Negative allosteric modulator of metabotropic glutamate receptor 2

Abstract

The report describes 6-arylisoindorin-1-one as a negative allosteric modulator of metabotropic glutamate receptor 2 (mGlu2), pharmaceutical compositions comprising these compounds, and methods of using the compounds and compositions to treat depression, anxiety, obsessive-compulsive disorder, cognitive impairment, Alzheimer's disease, or autism spectrum disorder in subjects.

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 487,786, filed on 1 March 2023, which is incorporated in its entirety by reference herein.

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

[0003] Metabotropic glutamate (mGlu) receptors, a type of G protein-coupled receptor (GPCR) family C, have recently emerged as targets with potential therapeutic value. They bind glutamate, an amino acid that is the most dominant excitatory neurotransmitter in the human central nervous system (CNS). It is known that mGlu activates a biochemical cascade, leading to modifications of other proteins. For example, this can result in changes in synaptic excitability by presynaptic inhibition of neurotransmission or by modulation, or even induction, of postsynaptic responses.

[0004] Metabotropic glutamate receptor 2 (mGlu2) is one of eight mGlu receptors that have been identified and, along with mGlu3, is classified as a group II mGlu. Among the others, group II mGlu plays a crucial role in synaptic plasticity, directly impacting cognitive function (including learning and memory). The effects of group II mGlu occur primarily presynaptically through their inhibition of glutamate release. These effects may also be due to the inhibition of non-vesicular glutamate release from glial cells. However, it is also known that group II receptors reduce postsynaptic potential activity in the cortex, both excitatory and inhibitory.

[0005] Dysfunction of mGlu2 has been associated with many diseases and / or disorders. Therefore, targeting mGlu2 activity has been the subject of many studies. Several reports have highlighted its relevance to 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,

Chemical formula

[0007] In another embodiment, 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 embodiment, the present invention provides a method for treating a disease or disorder associated with metabolic glutamate receptor 2 (mGlu2) dysfunction, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, to a subject in need thereof.

[0009] In another embodiment, the present invention provides a method for 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 embodiment, the present invention provides a method for 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 a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, to a subject in need thereof.

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

[0012] In another embodiment, 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 embodiment, the present invention provides a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, and instructions for use. [Modes for carrying out the invention]

[0014] Detailed explanation Disclosed herein are negative allosteric modulators (NAMs) of mGlu2. The modulator may be a compound of formula (I). Compounds of formula (I) may exhibit greater selectivity for mGlu2 than other mGlu receptors. By modulating mGlu2 activity using compounds of formula (I), mGlu2-associated diseases and disorders can be treated or prevented. mGlu2 has been associated with several different diseases and disorders, including, but is 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, there are few selective modulators of mGlu that have been identified to bind at orthosteric sites. One strategy for selectively binding and regulating mGlu involves identifying allosteric sites that are susceptible to regulation by small molecules. In particular, negative allosteric regulation of mGlu2 may lead to inhibition of processes governed by mGlu2 and offer 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 those commonly understood by those skilled in the art. In case of any conflict, this specification shall prevail, including the definitions. Preferred methods and materials are described below, but similar or equivalent methods and materials may be used in the implementation or testing described herein. All publications, patent applications, patents and other references referred herein are incorporated herein by reference in their entirety. The materials, methods and examples disclosed herein are illustrative and not intended to be limiting.

[0017] The terms “include,” “contain,” “have,” “possess,” “can contain,” and their variations are intended, when used herein, to be unrestricted transitional phrases, terms, or words that do not preclude the possibility of additional actions or structures. The singular forms “a,” “an,” and “the” refer to multiple things unless otherwise explicitly indicated by the context. This disclosure also intends other embodiments that “include,” “consist of,” and “be essentially derived from” the embodiments or elements provided herein, whether expressly or not.

[0018] The modifier "approximately" used in relation to quantity includes the stated value and has a meaning determined by the context (for example, it includes the smallest degree of error associated with measuring a particular quantity). The modifier "approximately" should also be considered to reveal a range defined by the absolute values ​​of two endpoints. For example, the expression "approximately 2 to approximately 4" also reveals the range "2 to 4". The term "approximately" can refer to plus or minus 10% of a given number. For example, "approximately 10%" can indicate a range of 9% to 11%, and "approximately 1" can mean 0.9 to 1.1. Other meanings of "approximately," such as rounding, may be evident from the context, and therefore, for example, "approximately 1" can also mean 0.5 to 1.4.

[0019] The definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this disclosure, chemical elements are defined as follows: Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Identification follows the Ed. (inside cover), and specific functional groups are generally defined as described therein. Furthermore, general principles of organic chemistry, as well as specific functional groups and reactivity, are as follows: Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March 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 This is described in Edition, Cambridge University Press, Cambridge, 1987 (the entire contents of each of these are incorporated herein by reference).

[0020] As used herein, the term "alkoxy" refers to the -O-alkyl group. Representative examples of alkoxys 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 term "lower alkyl" or "C" 1-6 "Alkyl" refers to a straight-chain or branched-chain hydrocarbon containing 1 to 6 carbon atoms. 1-4 "Alkyl" refers to a linear or branched hydrocarbon containing 1 to 4 carbon atoms. Representative examples of alkyls, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 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] As used herein, the term "alkenyl" means a linear 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, which is attached to the parent molecule via an alkyl group as defined herein.

[0024] The term "alkoxyfluoroalkyl," as used herein, refers to an alkoxy group as defined herein that is attached to the parent molecule via a fluoroalkyl group as defined herein.

[0025] As used herein, the term "alkylene" refers to a divalent group derived from a straight-chain or branched-chain saturated hydrocarbon. Representative examples of alkylenes include, but are not limited to, -CH2-, -CD2-, -CH2CH2-, -C(CH3)(H)-, -C(CH3)(D)-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2-.

[0026] The term "alkylamino," as used herein, means at least one alkyl group as defined herein, which is attached to the parent molecule via an amino group as defined herein.

[0027] As used herein, the term "amide" means -C(O)NR- or NRC(O)- (wherein R can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, alkenyl, or heteroalkyl).

[0028] The term "aminoalkyl," as used herein, means at least one amino group, as defined herein, attached to the parent molecule via an alkylene group, as defined herein.

[0029] The term "amino" as used herein is -NR x R y (In the formula, R x and R y (which can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, alkenyl or heteroalkyl). If aminoalkyl or amino is any other part to which two other parts are added together, amino is -NR x -(In the formula, R x (This can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, alkenyl, or heteroalkyl.)

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

[0031] The term "cyanoalkyl," as used herein, means at least one -CN group attached to the parent molecule via an alkylene group as defined herein.

[0032] The term "cyanofluoroalkyl," as used herein, means at least one -CN group attached to the parent molecule via a fluoroalkyl group as defined herein.

[0033] As used herein, the term "cycloalkoxy" refers to a cycloalkyl group as defined herein, which is attached to the parent molecule via an oxygen atom.

[0034] As used herein, the terms “cycloalkyl” or “cycloalkane” refer to a saturated ring system containing all carbon atoms and zero double bonds as ring members. The term “cycloalkyl” is used herein to refer to cycloalkanes when present as substituents. Cycloalkyls can be monocyclic cycloalkyls (e.g., cyclopropyl), condensed bicyclic cycloalkyls (e.g., decahydronaphthalenyl), or bridged cycloalkyls (where two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms) (e.g., bicyclo[2.2.1]heptanyl). Representative examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclo[1.1.1]pentanyl.

[0035] The terms "cycloalkenyl" or "cycloalkene," as used herein, mean a non-aromatic monocyclic or polycyclic ring system having all carbon atoms as ring members, at least one carbon-carbon double bond, and preferably 5 to 10 carbon atoms per ring. The term "cycloalkenyl" is used herein to refer to cycloalkenes when present as substituents. Cycloalkenyls can be monocyclic cycloalkenyls (e.g., cyclopentenyl), fused bicyclics (e.g., octahydronaphthalenyl), or bridged cycloalkenyls (where two non-adjacent atoms of the ring are linked 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.

[0036] The term "carbocyclyl" means "cycloalkyl" or "cycloalkenyl." The term "carbocyclic ring" means "cycloalkane" or "cycloalkene." The term "carbocyclyl" refers to a "carbocyclic ring" when it exists as a substituent.

[0037] The terms cycloalkylene and heterocyclylene refer to the divalent group derived from the base ring, i.e., the cycloalkane or heterocycline. For illustrative purposes, examples of cycloalkylene and heterocyclylene include, [ka] This includes cycloalkylenes and heterocyclylenes, which have geminal divalent groups, e.g., 1,1-C 3~6 Cycloalkylene (that is, [ka] ) includes. Further examples include 1,1-cyclopropylene (i.e., [ka] )

[0038] The term "fluoroalkyl," 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 fluorine. Representative examples of fluoroalkyls, but not limited to these, include 2-fluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trifluoropropyl, such as 3,3,3-trifluoropropyl.

[0039] The term "fluoroalkylene," as used herein, means an alkylene group as defined herein, in which 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms are replaced by fluorine. Representative examples of fluoroalkyls, but not limited to these, include -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] As used herein, the term "haloalkyl" means an alkyl group as defined herein, in which one, two, three, four, five, six, seven, or eight hydrogen atoms are replaced by halogens.

[0042] As used herein, the term "haloalkoxy" means at least one haloalkyl group, as defined herein, that is attached to the parent molecule via an oxygen atom.

[0043] As used herein, the term "halocycloalkyl" means a cycloalkyl group as defined herein, in which one or more hydrogen atoms are replaced by halogens.

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

[0045] As used herein, the term "heteroaryl" 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 also used herein to refer to heteroarenes when present as substituents. A monocyclic heteroaryl is a five- or six-membered ring containing at least one heteroatom independently selected from the group consisting of N, O, and S (for example, one, two, three, or four heteroatoms independently selected from the group consisting of O, S, and N). A five-membered aromatic monocyclic ring has two double bonds, and a six-membered aromatic monocyclic ring has three double bonds. Bicyclic heteroaryl groups are 8-12 membered ring systems, including fused bicyclic heteroaromatic ring systems (i.e., 10π electron systems), such as monocyclic heteroaryl rings fused with 6-membered allenes (e.g., quinoline-4-yl, indole-1-yl), monocyclic heteroaryl rings fused with monocyclic heteroarenes (e.g., naphthilidinyl), and phenyl groups fused with monocyclic heteroarenes (e.g., quinoline-5-yl, indole-4-yl). Bicyclic heteroaryl / heteralene groups include 9-membered fused bicyclic heteroaromatic ring systems having four double bonds and at least one heteroatom that donates 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 heteroaryls also include fused bicyclic systems consisting of one heteroaromatic ring and one nonaromatic 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 heterocycle (e.g., 2,3-dihydroflu[3,2-b]pyridinyl). The bicyclic heteroaryl is attached to the parent molecule at the aromatic ring atom.Other typical examples of heteroaryls include, but are not limited to, indolyl (e.g., indole-1-yl, indole-2-yl, indole-4-yl), pyridinyl (including pyridine-2-yl, pyridine-3-yl, pyridine-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl (e.g., pyrazole-4-yl), pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl (e.g., triazole-4-yl), 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl (e.g., thiazolyl-4-yl), isothiazolyl, thienyl, benzimidazolyl (e.g., Examples include benzimidazole-5-yl), benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzofuranil, isobenzofuranil, furanil, oxazolyl, isoxazolyl, prinyl, isoindolyl, quinoxalinil, indazolyl (e.g., indazole-4-yl, indazole-5-yl), quinazolinil, 1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinil, quinolinil, imidazo[1,2-a]pyridinyl (e.g., imidazo[1,2-a]pyridinyl), naphthilidinyl, pyridoimidazolyl, thiazolo[5,4-b]pyridinyl, and thiazolo[5,4-d]pyrimidine-2-yl.

[0046] The terms “heterocyclic” or “heterocyclic” as used herein mean monocyclic, bicyclic, or tricyclic heterocyclic rings. The term “heterocyclyl” is used herein to refer to a heterocyclic ring when it exists as a substituent. A monocyclic heterocyclic ring 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 0 or 1 double bond and 1 heteroatom selected from the group consisting of O, N, and S. A 5-membered ring contains 0 or 1 double bond and 1, 2, or 3 heteroatoms selected from the group consisting of O, N, and S. A 6-membered ring contains 0, 1, or 2 double bonds and 1, 2, or 3 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, though not limited to them, include azetidinyl, azepanyl, azilidinyl, 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, ox Examples include cetanyl, oxepanil, oxocanil, piperazinil, piperidinil, pyranil, pyrazolinil, pyrazolidinil, pyrrolinil, pyrrolidinil, tetrahydrofuranil, tetrahydropyranil, tetrahydropyridinil, tetrahydrothienyl, thiadiazolinil, thiadiazolidinil, 1,2-thiadinil, 1,3-thiadinil, thiazolinil, thiazolidinil, thiomorpholinil, 1,1-dioxidethiomorpholinil (thiomorpholine sulfone), thiopyranil, and trithianil.A bicyclic heterocycle is a monocyclic heterocycle fused with a 6-membered allene, or a monocyclic heterocycle fused with a monocyclic cycloalkane, or a monocyclic heterocycle fused with a monocyclic cycloalkene, or a monocyclic heterocycle fused with a monocyclic heterocycle, or a monocyclic heteroelene, or a spiroheterocyclic group, or a bridging monocyclic heterocycle system (where 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). In bicyclic heterocyclyls, the parent molecule is bonded at a non-aromatic ring atom (e.g., indoline-1-yl). Representative examples of bicyclic heterocyclils, though not limited to them, include croman-4-yl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzotin-2-yl, 1,2,3,4-tetrahydroisoquinoline-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), and azabicyclo[3.1.0]hexanyl (3-azabicyclo[3.1.0]hexane). Examples include (including -3-yl), 2,3-dihydro-1H-indole-1-yl, isoindorin-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]hexane-6-yl. Tricyclic heterocycles are exemplified by bicyclic heterocycles fused with a 6-membered allene, or bicyclic heterocycles fused with a monocyclic cycloalkane, or bicyclic heterocycles fused with a monocyclic cycloalkene, or bicyclic heterocycles fused with a monocyclic heterocycle, or bicyclic heterocycles in which two non-adjacent atoms of a 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 heterocyclines are linked to the parent molecule at the non-aromatic ring atom.

[0047] The term "hydroxyl" or "hydroxy" as used herein means the -OH group.

[0048] The term "hydroxyalkyl," as used herein, means at least one -OH group attached to the parent molecule via an alkylene group as defined herein.

[0049] The term "hydroxyfluoroalkyl," as used herein, means at least one -OH group attached to the parent molecule via a fluoroalkyl group as defined herein.

[0050] Terms such as "alkyl," "cycloalkyl," and "alkylene" are symbols that indicate the number of atoms present in the group in a specific example (for example, "C"). 1~4 Alkyl," "C 3~6 Cycloalkyl, C 1~4 The term "alkylene" may be preceded by "C". These symbols are used in the same way as is generally understood by those skilled in the art. For example, the expression "C" followed by a subscript number indicates the number of atoms present in the following group. Thus, "C3 alkyl" is an alkyl group containing three carbon atoms (i.e., n-propyl, isopropyl). 1~4 When a range is given, as in "C", the members of the subsequent group may have any number of carbon atoms within the indicated range. 1~4"Alkyl" refers to an alkyl group having 1 to 4 carbon atoms, regardless of its configuration (i.e., linear or branched).

[0051] The term "substituted" refers to a group that may be further substituted with one or more substituents other than hydrogen. Substituents include, but are not limited to, halogens, =O (oxo), =S (thioxo), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, 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] With respect to the compounds described herein, the groups and substituents can be selected and substituted according to the recognized valencies of the atoms and substituents, such that a stable compound (for example, one that does not spontaneously undergo transformations such as rearrangement, cyclization, or elimination) is obtained.

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

[0054] An unsubstituted or substituted ring, such as aryl, heteroaryl, etc. (i.e., optionally substituted), is composed of a ring system and any substituents of the ring system. Therefore, since the ring system can be defined independently of its substituents, by redefining only the ring system, all previous arbitrary substituents remain present. For example, a 5- to 12-member heteroaryl having any substituents can be further defined by specifying that the ring system of the 5- to 12-member heteroaryl is a 5- to 6-member heteroaryl (i.e., a 5- to 6-member heteroaryl ring system). In this case, unless otherwise indicated, any substituents of the 5- to 12-member heteroaryl still exist on the 5- to 6-member heteroaryl.

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

[0056] In the following, embodiments of the present invention are disclosed. The first embodiment is represented as E1, and other embodiments are represented as E2.1, E2.2, E2.3, E2.4, E3, etc.

[0057] E1. A compound of formula (I), or a pharmaceutically acceptable salt thereof

Chemical formula

[0058] E2.1.R 1a However, a compound of E1 that is hydrogen, or a pharmaceutically acceptable salt thereof.

[0059] E2.2.R 1a However, C 1~4 A compound of type E1 that is alkyl (e.g., methyl, ethyl), or a pharmaceutically acceptable salt thereof.

[0060] E2.3.R 1b However, it is a compound of E1, E2.1, or E2.2, which is hydrogen, or a pharmaceutically acceptable salt thereof.

[0061] E2.4.R 1b However, C 1~4 A compound of any of the following classes, E1, E2.1, or E2.2, which is alkyl (e.g., methyl, ethyl), or a pharmaceutically acceptable salt thereof.

[0062] E3.R 2 However, it is hydrogen, one of the compounds E1 to E2.4, or a pharmaceutically acceptable salt thereof.

[0063] E4.G 6 However, one of the E1 to E3 compounds, or a pharmaceutically acceptable salt thereof, is either unsubstituted or substituted 5- to 12-membered heteroaryl.

[0064] E5.G 6 A compound from E1 to E4, or a pharmaceutically acceptable salt thereof, wherein the unsubstituted or substituted 5-12 member heteroaryl ring system is a 9-10 member fully aromatic bicyclic heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S.

[0065] E5.1.G 6Compounds of type E5, or pharmaceutically acceptable salts thereof, wherein the 9-10 membered fully aromatic bicyclic heteroaryl ring system in the compound is quinolinyl, isoquinolinyl, quinoxalinyl, imidazo[1,2-a]pyridinyl, or benzo[b]thiophenyl.

