NEGATIVE ALLOSTERIC MODULATORS OF METABOTROPIC GLUTAMATE

RECEPTOR 2

RELATED APPLICATIONS

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

TECHNICAL FIELD

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

BACKGROUND

[0003] Metabotropic glutamate (mGlu) receptors, a class of G-protein coupled receptor (GPCR) family C, have recently emerged as targets of potential therapeutic value. They bind glutamate, an amino acid that is the most prominent excitatory neurotransmitter in the human central nervous system (CNS). mGlu ₃ arc known to activate biochemical cascades, leading to the modification of other proteins. For example, this can lead to changes in a synapse's excitability by presynaptic inhibition of neurotransmission, or modulation and even induction of postsynaptic responses.

[0004] Metabotropic glutamate receptor 2 ( mGlu ₃ ) is one of eight mGlu ₃ that have been identified, and, along with mGlu ₃ , is classified as a group II mGlu. Group II mGlu ₃ play an important role is synaptic plasticity, which directly effects cognitive function (including learning and memory), among other things. The effects of group II mGlu ₃ occur primarily prcsynaptically via their inhibition of glutamate release. These effects can also be due to the inhibition of non- vesicular glutamate release from glia. However, group II receptors are known to also reduce the activity of postsynaptic potentials, both excitatory and inhibitory, in the cortex. [0005] Dysfunction of mGlu ₂ has been implicated in many diseases and/or disorders. Hence, targeting mGlu ₂ activity has been the subject of much investigation. Several reports have highlighted its link to a variety of diseases, such as depression, anxiety, obsessive-compulsive disorder, cognitive disorders, Alzheimer’s disease, and autism spectrum disorders. Accordingly, there exists a need for selective modulators of mGlu ₂ .

SUMMARY

[0006] Tn one aspect, the invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof,

R ¹ R ² R ¹ J_ N

R® O

1

R ⁴ ^R ⁵

R ³

(I), wherein:

R ¹ , at each occurrence, is independently hydrogen, fluoro, or C _1-4 alkyl;

R ² is hydrogen or C _1-6 alkyl;

R ³ is a 6- to 12-membered aryl or 5- to 12-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S, wherein R ³ is unsubstituted or 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, OH, -OC _1-4 alkyl, and -OC _1-2 haloalkyl;

R ⁴ is G ⁴ , -C _1-4 alkylene-G ⁴ , Cy, or -C _1-4 alkylene-Cy;

G ⁴ is a 6- to 12-membered aryl or 5- to 12-membered heteroaryl, wherein G ⁴ is unsubstituted or substituted with a first substituent selected from the group consisting of C _1-4 alkyl, halogen, cyano, C _1-2 haloalkyl, oxo, -OR ^4a , -N(R ^4a ) ₂ , -N(R ^4a )C(O)R ^4a , -N(R ^4a )SO ₂ R ^4b , -C(O)N(R ^4a ) ₂ , -SO ₂ N(R ^4a ) ₂ , -SO ₂ R ^4b , -C _1-4 alkylene-OH, G ^4a . and -Ci- ₄ alkylene-G ^4a . and optionally further substituted with 1-3 substituents independently selected from the group consisting of C _1-4 alkyl, halogen, cyano, C _1-2 haloalkyl, -OC _1-4 alkyl, and -OC _1-2 haloalkyl;

R ^4a , at each occurrence, is independently hydrogen, C _1-4 alkyl, C _1-2 haloalkyl, G ^4a , or -C _1-4 alky lene-G ^4a ; R ^4b is C _1-4 alkyl, Ci-ihaloalkyl, G ^4a , or -C _1-4 alkylene-G ^4a ;

G ^4a is a phenyl, C _3-6 cycloalkyl, 5- to 6-mcmbcrcd hctcroaryl containing 1-3 hctcroatoms, or 4- to 6-membered heterocyclyl containing 1-2 heteroatoms, the heteroatoms in the heteroaryl and heterocyclyl being independently selected from the group consisting of O, N, and S, wherein G ^4a is optionally substituted with 1-4 substituents independently selected from the group consisting of C _1-4 alkyl, C _1-2 fluoroalkyl, halogen, cyano, oxo, OH, and -OC _1-4 alkyl;

Cy is a C _3-6 carbocyclyl or a 4- to 6-membered heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of N, O, and S, wherein Cy is optionally substituted with a first substituent independently selected from the group consisting of Ci- 4alkyl, C _1-2 fluoroalkyl, halogen, oxo, OH, -OC _1-4 alkyl, G ^4a , and Cnalkylcnc G ^4a , and optionally further substituted with 1-3 substituents independently selected from the group consisting of C _1-4 alkyl, Ci-ifluoroalkyl, and halogen; and

R ⁵ and R ⁶ are each independently hydrogen, C _1-4 alkyl, halogen, cyano, C _1-2 haloalkyl, -OCi- 4alkyl, or -OC _1-2 haloalkyl.

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

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

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

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

[0012] In another aspect, the 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 disorders, Alzheimer’s disease, and autism spectrum disorders. [0013] In another aspect, the invention provides a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, and instructions for use.

DETAILED DESCRIPTION

[0014] Disclosed herein are negative allosteric modulators (NAMs) of mGlu ₂ . The modulators can be compounds of formula (I). Compounds of formula (I) may exhibit selectivity for mGlu 2 over other mGlu receptors. Compounds of formula (I) can be used to treat or prevent diseases and disorders associated with mGlu ₂ by modulating mGlu ₂ activity. mGlu ₂ has been implicated in a number of different diseases and disorders including, but not limited to, depression, anxiety, obsessive-compulsive disorder, cognitive disorders, Alzheimer’s disease, and autism spectrum disorders.

[0015] Since the orthosteric binding sites of the mGlu isoforms are highly conserved, very few selective modulators of the mGlu ₃ that bind at the orthosteric site have been identified. One strategy to selectively bind and modulate the mGlu ₃ includes identifying allosteric sites which may be amenable to modulation by a small molecule. In particular, negative allosteric modulation of mGlu 2 can result in inhibition of processes governed by mGlu ₂ and provide therapeutic benefits for disorders caused by mGlu ₂ dysfunction.

1. Definitions

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety.

The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0017] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of’ and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.

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

[0019] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 ^th Ed., inside cover, and specific functional groups are generally defined as described therein.

Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, axe described in 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 Edition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

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

[0021] The term “alkyl,” as used herein, means a straight or branched, saturated hydrocarbon chain. The term “lower alkyl” or “Ci-ealkyl” means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. The term “C _1-4 alkyl” means a straight or branched chain hydrocarbon containing from 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, zz-propyl, zso-propyl, zz-butyl, sec-butyl, zso-butyl, tezl-butyl, n- pentyl, isopentyl, neopentyl, zz-hexyl, 3 -methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n- heptyl, zz-octyl, zi-nonyl, and zz-dccyl.

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

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

[0024] The term “alkoxyfluoroalkyl,” as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a fluoroalkyl group, as defined herein. [0025] The term “alkylene”, as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon. Representative examples of alkylene include, but are not limited to, -CH ₂ - -CD ₂ - -CH ₂ CH ₂ -, -C(CH ₃ )(H)-, -C(CH ₃ )(D)-, -CH ₂ CH ₂ CH ₂ - -CH ₂ CH ₂ CH ₂ CH ₂ -. and -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -.

[0026] The term “alkylamino,” as used herein, means at least one alkyl group, as defined herein, is appended to the parent molecular moiety through an amino group, as defined herein. [0027] The term “amide,” as used herein, means -C(O)NR- or -NRC(O)-, wherein R may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.

[0028] The term “aminoalkyl,” as used herein, means at least one amino group, as defined herein, is appended to the parent molecular moiety through an alkylene group, as defined herein. [0029] The term “amino,” as used herein, means NR _x R _y , wherein R _x and R _y may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl. In the case of an aminoalkyl group or any other moiety where amino appends together two other moieties, amino may be -NR _X -, wherein R _x may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, hctcrocyclc, alkenyl, or hctcroalkyl.

[0030] The term “aryl,” as used herein, refers to a phenyl or a phenyl appended to the parent molecular moiety and fused to a cycloalkane group (e.g., the aryl may be indan-4-yl), fused to a 6-membered arene group (i.e., the aryl is naphthyl), or fused to a non-aromatic heterocycle (e.g., the aryl may be benzo[d][l,3]dioxol-5-yl). The term “phenyl” is used when referring to a substituent and the term 6-membered arene is used when referring to a fused ring. The 6- membered arene is monocyclic (e.g., benzene or benzo). The aryl may be monocyclic (phenyl) or bicyclic (e.g., a 9- to 12-membered fused bicyclic system).

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

[0032] The term “cyanofluoroalkyl,” as used herein, means at least one -CN group, is appended to the parent molecular moiety through a fluoroalkyl group, as defined herein. [0033] The term “cycloalkoxy,” as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0034] The term “cycloalkyl” or “cycloalkane,” as used herein, refers to a saturated ring system containing all carbon atoms as ring members and zero double bonds. The term “cycloalkyl” is used herein to refer to a cycloalkane when present as a substituent. A cycloalkyl may be a monocyclic cycloalkyl (e.g., cyclopropyl), a fused bicyclic cycloalkyl (e.g., decahydronaphthalenyl), or a bridged cycloalkyl in which two non-adjacent atoms of a 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 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicy clo [ 1.1.1 ] pentany 1.

[0035] The term “cycloalkenyl” or “cycloalkene,” as used herein, means a non-aromatic monocyclic or multicyclic ring system containing all carbon atoms as ring members and at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring. The term “cycloalkenyl” is used herein to refer to a cycloalkene when present as a substituent. A cycloalkenyl may be a monocyclic cycloalkenyl (e.g., cyclopentenyl), a fused bicyclic cycloalkenyl (e.g., octahydronaphthalenyl), or a bridged cycloalkenyl in which two non-adjacent atoms of a 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, cyclohcxcnyl or cyclohcptcnyl. Exemplary monocyclic cycloalkcnyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.

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

[0037] The terms cycloalkylene and heterocyclylene refer to divalent groups derived from the base ring, i.e., cycloalkane, heterocycle. For purposes of illustration, examples of cycloalkylene /x

N— i and heterocyclylene include, respectively, and . Cycloalkylene and heterocyclylene include a geminal divalent groups such as fll-Cs-scycloalkylene (i.e., ^0-3 )

A further example is 1,1 -cyclopropylene (i.e., AA ).

[0038] The term “fluoroalkyl,” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by fluorine. Representative examples of fluoroalkyl include, but arc not limited to, 2-fluorocthyl, 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 one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by fluorine. Representative examples of fluoroalkylene include, but are not limited to -CF2-, -CH2CF2-, 1,2- difluoroethylene, 1,1,2,2-tetrafluoroethylene, 1,3,3,3-tetrafluoropropylene, 1, 1,2,3, 3- pentafluoropropylene, and perfluoropropylene such as 1,1,2,2,3,3-hexafluoropropylene.

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

[0041] The term “haloalkyl,” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by a halogen. [0042] The term “haloalkoxy,” as used herein, means at least one haloalkyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom. [0043] The term “halocycloalkyl,” as used herein, means a cycloalkyl group, as defined herein, in which one or more hydrogen atoms arc replaced by a halogen.

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

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

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

[0047] The term “hydroxyl” or “hydroxy,” as used herein, means an -OH group.

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

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

[0050] Terms such as "alkyl," "cycloalkyl," "alkylene," etc. may be preceded by a designation indicating the number of atoms present in the group in a particular instance (e.g., "C _1-4 alkyl," "C _3-6 cycloalkyl," "CMalkylene"). These designations are used as generally understood by those skilled in the art. For example, the representation "C" followed by a subscripted number indicates the number of carbon atoms present in the group that follows. Thus, "Cgalkyl" is an alkyl group with three carbon atoms (i.e., n-propyl, isopropyl). Where a range is given, as in "Ci- 4," the members of the group that follows may have any number of carbon atoms falling within the recited range. A "C _1-4 alkyl," for example, is an alkyl group having from 1 to 4 carbon atoms, however arranged (i.e., straight chain or branched).

[0051] The term “substituted” refers to a group that may be further substituted with one or more non-hydrogen substituent groups. Substituent groups include, but are not limited to, halogen, =0 (oxo), =S (thioxo), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketone, amide, carbamate, and acyl.

[0052] For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

2. Compounds

A. Compounds of Formula (I)

[0053] In one aspect, the invention provides compounds of formula (I), wherein R ¹ , R ² , R ³ ,

R ⁴ , R ⁵ , and R ⁶ are as defined herein.

[0054] Unsubstituted or substituted rings (i.e., optionally substituted) such as aryl, heteroaryl, etc. are composed of both a ring system and the ring system's optional substituents. Accordingly, the ring system may be defined independently of its substituents, such that redefining only the ring system leaves any previous optional substituents present. For example, a

5- to 12-membered heteroaryl with optional substituents may be further defined by specifying the ring system of the 5- to 12-membered heteroaryl is a 5- to 6-membered heteroaryl (i.e., 5- to

6-membered heteroaryl ring system), in which case the optional substituents of the 5- to 12- membered heteroaryl are still present on the 5- to 6-membered heteroaryl, unless otherwise expressly indicated.

[0055] Where heterocyclic and heteroaromatic ring systems are defined as "containing" specified heteroatoms (e.g., 1-3 heteroatoms independently selected from the group consisting of O, N, and S), any ring atoms of the heterocyclic and heteroaromatic ring systems that are not one of the specified hctcroatoms arc carbon atoms.

[0056] In the following, embodiments of the invention are disclosed. The first embodiment is denoted El, another embodiment is denoted El.l, E2 and so forth.

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

¹ R ²

R ¹ . H-N

R® O

R ⁴ R ⁵

R ³

(I), wherein:

R ¹ , at each occurrence, is independently hydrogen, fluoro, or C _1-4 alkyl;

R ² is hydrogen or Ci-ealkyl;

R ³ is a 6- to 12-membered aryl or 5- to 12-membered heteroaryl, wherein R ³ is unsubstituted or 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, OH, -OC _1-4 alkyl, and -OC _1-2 haloalkyl;

R ⁴ is G ⁴ , -C _1-4 alkylene-G ⁴ , Cy, or -C _1-4 alkylene-Cy;

G ⁴ is a 6- to 12-membered aryl or 5- to 12-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S, wherein G ⁴ is unsubstituted or substituted with a first substituent selected from the group consisting of C _1-4 alkyl, halogen, cyano, C _1-2 haloalkyl, oxo, -OR ^4a , -N(R ^4a ) ₂ , -N(R ^4a )C(O)R ^4a , -N(R ^4a )SO ₂ R ^4b , -C(O)N(R ^4a ) ₂ , -SO ₂ N(R ^4a ) ₂ , -SO ₂ R ^4b , -C _1-4 alkylene-OH, G ^4a , and -Ci- ₄ alkylene-G ^4a , and optionally further substituted with 1-3 substituents independently selected from the group consisting of C _1-4 alkyl, halogen, cyano, C _1-2 haloalkyl, -OC _1-4 alkyl, and -OC _1-2 haloalkyl;

R ^4a , at each occurrence, is independently hydrogen, C _1-4 alkyl, C _1-2 haloalkyl, G ^4a , or

-C _1-4 alky lcnc-G ^4a ;

R ^4b is C _1-4 alkyl, C _1-2 haloalkyl, G ^4a , or -Ci- ₄ alkylene-G ^4a ;

G ^4a is a phenyl, C3 ecycloalkyl, 5- to 6-membered heteroaryl containing 1-3 heteroatoms, or 4- to 6-membered heterocyclyl containing 1-2 heteroatoms, the heteroatoms in the heteroaryl and heterocyclyl being independently selected from the group consisting of O, N, and S, wherein G ^4a is optionally substituted with 1 -4 substituents independently selected from the group consisting of C _1-4 alkyl, Ci-ifluoroalkyl, halogen, cyano, oxo, OH, and -OC _1-4 alkyl;

Cy is a C _3-6 carbocyclyl or a 4- to 6-membered heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of N, O, and S, wherein Cy is optionally substituted with a first substituent independently selected from the group consisting of Ci- 4alkyl, C _1-2 fluoroalkyl, halogen, oxo, OH, -OC _1-4 alkyl, G ^4a , and -C _1-4 alkylene-G ^4a , and optionally further substituted with 1-3 substituents independently selected from the group consisting of C _1-4 alkyl, C _1-4 fluoroalkyl, and halogen; and

R ⁵ and R ⁶ are each independently hydrogen, C _1-4 alkyl, halogen, cyano, C _1-4 haloalkyl, -O C _1-4 alkyl, or -OC _1-4 haloalkyl.

[0058] EEll..ll.. The compound of El, or a pharmaceutically acceptable salt thereof, wherein:

R ³ is a 6- to 12-membered aryl or 5- to 12-membered heteroaryl, wherein R ³ is unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C _1-4 alkyl, halogen, cyano, Ci-zhaloalkyl, -OC _1-4 alkyl, and -OC _1-4 haloalkyl;

R ⁴ is G ⁴ , -C _1-4 alkylene-G ⁴ , or Cy;

R ^4a , at each occurrence, is independently hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, Cg^cycloalkyl, or -C _1-4 alkylene-C3-4cycloalkyl; and

R ^4b is C _1-4 alkyl, C _1-4 haloalkyl. Cwcycloalkyl. or -C _1-4 alkylene-C3-4cycloalkyl.

[0059] E2. The compound of El or El.l, or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen.

[0060] E3. The compound of any one of E1-E2, or a pharmaceutically acceptable salt thereof, wherein R ² is hydrogen.

[0061] E4. The compound of any one of E1-E3, or a pharmaceutically acceptable salt thereof, wherein G ⁴ is the unsubstituted or substituted 5- to 12-membered heteroaryl.

[0062] E5. The compound of any one of E1-E4, or a pharmaceutically acceptable salt thereof, wherein the ring system of the unsubstituted or substituted 5- to 12-membered heteroaryl at G ⁴ is a 9- to 10-membered fully aromatic bicyclic heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S. [0063] E5.1. The compound of E5, or a pharmaceutically acceptable salt thereof, wherein the 9- to 10-mcmbcrcd fully aromatic bicyclic hctcroaryl ring system is indazolyl, indolyl, benzo[d]imidazolyl, benzo [d] thiazolyl, benzo[d]oxazolyl, quinolinyl, isoquinolinyl, pyrazolo[3,4-b]pyridinyl, imidazo[l,2-a]pyridinyl, or pyrrolo[2,3-b]pyridinyl.

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

[0065] E5.3. The compound of any of E5-E5.2, or a pharmaceutically acceptable salt thereof, wherein G ⁴ is optionally substituted with 1-2 substituents independently selected from the group consisting of C _1-4 alkyl and halogen (e.g., methyl and fluoro).

[0066] E5.4. The compound of any of E5-E5.3. or a pharmaceutically acceptable salt

C ₁ . ₄ alkyl _x

N-N

, or halo [0067] E5.5. The compound of E5.4, or a pharmaceutically acceptable salt thereof,

F

, or

[0068] E6. The compound of any one of E1-E4, or a pharmaceutically acceptable salt thereof, wherein the ring system of the unsubstituted or substituted 5- to 12-membered heteroaryl at G ⁴ is a 5- to 6-membered monocyclic hctcroaryl containing 1-3 heteroatoms independently selected from the group consisting of N, O, and S.

[0069] EE66..11.. The compound of E6, or a pharmaceutically acceptable salt thereof, wherein the 5- to 6-membered monocyclic heteroaryl ring system is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrrolyl, thiazolyl, pyridinyl, pyridazinyl, or pyrimidinyl.

[0070] EE66..22.. The compound of E6.1, or a pharmaceutically acceptable salt thereof, wherein the 5- to 6-membered monocyclic heteroaryl ring system is pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, thiazolyl, pyridinyl, pyridazinyl, or pyrimidinyl.

[0071] EE66..33.. The compound of E6.1, or a pharmaceutically acceptable salt thereof, wherein the 5- to 6-membered monocyclic heteroaryl ring system is lH-pyrazol-3-yl, 1H- pyrazol-4-yl, lH-imidazol-4-yl, oxazol-5-yl, isoxazol-4-yl, lH-pyrrol-3-yl, thiazol-5-yl, pyridin- 2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-4-yl, or pyrimidin-5-yl.

[0072] EE66..44.. The compound of any of E6.1-E6.3, or a pharmaceutically acceptable salt thereof, wherein the 5- to 6-membered monocyclic heteroaryl ring system is lH-pyrazol-3-yl, lH-pyrazol-4-yl, oxazol-5-yl, isoxazol-4-yl, lH-pyrrol-3-yl, thiazol-5-yl, pyridin-2-yl, pyridin-3- yl, pyridin-4-yl, pyridazin-4-yl, or pyrimidin-5-yl.

