromoethyl)-4-methoxybenzoate (Intermediate A). To a flask was added methyl 5-bromo-4-methoxy-2-methylbenzoate (5.0 g, 19.3 mmol), N-bromosuccinimide (3.75 g, 21.1 mmol), and AIBN (330 mg, 2.0 mmol). The resulting mixture was diluted with carbon tetrachloride (90 mL), and the reaction mixture was stirred at 90 °C. After 16 h, the mixture was washed with water (30 mL) and separated. The aqueous layer was extracted with DCM (3 × 50 mL), and the combined organic layers were washed with brine (100 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by normal-phase column chromatography (0–10% hexanes:EtOAc) to give Intermediate A. H NMR(400MHz,DMSO-d6)δ 8.07(s,1H),7.39(s,1H),5.02(s,2H),3.94(s,3H),3.84(s,3H),ES-MS[M+1] + :337.8 and 339.8.

[0244] 6-Bromo-5-methoxyisoindolin-1-one (Intermediate B). Methyl 5-bromo-2-(bromomethyl)-4-methoxybenzoate (4.68 g, 13.9 mmol) was dissolved in a 7N solution of ammonia in methanol (51.4 mL). The reaction mixture was stirred in a Teflon® screw-neck flask and heated to 100°C. After 2 h, the cap was carefully removed, then the solvent was evaporated in vacuo, and the crude residue was purified by normal phase column chromatography (0-10% EtOAc:MeOH) to give the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.48(s,1H),7.78(s,1H),7.34(s,1H),4.32(t,J=1.0Hz,2H),3.93(s,3H);ES-MS[M+1] + :242.0 and 244.0.

[0245] Intermediate Example 2. 6-Bromo-5-hydroxyisoindolin-1-one (Intermediate C). [ka] To a round-bottom flask were added 6-bromo-5-methoxyisoindolin-1-one (796 mg, 3.3 mmol) and anhydrous DCM (16.5 mL). The reaction vessel was placed in an ice bath, and then BBr3 (624 μL, 6.57 mmol) was added slowly via syringe. The reaction mixture was stirred overnight at ambient temperature. The reaction vessel was reimmersed in an ice bath, and ice was then added to the vessel. After 30 min, the layers were separated, and the aqueous layer was extracted with DCM (3 × 50 mL) and a 3:1 ratio of chloroform:isopropanol (50 mL). The combined organic portions were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound. The aqueous layer was concentrated and diluted with a 1:1 chloroform:isopropanol solution (100 mL). The resulting precipitate was filtered by vacuum filtration to give the title compound, which was carried on to the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δ 10.96(s,1H),8.35(s,1H),7.69(s,1H),7.08(s,1H),4.25(s,2H);ES-MS[M+1] + :227.9 and 229.9.

[0246] Intermediate Example 3. 6-(4-Fluorophenyl)-1-oxoisoindolin-5-yl trifluoromethanesulfonate (Intermediate E). [ka] 6-(4-Fluorophenyl)-5-hydroxyisoindolin-1-one (Intermediate D). To a mixture of 6-bromo-5-hydroxyisoindolin-1-one (1 g, 4.38 mmol), Pd(dppf)Cl₂·DCM (359 mg, 0.438 mmol), 4-fluorophenylboronic acid (1.23 g, 8.77 mmol), and Cs₂CO₃ (1.44 g, 4.38 mmol), degassed 1,4-dioxane (8 mL) and water (800 μL) were added. The reaction atmosphere was evacuated and purged with nitrogen (3×), and the sealed reaction vessel was subjected to microwave irradiation at 120 °C. After 20 min, DCM (50 mL) was added to the resulting mixture, and the reaction mixture was passed through a hydrophobic phase separator. The organic layer was concentrated in vacuo to give a crude residue. The residue was purified by normal phase column chromatography (0-20% DCM:MeOH) to give the title compound. ES-MS [M+1] + :244.0.

[0247] 6-(4-Fluorophenyl)-1-oxoisoindolin-5-yl trifluoromethanesulfonate (Intermediate E). To a mixture of 6-(fluorophenyl)-5-hydroxyisoindolin-1-one (719 mg, 2.96 mmol), N-phenyl-bis(trifluoromethanesulfonimide) (1.12 g, 3.25 mmol), and DMAP (36 mg, 0.30 mmol) was added DCM (7 mL). The reaction mixture was cooled in an ice bath at 0 °C while triethylamine (825 μL, 5.92 mmol) was added dropwise. The reaction mixture was removed from the ice bath and, after 2 h at ambient temperature, the solvent was removed in vacuo. The residue was purified by normal phase column chromatography (0-10% DCM / MeOH) to give the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.87(s,1H),7.87(s,1H),7.77(s,1H),7.59(m,2H),7.36(m,2H),4.49(s,2H);ES-MS[M+1] + :375.9.

[0248] Intermediate Example 4. 6-(2,4-Difluorophenyl)-1-oxoisoindolin-5-yl trifluoromethanesulfonate (Intermediate G). [ka] 6-(2,4-Difluorophenyl)-5-hydroxyisoindolin-1-one (Intermediate F). To a mixture of 6-bromo-5-hydroxyisoindolin-1-one (1 g, 4.39 mmol), Pd(dppf)Cl₂·DCM (359 mg, 0.44 mmol), cesium carbonate (1.44 g, 4.39 mmol), and 2,4-difluorophenylboronic acid (1.38 g, 8.77 mmol) was added a solution of 1,4-dioxane (8 mL) and water (800 μL). The reaction mixture was heated to 120 °C under microwave irradiation. After 40 min, the reaction mixture was diluted with DCM, and the organic layer was passed through a hydrophobic phase separator. The organic layer was concentrated in vacuo, and the resulting residue was purified by normal-phase column chromatography (0–10% DCM / MeOH) to give Intermediate F. 1 H NMR(400MHz,DMSO-d6)δ 10.39(brs,1H),8.27(s,1H),7.45(td,J=8.6,6.7Hz,1H),7.39(s,1H),7.29(td,J= 9.8,2.6Hz,1H),7.14(td,J=8.6,2.5Hz,1H),7.07(s,1H),4.32(s,2H);ES-MS[M+1] + :262.1.

[0249] 6-(2,4-Difluorophenyl)-1-oxoisoindolin-5-yl trifluoromethanesulfonate (Intermediate G). To a solution of 6-(2,4-difluorophenyl)-5-hydroxyisoindolin-1-one (560 mg, 2.14 mmol), N-phenyl-bis(trifluoromethanesulfonimide) (843 mg, 2.36 mmol), and DMAP (26 mg, 0.21 mmol) in DCM (6 mL) was added triethylamine (598 μL, 4.29 mmol) dropwise at 0° C. The reaction mixture was allowed to warm to ambient temperature. After 2 h, the reaction mixture was concentrated in vacuo and purified by normal phase column chromatography (0-10% DCM / MeOH) to give the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.90(s,1H),7.91(s,1H),7.81(s,1H),7.60(td,J=8.6,6.5Hz,1H),7.47(ddd, J=10.4,9.3,2.6Hz,1H),7.28(td,J=8.6,2.6Hz,1H),4.51(s,2H);ES-MS[M+1] + :394.0.