[0066] E5.2.G 6 Compounds of E5.1, or pharmaceutically acceptable salts thereof, wherein the 9-10 membered fully aromatic bicyclic heteroaryl ring system in is quinoline-3-yl, quinoline-6-yl, quinoline-7-yl, isoquinoline-6-yl, isoquinoline-7-yl, quinoxaline-6-yl, imidazo[1,2-a]pyridine-6-yl, or benzo[b]thiophene-2-yl.

[0067] E5.3.G 6 However, C 1~4 A compound from E5 to E5.2, or a pharmaceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from the group consisting of alkyl and halogen (e.g., methyl and fluoro) elements.

[0068] E5.4.G 6 but, [ka] The E5.3 compound, or a pharmaceutically acceptable salt thereof.

[0069] E6.G 6 One of the compounds E1 to E4, or a pharmaceutically acceptable salt thereof, wherein the unsubstituted or substituted 5- to 12-membered heteroaryl ring system is a 5- to 6-membered monocyclic heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S.

[0070] E6.1.G 6Compounds of type E6, or pharmaceutically acceptable salts thereof, wherein the 5-6 membered monocyclic heteroaryl ring system in is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, pyridinyl, pyridadinyl, or pyrimidinyl.

[0071] E6.2. G 6 Compounds of E6.1, or pharmaceutically acceptable salts thereof, wherein the 5-6 membered monocyclic heteroaryl ring system in is 1H-pyrazole-3-yl, 1H-pyrazole-4-yl, 1H-pyrazole-5-yl, 1H-imidazole-5-yl, oxazole-5-yl, isoxazole-4-yl, 1H-pyrrole-3-yl, furan-2-yl, thiophene-3-yl, thiazole-5-yl, isothiazole-4-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyridazine-4-yl, or pyrimidine-5-yl.

[0072] E6.3.G 6 However, C 1~4 Alkyl, halogen, cyano, C 1~2 Haloalkyl, -OR 6a , -N(R 6a )2, -N(R 6a )C(O)R 6a ,-C(O)N(R 6a )2, -SO2N(R 6a )2, -SO2R 6b , -C 1~4 Alkylene-OH, G 6a , and -C 1~4 Alkilen-G 6a It is optionally substituted with one substituent selected from the group consisting of and C 1~4 Alkyl, halogen, cyano, C 1~2 Haloalkyl, -OC 1~4 Alkyl and -OC 1~2 A compound from E6 to E6.2, or a pharmaceutically acceptable salt thereof, which is optionally further substituted with one or two substituents independently selected from the group consisting of haloalkyl groups.

[0073] E6.4.G6 However, C 1~4 Alkyl, halogen, cyano, C 1~2 Haloalkyl, -OR 6a , -N(R 6a )2, -SR 6a , -N(R 6a )C(O)R 6a , -C 1~4 Alkylene-OH, G 6a , and -C 1~4 Alkilen-G 6a It is optionally substituted with one substituent selected from the group consisting of and C 1~4 Alkyl, halogen, cyano, C 1~2 Haloalkyl, -OC 1~4 Alkyl and -OC 1~2 Compounds of E6.3, or pharmaceutically acceptable salts thereof, that are optionally further substituted with a haloalkyl group.

[0074] E6.5.G 6 but, [ka] [ka] A compound of any type E6 to E6.4, or a pharmaceutically acceptable salt thereof.

[0075] E6.6. G 6a However, C 1~4 C is optionally substituted with 1-2 substituents independently selected from the group consisting of alkyls and halogens. 3~6 A cycloalkyl compound in the range E6 to E6.5, or a pharmaceutically acceptable salt thereof.

[0076] E6.7.G 6a However, non-substituted C 3~6 A cycloalkyl compound in the range E6 to E6.6, or a pharmaceutically acceptable salt thereof.

[0077] E6.8.G 6aHowever, it is a 4-6 membered heterocycline containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S, where the heterocycline is C 1~4 A compound in the E6 to E6.5 class, or a pharmaceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from the group consisting of alkyl and halogen compounds.

[0078] E6.9.G 6a However, the compound is an unsubstituted 4-6 membered heterocycline containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S, and is classified as E6-E6.5 or E6.8, or a pharmaceutically acceptable salt thereof.

[0079] E6.10 G 6a The ring system of 4-6 member heterocyclyls in [ka] A compound in the range of E6-E6.5 or E6.8-E6.9, or a pharmaceutically acceptable salt thereof.

[0080] E6.11.R 6a However, each time it appears, independently of hydrogen or C 1~4 Alkyl (e.g., methyl); R 6b However, each time it appears, C 1~4 A compound in the E6-E6.10 range that is alkyl (e.g., methyl), or a pharmaceutically acceptable salt thereof.

[0081] E6.12.G 6 but, [ka] [ka] A compound from E6 to E6.11, or a pharmaceutically acceptable salt thereof.

[0082] E6.13.G 6 but, [ka] The E6.12 compound, or a pharmaceutically acceptable salt thereof.

[0083] E7.G 6 However, one of the E1-E3 compounds, or a pharmaceutically acceptable salt thereof, is an unsubstituted or substituted 4-12 member heterocycline.

[0084] E8.G 6 The ring system of an unsubstituted or substituted 4-12 member heterocyclil in is a 4-7 member monocyclic heterocyclil, a 6-12 member bridged bicyclic heterocyclil, a 6-12 member spirocyclic heterocyclil, or an 8-12 member condensed bicyclic heterocyclil, wherein the heterocyclil contains one E1-E3 or E7 compound, or a pharmaceutically acceptable salt thereof, containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S.

[0085] E8.1.G 6 A compound of type E8, or a pharmaceutically acceptable salt thereof, wherein the ring system of an unsubstituted or substituted 4- to 12-membered heterocyclil is a 4- to 7-membered monocyclic heterocyclil, and the heterocyclil contains 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S.

[0086] E8.2.G 6 Compounds of E8.1, or pharmaceutically acceptable salts thereof, wherein the unsubstituted or substituted 4- to 12-membered heterocyclyl ring system in is thiomorpholinyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, dihydropyrrolyl, dihydropyranyl, tetrahydropyranyl, dihydropyridinyl, or tetrahydropyridinyl.

[0087] E8.3.G 6Compounds of E8.2, or pharmaceutically acceptable salts thereof, wherein the unsubstituted or substituted 4- to 12-membered heterocyclyl ring system in is thiomorpholino, morpholino, morpholin-3-yl, piperidine-1-yl, piperidine-3-yl, piperidine-4-yl, pyrrolidine-1-yl, azetidine-1-yl, 2,5-dihydro-1H-pyrrole-3-yl, 3,4-dihydro-2H-pyran-6-yl, tetrahydro-2H-pyran-2-yl, 1,2-dihydropyridine-3-yl, 1,6-dihydropyridine-3-yl, or 1,2,5,6-tetrahydropyridine-3-yl.

[0088] E8.4.G 6 However, C 1~4 Alkyl, halogen, cyano, C 1~2 Haloalkyl, oxo, -OR 6a , -N(R 6a )2, -C(O)OR 6a , -C 1~4 Alkylene-OH, G 6a , and -C 1~4 Alkilen-G 6a It is optionally substituted with one substituent selected from the group consisting of and C 1~4 Alkyl, halogen, cyano, C 1~2 Haloalkyl, oxo, -OC 1~4 Alkyl and -OC 1~2 A compound from E8.1 to E8.3, or a pharmaceutically acceptable salt thereof, which is further optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl groups.

[0089] E8.5.G 6 However, methyl, cyano, CHF2, CF3, oxo, -OH, -OCH3, -C(O)Ot-butyl, -C(CH3)2-OH, G 6a , and -C 1~4 Alkilen-G 6a Compounds of E8.4, or pharmaceutically acceptable salts thereof, which are optionally substituted with one substituent selected from the group consisting of , and optionally further substituted with 1 to 3 substituents independently selected from the group consisting of methyl, CHF2, CF3, and oxo.

[0090] E8.6.G 6 but, [ka] A compound in the range E8 to E8.5, or a pharmaceutically acceptable salt thereof.

[0091] E8.7.G 6a However, it is a 4-6 membered heterocycline containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S, where the heterocycline is C 1~4 A compound from E8 to E8.6, or a pharmaceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from the group consisting of alkyls and halogens.

[0092] E8.8.G 6a A compound of E8.7, or a pharmaceutically acceptable salt thereof, which is an unsubstituted 4-6 membered heterocycline containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S.

[0093] E8.9 G 6a The ring system of 4-6 member heterocyclyls in [ka] A compound of E8.7 or E8.8, or a pharmaceutically acceptable salt thereof.

[0094] E8.10.G 6a However, it is a 5-membered heteroaryl compound containing 1 to 3 heteroatoms independently selected from the group consisting of O, N, and S, where the heteroaryl compound contains 1 to 3 C 1~4 A compound from E8 to E8.6, or a pharmaceutically acceptable salt thereof, optionally substituted with an alkyl group.

[0095] E8.11.G 6aHowever, the compounds of E8.10, or pharmaceutically acceptable salts thereof, are pyrazolyl compounds optionally substituted with 1-2 methyl groups.

[0096] E8.12.R 6a However, each time it appears, independently of hydrogen or C 1~4 A compound from E8 to E8.11 that is alkyl (e.g., methyl, t-butyl), or a pharmaceutically acceptable salt thereof.

[0097] E8.13.G 6 but, [ka] A compound from E8 to E8.12, or a pharmaceutically acceptable salt thereof.

[0098] E8.14.G 6 However, the compound is an E8 compound or a pharmaceutically acceptable salt thereof, which is a 6-12 membered bridged bicyclic heterocycline, wherein the heterocycline contains 1-3 heteroatoms independently selected from the group consisting of N, O, and S.

[0099] E8.15.G 6 but, [ka] The compound of E8.14, or a pharmaceutically acceptable salt thereof.

[0100] E8.16.G 6 However, it is a 6-12 membered spirocyclic heterocycline, and the heterocycline contains 1-3 heteroatoms independently selected from the group consisting of N, O, and S, and C 1~4 E8 compounds, or pharmaceutically acceptable salts thereof, optionally substituted with one or two substituents independently selected from the group consisting of alkyl and oxo compounds.

[0101] E8.17.G 6 but, [Chemistry] A compound of E8.16 or a pharmaceutically acceptable salt thereof.

[0102] E8.18.G 6 A compound of E8 or a pharmaceutically acceptable salt thereof, wherein the unsubstituted or substituted 4- to 12-membered heterocyclyl ring system in 6 is an 8- to 12-membered fused bicyclic heterocyclyl, and the heterocyclyl contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S.

[0103] E8.19.G 6 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1~4 alkyl, C 1~2 fluoroalkyl, and oxo; a compound of E8.18 or a pharmaceutically acceptable salt thereof.

[0104] E8.20.G 6 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of methyl, CF3, and oxo; a compound of E8.19 or a pharmaceutically acceptable salt thereof.

[0105] E8.21.G 6 is [Chemistry] A compound of E8.20 or a pharmaceutically acceptable salt thereof.

[0106] E9.G 6 is unsubstituted or substituted phenyl; a compound of any one of E1 to E3 or a pharmaceutically acceptable salt thereof.

[0107] E9.1.G 6 is phenyl optionally substituted with 1 to 3 halogens; a compound of E9 or a pharmaceutically acceptable salt thereof.

[0108] E9.2.G 6 is phenyl optionally substituted with 1 to 3 fluoro, the compound of E9.1, or a pharmaceutically acceptable salt thereof.

[0109] E9.3.G 6 is

Chemical formula

[0110] E9.4.G 6 is

Chemical formula

[0111] E10.G 6 is

Chemical formula

Chemical formula

Chemical formula

[0112] <F E11.R 6 is G 6 the compound of any one of E1 to E10, or a pharmaceutically acceptable salt thereof.

[0113] E12.R 6 is -C 1~4 alkylene-G 6 the compound of any one of E1 to E10, or a pharmaceutically acceptable salt thereof.

[0114] E12.1.R 6 is -CH2-G 6 a compound of E12, or a pharmaceutically acceptable salt thereof.

[0115] E13.R 3 a compound of any one of E1 to E12.1, or a pharmaceutically acceptable salt thereof, wherein is unsubstituted or substituted 6- to 12-membered aryl.

[0116] E14.R 3 a compound of any one of E1 to E13, or a pharmaceutically acceptable salt thereof, wherein the ring system of the unsubstituted or substituted 6- to 12-membered aryl in is phenyl.

[0117] E14.1.R 3 is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of 1~4 C alkyl, halogen, cyano, C 1~2 haloalkyl, -OR 3a and C(O)R 3a a compound of E14, or a pharmaceutically acceptable salt thereof.

[0118] E14.2.R 3 is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of methyl, fluoro, cyano, CF3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, and C(O)H, a compound of E14.1, or a pharmaceutically acceptable salt thereof.

[0119] E14.3.R 3 is

Chemical formula

[0120] E15.R 3 is unsubstituted or substituted C 5~7A single carbocyclyl compound from E1 to E12.1, or a pharmaceutically acceptable salt thereof.

[0121] E15.1.R 3 but, [ka] The E15 compound, or a pharmaceutically acceptable salt thereof.

[0122] E15.2.R 3 but, [ka] The compound of E15.1, or a pharmaceutically acceptable salt thereof.

[0123] E16.R 3 However, one of the compounds E1 to E12.1, which are unsubstituted or substituted 5- to 12-membered heterocyclines, or a pharmaceutically acceptable salt thereof.

[0124] E16.1.R 3 Compounds of E16, or pharmaceutically acceptable salts thereof, wherein the ring system of an unsubstituted or substituted 5- to 12-membered heterocycline in E16 is a 5- to 7-membered heterocycline containing one heteroatom selected from the group consisting of O, N, and S.

[0125] E16.2.R 3 but, [ka] The compound of E16.1, or a pharmaceutically acceptable salt thereof.

[0126] E16.3.R 3Compounds of E16, or pharmaceutically acceptable salts thereof, wherein the unsubstituted or substituted 5-12 member heterocycline ring system in is a 6-12 member spirocyclic heterocycline containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S.

[0127] E16.4.R 3 but, [ka] The E16.3 compound, or a pharmaceutically acceptable salt thereof.

[0128] E17.R 3 However, one of the compounds E1 to E12.1, which is an unsubstituted or substituted 5-6 member heteroaryl, or a pharmaceutically acceptable salt thereof.

[0129] E17.1.R 3 Compounds of E17, or pharmaceutically acceptable salts thereof, wherein the unsubstituted or substituted 5-6 member heteroaryl ring system in is pyridinyl (e.g., pyridine-4-yl).

[0130] E17.2.R 3 However, is it non-substitutive, or C 1~4 Compounds of type E17 or E17.1, or pharmaceutically acceptable salts thereof, substituted with one, two, or three substituents independently selected from the group consisting of alkyl and halogen compounds.

[0131] E17.3.R 3 The compounds of E17.2, or pharmaceutically acceptable salts thereof, are either unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of methyl and fluoro compounds.

[0132] E17.4.R 3 but, [ka] The E17.3 compound, or a pharmaceutically acceptable salt thereof.

[0133] E18.R 3 but, [ka] A compound from E1 to E17.4, or a pharmaceutically acceptable salt thereof.

[0134] E19.R 4 and R 5 However, hydrogen, C 1~4 A compound from E1 to E18, independently selected from the group consisting of alkyl and halogen compounds, or a pharmaceutically acceptable salt thereof.

[0135] E20.R 4 and R 5 However, each is a hydrogen atom, and each is one of the compounds E1 to E19, or a pharmaceutically acceptable salt thereof.