[0073] E6.5. The compound of any of E6-E6.4, or a pharmaceutically acceptable salt thereof, wherein G ⁴ is optionally substituted with 1 substituent selected from the group consisting of Cmalkyl, halogen, cyano, CiJialoalkyl, -OR ^4a , -N(R ^4a )2, -N(R ^4a )C(O)R ^4a , -N(R ^4a )SO ₂ R ^4b , -C(O)N(R ^4a ) ₂ . -SO ₂ N(R ^4a ) ₂ , -SO ₂ R ^4b . -C _1-4 alkylene-OH. G ^4a , and -Ci- ₄ alkylene-G ^4a , and optionally further substituted with 1-2 substituents independently selected from the group consisting of Ci- ₄ alkyl, halogen, cyano, CiJialoalkyl, -OCi- ₄ alkyl, and -OCi- ihaloalkyl.

[0074] E6.6. The compound of E6.5, or a pharmaceutically acceptable salt thereof, wherein G ⁴ is optionally substituted with 1 substituent selected from the group consisting of Ci- ₄ alkyl, halogen, cyano, CiJialoalkyl, -OR ^4a , -N(R ^4a ) ₂ , -N(R ^4a )C(O)R ^4a , -SO ₂ R ^4b , -Cu ₄ alkylene-OH, G ^4a , and -Ci- ₄ alkylene-G ^4a , and optionally further substituted with 1-2 substituents independently selected from the group consisting of Ci- ₄ alkyl, halogen, cyano, Ci- ihaloalkyl, -OCi- ₄ alkyl, and -OC _1-2 haloalkyl.

[0075] EE66..77.. The compound of any of E6-E6.6, or a pharmaceutically acceptable salt thereof, wherein

I I I

^N' C ₁ _ ₄ alkyl C ₁ _ ₂ fluoroalkyl

•> •> halo •) HO-C^alkylene'

[0076] E6.8. The compound of E6.7, or a pharmaceutically acceptable salt thereof, wherein

I [I I

^N C-!_ ₄ alkyl ^X N 'C ₁ _ ₂ fluoroalkyl halo HO-C^zialkylene' ^N"

[0077] E6.9. The compound of any of E6-E6.8, or a pharmaceutically acceptable salt thereof, wherein G ^4a is a phenyl optionally substituted with 1-2 substituents independently selected from the group consisting of C _1-4 alkyl, Ci-ifluoroalkyl, halogen, cyano, oxo, OH, and

OC _1-4 alkyl.

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

[0079] E6.l l. The compound of any of E6-E6.8, or a pharmaceutically acceptable salt thereof, wherein G ^4a is C _3-6 cycloalkyl optionally substituted with 1-2 substituents independently selected from the group consisting of C _1-4 alkyl and halogen. [0080] E6.12. The compound of any of E6-E6.8 or E6.1 1 , or a pharmaceutically acceptable salt thereof, wherein G ^4a is unsubstituted C _3-6 cycloalkyl.

[0081] E6.13. The compound of any of E6-E6.8, or a pharmaceutically acceptable salt thereof, wherein G ^4a is a 4- to 6-membered heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S, wherein the heterocyclyl is optionally substituted with 1-2 substituents independently selected from the group consisting of C _1-4 alkyl and halogen.

[0082] E6.14. The compound of any of E6-E6.8 or E6.13, or a pharmaceutically acceptable salt thereof, wherein G ^4a is an unsubstituted 4- to 6-membered heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S. [0083] E6.15 The compound of any of E6-E6.8 or E6.13-E6.14, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 4- to 6-membered heterocyclyl at G ^4a is wherein X is O or S.

[0084] E6.16 The compound of E6.15, or a pharmaceutically acceptable salt thereof,

O, wherein the ring system of the 4- to 6-membered heterocyclyl at G ^4a is or 1-2 [0085] E6.17. The compound of any of E6-E6.16, or a pharmaceutically acceptable salt thereof, wherein R ^4a , at each occurrence, is independently hydrogen or C _1-4 alkyl (e.g., methyl); and R ^4b is C _1-4 alkyl (e.g., methyl).

[0086] EE66..1188.. The compound of any of E6-E6.17, or a pharmaceutically acceptable salt

C-|_ ₄ alkyl thereof, wherein G ⁴ is , N , ,

I

^X I I N C ₁ _ ₄ alkyl N C ₁ _ ₂ fluoroalkyl ^X N halo "'"N 9 HO-C^alkylene'

C-|_ ₄ alkyl

C ₁ _ ₄ alkyl C ₁ . ₄ alkyl halo' ^X N C ₁ _4alkyl 9 h _a io' halo' halo 9 [0087] E6.19. The compound of E6.18, or a pharmaceutically acceptable salt thereof, wherein

^X N 'C ₁ _ ₄ alkyl ^X N 'C ₁ _ ₂ fluoroalkyl ^X N halo 9 HO-C _M alkylene‘ ^X N

[0088] E6.20. The compound of E6.18, or a pharmaceutically acceptable salt thereof,

[0089] E6.21. The compound of any of E6.18-E6.20, or a pharmaceutically acceptable salt

J [I thereof, wherein G ⁴ is 9 9 ? 9 N N N

[0090] E7. The compound of any one of E1-E4, E5.5, or E6.20, or a pharmaceutically

[0091] E7.1.. The compou.nd of any one of. E1 -E4, E5.5, or E6.21-E7, or a pharmaceutically acceptable salt thereof, wherein G ⁴ i

[0092] E8. The compound of any one of E1-E3, or a pharmaceutically acceptable salt thereof, wherein G ⁴ is the unsubstituted or substituted 6- to 12-membered aryl.

[0093] E9. The compound of any one of E1-E3 or E8, or a pharmaceutically acceptable salt thereof, wherein the ring system of the unsubstituted or substituted 6- to 12-membered aryl at G ⁴ is phenyl.

[0094] E9.1. The compound of E9, or a pharmaceutically acceptable salt thereof, wherein

G ⁴ is optionally substituted with 1 substituent selected from the group consisting of C _1-4 alkyl, halogen, cyano, C _1-2 haloalkyl, -OR ^4a , -N(R ^4a ) ₂ , -N(R ^4a )C(O)R ^4a , -N(R ^4a )SO ₂ R ^4b , -C(O)N(R ^4a ) ₂ , -SO ₂ N(R ^4a ) ₂ , -SO ₂ R ^4b , -C _1-4 alkylene-OH, G ^4a , and -C _1-4 alkylene-G ^4a , and optionally further substituted with 1-2 substituents independently selected from the group consisting of C _1-4 alkyl, halogen, cyano, C _1-2 haloalkyl, -OC _1-4 alkyl, and -OC _1-2 haloalkyl.

[0095] E9.2. The compound of E9 or E9.1, or a pharmaceutically acceptable salt thereof, wherein G ⁴ is optionally substituted with 1 substituent selected from the group consisting of Ci- ₄ alkyl, halogen, cyano, C _1-2 haloalkyl, -OR ^4a , -N(R ^4a ) ₂ , -N(R ^4a )C(O)R ^4a , -N(R ^4a )SO ₂ R ^4b , - C(O)N(R ^4a ) ₂ , -SO ₂ N(R ^4a ) ₂ , -SO ₂ R ^4b , -C _1-4 alkylene-OH, and G ^4a and optionally further substituted with 1-2 substituents independently selected from the group consisting of C _1-4 alkyl, halogen, cyano, C _1-2 haloalkyl, -OC _1-4 alkyl, and -OC _1-2 haloalkyl.

[0096] EE99..33.. The compound of any of E9-E9.2, or a pharmaceutically acceptable salt thereof, wherein

O 0 o4a L O _R .A NH

V

R ^{4a R} V G ^4a

G ^4a

R ^4a halo halo halo , or

G ^4a

G ^4a . or

[0097] E9.4. The compound of E9.3, or a pharmaceutically acceptable salt thereof, wherein

NC.

CN I C _M a Iky I

NC. NC NC^

I I

C^alkyl C ₁ _ ₄ alkyl ^R4 -o- NC halo NC halo

°"R ^4a halo

CN ^R % ,

[0098] E9.5. The compound of any of E9-E9.4, or a pharmaceutically acceptable salt thereof, wherein G ^4a is a 5- to 6-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S, wherein G ^4a is optionally substituted with 1-4 substituents independently selected from the group consisting of C _1-4 alkyl, CiYluoroalkyl. halogen, cyano, OH, and -OC _1-4 alkyl.

[0099] E9.6. The compound of any of E9-E9.5, or a pharmaceutically acceptable salt thereof, wherein G ^4a is a 5- to 6-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S, wherein G ^4a is optionally substituted with 1-2 C _1-4 alkyl (e.g., methyl).

[00100] E9.7. The compound of any of E9-E9.6, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 5- to 6-membered heteroaryl at G ^4a is pyrazolyl (e.g., pyrazol-l-yl, pyrazol-4-yl), oxadiazolyl (e.g., l,3,4-oxadiazol-2-yl), triazolyl (e.g., triazol-4-yl), or thiazolyl (e.g., thiazol-5-yl). [00101] E9.8. The compound of E9.7, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 5- to 6-mcmbcrcd hctcroaryl at G ^4a is pyrazolyl (e.g., pyrazol-1- yl) or oxadiazolyl (e.g., l,3,4-oxadiazol-2-yl).

[00102] E9.9. The compound of any of E9-E9.4, or a pharmaceutically acceptable salt thereof, wherein G ^4a is a 4- to 6-membered heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S, wherein G ^4a is optionally substituted with 1-4 substituents independently selected from the group consisting of C _1-4 alkyl, Ci-ifluoroalkyl, halogen, cyano, oxo, OH, and -OCi- ₄ alkyl.

[00103] E9.10. The compound of any of E9-E9.4 or E9.9, or a pharmaceutically acceptable salt thereof, wherein G ^4a is a 4- to 6-membered heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S, wherein G ^4a is optionally substituted with 1-2 Ci- ₄ alkyl (e.g., methyl).

[00104] E9.ll. The compound of any of E9-E9.4 or E9.9-E9.10, or a pharmaceutically acceptable salt thereof, wherein the ring system of the 4- to 6-membered heterocyclyl at G ^4a contains at least one nitrogen atom and is attached at the at least one nitrogen atom (e.g., piperazin- 1-yl, piperidin-l-yl).

[00105] E9.12. The compound of any of E9-E9.l l, or a pharmaceutically acceptable salt thereof, wherein R ^4a , at each occurrence, is independently hydrogen or Ci- ₄ alkyl (e.g., methyl); and R ^4b is Ci- ₄ alkyl (e.g., methyl).

[00106] E9.13. The compound of any of E9-E9.12, or a pharmaceutically acceptable salt thereof, wherein NC •> halo

Ci^alkyl halo CN O

HO-C-i^alkylene^

II II

NC^ halo' halo^

0 O

H 0

C!_ ₄ alkyl C-|_ ₄ alkyl ?s' C ₁ _ ₄ alkyl -S' ^N N ^x N o' o H H

O O [00107] E9.14. The compound of E9.13, or a pharmaceutically acceptable salt thereof,

O

C ₁ . ₄ alkyl u S=O NH ₂ halo

NC NC NC

C ₁ _ ₄ alkyl

O halo' halo halo halo 9

,0

N'N halo , or

N

N

C! _ ₄ alkyl [00108] E9.15. The compound of any of E9-E9.13, or a pharmaceutically acceptable salt

O . 0 O

HO H 0

N ^x N o'b H H

O O

0

N NH ,N'N

H N J

N

H

Cl F

6 N

[00109] E9.16. The compound of any of E9-E9.15, or a pharmaceutically acceptable salt

o O

O

N NH

H

N Ck

H

Cl F N-N F , or

N

N

[00110] E10. The compound of any one of E1-E3 or E8, or a pharmaceutically acceptable salt thereof, wherein the ring system of the unsubstituted or substituted 6- to 12-membered aryl at G ⁴ is a phenyl fused to a 5- to 6-membered heterocycle containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S.

[00111] E10.1. The compound of E10, or a pharmaceutically acceptable salt thereof, wherein the 5- to 6-membered heterocycle fused to the phenyl is optionally substituted with oxo. [00112] E10.2. The compound of E10.1, or a pharmaceutically acceptable salt thereof,

HN O wherein G ⁴ is or

[00113] E10.3. The compound of E10.2, or a pharmaceutically acceptable salt thereof,

HN— . ok 1 X wherein G ⁴ is

[00114] El l. The compound of E8, or a pharmaceutically acceptable salt thereof, wherein

NC

NC NC. NC NC.

J

O O F

F NC. F CN O

NC

F NC F F

ZCD _{3 Z} CD ₂ CH ₃

N~ N~ 6 b N N N

N. _ N" _

,0 N

N-N F N

HN O

O

, or [00115] El 1.1. The compound of El 1 , or a pharmaceutically acceptable salt thereof, wherein G ⁴ is

NC

NC

NC. NC NC

O' O

F NC F CN O

NC NC.

F F NC F F

[00116] E12. The compound of any of El -El 1.1, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is G ⁴ .

[00117] E13. The compound of any of El -El 1.1, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is -C _1-4 alkylene-G ⁴ .

[00118] E14. The compound of any of El -El 1.1 , or a pharmaceutically acceptable salt thereof, wherein R ⁴ is Cy.

[00119] E15. The compound of any of El-El 1.1, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is -Chalky lene-Cy. [00120] El 5.1. The compound of El 5, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is -CH2-Cy.

[00121] E16. The compound of any of El-El l.1 or E14-E15.1, or a pharmaceutically acceptable salt thereof, wherein Cy is the optionally substituted C _3-6 carbocyclyl.

[00122] E16.1. The compound of any of El -El 1.1 or E14-E16, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted C _3-6 carbocyclyl at Cy is optionally substituted with -OC _1-4 alkyl.

[00123] E16.2. The compound of E16.1, or a pharmaceutically acceptable salt thereof,

),- ₂

Ox wherein Cy is ' '1-4 or C ₁ _ ₄ alkyl

[00124] El 6.3. The compound of E16.2, or a pharmaceutically acceptable salt thereof,

O' wherein Cy is or

[00125] E17. The compound of any of El -El 1.1 or E14-E15.1, or a pharmaceutically acceptable salt thereof, wherein Cy is the optionally substituted 4- to 6-membered heterocyclyl. [00126] E17.1. The compound of any of El-El 1.1, E14-E15.1, or E17, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4 to 6-membered heterocyclyl at Cy contains 1-2 heteroatoms independently selected from the group consisting of O, N, and S.

[00127] E17.2. The compound of E17.1, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4- to 6-membered heterocyclyl at Cy contains 1 heteroatom selected from the group consisting of O, N, and S.

[00128] E17.3. The compound of any of El-El 1.1, E14-E15.1, or E17-E17.2, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 4- to 6-membered heterocyclyl at Cy is optionally substituted with a first substituent selected from the group consisting of C _1-4 alkyl (e.g., methyl), C _1-2 fluoroalkyl, halogen, OH, oxo, and -Chalky lene-G' (e.g., benzyl), and optionally further substituted with 1-3 substituents independently selected from the group consisting of C _1-4 alkyl (e.g., methyl), halogen, and C _1-2 fluoroalkyl (e.g., CHF2). [00129] E17.4. The compound of E17.3, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 4- to 6-mcmbcrcd hctcrocyclyl at Cy is optionally substituted with a first substituent selected from the group consisting of Ci- ₄ alkyl (e.g., methyl), Ci- ifluoroalkyl, halogen, oxo, and -Ci- ₄ alkylene-G ^4a (e.g., benzyl), and optionally further substituted with 1-3 substituents independently selected from the group consisting of C _1-4 alkyl (e.g., methyl), halogen, and Ci-zfluoroalkyl (e.g., CHF2).

[00130] E17.5. The compound of E17.3, or a pharmaceutically acceptable salt thereof,

C-i^alkyl _or Chalky I o S

, or

[00131] E17.6. The compound of E17.4 or E17.5, or a pharmaceutically acceptable salt thereof, wherein

[00132] E17.7. The compound of El 7.5, or a pharmaceutically acceptable salt thereof,

^F 2 ^HC ' _N

HN Il HN wherein Cy is O O O. HN HN

HN HN HN HN

N HN N

N

HN HN N N HO

HN

O. S

, or F ₃ C [00133] E17.8. The compound of E17.6 or E17.7, or a pharmaceutically acceptable salt

^{F HC}

HN HN HN HN

N HN N

HN HN

HN

, or

[00134] E18. The compound of any of El -El l or E14-E15.1, or a pharmaceutically

^F2HC ^N

O'

O' O. acceptable salt thereof, wherein Cy is

HN HN HN

N

HN HN N HN HN HN N

HN

HN N O.

N

N HO

S

, or F ₃ C

[00135] E18.1. The compound of any of El-El 1.1, E14-E15.1, or E18, or a

O' pharmaceutically acceptable salt thereof, wherein Cy is

HN HN HN HN HN

HN N

HN

HN

, or

[00136] El 9. The compound of any one of El -El 8.1, or a pharmaceutically acceptable salt thereof, wherein R ³ is the unsubstituted or substituted 6- to 12-membered aryl.

[00137] E20. The compound of any one of El -El 9, or a pharmaceutically acceptable salt thereof, wherein the ring system of the unsubstituted or substituted 6- to 12-membered aryl at R ³ is phenyl. [00138] E20.1. The compound of E20, or a pharmaceutically acceptable salt thereof, wherein R ³ is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of C _1-4 alkyl, halogen, cyano, C _1-2 haloalkyl, OH, -OC _1-4 alkyl, and

OCi ihaloalkyl.

[00139] E20.2. The compound of E20.1 , or a pharmaceutically acceptable salt thereof, wherein R ³ is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of C _1-4 alkyl, halogen, cyano, and C _1-2 haloalkyl.

[00140] E21. The compound of E20 or E20.1, or a pharmaceutically acceptable salt wyv wyv wyv F

F

F thereof, wherein R ³ is F F F F F wyv wyv

F- F F

F

F CN NC CN CN F F CN wyv wyv wyv wyv

■Cl

F CN

O. o. o. o. OH CN o. wyv

CF ₃

NC , or CN [00141] E21.1. The compound of E20.2 or E21 , or a pharmaceutically acceptable salt ww «/vyv ww wyv wyv ww WW

F F

JI

F F thereof, wherein R ³ is F F F F ON

F , or CF ₃

[00142] E22. The compound of any one of E 1 -E21.1 , or a pharmaceutically acceptable salt thereof, wherein R ⁵ and R ⁶ are each independently selected from the group consisting of hydrogen, Cwalkyl, and halogen.

[00143] E23. The compound of any one of E1-E22, or a pharmaceutically acceptable salt thereof, wherein R ⁵ and R ⁶ are each hydrogen.