[0250] Synthesis of Example Compounds Example 1. 5-(3,6-Dihydro-2H-pyran-4-yl)-6-(4-fluorophenyl)isoindolin-1-one (Compound 55). [ka] To a solution of [6-(4-fluorophenyl)-1-oxo-isoindolin-5-yl]trifluoromethanesulfonate (50 mg) in degassed 1,4-dioxane / HO (3:1; 0.80 mL) was added (3,6-dihydro-2h-pyran-4-yl)-boronic acid (37 mg), sodium carbonate (45 mg), and Pd(dppf)Cl. CHCl (6 mg). The reaction mixture was evacuated and purged with N (3×) and stirred at 100 °C. After 5 h, the mixture was diluted with DCM (20 mL) and water (2 mL), and the organic phase was separated. The aqueous layer was extracted with DCM (3 × 5 mL). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by normal-phase column chromatography (0–10% DCM / MeOH) to give the title compound. 1 H NMR(400MHz,DMSO)δ 8.59(s,1H),7.51(s,1H),7.49-7.41(m,3H),7.31-7.22(m,2H),5.78-5.71(m,1H),4. 41(s,2H),4.10(q,J=2.7Hz,2H),3.53(t,J=5.3Hz,2H),1.90-1.83(m,2H).ES-MS[M+1] + :310.0.

[0251] Example 2. 5-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(4-fluorophenyl)isoindolin-1-one (Compound 56). [ka] The title compound was prepared using a procedure similar to the preparation of compound 55, but starting from 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine. 1H NMR(400MHz,DMSO)δ 8.57(s,1H),7.49(s,1H),7.47-7.39(m,3H),7.34-7.21(m,7H),5.65-5.62(m,1H) ,4.39(s,2H),3.50(s,2H),2.95(d,J=3.2Hz,2H),2.37(t,J=5.5Hz,2H),1.90(app s,2H).ES-MS[M+1] + :399.2.

[0252] Example 3. 6-(4-Fluorophenyl)-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)isoindolin-1-one (Compound 58). [ka] The title compound was prepared using a procedure similar to the preparation of compound 55. 1 H NMR(400MHz,DMSO)δ 8.57(s,1H),7.49(s,1H),7.46-7.39(m,3H),7.31-7.21(m,2H),5.67-5.61(m,1H),4.39(s,2) H),2.89(q,J=2.9Hz,2H),2.27(t,J=5.5Hz,2H),2.18(s,3H),1.94-1.86(m,2H).ES-MS[M+1] + :323.0.

[0253] Example 4. 6-(4-Fluorophenyl)-5-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)isoindolin-1-one (Compound 57). [ka] The title compound was prepared using a procedure similar to the preparation of compound 55. 1H NMR(400MHz,DMSO)δ 8.58(s,1H),7.49(s,1H),7.45(s,1H),7.44-7.39(m,2H),7.27-7.20(m,2H),5.64-5.57(m,1H),4. 39(s,2H),2.66(q,J=2.4Hz,2H),2.33(t,J=5.7Hz,2H),2.14-2.05(m,2H),2.08(s,3H).ES-MS[M+1] + :323.1.

[0254] Example 5. 6-(4-Fluorophenyl)-5-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)isoindolin-1-one (Compound 59). [ka] The title compound was prepared using a procedure similar to the preparation of compound 55. 1 H NMR(400MHz,DMSO)δ 8.57(s,1H),7.46(s,1H),7.40(s,1H),7.39-7.34(m,2H),7.28-7.17(m,2H),5.39(app t,J=1.6Hz,1H),4.40(s,2H),1.77(app d,J=1.7Hz,2H),0.98(s,6H),0.94(s,6H).ES-MS[M+1] + :365.2.

[0255] Example 6. 4-(6-(2,4-Difluorophenyl)-1-oxoisoindolin-5-yl)-1,5-dimethyl-1H-pyrrole-2-carbonitrile (Compound 90). [ka] To a mixture of 6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl trifluoromethanesulfonate (600 mg, 1.53 mmol), Pd(dppf)Cl₂·DCM (124.9 mg, 0.15 mmol), 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carbonitrile (751 mg, 3.05 mmol), and potassium phosphate (985 mg, 4.58 mmol) was added a solution of 1,4-dioxane and water (10:1; 8.8 mL). The reaction mixture was evacuated and purged with N₂ (3×) and heated at 120 °C under microwave irradiation. After 3 h, the reaction mixture was diluted with DCM, passed through a hydrophobic phase separator, and the organic layer was concentrated in vacuo. The residue was purified by normal phase column chromatography (0-10% DCM / MeOH). The material was then subjected to reverse phase purification (20-65% H2O:MeCN w / 0.05% NH4OH) to give the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.64(s,1H),7.57(s,1H),7.51(s,1H),7.33-7.25(m,1H),7.20(td,J=9.8,2.6Hz,1H ),7.11-7.05(m,1H),6.56(s,1H),4.45(s,2H),3.56(s,3H),1.93(s,3H);ES-MS[M+1] + :364.2.

[0256] Example 7. 6-(2,4-Difluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)isoindolin-1-one (Compound 87). [ka] To a mixture of 6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl trifluoromethanesulfonate (20 mg, 0.05 mmol), Pd(dppf)Cl₂·DCM (4.16 mg, 0.005 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (mg, mmol), and potassium phosphate (32.8 mg, 0.15 mmol) was added a solution of 1,4-dioxane and water (10:1; 352 μL). The reaction mixture was evacuated and purged with N₂ (3×) and heated to 100 °C. After 16 h, the reaction mixture was diluted with DCM, passed through a hydrophobic phase separator, and the organic layer was concentrated in vacuo. The residue was purified by normal-phase column chromatography (0–10% DCM / MeOH). The material was subjected to reverse phase purification (18-57% H2O:MeCN w / 0.05% NH4OH) to give the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.68(s,1H),7.91(d,J=2.1 Hz,1H),7.73(d,J=2.2Hz,1H),7.71(s,1H),7.63(s,1H),7.45(dd,J=3.4,2.4Hz,1H) ,7.39(td,J=8.8,6.8Hz,1H),7.08(m,2H),6.38(dd,J=3.4,1.7Hz,2H),4.49(s,2H); ES-MS[M+1] + :362.3.