[0136] E21.4-(1-cyclopropyl-1H-pyrazole-3-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(isothiazol-4-yl)isoindorin-1-one 4-(6-(2,4-difluorophenyl)-1-oxoisoindorin-4-yl)-1-methyl-1H-pyrazole-5-carbonitrile 4,6-Bis(2,4-difluorophenyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(6-methylpyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(oxazol-5-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1-methyl-1H-imidazole-5-yl)isoindorin-1-one 4-(1-(difluoromethyl)-1H-pyrazole-4-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(3,5-dimethylisoxazol-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(pyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(pyridine-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(pyridazin-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(6-methylpyridazine-4-yl)isoindorin-1-one 4-(6-(2,4-difluorophenyl)-1-oxoisoindorin-4-yl)-1-methyl-1H-pyrrole-2-carbonitrile 6-(2,4-difluorophenyl)-4-(thiophen-3-yl)isoindorin-1-one 4-(1-cyclopentyl-1H-pyrazole-4-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 4-(1-cyclobutyl-1H-pyrazole-4-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 4-(1-cyclopropyl-1H-pyrazole-4-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1-methyl-1H-pyrazole-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2,4,5-trimethylthiophen-3-yl)isoindorin-1-one 4-(1-cyclohexyl-1H-pyrazole-4-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(quinoline-7-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(isoquinoline-6-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(quinoline-6-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(quinoline-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(isoquinoline-7-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(quinoxaline-6-yl)isoindorin-1-one 4-(benzo[b]thiophen-2-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(furan-2-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1-isopropyl-1H-pyrazole-5-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(thiazole-5-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2-(trifluoromethyl)pyrimidine-5-yl)isoindorin-1-one 5-(6-(2,4-difluorophenyl)-1-oxoisoindorin-4-yl)picolinonitrile N-(5-(6-(2,4-difluorophenyl)-1-oxoisoindorin-4-yl)pyridine-2-yl)acetamide 6-(2,4-difluorophenyl)-4-(4-isopropylpyrimidine-5-yl)isoindorin-1-one 4-(6-cyclopropylpyridine-3-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(pyrimidine-5-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(imidazo[1,2-a]pyridine-6-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2-(methylthio)pyrimidine-5-yl)isoindorin-1-one 4-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1-(2-hydroxy-2-methylpropyl)-3,5-dimethyl-1H-pyrazole-4-yl)isoindorin-1-one 5-Fluoro-2-(7-(isothiazol-4-yl)-3-oxoisoindorin-5-yl)benzonitrile 3-Fluoro-4-(7-(isothiazol-4-yl)-3-oxoisoindorin-5-yl)benzonitrile 6-(2-fluoro-4-methoxyphenyl)-4-(isothiazol-4-yl)isoindorin-1-one 4-(isothiazol-4-yl)-6-(2,4,6-trifluorophenyl)isoindorin-1-one 6-(4-(difluoromethoxy)-2-fluorophenyl)-4-(isothiazol-4-yl)isoindorin-1-one 4-(isothiazol-4-yl)-6-(2,3,4-trifluorophenyl)isoindorin-1-one 6-(4-fluoro-2-methoxyphenyl)-4-(isothiazol-4-yl)isoindorin-1-one 6-(2,3-difluoro-4-methoxyphenyl)-4-(isothiazol-4-yl)isoindorin-1-one 6-(2,4-difluoro-5-methylphenyl)-4-(isothiazol-4-yl)isoindorin-1-one 5-Fluoro-4-(7-(isothiazol-4-yl)-3-oxoisoindorin-5-yl)-2-methylbenzonitrile 6-(2,5-difluoro-4-methoxyphenyl)-4-(isothiazol-4-yl)isoindorin-1-one 4-(7-(isothiazol-4-yl)-3-oxoisoindorin-5-yl)-3-methoxybenzonitrile 6-(4-ethoxy-2,3-difluorophenyl)-4-(isothiazole-4-yl)isoindorin-1-one 2,6-Difluoro-3-(7-(Isothiazol-4-yl)-3-oxoisoindorin-5-yl)benzonitrile 6-(2,6-difluoro-4-methoxyphenyl)-4-(isothiazol-4-yl)isoindorin-1-one 2,6-Difluoro-4-(7-(Isothiazol-4-yl)-3-oxoisoindorin-5-yl)benzonitrile 2,3-difluoro-4-(7-(isothiazol-4-yl)-3-oxoisoindorin-5-yl)benzaldehyde 4-(isothiazol-4-yl)-6-(3,4,5-trifluorophenyl)isoindorin-1-one 6-(5-fluoro-2-methylpyridine-4-yl)-4-(isothiazol-4-yl)isoindorin-1-one 2-Isopropoxy-4-(7-(isothiazol-4-yl)-3-oxoisoindorin-5-yl)benzonitrile 6-(2,4-difluorophenyl)-4-(1-(tetrahydrofuran-3-yl)-1H-pyrazole-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2-oxo-1,2-dihydropyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2-(dimethylamino)pyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2-(pyrroridine-1-yl)pyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2,6-dimethylpyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2-(trifluoromethyl)pyridine-3-yl)isoindorin-1-one 4-(2-cyclopropylpyridine-3-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 3-(6-(2,4-difluorophenyl)-1-oxoisoindorin-4-yl)picolinonitrile 6-(2,4-difluorophenyl)-4-(2-methoxypyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(6-fluoro-2-methylpyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2,6-difluoropyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2-methylpyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2-isopropoxypyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1-isobutyl-1H-pyrazole-5-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(3,5-dimethyl-1H-pyrazole-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1,3-dimethyl-1H-pyrazole-5-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1-ethyl-3-(trifluoromethyl)-1H-pyrazole-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1-ethyl-1H-pyrazole-5-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1,4-dimethyl-1H-pyrazole-5-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1,5-dimethyl-1H-pyrazole-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1,3,5-trimethyl-1H-pyrazole-4-yl)isoindorin-1-one 4-(1-isopropyl-1H-pyrazole-5-yl)-6-(4-methoxycyclohexa-1-en-1-yl)isoindorin-1-one 6-(3,6-dihydro-2H-pyran-4-yl)-4-(1-isopropyl-1H-pyrazole-5-yl)isoindorin-1-one 4-(1-isopropyl-1H-pyrazole-5-yl)-6-(1,4-dioxaspiro[4.5]deca-7-en-8-yl)isoindorin-1-one 4-(1-isopropyl-1H-pyrazole-5-yl)-6-(tetrahydro-2H-pyran-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(4-methylpyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2-(trifluoromethyl)pyridine-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2-methoxy-6-methylpyridine-4-yl)isoindorin-1-one 6-(3,6-dihydro-2H-pyran-4-yl)-4-(1,3,5-trimethyl-1H-pyrazole-4-yl)isoindorin-1-one 6-(3,6-dihydro-2H-pyran-4-yl)-4-(1,5-dimethyl-1H-pyrazole-4-yl)isoindorin-1-one 6-(3,6-dihydro-2H-pyran-4-yl)-4-(1,4-dimethyl-1H-pyrazole-5-yl)isoindorin-1-one 6-(3,6-dihydro-2H-pyran-4-yl)-4-(1-ethyl-1H-pyrazole-5-yl)isoindorin-1-one 6-(3,6-dihydro-2H-pyran-4-yl)-4-(1,3-dimethyl-1H-pyrazole-5-yl)isoindorin-1-one 6-(3,6-dihydro-2H-pyran-4-yl)-4-(2-methylpyridine-3-yl)isoindorin-1-one 6-(tetrahydro-2H-pyran-4-yl)-4-(1,3,5-trimethyl-1H-pyrazole-4-yl)isoindorin-1-one 4-(1,5-dimethyl-1H-pyrazole-4-yl)-6-(tetrahydro-2H-pyran-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-((3aR,6aS)-1,1-dioxide-3a-(trifluoromethyl)hexahydro-5H-thieno[2,3-c]pyrrole-5-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2,3-dihydro-1H-imidazo[1,2-b]pyrazole-1-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1,1-dioxidethiomorpholino)isoindorin-1-one 6-(2,4-difluorophenyl)-4-morpholinisoindorin-1-one 6-(2,4-difluorophenyl)-4-thiomorpholinisoindorin-1-one 6-(2,4-difluorophenyl)-4-(2,2,6,6-tetramethylmorpholino)isoindorin-1-one 1-(6-(2,4-difluorophenyl)-1-oxoisoindorin-4-yl)-3-methylpyrrolidine-3-carbonilicate 6-(2,4-difluorophenyl)-4-(3-(2-hydroxypropan-2-yl)pyrrolidine-1-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(4-(1-methyl-1H-pyrazole-3-yl)piperidine-1-yl)isoindorin-1-one 1-(6-(2,4-difluorophenyl)-1-oxoisoindorin-4-yl)piperidine-3-carbonitrile 6-(2,4-difluorophenyl)-4-(3-(trifluoromethyl)piperidine-1-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(3-(2-hydroxypropan-2-yl)piperidine-1-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1-oxa-4-thia-8-azaspiro[4,5]decane-8-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1,4-dioxa-8-azaspiro[4,5]decane-8-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(4-(pyrrolidine-1-yl)piperidine-1-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(4,4-dimethylpiperidine-1-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(hexahydro-2H-pyrano[3,2-c]pyridine-6(5H)-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(3-methoxypiperidine-1-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(3-hydroxy-3-(trifluoromethyl)azetidine-1-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(7-oxo-2,6-diazaspiro[3,4]octan-2-yl)isoindorin-1-one 4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(6-methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-1-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(thiomorpholinomethyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(morpholinomethyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1-methylpiperidine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1-methylpiperidine-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(morpholine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(pyrrolidine-3-yl)isoindorin-1-one 4-((8-oxa-3-azabicyclo[3.2.1]octan-3-yl)methyl)-6-(2,4-difluorophenyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-((3-hydroxy-3-(trifluoromethyl)azetidine-1-yl)methyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(3,4-dihydro-2H-pyran-6-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(tetrahydro-2H-pyran-2-yl)isoindorin-1-one A compound of type E1 selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

[0137] A pharmaceutical composition comprising one compound from E22.E1 to E21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0138] E23. A method for treating a disease or disorder associated with metabolic glutamate receptor 2 (mGlu2) dysfunction, comprising administering a therapeutically effective amount of one of the compounds E1 to E21, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of E22 to a subject in need thereof.

[0139] E24. The method of E23, 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.

[0140] E25. Any one compound from E1 to E21, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of E22, for use in the treatment of a disorder or condition selected from at least one of depression, anxiety, obsessive-compulsive disorder, cognitive impairment, Alzheimer's disease, and autism spectrum disorder.

[0141] E26. Use of any one compound from E1 to E21, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of E22 in the manufacture of a pharmaceutical 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.

[0142] The compound name can be assigned by using the Struct=Name naming algorithm as part of the CHEMDRAW(registered trademark)ULTRA portion.

[0143] Compounds may exist as stereoisomers containing a chiral or asymmetric center. Stereoiomers are designated "R" or "S" depending on the arrangement of substituents around the chiral carbon atom. The terms "R" and "S" as used herein refer to arrangements as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45:13-30. This disclosure intends various stereoisomers and mixtures thereof, which are particularly included within the scope of the invention. Stereoiomers include enantiomers and diastereomers, as well as mixtures of enantiomers or diastereomers. In the compounds disclosed herein, chiral atoms described or referred to without specific stereochemical arrangements (e.g., straight bonds, non-wedge-shaped or dashed-line bonds, HC(OH)(CH3)(CH2CH3)) encompass any stereochemical arrangement of the chiral atom.

[0144] Each stereoisomer of this compound can be prepared from commercially available starting materials containing a chiral or asymmetric center by synthesis or by preparation of a racemic mixture followed by separation methods well known to those skilled in the art. These separation methods are exemplified by (1) attachment of the 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 the mixture of optically enantiomers in a chiral chromatography column, or (3) fractional recrystallization methods.

[0145] It should be understood that this compound may have tautomers and geometric isomers, and that these also constitute aspects of this disclosure.

[0146] In compounds of formula (I) and any subformula, any "hydrogen" or "H", whether explicitly or implicitly indicated in the structure, is a hydrogen isotope. 1 H (protium) and 2 It contains H (deuterium).

[0147] This disclosure also includes isotope-labeled compounds (e.g., deuterium-labeled), where the atoms in the isotope-labeled compounds are identified as specific isotopes of the atoms. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are 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 Cl is one example.

[0148] Isotope-enriched forms of compounds of formula (I), or any subformula, can generally be prepared by the prior art known to those skilled in the art, or by processes similar to those described in the appended examples, using appropriate isotope-enriched reagents instead of non-isotope-enriched reagents. The degree of isotope enrichment can be characterized as the percentage of a particular isotope incorporated into the isotope-labeled atom (e.g., deuterium incorporation %) in deuterium labeling.

[0149] Allosteric regulation of B.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 facilitative and neuroprotective even in the presence of mGlu2 dysfunction.

[0150] The compound of formula (I) is an IC in the range of approximately 1 nM to approximately 30 μM. 50 The compound can inhibit mGlu2 accompanied by [a specific reaction]. The compound is available in concentrations of approximately 30 μM, 29 μM, 28 μM, 27 μM, 26 μM, 25 μM, 24 μM, 23 μM, 22 μM, 21 μM, 20 μM, 19 μM, 18 μM, 17 μM, 16 μM, 15 μM, 14 μM, 13 μM, 12 μM, 11 μM, 10 μM, 9 μM, 8 μM, 7 μM, 6 μM, 5 μM, 4 μM, 3 μM, and 2 μM. ICs with a microparticle size of approximately 1 μM, 950 nM, 900 nM, 850 nM, 800 nM, 850 nM, 800 nM, 750 nM, 700 nM, 650 nM, 600 nM, 550 nM, 500 nM, 450 nM, 400 nM, 350 nM, 300 nM, 250 nM, 200 nM, 150 nM, 100 nM, 50 nM, 10 nM, 5 nM, or 1 nM 50Compounds of formula (I) may contain 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, 9 It is possible to inhibit mgl2 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.

[0151] The compound of formula (I) may be a selective modulator of mGlu2 rather than mGlu3. The compound may contain 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 mGlu2IC 50 and mGlu3EC 50The compound of formula (I) may have the following ratios: 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 mGlu2IC 50 and mGlu3EC 50 It may have a ratio of .

[0152] Compounds of formula (I) may be selective modulators of mGlu2 rather than mGlu5. Compounds may contain 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 mGlu2IC 50 and mGlu5EC 50 The compound of formula (I) may have the following ratios: 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 mGlu2IC 50 and mGlu5EC 50 It may have a ratio of .

[0153] C. Medicinal Salt The disclosed compounds may 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 that is suitable for the treatment of a disorder without excessive toxicity, irritation, and allergic reactions, and is effective for its intended use, with a reasonable benefit-risk ratio. These salts may 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 may be dissolved in a suitable solvent such as methanol and water, but is not limited to, and treated with at least one acid equivalent such as hydrochloric acid. The resulting salt may be precipitated, isolated by filtration, and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide the salt. Typical salts include acetate, adipine, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, 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, and phosphate. The amino group of this compound can also be quaternized by chlorination, bromide, and alkyl iodide, such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, and stearyl.

[0154] Base addition salts can be prepared during the final isolation and purification of the disclosed compounds by reacting a carboxyl group with a hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or with a suitable base such as 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.

[0155] D. General synthesis The compound of formula (I) can be prepared by synthetic or metabolic processes. Metabolic preparations of this compound include processes that occur in the human or animal body (in vivo) or in vitro.

[0156] Compounds of formula (I), or any of its subformulas, can be synthesized as shown in the following scheme.

[0157] General Scheme 1 [ka] As shown in General Scheme 1, methyl 4,6-dihalogenated-2-methylbenzoate (where X and X 1 The compound (which may be fluorine, chlorine, bromine, or iodide) can be subjected to radical bromination conditions (e.g., N-bromosuccinimide, AIBN, and carbon tetrachloride) while being heated to about 90°C to provide intermediate compound (i). Intermediate (i), with heating to about 85-100°C in the presence of ammonia and a solvent (e.g., methanol), can form the intermediate of formula (ii).

[0158] General Scheme 2 [ka] As shown in General Scheme 2, the intermediate compound of formula (iii) can be subjected to Suzuki reaction conditions, where compound (iii) is subjected to appropriate R in the presence of a base (e.g., sodium carbonate, cesium carbonate) in a solvent, e.g., dioxane or a dioxane / water mixture. 3 - Reacts with a substituted boronic acid or ester reagent, R 3 It forms an intermediate compound (iv) that presents substituents.

[0159] General Scheme 3 [ka] As shown in general scheme 3, intermediate (iv) can be subjected to Suzuki reaction conditions, where intermediate (iv) is a boronic acid or ester (e.g., G 6 -(OR)2) reacts with a palladium catalyst (e.g., PdCl2(dppf)), a base (e.g., sodium carbonate, cesium carbonate), and a solvent (e.g., dioxane or a dioxane / water mixture) to obtain compound (v).

[0160] General Scheme 4 [ka] As shown in General Scheme 4, the intermediate compound of formula (vi) can be subjected to Suzuki reaction conditions, where compound (vi) is subjected to appropriate G in the presence of a base (e.g., sodium carbonate, cesium carbonate) in a solvent, e.g., dioxane or a dioxane / water mixture. 6 - Reacts with a substituted boronic acid or ester reagent, G 6 It forms an intermediate compound (vii) that presents substituents.

[0161] General Scheme 5 [ka] As shown in General Scheme 5, compound (vii) can be subjected to standard Suzuki reaction conditions and heat with a boronic acid or ester, a palladium catalyst (e.g., Pd(dppf)Cl2·DCM), a base (e.g., Na2CO3), and a solvent (e.g., 1,4-dioxane / water) to obtain compound (viii). Non-aromatic R 3 Regarding this, boronic acids or esters can be substituted on cycloalkenes or unsaturated carbon atoms of heterocyclic rings. The products of the Suzuki reaction can be converted to further compounds of the present invention, such as by hydrogenation of the double bond, and saturated R 3 A compound having the characteristic (e.g., Example 11) is obtained.

[0162] General Scheme 6 [ka] General scheme 6 illustrates the formation of the compound of formula (ix). Compound (ix) can be provided by the reaction of intermediate compound (iv) (e.g., where X is a halogen or triflate) with an amine, a palladium catalyst (e.g., Pd-PEPPSI-IPent), a base (e.g., Cs2CO3), and a solvent (e.g., 1,2-dimethoxyethane) with heat to about 120°C, according to standard Buchwald conditions. The reaction can be accelerated by microwave irradiation. In general scheme 6, R 7a and R 7b Together with the nitrogen to which they are attached, G 6 It forms unsubstituted or substituted 4- to 12-membered heterocyclines, or their synthetic precursors.

[0163] General Scheme 7 [ka] As shown in general scheme 7, intermediate compound (x) can be provided by the intermediate compound of formula (iv) in the presence of a palladium catalyst (e.g., RuPhos palladium cycle G3), a base (e.g., K2CO3, Cs2CO3), a vinylboronic acid ester, or potassium trifluoro(vinyl)borate (I) in an organic solvent and water, such as THF or a solvent mixture of dioxane and water, while heating to about 120-140°C. The reaction can be accelerated by microwave irradiation.

[0164] General Scheme 8 [ka] General scheme 8 illustrates the formation of a compound having formula (xi). The intermediate compound (x) can be subjected to the addition of an organic solvent and water, such as THF and osmium tetroxide in water, an antioxidant (such as N-methylmorpholine N-oxide), and then NaIO4 to obtain the intermediate compound of formula (xi).

[0165] General Scheme 9 [ka] As shown in general scheme 9, the compound of formula (xii) can be prepared from intermediate compound (xi). Intermediate (xi) can be subjected to CaSO4, a 4Å molecular sieve, and 2-((tributylstannyl)methoxy)ethane-1-amine in a solvent (e.g., DCM) while being heated to about 35-40°C. This mixture can be added to separate mixtures of Cu(OTf)2, hexafluoroisopropanol, and 2,6-lutidine. Treatment with SnAP reagents can yield the compound of formula (xii). See Luescher MU, Vo CT, Bode JW., “SnAP Reagents for the Synthesis of Piperazines and Morpholines,” Org. Lett. (2014) 16(4):1236-1239.

[0166] General Scheme 10 [ka] As shown in general scheme 10, the intermediate compound of formula (xi) may be subjected to an amine in a solvent (e.g., DCM) and a reducing agent (e.g., NaBH(OAc)3) to obtain the compound of formula (xiii).

[0167] General Scheme 11 [ka] As shown in general scheme 11, the intermediate compound of formula (iv) can be obtained in the presence of a solvent mixture of an organic solvent and water, e.g., THF or dioxane and water, a palladium catalyst (e.g., RuPhos palladium cycle G3), a base (e.g., K2CO3, Cs2CO3), and potassium trifluoro(aminomethyl)borate (I), with heating to about 120-140°C, and intermediate compound (xiv). The reaction can be accelerated by microwave irradiation.