[00144] E24. The compound of El, selected from the group consisting of:

6-(4-fluorophenyl)-5-(l-methyl-lH-pyrazol-4-yl)isoindolin -l-one;

6-(4-fluorophenyl)-5-(oxazol-5-yl)isoindolin- 1-one;

6-(4-fluorophenyl)-5-(l-(oxetan-3-yl)-lH-pyrazol-4-yl)iso indolin-l-one;

6-(4-fluorophenyl)-5-(pyridin-4-yl)isoindolin- 1-one;

6-(4-fluorophenyl)-5-(2-methylthiazol-5-yl)isoindolin-l-o ne;

6-(4-fluorophenyl)-5-(6-methylpyridin-3-yl)isoindolin-l-o ne;

6-(4-fluorophenyl)-5-(2-methyl-2H-indazol-5-yl)isoindolin -l-one;

6-(4-fluorophenyl)-5-(2-methyl-2H-indazol-6-yl)isoindolin - 1-one;

6-(4-fluorophenyl)-5-(4-methyl-lH-indazol-5-yl)isoindolin -l-one;

6-(4-fluorophenyl)-5-(2-methyl-lH-benzo[d]imidazol-5-yl)i soindolin-l-one;

5-(benzo[d]thiazol-6-yl)-6-(4-fluorophenyl)isoindolin- 1-one;

5-(benzo[d]oxazol-5-yl)-6-(4-fluorophenyl)isoindolin- 1-one; 5-(benzo[d]thiazol-5-yl)-6-(4-fluorophenyl)isoindolin- 1-one;

6-(4-fluorophenyl)-5-(isoquinolin-6-yl)isoindolin-l-one;

6-(4-fluorophenyl)-5-(isoquinolin-7-yl)isoindolin-l-one;

6-(4-fluorophenyl)-5-(2-methyl-2H-pyrazolo[3,4-b]pyridin- 5-yl)isoindolin-l-one;

6-(4-fluorophenyl)-5-(2-methyl-2H-indazol-7-yl)isoindolin - 1-one;

6-(4-fluorophenyl)-5-(quinolin-7-yl)isoindolin-l-one;

6-(4-fluorophenyl)-5-(quinolin-6-yl)isoindolin-l-one;

6-(4-fluorophenyl)-5-(imidazo[l,2-a]pyridin-6-yl)isoindol in-l-one;

5-(5,8-difluoroquinolin-6-yl)-6-(4-fluorophenyl)isoindoli n-l-one;

6-(4-fluorophenyl)-5-(pyridazin-4-yl)isoindolin-l-one;

5-(benzo[d]thiazol-5-yl)-6-(2,4-difluorophenyl)isoindolin -l-one;

5-(benzo[d]oxazol-5-yl)-6-(2,4-difluorophenyl)isoindolin- l-one;

6-(2,4-difluorophenyl)-5-(2-methyl-2H-indazol-6-yl)isoind olin-l-one;

5-(6-cyclopropylpyridin-3-yl)-6-(4-fluorophenyl)isoindoli n-l-one;

6-(4-fluorophenyl)-5-(6-(trifluoromethyl)pyridin-3-yl)iso indolin-l-one;

6-(4-fluorophenyl)-5-(2-methyl-2H-indazol-4-yl)isoindolin -l-one;

5-(2,6-dimethylpyridin-3-yl)-6-(4-fluorophenyl)isoindolin -l-one;

5-(6-fluoro-2-methylpyridin-3-yl)-6-(4-fluorophenyl)isoin dolin-l-one;

6-(4-fluorophenyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)i soindolin-l-one;

5-(2,6-difluoropyridin-3-yl)-6-(4-fluorophenyl)isoindolin -l-one;

5-(6-(4-fluorophenyl)-l-oxoisoindolin-5-yl)picolinonitril e;

5-(6-(dimethylamino)pyridin-3-yl)-6-(4-fluorophenyl)isoin dolin-l-one; 6-(4-fluorophenyl)-5-(l-methyl-lH-pyrazol-3-yl)isoindolin- 1-one;

N-(5-(6-(4-fluorophenyl)-l-oxoisoindolin-5-yl)pyridin-2-y l)acetamide;

5-(6-fluoro-4-methylpyridin-3-yl)-6-(4-fluorophenyl)isoin dolin-l-one;

6-(4-fluorophenyl)-5-(lH-pyrrolo[2,3-b]pyridin-5-yl)isoin dolin-l-one;

5-(2-(dimethylamino)pyridin-3-yl)-6-(4-fluorophenyl)isoin dolin-l-one;

6-(4-fluorophenyl)-5-(2-fluoropyridin-3-yl)isoindolin-l-o ne;

6-(4-fluorophenyl)-5-(2-methylpyridin-3-yl)isoindolin-l-o ne;

6-(4-fluorophenyl)-5-(2-isopropylpyridin-3-yl)isoindolin- l-one;

5-(2-cyclopropylpyridin-3-yl)-6-(4-fluorophenyl)isoindoli n-l-one;

6-(4-fluorophenyl)-5-(pyridin-3-yl)isoindolin-l-one;

6-(4-fluorophenyl)-5-(pyridin-2-yl)isoindolin-l-one;

6-(4-fluorophenyl)-5-(6-methylpyridazin-4-yl)isoindolin-l -one;

6-(4-fluorophenyl)-5-(3-methyl-1H-indazol-5-yl)isoindolin -l-one;

6-(4-fluorophenyl)-5-(4-methylpyridin-3-yl)isoindolin-l-o ne;

6-(4-fluorophenyl)-5-(lH-indol-5-yl)isoindolin-l-one;

6-(4-fluorophenyl)-5-(6-(2-hydroxypropan-2-yl)pyridin-3-y l)isoindolin-l-one;

6-(4-fluorophenyl)-5-(p-tolyl)isoindolin-l-one;

6-(4-fluorophenyl)-5-(5-methylpyridin-2-yl)isoindolin-l-o ne;

4-(6-(4-fluorophenyl)-l-oxoisoindolin-5-yl)-l,5-dimethyl- lH-pyrrole-2-carbonitrile;

6-(4-fluorophenyl)-5-(4-methoxycyclohex- 1 -en- 1 -yl)isoindolin- 1 -one;

5-(3,6-dihydro-2H-pyran-4-yl)-6-(4-fluorophenyl)isoindoli n-l-one;

5-(l-benzyl-l,2,3,6-tetrahydropyridin-4-yl)-6-(4-fluoroph enyl)isoindolin-l-one; 6-(4-fluorophenyl)-5-(l-methyl-l,2,5,6-tetrahydropyridin-3-y l)isoindolin-l-one;

6-(4-fluorophenyl)-5-(l-methyl-l,2,3,6-tetrahydropyridin- 4-yl)isoindolin-l-one;

6-(4-fluorophenyl)-5-(2,2,6,6-tetramethyl-l,2,3,6-tetrahy dropyridin-4-yl)isoindolin-l-one;

6-(4-fluorophenyl)-5-(l,2,3,6-tetrahydropyridin-4-yl)isoi ndolin-l-one;

6-(4-fluorophenyl)-5-(l,2,5,6-tetrahydropyridin-3-yl)isoi ndolin-l-one;

5-(2,6-dimethyl-l,2,3,6-tetrahydropyridin-4-yl)-6-(4-fluo rophenyl)isoindolin-l-one;

5-cyclohexyl-6-(4-fluorophenyl)isoindolin-l-one;

6-(4-fluorophenyl)-5-(tetrahydro-2H-pyran-4-yl)isoindolin -l-one;

6-(4-fluorophenyl)-5-(l-methylpiperidin-3-yl)isoindolin- 1-one;

6-(4-fluorophenyl)-5-(l-methylpiperidin-4-yl)isoindolin-l -one;

6-(4-fluorophenyl)-5-(piperidin-4-yl)isoindolin-l-one;

5-(2,6-dimethylpiperidin-4-yl)-6-(4-fluorophenyl)isoindol in-l-one;

6-(2,4-difluorophenyl)-5-(6-methylpyridin-3-yl)isoindolin -l-one;

5-(6-cyclopropylpyridin-3-yl)-6-(2,4-difluorophenyl)isoin dolin-l-one;

6-(2,4-difluorophenyl)-5-(2-(dimethylamino)pyridin-3-yl)i soindolin-l-one;

6-(2,4-difluorophenyl)-5-(2-fluoropyridin-3-yl)isoindolin -l-one;

6-(2,4-difluorophenyl)-5-(2-methylpyridin-3-yl)isoindolin -l-one;

5-(2-cyclopropylpyridin-3-yl)-6-(2,4-difluorophenyl)isoin dolin-l-one;

6-(4-fluorophenyl)-5-(2,2,6,6-tetramethylpiperidin-4-yl)i soindolin-l-one;

5-(3,3-dimethyl-l,2,3,6-tetrahydropyridin-4-yl)-6-(4-fluo rophenyl)isoindolin-l-one;

6-(4-fluorophenyl)-5-(3-methylpiperidin-4-yl)isoindolin-l -one;

6-(4-fluorophenyl)-5-(piperidin-3-yl)isoindolin-l-one; 6-(2,4-difluorophenyl)-5-(6-(trifluoromethyl)pyridin-3-yl)is oindolin-l-one;

6-(2,4-difluorophenyl)-5-(l-methyl-lH-pyrazol-3-yl)isoind olin-l-one;

6-(2,4-difluorophenyl)-5-(6-fluoro-4-methylpyridin-3-yl)i soindolin-l-one;

5-(2,5-dihydro-lH-pyrrol-3-yl)-6-(4-fluorophenyl)isoindol in-l-one;

6-(4-fluorophenyl)-5-(pyrrolidin-3-yl)isoindolin-l-one;

6-(4-fluorophenyl)-5-(2-methyl-l, 2,3, 6-tetrahydropyridin-4-yl)isoindolin- 1-one;

6-(4-fluorophenyl)-5-(2-methylpiperidin-4-yl)isoindolin-l -one;

6-(2,4-difluorophenyl)-5-(2-(trifluoromethyl)pyrimidin-5- yl)isoindolin-l-one;

6-(2,4-difluorophenyl)-5-(lH-pyrrolo[2,3-b]pyridin-5-yl)i soindolin-l-one;

6-(2,4-difluorophenyl)-5-(pyridin-3-yl)isoindolin-l-one;

6-(2,4-difluorophenyl)-5-(lH-indol-5-yl)isoindolin-l-one;

4-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)-l,5-dimet hyl-lH-pyrrole-2-carbonitrile;

3-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)-5-methylb enzonitrile;

5-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)-2-methoxy benzonitrile;

5-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)-2-fluorob enzonitrile;

3-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)-2-fluorob enzonitrile;

3-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)-5-methoxy benzonitrile;

3-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)-4-methylb enzonitrile;

6-(2,4-difluorophenyl)-5-(l,2,5-trimethyl-lH-pyrrol-3-yl) isoindolin-l-one;

3-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)-l,5-dimet hyl-lH-pyrrole-2-carbonitrile;

3-(4-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)-lH-pyr azol-l-yl)benzonitrile;

6-(2,4-difluorophenyl)-5-(2-methoxypyridin-3-yl)isoindoli n-l-one; 6-(2,4-difluorophenyl)-5-(5-methoxypyridin-3-yl)isoindolin-l -one;

6-(2,4-difluorophenyl)-5-(2-(pyrrolidin-l-yl)pyridin-3-yl )isoindolin-l-one;

4-(6-(2,4-difhiorophenyl)-l-oxoisoindolin-5-yl)-3-fluorob enzonitrile;

4-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)picolinoni trile;

6-(2,4-difluorophenyl)-5-(4-fluoro-2-methoxyphenyl)isoind olin-l-one;

3-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)-5-fluorob enzonitrile;

3-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)benzonitri le;

5-(l-cyclopropyl-lH-pyrazol-3-yl)-6-(2,4-difluorophenyl)i soindolin-l-one;

3-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)-2-methylb enzonitrile;

6-(2,4-difluorophenyl)-5-(2-(trifluoromethyl)pyridin-3-yl )isoindolin-l-one;

4-(4-(6-(2,4-difluorophenyl)- l-oxoisoindolin-5-yl)- IH-pyrazol- l-yl)benzonitrile;

6-(2,4-difluorophenyl)-5-(3-fluoro-4-(5-methyl-l,3,4-oxad iazol-2-yl)phenyl)isoindolin-l-one;

6-(2,4-difluorophenyl)-5-(4-(4-methylpiperazin-l -yl)phenyl)isoindolin-l-one;

6-(2,4-difluorophenyl)-5-(3-(trifluoromethyl)-lH-pyrazol- 4-yl)isoindolin-l-one;

4-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)-l-methyl- l//-pyrazole-5-caibonitrile;

2V-(3-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)phenyl )methanesulfonamide;

3-chloro-5-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)- N-methylbenzamide;

3-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)-N-isoprop ylbenzamide;

3-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)-N-methylb enzenesulfonamide;

N-(2-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)phenyl) acetamide;

3-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)-4-fluoro- N-methylbenzamide;

6-(2,4-difluorophenyl)-5-(3-(methylsulfonyl)phenyl)isoind olin- 1-one; 2-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)-5-fluorobenz onitrile;

2-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)benzonitri le;

4-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)-l-methyl- lH-pyrrole-2-carbonitrile;

6-(2,4-difluorophenyl)-5-(3,5-dimethylisoxazol-4-yl)isoin dolin-l-one;

6-(2,4-difluorophenyl)-5-(l-(methylsulfonyl)-lH-pyrazol-4 -yl)isoindolin-l-one;

6-(2,4-difluorophenyl)-5-(2-(methylsulfonyl)phenyl)isoind olin-l-one;

6-(2,4-difluorophenyl)-5-(l-ethyl-3-(trifluoromethyl)-lH- pyrazol-4-yl)isoindolin-l-one;

6-(2,4-difluorophenyl)-5-(l-isobutyl-lH-pyrazol-4-yl)isoi ndolin-l-one;

6-(2,4-difluorophenyl)-5-(l-(2,2,2-trifluoroethyl)-lH-pyr azol-4-yl)isoindolin-l-one;

5-(l-(cyclopropylmethyl)-lH-pyrazol-4-yl)-6-(2,4-difluoro phenyl)isoindolin-l-one;

6-(2,4-difluorophenyl)-5-(l-isopropyl-lH-pyrazol-4-yl)iso indolin-l-one;

6-(2,4-difluorophenyl)-5-(l-ethyl-lH-pyrazol-4-yl)isoindo lin-l-one;

5-(l-(difluoromethyl)-6-oxo-l ,6-dihydropyridin-3-yl)-6-(2,4-difluorophenyl)isoindolin-l-o ne;

6'-(2,4-difluorophenyl)- [4,5'-biisoindoline] -1,1 '-dione;

5-(2-aminophenyl)-6-(2,4-difluorophenyl)isoindolin-l-one;

4-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-3-fluorobenzon itrile;

3-(l-oxo-6-(2,3,4-trifluorophenyl)isoindolin-5-yl)benzoni trile;

3-(l-oxo-6-(2,4,5-trifluorophenyl)isoindolin-5-yl)benzoni trile;

2-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-5-fluorobenzon itrile;

3-(6-(2-fluoro-4-methylphenyl)-l-oxoisoindolin-5-yl)benzo nitrile;

3-(6-(4-fluoro-2-methylphenyl)-l-oxoisoindolin-5-yl)benzo nitrile;

3-(6-(2-fluoro-4-(trifluoromethyl)phenyl)-l-oxoisoindolin -5-yl)benzonitrile; 6-(2,4-difluorophenyl)-5-(3-(2-hydroxypropan-2-yl)phenyl)iso indolin-l-one;

5-(3-(lH-pyrazol-l-yl)phenyl)-6-(2,4-difluorophenyl)isoin dolin-l-one;

6-(2,4-difluorophenyl)-5-(l-(tetrahydro-2H-pyran-2-yl)-lH -pyrazol-5-yl)isoindolin-l-one;

5-(2-chloro-l-(tetrahydro-2H-pyran-2-yl)-lH-imidazol-5-yl )-6-(2,4-difluorophenyl)isoindolin- 1-one;

6-(2,4-difluorophenyl)-5-(2,3-dihydrobenzofuran-7-yl)isoi ndolin-l-one;

6-(2,4-difluorophcnyl)-5-(2-(4-mcthylpipcrazin-l-yl)phcny l)isoindolin-l-onc;

6-(2,4-difluorophenyl)-5-(3-(l-methyl- 1H- 1 ,2,3-triazol-5-yl)phenyl)isoindolin- l-one;

6-(2,4-difluorophenyl)-5-(3-(l-(methyl-d3)-lH-l,2,3-triaz ol-5-yl)phenyl)isoindolin-l-one;

6-(2,4-difluorophenyl)-5-(3-(l-(ethyl-l,l-d2)-lH-l,2,3-tr iazol-5-yl)phenyl)isoindolin-l-one;

6-(2,4-difluorophenyl)-5-(l-(2-morpholinoethyl)-lH-pyrazo l-4-yl)isoindolin-l-one;

6-(2,4-difluorophenyl)-5-(l-(oxetan-3-yl)-lH-pyrazol-4-yl )isoindolin- 1-one;

3-(6-(4-fluoro-2-methoxyphenyl)-l-oxoisoindolin-5-yl)benz onitrile;

3-(6-(2-fluoro-4-methoxyphenyl)-l-oxoisoindolin-5-yl)benz onitrile;

3-(6-(3,4-difluorophenyl)-l-oxoisoindolin-5-yl)benzonitri le;

3-(6-(2-fluorophenyl)-l-oxoisoindolin-5-yl)benzonitrile;

3-(l-oxo-6-(2,4,6-trifluorophenyl)isoindolin-5-yl)benzoni trile;

3-(6-(2,4-dimethylphenyl)-l-oxoisoindolin-5-yl)benzonitri le;

3-(6-(4-(difluoromethoxy)-2-fluorophenyl)-l-oxoisoindolin -5-yl)benzonitrile;

N-(2-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)phenyl) -l-methyl-lH-l,2,3-triazole-4- sulfonamide;

N-(2-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)phenyl) -2-methylthiazole-5-sulfonamide;

N-(2-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)phenyl) -l-methyl-lH-pyrazole-4- sulfonamide; 4-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-3-methoxybenzonit rile;

4-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-2-fluorobenzon itrile;

3-(6-(2-fluoro-4-hydroxyphenyl)-l-oxoisoindolin-5-yl)benz onitrile;

3-(6-(2-chloro-4-fluorophenyl)-l-oxoisoindolin-5-yl)benzo nitrile;

3-(6-(2-fluoro-5-methoxyphenyl)-l-oxoisoindolin-5-yl)benz onitrile;

3-(6-(3-fluoro-4-methoxyphenyl)-l-oxoisoindolin-5-yl)benz onitrile;

5-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-2-methoxybenzo nitrile;

3-(6-(2-chloro-4-methoxyphenyl)-l-oxoisoindolin-5-yl)benz onitrile;

3-(6-(2,5-difluoro-4-methoxyphenyl)-l-oxoisoindolin-5-yl) benzonitrile;

3-(6-(4-methoxy-2-methylphenyl)-l-oxoisoindolin-5-yl)benz onitrile;

3-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-4-fluorobenzon itrile;

3-(6-(2,4-difluoro-5-methylphenyl)-l-oxoisoindolin-5-yl)b enzonitrile;

5-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-2-fluorobenzon itrile;

4-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-2-(trifluorome thyl)benzonitrile;

3-(6-(2-fluoro-5-(trifluoromethyl)phenyl)-l-oxoisoindolin -5-yl)benzonitrile;

4-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-5-fluoro-2-met hylbenzonitrile;

3-(6-(3,5-difluoro-4-methoxyphenyl)-l-oxoisoindolin-5-yl) benzonitrile;

3-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-2-fluorobenzon itrile;

3-(6-(2,3-difluoro-4-methoxyphenyl)-l-oxoisoindolin-5-yl) benzonitrile;

3-(6-(2,5-difluorophenyl)-l-oxoisoindolin-5-yl)benzonitri le;

3-(6-(5-fluoro-2-methoxyphenyl)-l-oxoisoindolin-5-yl)benz onitrile;

2-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-4-fluorobenzon itrile; 3-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-4-methylbenzonitr ile;

3-(6-(3-cyanophenyl)-3-oxoisoindolin-5-yl)-5-fluorobenzon itrile;

6-(2,4-difluorophenyl)-5-(2-(l-methyl-l/7-pyrazol-3-yl)et hyl)isoindolin-l-one;

6-(2,4-difluorophenyl)-5-(2-(pyrimidin-5-yl)ethyl)isoindo lin-l-one;

6-(2,4-difluorophenyl)-5-(2-( 1 -methyl- l//-pyrazol-3-yl)ethyl- 1 , 1 ,2,2-<i/)isoindolin- 1 -one;

3-(2-(6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl)ethyl)b enzonitrile;

6-(2,4-difhiorophenyl)-5-(2-(l-methyl-lH-pyrazol-3-yl)eth yl-l,l,2,2-<i/)isoindolin-l-one-3,3- ch;

6-(2,4-difluorophenyl)-5-(2-( 1 -methyl- 1 H-pyrazol-5-yl)ethyl- 1 , 1 ,2,2-<i/)isoindolin- 1 -one;

6-(2,4-difluorophenyl)-5-(2-(l-methyl-lH-pyrazol-5-yl)eth yl)isoindolin-l-one;

5-(2-(l -cyclopropyl- l/7-pyrazol-3-yl)ethyl)-6-(2,4-difluorophenyl)isoindolin-l -one;

3-(2-(6-(2,4-difluorophcnyl)-l-oxoisoindolin-5-yl)cthyl)- l-mcthyl-lH-pyrazolc-5-carbonitrilc;

6-(2,4-difluorophenyl)-5-(thiomorpholinomethyl)isoindolin -l-one;

6-(2,4-difluorophenyl)-5-(morpholinomethyl)isoindolin-l-o ne;

6-(2,4-difluorophenyl)-5-((3-hydroxy-3-(trifluoromethyl)a zetidin-l-yl)methyl)isoindolin-l-one; or a pharmaceutically acceptable salt thereof.

[00145] E25. A pharmaceutical composition comprising the compound of any one of El- E24, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [00146] E26. A method for treating a disease or disorder associated with dysfunction of metabotropic glutamate receptor 2 (mGlu ₂ ) comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of any one of E1-E24, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E25.

[00147] E27. The method of E26, wherein the disease or disorder is selected from at least one of depression, anxiety, obsessive-compulsive disorder, cognitive disorders, Alzheimer’s disease, and autism spectrum disorders. [00148] E28. A compound of any one of E1-E24, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E25, for use in the treatment of a disease or disorder selected from at least one of depression, anxiety, obsessive-compulsive disorder, cognitive disorders, Alzheimer’s disease, and autism spectrum disorders.

[00149] E29. Use of a compound of any one of E1-E24, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E25, in the manufacture of a medicament for the treatment of a disease or disorder selected from at least one of depression, anxiety, obsessive- compulsive disorder, cognitive disorders, Alzheimer’s disease, and autism spectrum disorders. [00150] Compound names can be assigned by using Struct=Name naming algorithm as part of CHEMDRAW® ULTRA.

[00151] The compound may exist as a stereoisomer wherein asymmetric or chiral centers are present. The stereoisomer is “7?” or “5” depending on the configuration of substituents around the chiral carbon atom. The terms “7?” and “5” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The disclosure contemplates various stereoisomers and mixtures thereof and these are specifically included within the scope of this invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. In the compounds disclosed herein, a chiral atom depicted or described without a specific stereochemical configuration (e.g., a straight bond, not wedged or dashed bond, HC(OH)(CH3)(CH2CH3)) encompasses any stereochemical configuration at the chiral atom. [00152] Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials, which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and optional liberation of the optically pure product from the auxiliary as described in Furniss, Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns or (3) fractional recrystallization methods. [00153] It should be understood that the compound may possess tautomeric forms, as well as geometric isomers, and that these also constitute an aspect of the invention.

