BENZOISOXAZ0LE-SUBSTITUTED COMPOUNDS AS MGLUR4 ALLOSTERIC

POTENTiATORS, COMPOSITIONS, AND METHODS OF TREATING NEiJROLOGlCAL

DYSFUNCTION

BACKG OU D

{00011 The amino acid L-glutamate (referred to herein simply as glutamate) is the principal excitatory neurotransmitter in the mammalian central nervous system (CNS). Within the CNS, giutaraate plays a ke role in synaptic plasticity (e.g., long term potentiation (the basis of learning and memory)), motor control and. sensory perception. It is now welt understood that a variet of neurological and psychiatric disorders, including, but not limited to, schizophrenia general psychosis and cognitive deficits, are associatet! with dysfunctions in the glulamaiergic system. Thus, modulation of the ghitamatergic system is an important therapeutic goal, Glutamate acts through two distinct receptors: ioiiotropic and metabotropic ghitamate receptors. The first class, the ionotropic glutamate receptors, is comprised of raulti-subuuit li gaud-gate ion channels that mediate excitatory post-synaptic currents. Three subtypes of ionotropic ghitamate receptors have been identified, and despite ghitamate serving as agonist for all three receptor subtypes, selective !igands have been discovered that activate each subtype. The ionotropic ghitamate receptors are named after their respective selective ligands: kainate receptors,, AMP A receptors and NMDA receptors.

{0002J The second class of ghitamate receptor, termed metabotropic giutaraate receptors, (mGluRs), are G-proteio coupled receptors (GPCRs) that modulate neurotransmitter release or the strength of synaptic transmission, based on their location (pre-or post-synaptic). The tnGluRs are famil C GPCR, characterized by large (-"560 amino acid) "venus fly trap" agonist binding domain in the amino- terminal domain of the receptor. This unique agonist binding domain distinguishes family C GPCRs from family A and B GPCRs wherein the agonist binding domains are located within the 7-strand transmembrane spanning (7TM) region or within the extracellular loops that connect the strands to this region. To date, eight distinct mGluRs have been identified, cloned and sequenced. Based on structural similarity, primary coupling to intracellular signaling pathways and pharmacology, the mGluRs have been assigned to three groups; Group Ϊ (mGlu l and mGSuRi ), Group 11 (mOIuR2 and mGluR3) and Group 111 (raGhrR4, mGluR(>, mGlu 7 and raGiuR8).Group 1 mGluRs are coupled through Ga /i 1 to increase inositol phosphate and metabolism and resultant increases in intracellular calcium. Group 1 mGluRs are primarily located post-synapfically and have a modulatory effect on ion channel activity and neuronal excitability. Group II (mGluRl and raGiuR3) and Group 111 (mGluR4, mGluR6, raGiuR ^' 7 and raGluRS) mGluRs ate primarily located pre-synaptically where they regulate the release of neurotransmitters, such as ghitamate. Group II and Group Hi mGluRs are coupled to Gai and its associated effectors such as adenylate cyclase. [0003 mGluR4 belongs to the group Hi raG!uR subfamily and is located in predominantly presynaptic locations in the central nervous system (Benitez et at., 2000; Bradley et al., 1996; Bradle et a!,, 1 99; Mateos et at., 1998; Phillips et ai,, 1 97) where it is functions as an auto- and heteroreceptor to regulate the release of both GABA and gfutamaie. mGluR4 has also been shown to be expressed at a low level in some postsynaptic locations (Benito?, et aL 2000). Numerous reports indicate that mGluR4 is expressed in most brain regions, particularly in neurons known to play key roies in functions of the basal ganglia (Bradley et al., 1 99; Corti et al, 2002; Kuramoto et al, 2007; Marino et ai, 2003a), learning and memory (Bradley et al, 1996), vision (Akazawa et al, 1994; ouiert et a!., 1996; Quraishi et L, 2007), cerebellar functions ( akoff et al., 1996), feeding and the regulation of hypothalamic hormones (Flor et ai, 1995), sleep and wakefulness (Noriega et at, 2007) as well as many others. There are now a number of literature reports describing a role for mGfuR4 modulation in Parkinson's disease (Battagiia et al, 2006; Lopez et al, 2007; Marino et al., 2005; Marino et al., 2003b; Ossowska et al, 2007; Va!enti et al, 2003), anxiety (Stachowtcz et al, 2006; Stachowtcz et al., 2004), motor effects after alcohol consumption (BJednov et al, 2004), neurogenic fate commitment and neuronal survival (Saxe et al, 2007), epilepsy (Chapman et al, 2001 ; Pi isch et al, 2007; Snead. et al, 2000; Wang et al, 2005) and cancer, particularly medislio astooia (lacovelli et aL 2004).

}0004] in addition, there is evidence that activation of mGluR4 receptors (expressed in islets of Langerhans) would inhibit glucagon secretion (Uehara et al, 2004), Thus, activation of mGluR4 may ^¬ be an effective treatment for disorders involving defects in glucose metabolism such ashypog.lyce.oiia. Type 2 diabetes, and obesity,

{0005] Also, there are reports that activation of Group III raGiuRs, specifically niGluR4, may be an effective treatment for neuroinflammatory diseases, such as multiple sclerosis and related disorders (Besong et al, 2002).

{0006} Also, that activation of Group III mGluRs, specifically mGIu4 positive allosteric modulators (PAMs), may be an effective treatment for neuroinilamrnatory diseases, such as multiple sclerosis and related disorders (Besong et al, 2002; Taylor et al, 2003; Fa!Sarino et al, 2010).

{0007] There are two variants of the mGluR4 receptor which are expressed in taste tissues; and thus acti vation of mGluR4 may be used as taste enhancers, blockade of certain tastes, or taste agents, flavoring agents or other food additives ( urihara, 2009; Chaudhari et al, 2009).