[0168] Suitable Suzuki coupling conditions for use in the synthesis processes described herein are well known in the art. Suitable Suzuki conditions include those generally outlined in the general scheme and examples.

[0169] Boronic acids and ester reagents can be purchased from commercial sources or prepared from the corresponding halides (e.g., bromides) using known procedures.

[0170] Compounds and intermediates can be isolated and purified by methods well known to those skilled in the field of organic synthesis. Examples of conventional methods for isolating and purifying compounds include, but are not limited to, chromatography, thin-layer chromatography, distillation at various pressures, sublimation in vacuum, and trituration 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 "Vogel's Textbook of Practical Organic Chemistry" 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England.

[0171] The disclosed compounds may have at least one basic nitrogen (so that the compound can 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 a 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, as well as 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 hydrogen bromide, sulfuric acid, citric acid, hydroxybutyric acid, camphorsulfonic acid, malic acid, phenylacetic acid, aspartic acid, or glutamic acid.

[0172] The optimal reaction conditions and reaction times for each individual step may vary depending on the specific reactants used and the substituents present in them. Specific procedures are provided in the Examples section. The reaction can be post-treated 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, polishing, and chromatography. Unless otherwise stated, starting materials and reagents are commercially available or can be prepared by those skilled in the art from commercially available materials using methods described in the chemical literature. If not commercially available, starting materials can be prepared by procedures selected from standard organic chemistry techniques, techniques similar to the synthesis of known structurally similar compounds, or techniques similar to the schemes or synthesis examples described above.

[0173] Conventional experimental methods, including reaction conditions, reagents and the order of the synthesis route, and appropriate handling of the protection and deprotection of any chemical functionalities that are not compatible with the reaction conditions and the appropriate timing of deprotection in the reaction sequence of the method, are 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, and examples thereof are incorporated herein by reference in Protective Groups in Organic Synthesis (4) th This can be referenced in Greene's book titled (ed.) PGM Wuts and TW Greene, John Wiley & Sons, NY (2006). The synthesis of the compounds of the present invention can be achieved by methods similar to those described in the synthesis schemes described above and in the specific examples.

[0174] If an optically active form of the disclosed compound is required, it can be obtained by performing one of the procedures described herein using an optically active starting material (e.g., prepared by asymmetric induction of the appropriate reaction step), or by dividing a mixture of stereoisomers of the compound or intermediate using a standard procedure (such as chromatographic separation, recrystallization, or enzymatic resolution).

[0175] Similarly, if a pure geometric isomer of this compound is required, it can be obtained by performing one of the above procedures using the pure geometric isomer as a starting material, or by dividing a mixture of geometric isomers of the compound or intermediate using standard procedures such as chromatographic separation.

[0176] It should be understood that the described synthesis schemes and specific examples are illustrative and should not be construed as limiting the scope of the invention as defined in the appended claims. All alternative forms, modifications, and equivalents of the synthesis methods and specific examples are included within the scope of the claims.

[0177] 3. Pharmaceutical Compositions The disclosed compounds may be incorporated into pharmaceutical compositions suitable for administration to subjects (e.g., patients, which may be human or non-human).

[0178] These pharmaceutical compositions may contain a “therapeutic dose” or a “preventive dose.” “Therapeutic dose” refers to the amount effective in the dosage and duration required to achieve the desired therapeutic outcome. The therapeutic dose of this composition can be determined by those skilled in the art and may vary depending on factors such as the individual’s disease state, age, sex, and weight, as well as the composition’s ability to elicit the desired response in the individual. The therapeutic dose is also the 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. “Preventive dose” refers to the amount effective in the dosage and duration required to achieve the desired preventive outcome. Generally, since preventive doses are used for targets before or in the early stages of disease, the preventive dose will be lower than the therapeutic dose.

[0179] For example, the therapeutically effective doses of compounds in the subformula of formula (I) are approximately 1 mg / kg to 1000 mg / kg, approximately 5 mg / kg to 950 mg / kg, approximately 10 mg / kg to 900 mg / kg, approximately 15 mg / kg to 850 mg / kg, approximately 20 mg / kg to 800 mg / kg, approximately 25 mg / kg to 750 mg / kg, approximately 30 mg / kg to 700 mg / kg, approximately 35 mg / kg to 650 mg / kg, approximately 40 mg / kg to 600 mg / kg, and approximately The dosage may range from 45 mg / kg to approximately 550 mg / kg, approximately 50 mg / kg to approximately 500 mg / kg, approximately 55 mg / kg to approximately 450 mg / kg, approximately 60 mg / kg to approximately 400 mg / kg, approximately 65 mg / kg to approximately 350 mg / kg, approximately 70 mg / kg to approximately 300 mg / kg, approximately 75 mg / kg to approximately 250 mg / kg, approximately 80 mg / kg to approximately 200 mg / kg, approximately 85 mg / kg to approximately 150 mg / kg, and approximately 90 mg / kg to approximately 100 mg / kg.

[0180] This pharmaceutical composition may contain pharmaceutically acceptable carriers. The term “pharmaceutically acceptable carrier” as used herein means any non-toxic, inert solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation aid of any kind. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, e.g., cocoa butter and suppository waxes; oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and Soybean oil; glycols; for example, propylene glycol; esters, for example, ethyl oleate and ethyl laurate (but not limited); agar; buffers, for example, magnesium hydroxide and aluminum hydroxide (but not limited); alginic acid; pyrogen-free water; isotonic saline solution; Ringer's solution; ethyl alcohol and phosphate buffer; and other non-toxic, suitable lubricants, for example, sodium lauryl sulfate and magnesium stearate (but not limited), as well as colorants, release agents, coating agents, sweeteners, flavorings and fragrances, preservatives and antioxidants may also be present in the composition at the discretion of the compounder.

[0181] Therefore, this compound, its physiologically acceptable salts, and solvents can be formulated, for example, in solid tablets, eye drops, oil-based topical preparations, injection, inhalation (through the mouth or nose), implantable tablets, or for oral, buccal, parenteral, or rectal administration. The techniques and formulations can generally be referenced in "Remington's Pharmaceutical Sciences" (Meade Publishing Co., Easton, Pa.). Therapeutic compositions should generally be sterile and stable under manufacturing and storage conditions.

[0182] The route by which the disclosed compound is administered and the form of the composition determine the type of carrier used. The composition may be in various forms suitable for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implantable, or parenteral) or topical administration (e.g., skin, lung, nose, ear, eye, liposome delivery system, or iontophoresis).

[0183] Carriers for systemic administration generally include at least one of the following: diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, fluidizers, solvents, suspending agents, wetting agents, surfactants, or combinations thereof. All carriers are optional within the composition.

[0184] 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 50-90%.

[0185] 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 composition for whole-body or topical use is generally about 5 to about 10%.

[0186] Suitable binders include polyvinylpyrrolidone; magnesium aluminum silicate; starch, such as sorghum 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 the whole composition is generally about 5 to 50%.

[0187] Suitable disintegrants include agar, alginic acid and its sodium salts, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clay, and ion exchange resins. The amount of disintegrant in a whole-body or topical composition is generally about 0.1 to about 10%.

[0188] Suitable colorants include FD&C dyes. When used, the amount of colorant in a whole-body or topical composition is generally about 0.005 to 0.1%.

[0189] Suitable flavors include menthol, peppermint, and fruit flavors. When used, the amount of flavor in a systemic or topical composition is generally about 0.1 to 1.0%.

[0190] Suitable sweeteners include aspartame and saccharin. The amount of sweetener in a whole-body or topical composition is generally about 0.001% to about 1%.

[0191] Suitable antioxidants include butylhydroxyanisole ("BHA"), butylhydroxytoluene ("BHT"), and vitamin E. The amount of antioxidant in a systemic or topical composition is generally about 0.1 to 5%.

[0192] Suitable preservatives include benzalkonium chloride, methylparaben, and sodium benzoate. The amount of preservative in a systemic or topical composition is generally about 0.01 to 5%.

[0193] A suitable fluidizing agent is silicon dioxide. The amount of fluidizing agent in a whole-body or topical composition is generally about 1 to 5%.

[0194] Suitable solvents include water, isotonic saline, ethyl oleate, glycerin, castor oil hydroxide, alcohols such as ethanol, and phosphate buffer. The amount of solvent in a whole-body or topical composition is generally about 0 to 100%.

[0195] 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 8%.

[0196] Suitable surfactants include lecithin, polysorbate 80, sodium lauryl sulfate, and TWEENS (from Atlas Powder Company of Wilmington, Delaware). Other suitable surfactants are disclosed in CTFA Cosmetic Ingredient Handbook, 1992, pp. 587-592; Wilmington'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%.

[0197] The amounts of components in a systemic composition may vary depending on the type of systemic composition being prepared, but generally, a systemic composition contains 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 the active substance and 90% to 99.9% of a carrier (including diluents and solvents).

[0198] Compositions for oral administration may have 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 the active substance, usually at least about 5%, more specifically about 25% to about 50%. These oral medication compositions contain about 50% to about 95%, more specifically about 50% to about 75% of the carrier.

[0199] Tablets can be compressed, wet-coated (tablet triturate), enteric-coated, sugar-coated, film-coated, or multi-compressed. Tablets generally contain an active ingredient and a carrier containing an ingredient selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, fluidizers, 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 colorants are FD&C dyes that can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or combinations thereof.

[0200] Capsules (including implantable tablets, sustained-release and sustained-release formulations) generally comprise an active compound [e.g., a compound of a subformula of formula (I)] and a carrier containing one or more of the disclosed diluents in a gelatin-containing capsule. Granules generally comprise the disclosed compound and a fluidizing agent, preferably silicon dioxide, to improve flow properties. Implantable tablets may be biodegradable or non-biodegradable.

[0201] The selection of components in the carrier for oral compositions depends on auxiliary considerations such as taste, cost, and storage stability, which are not important to the purpose of the present invention.

[0202] The solid composition can be conventionally coated with a pH or time-dependent coating so that the disclosed compound is released into the gastrointestinal tract or near the desired site of application, or at various locations and times, in order to maintain the desired effect. The coating generally comprises one or more components selected from the group consisting of cellulose phthalate acetate, vinyl polyphthalate acetate, hydroxypropyl methylcellulose phthalate, ethylcellulose, EUDRAGIT coating (available from Rohm & Haas GmbH of Darmstadt, Germany), wax, and shellac.

[0203] Compositions for oral administration can take the form of a liquid. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-foaming granules, suspensions reconstituted from non-foaming granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, and syrups. Liquid compositions for oral administration generally comprise the disclosed compound and a carrier, i.e., a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Oral liquid compositions preferably contain one or more components selected from colorants, flavors, and sweeteners.

[0204] Other compositions useful for achieving systemic delivery of the target compound include sublingual, buccal, and nasal dosage forms. These compositions generally contain diluents, including sucrose, sorbitol, and mannitol; and one or more soluble fillers, such as gum arabic, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose. These compositions may further contain lubricants, colorants, flavors, sweeteners, antioxidants, and fluidizers.

[0205] The disclosed compounds can be administered topically. Topical compositions that can be applied topically to the skin may 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, and the like. A topical composition comprises the disclosed compound [for example, a compound of a 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.

[0206] The amount of carrier used with the disclosed compound is sufficient to provide a composition of a useful dose for administration per unit dose of the compound. Techniques and compositions for producing useful dosage forms in the method 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).

[0207] The carrier may consist of a single component or a combination of two or more components. In topical compositions, this carrier includes 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, and even more specifically, phosphate-buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.

[0208] The carrier for the topical composition may further include one or more components selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, dyes, and preservatives (all of which are optional).

[0209] 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, and sebaci. Examples 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, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for the skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient in topical compositions for skin use is generally about 5% to about 95%.

[0210] 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 about 0% to about 95%.

[0211] 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 examples of solvents include ethyl alcohol and homotopic alcohol. The amount of solvent in a topical composition is generally about 0% to about 95%.

[0212] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. A specific example of a humectant is glycerin. The amount of humectant in a topical composition is generally between 0% and 95%.

[0213] The amount of thickener in topical compositions is generally between approximately 0% and 95%.

[0214] Suitable powders include β-cyclodextrin, hydroxypropyl cyclodextrin, chalk, talc, fuller's clay, kaolin, starch, rubber, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, aluminum silicate hydrate, 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%.

[0215] The amount of fragrance in topical compositions is generally about 0% to 0.5%, and especially about 0.001% to 0.1%.

[0216] Suitable pH-adjusting additives include HCl or NaOH in sufficient quantities to adjust the pH of the topical pharmaceutical composition.

[0217] 4. Treatment Method The disclosed compounds and compositions may be used in methods for treating medical disorders and / or diseases related to mGlu2. Methods of treatment may include administering a therapeutically effective amount of a composition containing the compound of formula (I) to a subject requiring such treatment.

[0218] The composition can be administered to subjects that require it to modulate mGlu2 for various diverse biological processes. This disclosure relates to a method for administering the composition to inhibit mGlu2, a GPCR that plays a role in synaptic plasticity and directly affects, for example, cognitive function and memory.

[0219] The compositions may be useful for treating and preventing certain diseases and disorders in humans and animals associated with mGlu2 dysfunction. Treatment or prevention of such diseases and disorders can be achieved by modulating mGlu2 in a subject by administering the compounds or compositions of the present invention to the subject in need, either alone or in combination with another activator as part of a therapeutic regimen.

[0220] A. Depression mGlu 2 / 3 The receptor antagonists MGS0039 and LY341495 were first shown to exhibit antidepressant-like effects in rat forced swimming tests (FST) and mouse tail suspension tests (TST) using normal animals (Chaki et al. Neuropharmacology, 2004, 46, 457-467). More recently, studies have attempted to evaluate the effects of these drugs within the paradigm linked to the causes of human depression. MGS0039 showed antidepressant effects in the learned helplessness test, where 7 days of treatment with MGS0039 significantly reduced the number of escape failures (Yoshimizu et al. Psychopharmacology, 2006, 186, 587-593).

[0221] Pa1ucha-Poniewiera et al. Psychopharmacology, 2010, 212, 523-535 evaluated the potential antidepressant-like effects of MGS0039 in a rat model of depression with olfactory bulbectomy (OB). Surgical lesions of the olfactory bulb in animals are known to induce significant 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 reduced hyperactivity in olfactory bulbectomized rats in the open-field test and reduced learning impairment in the passive avoidance test.

[0222] Kawasaki et al. Neuropharmacology, 2011, 60, 397-404 also examined the effect of MGS0039 on the behavior of socially isolated mice in FST. It is known that isolating rodents after weaning leads to neurochemical changes that cause behavioral disruption. Chronic social isolation after weaning for more than 6 weeks increased immobility in FST, suggesting that isolation leads to depressive-like behavior. MGS0039 reversed the increase in immobility in socially isolated mice in the study.

[0223] Campo, B. et al. J. Neurogenetics 2011, 25, 152-166 showed that a selective group II (mGlu2 and mGlu3) negative allosteric modulator (RO4491533) was effective in several in vitro biochemical assays and in vivo models of depression. RO4491533 is a compound that is mGlu 2 / 3 The agonist (LY379268) reversed its spontaneous movement inhibitory effect in a target-specific manner, demonstrating its ability to bind to central mGlu2 and mGlu3 receptors. 2 / 3The antagonist LY341495 achieved the same results. RO4491533 and LY341495 dose-dependently reduced immobility time in C57Bl6 / J mice during the fasting test (FST). RO4491533 and LY341495 were also active in the tail suspension test in a strain of astheno(H) mice, a putative genetic model of depression.

[0224] mGlu 2 / 3 Blocking of receptors and ketamine may converge on the same neural circuit, including activation of AMPA receptors and mTOR signaling. Since both AMPA receptor stimulation and subsequent mTOR signaling activation are presumed to be involved in the rapid action of ketamine in patients with refractory depression (TRD), mGlu 2 / 3 Receptor antagonists were able to exert the same effect in humans. This hypothesis is supported by several animal studies. Firstly, mGlu 2 / 3 The receptor antagonist MGS0039 showed antidepressant effects in an animal model in which currently prescribed antidepressants were ineffective (learned helplessness paradigm) (Yoshimizu et al. Psychopharmacology, 2006, 186, 587-593). Secondly, mGlu 2 / 3 Although there is no evidence of rapid onset of action by receptor antagonists, AMPA receptor enhancers (AMPA receptor enhancers are mGlu 2 / 3 LY341495 (which mediates the antidepressant effect of receptor antagonists) showed a faster effect (during the first week of treatment) compared to fluoxetine (after 2 weeks) in a dominance-dependency study (Knapp et al. Eur. J. Pharmacol. 2002, 440, 121-125). Furthermore, LY341495 showed a potent antidepressant effect in asthenic mice following acute administration, while fluoxetine exerted a complete antidepressant effect following chronic (21-day) treatment (Campo, B. et al. J. Neurogenetics 2011, 25, 152-166; El Yacoubi et al. PNAS, 2003, 100, 6227-6232). Therefore, mGlu 2 / 3Receptor blockade can produce rapid and potent antidepressant effects in humans.

[0225] B. Cognitive impairment Woltering et al. Bioorg. Med. Chem. Lett. 2010, 20, 6969-74 mGlu 2 / 3 The negative allosteric modulator of mGlue is used in delayed position matching (DMTP) tasks (a measure of working memory) in rodents. 2 / 3 It was shown that it reversed working memory deficits induced by agonists or scopolamine. Furthermore, Woltering showed that low doses of mGlu 2 / 3 When the negative allosteric modulator of mGlu2 was combined with donezepil, an acetylcholinesterase inhibitor at the tolerable limit dose, a synergistic reversal of scopolamine-induced deficiency in DMTP was observed. Given the efficacy of donepezil and other acetylcholinesterase inhibitors in treating cognitive decline in Alzheimer's disease, the negative allosteric modulator of mGlu2 may be effective as a cognitive enhancer.

[0226] C. Obsessive-Compulsive Disorder Shimazaki, T. et al. (Eur. J. Pharmacol. 2004, 501, 121-125) demonstrated that MGS0039 induced glutamatergic changes in mice, resulting in an anti-obsessive-compulsive disorder (OCD) effect. These studies utilized the glass marble twiping test as a model for OCD, which is recognized as a useful model for evaluating the clinical potential of anti-OCD drugs. Specifically, mice treated with MGS0039 showed a significant and dose-dependent reduction in glass marble twiping behavior, while no significant changes were observed in spontaneous motor activity. Furthermore, LY341495, another potent antagonist of the group II mGlu receptor, was also shown to significantly reduce glass marble twiping behavior in treated mice.