[00154] In the compounds of formula (I), and any subformulas, any "hydrogen" or "H, fl whether explicitly recited or implicit in the structure, encompasses hydrogen isotopes (protium) and ² H (deuterium).

[00155] The present disclosure also includes isotopically-labeled compounds (e.g., deuterium labeled), where an atom in the isotopically-labeled compound is specified as a particular isotope of the atom. Examples of isotopes suitable for inclusion in the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ C1, respectively.

[00156] Isotopically-enriched forms of compounds of formula (I), or any subformulas, may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-enriched reagent in place of a non-isotopically-enriched reagent. The extent of isotopic enrichment can be characterized as a percent incorporation of a particular isotope at an isotopically-labeled atom (e.g., % deuterium incorporation at a deuterium label).

B. Allosteric Modulation of mGlu ₂

[00157] The disclosed compounds may act or function as non-competitive antagonists, allosteric inhibitors, allosteric antagonists, or negative allosteric modulators (NAM) of mGlu ₂ . The compounds may be procognitive and neuroprotective even in the presence of mGlui dysfunction.

[00158] Compounds of formula (I) can inhibit mGlu ₂ with an IC50 ranging from about 1 nM to about 30 |1M. The compounds may have an IC50 of about 30 pM, about 29 pM, about 28 pM, about 27 pM, about 26 pM, about 25 pM, about 24 pM, about 23 pM, about 22 pM, about 21 pM, about 20 pM, about 19 pM, about 18 pM, about 17 pM, about 16 pM, about 15 pM, about

14 pM, about 13 pM, about 12 pM, about 11 pM, about 10 pM, about 9 pM, about 8 pM, about

7 pM, about 6 pM, about 5 pM, about 4 pM, about 3 pM, about 2 pM, about 1 pM, about 950 nM, about 900 nM, about 850 nM, about 800 nM, about 850 nM, about 800 nM, about 750 nM, about 700 nM, about 650 nM, about 600 nM, about 550 nM, about 500 nM, about 450 nM, about

400 nM, about 350 nM, about 300 nM, about 250 nM, about 200 nM, about 150 nM, about 100 nM about 50 nM about 10 nM about 5 nM or about 1 nM Compounds of formula (I) can inhibit mGlu ₃ with an IC50 of less than 30 pM, less than 29 pM, less than 28 pM, less than 27 pM, less than 26 pM, less than 25 pM, less than 24 pM, less than 23 pM, less than 22 pM, less than 21 pM, less than 20 pM, less than 19 pM, less than 18 pM, less than 17 pM, less than 16 pM, less than 15 pM, less than 14 pM, less than 13 pM, less than 12 pM, less than 11 pM, less than 10 pM, less than 9 pM, less than 8 pM, less than 7 pM, less than 6 pM, less than 5 pM, less than 4 pM, less than 3 pM, less than 2 pM, less than 1 pM, less than 950 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.

[00159] Compounds of formula (I) may be selective modulators of mGlui over mGlu ₃ . The compounds may have a ratio of mGlu ₃ ICso to mGlu ₃ ECso of at least 100, at least 95, at least 90, at least 85, at least 80, at least 75, at least 70, at least 64, at least 60, at least 55, at least 50, at least 45, at least 40, at least 35, at least 33, at least 31, at least 30, at least 29, at least 28, at least

27, at least 26, at least 25, at least 24, at least 23, at least 22, at least 21, at least 20, at least 19, at least 18, at least 17, at least 16. at least 15, at least 14, at least 13, at least 12, at least 11, at least

10, at least 9, at least 8, at least 7, at least 6, at least 5, at least 4, at least 3, or at least 2.

Compounds of formula (I) may have a ratio of mGlu ₃ ICso to mGlu ₃ ECso of about 100, about 95, about 90, about 85, about 80, about 75, about 70, about 64, about 60, about 55, about 50, about

45, about 40, about 35, about 33, about 31, about 30, about 29, about 28, about 27, about 26, about 25, about 24, about 23, about 22, about 21, about 20, about 19, about 18, about 17, about

16, about 15, about 14, about 13, about 12, about 11, about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, or about 2.

[00160] Compounds of formula (I) may be selective modulators of mGlu ₃ over mGlu ₃ . The compounds may have a ratio of mGlu ₃ ICso to mGlu ₃ ECso of at least 100, at least 95, at least 90, at least 85, at least 80, at least 75, at least 70, at least 64, at least 60, at least 55, at least 50, at least 45, at least 40, at least 35, at least 33, at least 31, at least 30, at least 29, at least 28, at least

27, at least 26, at least 25, at least 24, at least 23, at least 22, at least 21, at least 20, at least 19, at least 18, at least 17, at least 16, at least 15, at least 14, at least 13, at least 12, at least 11, at least

10 at least 9 at least 8 at least 7 at least 6 at least 5 at least 4 at least 3 or at least 2 Compounds of formula (I) may have a ratio of mGluo ICso to mGlu ₃ EC so of about 100, about 95, about 90, about 85, about 80, about 75, about 70, about 64, about 60, about 55, about 50, about

45, about 40. about 35, about 33, about 31, about 30, about 29, about 28, about 27, about 26, about 25, about 24, about 23, about 22, about 21, about 20, about 19, about 18, about 17, about

16, about 15, about 14, about 13, about 12, about 11, about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, or about 2.

C. Pharmaceutical Salts

[00161] The disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit/risk ratio and effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide a salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 -phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, thrichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric and the like. The amino groups of the compounds may also be quaternized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like.

[00162] Basic addition salts may be prepared during the final isolation and purification of the disclosed compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N- dimcthylanilinc, N-mcthylpipcridinc, N-mcthylmorpholinc, dicyclohcxylaminc, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine and N,N’- dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

D. General Synthesis

[00163] Compounds of formula (I) may be prepared by synthetic processes or by metabolic processes. Preparation of the compounds by metabolic processes includes those occurring in the human or animal body (in vivo) or processes occurring in vitro.

[00164] Abbreviations in the Schemes that follow are: DMF is dimethylformamide; EtgN is triethylamine; MeOH is methanol; min or min. is minute(s); mw or u W is microwave irradiation; PhNTfo is N-phenyl-bis(trifhioromethanesulfonimide); Pd(dppf)C12 is [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(PPh3)2Ch is Bis(triphenylphosphine)palladium (II) dichloride; PPhg is triphenyl phosphine; TBAI is Tetrabutylammonium iodide.

[00165] Compounds of formula (I) or any of its subformulas may be synthesized as shown in the following schemes.

General Scheme 1

[00166] As shown in General Scheme 1, 6-bromo-5-hydroxyisoindolin-l-one compounds of formula A may be subjected to Suzuki reaction conditions, wherein compound A is reacted with an appropriate R ³ -substituted boronic acid or ester reagent in the presence of a base (e.g., sodium carbonate, cesium carbonate) in solvents such as dioxane or dioxane/water mixtures to form intermediate compound B-I presenting the R ³ substituent. General Scheme 2

R ¹ R ² R ¹ R ² R ¹ R ² R ¹ J N R ¹ 3_ N G ⁴ R ¹ 3- N

R ⁶ _X /L o PhNTf ₂ R® ■O R® Z==O

O, ,O Pd(PPh ₃ ) ₂ CI ₂ , Et ₃ N, TBAI

HO^T R ⁵ Base F ₃ C X ^X 'O' R ⁵ Gul, DMF, heat R ⁵

R ³ R ³ G ⁴ R ³

B-l B-la D-l

[00167] As shown in General Scheme 2, intermediate B-I may be transformed to the intermediate B-la with N-phenyl-bis(trifluoromethanesulfonimide) and base (e.g., EtgN). Intermediate B-la may be subjected to standard Sonogashira coupling conditions with alkyne, palladium catalyst (e.g. PdCPPhgjrCb), base (e.g. EtgN), copper (I) iodide and solvent (e.g. DMF) to afford compound D-I.

General Scheme 3

MeOH R ³

D-l E-l

[00168] As shown in General Scheme 3, compound E-I is formed by subjecting compound D-I to hydrogenation conditions with palladium catalyst (e.g., palladium on carbon) in solvent (e.g., methanol) in a hydrogen atmosphere. Conducting the reaction in the presence of deuterium gas ² H2 may provide compound E-I enriched in deuterium.

General Scheme 4 pH O R ¹ R B _X or ²

G ⁴ - G ⁴ -B ^R1 J o N

OH

^R s O

Pd(dppf)CI ₂ CH ₂ CI ₂

Na ₂ CO ₃

G ⁴ R ⁵ 1 ,4-dioxane/H ₂ O, 100 °C R ³

B-la F-l [00169] As shown in General Scheme 4, compound B-Ia may be subjected to standard Suzuki reaction conditions with boronic acid or esters, a palladium catalyst (e.g., Pd(dppf)Ch • DCM), base (e.g., NaiCOa), solvent (e.g., 1,4-dioxane/water) and heat to afford compound F-I. An

_/0 H P Cy-B _s Cy-B _x analogous reaction with OOHH _or X , where the boronic acid or ester is substituted on an unsaturated carbon of Cy may provide compounds with Cy substituted at R ⁴ in the compounds of formula (I). Products of the Suzuki reaction may be transformed into further compounds of the invention, such as by hydrogenation of a double bond in Cy to provide compounds with saturated Cy (e.g., Example 15).

[00170] Suzuki coupling conditions suitable for use in the synthetic processes described herein are well known in the art. Suitable Suzuki conditions include those generally outlined in the General Schemes and Examples.

[00171] Boronic acid and ester reagents may be purchased from commercial sources or prepared from the corresponding halide (e.g., bromide) using known procedures.

[00172] The compounds and intermediates may be isolated and purified by methods well- known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described for instance in "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM202JE, England.

[00173] A disclosed compound may have at least one basic nitrogen whereby the compound can be treated with an acid to form a desired salt. For example, a compound may be reacted with an acid at or above room temperature to provide the desired salt, which is deposited, and collected by filtration after cooling. Examples of acids suitable for the reaction include, but are not limited to tartaric acid, lactic acid, succinic acid, as well as mandelic, atrolactic, methanesulfonic, ethanesulfonic, toluenesulfonic, naphthalenesulfonic, benzenesulfonic, carbonic, fumaric, maleic, gluconic, acetic, propionic, salicylic, hydrochloric, hydrobromic, phosphoric, sulfuric, citric, hydroxybutyric, camphorsulfonic, malic, phenylacetic, aspartic, or glutamic acid, and the like.

[00174] Optimum reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Specific procedures are provided in the Examples section. Reactions can be worked up in the conventional manner, e.g., by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starling materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. Starting materials, if not commercially available, can be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above-described schemes or the procedures described in the synthetic examples section.

[00175] Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that cannot be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the invention. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in PGM Wuts and TW Greene, in Greene’s book titled Protective Groups in Organic Synthesis (4 ^th ed.), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the invention can be accomplished by methods analogous to those described in the synthetic schemes described hereinabove and in specific examples.

[00176] When an optically active form of a disclosed compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).

[00177] Similarly, when a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.

[00178] It can be appreciated that the synthetic schemes and specific examples as described arc illustrative and are not to be read as limiting the scope of the invention as it is defined in the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims.

3. Pharmaceutical compositions

[00179] The disclosed compounds may be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which may be a human or non-human). [00180] The pharmaceutical compositions may include a “therapeutically effective amount” or a “prophylactically effective amount” of the agent. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the composition may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of a compound of the invention [e.g., a compound of formula (I)] are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[00181] For example, a therapeutically effective amount of a compound of formula (I), may be about 1 mg/kg to about 1000 mg/kg, about 5 mg/kg to about 950 mg/kg, about 10 mg/kg to about 900 mg/kg, about 15 mg/kg to about 850 mg/kg, about 20 mg/kg to about 800 mg/kg, about 25 mg/kg to about 750 mg/kg, about 30 mg/kg to about 700 mg/kg, about 35 mg/kg to about 650 mg/kg, about 40 mg/kg to about 600 mg/kg, about 45 mg/kg to about 550 mg/kg, about 50 mg/kg to about 500 mg/kg, about 55 mg/kg to about 450 mg/kg, about 60 mg/kg to about 400 mg/kg, about 65 mg/kg to about 350 mg/kg, about 70 mg/kg to about 300 mg/kg, about 75 mg/kg to about 250 mg/kg, about 80 mg/kg to about 200 mg/kg, about 85 mg/kg to about 150 mg/kg, and about 90 mg/kg to about 100 mg/kg. [00182] The pharmaceutical compositions may include pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier," as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. [00183] Thus, the compounds and their physiologically acceptable salts and solvates may be formulated for administration by, for example, solid dosing, eyedrop, in a topical oil-based formulation, injection, inhalation (either through the mouth or the nose), implants, or oral, buccal, parenteral, or rectal administration. Techniques and formulations may generally be found in "Remington's Pharmaceutical Sciences", (Meade Publishing Co., Easton, Pa.).

Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage.

[00184] The route by which the disclosed compounds are administered, and the form of the composition will dictate the type of carrier to be used. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral) or topical administration (e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery systems, or iontophoresis).

[00185] Carriers for systemic administration typically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives. glidants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and others. All carriers arc optional in the compositions.

[00186] 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(s) in a systemic or topical composition is typically about 50 to about 90%.

[00187] Suitable lubricants include silica, talc, stearic acid and its magnesium salts 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, com oil and oil of theobroma. The amount of lubricant(s) in a systemic or topical composition is typically about 5 to about 10%. [00188] Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, microcry stalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition is typically about 5 to about 50%.

[00189] Suitable disintegrants include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmelose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0.1 to about 10%.

[00190] Suitable colorants include a colorant such as an FD&C dye. When used, the amount of colorant in a systemic or topical composition is typically about 0.005 to about 0.1%.

[00191] Suitable flavors include menthol, peppermint, and fruit flavors. The amount of flavor(s), when used, in a systemic or topical composition is typically about 0.1 to about 1.0%. [00192] Suitable sweeteners include aspartame and saccharin. The amount of sweetener(s) in a systemic or topical composition is typically about 0.001 to about 1%.

[00193] Suitable antioxidants include butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically about 0.1 to about 5%.

[00194] Suitable preservatives include benzalkonium chloride, methyl paraben and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically about 0.01 to about 5%. [00195] Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5%.

[00196] Suitable solvents include water, isotonic saline, ethyl oleate, glycerine, hydroxylated castor oils, alcohols such as ethanol, and phosphate buffer solutions. The amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100%.

[00197] Suitable suspending agents include AVICEL RC-591 (from EMC Corporation of Philadelphia, PA) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is typically about 1 to about 8%.

[00198] Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS from Atlas Powder Company of Wilmington, Delaware. Suitable surfactants include those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp.587-592; Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant(s) in the systemic or topical composition is typically about 0.1% to about 5%.

[00199] Although the amounts of components in the systemic compositions may vary depending on the type of systemic composition prepared, in general, systemic compositions include 0.01% to 50% of active [e.g., compound of formula (I)] and 50% to 99.99% of one or more carriers. Compositions for parenteral administration typically include 0.1% to 10% of actives and 90% to 99.9% of a earner including a diluent and a solvent.

[00200] Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms include a safe and effective amount, usually at least about 5%, and more particularly from about 25% to about 50% of actives. The oral dosage compositions include about 50% to about 95% of carriers, and more particularly, from about 50% to about 75%.

[00201] Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed. Tablets typically include an active component, and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, glidants, 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 croscarmelose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are the FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or a combination thereof. [00202] Capsules (including implants, time release and sustained release formulations) typically include an active compound [e.g., a compound of formula (I)], and a carrier including one or more diluents disclosed above in a capsule comprising gelatin. Granules typically comprise a disclosed compound, and preferably glidants such as silicon dioxide to improve flow characteristics. Implants can be of the biodegradable or the non-biodegradable type.

[00203] The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this invention.

[00204] Solid compositions may be coated by conventional methods, typically with pH or time-dependent coatings, such that a disclosed compound is released in the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action. The coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT coatings (available from Rohm & Haas G.M.B.H. of Darmstadt, Germany), waxes and shellac.

[00205] Compositions for oral administration can have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid orally administered compositions typically include a disclosed compound and a carrier, namely, a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Peroral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners.

[00206] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more of soluble filler substances such as diluents including sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Such compositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants. [00207] The disclosed compounds can be topically administered. Topical compositions that can be applied locally to the skin may be in any form including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. Topical compositions include: a disclosed compound [e.g., a compound of formula (I)], and a carrier. The carrier of the topical composition preferably aids penetration of the compounds into the skin. The carrier may further include one or more optional components.

[00208] The amount of the carrier employed in conjunction with a disclosed compound is sufficient to provide a practical quantity of composition for administration per unit dose of the medicament. Techniques and compositions for making dosage forms useful in the methods of this 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).

[00209] A carrier may include a single ingredient or a combination of two or more ingredients. In the topical compositions, the carrier includes a topical carrier. Suitable topical carriers include one or more ingredients 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, combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.

[00210] The carrier of a topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional.

[00211] 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, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, 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 skin include stearyl alcohol and poly dimethylsiloxane. The amount of emollient(s) in a skin-based topical composition is typically about 5% to about 95%.

[00212] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant(s) in a topical composition is typically about 0% to about 95%.

[00213] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent(s) in a topical composition is typically about 0% to about 95%.

[00214] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant(s) in a topical composition is typically 0% to 95%. [00215] The amount of thickener(s) in a topical composition is typically about 0% to about 95%.

[00216] Suitable powders include beta-cyclodextrins, hydroxypropyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically-modified magnesium aluminum silicate, organically-modified Montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder(s) in a topical composition is typically 0% to 95%.

[00217] The amount of fragrance in a topical composition is typically about 0% to about 0.5%, particularly, about 0.001% to about 0.1%.

[00218] Suitable pH adjusting additives include HC1 or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition.

4. Methods of Treatment

[00219] The disclosed compounds and compositions may be used in methods for treatment of mGlu ₂ related medical disorders and/or diseases. The methods of treatment may comprise administering to a subject in need of such treatment a composition comprising a therapeutically effective amount of the compound of formula (I).

[00220] The compositions can be administered to a subject in need thereof to modulate mGlu ₂ , for a variety of diverse biological processes. The present disclosure is directed to methods for administering the composition to inhibit mGlu ₂ , a GPCR that plays a role in synaptic plasticity, which directly affects cognitive function and memory, for example.

[00221] The compositions may be useful for treating and preventing certain diseases and disorders in humans and animals related to mGlu ₂ dysfunction. Treatment or prevention of such diseases and disorders can be effected by modulating mGlu ₂ in a subject, by administering a compound or composition of the invention, either alone or in combination with another active agent as part of a therapeutic regimen to a subject in need thereof.

A. Depression

[00222] Antidepressant-like effects of the mGlu ₂ /3 receptor antagonists, MGS0039 and LY341495, were first demonstrated in the rat forced swim test (FST) and mouse tail-suspension test (TST) using normal animals (Chaki et al. Neuropharmacology, 2004, 46, 457-467). More recently, studies have attempted to evaluate the effects of these drugs in paradigms implicated in the etiology of human depression. MGS0039 exhibited antidepressant effects in the learned helplessness test where treatment with MGS0039 for 7 days significantly reduced the number of escape failures (Yoshimizu et al. Psychopharmacology, 2006, 186, 587-593).

[00223] Palucha-Poniewiera et al. Psychopharmacology, 2010, 272, 523-535 evaluated a potential antidepressant-like effect of MGS0039 in the olfactory bulbectomy (OB) model of depression in rats. A surgical lesion of the olfactory bulbs in animals is known to induce significant behavioral, physiological, endocrine and immune changes, many of which are qualitatively similar to those observed in depressive patients. Repeated administration of MGS0039 for 14 days attenuated the hyperactivity of olfactory bulbectomized rats in the open field test and attenuated the learning deficit in the passive avoidance test.

[00224] Kawasaki et al. Neuropharmacology, 2011, 60, 397-404 also examined the effect of MGS0039 on behaviors of social isolation-reared mice in the FST. Rearing rodents in isolation after weaning is known to lead to changes in brain neurochemistry that produce perturbations in behavior. Post-weaning chronic social isolation for more than 6 weeks increased immobility in the FST, suggesting that isolation rearing caused depression-like behavior. MGS0039 reversed the increased immobility of social isolation reared mice in the test.