[0257] Example 8. 6-(4-Fluorophenyl)-5-(6-methylpyridin-3-yl)isoindolin-1-one (Compound 6). [ka] To a mixture of 6-(4-fluorophenyl)-1-oxoisoindolin-5-yl trifluoromethanesulfonate (1 g, 2.66 mmol), Pd(dppf)Cl₂·DCM (218 mg, 0.27 mmol), (6-methylpyridin-3-yl)boronic acid (730 mg, 5.33 mmol), and potassium phosphate (574 mg, 2.66 mmol) was added a solution of 1,4-dioxane and water (5:1; 9.6 mL). The reaction mixture was evacuated and purged with N₂ (3×) and heated at 120 °C under microwave irradiation. After 3 h, the reaction mixture was diluted with DCM, dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by normal-phase column chromatography (0–10% DCM / MeOH). The material was subjected to reverse phase purification (18-59% H2O:MeCN w / 0.05% NH4OH) to give the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.68(s,1H),8.20(dd,J=2.4,0.8Hz,1H),7.65(d,J=0.7Hz,1H),7.62(s,1H),7.4 0(dd,J=8.0,2.4Hz,1H),7.22-7.09(m,5H),4.47(s,2H),2.43(s,3H);ES-MS[M+1] + :319.0.

[0258] Example 9. 3-(6-(2,4-Difluorophenyl)-1-oxoisoindolin-5-yl)-5-fluorobenzonitrile (Compound 106). [ka] To a mixture of 6-(4-fluorophenyl)-1-oxoisoindolin-5-yl trifluoromethanesulfonate (20 mg, 0.05 mmol), Pd(dppf)Cl₂·DCM (4.16 mg, 0.005 mmol), (3-cyano-5-fluorophenyl)boronic acid (16.8 mg, 0.10 mmol), and potassium phosphate (32.8 mg, 0.15 mmol) was added a solution of 1,4-dioxane and water (10:1; 600 μL). The reaction mixture was evacuated and purged with N₂ (3×) and heated to 85 °C. After 16 h, the reaction mixture was diluted with DCM, passed through a hydrophobic phase separator, and the organic layer was concentrated in vacuo. The residue was purified by reverse-phase chromatography (23–65% HO:MeCN with 0.05% NH₄OH) to give the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.78(s,1H),7.80(ddd,J=8.6,2.5,1.3Hz,1H),7.77(s,1H),7.67(s,1H),7.49(t,1.5Hz, 1H),7.45(m,1H),7.37(ddd,J=9.7,2.6,1.5Hz,1H),7.18(m,2H),4.50(s,2H);ES-MS[M+1] + :365.2.

[0259] Example 10. 6-(4-Fluorophenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)isoindolin-1-one (Compound 60). [ka] tert-Butyl 4-(6-(4-fluorophenyl)-1-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate. The title compound was prepared using a procedure similar to the preparation of compound 55. ES-MS [M+1] + :409.3.

[0260] 6-(4-Fluorophenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)isoindolin-1-one (Compound 60). To a solution of tert-butyl 4-(6-(4-fluorophenyl)-1-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (40 mg) in DCM (0.25 mL) was added TFA (0.15 mL) and the solution was stirred at ambient temperature. After 1 h, the reaction mixture was concentrated in vacuo, and the crude material was dissolved in DMSO (1 mL) and purified by RP-HPLC (5-60% MeCN / 0.05% NH4OH in water) to give the title compound. 1 H NMR(400MHz,DMSO)δ 8.56(s,1H),7.49(s,1H),7.47-7.39(m,3H),7.29-7.21(m,2H),5.71-5.64(m,1H),4. 39(s,2H),3.24(q,J=2.9Hz,2H),2.60(t,J=5.4Hz,2H),1.80-1.72(m,2H).ES-MS[M+1] + :309.1.

[0261] Example 11. 6-(4-Fluorophenyl)-5-(1,2,5,6-tetrahydropyridin-3-yl)isoindolin-1-one (Compound 61). [ka] tert-Butyl 5-(6-(4-fluorophenyl)-1-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate. The title compound was prepared using a procedure similar to the preparation of compound 55. ES-MS [M+1] + :409.2.

[0262] 6-(4-Fluorophenyl)-5-(1,2,5,6-tetrahydropyridin-3-yl)isoindolin-1-one (Compound 61). The title compound was prepared using a deprotection procedure similar to the preparation of Compound 60. 1H NMR(400MHz,DMSO)δ 8.57(s,1H),7.49(s,1H),7.48-7.41(m,3H),7.30-7.19(m,2H),5.72-5.66(m,1H),4.39(s,2H),3.00(app s,2H),2.69(t,J=5.7Hz,2H),2.06-1.96(m,2H).ES-MS[M+1] + :309.1.

[0263] Example 12. 6-(4-Fluorophenyl)-5-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)isoindolin-1-one (Compound 84). [ka] tert-Butyl 4-(6-(4-fluorophenyl)-1-oxoisoindolin-5-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate. The title compound was prepared using a procedure similar to the preparation of compound 55. ES-MS [M+1] + :423.4.

[0264] 6-(4-Fluorophenyl)-5-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)isoindolin-1-one (Compound 84). The title compound was prepared using a deprotection procedure similar to the preparation of Compound 60. 1 H NMR(400MHz,DMSO)δ 8.58(s,1H),7.48(s,1H),7.47-7.40(m,3H),7.29-7.19(m,2H),5.65(app dd,J=5.1,2.3Hz,1H),4.39(s,2H),3.17-2.97(m,2H),2.68-2.57(m,1H) ,2.11-1.98(m,1H),1.81-1.67(m,1H),1.00(d,J=6.3Hz,3H).ES-MS[M+1] + :323.3.

[0265] Example 13. 5-(3,3-Dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(4-fluorophenyl)isoindolin-1-one (Compound 76). [ka] tert-Butyl 4-(6-(4-fluorophenyl)-1-oxoisoindolin-5-yl)-3,3-dimethyl-3,6-dihydropyridine-1(2H)-carboxylate. The title compound was prepared using a procedure similar to the preparation of compound 55. ES-MS [M+1] + :437.4.

[0266] 5-(3,3-Dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(4-fluorophenyl)isoindolin-1-one (Compound 76). The title compound was prepared using a procedure similar to the preparation of Compound 60. 1 H NMR(400MHz,DMSO)δ 8.57(s,1H),7.49(s,1H),7.46-7.39(m,2H),7.30(s,1H),7.25-7.17(m,2H),5 .56(t,J=3.1Hz,1H),4.41(s,2H),3.26(d,J=3.2Hz,2H),2.36(s,2H),0.59(br s,6H).ES-MS[M+1] + :337.2.

[0267] Example 14. 5-(2,5-Dihydro-1H-pyrrol-3-yl)-6-(4-fluorophenyl)isoindolin-1-one (Compound 82). [ka] tert-Butyl 3-(6-(4-fluorophenyl)-1-oxoisoindolin-5-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate. The title compound was prepared using a procedure similar to the preparation of compound 55. ES-MS [M+1] + :395.3.