[0227] D. Alzheimer's disease Kim, SH et al. Moecular Psychiatry 2014, 1-8 assessed the therapeutic potential of chronic pharmacological inhibition of group II mGlu receptors (mGlu2 and mGlu3) with group II mGlu receptor antagonists in an APP transgenic mouse model that develops learning and behavioral impairments associated with the accumulation of mutant Aβ oligomers that do not form amyloid plaques. Once-daily administration of BCI-838, an orally bioavailable prodrug, delivered sufficient brain concentrations of its active metabolite BCI-632, which inhibits group II mGlu receptors for 22 hours. Three months of treatment with BCI-838 achieved an anxiolytic effect, reversed learning and memory impairments associated with the Dutch APP transgene, and reduced monomer and oAβ peptide levels in the hippocampus and cortex of two different AD mouse models. In particular, BCI-838 administration stimulated hippocampal progenitor cell proliferation for 3 months in both wild-type and Alzheimer's disease mice, resulting in a significantly increased number of neoneurons in the hippocampus of Dutch APP transgenic mice. In addition to the treatment, its proneurogenesis makes the compound attractive for potential use in reversing some of the early symptoms of Alzheimer's disease (AD), possibly through its neoneurorepair effect. These findings suggest that chronic pharmacological inhibition of group II mGlu receptors may be a disease-modifying treatment for AD, targeting cognitive / emotional impairments and modulating neurogenesis.

[0228] 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 observed in mGlu2. 2 / 3 This was shown to be prevented by the receptor antagonist LY341495.

[0229] E. Anxiety Yoshimizu et al. Psychopharmacology, 2006, 186, 587-593 also demonstrated the anxiolytic effect of MGS0039, a potent antagonist of group II mGlu receptors (mGlu2 and mGlu3), by using a fear-conditioned stress (CFS) model representing emotional abnormalities, including anxiety. The CFS model reflects mental stress without physical stimuli and is useful in predicting the clinical efficacy of anxiolytics. In these studies, MGS0039 significantly reduced freezing behavior, similar to diazepam and fluvoxamine, suggesting the anxiolytic potential of MGS0039. 2 / 3 The receptor, as an autoreceptor located on glutamatergic terminals, inhibits neurotransmitter release, and in vivo mGlu 2 / 3 Treatment with an antagonist, such as MGS0039, results in an increase in extracellular glutamate. Therefore, a moderate increase in glutamate levels in specific brain regions induced by MGS0039 may produce an anxiolytic-like effect observed in CFS models. These results suggest that MGS0039 may lead to mGlu 2 / 3 This suggests that blocking [the signal] may be effective in treating anxiety disorders.

[0230] F. Mode of administration The therapeutic method may include any number of forms of administration of the disclosed composition. Forms of administration may include tablets, pills, sugar-coated tablets, 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. For the preparation of pharmaceutical compositions for oral administration, the drug may be mixed with commonly known and used adjuvants and excipients, such as gum arabic, talc, starch, sugars (e.g., mannitose, methylcellulose, lactose, etc.), gelatin, surfactants, magnesium stearate, aqueous or non-aqueous solvents, paraffin derivatives, crosslinking agents, dispersants, emulsifiers, lubricants, preservatives, flavoring agents (e.g., etheric 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 fine particles, such as nanoparticle compositions.

[0231] 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. Examples of 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 it may be administered in the form of liposomes or nanosuspensions.

[0232] As used herein, the term "parenteral" refers to modes of administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, and intra-articular injections and infusions.

[0233] G. Combination therapy Further therapeutic agents may be administered concurrently or sequentially with the disclosed compounds and compositions. Sequential administration includes administration before or after the disclosed compounds and compositions. In some embodiments, further therapeutic agents or agents may be administered in the same composition as the disclosed compounds. In other embodiments, there may be a time interval between the administration of the further therapeutic agent and the disclosed compound. In some embodiments, administration of the further therapeutic agent with the disclosed compound may allow for lower doses of other therapeutic agents and / or less frequent administration. When used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used alone. Accordingly, the 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 compounds of the present invention with not only one other active compound, but also two or more other active compounds. For example, the compound of formula (I) can be combined with various antidepressants, Alzheimer's disease drugs, and anxiolytics.

[0234] Compounds of formula (I) can be combined with the following antidepressants, but are not limited to: selective serotonin reuptake inhibitors (SSRIs), e.g., citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, indalpine, paroxetine, sertraline, and dimmerizine; serotonin-norepinephrine reuptake inhibitors (SNRIs), e.g., venlafaxine, desvenlafaxine, duloxetine, milnacipran, levomirnacipran, and sibutramine; noradrenergic and specific Serotonin-mediated antidepressants (NaSSAs) or tetracyclic antidepressants (TeCAs), e.g., aptazapine, esmirtazapine, mianserin, mirtazapine, and setiptiline; serotonin antagonists and reuptake inhibitors (SARIs), e.g., etoperidone, lorpiprazole, mepiprazole, nefazodone, trazodone, bilazodone, and niaprazine; norepinephrine-dopamine reuptake inhibitors (NDRIs), e.g., almodafinil, bupropion, desoxypipradrol, dexmethylphenidate, meth Luphenidate, modafinil, prolyntan, and tametraline; serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs), e.g., nehopam, amitifadine, tesofensin, and tedachioxetine; tricyclic antidepressants (TCAs), e.g., clomipramine, desipramine, imipramine, dibenzepine, lofepramine, nortriptyline, protriptyline, amitriptyline, amitriptylinoxide, amoxapine, buttriptyline, demexiptyline, dimethacrine, dosurepin, doxepin imipraminooxide, melitracene, metapramine, nitroxazepine, noxyptyline, pipofezin, propizepine, quinupramine, amineptin, iprendol, opipramole, thianeptin, and trimipramine; as well as negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu5), such as maboglucant, basimuglucant, dipraglucant, STX107, and N-(5-fluoropyridine-2-yl)-6-methyl-4-(pyrimidine-5-yloxy)picolinamide.

[0235] Compounds of formula (I) can be combined with the following Alzheimer's disease drugs, but are not limited to: acetylcholinesterase inhibitors, e.g., tacrine, rivastigmine, galantamine, donepezil, edrophonium, physostigmine, pyridostigmine, ambenonium, rivastigmine, radostigyl, and ungeremin; and NMDA receptor antagonists, e.g., memantine, amantadine, dersemin, and ketamine.

[0236] The compound of formula (I) can be combined with the following anxiolytics, but is not limited to: buspirone, tandosprine, gepirone, adaptol, afobazole, hiroxidine, validol, melatonin, and benzodiazepines, such as alprazolam, chlordiazepoxide, clonazepam, diazepam, etizolam, lorazepam, oxazepam, and tofisopam.

[0237] The disclosed compounds may be compounds [e.g., one or more compounds of formula (I)], the systemic or topical compositions described above, or both; and may be included in a kit comprising information, instructions, or both, on how the use of the kit provides treatment for medical conditions in mammals (especially humans). The information and instructions may be in the form of words, pictures, or both. Further or otherwise, the kit may preferably include drugs, compositions, or both, which have the benefit of treating or preventing medical conditions in mammals (e.g., humans); and information, instructions, or both, on how to apply the drugs or compositions.

[0238] The compounds and processes of the present invention will be better understood by referring to the following examples, which are intended to illustrate but not limit the scope of the invention. [Examples]

[0239] 5. Examples All NMR spectra were recorded using a 400 MHz AMX Bruker NMR spectrometer. 1The H chemical shift is reported as a δ value at ppm (low field) using a deuterated solvent as an internal standard. The data are reported as follows: chemical shift, multiplicity (s=single line, bs=broad single line, d=double line, t=triple line, q=quadruple line, dd=double line of double lines, m=multiple line, ABq=AB quadruple line), coupling constant, and integral value. Reverse-phase LCMS analysis was performed using an Agilent 1200 system consisting of a binary pump with degasser, high-performance autosampler, thermostat-equipped column compartment, C18 column, diode array detector (DAD), and Agilent 6150 MSD, with the following parameters. The gradient condition was 5% to 95% acetonitrile over 1.4 minutes (aqueous phase: 0.1% TFA (in water)). The sample was separated at 0.5 mL / min using a Waters Acquity UPLC BEH C18 column (1.7 μm, 1.0 × 50 mm) while maintaining the column and solvent temperature at 55°C. The DAD was set to scan at 190–300 nm, and the signals used were at 220 nm and 254 nm (both using a 4 nm wide band). The MS detector was set up with an electrospray ionization source, and low-resolution mass spectra were obtained by scanning at 140–700 AMU with a step size of 0.2 AMU and a peak width of 0.008 min at 0.13 cycles / second. 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 fragmenter voltage was set to 100 V. Data was acquired using Agilent Chemstation and Analytical Studio Reviewer software.

[0240] The following abbreviations may be used in the examples and schemes: AIBN is 2,2'-azobis(2-methylpropionitrile); ATM stands for atmospheric pressure; Celite® is diatomaceous earth; DCM is dichloromethane; DIAD is diisopropyl azodicarboxylate; DME is 1,2-dimethoxyethane; DMF is N,N-dimethylformamide; DMAP is 4-dimethylaminopyridine; DMSO is dimethyl sulfoxide; eq, eq., or equiv means equivalent; Et3N is triethylamine;  is ethyl acetate; h or hr is time; Hz stands for Hertz; LCMS is a liquid chromatography-mass spectrometry method; MeCN is acetonitrile; MeOH is methanol; MeOD is CH3OD; min or min. means minutes; mW or μW refers to microwave irradiation; NBS is N-bromosuccinimide; NMO is 4-methylmorpholine N-oxide; Ph stands for phenyl, PhNTf2 is N-phenyl-bis(trifluoromethanesulfonimide); Pd(dppf)Cl2 is [1,1'-bis(diphenylphosphin)ferrocene]dichloropalladium(II); The Pd-PEPPSI(trademark)-IPent catalyst is dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-ylidene](3-chloropyridyl)palladium(II) (CAS#1158652-41-5); PPh3 is triphenylphosphine; ppm is parts per million; PTFE is polytetrafluoroethylene; rt, RT, or rt is room temperature; The third generation of the RuPhos palladium cycle is (2-dicyclohexylphosphin-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate; sat. is saturated; Tf is triflate; TFA is trifluoroacetic acid; THF stands for tetrahydrofuran.

[0241] Preparation of intermediates Intermediate Example 1. 6-Bromo-4-chloroisoindorin-1-one (Intermediate B). [ka] Methyl 5-bromo-2-(bromomethyl)-3-chlorobenzoate (intermediate A). To a solution of methyl 5-bromo-3-chloro-2-methylbenzoate (3.0 g, 11.4 mmol) in carbon tetrachloride (53 mL), N-bromosuccinimide (2.21 g, 1.1 mmol) and AIBN (195 mg, 0.1 mmol) were added. The reaction mixture was heated to 90°C. After 3 hours, the reaction mixture was washed with water (20 mL) and separated. The aqueous layer was extracted with DCM (2 × 20 mL), and the combined organic layers were washed with brine (100 mL). The organic layers were passed through a hydrophobic phase separator and concentrated under vacuum to obtain the crude residue. The residue was purified by normal-phase column chromatography (0-100% hexane / Depositphotos) to obtain intermediate A. 1 H NMR(400MHz,DMSO-d6)δ 8.11(d,J=2.1Hz,1H),7.99(d,J=2.1Hz,1H),4.96(s,2H),3.89(s,3H);ES-MS[M+1] + :343.8.

[0242] 6-Bromo-4-chloroisoindorin-1-one (intermediate B). Methyl 5-bromo-2-(bromomethyl)-3-chlorobenzoate (3.49 g, 10.2 mmol) was dissolved in a 7N solution of ammonia in methanol (29.5 mL). The reaction mixture was stirred in a Teflon® screw-cap flask and heated to 100°C. After 3 hours, the cap was carefully removed, and the solvent was evaporated under vacuum. The crude residue was purified by normal-phase column chromatography (0-10% siRNA / MeOH) to obtain the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.95(s,1H),7.97(d,J=1.6Hz,1H),7.79(d,J=1.6Hz,1H),4.36(s,2H);ES-MS[M+1] + :245.9 and 247.9.

[0243] Intermediate Example 2. 4-Chloro-6-(2,4-difluorophenyl)isoindorin-1-one (Intermediate C). [ka] A mixture of 6-bromo-4-chloroisoindorin-1-one (500 mg, 2.03 mmol), Pd(dppf)Cl2·DCM (166 mg, 0.20 mmol), 2,4-difluorophenylboronic acid (352 mg, 2.23 mmol), and Cs2CO3 (665 mg, 2.03 mmol) was mixed with degassed 1,4-dioxane (7.4 mL) and water (740 μL). The reaction atmosphere was removed, the vessel was purged with nitrogen (3×), and the sealed vessel was subjected to microwave irradiation at 120°C. After 15 min, DCM (15 mL) was added to the reaction mixture thus obtained, and a precipitate formed. The reaction mixture was filtered, the precipitate was isolated, and the title compound was obtained. 1H NMR(400MHz,DMSO-d6)δ 8.91(s,1H),7.86-7.82(m,1H),7.76-7.73(m,1H),7.73-7.68(m,1H),7.43(ddd ,J=11.5,9.3,2.6Hz,1H),7.23(td,J=8.2,2.4Hz,1H),4.44(s,2H);ES-MS[M+1] + :280.1.

[0244] Intermediate Example 3. 6-(2,4-difluorophenyl)-1-oxoisoindoline-4-carbaldehyde (Intermediate E). [ka] 6-(2,4-difluorophenyl)-4-vinylisoindorin-1-one (intermediate D). A mixture of 4-chloro-6-(2,4-difluorophenyl)isoindorin-1-one (100 mg, 0.36 mmol), RuPhos Paradacycle 3rd generation (29.9 mg, 0.04 mmol), potassium carbonate (150.4 mg, 1.07 mmol), and potassium(I) trifluoro(vinyl)borate (119.7 mg, 0.89 mmol) was mixed with a degassed solution of THF (11 mL) and water (3.3 mL). The reaction mixture was subjected to microwave irradiation at 140°C. After 15 min, the reaction mixture was diluted with DCM, and the organic layer was passed through a hydrophobic phase separator. The organic layer was concentrated under vacuum, and the resulting residue was purified by normal-phase column chromatography (0-10% DCM / MeOH) to obtain intermediate D. ES-MS[M+1] + :372.0.

[0245] 6-(2,4-difluorophenyl)-1-oxoisoindorin-4-carbaldehyde (intermediate E). 6-(2,4-difluorophenyl)-4-vinylisoindorin-1-one (54.7 mg, 0.2 mmol) was suspended in a solution of THF (1.61 mL) and water (1.61 mL) at 0°C. Osmium tetroxide (253 μL, 2.5 wt% in tert-butanol) and 4-methylmorpholine N-oxide (25 μL, 50 wt% in H2O) were added to this mixture. The reaction mixture was stirred for 10 minutes, and then stirred at ambient temperature. After 1 hour, sodium periodate (108.3 mg, 0.50 mmol) was added, and the mixture was stirred for a further 1 hour. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with a 10% saturated sodium thiosulfate aqueous solution (2 × 10 mL). The aqueous layer was extracted with ethyl acetate (3 × 10 mL), and the combined organic extract was washed with brine (50 mL). The organic layer was passed through a hydrophobic phase separator and concentrated under vacuum to obtain the title compound. 1 H NMR(400MHz,DMSO-d6)δ 10.24(s,1H),8.88(s,1H),8.37(t,J=1.5Hz,1H),8.07(t,J=1.7Hz,1H),7.78(td,J=8.9,6.5Hz,1H),7 .47(ddd,J=11.6,9.3,2.6Hz,1H),7.28(tdd,J=8.4,2.6,1.0Hz,1H),4.71(d,J=1.1Hz,2H);ES-MS[M+1] + :274.1.

[0246] Intermediate Example 4. 7-(1-cyclopropyl-1H-pyrazole-3-yl)-3-oxoisoindoline-5-yltrifluoromethanesulfonate (Intermediate G). [ka] 4-(1-cyclopropyl-1H-pyrazole-3-yl)-6-hydroxyisoindoline-1-one (intermediate F). A mixture of 4-bromo-6-hydroxyisoindole-1-one (50 mg, 0.22 mmol), Pd(dppf)Cl2·DCM (18 mg, 0.02 mmol), cesium carbonate (71.8 mg, 0.22 mmol), and 1-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (102.7 mg, 0.44 mmol) was mixed with a solution of 1,4-dioxane (383 μL) and water (38.3 μL). The reaction mixture was heated to 120°C under microwave irradiation. After 30 min, the reaction mixture was diluted with DCM, and the organic layer was passed through a hydrophobic phase separator. The precipitate was collected on a filter to obtain intermediate F. The material was carried over without refining. ES-MS[M+1] + :256.1.

[0247] 7-(1-cyclopropyl-1H-pyrazole-3-yl)-3-oxoisoindoline-5-yltrifluoromethanesulfonate (intermediate G). A mixture of 4-(1-cyclopropyl-1H-pyrazole-3-yl)-6-hydroxyisoindoline-1-one (27.1 mg, 0.11 mmol), N-phenyl-bis(trifluoromethanesulfonimide) (41.7 mg, 0.12 mmol), and DMAP (1.3 mg, 0.01 mmol) was mixed with DCM (312 μL). The reaction mixture was cooled to 0°C in an ice bath while adding triethylamine (29.6 μL, 0.21 mmol) dropwise. The reaction mixture was removed from the ice bath and allowed to stand at ambient temperature for 3 hours, after which the solvent was removed under vacuum. The residue was purified by normal-phase column chromatography (0-10% DCM / MeOH) to obtain the title compound. ES-MS[M+1] + :388.3.