[00225] Campo, B. et al. J. Neurogenetics 2011, 25, 152-166, demonstrated a selective group II (mGlu ₂ and mGlug) negative allosteric modulator (RO4491533) to be effective in several in vitro biochemical assays and in vivo models of depression. RO4491533 was shown to engage the central mGlu ₂ and mGlug receptors as the compound reversed the hypolocomotor effect of an mGlu ₂ /3 agonist (LY379268) in a target- specific manner. The known group II mGlu ₂ /3 antagonist LY341495 achieved the same result. RO4491533 and LY341495 dose-dependently reduced immobility time of C57B16/J mice in the FST. RO4491533 and LY341495 were also active in the tail suspension test in a line of Helpless (H) mice, a putative genetic model of depression. [00226] Blockade of mGlu ₂ /3 receptors and ketamine may converge to the same neuronal circuits, which include activation of AMPA receptor and mTOR signaling. Because both AMPA receptor stimulation and subsequent mTOR signaling activation are presumed to be involved in rapid action of ketamine for patients with treatment-resistant depression (TRD), mGlu ₂ /3 receptor antagonists could exert the same effects in humans. This assumption is underpinned by several animal studies. First, the mGlu ₂ /3 receptor antagonist MGS0039 exhibited antidepressant effects in an animal model (the learned helplessness paradigm) which is refractory to currently prescribed antidepressants (Yoshimizu et al. Psychopharmacology, 2006, 186, 587-593). Second, although evidence of rapid onset of action with 111GIU2/3 receptor antagonists are absent, an AMPA receptor potentiator (AMPA receptor potentiation mediates antidepressant effects of mGlu ₂ /3 receptor antagonists) showed faster effects (during the first week of treatment) compared to fluoxetine (after two weeks) in a dominant-submissive test (Knapp et al. Eur. J. Pharmacol. 2002, 440, 121-125). Moreover, LY341495 exhibited a potent antidepressant effect in helpless mice following acute administration, while fluoxetine exerts a full antidepressant effect following chronic (21 days) treatment (Campo, B. et al. J. Neurogenetics 2011, 25, 152-166; El Yacoubi et al. PNAS, 2003, 700, 6227-6232). Therefore, blockade of mGlu ₂ /3 receptors may show rapid and potent antidepressant effects in humans.

B. Cognitive Disorders

[00227] Weltering et al. Bioorg. Med. Chem. Lett. 2010, 20, 6969-74, demonstrated that a negative allosteric modulator of mGlu ₂ /3 reversed mGlu ₂ /3 agonist or scopolamine-induced working memory deficits in the delayed match to position (DMTP) task in rodents, a measure of working memory. Additionally, Woltering demonstrated a synergistic reversal of scopolamine- induced deficits in DMTP when low doses of a negative allosteric modulator of mGlu ₂ /3 were combined with a threshold dose of the acetylcholinesterase inhibitor donezepil. Given the efficacy of donepezil and other acetylcholinesterase inhibitors in the treatment of the cognitive impairments in Alzheimer’s disease, negative allosteric modulators of mGlu ₂ may have efficacy as cognitive enhancers.

C. Obsessive-Compulsive Disorder

[00228] Shimazaki, T. et al. Eur. J. Pharmacol. 2004, 507, 121-125, demonstrated that

MGS0039 induced glutamatergic change in mice, resulting in anti-obsessive-compulsive disorder activity. In these studies, a marble-burying behavioral test was utilized as a model for obsessive-compulsive disorder. The marble-burying behavior test is recognized as a useful model for evaluating the clinical potential of anti-obsessive-compulsive disorder drugs. Specifically, MGS0039 treated mice exhibited reduced marble-burying behavior in a significant and dose dependent manner, while no significant change was observed in spontaneous locomotor activity. In addition, LY341495, another potent antagonist of group II mGlu receptors, was also shown to significantly reduce marble-burying behavior in treated mice.

D. Alzheimer’s disease

[00229] Kim, S.H. et al. Moecular Psychiatry 2014, 1-8, have assessed the therapeutic potential of chronic pharmacological inhibition of group II mGlu receptors (mGlu ₂ and mGlug) with a group II mGlu receptor antagonist in an APP transgenic mouse model that develops impaired learning behavior in relation to accumulation of mutant A0 oligomers that never form amyloid plaques. Once-daily dosing of the orally bioavailable prodrug, BCI-838, delivered a sufficient brain concentration of its active metabolite BCI-632 to inhibit group II mGlu receptors for 22 hours. Three months of treatment with BCI-838 provided anxiolytic effects, reversed Dutch APP transgene-associated learning and memory impairment, and decreased the levels of monomeric and oAP peptides in the hippocampus and cortex of the two different AD mouse models. Notably, BCI-838 administration stimulated hippocampal progenitor cell proliferation in both wild-type and Alzheimer’s diseased mice for 3 months, which resulted in significantly increased numbers of newborn neurons in the hippocampi of Dutch APP transgenic mice. In addition to treatment, the proneurogenic properties make the compound attractive for potential use in reversing some of the early symptoms of Alzheimer’s disease (AD), possibly through reparative effects of the newborn neurons. These findings suggest that chronic pharmacological inhibition of group II mGlu receptors has the potential to be a disease-modifying treatment for AD that targets cognitive/emotional defects and modulates neurogenesis.

[00230] Additional studies by Caraci, F. et al Mol. Pharmacol. 2011, 79, 618-626, showed that a positive allosteric modulator of mGlu ₂ (LY566332) amplified A|3-induced neurodegeneration, but this effect was prevented by the mGlu ₂ /3 receptor antagonist, LY341495.

E. Anxiety

[00231] Yoshimizu et al. Psychopharmacology, 2006, 186, 587-593 also demonstrated the anxiolytic effects of MGS0039, a potent antagonist of group II mGlu receptors (mGlu ₂ and mGlug), by use of a conditioned fear stress (CFS) model, which represents emotional abnormality, including anxiety. The CFS model reflects psychological stress without physical stimuli and is useful in predicting the clinical efficacy of anxiolytic drugs. In these studies, MGS0039 significantly decreased freezing behavior, as did diazepam and fluvoxamine, indicating the anxiolytic-like potential of MGS0039. The mGlu ₂ /3 receptors inhibit neurotransmitter release as autoreceptors located on glutamatergic terminals and treatment with mGlu ₂ /3 antagonists such as MGS0039 in vivo lead to an increase in extracellular glutamate. Therefore, the moderate elevation of glutamate levels in specific areas of the brain by MGS0039 may cause the anxiolytic-like effects seen in the CFS model. These results suggest that the blockade of mGlu ₂ /3 with MGS0039 may be effective in the treatment of anxiety disorders.

F. Modes of Administration

[00202] Methods of treatment may include any number of modes of administering a disclosed composition. Modes of administration may include tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions or dispersible powders. For the preparation of pharmaceutical compositions for oral administration, the agent may be admixed with commonly known and used adjuvants and excipients such as for example, gum arabic, talcum, starch, sugars (such as, e.g., mannitose, methyl cellulose, lactose), gelatin, surface-active agents, magnesium stearate, aqueous or nonaqueous solvents, paraffin derivatives, cross-linking agents, dispersants, emulsifiers, lubricants, conserving agents, flavoring agents (e.g., ethereal oils), solubility enhancers (e.g., benzyl benzoate or benzyl alcohol) or bioavailability enhancers (e.g. Gelucire.TM.). In the pharmaceutical composition, the agent may also he dispersed in a microparticle, e.g. a nanoparticulate composition.

[00203] For parenteral administration, the agent can be dissolved or suspended in a physiologically acceptable diluent, such as, e.g., water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers. As oils for example and without limitation, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil may be used. More generally spoken, for parenteral administration, the agent can be in the form of an aqueous, lipid, oily or other kind of solution or suspension or even administered in the form of liposomes or nano-suspensions.

[00204] The term "parenterally," as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

G. Combination Therapies

[00205] Additional therapeutic agent(s) may be administered simultaneously or sequentially with the disclosed compounds and compositions. Sequential administration includes administration before or after the disclosed compounds and compositions. In some embodiments, the additional therapeutic agent or agents may be administered in the same composition as the disclosed compounds. In other embodiments, there may be an interval of time between administration of the additional therapeutic agent and the disclosed compounds. In some embodiments, administration of an additional therapeutic agent with a disclosed compound may allow lower doses of the other therapeutic agents and/or administration at less frequent intervals. 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 singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula (I). The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds. For example, the compound of Formula (I) can be combined with a variety of antidepressants, Alzheimer’s disease medications, and anxiolytics.

[00206] The compound of Formula (I) can be combined with the following antidepressants, but not limited to: Selective serotonin reuptake inhibitors (SSRIs) such as citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, indalpine, paroxetine, sertraline, and zimelidine; Scrotonin-norcpincphrinc reuptake inhibitors (SNRIs) such as venlafaxine, dcsvcnlafaxinc, duloxetine, milnacipran, levomilnacipran, and sibutramine; Noradrenergic and specific serotonergic antidepressants (NaSSAs) or tetracyclic antidepressants (TeCAs) such as aptazapine, esmirtazapine, mianserin, mirtazapine, and setiptiline; Serotonin antagonist and reuptake inhibitors (SARIs) such as etoperidone, lorpiprazole, mepiprazole, nefazodone, trazodone, vilazodone, and niaprazine; Norepinephrine-dopamine reuptake inhibitors (NDRIs) such as armodafinil, bupropion, desoxypipradrol, dexmethylphenidate, methylphenidate, modafinil, prolintane, and tametraline; Serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs) such as nefopam, amitifadine, tesofensine, and tedatioxetine; Tricyclic antidepressants (TCAs) such as clomipramine, desipramine, imipramine, dibenzepin, lofepramine, nortriptyline, protriptyline, amitriptyline, amitriptylinoxide, amoxapine, butriptyline, demexiptiline, dimetacrine, dosulepin, doxepin, imipraminoxide, melitracen, metapramine, nitroxazepine, noxiptiline, pipofezine, propizepine, quinupramine, amineptine, iprindole, opipramol, tianeptine, and trimipramine; and Negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu ₃ ) such as mavoglurant, basimglurant, dipraglurant, STX107, and 2V-(5-fluoropyridin-2- yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide.

[00207] The compound of Formula (I) can be combined with the following Alzheimer’s disease medications, but not limited to: Acetylcholinesterase inhibitors such as tacrine, rivastigmine, galantamine, donepezil, edrophonium, physostigmine, pyridostigmine, ambenonium, rivastigmine, ladostigil, and ungeremine; and NMD A receptor antagonists such as memantine, amantadine, delucemine, and ketamine.

[00208] The compound of Formula (I) can be combined with the following anxiolytics, but not limited to: buspirone, tandosprione, gepirone, adaptol, afobazole, hyroxyzine, validol, melatonin, and benzodiazepines such as alprazolam, chlordiazepoxide, clonazepam, diazepam, etizolam, lorazepam, oxazepam, and tofisopam.

[00209] The disclosed compounds may be included in kits comprising the compound [e.g., one or more compounds of formula (I)], a systemic or topical composition described above, or both; and information, instructions, or both that use of the kit will provide treatment for medical conditions in mammals (particularly humans). The information and instructions may be in the form of words, pictures, or both, and the like. In addition or in the alternative, the kit may include the medicament, a composition, or both; and information, instructions, or both, regarding methods of application of medicament, or of composition, preferably with the benefit of treating or preventing medical conditions in mammals (e.g., humans).

[00210] The compounds and processes of the invention will be better understood by reference to the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention.

5. Examples

[00211] All NMR spectra were recorded on a 400 MHz AMX Bruker NMR spectrometer. ¹ H chemical shifts are reported in 5 values in ppm downfield with the deuterated solvent as the internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet, ABq = AB quartet), coupling constant, integration. Reversed-phase LCMS analysis was performed using an Agilent 1200 system comprised of a binary pump with degasser, high-performance autosampler, thermostatted column compartment, C18 column, diode-array detector (DAD) and an Agilent 6150 MSD with the following parameters. The gradient conditions were 5% to 95% acetonitrile with the aqueous phase 0.1% TFA in water over 1.4 minutes. Samples were separated on a Waters Acquity UPLC BEH C18 column (1.7 pm, 1.0 x 50 mm) at 0.5 mL/min, with column and solvent temperatures maintained at 55 °C. The DAD was set to scan from 190 to 300 nm, and the signals used were 220 nm and 254 nm (both with a band width of 4nm). The MS detector was configured with an electrospray ionization source, and the low-resolution mass spectra were acquired by scanning from 140 to 700 AMU with a step size of 0.2 AMU at 0.13 cycles/second, and peak width of 0.008 minutes. The drying gas flow was set to 13 liters per minute at 300 °C and the nebulizer pressure was set to 30 psi. The capillary needle voltage was set at 3000 V, and the fragmentor voltage was set at 100V. Data acquisition was performed with Agilent Chemstation and Analytical Studio Reviewer software.

[00212] Abbreviations that may be used in the examples that follow are:

AIBN is 2,2’-Azobis(2-methylpropionitrile); atm is atmospheres;

Celite® is diatomaceous earth;

DCM for dichloromethane;

DIAD is diisopropyl azodicarboxylate; DMF is A,A-dimethylformamide;

DMAP is 4-dimcthylaminopyridinc;

DMSO is dimethylsulfoxide; eq, eq., or equiv is equivalent(s);

EtgN is triethylamine;

EtOAc is ethyl acetate; h is hours;

LCMS is liquid chromatography mass spectrometry;

MeCN is acetonitrile;

MeOH is methanol;

MeOD is CH3OD; min or min. is minute(s); mw or pW is microwave irradiation;

NBS is N-Bromosuccinimide;

PhNTf2 is N-phenyl-bis(trifluoromethanesulfonimide);

Pd(dppf)Ch is [l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(II);

PPhs is triphenyl phosphine; rt, RT, or r.t. is room temperature; sat. is saturated;

Tf is triflate;

TFA is trifluoroacetic acid;

THF is tetrahydrofuran.

Preparation of Intermediates

Intermediate Example 1. 6-Bromo-5-methoxyisoindolin-l-one (B). o o

Br- Br-

O' NBS, AIBN O NH ₃

CCI ₄ , 90 °C Br

O' O' MeOH, 100 °C

A

[00213] Methyl 5-bromo-2-(bromoethyl)-4-methoxybenzoate (Intermediate A). To a flask was added methyl 5-bromo-4-methoxy-2-methylbenzoate (5.0 g, 19.3 mmol), N- bromosuccinimide (3.75 g, 21.1 mmol), and AIBN (330 mg, 2.0 mmol). The resulting mixture was diluted in carbon tetrachloride (90 mL) and the reaction mixture stirred at 90 °C. After 16 h, the mixture was washed with water (30 mL) and separated. The aqueous layer was extracted with DCM (3 x 50 mL) and the combined organic layers were washed with brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (0-10% hexanes :EtO Ac) to provide Intermediate A. ¹ H NMR (400 MHz, DMSO-t/6) 8 8.07 (s, 1H), 7.39 (s, 1H), 5.02 (s, 2H), 3.94 (s, 3H), 3.84 (s, 3H), ES-MS [M+l] ⁺ : 337.8 and 339.8.

[00214] 6-Bromo-5-methoxyisoindolin-l-one (Intermediate B). Methyl 5-bromo-2- (bromomethyl)-4-methoxybenzoate (4.68 g, 13.9 mmol) was dissolved in a 7N solution of ammonia in methanol (51.4 mL). The reaction mixture stirred in a Teflon® screwcap flask and was heated to 100 °C. After 2 h, the cap was carefully removed and the solvent was then evaporated in vacuo and the crude residue was purified by normal phase column column chromatography (0-10% EtOAc:MeOH) to give the title compound. NMR (400 MHz, DMSO-ri6) 8 8.48 (s, 1H), 7.78 (s, 1H), 7.34 (s, 1H), 4.32 (t, 7 = 1.0 Hz, 2 H), 3.93 (s, 3H); ESMS [M+l] ⁺ : 242.0 and 244.0.

Intermediate Example 2. 6-Bromo-5-hydroxyisoindolin-l-one (Intermediate C). o O

Br- Brx

NH BBr ₃ NH

'<T DCM, 0 °C to rt HCX

C

[00215] To a round- bottomed flask was added 6-bromo-5-methoxyisoindolin- 1-one (796 mg, 3.3 mmol) and anhydrous DCM (16.5 mL). After the reaction vessel was placed in an ice bath, BBrg (624 μL, 6.57 mmol) was added slowly via syringe. The reaction mixture was allowed to stir at ambient temperature overnight. After resubmerging the rection vessel in the ice bath, ice was then added to the vessel. After 30 min, the layers were then separated, and the aqueous layer was extracted with DCM (3 x 50 mL) and a 3:1 ratio of chloroforrmisopropanol (50 mL). The combined organic portions were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound. The aqueous layers were concentrated and diluted with a 1: 1 chloroform: isopropanol solution (100 mL). The resulting precipitant was filtered by vacuum filtration to provide the title compound, which was taken to the next step without further purification. ¹ H NMR (400 MHz, DMSO-t/6) 3 10.96 (s, 1H), 8.35 (s, 1H), 7.69 (s, 1H), 7.08 (s, 1H), 4.25 (s, 2H); ES-MS [M+l] ⁺ : 227.9 and 229.9.

Intermediate Example 3. 6-(4-Fluorophenyl)-l-oxoisoindolin-5-yl trifluoromethanesulfonate (Intermediate E).

[00216] 6-(4-Fluorophenyl)-5-hydroxyisoindolin-l-one (Intermediate D). To a mixture of 6-bromo-5-hydroxyisoindolin-l-one (1 g, 4.38 mmol), Pd(dppf)Ch • DCM (359 mg, 0.438 mmol), 4-fluorophenylboronic acid (1.23 g, 8.77 mmol), and CS ₂ CO ₃ (1.44 g, 4.38 mmol) was added degassed 1,4-dioxane (8 mL) and water (800 μL). The reaction atmosphere was evacuated and purged with nitrogen (3x) and the sealed reaction vessel underwent microwave irradiation at 120 °C. After 20 min, to the resulting mixture was added DCM (50 mL) and the rection mixture was passed through a hydrophobic phase separator. The organic layer was concentrated in vacuo to give a crude residue. The residue was purified via normal phase column chromatography (0- 20% DCM:MeOH) to afford the title compound. ES-MS [M+l] ⁺ : 244.0.

[00217] 6-(4-Fluorophenyl)-l-oxoisoindolin-5-yl trifluoromethanesulfonate (Intermediate

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

[00218] 6-(2,4-Difluorophenyl)-5-hydroxyisoindolin-l-one (Intermediate F). To a mixture of 6-bromo-5-hydroxyisoindolin-l-one (1 g, 4.39 mmol), Pd(dppf)Ch • DCM (359 mg, 0.44 mmol), cesium carbonate (1.44 g, 4.39 mmol), and 2,4-difluorophenylboronic acid (1.38 g, 8.77 mmol) was added a solution of 1,4-dioxane (8 mL) and water (800 μL). The reaction mixture was heated to 120 °C under microwave irradiation. After 40 min, the reaction mixture was diluted with DCM and the organic layer was passed through a hydrophobic phase separator. The organic layer was concentrated in vacuo and the resulting residue was purified by normal phase column chromatography (0-10% DCM/MeOH) to afford Intermediate F. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.39 (brs, 1H), 8.27 (s, 1H), 7.45 (td, J = 8.6, 6.7 Hz, 1H), 7.39 (s, 1H), 7.29 (td, J = 9.8, 2.6 Hz, 1H), 7.14 (td, J = 8.6, 2.5 Hz, 1H), 7.07 (s, 1H), 4.32 (s, 2H); ES-MS [M+l] ⁺ : 262.1.

[00219] 6-(2,4-Difluorophenyl)-l-oxoisoindolin-5-yl trifluoromethanesulfonate

(Intermediate G). To a solution of 6-(2,4-difluorophenyl)-5-hydroxyisoindolin-l-one (560 mg, 2.14 mmol), N-phenyl-bis(trifluoromethanesulfonimide) (843 mg, 2.36 mmol), and DMAP (26 mg, 0.21 mmol) in DCM (6 mL) was added triethylamine (598 μL, 4.29 mmol) dropwise at 0 °C. The reaction mixture was allowed to warm to ambient temperature. After 2 hours, the reaction mixture was concentrated in vacuo and was purified by normal phase column chromatography (0-10% DCM/MeOH) to give the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.90 (s, 1H), 7.91 (s, 1H), 7.81 (s. 1H), 7.60 (td, J = 8.6, 6.5 Hz, 1H), 7.47 (ddd, 7 = 10.4, 9.3, 2.6 Hz. 1H), 7.28 (td, J = 8.6, 2.6 Hz, 1H), 4.51 (s, 2H); ES-MS [M+l] ⁺ : 394.0. Synthesis of Example Compounds

Example 1. 5-(3,6-Dihydro-2H-pyran-4-yl)-6-(4-fluorophenyl)isoindolin-l -one (Compound 55).

Pd(dppf)CI ₂ CH ₂ CI ₂

TKT Na ₂ CO ₃

1 ,4-dioxane/H ₂ O, 100 °C O.

F F

E

[00220] To a solution of [6-(4-fhiorophenyl)-l-oxo-isoindolin-5-yl] trifluoromethanesulfonate (50 mg) in degassed l.d-dioxane/H ₂ O (3: 1; 0.80 mL) were added (3,6-dihydro-2h-pyran-4-yl)- boronic acid (37 mg), sodium carbonate (45 mg), and Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (6 mg). The reaction mixture was evacuated and purged with N2 (3x) and allowed to stir at 100 °C. After 5 h, the mixture was diluted with DCM (20 mL) and water (2 mL), and the organic phase was separated. The aqueous layer was extracted with DCM (3 x 5 mL). The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by normal phase column chromatography (0-10% DCM/MeOH) to afford the title compound. ¹ H NMR (400 MHz, DMSO) δ 8.59 (s, 1H), 7.51 (s, 1H), 7.49 - 7.41 (m, 3H), 7.31 - 7.22 (m, 2H), 5.78 - 5.71 (m, 1H), 4.41 (s, 2H), 4.10 (q, 7 = 2.7 Hz, 2H), 3.53 (t, 7 = 5.3 Hz, 2H), 1.90 - 1.83 (m, 2H). ES-MS [M+l] ⁺ : 310.0.