[0268] 5-(2,5-Dihydro-1H-pyrrol-3-yl)-6-(4-fluorophenyl)isoindolin-1-one (Compound 82). The title compound was prepared using a procedure similar to the preparation of Compound 60. 1 H NMR(400MHz,DMSO)δ 8.60(s,1H),7.55(s,1H),7.45(s,1H),7.40-7.34(m,2H),7.28-7.21(m,2H),5.66(p,J=2. 0Hz,1H),4.40(s,2H),3.60(td,J=4.3,2.1Hz,2H),3.46(td,J=4.3,2.0Hz,2H).ES-MS[M+1] + :295.2.

[0269] Example 15. 6-(4-Fluorophenyl)-5-(tetrahydro-2H-pyran-4-yl)isoindolin-1-one (Compound 64). [ka] To a slurry of Pd—C (10 wt%; 27 mg) in MeOH (0.5 mL) was added 5-(3,6-dihydro-2H-pyran-4-yl)-6-(4-fluorophenyl)isoindolin-1-one (20 mg). The reaction mixture was evacuated and purged with N (3×), followed by evacuating and purging with hydrogen (3×; 1 atm). After 16 h, the mixture was filtered through a pad of Celite®, and the filtrate was concentrated in vacuo to give the title compound. 1 H NMR(400MHz,DMSO)δ 8.53(s,1H),7.65(s,1H),7.39-7.33(m,3H),7.33-7.26(m,2H),4.40(s,2H),3.86(dd,J=11.6,3.9Hz,2H),3 .16(td,J=11.8,1.9Hz,2H),2.86(tt,J=11.9,3.6Hz,1H),1.82-1.67(m,2H),1.60-1.51(m,2H).ES-MS[M+1] + :312.0.

[0270] Example 16. 6-(4-Fluorophenyl)-5-(1-methylpiperidin-4-yl)isoindolin-1-one (Compound 66). [ka] The title compound was prepared using a procedure similar to the preparation of compound 64. 1 H NMR(400MHz,DMSO)δ 8.52(s,1H),7.60(s,1H),7.39-7.24(m,5H),4.39(s,2H),2.81-2.74(m,2H),2.59-2.50(m,1H),2.11(s,3H),1.79-1.55(m,6H).ES-MS[M+1] + :325.2.

[0271] Example 17. 6-(4-Fluorophenyl)-5-(1-methylpiperidin-3-yl)isoindolin-1-one (Compound 65). [ka] The title compound was prepared using a procedure similar to the preparation of compound 64. 1 H NMR(400MHz,DMSO)δ 8.53(s,1H),7.63(s,1H),7.39-7.25(m,5H),4.38(s,2H),2.84(tt,J=11.2,3.6Hz,1H ),2.74-2.61(m,2H),2.09(s,3H),1.97(t,J=10.9Hz,1H),1.90-1.79(m,1H),1.72(app d,J=12.2Hz,1H),1.66-1.58(m,1H),1.50-1.27(m,2H).ES-MS[M+1] + :325.2.

[0272] Example 18. 6-(4-Fluorophenyl)-5-(2,2,6,6-tetramethylpiperidin-4-yl)isoindolin-1-one (Compound 75). [ka] To a slurry of 20 wt% Pd(OH)-C (12 mg) in EtOH (0.5 mL) was added 6-(4-fluorophenyl)-5-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)isoindolin-1-one (63 mg) and HCONH (130 mg) under a N atmosphere. The resulting mixture was subjected to microwave irradiation at 80 °C for 15 min. The mixture was diluted with MeOH (5 mL), filtered through a pad of Celite®, and the filtrate was concentrated in vacuo to give the title compound. ES-MS [M+1] + :367.3.

[0273] Example 19. 6-(4-Fluorophenyl)-5-(piperidin-4-yl)isoindolin-1-one (Compound 67). [ka] tert-Butyl 4-(6-(4-fluorophenyl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate was prepared in a similar manner to Compound 64 and was carried on to the next step without further purification. To a solution of tert-butyl 4-(6-(4-fluorophenyl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate (40 mg) in DCM (0.25 mL) was added TFA (0.15 mL) and the solution was stirred at ambient temperature. After 1 h, the reaction mixture was concentrated in vacuo, and the crude material was dissolved in DMSO (1 mL) and purified by RP-HPLC (5-60% MeCN / 0.05% NH4OH in water) to give the title compound. 1 H NMR(400MHz,DMSO)δ 8.51(s,1H),7.59(s,1H),7.38-7.23(m,5H),4.39(s,2H),2.92(dt,J=12.1,3. 2Hz,2H),2.73-2.61(m,1H),2.34-2.21(m,2H),1.64-1.51(m,4H).ES-MS[M+1] + :311.2.

[0274] Example 20. 6-(4-Fluorophenyl)-5-(3-methylpiperidin-4-yl)isoindolin-1-one (Compound 77). [ka] The title compound was prepared using a reduction procedure similar to that used to prepare compound 75, followed by a deprotection procedure similar to that used to prepare compound 67. 1 H NMR(400MHz,DMSO)δ 8.52(s,1H),7.41(s,1H),7.38-7.23(m,5H),4.43(d,J=17.8Hz,1H),4.37(d,J=17.8Hz,1H),3.06(dt,J=12.7,3.5Hz,1H),3.00(app d,J=11.9Hz,1H),2.57(d,J=11.8Hz,1H),2.43-2.34(m,1H),2.28(dd,J=11.9,3.1Hz,1 H),2.01(qd,J=12.3,4.0Hz,1H),1.46-1.32(m,2H),0.70(d,J=7.0Hz,3H).ES-MS[M+1] + :325.2.

[0275] Example 21. 6-(4-Fluorophenyl)-5-(pyrrolidin-3-yl)isoindolin-1-one (Compound 83). [ka] The title compound was prepared using a reduction procedure similar to that used to prepare compound 75, followed by a deprotection procedure similar to that used to prepare compound 67. 1 H NMR(400MHz,DMSO)δ 8.51(s,1H),7.67(s,1H),7.39-7.25(m,5H),4.38(s,2H),3.11(p,J=8.0Hz,1H),3.05-2.93(m,2H),2.80(dt,J=10.7, 7.3Hz,1H),2.65(dd,J=10.5,7.5Hz,1H),2.01(dtd,J=12.7,8.2,4.7Hz,1H),1.70(dq,J=12.3,7.9Hz,1H).ES-MS[M+1] + :297.2.

[0276] Example 22. 6-(2,4-Difluorophenyl)-5-(2-(1-methyl-1H-pyrazol-3-yl)ethyl)isoindolin-1-one (Compound A1) [ka] 6-(2,4-Difluorophenyl)-5-((1-methyl-1H-pyrazol-3-yl)ethynyl)isoindolin-1-one. To a mixture of 6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl trifluoromethanesulfonate (100 mg, 0.25 mmol), Pd(PPh)Cl (4.47 mg, 0.006 mmol), 3-ethynyl-1-methylpyrazole (27 mg, 0.25 mmol), CuI (4.84 mg, 0.025 mmol), tetrabutylammonium iodide (14 mg, 0.038 mmol), and triethylamine (44 μL, 0.32 mmol) was added DMF (1.25 mL). The reaction mixture was heated at 110 °C. After 16 h, the reaction mixture was cooled to ambient temperature and diluted with DCM (10 mL). The reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (0-10% DCM / MeOH) to give the title compound. ES-MS [M+1] + :350.0.