[0248] Intermediate Example 5. 7-(5-cyano-1-methyl-1H-pyrazole-4-yl)-3-oxoisoindoline-5-yltrifluoromethanesulfonate (Intermediate I). [ka] 4-(6-hydroxy-1-oxoisoindolin-4-yl)-1-methyl-1H-pyrazole-5-carbonitrile (intermediate H). A mixture of 4-bromo-6-hydroxyisoindole-1-one (40 mg, 0.17 mmol), Pd(dppf)Cl2·DCM (14.4 mg, 0.02 mmol), potassium phosphate (113 mg, 0.53 mmol), and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-carbonitrile (81.8 mg, 0.35 mmol) was mixed with a solution of 1,4-dioxane (442 μL) and water (44.2 μL). The reaction mixture was heated to 120°C under microwave irradiation. After 4 hours, the reaction mixture was diluted with DCM and the organic layer was passed through a hydrophobic phase separator. The precipitate was collected on a filter to obtain intermediate H. The material was carried over without purification. ES-MS[M+1] + :255.1.

[0249] 7-(5-cyano-1-methyl-1H-pyrazole-4-yl)-3-oxoisoindoline-5-yltrifluoromethanesulfonate (intermediate I). A mixture of 4-(6-hydroxy-1-oxoisoindoline-4-yl)-1-methyl-1H-pyrazole-5-carbonitrile (44 mg, 0.17 mmol), N-phenyl-bis(trifluoromethanesulfonimide) (67.7 mg, 0.19 mmol), and DMAP (2.1 mg, 0.02 mmol) was mixed with DCM (509 μL). The reaction mixture was cooled to 0°C in an ice bath while adding triethylamine (48.2 μL, 0.35 mmol) dropwise. The reaction mixture was removed from the ice bath and allowed to stand at ambient temperature for 3 hours, after which the solvent was removed under vacuum. The residue was purified by normal-phase column chromatography (0-10% DCM / MeOH) to obtain the title compound. 1 H NMR(400MHz,DMSO-d6)δ 9.09(s,1H),8.21(s,1H),7.87(d,J=2.3Hz,1H),7.83(d,J=2.3Hz,1H),4.61(s,2H),4.11(s,3H);ES-MS[M+1] + :387.0.

[0250] Intermediate Example 6. 7-(isothiazole-4-yl)-3-oxoisoindoline-5-yltrifluoromethanesulfonate (Intermediate K). [ka] 6-Hydroxy-4-(isothiazole-4-yl)isoindorin-1-one (intermediate J). A mixture of 4-bromo-6-hydroxyisoindole-1-one (40 mg, 0.18 mmol), Pd(dppf)Cl2·DCM (14.4 mg, 0.02 mmol), potassium phosphate (113.3 mg, 0.53 mmol), and isothiazole-4-ylboronic acid (45.2 mg, 0.35 mmol) was mixed with a solution of 1,4-dioxane (442 μL) and water (44.2 μL). The reaction mixture was heated to 100°C and stirred. After 4 hours, the reaction mixture was diluted with DCM, and the organic layer was passed through a hydrophobic phase separator. The precipitate was collected on a filter to obtain intermediate F. The material was carried over without purification. ES-MS[M+1] + :233.1.

[0251] 7-(isothiazol-4-yl)-3-oxoisoindorin-5-yltrifluoromethanesulfonate (intermediate K). A mixture of 6-hydroxy-4-(isothiazol-4-yl)isoindorin-1-one (40 mg, 0.17 mmol), N-phenyl-bis(trifluoromethanesulfonimide) (67.7 mg, 0.19 mmol), and DMAP (2.1 mg, 0.02 mmol) was mixed with DCM (312 μL). The reaction mixture was cooled to 0°C in an ice bath while adding triethylamine (48 μL, 0.34 mmol) dropwise. The reaction mixture was removed from the ice bath and the solvent was removed under vacuum at ambient temperature after 3 hours. The residue was purified by normal-phase column chromatography (0-10% DCM / MeOH) to obtain the title compound. 1H NMR(400MHz,DMSO)δ 9.52(s,1H),9.10(d,J=2.3Hz,2H),8.17(d,J=2.3Hz,1H),7.74(d,J=2.3Hz,1H),4.69(s,2H);ES-MS[M+1] + :365.1. [ka]

[0252] Intermediate Example 7. 6-Chloro-4-(isothiazol-4-yl)isoindorin-1-one (Intermediate L). A mixture of 4-bromo-6-chloroisoindorin-1-one (50 mg, 0.20 mmol), Pd(dppf)Cl2·DCM (16.61 mg, 0.02 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazol (64.23 mg, 0.30 mmol), and Cs2CO3 (199.50 mg, 0.61 mmol) was mixed with degassed 1,4-dioxane (2 mL) and water (0.5 mL). The reaction atmosphere was removed, the vessel was purged with nitrogen (3 ×), and the sealed vessel was microwaved at 120°C. After 15 min, the reaction product was concentrated to obtain the crude residue. Next, the reaction products were purified by reverse-phase chromatography (5-30% H2O:MeCN w / 0.1% TFA). The desired fraction was basicized with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the combined organic layer was concentrated. The residue was purified by normal-phase chromatography (0-90% hexane / ethyl acetate) to obtain the title compound. 1 H NMR(400MHz,DMSO-d6)δ 9.49(s,1H),9.10(s,1H),8.96(s,1H),8.06(d,J=1.90Hz,1H),7.69(d,J=1.87Hz,1H),4.62(s,2H);ES-MS[M+1] + :251.0. [ka]

[0253] Intermediate Example 8. 6-Chloro-4-(1-isopropyl-1H-pyrazole-5-yl)isoindorin-1-one (Intermediate M). Prepared in the same manner as Intermediate L. 1 H NMR(400MHz,DMSO-d6)δ 8.88(s,1H),7.77(d,J=1.90Hz,1H),7.66(d,J=1.90Hz,1H),7.61(d,J=1.74Hz,1H),6.54(d,J=1.83Hz,1H),4.38(quintet,J=12.96,6.54Hz 1H),4.28(s,2H),1.36(d,J=6.52Hz,6H);ES-MS[M+1] + :276.1.

[0254] Example: Compound Synthesis Example 1. 6-(2,4-difluorophenyl)-4-(6-methylpyridine-3-yl)isoindorin-1-one (Compound 5). [ka] A mixture of 4-chloro-6-(2,4-difluorophenyl)isoindorin-1-one (20 mg, 0.07 mmol), RuPhos Paradacycle third generation (6.0 mg, 0.007 mmol), potassium carbonate (30.1 mg, 0.21 mmol), and (6-methylpyridine-3-yl)boronic acid (24.5 mg, 0.18 mmol) was mixed with a degassed solution of THF (2.2 mL) and water (662 μL). The reaction mixture was subjected to microwave irradiation at 140°C. After 15 min, the reaction mixture was diluted with DCM, and the organic layer was passed through a hydrophobic phase separator. The organic layer was concentrated under vacuum, and the resulting residue was purified by reverse-phase column chromatography to obtain the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.81(s,1H),8.77(d,J=2.5Hz,1H),8.03(dd,J=8.0,2.5Hz,1H),7.82-7.76(m,3H) ,7.46-7.37(m,2H),7.28-7.20(m,1H),4.61-4.55(m,2H),2.54(s,3H);ES-MS[M+1] + :337.0.

[0255] Example 2. 6-(2,4-difluorophenyl)-4-(1-methyl-1H-imidazole-5-yl)isoindorin-1-one (compound 7). [ka] A mixture of 4-chloro-6-(2,4-difluorophenyl)isoindorin-1-one (20 mg, 0.07 mmol), RuPhos Paradacycle third generation (6.0 mg, 0.007 mmol), potassium carbonate (30.1 mg, 0.21 mmol), and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole (37.2 mg, 0.18 mmol) was mixed with a degassed solution of THF (2.2 mL) and water (662 μL). The reaction mixture was subjected to microwave irradiation at 140°C. After 15 min, the reaction mixture was diluted with DCM, and the organic layer was passed through a hydrophobic phase separator. The organic layer was concentrated under vacuum, and the resulting residue was purified by reverse-phase column chromatography to obtain the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.79(s,1H),7.83-7.68(m,4H),7.42(ddd,J=11.1,9.3,2.6Hz,1H),7.30(d,J=1. 1Hz,1H),7.23(tdd,J=8.5,2.7,1.0Hz,1H),4.47(s,2H),3.68(s,3H);ES-MS[M+1] + :326.0.

[0256] Example 3. 4-(1-cyclopropyl-1H-pyrazole-4-yl)-6-(2,4-difluorophenyl)isoindorin-1-one (compound 18). [ka] A mixture of 4-chloro-6-(2,4-difluorophenyl)isoindorin-1-one (20 mg, 0.07 mmol), RuPhos Paradacycle third generation (6.0 mg, 0.007 mmol), potassium carbonate (30.1 mg, 0.21 mmol), and 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (41.9 mg, 0.18 mmol) was mixed with a degassed solution of THF (2.2 mL) and water (662 μL). The reaction mixture was subjected to microwave irradiation at 140°C. After 15 min, the reaction mixture was diluted with DCM, and the organic layer was passed through a hydrophobic phase separator. The organic layer was concentrated under vacuum, and the resulting residue was purified by reverse-phase column chromatography to obtain the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.84(s,1H),8.34(s,1H),8.00-7.96(m,1H),7.95(t,J=1.4Hz,1H),7.74 (td,J=8.9,6.6Hz,1H),7.62(t,J=1.8Hz,1H),7.42(ddd,J=11.0,9.3,2. ES-MS[M+1] + :352.0.

[0257] Example 4. 4-(1-cyclopropyl-1H-pyrazole-3-yl)-6-(2,4-difluorophenyl)isoindorin-1-one (compound 1). [ka] A mixture of 7-(1-cyclopropyl-1H-pyrazole-3-yl)-3-oxoisoindoline-5-yltrifluoromethanesulfonate (25 mg, 0.06 mmol), Pd(dppf)Cl2·DCM (5.3 mg, 0.006 mmol), potassium phosphate (41.7 mg, 0.19 mmol), and (2,4-difluorophenyl)boronic acid (20.4 mg, 0.13 mmol) was mixed with a solution of 1,4-dioxane (209 μL) and water (20.9 μL). The reaction mixture was heated to 120°C under microwave irradiation and stirred. After 15 min, the reaction mixture was diluted with DCM, passed through a hydrophobic phase separator, and concentrated under vacuum. The resulting residue was purified by normal-phase column chromatography (0-10% DCM / MeOH) and reverse-phase column chromatography to obtain the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.75(s,1H),8.10(t,J=1.5Hz,1H),7.93(d,J=2.4Hz,1H),7.77-7.67(m,2H),7.42(ddd,J=11.6,9.4,2.6Hz,1H),7.28-7. 20(m,1H),6.91(d,J=2.4Hz,1H),4.65(s,2H),3.84(hept,J=3.8Hz,1H),1.20-1.12(m,2H),1.06-0.97(m,2H).ES-MS[M+1] + :352.3.

[0258] Example 5. 6-(2,4-difluorophenyl)-4-(isothiazol-4-yl)isoindorin-1-one (compound 2). [ka] A mixture of 7-(isothiazol-4-yl)-3-oxoisoindoline-5-yltrifluoromethanesulfonate (20 mg, 0.06 mmol), Pd(dppf)Cl2·DCM (4.6 mg, 0.006 mmol), potassium phosphate (35.4 mg, 0.16 mmol), and (2,4-difluorophenyl)boronic acid (17.3 mg, 0.11 mmol) was mixed with a solution of 1,4-dioxane (196 μL) and water (19.6 μL). The reaction mixture was heated to 110°C and stirred. After 16 hours, the reaction mixture was diluted with DCM, passed through a hydrophobic phase separator, and concentrated under vacuum. The resulting residue was purified by normal-phase column chromatography (0-10% DCM / MeOH), and the impure material was concentrated. The residue was purified by reverse-phase column chromatography (5-45% H2O:MeCN w / 0.05% NH4OH) to obtain the title compound. ES-MS[M+1] + :329.1.

[0259] Example 6. 3-Fluoro-4-(7-(isothiazol-4-yl)-3-oxoisoindorin-5-yl)benzonitrile (Compound 43). [ka] A mixture of 6-chloro-4-(isothiazol-4-yl)isoindorin-1-one (10 mg, 0.04 mmol), Ruphos Paradacycle G3 (3.3 mg, 0.001 mmol), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (14.8 mg, 0.06 mmol), and K2CO3 (16.8 mg, 0.12 mmol) was mixed with degassed THF (2 mL) and water (0.5 mL). The reaction atmosphere was removed, the reactor was purged with nitrogen (3 ×), and the sealed reactor was subjected to microwave irradiation at 140 °C. After 15 min, the reaction product was concentrated to obtain the crude residue. The reaction product was then purified by reverse-phase column chromatography (5-45% H2O:MeCN w / 0.05% NH4OH) to obtain the title compound. 1H NMR(400MHz,DMSO-d6)δ 9.50(s,1H),9.14(s,1H),8.93(s,1H),8.16(s,1H),8.05(dd,J=10.68,1. 44Hz,1H),7.98(t,7.99Hz,1H),7.90-7.8(m,2H),4.70(s,2H);ES-MS[M+1] + :335.9

[0260] Example 7. 4-(isothiazol-4-yl)-6-(2,4,6-trifluorophenyl)isoindorin-1-one (compound 45). [ka] A mixture of 6-chloro-4-(isothiazol-4-yl)isoindorin-1-one (10 mg, 0.04 mmol), Ruphos Paradacycle G3 (3.3 mg, 0.004 mmol), (2,4,6-trifluorophenyl)boronic acid (10.5 mg, 0.06 mmol), and K2CO3 (16.8 mg, 0.12 mmol) was mixed with degassed THF (2 mL) and water (0.5 mL). The reaction atmosphere was removed, the reactor was purged with nitrogen (3 ×), and the sealed reactor was subjected to microwave irradiation at 140 °C. After 15 min, the reaction product was concentrated to obtain the crude residue. The reaction product was then purified by reverse-phase column chromatography (10-50% H2O: MeCN w / 0.05% NH4OH) to obtain the title compound. 1 H NMR(400MHz,DMSO-d6)δ 9.46(s,1H),9.08(s,1H),8.91(s,1H),8.04(s,1H),7.73(s,1H),7.40(t,J=8.61Hz,2H),4.69(s,2H);ES-MS[M+1] + :346.9.

[0261] Example 8. 5-Fluoro-2-(7-(isothiazol-4-yl)-3-oxoisoindorin-5-yl)benzonitrile (Compound 42). [ka] A mixture of 6-chloro-4-(isothiazol-4-yl)isoindorin-1-one (10 mg, 0.04 mmol), Ruphos Paradacycle G3 (3.3 mg, 0.004 mmol), 5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (14.8 mg, 0.06 mmol), and K2CO3 (16.8 mg, 0.12 mmol) was mixed with degassed THF (2 mL) and water (0.5 mL). The reaction atmosphere was removed, the reactor was purged with nitrogen (3 ×), and the sealed reactor was subjected to microwave irradiation at 140 °C. After 15 min, the reaction product was concentrated to obtain the crude residue. The reaction product was then purified by reverse-phase column chromatography (5-35% H2O: MeCN w / 0.1% TFA). The desired fraction was basicized with saturated sodium bicarbonate solution, extracted with ÃO, and the organic layer was concentrated to obtain the title compound. 1 H NMR(400MHz,DMSO-d6)δ 9.49(s,1H),9.13(s,1H),8.94(s,1H),8.17(d,J=1.62Hz,1H),8.05(dd,J=8.70,2.7 1Hz,1H),7.91-7.85(m,2H),7.75(td,J=8.56,2.82Hz,1H),4.71(s,2H);ES-MS[M+1] + :336.0.

[0262] Example 9. 4-(isothiazol-4-yl)-6-(2,3,4-trifluorophenyl)isoindorin-1-one (compound 47). [ka] A mixture of 6-chloro-4-(isothiazol-4-yl)isoindorin-1-one (10 mg, 0.04 mmol), Ruphos Paradacycle G3 (3.3 mg, 0.001 mmol), 4,4,5,5-tetramethyl-2-(2,3,4-trifluorophenyl)-1,3,2-dioxaborolane (10.5 mg, 0.06 mmol), and K2CO3 (16.8 mg, 0.12 mmol) was mixed with degassed THF (2 mL) and water (0.5 mL). The reaction atmosphere was removed, the reactor was purged with nitrogen (3 ×), and the sealed reactor was subjected to microwave irradiation at 140 °C. After 15 min, the reaction product was concentrated to obtain the crude residue. The reaction product was then purified by reverse-phase column chromatography (5-35% H2O: MeCN w / 0.1% TFA). The fraction was basicized with saturated sodium bicarbonate solution, extracted with ÃO, and the organic layer was concentrated to obtain the title compound. 1 H NMR(400MHz,DMSO-d6)δ 9.50(s,1H),9.13(s,1H),8.92(s,1H),8.11(s,1H),7.84(s,1H),7.67-7.59(m,1H),7.53-7.45(m,1H),4.69(s,2H);ES-MS[M+1] + :347.1.

[0263] Example 10. 6-(3,6-dihydro-2H-pyran-4-yl)-4-(1-isopropyl-1H-pyrazole-5-yl)isoindorin-1-one (compound 86). [ka] A mixture of 6-chloro-4-(1-isopropyl-1H-pyrazole-5-yl)isoindorin-1-one (10 mg, 0.04 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11.4 mg, 0.05 mmol), Ruphos paradacycle G3 (3.04 mg, 0.004 mmol), and K2CO3 (15.3 mg, 0.11 mmol) was mixed with degassed THF (2 mL) and water (0.5 mL). The reaction atmosphere was removed, the reactor was purged with nitrogen (3 ×), and the sealed reactor was subjected to microwave irradiation at 140°C. After 15 min, the reaction product was concentrated to obtain the crude residue. Next, the reaction product was purified by reverse-phase column chromatography (2-30% H2O:MeCN w / 0.05% NH4OH) to obtain the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.71(s,1H),7.78(d,J=1.43Hz),7.60(dd,J=4.51,1.54Hz),6.51(d,J=1.77Hz),6.47(s,1H),4. 39(quintet,13.01,6.42Hz,1H),4.28(s,2H),4.26(d,J=2.58Hz,2H),3.85(t,J=5.36Hz,2H),2.54(d J=1.54Hz,2H),1.37(d,J=6.51Hz,6H);ES-MS[M+1] + :324.3.