Example 2. 5-(l-Benzyl-l,2,3,6-tetrahydropyridin-4-yl)-6-(4-fluoropheny l)isoindolin-l-one (Compound 56).

NH NH o O

Pd(dppf)CI ₂ CH ₂ CI ₂

TfO' Na ₂ CO ₃ v

1 ,4-dioxane/H ₂ O, 100 °C N

F F

E

[00221] The title compound was prepared using a procedure analogous to the preparation of Compound 55, but starting with l-bcnzyl-4-(4,4,5,5-tctramcthyl-l,3,2-dioxaborolan-2-yl)- 1,2,3,6-tetrahydropyridine. ¹ H NMR (400 MHz. DMSO) 5 8.57 (s, 1H). 7.49 (s, 1H), 7.47 - 7.39 (m, 3H), 7.34 - 7.21 (m, 7H), 5.65 - 5.62 (m, 1H), 4.39 (s, 2H), 3.50 (s, 2H), 2.95 (d, J = 3.2 Hz, 2H), 2.37 (t, J = 5.5 Hz, 2H), 1.90 (app s, 2H). ES-MS [M+l] ⁺ : 399.2.

Example 3. 6-(4-Fhiorophenyl)-5-(l-methyl-l,2,3,6-tetrahydropyridin-4-y l)isoindolin-l-one (Compound 58).

NH NH

O

JI Pd(dppf)CI ₂ CH ₂ CI ₂

TfCT Na ₂ CO ₃

1 ,4-dioxane/H ₂ O, 100 °C N

F F

E

[00222] The title compound was prepared using a procedure analogous to the preparation of Compound 55. ¹ H NMR (400 MHz. DMSO) 5 8.57 (s. 1H). 7.49 (s, 1H). 7.46 - 7.39 (m. 3H), 7.31 - 7.21 (m, 2H), 5.67 - 5.61 (m, 1H), 4.39 (s, 2H), 2.89 (q, J - 2.9 Hz, 2H), 2.27 (t, 7= 5.5 Hz, 2H), 2.18 (s, 3H), 1.94 - 1.86 (m, 2H). ES-MS [M+l] ⁺ : 323.0.

Example 4. 6-(4-Fluorophenyl)-5-(l-methyl-l,2,5,6-tetrahydropyridin-3-y l)isoindolin-l-one (Compound 57).

E

[00223] The title compound was prepared using a procedure analogous to the preparation of Compound 55. ¹ H NMR (400 MHz, DMSO) 5 8.58 (s, 1H), 7.49 (s, 1H), 7.45 (s, 1H), 7.44 - 7.39 (m, 2H), 7.27 - 7.20 (m, 2H), 5.64 - 5.57 (m, 1H), 4.39 (s, 2H), 2.66 (q, J = 2.4 Hz, 2H), 2.33 (t, J = 5.7 Hz. 2H). 2.14 - 2.05 (m, 2H), 2.08 (s. 3H). ES-MS [M+l] ⁺ : 323.1.

Example 5. 6-(4-Fluorophenyl)-5-(2,2,6,6-tetramethyl-l,2,3,6-tetrahydro pyridin-4- yl)isoindolin-l-one (Compound 59).

NH NH

O

Tfcr

HN

1,4-dioxane/H ₂ O, 100 °C

F F

E

[00224] The title compound was prepared using a procedure analogous to the preparation of Compound 55. ¹ H NMR (400 MHz. DMSO) 5 8.57 (s, 1H). 7.46 (s, 1H), 7.40 (s, 1H), 7.39 - 7.34 (m, 2H), 7.28 - 7.17 (m, 2H), 5.39 (app t. 7 - 1.6 Hz, 1H), 4.40 (s, 2H), 1.77 (app d, 7 = 1.7 Hz, 2H), 0.98 (s, 6H), 0.94 (s, 6H). ES-MS [M+l] ⁺ : 365.2.

Example 6. 4-(6-(2,4-Difluorophenyl)-l-oxoisoindolin-5-yl)-l,5-dimethyl -lH-pyrrole-2- carbonitrile (Compound 90).

[00225] To a mixture of 6-(2,4-difluorophenyl)-l -oxoisoindo lin-5-yl trifluoromethanesulfonate (600 mg, 1.53 mmol), Pd(dppf)Ch • DCM (124.9 mg, 0.15 mmol), l,5-dimethyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrole-2-carbonitri le (751 mg, 3.05 mmol), and potassium phosphate (985 mg, 4.58 mmol) was added a solution of 1,4-dioxane and water (10: 1;

8.8 mL). The reaction mixture was evacuated and purged with N2 (3x) and heated at 120 °C under microwave irradiation. After 3 hours, the reaction mixture was diluted with DCM, passed through a hydrophobic phase separator, and the organic layer was concentrated in vacuo. The residue was purified by normal phase column chromatography (0-10% DCM/MeOH). The material was then subjected to reverse phase purification (20-65% PDCkMeCN w/ 0.05% NH4OH) to afford the title compound. ¹ H NMR (400 MHz, DMSO-t/6) 6 8.64 (s, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.33 - 7.25 (m, 1H), 7.20 (td, J = 9.8, 2.6 Hz, 1H), 7.11 - 7.05 (m, 1H), 6.56 (s, 1H), 4.45 (s, 2H). 3.56 (s, 3H), 1.93 (s, 3H); ES-MS [M+l] ⁺ : 364.2.

Example 7. 6-(2,4-Difhiorophenyl)-5-(lH-pyrrolo[2,3-b]pyridin-5-yl)isoi ndolin-l-one (Compound 87).

G

[00226] To a mixture of 6-(2,4-difluorophenyl)-l-oxoisoindolin-5-yl trifluoromethanesulfonate

(20 mg, 0.05 mmol), Pd(dppf)Ch • DCM (4.16 mg, 0.005 mmol), 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l/7-pyrrolo[2,3-/?]pyridine (mg, mmol), and potassium phosphate (32.8 mg, 0.15 mmol) was added a solution of 1,4-dioxanc and water (10: 1; 352 μL). The reaction mixture was evacuated and purged with N ₂ (3x) and heated at 100 °C. After 16 h, the reaction mixture was diluted with DCM, passed through a hydrophobic phase separator, and the organic layer was concentrated in vacuo. The residue was purified by normal phase column chromatography (0- 10% DCM/MeOH). The material was subjected to reverse phase purification (18-57% H ₂ O:MeCN w/ 0.05% NH ₄ OH) to afford the title compound. ¹ H NMR (400 MHz, DMSO-76) 3 8.68 (s, 1H), 7.91 (d, 7 = 2.1 Hz, 1H), 7.73 (d, J = 2.2 Hz, 1H), 7.71 (s, 1H), 7.63 (s, 1H), 7.45 (dd, J = 3.4, 2.4 Hz, 1H), 7.39 (td, J = 8.8, 6.8 Hz, 1H), 7.08 (m, 2H), 6.38 (dd, 7 = 3.4, 1.7 Hz, 2H), 4.49 (s, 2H); ES-MS [M+l] ⁺ : 362.3.

Example 8. 6-(4-Fluorophenyl)-5-(6-methylpyridin-3-yl)isoindolin-l-one (Compound 6).

E

[00227] To a mixture of 6-(4-fluorophenyl)-l-oxoisoindolin-5-yl trifluoromethanesulfonate (1 g, 2.66 mmol), Pd(dppf)Cl ₂ • DCM (218 mg, 0.27 mmol), (6-methylpyridin-3-yl)boronic acid (730 mg, 5.33 mmol), and potassium phosphate (574 mg, 2.66 mmol) was added a solution of 1,4-dioxane and water (5: 1; 9.6 mL). The reaction mixture was evacuated and purged with N ₂ (3x) and heated at 120 °C under microwave irradiation. After 3 h, the reaction mixture was diluted with DCM, dried over MgSCU, filtered, and concentrated in vacuo. The residue was purified by normal phase column chromatography (0-10% DCM/MeOH). The material was subjected to reverse phase purification (18-59% H ₂ O:MeCN w/ 0.05% NH4OH) to afford the title compound.. ' H NMR (400 MHz, DMSO-t/6) 3 8.68 (s, 1H), 8.20 (dd, 7 = 2.4, 0.8 Hz. 1H). 7.65 (d, 7 = 0.7 Hz, 1H), 7.62 (s, 1H), 7.40 (dd, 7 = 8.0, 2.4 Hz, 1H), 7.22 - 7.09 (m, 5H), 4.47 (s, 2H), 2.43 (s, 3H); ES-MS [M+l] ⁺ : 319.0. Example 9. 3-(6-(2,4-Difluorophenyl)-l-oxoisoindolin-5-yl)-5-fluorobenz onitrile (Compound 106).

[00228] To a mixture of 6-(4-fluorophenyl)-l-oxoisoindolin-5-yl trifluoromethanesulfonate (20 mg, 0.05 mmol), Pd(dppf)C12 • DCM (4.16 mg, 0.005 mmol), (3-cyano-5-fluorophenyl)boronic acid (16.8 mg, 0.10 mmol), and potassium phosphate (32.8 mg, 0.15 mmol) was added a solution of 1,4-dioxane and water (10: 1; 600 μL). The reaction mixture was evacuated and purged with N2 (3x) and heated at 85 °C. After 16 h, the reaction mixture was diluted with DCM, passed through a hydrophobic phase separator, and the organic layer was concentrated in vacuo. The residue was purified by reverse phase chromatography (23-65% H2O:MeCN w/ 0.05% NH4OH) to afford the title compound. NMR (400 MHz, DMSO-76) 5 8.78 (s, 1H), 7.80 (ddd, 7= 8.6,

2.5, 1.3 Hz. 1H), 7.77 (s, 1H), 7.67 (s, 1H), 7.49 (t, 1.5 Hz. 1H), 7.45 (m, 1H), 7.37 (ddd, J = 9.7.

2.6, 1.5 Hz, 1H), 7.18 (m, 2H), 4.50 (s, 2H); ES-MS [M+l] ⁺ : 365.2.

Example 10. 6-(4-Fluorophenyl)-5-(l,2,3,6-tetrahydropyridin-4-yl)isoindo lin-l-one (Compound 60).

E [00229] tert-Butyl 4-(6-(4-fluorophenyl)-l-oxoisoindolin-5-yl)-3,6-dihydropyrid ine-l(2H)- carboxylate. The title compound was prepared using a procedure analogous to the preparation of Compound 55. ES-MS [M+l] ⁺ : 409.3.

[00230] 6-(4-Fluorophenyl)-5-(l,2,3,6-tetrahydropyridin-4-yl)isoindo lin-l-one

(Compound 60). To a solution of tert-butyl 4-(6-(4-fluorophenyl)-l-oxoisoindolin-5-yl)-3,6- dihydropyridine-l(2H)-carboxylate (40 mg) in DCM (0.25 mL) was added TEA (0.15 mL) and the solution was allowed to stir at ambient temperature. After 1 h, the reaction mixture was concentrated in vacuo and the crude material was dissolved in DMSO (1 mL) and purified via RP-HPLC (5-60% MeCN/0.05% aqueous NH ₄ OH) to afford the title compound. NMR (400 MHz, DMSO) 8 8.56 (s, 1H), 7.49 (s, 1H), 7.47 - 7.39 (m, 3H), 7.29 - 7.21 (m, 2H), 5.71 - 5.64 (m, 1H), 4.39 (s, 2H), 3.24 (q, 7 = 2.9 Hz, 2H), 2.60 (t, 7= 5.4 Hz. 2H). 1.80 - 1.72 (m, 2H). ESMS [M+l] ⁺ : 309.1.

Example 11. 6-(4-Fluorophenyl)-5-(l,2,5,6-tetrahydropyridin-3-yl)isoindo lin-l-one (Compound 61).

NH zf

[00231] tert-Butyl 5-(6-(4-fluorophenyl)-l-oxoisoindolin-5-yl)-3,6-dihydropyrid ine-l(2H)- carboxylate. The title compound was prepared using a procedure analogous to the preparation of Compound 55. ES-MS [M+l] ⁺ : 409.2.

[00232] 6-(4-Fluorophenyl)-5-(l,2,5,6-tetrahydropyridin-3-yl)isoindo lin-l-one

(Compound 61). The title compound was prepared using a deprotection procedure analogous to the preparation of Compound 60. ¹ H NMR (400 MHz, DMSO) 8 8.57 (s. 1H), 7.49 (s, 1H), 7.48 - 7.41 (m, 3H), 7.30 - 7.19 (m, 2H), 5.72 - 5.66 (m, 1H), 4.39 (s, 2H), 3.00 (app s, 2H), 2.69 (t, J = 5.7 Hz, 2H), 2.06 - 1.96 (m, 2H). ES-MS [M+l] ⁺ : 309.1. Example 12. 6-(4-Fluorophenyl)-5-(2-methyl-l,2,3,6-tetrahydropyridin-4-y l)isoindolin-l- one (Compound 84).

[00233] tert-Butyl 4-(6-(4-fluorophenyl)-l-oxoisoindolin-5-yl)-2-methyl-3,6- dihydropyridine-l(2H)-carboxylate. The title compound was prepared using a procedure analogous to the preparation of Compound 55. ES-MS [M+l] ⁺ : 423.4.

[00234] 6-(4-Fluorophenyl)-5-(2-methyl-l,2,3,6-tetrahydropyridin-4-y l)isoindolin-l-one (Compound 84). The title compound was prepared using a deprotection procedure analogous to the preparation of Compound 60. ¹ H NMR (400 MHz. DMSO) 5 8.58 (s, 1H). 7.48 (s, 1H), 1A1 - 7.40 (m, 3H), 7.29 - 7.19 (m, 2H), 5.65 (app dd, J = 5.1, 2.3 Hz, 1H), 4.39 (s, 2H), 3.17 - 2.97 (m, 2H), 2.68 - 2.57 (m. 1H), 2.11 - 1.98 (m, 1H), 1.81 - 1.67 (m, 1H), 1.00 (d, 7 = 6.3 Hz, 3H). ES-MS [M+l] ⁺ : 323.3.

Example 13. 5-(3,3-Dimethyl-l,2,3,6-tetrahydropyridin-4-yl)-6-(4-fluorop henyl)isoindolin- 1-one (Compound 76).

[00235] tert-Butyl 4-(6-(4-fluorophenyl)-l-oxoisoindolin-5-yl)-3,3-dimethyl-3,6 - dihydropyridine-l(2H) -carboxylate. The title compound was prepared using a procedure analogous to the preparation of Compound 55. ES-MS [M+l] ⁺ : 437.4. [00236] 5-(3,3-Dimethyl-l,2,3,6-tetrahydropyridin-4-yl)-6-(4-fluorop henyl)isoindolin-l- one (Compound 76). The title compound was prepared using a procedure analogous to the preparation of Compound 60. ¹ H NMR (400 MHz. DMSO) 8 8.57 (s, 1H). 7.49(s. 1H), 7.46 - 7.39 (m, 2H), 7.30 (s, 1H), 7.25 - 7.17 (m, 2H), 5.56 (t, 7 = 3.1 Hz, 1H), 4.41 (s, 2H), 3.26 (d, J = 3.2 Hz, 2H), 2.36 (s, 2H), 0.59 (br s, 6H). ES-MS [M+l] ⁺ : 337.2.

Example 14. 5-(2,5-Dihydro-lH-pyrrol-3-yl)-6-(4-fluorophenyl)isoindolin- l-one (Compound 82).

E

[00237] tert-Butyl 3-(6-(4-fluorophenyl)-l-oxoisoindolin-5-yl)-2,5-dihydro-lH-p yrrole-l- carboxylate. The title compound was prepared using a procedure analogous to the preparation of Compound 55. ES-MS [M+l] ⁺ : 395.3.

[00238] 5-(2,5-Dihydro-lH-pyrrol-3-yl)-6-(4-fluorophenyl)isoindolin- l-one (Compound

82). The title compound was prepared using a procedure analogous to the preparation of Compound 60. ¹ H NMR (400 MHz, DMSO) 8 8.60 (s. 1H), 7.55 (s, 1H), 7.45 (s, 1H), 7.40 - 7.34 (m, 2H), 7.28 - 7.21 (m, 2H), 5.66 (p, J = 2.0 Hz, 1H), 4.40 (s, 2H), 3.60 (td, J = 4.3, 2.1 Hz, 2H), 3.46 (td, J = 4.3, 2.0 Hz, 2H). ES-MS [M+l] ⁺ : 295.2.

Example 15. 6-(4-Fluorophenyl)-5-(tetrahydro-2H-pyran-4-yl)isoindolin-l- one (Compound 64). NH

O

10 wt. % Pd-C o. H ₂ atm, MeOH

F

[00239] To a slurry of Pd-C (10 wt%; 27 mg) in MeOH (0.5 mL) was added 5-(3,6-dihydro- 2H-pyran-4-yl)-6-(4-fluorophenyl)isoindolin-l-one (20 mg). The reaction mixture was evacuated and purged with N2 (3x), followed by evacuating and purging with hydrogen (3x; 1 atm). After 16 h, the mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to afford the title compound. ^r H NMR (400 MHz, DMSO) 5 8.53 (s, 1H), 7.65 (s, 1H), 7.39 - 7.33 (m, 3H), 7.33 - 7.26 (m, 2H), 4.40 (s, 2H), 3.86 (dd, 7 = 11.6, 3.9 Hz, 2H), 3.16 (td, J =

11.8, 1.9 Hz, 2H), 2.86 (tt, 7 = 11.9, 3.6 Hz, 1H), 1.82 1.67 (m, 2H). 1.60 - 1.51 (m, 2H). ES-

MS [M+l] ⁺ : 312.0.

Example 16. 6-(4-Fluorophenyl)-5-(l-methylpiperidin-4-yl)isoindolin-l-on e (Compound

66).

NH

O

10 wt. % Pd-C

H ₂ atm, MeOH N F

[00240] The title compound was prepared using a procedure analogous to the preparation of Compound 64. ¹ H NMR (400 MHz, DMSO) 5 8.52 (s, 1H), 7.60 (s, 1H), 7.39 - 7.24 (m, 5H), 4.39 (s, 2H), 2.81 - 2.74 (m, 2H), 2.59 - 2.50 (m, 1H), 2.11 (s. 3H), 1.79 - 1.55 (m, 6H). ES-MS [M+l] ⁺ : 325.2.

Example 17. 6-(4-Fluorophenyl)-5-(l-methylpiperidin-3-yl)isoindolin-l-on e (Compound

65). NH NH

O

10 wt. % Pd-C

N N

H ₂ atm, MeOH

F F

[00241] The title compound was prepared using a procedure analogous to the preparation of Compound 64. ¹ H NMR (400 MHz. DMSO) 5 8.53 (s. 1H). 7.63 (s, 1H). 7.39 - 7.25 (m. 5H), 4.38 (s, 2H), 2.84 (tt, 7 = 11.2, 3.6 Hz, 1H), 2.74 - 2.61 (m, 2H), 2.09 (s, 3H), 1.97 (t, 7 = 10.9 Hz, 1H), 1.90 - 1.79 (m, 1H), 1.72 (app d, 7 = 12.2 Hz, 1H), 1.66 - 1.58 (m, 1H), 1.50 - 1.27 (m. 2H). ES-MS [M+l] ⁺ : 325.2.

Example 18. 6-(4-Fluorophenyl)-5-(2,2,6,6-tetramethylpiperidin-4-yl)isoi ndolin-l-one (Compound 75).

NH

20 wt. % Pd(OH) ₂ -C

HN

HCO ₂ NH ₄ , EtOH

F

[00242] To a slurry of 20 wt.% Pd(OH)2-C (12 mg) in EtOH (0.5 mL) was added 6-(4- fluorophenyl)-5-(2,2,6,6-tetramethyl-L2,3,6-tetrahydropyridi n-4-yl)isoindolin-l-one (63 mg) and HCO2NH4 (130 mg) under N2 atmosphere. The resulting mixture was subjected to microwave irradiation at 80 °C for 15 min. The mixture was diluted with MeOH (5 mL), filtered through a pad of Celite® and the filtrate was concentrated in vacuo to afford the title compound.

ES-MS [M+l] ⁺ : 367.3.

Example 19. 6-(4-Fluorophenyl)-5-(piperidin-4-yl)isoindolin-l-one (Compound 67).