[0277] 6-(2,4-Difluorophenyl)-5-(2-(1-methyl-1H-pyrazol-3-yl)ethyl)isoindolin-1-one (Compound A1). To a solution of 6-(2,4-difluorophenyl)-5-((1-methyl-1H-pyrazol-3-yl)ethynyl)isoindolin-1-one (28 mg, 0.08 mmol) in methanol (0.8 mL) was added 10% Pd / C (40 mg). The reaction atmosphere was evacuated and purged with hydrogen three times. After 3 hours, the reaction mixture was diluted with 1:1 DCM:MeOH solution, filtered over Celite®, and concentrated in vacuo. The crude residue was purified by reverse phase chromatography to give the title compound. 1H NMR(400MHz,DMSO-d6)δ 8.56(s,1H),7.62(s,1H),7.46(d,J=2.1Hz,1H),7.42-7.33(m,3H),7.20(ddd,J=8.7,7.2,2.6Hz,1H), 5.77(d,J=2.2Hz,1H),4.40(s,2H),3.70(s,3H),2.85-2.73(m,2H),2.64(t,J=8.1Hz,2H);ESI-MS[M+1] + :354.1.

[0278] Example 23. 6-(2,4-difluorophenyl)-5-(2-(1-methyl-1H-pyrazol-3-yl)ethyl-1,1,2,2-d4)isoindolin-1-one (Compound A3) [ka] To a solution of 6-(2,4-difluorophenyl)-5-((1-methyl-1H-pyrazol-3-yl)ethynyl)isoindolin-1-one (44 mg, 0.126 mmol) and methanol-OD (1.26 mL) was added 10% Pd / C (63 mg). The reaction atmosphere was evacuated and purged with deuterium gas three times. After 2 h, the reaction mixture was diluted with a 1:1 DCM:MeOH solution, filtered over Celite®, and concentrated in vacuo to give a crude residue. The crude residue was purified by normal phase flash chromatography (0-10% DCM / MeOH) to give the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.56(s,1H),7.62(s,1H),7.46(d,J=2.1Hz,1H),7.42-7.33(m,3H),7.20(td,J=8.3 ,2.6Hz,1H),5.77(d,J=2.1Hz,1H),4.40(s,2H),3.69(s,3H);ESI-MS[M+1]+:358.0.

[0279] The compounds shown in Tables 1A and 1B may be prepared similarly to the compounds described above with appropriate starting materials that are generally available from commercial sources.

[0280]

Table 1-1

[0281]

Table 1-2

[0282]

Table 1-3

[0283]

Table 1-4

[0284]

Table 1-5

[0285]

Table 1-6

[0286]

Table 1-7

[0287]

Table 1-8

[0288]

Table 1-9

[0289]

Table 1-10

[0290]

Table 1-11

[0291]

Table 1-12

[0292]

Table 1-13

[0293]

Table 1-14

[0294]

Table 1-15

[0295]

Table 1-16

[0296]

Table 1-17

[0297]

Table 1-18

[0298]

Table 1-19

[0299]

Table 1-20

[0300]

Table 1-21

[0301]

Table 1-22

[0302]

Table 1-23

[0303]

Table 1-24

[0304]

Table 1-25

[0305]

Table 1-26

[0306]

Table 1-27

[0307]

Table 1-28

[0308]

Table 1-29

[0309]

Table 1-30

[0310]

Table 1-31

[0311] [Table 1-32]

[0312] [Table 1-33]

[0313] [Table 1-34]

[0314] biological activity A. Cell lines co-expressing mGlu and GIRK Human embryonic kidney (HEK-293) cell lines stably co-expressing human or rat mGlu2 and G protein-coupled inwardly rectifying potassium (GIRK) channels, or human mGlu3 and GIRK, were used for in vitro evaluation of compound activity in thallium flux assays using fluorescent thallium indicator dyes.

[0315] B. Cell-based Tl flux assays for mGlu and GIRK activity The day before the assay, GIRK cells co-expressing human mGlu3, human, or rat mGlu2 as described above were plated at a density of 15,000 cells / 20 μL / well in assay medium (glutamine-depleted basal DMEM supplemented with 10% modified FBS, 20 mM HEPES, and 1 mM sodium pyruvate) in black-walled, clear-bottom, amine-coated 384-well plates. Cells were incubated at 37°C in the presence of 5% CO2. The following day, assay buffer (Hank's balanced salt solution, 20 mM HEPES, 4.16 mM sodium bicarbonate, pH 7.2) was prepared and the compounds and Thallos AM fluorescent dye solutions were diluted. 2x Thallos dye solution (final concentration on cells: 0.34 μM) was prepared by mixing the dye stock (2.97 mM in DMSO) 1:1 with 10% pluronic acid before adding it to assay buffer. Cells were washed with assay buffer using a microplate washer, and the medium was removed, resulting in 20 μL of buffer remaining in each well. Immediately, 20 μL of 2× Thallos dye solution was added to the cells and incubated for 1 hour at 25°C. During the cell dye loading incubation period, a 10-point concentration serial dilution of compound was obtained from a 10 mM DMSO compound stock by performing a 1:3 serial dilution in DMSO using a Bravo liquid handler. A 2× compound plate was generated by transferring 0.24 μL of diluted compound in each well to a daughter plate using an Echo acoustic liquid handler. This was further diluted in 40 μL of assay buffer, resulting in a final concentration range of 30 μM to 1.5 nM in the assay. Prepare agonist plates (5x) and measure EC2 in thallium buffer (125 mM sodium bicarbonate, 1 mM magnesium sulfate, 1.8 mM calcium sulfate, 5 mM glucose, 10 mM HEPES, pH 7.2, 12.5 mM thallium sulfate). 80 Glutamate concentrations (concentrations that elicit 80% of the maximally effective glutamate concentration) were included.

[0316] After dye addition, the cell plate was washed with assay buffer and excess extracellular dye was removed using a microplate washer, resulting in 20 μL of buffer remaining in each well. After a 10-minute equilibration period, the cell, compound, and agonist plates were loaded into a Hamamatsu μCell Kinetic Imaging Plate Reader equipped with a liquid handler that monitored changes in fluorescence at 480 nm excitation and 540 nm emission settings. Briefly, after baseline fluorescence collection, 20 μL of compound was added and incubated for 2 minutes and 20 seconds. Immediately after this, 10 μL of glutamate-thallium buffer was added to the compound-containing wells. Fluorescence signals were monitored for an additional 2.5 minutes after glutamate addition. Multiple reference wells containing no compound were used: no glutamate (for baseline reference), EC 80 Glutamic acid, or EC max Glutamate (for normalization to the maximum response) was received. Fluorescence was measured throughout the experiment at a frequency of one measurement every 2 seconds before glutamate addition and one measurement every second after glutamate addition. A concentration series of each compound was generated once on each plate, and replicates from two or three plates were used in each experimental run. Thallium solutions were handled and processed according to guidelines from the Vanderbilt University Chemical Safety Department.