[0264] Example 11. 4-(1-isopropyl-1H-pyrazole-5-yl)-6-(tetrahydro-2H-pyran-4-yl)isoindorin-1-one (compound 88). [ka] To a solution of 6-(3,6-dihydro-2H-pyran-4-yl)-4-(1-isopropyl-1H-pyrazole-5-yl)isoindorin-1-one (12 mg, 0.04 mmol) in MeOH (2 mL), palladium-supported activated carbon (0.40 mg, 0.004 mmol) was added, then the reaction atmosphere was removed and the mixture was purged with nitrogen (3×). The reaction atmosphere was removed again and the mixture was purged with hydrogen (3×). After 12 hours at rt, the reaction mixture was filtered through a Celite® pad and washed with MeOH / DCM. The collected organic layer was concentrated. The crude residue was purified by reverse-phase column chromatography (15-45% H2O:MeCN w / 0.1% TFA). The desired fraction was basicized with saturated sodium bicarbonate solution, extracted with Â, and the organic layer was concentrated to obtain the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.66(s,1H),7.62(d,J=1.27Hz,1H),7.59(d,J=1.78Hz,1H),7.43(d,J=1 .32Hz,1H),6.49(d,J=1.84Hz,1H),4.38(quintet,J=13.07,6.47Hz,1H),4.2 5(s,2H),3.98(dd,10.60,3.16Hz,2H),3.47(td,J=11.48,2.30Hz,2H),3 .05-2.95(m,1H),1.80-1.68(m,4H),1.37(d,J=6.57Hz,6H);ES-MS[M+1] + :326.1.

[0265] The compounds shown in Table 1A can be prepared in the same manner as the compounds described above, using appropriate starting materials.

[0266] [Table 1A-1]

[0267] [Table 1A-2]

[0268] [Table 1A-3]

[0269] Table 1A-4

[0270] Table 1A-5

[0271] Table 1A-6

[0272] Table 1A-7

[0273] Table 1A-8

[0274]

Table 1A-9

[0275]

Table 1A-10

[0276]

Table 1A-11

[0277]

Table 1A-12

[0278]

Table 1A-13

[0279] [Table 1A-14]

[0280] [Table 1A-15]

[0281] [Table 1A-16]

[0282] [Table 1A-17]

[0283] Example 12. 6-(2,4-difluorophenyl)-4-(2,3-dihydro-1H-imidazo[1,2-b]pyrazole-1-yl)isoindorin-1-one (compound A2). [ka] A mixture of cesium carbonate (70.3 mg, 0.21 mmol) and Pd-PEPPSI-IPent (2.3 mg, 0.003 mmol) was removed, and the mixture was purged with nitrogen (3×). To this mixture, 4-chloro-6-(2,4-difluorophenyl)isoindorin-1-one (20 mg, 0.07 mmol), 2,3-dihydro-1H-imidazo[1,2-b]pyrazole (11.7 mg, 0.11 mmol), and 1,2-dimethoxyethane (200 μL) were added. The reaction mixture was heated at 120°C under microwave irradiation. After 30 min, the reaction mixture was passed through a hydrophobic phase separator and concentrated under vacuum. The resulting residue was purified by reverse-phase column chromatography to obtain the title compound. 1H NMR(400MHz,DMSO-d6)δ 8.81(s,1H),7.71(td,J=8.9,6.6Hz,1H),7.55(t,J=1.5Hz,1H),7.45-7.35(m,3H),7.2 7-7.16(m,1H),5.79(d,J=1.9Hz,1H),4.68-4.56(m,4H),4.40-4.28(m,2H);ES-MS[M+1] + :353.3.

[0284] Example 13. 6-(2,4-difluorophenyl)-4-(3-hydroxy-3-(trifluoromethyl)azetidine-1-yl)isoindorin-1-one (compound A19). [ka] A mixture of cesium carbonate (70.3 mg, 0.21 mmol) and Pd-PEPPSI-IPent (2.3 mg, 0.003 mmol) was removed and the mixture was purged with nitrogen (3×). To this mixture, 4-chloro-6-(2,4-difluorophenyl)isoindorin-1-one (20 mg, 0.07 mmol), 3-(trifluoromethyl)azetidine-3-ol hydrochloride (19 mg, 0.11 mmol), and 1,2-dimethoxyethane (200 μL) were added. The reaction mixture was heated at 120°C under microwave irradiation. After 2 hours, the reaction mixture was passed through a hydrophobic phase separator and concentrated under vacuum. The resulting residue was purified by reverse-phase column chromatography to obtain the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.65(s,1H),7.64(td,J=8.9,6.7Hz,1H),7.37(ddd,J=11.0,9.3,2.6Hz,1H),7.23-7.16(m,1H),7.15- 7.12(m,1H),6.73-6.65(m,1H),4.44(s,2H),4.34(d,J=9.0Hz,2H),4.08(d,J=8.9Hz,2H);ES-MS[M+1] + :385.2.

[0285] Example 14. 1-(6-(2,4-difluorophenyl)-1-oxoisoindorin-4-yl)-3-methylpyrrolidine-3-carbonitrile (compound A7). [ka] A mixture of Cs2CO3 (70.3 mg, 0.21 mmol) and PEPPSI catalyst (2.3 mg, 0.003 mmol) was added to a vial and purged with nitrogen. Then, a mixture of 4-chloro-6-(2,4-difluorophenyl)isoindorin-1-one (20 mg, 0.07 mmol), 3-methylpyrrolidine-3-carbonitrile (11.8 mg, 0.11 mmol), and 1,2-dimethoxyethane (0.5 mL) was added, and the reaction mixture was purged with nitrogen (3×). The sealed reaction vessel was subjected to microwave irradiation at 140°C. After 30 minutes, the reaction mixture was diluted with DCM and passed through a PTFE filter. The reaction mixture was concentrated and then purified by reverse-phase column chromatography (15-45% H2O: MeCN w / 0.1% TFA). The fraction was basicized with saturated sodium bicarbonate solution, extracted with ÃO, and the organic layer was concentrated to obtain the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.67(s,1H),7.66(ddd,J=8.88,8.88,6.75Hz,1H),7.37(ddd,J=11.42,9.39,2.59Hz,1H),7.23-7.16(m,1H),7.10(s,1H),6.76(s,1H),4. 67(dd,J=41.11,17.51Hz,2H),3.96(d,J=9.62Hz,1H),3.76-3.64(m,2H),3.51(d,J=9.70Hz,1H),2.46-2.38(m,1H),2.14-2.05(m,1H),.52 s,1H);ES-MS[M+1] + :354.2.

[0286] The compounds shown in Table 1B can be prepared in the same manner as the compounds described above, using appropriate starting materials.

[0287] [Table 1B-1]

[0288] [Table 1B-2]

[0289] [Table 1B-3]

[0290] [Table 1B-4]

[0291] [Table 1B-5]

[0292] Example 15. 6-(2,4-difluorophenyl)-4-(morpholinomethyl)isoindorin-1-one (compound B2). [ka] A mixture of 4-chloro-6-(2,4-difluorophenyl)isoindorin-1-one (20 mg, 0.07 mmol), RuPhos Paradacycle third generation (6.0 mg, 0.007 mmol), potassium carbonate (30.1 mg, 0.21 mmol), and potassium trifluoro(morpholinomethyl)borate (37 mg, 0.18 mmol) was mixed with a degassed solution of THF (2.2 mL) and water (662 μL). The reaction mixture was subjected to microwave irradiation at 140°C. After 15 min, the reaction mixture was diluted with DCM, and the organic layer was passed through a hydrophobic phase separator. The organic layer was concentrated under vacuum, and the resulting residue was purified by reverse-phase column chromatography to obtain the title compound. 1H NMR(400MHz,DMSO-d6)δ 8.65(s,1H),7.71-7.59(m,3H),7.40(ddd,J=11.6,9.3,2.6Hz,1H),7.22(tdd,J=8.5,2.6 ,1.0Hz,1H),4.47(s,2H),3.62(s,2H),3.60-3.53(m,4H),2.43-2.34(m,4H);ES-MS[M+1] + :345.0.

[0293] Example 16. 6-(2,4-difluorophenyl)-4-(1-methylpiperidine-3-yl)isoindorin-1-one (compound B3). [ka] 6-(2,4-difluorophenyl)-4-(1-methyl-1,2,5,6-tetrahydropyridine-3-yl)isoindorin-1-one. A mixture of 4-chloro-6-(2,4-difluorophenyl)isoindorin-1-one (20 mg, 0.07 mmol), RuPhos Paradacycle 3rd generation (6.0 mg, 0.007 mmol), potassium carbonate (30.1 mg, 0.21 mmol), and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (39.9 mg, 0.18 mmol) was mixed with a degassed solution of THF (2.2 mL) and water (662 μL). The reaction mixture was subjected to microwave irradiation at 140°C. After 15 minutes, the reaction mixture was diluted with DCM, and the organic layer was passed through a hydrophobic phase separator. The organic layer was concentrated under vacuum to obtain the title compound as a crude residue, which was carried over without further purification. ES-MS[M+1] + :341.3.

[0294] 6-(2,4-difluorophenyl)-4-(1-methylpiperidine-3-yl)isoindorin-1-one (compound B3). 6-(2,4-difluorophenyl)-4-(1-methyl-1,2,5,6-tetrahydropyridine-3-yl)isoindorin-1-one (9.8 mg, 0.03 mmol) was added to a slurry of Pd-C (10 wt%; 12.5 mg) in MeOH (500 μL). The reaction mixture was removed, purged with N2 (3×), then removed again, and purged with hydrogen (3×; 1 atm). After 16 hours with stirring at ambient temperature, the mixture was filtered through a Celite® pad, and the filtrate was concentrated under vacuum to obtain the title compound. 1 1H NMR (400MHz, DMSO-d6)δ 8.67(s,1H),7.70-7.63(m,1H),7.63-7.59(m,2H),7.39(ddd,J=11.7,9.4 ,2.6Hz,1H),7.25-7.17(m,1H),4.47(s,2H),2.96-2.81(m,2H),2.81-2.73 (m,1H),2.18(s,3H),2.09-2.00(m,1H),1.94(td,J=11.2,2.9Hz,1H),1.88 -1.79(m,1H),1.76-1.56(m,2H),1.50(qd,J=11.9,4.0Hz,1H);ES-MS[M+1] + :343.1.

[0295] Example 17. 6-(2,4-difluorophenyl)-4-(pyrrolidine-3-yl)isoindorin-1-one (compound B6). [ka] A mixture of tert-butyl 3-(6-(2,4-difluorophenyl)-1-oxoisoindorin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate, 4-chloro-6-(2,4-difluorophenyl)isoindorin-1-one (60 mg, 0.21 mmol), RuPhos Paradacycle 3rd generation (18 mg, 0.02 mmol), potassium carbonate (90.2 mg, 0.64 mmol), and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (158.3 mg, 0.54 mmol) was mixed with a degassed solution of THF (10 mL) and water (2 mL). The reaction mixture was subjected to microwave irradiation at 140°C. After 15 minutes, the reaction mixture was diluted with DCM, and the organic layer was passed through a hydrophobic phase separator. The organic layer was concentrated under vacuum to obtain the title compound as a crude residue, which was carried over without further purification. ES-MS[M+1] + :413.4.

[0296] 6-(2,4-difluorophenyl)-4-(2,5-dihydro-1H-pyrrole-3-yl)isoindorin-1-one. A solution of tert-butyl 3-(6-(2,4-difluorophenyl)-1-oxoisoindorin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (66.4 mg, 0.16 mmol) in DCM (0.5 mL) was cooled to 0°C. Then, TFA (0.5 mL) was added, and the solution was stirred at ambient temperature. After 2 hours, saturated NaHCO3 aqueous solution (5 mL) was added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with DCM (3 × 15 mL). The combined organic extracts were concentrated under vacuum to obtain the title compound as a crude residue, which was carried over without further purification. ES-MS[M+1] + :313.2.

[0297] 6-(2,4-difluorophenyl)-4-(pyrrolidin-3-yl)isoindorin-1-one (compound B6). 6-(2,4-difluorophenyl)-4-(2,5-dihydro-1H-pyrrole-3-yl)isoindorin-1-one (62 mg, 0.2 mmol) was dissolved in MeOH (0.5 mL) and 10 wt% Pd-C (84 mg, 0.08 mmol) was added. The reaction mixture was removed, purged with N2 (3×), then removed again, and purged with hydrogen (3×, 1 atm). After 16 h, the mixture was filtered through a Celite® pad, and the filtrate was concentrated under vacuum to obtain the title compound. ES-MS[M+1] + :315.2.

[0298] Example 18. 6-(2,4-difluorophenyl)-4-(morpholine-3yl)isoindorin-1-one (compound B5). [ka] To a solution of 6-(2,4-difluorophenyl)-1-oxoisoindoline-4-carbaldehyde (20 mg, 0.07 mmol) in DCM (300 μL), calcium sulfate (23.9 mg, 0.18 mmol), a 4 Å molecular sieve, and 2-((tributylstannyl)methoxy)ethane-1-amine (26.7 mg, 0.07 mmol) were added. The reaction mixture was heated at 40°C for 4 hours. Separate reaction mixtures of copper(II) trifluoromethanesulfonate (53.2 mg, 0.15 mmol) and hexafluoroisopropanol (300 μL) in 2,6-lutidine (20 μL) were stirred at ambient temperature. After 2 hours, calcium sulfate (23.9 mg, 0.18 mmol) was added to the solution. The first reaction mixture was diluted with DCM (1 mL) and passed directly through a PTFE filter into the second reaction mixture. The combined solution was stirred overnight at ambient temperature. A 15% NH4OH aqueous solution (1 mL) was added to the reaction mixture. After 10 minutes, the aqueous layer was extracted using DCM (3 × 15 mL). The combined organic portion was concentrated under vacuum. The resulting residue was purified by normal-phase column chromatography (0-100% hexane / RINKAN) to obtain an impure residue. This residue was then purified by reverse-phase column chromatography to obtain the title compound. ES-MS[M+1] + :331.2.

[0299] Example 19. 4-((8-oxa-3-azabicyclo[3.2.1]octan-3-yl)methyl)-6-(2,4-difluorophenyl)isoindorin-1-one (compound B7). [ka] A mixture of 6-(2,4-difluorophenyl)-1-oxoisoindoline-4-carbaldehyde (20 mg, 0.07 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane (16.6 mg, 0.15 mmol) in DCM (1.41 mL) was mixed with sodium triacetoxyborohydride (31 mg, 0.15 mmol). After 1 hour, saturated aqueous NaHCO3 solution (10 mL) was added to the reaction mixture. After separating the layers, the aqueous layer was extracted with a 3:1 chloroform / i-PrOH solution (20 mL). The combined organic extract was filtered through a hydrophobic phase separator. The resulting residue was purified by reverse-phase column chromatography to obtain the title compound. 1 H NMR(400MHz,DMSO-d6)δ 8.63(s,1H),7.70-7.60(m,3H),7.40(ddd,J=11.6,9.3,2.6Hz,1H),7.26-7.18(m,1H),4.47(s,2H), 4.26-4.16(m,2H),3.57(s,2H),2.55-2.51(m,2H),2.29-2.20(m,2H),1.86-1.66(m,4H);ES-MS[M+1] + :371.2.

[0300] The compounds shown in Table 1C can be prepared in the same manner as the compounds described above, provided that appropriate starting materials are used.

[0301] [Table 1C-1]

[0302] [Table 1C-2]

[0303] [Table 1C-3]

[0304] biological activity Cell lines that co-express A.mGlu and GIRK Human or rat mGlu2 and G protein-coupled inward-rectifying potassium (GIRK) channels, or human embryonic kidney (HEK-293) cell lines stably co-expressing human mGlu3 and GIRK, were used for in vitro evaluation of compound activity in thallium flux assays using fluorescent thallium indicator dyes.

[0305] Cell-based Tl flux assay of B.mGlu and GIRK activity The day before the assay, GIRK cells co-expressing human mGlu3 and human or rat mGlu2 as described above were seeded at a density of 15,000 cells / 20 μL / well in assay medium (glutamine-depleted basal DMEM supplemented with 10% prepared FBS, 20 mM HEPES, and 1 mM sodium pyruvate) in amine-coated 384-well plates with blackwall clear bottoms. The cells were incubated at 37°C in the presence of 5% CO2. The following day, assay buffer (Hanks equilibrium 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. Before adding the 2× Thallos dye solution (final concentration 0.34 μM relative to cells) to the assay buffer, the dye stock (2.97 mM in DMSO) was mixed with 10% pluronic acid to a 1:1 ratio. The cells were washed with assay buffer using a microplate washer to remove the culture medium, 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 at 25°C for 1 hour. During the cell staining incubation period, 10-point serial dilutions of the compound were obtained from a 10 mM DMSO compound stock by performing 1:3 serial dilutions in DMSO using a Bravo liquid handler. The 2× compound plates were generated by transferring 0.24 μL of the diluted compound from each well to a daughter plate using an Echo acoustic liquid handler. This was further diluted in 40 μL of assay buffer to obtain final concentrations ranging from 30 μM to 1.5 nM in the assay. Prepare an agonist plate (5×) and measure the EC 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 This includes the glutamate concentration (the concentration that extracts 80% of the most effective glutamate concentration).

[0306] After adding the dye, 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 to monitor changes in fluorescence in 480 nm excitation and 540 nm emission settings. Briefly, after collecting baseline fluorescence, 20 μL of the compound was added and incubated for 2 minutes and 20 seconds. Immediately after this, 10 μL of glutamate-thallium buffer was added to the wells containing the compound. The fluorescence signal was monitored for a further 2.5 minutes after glutamate addition. Multiple reference wells without the compound were glutamate-free (for baseline reference), EC 80 Glutamic acid, or EC max Glutamate was added (for normalization to the maximum response). Throughout the experiment, fluorescence was measured at a frequency of once every 2 seconds before glutamate addition and once every 1 second after glutamate addition. Each compound at a range of concentrations was generated once on each plate, and replicas from two or three plates were used in each experimental operation. Thallium solutions were handled and processed according to guidelines from the Department of Chemical Safety, Vanderbilt University.