[00243] tert-Butyl 4-(6-(4-fluorophenyl)-l-oxoisoindolin-5-yl)piperidine-l-carb oxylate was prepared in a similar manner as Compound 64, which was taken to the next step without further purification. To a solution of tert-butyl 4-(6-(4-fluorophenyl)-l-oxoisoindolin-5-yl)piperidine-l- carboxylate (40 mg) in DCM (0.25 mL) was added TFA (0.15 mL) and the solution was allowed to stir at ambient temperature. After 1 h, the reaction mixture was concentrated in vacuo and the crude material was dissolved in DMSO (1 mL) and purified via RP-HPLC (5-60% MeCN/0.05% aqueous NH4OH) to afford the title compound. ’ H NMR (400 MHz, DMSO) 5 8.51 (s, 1H), 7.59 (s, 1H), 7.38 - 7.23 (m, 5H), 4.39 (s, 2H), 2.92 (dt, J = 12.1, 3.2 Hz, 2H), 2.73 - 2.61 (m, 1H),

2.34 - 2.21 (m, 2H), 1.64 1.51 (m, 4H). ES-MS [M+l] ⁺ : 311.2.

Example 20. 6-(4-Fluorophenyl)-5-(3-methylpiperidin-4-yl)isoindolin-l-on e (Compound 77).

[00244] The title compound was prepared using a reduction procedure analogous to the preparation of Compound 75 followed by a deprotection procedure analogous to the preparation of Compound 67. ¹ H NMR (400 MHz, DMSO) 5 8.52 (s, 1H), 7.41 (s, 1H), 7.38 - 7.23 (m, 5H), 4.43 (d, J = 17.8 Hz, 1H), 4.37 (d, J = 17.8 Hz, 1H), 3.06 (dt, J = 12.7, 3.5 Hz, 1H), 3.00 (app d, J = 11.9 Hz, 1H), 2.57 (d, J= 11.8 Hz, 1H), 2.43 - 2.34 (m, 1H), 2.28 (dd, J = 11.9, 3.1 Hz, 1H),

2.01 (qd, J = 12.3, 4.0 Hz. 1H), 1.46 1.32 (m, 2H), 0.70 (d. J = 7.0 Hz, 3H). ES-MS [M+l] ⁺ : 325.2.

Example 21. 6-(4-Fluorophenyl)-5-(pyrrolidin-3-yl)isoindolin-l-one (Compound 83).

[00245] The title compound was prepared using a reduction procedure analogous to the preparation of Compound 75 followed by a deprotection procedure analogous to the preparation of Compound 67. ' H NMR (400 MHz, DMSO) 8 8.51 (s, 1H), 7.67 (s, 1H), 7.39 - 7.25 (m, 5H), 4.38 (s, 2H), 3.11 (p, 7 = 8.0 Hz, 1H), 3.05 - 2.93 (m, 2H), 2.80 (dt, J = 10.7, 7.3 Hz, 1H), 2.65 (dd, 7 = 10.5, 7.5 Hz, 1H), 2.01 (dtd, J = 12.7, 8.2, 4.7 Hz, 1H), 1.70 (dq, 7 = 12.3, 7.9 Hz, 1H). ES-MS [M+l] ⁺ : 297.2.

Example 22. 6-(2,4-Difluorophenyl)-5-(2-(l-methyl-lH-pyrazol-3-yl)ethyl) isoindolin-l-one (Compound Al)

[00246] 6-(2,4-Difluorophenyl)-5-((l-methyl-lH-pyrazol-3-yl)ethynyl) isoindolin-l-one. To a mixture of 6-(2,4-difluorophenyl)-l -oxoisoindo lin-5-yl trifluoromethanesulfonate (100 mg, 0.25 mmol), Pd(PPh3)2Ch (4.47 mg, 0.006 mmol), 3-ethynyl-l-methylpyrazole (27 mg, 0.25 mmol), Cui (4.84 mg, 0.025 mmol), tetrabutylammonium iodide (14 mg, 0.038 mmol), and triethylamine (44 μL, 0.32 mmol) was added DMF (1.25 mL). The reaction mixture was heated at 110 °C. After 16 h, the reaction mixture was allowed to cool to ambient temperature and was diluted with DCM (10 mL). The reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by normal phase column chromatography (0-10% DCM/MeOH) to afford the title compound. ES-MS [M+l] ⁺ : 350.0.

[00247] 6-(2,4-Difluorophenyl)-5-(2-(l-methyl-lH-pyrazol-3-yl)ethyl) isoindolin-l-one

(Compound Al). To a solution of 6-(2,4-difluorophenyl)-5-((l-methyl-lH-pyrazol-3- yl)ethynyl)isoindolin l one (28 mg 008 mmol) in methanol (0 8 mL) was added 10 % Pd/C (40 mg). The reaction atmosphere was evacuated and purged three times with hydrogen. After 3 hrs, the reaction mixture was diluted with a 1: 1 DCM:McOH solution, filtered over Cclitc®, and concentrated in vacuo. The crude residue was purified by reverse phase chromatography to afford the title compound. ¹ H NMR (400 MHz, DMSO-i/6) 8 8.56 (s, 1H), 7.62 (s, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.42 - 7.33 (m, 3H), 7.20 (ddd, J = 8.7, 7.2, 2.6 Hz, 1H). 5.77 (d, J = 2.2 Hz, 1H), 4.40 (s. 2H), 3.70 (s. 3H). 2.85 - 2.73 (m, 2H), 2.64 (t, J = 8.1 Hz. 2H); ESI-MS [M+l] ⁺ : 354.1.

Example 23. 6-(2,4-Difluorophenyl)-5-(2-(l-methyl-lH-pyrazol-3-yl)ethyl- l, 1,2,2- d4)isoindolin-l-one (Compound A3)

NH

[00248] To a solution of 6-(2,4-difluorophenyl)-5-((l-methyl-lH-pyrazol-3- yl)ethynyl)isoindolin-l-one (44 mg, 0.126 mmol) and methanol-OD (1.26 mL) was added 10% Pd/C (63 mg). The reaction atmosphere was evacuated and purged three times with deuterium gas. After 2 hrs, the reaction mixture was diluted with a 1: 1 DCM:MeOH solution, filtered over Celite®, and concentrated in vacuo, to give a crude residue. The crude residue was purified by normal phase flash chromatography (0-10% DCM/MeOH) to afford the title compound.

NMR (400 MHz, DMSO-d6) 8 8.56 (s, 1H), 7.62 (s, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.42 - 7.33 (m, 3H), 7.20 (td, J = 8.3, 2.6 Hz. 1H). 5.77 (d, J = 2.1 Hz, 1H), 4.40 (s. 2H). 3.69 (s, 3H); ESIMS [M+l]+: 358.0.

[00249] The compounds shown in Tables 1A and IB may be prepared similarly to the compounds described above, with appropriate starting materials generally available from commercial sources. Table 1A

ES-

No. Name Structure MS

[M+l] ⁺

6-(4-fluorophenyl)-5-(l-methyl-lH-

1 308.1 pyrazol-4-yl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(oxazol-5-

2 yl)isoindolin- 1 -one 295

6-(4-fluorophcnyl)-5-(l-(oxctan-3-

3 350.1 yl) - 1 H-pyrazol-4-yl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(pyridin-4-

4 yl)isoindolin- 1 -one 305

6-(4-fluorophenyl)-5-(2-

5 325 methylthiazol-5-yl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(6-

6 319 methylpyridin-3-yl)isoindolin- 1 -one 6-(4-fluorophenyl)-5-(2-methyl-2H-

7 358.1 indazol-5-yl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(2-methyl-2H-

8 358.1 indazol-6-yl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(4-methyl- 1 H-

9 358.1 indazol-5-yl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(2-methyl- 1 H-

10 benzo[d]imidazol-5-yl)isoindolin- 1 - 358.2 one

5-(benzo[d]thiazol-6-yl)-6-(4-

11 361.1 fluorophenyl)isoindolin- 1 -one

5-(benzo[d]oxazol-5-yl)-6-(4-

12 fluoropheny l)isoindolin- 1 -one 345.1 ■NH y^o

5-(benzo[d]thiazol-5-yl)-6-(4- N^,

13 361 fluorophenyl)isoindolin- 1 -one u

F

NH

Z=O

14 6-(4-fluorophenyl)-5-(isoquinolin-6-

N^ 355.1 yl)isoindolin- 1 -one

F

■NH y^o

6-(4-fluorophenyl)-5-(isoquinolin-7-

15 355 yl)isoindolin- 1 -one

F

•NH y=o

6-(4-fluorophenyl)-5-(2-methyl-2H

16 pyrazolo [3 ,4-b ]pyridin-5 - — N 359.1 yl)isoindolin- 1 -one N ^15- N

F

•NH

\ N-N y=xD Z. W

6-(4-fluorophenyl)-5-(2-methyl-2H-

17 358.1 indazol-7 -yl)isoindolin- 1 -one

F

■NH >=O

6-(4-fluorophenyl)-5-(quinolin-7- _N.

18 yl)isoindolin- 1 -one f 355

F 6 - (4-fluor opheny 1) -5 - (quinolin- 6 -

19 355 yl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(imidazo[l,2-

20 344.1 a]pyridin-6-yl)isoindolin- 1 -one

5-(5,8-difluoroquinolin-6-yl)-6-(4-

21 391 fluorophenyl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(pyridazin-4-

22 306 yl)isoindolin- 1 -one

5-(benzo[d]thiazol-5-yl)-6-(2,4-

23 379 difluoropheny l)isoindolin- 1 -one

5-(benzo[d]oxazol-5-yl)-6-(2,4-

24 363 difluorophenyl)isoindolin- 1 -one 6-(2,4-difluorophenyl)-5-(2-methyl-

25 376.1

2H-indazol-6-yl)isoindolin- 1 -one

5-(6-cyclopropylpyridin-3-yl)-6-(4-

26 345 fluorophenyl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(6-

27 (trifluoromethyl)pyri din-3 - 373 yl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(2-methyl-2H-

28 indazol-4-yl)isoindolin- 1 -one 358

5-(2,6-diinethylpyridin-3-yl)-6-(4-

29 333.2 fluorophenyl)isoindolin- 1 -one

5-(6-fluoro-2-methylpyridin-3-yl)-6-

30 337.1 (4-fluorophenyl)isoindolin- 1 -one 6-(4-fluorophenyl)-5-(2-

31 (trifluoromethyl)pyrimidin-5 - 374.1 yl)isoindolin- 1 -one

5-(2,6-difluoropyridin-3-yl)-6-(4-

32 341.1 fluorophenyl)isoindolin- 1 -one

5-(6-(4-fluorophenyl)- 1 -

33 330 oxoisoindolin-5-yl)picolinonitrile

5-(6-(dimethylamino)pyridin-3-yl)-6-

34 (4-fluorophenyl)isoindolin- 1 -one 348.1

6-(4-fluorophenyl)-5-(l-methyl-lH-

35 308 pyrazol-3-yl)isoindolin- 1 -one

N-(5-(6-(4-fluorophenyl)-l-

36 oxoisoindolin-5-yl)pyridin-2- 362.1 yl) acetamide 5-(6-fluoro-4-methylpyridin-3-yl)-6-

37 337 (4-fluorophenyl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(lH-

38 pyrrolo[2 ,3 -b] pyridin-5 -yl)isoindolin- 344 1-one

5-(2-(diinethylainino)pyridin-3-yl)-6-

39 348.1 (4-fluorophenyl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(2-

40 fluoropyridin-3-yl)isoindolin- 1 -one 323

6-(4-fluorophenyl)-5-(2-

41 319.1 methylpyridin-3-yl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(2-

42 isopropylpyridin-3-yl)isoindolin- 1 - 347.1 one 5-(2-cyclopropylpyridin-3-yl)-6-(4-

43 345 fluorophenyl)isoindolin- 1 -one

44 6-(4-fluorophenyl)-5-(pyridin-3-

305 yl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(pyridin-2-

45 305 yl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(6-

46 methylpyridazin-4-yl)isoindolin- 1 - 320 one

6-(4-fluorophenyl)-5-(3-methyl-lH-

47 358.2 indazol-5-yl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(4-

48 methylpyridin-3 -yl)isoindolin- 1 -one 319 6-(4-fluorophenyl)-5-( 1 H-indol-5-

49 343.1 yl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(6-(2-

50 hydroxypropan-2-yl)pyridin-3- 363.1 yl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(p-

51 318 tolyl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(5-

52 319 methylpyridin-2-yl)isoindolin- 1 -one

4-(6-(4-fluorophenyl)-l-

53 oxoisoindolin-5-yl)- 1 ,5-dimethyl- 1H- 363.1 pyrrole-2-carbonitrile

6-(4-fluorophenyl)-5-(4-

54 methoxy cyclohex- 1 -en- 1 - 338.2 yl)isoindolin- 1 -one 5-(3,6-dihydro-2H-pyran-4-yl)-6-(4-

55 310 fluorophenyl)isoindolin- 1 -one

5-(l -benzyl- 1, 2,3,6-

56 tetrahydropyridin-4-yl)-6-(4- 399.2 fluorophenyl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(l-methyl-

57 l,2,5,6-tetrahydropyridin-3- 323.1 yl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(l-methyl-

58 l,2,3,6-tetrahydropyridin-4- 323 yl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(2, 2,6,6-

59 tetramethyl- 1,2,3, 6-tetrahydropyridin- 365.2 4-yl)isoindolin- 1 -one

6 - (4-fluoropheny 1) -5 - ( 1 , 2 , 3 , 6 -

60 tetrahydropyridin-4-yl)isoindolin- 1 - 309.1 one 6-(4-fluorophenyl)-5-(l, 2,5,6-

61 tetrahydropyridin-3-yl)isoindolin- 1 - 309.1 one

5-(2,6-dimethyl-l,2,3,6-

62 tetrahydropyridin-4-yl)-6-(4- 337.2 fluorophenyl)isoindolin- 1 -one

5-cyclohexyl-6-(4-

63 310.1 fluorophenyl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(tetrahydro-2H-

64 312 pyran-4-yl)isoindolin- 1 -one

65 6-(4-fluorophenyl)-5-( 1 - 325.2 methylpiperidin-3-yl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(1 -

66 325.2 methylpiperidin-4-yl)isoindolin- 1 -one 6-(4-fluorophenyl)-5-(piperidin-4-

67 311.2 yl)isoindolin- 1 -one

5-(2.6-dimethylpiperidin-4-yl)-6-(4-

68 311.2 fluorophenyl)isoindolin- 1 -one

6-(2,4-difluorophenyl)-5-(6-

69 337 methylpyridin-3-yl)isoindolin- 1 -one

5-(6-cyclopropylpyridin-3-yl)-6-(2,4-

70 363.2 difluorophenyl)isoindolin- 1-one

6-(2,4-difluorophenyl)-5-(2-

71 (dimethylamino)pyridin-3- 366.2 yl)isoindolin- 1 -one

6-(2,4-difluorophenyl)-5-(2-

72 341 fluoropyridin-3-yl)isoindolin- 1 -one 6-(2,4-difluorophenyl)-5-(2-

73 337.2 methylpyridin-3-yl)isoindolin- 1 -one

5-(2-cyclopropylpyridin-3-yl)-6-(2,4-

74 362 difluorophenyl)isoindolin- 1-one

6-(4-fluorophenyl)-5-(2, 2,6,6-

75 tetramethylpiperidin-4-yl)isoindolin- 367.3 1-one

5-(3, 3-dimethyl-l, 2,3,6-

76 tetrahydropyridin-4-yl)-6-(4- 337.2 fluorophenyl)isoindolin- 1 -one

77 6-(4-fluorophenyl)-5-(3- 325.2 methylpiperidin-4-yl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(piperidin-3-

78 311.2 yl)isoindolin- 1 -one 6-(2,4-difluorophenyl)-5-(6-

79 (trifluoromethyl)pyri din-3 - F 391.2 yl)isoindolin- 1 -one F

6-(2.4-difluorophenyl)-5-(l-methyl-

80 326.1 lH-pyrazol-3-yl)isoindolin- 1 -one

6-(2,4-difluorophenyl)-5-(6-fluoro-4-

81 355.2 methylpyridin-3-yl)isoindolin- 1 -one

5-(2.5-dihydro-lH-pyrrol-3-yl)-6-(4-

82 295.2 fluorophenyl)isoindolin- 1 -one

6-(4-fhiorophenyl)-5-(pyrrolidin-3-

83 297.2 yl)isoindolin- 1 -one

6-(4-fluorophenyl)-5-(2-methyl-

84 l,2,3,6-tetrahydropyridin-4- 323.3 yl)isoindolin- 1 -one 6-(4-fluorophenyl)-5-(2-

85 325.3 methylpiperidin-4-yl)isoindolin- 1 -one

6-(2,4-difluorophenyl)-5-(2-

86 (trifluoromethyl)pyrimidin-5 - 392.3 yl)isoindolin- 1 -one

6-(2,4-difluorophenyl)-5-(lH-

87 pyrrolo[2 ,3 -b] pyridin-5 -yl)isoindolin- 362.3 1-one

6-(2,4-difluorophenyl)-5-(pyridin-3-

88 323.2 yl)isoindolin- 1 -one

6-(2,4-difluorophenyl)-5-(lH-indol-5-

89 361.3 yl)isoindolin- 1 -one

4-(6-(2,4-difluorophenyl)- 1 -

90 oxoisoindolin-5-yl)- 1 ,5-dimethyl- 1H- 364.3 pyrrole-2-carbonitrile 3-(6-(2,4-difluorophenyl)-l-

91 oxoisoindolin-5-yl)-5- 361 methylbenzonitrile

5-(6-(2,4-difluorophenyl)-l-

92 oxoisoindolin-5-yl)-2- 377 methoxybenzonitrile

5-(6-(2,4-difluorophenyl)-l-

93 oxoisoindolin-5-yl)-2- 365 fluorobenzonitrile

3-(6-(2,4-difluorophenyl)-l

94 oxoisoindolin-5-yl)-2- 365 fluorobenzonitrile

3-(6-(2,4-difluorophenyl)-l-

95 oxoisoindolin-5-yl)-5- 377 methoxybenzonitrile

3-(6-(2,4-difluorophenyl)-l-

96 oxoisoindolin-5-yl)-4- 361.1 methylbenzonitrile 6-(2,4-difluorophenyl)-5-(l,2,5-

97 trimethyl- 1 H-pyrrol-3 -yl)isoindolin- 353 1-one

3-(6-(2,4-difluorophenyl)-l-

98 oxoisoindolin-5-yl)- 1 ,5-dimethyl- 1H- 364 pyrrole-2-carbonitrile

3-(4-(6-(2,4-difluorophenyl)-l-

99 oxoisoindolin-5-yl)- IH-pyrazol- 1 - 413.1 yl)benzonitrile

6-(2,4-difluorophenyl)-5-(2-

100 353 methoxypyridin-3-yl)isoindolin- 1 -one

6-(2,4-difluorophenyl)-5-(5-

101 353 methoxypyridin-3-yl)isoindolin- 1 -one

6-(2.4-difluorophenyl)-5-(2-

102 (pyrrolidin- 1 -y l)pyridin-3 - 392.1 yl)isoindolin- 1 -one

4-(6-(2,4-difluorophenyl)- 1 -

103 oxoisoindolin-5-yl)-3- 365 fluorobcnzonitrilc 4-(6-(2,4-difluorophenyl)- 1 -

104 348 oxoisoindolin-5-yl)picolinonitrile

6-(2,4-difluorophenyl)-5-(4-fluoro-2-

105 370 methoxyphenyl)isoindolin- 1 -one

3-(6-(2,4-difluorophenyl)-l-

106 oxoisoindolin-5-yl)-5- 365.2 fluorobenzonitrile

3-(6-(2,4-difluorophenyl)-l-

107 347.1 oxoisoindolin-5 -yl)benzonitrile

5-( 1 -cyclopropyl- 1 H-pyrazol-3-yl)-6-

108 352.2 (2.4-difluorophenyl)isoindolin- 1 -one

3-(6-(2,4-difluorophenyl)-l

109 oxoisoindolin-5-yl)-2- 361.2 methylbenzonitrile 6-(2,4-difluorophenyl)-5-(2-

110 (trifluoromethyl)pyri din-3 - 391 yl)isoindolin- 1 -one

4-(4-(6-(2,4-difluorophenyl)-l- N

111 oxoisoindolin-5-yl)- IH-pyrazol- 1 - 413.1 yl)benzonitrile

6-(2,4-difluorophenyl)-5-(3-fluoro-4-

112 (5-methyl- 1 ,3 ,4-oxadiazol-2- 422.2 yl)phenyl)isoindolin- 1 -one

6-(2,4-difluorophenyl)-5-(4-(4-

113 methylpiperazin- 1 - 420.3 yl)phenyl)isoindolin- 1 -one

6-(2,4-difluorophenyl)-5-(3-

114 ( trifluor ome thy 1)- 1 H-pyrazol-4- 380.2 yl)isoindolin- 1 -one

4-(6-(2,4-difluorophenyl)- 1 -

115 oxoisoindolin-5 -yl) - 1 -methyl- 1 H- 351.3 pyrazole-5-carbonitrile Af-(3-(6-(2,4-difluorophenyl)-l-