[0317] Data were normalized using a static ratio function (F / F0) by dividing all fluorescence measurements by the initial fluorescence value for the corresponding well. The increase in signal resulting from the second addition of glutamate / thallium was measured by determining the slope from 3 to 13 seconds after addition. The average of all baseline slopes (no compound, no glutamate) was determined and this value was subtracted from all other slope values. All EC max Determine the average of the slopes and use this value to calculate the baseline-corrected slope as percent maximum (%E max ) for each compound in the series. maxValues ​​were plotted against the logarithm of concentration and fit to a four-parameter logistic equation with no fixed parameters.

[0318] Efficacy is derived from curve fitting, IC 50 If no plateau is reached and E max A low potency value of >10,000 nM is assigned to compounds that do not inhibit the glutamate response to less than 20% of the E. max Compounds that do not inhibit less than 60% of the E are assigned a potency of >30,000 nM. max IC from curve fitting, where the inhibition plateau is reached at 50 and assign the category of "Partial NAM."

[0319] C. Activity of compounds in the mGlu GIRK cell-based Tl flux assay The compounds were synthesized as described above. Activity (IC 50 ) was determined in the mGlu GIRK cell-based Tl flux assay as described above, and the data are shown in Tables 2, 3, and 4. Data are from a single experiment unless otherwise noted.

[0320] [Table 2-1]

[0321] [Table 2-2]

[0322] [Table 2-3]

[0323] [Table 2-4]

[0324] [Table 2-5]

[0325] [Table 2-6]

[0326] [Table 2-7]

[0327] [Table 3]

[0328] [Table 4]

[0329] It is understood that the above detailed description and accompanying examples are merely illustrative and are not to be taken as limitations on the scope of the invention, which is defined solely by the appended claims and their equivalents.

[0330] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including but not limited to, with respect to chemical structure, substituents, derivatives, intermediates, synthesis, compositions, formulations, or methods of use of the invention, may be made without departing from the spirit and scope thereof.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof 【Chemical 1】 (In the formula: R １ is independently at each occurrence hydrogen, fluoro, or C １～４ is alkyl; R ２ is hydrogen or C １～６ is alkyl; R ３ is a 6- to 12-membered aryl or a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S, where R ３ is unsubstituted or C １～４ Alkyl, halogen, cyano, C １～２ Haloalkyl, OH, —OC １～４ Alkyl, and —OC １～２ substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of haloalkyl; R ４ is G ４ , -C １～４ Alkylene-G ４ , Cy, or -C １～４ alkylene-Cy; G ４ is a 6- to 12-membered aryl or a 5- to 12-membered heteroaryl, wherein G ４ is unsubstituted or C １～４ Alkyl, halogen, cyano, C １～２ Haloalkyl, oxo, -OR ４ａ , -N(R ４ａ ) ２ , -N(R ４ａ ) C(O)R ４ａ , -N(R ４ａ ) SO ２ R ４ｂ , -C(O)N(R ４ａ ) ２ , -SO ２ N (R ４ａ ) ２ , -SO ２ R ４ｂ , -C １～４ Alkylene-OH, G ４ａ , and -C １～４ Alkylene-G ４ａ and C １～４ Alkyl, halogen, cyano, C １～２ Haloalkyl, —OC １～４ Alkyl, and —OC １～２ optionally further substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl; R ４ａ represents independently at each occurrence hydrogen, C １～４ Alkyl, C １～２ Haloalkyl, G ４ａ , or -C １～４ Alkylene-G ４ａ and R ４ｂ is C １～４ Alkyl, C １～２ Haloalkyl, G ４ａ , or -C １～４ Alkylene-G ４ａ and G ４ａ is phenyl, C ３～６ cycloalkyl, 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms, or 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms, wherein the heteroatoms in the heteroaryl and heterocyclyl are independently selected from the group consisting of O, N, and S; ４ａ is C １～４ Alkyl, C １～２ Fluoroalkyl, halogen, cyano, oxo, OH, and —OC １～４ optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl; Cy is C ３～６ carbocyclyl or a 4- to 6-membered heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of N, O, and S, where Cy is C １～４ Alkyl, C １～２ Fluoroalkyl, halogen, oxo, OH, —OC １～４ Alkyl, G ４ａ , and -C １～４ Alkylene-G ４ａ and C １～４ Alkyl, C １～２ optionally further substituted with 1 to 3 substituents independently selected from the group consisting of fluoroalkyl, and halogen; R ５ and R ６ are each independently hydrogen, C １～４ Alkyl, halogen, cyano, C １～２ Haloalkyl, —OC １～４ Alkyl, or —OC １～２ haloalkyl).

2. R １ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

3. R ２ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

4. G ４ The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is unsubstituted or substituted 5-12 membered heteroaryl.

5. G ４ The compound according to any one of claims 1 to 4, wherein the unsubstituted or substituted 5- to 12-membered heteroaryl ring system in the formula (I) is a 9- to 10-membered fully aromatic bicyclic heteroaryl, or a pharmaceutically acceptable salt thereof.

6. G ４ The compound according to any one of claims 1 to 4, wherein the unsubstituted or substituted 5- to 12-membered heteroaryl ring system in the formula (I) is a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S, or a pharmaceutically acceptable salt thereof.

7. G ４ but, 【Chemistry 2】 【Chemistry 3】 5. The compound according to any one of claims 1 to 4, wherein:

8. G ４ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is unsubstituted or substituted 6-12 membered aryl.

9. G ４ 9. The compound of any one of claims 1 to 3 or 8, wherein the unsubstituted or substituted 6-12 membered aryl ring system in the formula: is phenyl, or a pharmaceutically acceptable salt thereof.

10. G ４ 9. The compound of any one of claims 1 to 3 or 8, wherein the unsubstituted or substituted 6- to 12-membered aryl ring system in the formula (I) is phenyl fused to a 5- to 6-membered heterocycle containing 1 to 2 heteroatoms independently selected from the group consisting of O, N, and S, or a pharmaceutically acceptable salt thereof.

11. G ４ but, 【Chemistry 4】 9. The compound of claim 8, wherein:

12. R ４ But, G ４ 12. The compound according to any one of claims 1 to 11, wherein:

13. R ４ But, -C １～４ Alkylene-G ４ 12. The compound according to any one of claims 1 to 11, wherein:

14. R ４ The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein is Cy.

15. R ４ But, -C １～４ The compound according to any one of claims 1 to 11, which is alkylene-Cy, or a pharmaceutically acceptable salt thereof.