[0307] Data were normalized using a static ratio function (F / F0) by dividing all fluorescence measurements for the corresponding wells by the initial fluorescence value. The increase in signal resulting from the second addition of glutamate / thallium was measured by determining the gradient from 3 to 13 seconds after addition. The mean of all baseline gradients (compound-free, glutamate-free) was determined and this value was subtracted from all other gradient values. All EC max Determine the average of the gradient and use this value to set the baseline-corrected gradient to the maximum percentage (%E) max ) was standardized. %E for each compound in the series max The values ​​were plotted against the logarithm of the concentration and fitted to a four-parameter logistic equation without fixed parameters.

[0308] The effectiveness is derived from the fitting of the curve to the IC. 50 Report as follows: No plateau was reached, and E max For compounds that do not inhibit the glutamate response down to less than 20%, a low potency value of >10,000 nM is assigned. max For compounds that do not inhibit less than 60%, a potency of >30,000 nM is assigned. Compounds that inhibit more than 20% and less than 60% E max If a plateau of inhibition is reached, the IC from the curve fitting is 50 Report this and assign the category "Partial NAM".

[0309] Activity of compounds in C.mGlu GIRK cell-based Tl flux assay The compound was synthesized as described above. Activity (IC) 50 The ) was determined using the mGlu GIRK cell-based Tl flux assay described above, and the data are shown in Tables 2, 3, and 4. Unless otherwise noted, the data are from a single experiment.

[0310] [Table 2-1]

[0311] [Table 2-2]

[0312] [Table 2-3]

[0313] [Table 2-4]

[0314] [Table 3-1]

[0315] [Table 3-2]

[0316] [Table 4]

[0317] D. Novel object recognition testing The compound can be evaluated for its effects on cognition and cognitive memory in novel object recognition tests.

[0318] Male Sprague-Dawley rats (290-330g) from Envigo (Indianapolis, IN) are acclimated in an animal facility for at least one week. A novel object recognition test is performed as previously described (Rook et al., ACS Chem. Neurosci. 2017, 8, 866-883). Briefly, the animals are acclimated to empty test chambers for 10 minutes each for two consecutive days. On the third day (training day [T1]), the animals are pre-treated for 1 hour with a dose of the vehicle or test compound, and then placed for 10 minutes in a test chamber containing two identical objects (two metal boxes or two plastic bottles filled with water). 24 hours later (test day [T2]), the animals are placed for 5 minutes in a test chamber containing two distinct objects (one metal box and one plastic bottle), i.e., one familiar object and one object not previously exposed to contact. The animal's behavior is videotaped for analysis following object search by an observer blinded to the procedure. Different object searches are performed offline, and the time spent searching for different objects is measured. From this, the recognition index is determined as follows:

number

[0319] The recognition indices of vehicle-treated and compound-treated animals are compared using one-way ANOVA followed by Tukey's test.

[0320] The above detailed description and attached examples are for illustrative purposes only and should not be considered as limitations to the scope of the invention as defined solely by the attached claims and their equivalents.

[0321] 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 those relating to chemical structure, substituents, derivatives, intermediates, synthesis, composition, formulation, or method of use of the invention, may be made without departing from the spirit and scope thereof.

Claims

1. Compound of formula (I), or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (In the formula: R １ａ and R １ｂ These are independently hydrogen or C １～４ It is alkyl; R ２ is hydrogen or C １～６ It is alkyl; R ３ is a 6- to 12-membered aryl, C ５～７ carbocyclic ring, a 5- to 12-membered heterocyclic ring containing 1 to 3 heteroatoms, or a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms, wherein the heteroatoms are independently selected from the group consisting of N, O, and S, and wherein R ３ is unsubstituted or is substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C １～４ alkyl, halogen, cyano, C １～２ haloalkyl, -OR ３ａ and C(O)R ３ａ ; R ３ａ Each time they appear, hydrogen and C appear independently. １～４ Alkyl, C １～２ Haloalkyl, or C ３～４ It is cycloalkyl; R ４ and R ５ These are, independently, hydrogen and C １～４ Alkyl, halogen, cyano, C １～２ Haloalkyl, -OC １～４ Alkyl, or -OC １～２ It is a haloalkyl; R ６ G ６ or -C １～４ Alkilen-G ６ And; G ６ is a 5-12 member heteroaryl, a 4-12 member heterocyclil, or a phenyl, wherein the heteroaryl and heterocyclil contain 1 to 3 heteroatoms independently selected from the group consisting of O, N, and S, where G ６ is either non-substituted or C １～４ Alkyl, halogen, cyano, C １～２ Haloalkyl, oxo, -OR ６ａ , -N(R ６ａ ) ２ ,-SR ６ａ , -N(R ６ａ ) C(O)R ６ａ , -C(O)OR ６ａ , -C(O)N(R ６ａ ) ２ , -SO ２ N(R) ６ａ ) ２ , -SO ２ R ６ｂ , -C １～６ Alkylene-OH, G ６ａ , and -C １～４ Alkilen-G ６ａ It is substituted with a first substituent selected from the group consisting of and optionally C １～４ Alkyl, halogen, cyano, C １～２ Haloalkyl, oxo, -OC １～４ Alkyl and -OC １～２ It is further substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl groups; R ６ａ Each time they appear, hydrogen and C appear independently. １～４ Alkyl, C １～２ Haloalkyl, C ３～４ Cycloalkyl, or -C １～４ Alkylene-C ３～４ It is cycloalkyl; R ６ｂ Each time it appears, C １～４ Alkyl, C １～２ Haloalkyl, C ３～４ Cycloalkyl, or -C １～４ Alkylene-C ３～４ It is cycloalkyl; and G ６ａ Phenylenide, C ３～６ A cycloalkyl, a 5-6 membered heteroaryl containing 1-3 heteroatoms, or a 4-6 membered heterocyclil containing 1-2 heteroatoms, wherein the heteroatoms in the heteroaryl and heterocyclil are independently selected from the group consisting of O, N, and S, where G ６ａ C １～４ Alkyl, C １～２ Fluoroalkyl, halogen, cyano, oxo, OH, and -OC １～４ It is optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl groups; However, the aforementioned compound is 4,6-bis[4-(1,1-dimethylethyl)phenyl]-2,3-dihydro-2-methyl-1H-isoindole-1-one; or 4-(3-fluoro-5-hydroxyphenyl)-6-(3-fluorophenyl)-2,3-dihydro-1H-isoindole-1-one isn't it).

2. R １ａ and R １ｂ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

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

4. G ６ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound is an unsubstituted or substituted 5- to 12-membered heteroaryl.

5. G ６ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the unsubstituted or substituted 5- to 12-membered heteroaryl ring system in is a 9- to 10-membered fully aromatic bicyclic heteroaryl.

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

7. G ６ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is an unsubstituted or substituted 4 to 12-membered heterocycline.

8. G ６ The compound according to any one of claims 1 to 3 or 7, or a pharmaceutically acceptable salt thereof, wherein the ring system of the unsubstituted or substituted 4- to 12-membered heterocyclil in is a 4- to 7-membered monocyclic heterocyclil, a 6- to 12-membered bridged bicyclic heterocyclil, a 6- to 12-membered spirocyclic heterocyclil, or an 8- to 12-membered condensed bicyclic heterocyclil, and the heterocyclil contains 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S.

9. G ６ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is an unsubstituted or substituted phenyl.

10. G ６ but, 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

11. R ６ However, G ６ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. R ６ However, -C １～４ Alkilen-G ６ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

13. R ３ The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein the compound is an unsubstituted or substituted 6- to 12-membered aryl compound.

14. R ３ The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein the unsubstituted or substituted 6- to 12-membered aryl ring system in is phenyl.

15. R ３ However, the non-substituted or substituted C ５～７ A compound according to any one of claims 1 to 12, which is a carbocyclyl, or a pharmaceutically acceptable salt thereof.

16. R ３ is the unsubstituted or substituted 5- to 12-membered heterocyclyl, the compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

17. R ３ The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein the compound is an unsubstituted or substituted 5- to 6-membered heteroaryl.

18. R ３ but, 【Transformation 5】 The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof.

19. R ４ and R ５ However, hydrogen, C １～４ A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of alkyl and halogen.

20. R ４ and R ５ is hydrogen, respectively, the compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof.

21. 4-(1-cyclopropyl-1H-pyrazole-3-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(isothiazole-4-yl)isoindorin-1-one 4-(6-(2,4-difluorophenyl)-1-oxoisoindorin-4-yl)-1-methyl-1H-pyrazole-5-carbonitrile 4,6-Bis(2,4-difluorophenyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(6-methylpyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(oxazole-5-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1-methyl-1H-imidazole-5-yl)isoindorin-1-one 4-(1-(difluoromethyl)-1H-pyrazole-4-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(3,5-dimethylisoxazole-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(pyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(pyridine-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(pyridazine-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(6-methylpyridazine-4-yl)isoindorin-1-one 4-(6-(2,4-difluorophenyl)-1-oxoisoindorin-4-yl)-1-methyl-1H-pyrrole-2-carbonitrile 6-(2,4-difluorophenyl)-4-(thiophen-3-yl)isoindorin-1-one 4-(1-cyclopentyl-1H-pyrazole-4-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 4-(1-cyclobutyl-1H-pyrazole-4-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 4-(1-cyclopropyl-1H-pyrazole-4-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1-methyl-1H-pyrazole-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2,4,5-trimethylthiophen-3-yl)isoindorin-1-one 4-(1-cyclohexyl-1H-pyrazole-4-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(quinoline-7-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(isoquinoline-6-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(quinoline-6-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(quinoline-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(isoquinoline-7-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(quinoxaline-6-yl)isoindorin-1-one 4-(benzo[b]thiophen-2-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(furan-2-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1-isopropyl-1H-pyrazole-5-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(thiazole-5-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2-(trifluoromethyl)pyrimidine-5-yl)isoindorin-1-one 5-(6-(2,4-difluorophenyl)-1-oxoisoindorin-4-yl)picolinonitrile N-(5-(6-(2,4-difluorophenyl)-1-oxoisoindorin-4-yl)pyridine-2-yl)acetamide 6-(2,4-difluorophenyl)-4-(4-isopropylpyrimidine-5-yl)isoindorin-1-one 4-(6-cyclopropylpyridine-3-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(pyrimidine-5-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(imidazo[1,2-a]pyridine-6-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2-(methylthio)pyrimidine-5-yl)isoindorin-1-one 4-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1-(2-hydroxy-2-methylpropyl)-3,5-dimethyl-1H-pyrazole-4-yl)isoindorin-1-one 5-Fluoro-2-(7-(isothiazole-4-yl)-3-oxoisoindorin-5-yl)benzonitrile 3-Fluoro-4-(7-(isothiazole-4-yl)-3-oxoisoindorin-5-yl)benzonitrile 6-(2-fluoro-4-methoxyphenyl)-4-(isothiazole-4-yl)isoindorin-1-one 4-(isothiazole-4-yl)-6-(2,4,6-trifluorophenyl)isoindorin-1-one 6-(4-(difluoromethoxy)-2-fluorophenyl)-4-(isothiazole-4-yl)isoindorin-1-one 4-(isothiazole-4-yl)-6-(2,3,4-trifluorophenyl)isoindorin-1-one 6-(4-fluoro-2-methoxyphenyl)-4-(isothiazole-4-yl)isoindorin-1-one 6-(2,3-difluoro-4-methoxyphenyl)-4-(isothiazole-4-yl)isoindorin-1-one 6-(2,4-difluoro-5-methylphenyl)-4-(isothiazole-4-yl)isoindorin-1-one 5-Fluoro-4-(7-(isothiazole-4-yl)-3-oxoisoindorin-5-yl)-2-methylbenzonitrile 6-(2,5-difluoro-4-methoxyphenyl)-4-(isothiazole-4-yl)isoindorin-1-one 4-(7-(isothiazole-4-yl)-3-oxoisoindoline-5-yl)-3-methoxybenzonitrile 6-(4-ethoxy-2,3-difluorophenyl)-4-(isothiazole-4-yl)isoindorin-1-one 2,6-Difluoro-3-(7-(Isothiazole-4-yl)-3-oxoisoindorin-5-yl)benzonitrile 6-(2,6-difluoro-4-methoxyphenyl)-4-(isothiazole-4-yl)isoindorin-1-one 2,6-Difluoro-4-(7-(isothiazole-4-yl)-3-oxoisoindorin-5-yl)benzonitrile 2,3-difluoro-4-(7-(isothiazole-4-yl)-3-oxoisoindorin-5-yl)benzaldehyde 4-(isothiazole-4-yl)-6-(3,4,5-trifluorophenyl)isoindorin-1-one 6-(5-fluoro-2-methylpyridine-4-yl)-4-(isothiazole-4-yl)isoindorin-1-one 2-Isopropoxy-4-(7-(isothiazole-4-yl)-3-oxoisoindorin-5-yl)benzonitrile 6-(2,4-difluorophenyl)-4-(1-(tetrahydrofuran-3-yl)-1H-pyrazole-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2-oxo-1,2-dihydropyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2-(dimethylamino)pyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2-(pyrroridine-1-yl)pyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2,6-dimethylpyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2-(trifluoromethyl)pyridine-3-yl)isoindorin-1-one 4-(2-cyclopropylpyridine-3-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 3-(6-(2,4-difluorophenyl)-1-oxoisoindorin-4-yl)picolinonitrile 6-(2,4-difluorophenyl)-4-(2-methoxypyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(6-fluoro-2-methylpyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2,6-difluoropyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2-methylpyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2-isopropoxypyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1-isobutyl-1H-pyrazole-5-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(3,5-dimethyl-1H-pyrazole-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1,3-dimethyl-1H-pyrazole-5-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1-ethyl-3-(trifluoromethyl)-1H-pyrazole-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1-ethyl-1H-pyrazole-5-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1,4-dimethyl-1H-pyrazole-5-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1,5-dimethyl-1H-pyrazole-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1,3,5-trimethyl-1H-pyrazole-4-yl)isoindorin-1-one 4-(1-isopropyl-1H-pyrazole-5-yl)-6-(4-methoxycyclohexa-1-en-1-yl)isoindorin-1-one 6-(3,6-dihydro-2H-pyran-4-yl)-4-(1-isopropyl-1H-pyrazole-5-yl)isoindorin-1-one 4-(1-isopropyl-1H-pyrazole-5-yl)-6-(1,4-dioxaspiro[4.5]deca-7-en-8-yl)isoindorin-1-one 4-(1-isopropyl-1H-pyrazole-5-yl)-6-(tetrahydro-2H-pyran-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(4-methylpyridine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2-(trifluoromethyl)pyridine-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2-methoxy-6-methylpyridine-4-yl)isoindorin-1-one 6-(3,6-dihydro-2H-pyran-4-yl)-4-(1,3,5-trimethyl-1H-pyrazole-4-yl)isoindorin-1-one 6-(3,6-dihydro-2H-pyran-4-yl)-4-(1,5-dimethyl-1H-pyrazole-4-yl)isoindorin-1-one 6-(3,6-dihydro-2H-pyran-4-yl)-4-(1,4-dimethyl-1H-pyrazole-5-yl)isoindorin-1-one 6-(3,6-dihydro-2H-pyran-4-yl)-4-(1-ethyl-1H-pyrazole-5-yl)isoindorin-1-one 6-(3,6-dihydro-2H-pyran-4-yl)-4-(1,3-dimethyl-1H-pyrazole-5-yl)isoindorin-1-one 6-(3,6-dihydro-2H-pyran-4-yl)-4-(2-methylpyridine-3-yl)isoindorin-1-one 6-(tetrahydro-2H-pyran-4-yl)-4-(1,3,5-trimethyl-1H-pyrazole-4-yl)isoindorin-1-one 4-(1,5-dimethyl-1H-pyrazole-4-yl)-6-(tetrahydro-2H-pyran-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-((3aR,6aS)-1,1-dioxide-3a-(trifluoromethyl)hexahydro-5H-thieno[2,3-c]pyrrole-5-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2,3-dihydro-1H-imidazo[1,2-b]pyrazole-1-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1,1-dioxidethiomorpholino)isoindorin-1-one 6-(2,4-difluorophenyl)-4-morpholinisoindorin-1-one 6-(2,4-difluorophenyl)-4-thiomorpholinisoindorin-1-one 6-(2,4-difluorophenyl)-4-(2,2,6,6-tetramethylmorpholino)isoindorin-1-one 1-(6-(2,4-difluorophenyl)-1-oxoisoindorin-4-yl)-3-methylpyrrolidine-3-carbonitrile 6-(2,4-difluorophenyl)-4-(3-(2-hydroxypropan-2-yl)pyrrolidine-1-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(4-(1-methyl-1H-pyrazole-3-yl)piperidine-1-yl)isoindorin-1-one 1-(6-(2,4-difluorophenyl)-1-oxoisoindorin-4-yl)piperidine-3-carbonitrile 6-(2,4-difluorophenyl)-4-(3-(trifluoromethyl)piperidine-1-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(3-(2-hydroxypropan-2-yl)piperidine-1-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1-oxa-4-thia-8-azaspiro[4.5]decane-8-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(4-(pyrroridine-1-yl)piperidine-1-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(4,4-dimethylpiperidine-1-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(hexahydro-2H-pyrano[3,2-c]pyridine-6(5H)-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(3-methoxypiperidine-1-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(3-hydroxy-3-(trifluoromethyl)azetidine-1-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(7-oxo-2,6-diazaspiro[3,4]octan-2-yl)isoindorin-1-one 4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-(2,4-difluorophenyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(6-methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-1-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(thiomorpholinomethyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(morpholinomethyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1-methylpiperidine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(1-methylpiperidine-4-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(morpholine-3-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(pyrrolidine-3-yl)isoindorin-1-one 4-((8-oxa-3-azabicyclo[3.2.1]octan-3-yl)methyl)-6-(2,4-difluorophenyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-((3-hydroxy-3-(trifluoromethyl)azetidine-1-yl)methyl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(3,4-dihydro-2H-pyran-6-yl)isoindorin-1-one 6-(2,4-difluorophenyl)-4-(tetrahydro-2H-pyran-2-yl)isoindorin-1-one A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

23. The method involves administering to a subject in need of a therapeutically effective amount of the compound described in any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in claim 22, to a subject in need of it. ２ A method for treating diseases or disorders associated with dysfunction of the organ.

24. The method according to claim 23, 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.

25. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, 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.

26. Use of a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, in the manufacture of a pharmaceutical 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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