116 oxoisoindolin-5- 415 yl)phenyl)methanesulfonamide

3-chloro-5-(6-(2,4-difluorophenyl)-l-

117 oxoisoindolin-5 -yl)-N- 413 methylbenzamide

3-(6-(2,4-difluorophenyl)-l-

118 oxoisoindolin-5 -yl)-N- 407.3 isopropylbenz amide

3-(6-(2,4-difluorophenyl)-l-

119 oxoisoindolin-5 -yl)-N- 415 methylbenzenesulfonamide

N-(2-(6-(2,4-difluorophenyl)-l-

120 379.3 oxoisoindolin-5-yl)phenyl)acetamide

3-(6-(2,4-difluorophenyl)-l-

121 oxoisoindolin-5 -yl) -4-fluoro-N - 397 methylbenzamide

6-(2,4-difluorophenyl)-5-(3-

122 (methylsulfonyl)phenyl)isoindolin- 1 - 400.3 one 2-(6-(2,4-difluorophenyl)- 1 -

123 oxoisoindolin-5-yl)-5- 365.0 fluorobenzonitrile

2-(6-(2,4-difluorophenyl)-l-

124 347.0 oxoisoindolin-5 -yl)benzonitrile

4-(6-(2,4-difluorophenyl)- 1 -

125 oxoisoindolin-5-yl)- 1 -methyl- 1H- 350.0 pyrrole-2-carbonitrile

6-(2,4-difluorophenyl)-5-(3,5-

126 dimethylisoxazol-4-yl)isoindolin- 1 - 341.2 one

6-(2,4-difluorophenyl)-5-(l-

127 (methylsulfonyl)- 1 H-pyrazol-4- 390.2 yl)isoindolin- 1 -one

6-(2,4-difluorophenyl)-5-(2-

128 (mcthylsulfonyl)phcnyl)isoindolin- 400.3 1-one 6'-(2,4-difluorophenyl)-[4,5'-

136 377.1 biisoindoline] -1,1 '-dione

5-(2-aminophenyl)-6-(2,4-

137 337.2 difluorophenyl)isoindolin- 1 -one

4-(6-(3-cyanophenyl)-3-

138 oxoisoindolin-5-yl)-3 - 354.1 fluorobenzonitrile

3-(l-oxo-6-(2,3.4-

139 trifluorophenyl)isoindolin-5- 365.1 yl)benzonitrile

3-(l-oxo-6-(2,4,5-

140 trifluoropheny l)isoindolin-5- 365.1 yl)benzonitrile

2-(6-(3-cyanophenyl)-3-

141 oxoisoindolin-5-yl)-5- 354.1 fluorobenzonitrile F o

3-(6-(2-fluoro-4-methylphenyl)-l-

142 N NH 343.2 oxoisoindolin-5-yl)benzo nitrile

F^

O

3-(6-(4-fluoro-2-methylphenyl)-l-

143 N NH 343.2 oxoisoindolin-5-yl)benzo nitrile

F

3-(6-(2-fluoro-4- r O

144 (trifluoromethyl)phenyl)- 1 - 397.1 oxoisoindolin-5 -yl)benzo nitrile N NH

F. F

I O

6-(2,4-difluorophenyl)-5-(3-(2-

145 hydroxypropan-2- HO. NH 380.3 yl)pheny l)isoindolin- 1 -one

F. F

1 O

5-(3 -( 1 H-pyrazol- 1 -yl)phenyl)-6-

146 (2,4-difluorophenyl)isoindolin- 1 - NH 388.3 one > N ,N ^N

■NH

6-(2,4-difluorophenyl)-5-(l-

147 (tetrahydro-2H-pyran-2-yl)-lH- Q

M ,_ -F 396.4 pyrazol-5-yl)isoindolin- 1-one

F

■NH

5-(2-chloro-l-(tetrahydro-2H- Q 346.1 pyran-2-yl)-lH-imidazol-5-yl)-6-

148 (M- (2,4-difluorophenyl)isoindolin- 1 - N F r THP one

F 6-(2,4-difluorophenyl)-5-(2,3-

149 dihydrobenzofuran-7 - 364 yl)isoindolin- 1 -one

6-(2,4-difluorophenyl)-5-(2-(4-

150 methylpiperazin- 1- 320.3 yl)phenyl)isoindolin- 1 -one

6-(2,4-difluorophenyl)-5-(3-(l-

151 methyl-lH-l,2,3-triazol-5- 403.4 yl)phenyl)isoindolin- 1 -one

6-(2,4-difluorophenyl)-5-(3-(l-

152 (methyl-d3)-lH-l ,2,3-triazol-5- 406.3 yl)pheny l)isoindolin- 1 -one

6-(2,4-difluorophenyl)-5-(3-(l-

153 (ethyl- 1 , 1 -d2)- 1H- 1 ,2,3-triazol-5- 419.3 yl)phenyl)isoindolin- 1 -one

6-(2,4-difluorophenyl)-5-(l-(2- O

154 morpholinoethyl)- 1 H-pyrazol-4- 425.1 yl)isoindolin- 1-one 6-(2,4-difluorophenyl)-5-(l-

155 (oxetan-3-yl)-lH-pyrazol-4- 368.3 yl)isoindolin- 1 -one

3-(6-(4-fluoro-2-methoxyphenyl)-

156 359

1 -oxoisoindolin-5-y l)benzonitrile

3-(6-(2-fluoro-4-methoxyphenyl)-

157 359

1 -oxoisoindolin-5-yl)benzonitrile

3-(6-(3,4-difluorophenyl)-l-

158 347 oxoisoindolin-5-yl)benzo nitrile

3-(6-(2-fluorophenyl)- 1 -

159 329 oxoisoindolin-5-yl)benzo nitrile

3-(l-oxo-6-(2,4,6-

160 trifluorophenyl)isoindolin-5- 365 yl)benzonitrile

3-(6-(2,4-dimethylphenyl)-l-

161 339.1 oxoisoindolin-5-yl)benzo nitrile 3-(6-(4-(difluoromethoxy)-2-

162 fluorophenyl)-! -oxoisoindolin-5- 395 yl)benzonitrile

N-(2-(6-(2,4-difluorophenyl)- 1 - oxoisoindolin-5-yl)phenyl)- 1 -

163 482 methyl- 1H-1, 2, 3-triazole-4- sulfonamide

N-(2-(6-(2,4-difluorophenyl)- 1 -

164 oxoisoindolin-5-yl)phenyl)-2- 497.9 methy Ithiazole- 5 - s ulfonamide

N-(2-(6-(2,4-difluorophenyl)- 1 - oxoisoindolin-5-yl)phenyl)- 1 -

165 481 methyl- 1 H-pyrazole-4- sulfonamide

4-(6-(3-cyanophenyl)-3-

166 oxoisoindolin-5-y l)-3 - 366.3 methoxybenzonitrile

4-(6-(3-cyanophenyl)-3-

167 oxoisoindolin-5-yl)-2- 354.3 fluorobenzonitrile 3-(6-(2-fluoro-4-hydroxyphenyl)-

168 345

1 -oxoisoindolin-5 -yl)benzonitrile

3-(6-(2-chloro-4-fluorophenyl)-l-

169 363.2 oxoisoindolin-5-yl)benzo nitrile

3-(6-(2-fluoro-5-methoxyphenyl)-

170 359.2 1 -oxoisoindolin-5-y l)benzo nitrile

3-(6-(3-fluoro-4-methoxyphenyl)-

171 359.2 1 -oxoisoindolin-5-y l)benzo nitrile

5-(6-(3-cyanophenyl)-3-

172 oxoisoindolin-5-yl)-2- 366.3 methoxybenzonitrile

3-(6-(2-chloro-4-methoxyphenyl)-

173 375.1 1 -oxoisoindolin-5-y l)benzo nitrile

3-(6-(2,5-difluoro-4-

174 methoxyphenyl)-l-oxoisoindolin- 377.2 5-yl)benzonitrile 3-(6-(4-methoxy-2-methylphenyl)-

175 355.4

1 -oxoisoindolin-5 -yl)benzonitrile

3-(6-(3-cyanophenyl)-3-

176 oxoisoindolin-5-yl)-4- 354.1 fluorobenzonitrile

3-(6-(2,4-difluoro-5-

177 methylphenyl)-l-oxoisoindolin-5- 361.2 yl)benzonitrile

5-(6-(3-cyanophenyl)-3-

178 oxoisoindolin-5-yl)-2- 354.2 fluorobenzonitrile

4-(6-(3-cyanophenyl)-3-

179 oxoisoindolin-5-yl)-2- 404.2 (trifluoromethyl)benzonitrile

3-(6-(2-fluoro-5-

180 (trifluoromethyl)phenyl)- 1 - 397.1 oxoisoindolin-5 -yl)benzo nitrile 4-(6-(3-cyanophenyl)-3-

181 oxoisoindolin-5-yl)-5-fluoro-2- 368.2 methylbenzonitrile

3 -(6-(3 ,5 -difluoro-4-

182 methoxyphenyl)- 1 -oxoi soindolin- 377.2 5-yl)benzonitrile

3-(6-(3-cyanophenyl)-3-

183 oxoisoindolin-5-yl)-2- 354.1 fluorobenzonitrile

3-(6-(2,3-difluoro-4-

184 methoxyphenyl)-l-oxoisoindolin- 377.2 5-yl)benzonitrile

3-(6-(2,5-difluorophenyl)-l-

185 346.9 oxoisoindolin-5-yl)benzo nitrile

3-(6-(5-fluoro-2-methoxyphenyl)-

186 359.3

1 -oxoisoindolin-5-y l)benzonitrile

2-(6-(3-cyanophenyl)-3-

187 oxoisoindolin-5-yl)-4- 354.1 fluorobenzonitrile 3-(6-(3-cyanophenyl)-3-

188 oxoisoindolin-5-yl)-4- 350.3 mcthylbcnzonitrilc

3-(6-(3-cyanophenyl)-3-

189 oxoisoindolin-5-y l)-5- 354.1 fluorobenzonitrile

Table IB.

ES-MS

No. Name Structure

[M+l] ⁺

F. F

O

6-(2,4-difluorophenyl)-5-(2-( 1 -methyl- T

Al NH 354.1 l//-pyrazol-3-yl)ethyl)isoindolin-l-one N —N'

F o

6-(2,4-difluorophenyl)-5-(2-(pyrimidin-

A2 NH 352.3

5 -yl)ethy l)isoindolin- 1 -one N

I N ^/

F^ F

O

6-(2,4-difluorophenyl)-5-(2-( 1 -methyl-

NH

A3 177-pyrazol-3-yl)ethyl- 1 , 1 ,2,2- D 358 D- <5?4)isoindolin- 1 -one N^ / -0

— N 7 D

F. F

1 O

3-(2-(6-(2,4-difluorophenyl)- 1 -

A4 N NH 375.3 oxoisoindolin-5-yl)ethyl)benzonitrile — N D

6-(2,4-difluorophenyl)-5-(2-( 1 -methyl- 'N ^L D D ,D

0-

A5 l//-pyrazol-3-yl)ethyl- 1 , 1 ,2,2- D 360

NH </v)isoindolin- 1 -one-3 ,3 -di

0 O F^ F

F^, F

II O

6-(2,4-difluorophenyl)-5-(2-(l-methyl-

D NH

A6 lH-pyrazol-5-yl)ethyl- 1 , 1 ,2,2- D- 358.2 <i/)isoindolin- 1 -one — D D

N'N

F

1 O

6-(2,4-difluorophenyl)-5-(2-(l-methyl- NH

A7 354.3 lH-pyrazol-5-yl)ethyl)isoindolin-l-one

N-N

5-(2-(l-cyclopropyl-lH-pyrazol-3- F^, F y O yl)ethyl)-6-(2,4-

A8 NH 380.2 difluorophenyl)isoindolin- 1 -one N

N'

3-(2-(6-(2,4-difluorophenyl)- 1 - F^ F

O oxoisoindolin-5-yl)ethyl)- 1 -methyl- 1H-

A9 NH pyrazole-5 -carbonitrile 379.3

NS-

\ II

N-N

I

6-(2,4-difluorophenyl)-5- ■NH

S'

(thiomorpholinomethyl)isoindolin- 1 - N

A10 one 361.2

F 6-(2,4-difluorophenyl)-5- ■NH

O'

(morpholinomethyl)isoindolin- 1 -one N

All F 345.2

F

6-(2,4-difluorophenyl)-5-((3-hydroxy-3-

(trifluoromethyl)azetidin- 1 -

A12 yl)methy l)isoindolin- 1 -one 399.2

Biological Activity

A. Cell Lines Co-Expressing mGlu and GIRK

[00250] Human embryonic kidney (HEK-293) cell lines stably co-expressing human or rat mGlu ₂ and G protein-coupled inwardly rectifying potassium (GIRK) channels, or human mGlug and GIRK, were used for in vitro evaluation of compound activity in thallium flux assay using a fluorescent thallium indicator dye.

B. Cell-Based T1 Flux Assay of mGlu and GIRK Activity

[00251] The day before the assay, GIRK cells co-expressing human mGlug, human or rat mGlu ₂ , as described above, were plated in black-walled, clear-bottomed, amine-coated 384-well plates at a density of 15,000 cells/20 μL/well in the assay medium (glutamine-depleted basal DMEM supplemented with 10% dialyzed FBS, 20 mM HEPES, 1 mM sodium pyruvate). Cells were incubated at 37 °C in the presence of 5% CO2. The next day, assay buffer (Hanks balanced salt solution, 20 mM HEPES, 4.16 mM sodium bicarbonate, pH 7.2) was prepared to dilute compounds and Thallos AM fluorescent dye solution. The 2X Thallos dye solution (final concentration 0.34 pM to the cells) was prepared by mixing the dye stock (2.97 mM in DMSO) to 1: 1 with 10% pluronic acid before adding to the assay buffer. Cells were washed with assay buffer using a microplate washer to remove the medium, resulting in 20 μL of buffer remaining in each well. Immediately, 20 μL of 2X Thallos dye solution was added to cells, and incubated for one hour at 25 °C. During the cell dye loading incubation period, a 10-point concentration serial dilution of compound was created from a 10 mM DMSO compound stock by performing a 1:3 serial dilution in DMSO using the Bravo liquid handler. The 2X compound plate was generated by transferring 0.24 μL of the diluted compound in each well to a daughter plate using an Echo acoustic liquid handler. This is further diluted in 40 μL assay buffer, resulting in a range from 30 pM to 1.5 nM final concentration in the assay. The agonist plate (5X) was prepared to include ECso glutamate concentration (a concentration to elicit 80% of a maximally effective glutamate concentration) 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).

[00252] After dye-loading, cell plates were washed with assay buffer to remove excess extracellular dye using a microplate washer, resulting in 20 μL of buffer remaining in each well. After a ten-minute equilibration period, cell, compound and agonist plates were loaded into a Hamamatsu pCell kinetic imaging plate reader equipped with liquid handler to monitor fluorescence changes at 480 nm excitation and 540 nm emission settings. Briefly, after collection of baseline fluorescence, 20 μL of compound was added and incubated for two minutes and twenty seconds. This is immediately followed by adding 10 μL of glutamate- thallium buffer to the wells containing compound. The fluorescent signal was monitored an additional 2.5 minutes after the glutamate addition. Multiple reference wells containing no compound received either no glutamate (for a baseline reference), ECso glutamate, or ECmax glutamate (for normalization to maximum response). Fluorescence was measured throughout the experiment at a frequency of 1 measurement per every 2 seconds before the glutamate addition and a frequency of 1 measurement per every 1 second after the glutamate addition. Each compound concentration series occurred one time in each plate, and replicates from two or three plates were used in each experimental run. Thallium solutions were handled and disposed of according to guidelines from the Vanderbilt University Chemical Safety department.

[00253] Data were normalized using a static ratio function (F/Fo) by dividing every fluorescent measurement by the initial fluorescent value for the corresponding well. The increase in signal resulting from the glutamate/thallium addition of the second add was measured by determining the slope from 3 seconds to 13 seconds after the addition. The average of all baseline slopes (no compound, no glutamate) was determined and this value was subtracted from all other slope values. The average of all ECmax slopes was determined and this value was used to normalize the baseline-corrected slopes to a percent max value (%E _m ax). The %E _m ax values for each compound series were plotted versus the log of the concentration and fit to a 4-parameter logistical equation with no fixed parameters.

[00254] Potency is reported as the ICso resulting from the curve fit. For compounds that do not plateau and do not inhibit the glutamate response to less than 20% of the Emax, a low potency value of >10,000 nM is assigned. For those that do not inhibit lower than 60% of the E _max at 30 pM compound, a >30,000 nM potency is assigned. If a compound reaches a plateau of inhibition above 20% and below 60% E _m ax, the ICso from the curve fit is reported and a category of “partial

NAM” is assigned.

C. Activity of Compounds in a mGlu GIRK Cell-Based T1 Flux Assay [00255] Compounds were synthesized as described above. Activity (ICso) was determined in the mGlu GIRK cell-based T1 flux assay as described above and the data are shown in Tables 2, 3 and 4. Data is from a single experiment unless otherwise noted.

Table 2.

Human Rat mGluz mGluz GIRK

Compound GIRK ICso (nM) ICso (nM)

1 10000 10000

2 5840 10000

3 10000 300000

4 10000 10000

5 ND 839

6 ND 2460

7 1560 10000

8 6330 2070

9 ND 1280

10 ND 10000

11 ND 10000

12 ND 94

13 ND 161

14 ND 2250 15 ND 4060

16 ND 10000

17 ND 1240

18 ND 4330

19 ND 4310

20 ND 8310

21 ND 3810

22 ND 300000

23 ND 2150

24 ND 953

25 ND 2350

26 ND 10000

27 ND 10000

28 ND 1930

29 ND 3600

30 ND 10000

31 ND 300000

32 ND 10000

33 ND 10000

34 ND 10000

35 ND 1030

36 ND 10000

37 ND 10000

38 ND 1960

39 ND 10000

40 ND 10000

41 ND 10000

42 ND 7550

43 ND 10000

44 ND 10000 45 ND 10000

46 ND 300000

47 ND 10000

48 ND 10000

49 ND 10000

50 ND 10000

51 ND 300000

52 ND 953

53 ND 10000

54 ND 10000

55 ND 10000

56 ND 10000

57 ND 10000

58 ND 10000

59 ND 10000

60 ND 10000

61 ND 10000

62 ND 10000

63 ND 2620

64 ND 762

65 ND 10000

66 ND 10000

67 ND 10000

68 ND 10000

69 ND 659

70 ND 1980

71 ND 5100

72 ND 999

73 ND 4410

74 ND 693 75 ND 10000

76 ND 10000

77 ND 10000

78 ND 10000

79 ND 1860

80 ND 1090

81 ND 1140

82 ND 10000

83 ND 10000

84 ND 10000

85 ND 10000

86 ND 10000

87 ND 618

88 ND 1650

89 ND 925

90 185 225

91 ND 697

92 ND 618

93 ND 1500

94 ND 477

95 ND 1440

96 ND 585

97 ND 938

98 ND 136

99 ND 10000

100 ND 1120

101 ND 534

102 ND 10000

103 ND 2880

104 ND 10000 105 ND 4490

106 ND 1420

107 ND 589

108 ND 347

109 ND 1130

110 ND 10000

111 ND 10000

112 ND 10000

113 ND 10000

114 ND 10000

115 234 ND

116 931 ND

117 737 ND

118 1990 ND

1 19 2700 ND

120 1050 ND

121 1440 ND

122 1290 ND

123 447 ND

124 496 ND

125 1140 ND

126 10000 ND

127 7940 ND

128 3410 ND

129 767 ND

130 1000 ND

131 366 ND

132 529 ND

133 1820 ND

134 2350 ND 135 2020 ND

136 3180 ND

137 816 ND

138 537 ND

139 728 ND

140 1520 ND

141 220 ND

142 1310 ND

143 1670 ND

144 3070 ND

145 ND ND

146 ND ND

147 5914 ND

148 454 ND

149 532 ND

150 >10,000 ND

151 857 ND

152 693 ND

153 727 ND

154 >10,000 ND

155 >10,000 ND

156 660 ND

157 736 ND

158 3730 ND

159 1717 ND

160 218 ND

161 4593 ND

162 891 ND

163 1115 ND

164 955 ND 165 637 ND

166 2452 ND

167 >10,000 ND

168 >10,000 ND

169 2250 ND

170 >10,000 ND

171 3552 ND

172 >10,000 ND

173 7342 ND

174 >10,000 ND

175 >10,000 ND

176 >10.000 ND

177 1347 ND

178 >10,000 ND

179 >10,000 ND

180 >10,000 ND

181 >10,000 ND

182 >10,000 ND

183 >10.000 ND

184 1132 ND

185 >10,000 ND

186 >10,000 ND

187 9582 ND

188 >10.000 ND

189 >10,000 ND

Table 3.

Human

Rat mGluz H1G1U2

Compound GIRK GIRK ICso (nM) ICso(nM) Al 191 ND

A2 667 ND

A3 218 ND

A4 481 ND

A5 205 ND

A6 287 ND

A7 208 ND

A8 413 ND

A9 273 ND

A10 >10,000 ND

All >10,000 ND

A12 528 >10,000

Table 4.

Rat mGlu3

Compound GIRK ICso(nM)

5 5820

9 1980

24 >10,000

52 >10.000

64 >10,000

69 >10,000

74 >10,000

87 >10,000

91 >10,000

94 >10,000

96 >10,000

98 2620

101 >10,000

108 4790 [00256] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents.

[00257] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, compositions, formulations, or methods of use of the invention, may be made without departing from the spirit and scope thereof.