16. Cy is optionally substituted C ３～６ 16. The compound of any one of claims 1 to 11, or 14, or 15, which is carbocyclyl, or a pharmaceutically acceptable salt thereof.

17. 16. The compound of any one of claims 1 to 11, or 14, or 15, wherein Cy is an optionally substituted 4- to 6-membered heterocyclyl, or a pharmaceutically acceptable salt thereof.

18. Cy is, 【Chemistry 5】 16. The compound of any one of claims 1 to 11, 14 or 15, wherein:

19. R ３ The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein is said unsubstituted or substituted 6- to 12-membered aryl.

20. R ３ 20. The compound of any one of claims 1 to 19, wherein the unsubstituted or substituted 6- to 12-membered aryl ring system in the formula: is phenyl, or a pharmaceutically acceptable salt thereof.

21. R ３ but, 【Chemistry 6】 21. The compound of claim 20, wherein:

22. R ５ and R ６ But hydrogen, C １～４ 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein each of the radicals is independently selected from the group consisting of alkyl, and halogen.

23. R ５ and R ６ 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein each is hydrogen.

24. 6-(4-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(oxazol-5-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(pyridin-4-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-methylthiazol-5-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(6-methylpyridin-3-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-methyl-2H-indazol-5-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-methyl-2H-indazol-6-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(4-methyl-1H-indazol-5-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-methyl-1H-benzo[d]imidazol-5-yl)isoindolin-1-one; 5-(benzo[d]thiazol-6-yl)-6-(4-fluorophenyl)isoindolin-1-one; 5-(benzo[d]oxazol-5-yl)-6-(4-fluorophenyl)isoindolin-1-one; 5-(benzo[d]thiazol-5-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(isoquinolin-6-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(isoquinolin-7-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-methyl-2H-indazol-7-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(quinolin-7-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(quinolin-6-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(imidazo[1,2-a]pyridin-6-yl)isoindolin-1-one; 5-(5,8-difluoroquinolin-6-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(pyridazin-4-yl)isoindolin-1-one; 5-(benzo[d]thiazol-5-yl)-6-(2,4-difluorophenyl)isoindolin-1-one; 5-(benzo[d]oxazol-5-yl)-6-(2,4-difluorophenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2-methyl-2H-indazol-6-yl)isoindolin-1-one; 5-(6-cyclopropylpyridin-3-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(6-(trifluoromethyl)pyridin-3-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-methyl-2H-indazol-4-yl)isoindolin-1-one; 5-(2,6-dimethylpyridin-3-yl)-6-(4-fluorophenyl)isoindolin-1-one; 5-(6-fluoro-2-methylpyridin-3-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)isoindolin-1-one; 5-(2,6-difluoropyridin-3-yl)-6-(4-fluorophenyl)isoindolin-1-one; 5-(6-(4-fluorophenyl)-1-oxoisoindolin-5-yl)picolinonitrile; 5-(6-(dimethylamino)pyridin-3-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(1-methyl-1H-pyrazol-3-yl)isoindolin-1-one; N-(5-(6-(4-fluorophenyl)-1-oxoisoindolin-5-yl)pyridin-2-yl)acetamide; 5-(6-fluoro-4-methylpyridin-3-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)isoindolin-1-one; 5-(2-(dimethylamino)pyridin-3-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-fluoropyridin-3-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-methylpyridin-3-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-isopropylpyridin-3-yl)isoindolin-1-one; 5-(2-cyclopropylpyridin-3-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(pyridin-3-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(pyridin-2-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(6-methylpyridazin-4-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(3-methyl-1H-indazol-5-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(4-methylpyridin-3-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(1H-indol-5-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(p-tolyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(5-methylpyridin-2-yl)isoindolin-1-one; 4-(6-(4-fluorophenyl)-1-oxoisoindolin-5-yl)-1,5-dimethyl-1H-pyrrole-2-carbonitrile; 6-(4-fluorophenyl)-5-(4-methoxycyclohex-1-en-1-yl)isoindolin-1-one; 5-(3,6-dihydro-2H-pyran-4-yl)-6-(4-fluorophenyl)isoindolin-1-one; 5-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(1,2,5,6-tetrahydropyridin-3-yl)isoindolin-1-one; 5-(2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(4-fluorophenyl)isoindolin-1-one; 5-cyclohexyl-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(tetrahydro-2H-pyran-4-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(1-methylpiperidin-3-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(1-methylpiperidin-4-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(piperidin-4-yl)isoindolin-1-one; 5-(2,6-dimethylpiperidin-4-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(6-methylpyridin-3-yl)isoindolin-1-one; 5-(6-cyclopropylpyridin-3-yl)-6-(2,4-difluorophenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2-(dimethylamino)pyridin-3-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2-fluoropyridin-3-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2-methylpyridin-3-yl)isoindolin-1-one; 5-(2-cyclopropylpyridin-3-yl)-6-(2,4-difluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2,2,6,6-tetramethylpiperidin-4-yl)isoindolin-1-one; 5-(3,3-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(3-methylpiperidin-4-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(piperidin-3-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(6-(trifluoromethyl)pyridin-3-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1-methyl-1H-pyrazol-3-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(6-fluoro-4-methylpyridin-3-yl)isoindolin-1-one; 5-(2,5-dihydro-1H-pyrrol-3-yl)-6-(4-fluorophenyl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(pyrrolidin-3-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)isoindolin-1-one; 6-(4-fluorophenyl)-5-(2-methylpiperidin-4-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(pyridin-3-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1H-indol-5-yl)isoindolin-1-one; 4-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-1,5-dimethyl-1H-pyrrole-2-carbonitrile; 3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-5-methylbenzonitrile; 5-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-2-methoxybenzonitrile; 5-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-2-fluorobenzonitrile; 3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-2-fluorobenzonitrile; 3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-5-methoxybenzonitrile; 3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-4-methylbenzonitrile; 6-(2,4-difluorophenyl)-5-(1,2,5-trimethyl-1H-pyrrol-3-yl)isoindolin-1-one; 3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-1,5-dimethyl-1H-pyrrole-2-carbonitrile; 3-(4-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-1H-pyrazol-1-yl)benzonitrile; 6-(2,4-difluorophenyl)-5-(2-methoxypyridin-3-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(5-methoxypyridin-3-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2-(pyrrolidin-1-yl)pyridin-3-yl)isoindolin-1-one; 4-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-3-fluorobenzonitrile; 4-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)picolinonitrile; 6-(2,4-difluorophenyl)-5-(4-fluoro-2-methoxyphenyl)isoindolin-1-one; 3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-5-fluorobenzonitrile; 3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)benzonitrile; 5-(1-cyclopropyl-1H-pyrazol-3-yl)-6-(2,4-difluorophenyl)isoindolin-1-one; 3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-2-methylbenzonitrile; 6-(2,4-difluorophenyl)-5-(2-(trifluoromethyl)pyridin-3-yl)isoindolin-1-one; 4-(4-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-1H-pyrazol-1-yl)benzonitrile; 6-(2,4-difluorophenyl)-5-(3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(4-(4-methylpiperazin-1-yl)phenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)isoindolin-1-one; 4-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-1-methyl-1H-pyrazole-5-carbonitrile; N-(3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)phenyl)methanesulfonamide; 3-chloro-5-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-N-methylbenzamide; 3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-N-isopropylbenzamide; 3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-N-methylbenzenesulfonamide; N-(2-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)phenyl)acetamide; 3-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-4-fluoro-N-methylbenzamide; 6-(2,4-difluorophenyl)-5-(3-(methylsulfonyl)phenyl)isoindolin-1-one; 2-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-5-fluorobenzonitrile; 2-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)benzonitrile; 4-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 6-(2,4-difluorophenyl)-5-(3,5-dimethylisoxazol-4-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1-(methylsulfonyl)-1H-pyrazol-4-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2-(methylsulfonyl)phenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1-isobutyl-1H-pyrazol-4-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)isoindolin-1-one; 5-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-6-(2,4-difluorophenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1-isopropyl-1H-pyrazol-4-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1-ethyl-1H-pyrazol-4-yl)isoindolin-1-one; 5-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridin-3-yl)-6-(2,4-difluorophenyl)isoindolin-1-one; 6'-(2,4-difluorophenyl)-[4,5'-bisisoindoline]-1,1'-dione; 5-(2-aminophenyl)-6-(2,4-difluorophenyl)isoindolin-1-one; 4-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-3-fluorobenzonitrile; 3-(1-oxo-6-(2,3,4-trifluorophenyl)isoindolin-5-yl)benzonitrile; 3-(1-oxo-6-(2,4,5-trifluorophenyl)isoindolin-5-yl)benzonitrile; 2-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-5-fluorobenzonitrile; 3-(6-(2-fluoro-4-methylphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(4-fluoro-2-methylphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(2-fluoro-4-(trifluoromethyl)phenyl)-1-oxoisoindolin-5-yl)benzonitrile; 6-(2,4-difluorophenyl)-5-(3-(2-hydroxypropan-2-yl)phenyl)isoindolin-1-one; 5-(3-(1H-pyrazol-1-yl)phenyl)-6-(2,4-difluorophenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)isoindolin-1-one; 5-(2-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-5-yl)-6-(2,4-difluorophenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2,3-dihydrobenzofuran-7-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2-(4-methylpiperazin-1-yl)phenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(3-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(3-(1-(methyl-d ３ )-1H-1,2,3-triazol-5-yl)phenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(3-(1-(ethyl-1,1-d ２ )-1H-1,2,3-triazol-5-yl)phenyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)isoindolin-1-one; 3-(6-(4-fluoro-2-methoxyphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(2-fluoro-4-methoxyphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(3,4-difluorophenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(2-fluorophenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(1-oxo-6-(2,4,6-trifluorophenyl)isoindolin-5-yl)benzonitrile; 3-(6-(2,4-dimethylphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(4-(difluoromethoxy)-2-fluorophenyl)-1-oxoisoindolin-5-yl)benzonitrile; N-(2-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)phenyl)-1-methyl-1H-1,2,3-triazole-4-sulfonamide; N-(2-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)phenyl)-2-methylthiazole-5-sulfonamide; N-(2-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide; 4-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-3-methoxybenzonitrile; 4-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-2-fluorobenzonitrile; 3-(6-(2-fluoro-4-hydroxyphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(2-chloro-4-fluorophenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(2-fluoro-5-methoxyphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(3-fluoro-4-methoxyphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 5-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-2-methoxybenzonitrile; 3-(6-(2-chloro-4-methoxyphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(2,5-difluoro-4-methoxyphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(4-methoxy-2-methylphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-4-fluorobenzonitrile; 3-(6-(2,4-difluoro-5-methylphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 5-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-2-fluorobenzonitrile; 4-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-2-(trifluoromethyl)benzonitrile; 3-(6-(2-fluoro-5-(trifluoromethyl)phenyl)-1-oxoisoindolin-5-yl)benzonitrile; 4-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-5-fluoro-2-methylbenzonitrile; 3-(6-(3,5-difluoro-4-methoxyphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-2-fluorobenzonitrile; 3-(6-(2,3-difluoro-4-methoxyphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(2,5-difluorophenyl)-1-oxoisoindolin-5-yl)benzonitrile; 3-(6-(5-fluoro-2-methoxyphenyl)-1-oxoisoindolin-5-yl)benzonitrile; 2-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-4-fluorobenzonitrile; 3-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-4-methylbenzonitrile; 3-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-5-fluorobenzonitrile; 6-(2,4-difluorophenyl)-5-(2-(1-methyl-1H-pyrazol-3-yl)ethyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2-(pyrimidin-5-yl)ethyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2-(1-methyl-1H-pyrazol-3-yl)ethyl-1,1,2,2-d ４ ) isoindolin-1-one; 3-(2-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)ethyl)benzonitrile; 6-(2,4-difluorophenyl)-5-(2-(1-methyl-1H-pyrazol-3-yl)ethyl-1,1,2,2-d ４ ) Isoindolin-1-one-3,3-d ２ ; 6-(2,4-difluorophenyl)-5-(2-(1-methyl-1H-pyrazol-5-yl)ethyl-1,1,2,2-d ４ ) isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(2-(1-methyl-1H-pyrazol-5-yl)ethyl)isoindolin-1-one; 5-(2-(1-cyclopropyl-1H-pyrazol-3-yl)ethyl)-6-(2,4-difluorophenyl)isoindolin-1-one; 3-(2-(6-(2,4-difluorophenyl)-1-oxoisoindolin-5-yl)ethyl)-1-methyl-1H-pyrazole-5-carbonitrile; 6-(2,4-difluorophenyl)-5-(thiomorpholinomethyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-(morpholinomethyl)isoindolin-1-one; 6-(2,4-difluorophenyl)-5-((3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)methyl)isoindolin-1-one 10. The compound of claim 1 selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

26. A method for treating metabotropic glutamate receptor 2 (mGluR2) comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 25. ２ 2. A method for treating a disease or disorder associated with dysfunction of the thyroid gland (thyroid hormone).

27. 27. The method of claim 26, wherein the disease or disorder is selected from at least one of depression, anxiety, obsessive-compulsive disorder, cognitive impairment, Alzheimer's disease, and autism spectrum disorder.

28. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 25, for use in treating a disease or disorder selected from at least one of depression, anxiety, obsessive-compulsive disorder, cognitive impairment, Alzheimer's disease, and autism spectrum disorder.

29. Use of a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 25, in the manufacture of a medicament for the treatment of a disease or disorder selected from at least one of depression, anxiety, obsessive-compulsive disorder, cognitive impairment, Alzheimer's disease, and autism spectrum disorder.

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