10008} Despite advances in mGluR4 research, there is still a scarcity of compounds that, effecti vel potentiate mGluR4 which are also effective in the treatment of neurological and psychiatric disorders associated with glutainatergic neurotransmission dysfunction and diseases. As well as inflammatory central nervous system disorders, medulioblastomas, metabolic disorders and taste enhancing associated with glutamatergic dysfunction and diseases in which mGiu.R4 receptor is involved. Further, conventional mGluR4 receptor modulators typically lack satisfactory aqueous solubility and exhibit poor oral bioavailability. These needs and other needs are satisfied by the present invention.

SUMMARY 000 | in accordance with the pitrposefs) of the invention, as embodied and broadly descri ed herein, the invention, in one aspect, relates to compounds useful as aliosteric modulators of mGluR4 receptor activity, methods of making same, pharmaceutical compositions comprising same, and methods of treating neurological and psychiatric disorders associated with glutainate dysfunction, for example Parkinson's disease, using same. Further disclosed are methods and pharmaceutical

compositions useful for treating a disease related to mGluR4 activity. In one aspect, the disclosed compounds can affect the sensitivity of niGluR4 receptors to agonists without binding to the orthosterie agonist binding site or acting as orthosterie agonists themselves. A "receptor aliosteric agonist", as used herein, is generally defined as a hgand that functions as both an aliosteric .modulator and as an agonist on its own (though the latter is usually only at higher concentrations). The presence of a the receptor aliosteric agonist (Ago-FAM) activity may offer advantages in various CNS and neurological disorders where the basal glutartiatergic tone is low in given brain regions.

[0010] Disclosed are methods for the treatment of neurotransmission dysfunction or other disease state associated with mGluR4 activity in a mammal comprising the step of administering to the mammal at least one compound in a dosage and amount effective to treat the dysfunction in the mammal, the compound having a structure represented by formula (I):

X is Cli. C-alky!, N, NH, -alkyl alkoxy, or may form a 6-membered ring with Y optionally substituted with at least one R; Y is CH, C-alkyl, N, or may form a 6-inembered ring with X optionally substituted with at least one R; Z is independently N, CH, C-a kyl, C-halogen. C-Me, C-Oa kyl, C- OMe: j is 0 or C-R ₅ ; X _? . is O or C-R?; R is independently H, halogen, CN ₅ Me, alkyl, alkoxy, OMe, aryl, heteroaryl, alkyl-aryl, alkyl -heteroaryl, eycl.oal.kyi, alkyi-cyci.oaikyi; R _i: is independently H, alkoxy, amino, alkyl-alkoxy, alkyl CN, cycloalkyl, alkyl-eycioalkyi, cyeioheteroalkyl, alkyl- cyeioheteroalkyl, CF _3> halogen, CDs, CD ₂ R, CDRR _¾ CONR.A, aryl, heteroaryl, alky -aryl, alkyl- tietcroaryl SO _? .R ₂ , OR, ORj, Oaryl, Oheteroaryl, NHR, NR _S R ₄ , fluorinated aikyl, dtfluor ated alkyl, trifluormated alkyl, heteroaikyl, benzyl, heteroaryl benzyl (CHjheteroatylS, prop&iamide,

diethy!propanaraide, CH ₂ CONR ₃ R ; CHVNHR; CH3NHR3R ; R∑ is independently H, aikoxv, amino, alkyl-alkoxy, alkyl, CN, cycloalkyi, aikyl-cycloalkyi, cycloheteroalkyl, aikyl-cycloheteroaikyl, CF _; , halogen, CD ₃ , CD R _f CDRR CONR ₃ R,, aryl, heteroaryl, aikyl-aryl, aikyl-heteroaryi, S0 ₂ R _t , OR, OR Oaryl, Oheteroaryl, NHR, NR ₃ R ₄ , iiuormated alkyl, difluorinated alkyl, trifluormated alkyi, heteroaik l, benzyl, heteroaryl benzyl (C%heteroaryl), propanamide, diethy!propanamide, CH^CONRs *,

CH ₂ NHR; CH2NHR5R ; j is H, alkoxy, amino, alkyl-alkoxy, alkyi, CN, cycloalkyi, alkyl-eycloalkyl, cycloheteroalkyl, alkyl-cycloheteroalkyl CF?, halogen, CDs, CD?.R, CDRR2, aryl, heteroaryl aikyl-aryl, alkyi-heteroaryl, S0 ₂ R _2; OR, OR ₂ , Oaryl, Oheteroaryl, NHR, fluorinated aikyl, difluorinated alkyi, iri.fiitorinated aikyl, heteroaikyl, benzyl, heteroaryl benzyl (C¾heieroaryl), propanamide,

diethylpropanainide, C¾NHR; R _t is H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycloalkyi, alkyl- eycloaikyi, cycloheteroalkyl , alkyl-cycloheteroalkyl, CF ₃ , halogen, CD _S , CD ₂ R, CDRRj, aryl,

heteroaryl, aikyl-aryl, alkyl-heteroaryi, S0 ₂ R ₂ , OR, 0¾, Oaryl Oheteroaryl, NHR, fluormated alkyi, difluorinated alkyl, tritluorinated alkyl, ^' heteroaikyl, benzyl, heteroaryl benzyl (CH ₂ heteraaryl), propanamide, dietirylpropanamide, CHjNHR; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable deri ative thereof

{00 J 11 Also disclosed are methods for potentiating mGluR4 activity in a subject comprising the step of administering to ike subject at least one compound at least one compound having a structure represented by formula (I).

X is CH, C-alkyl, N, NH, N-alkyl, alkoxy, or may form a 6-membered ring with Y optionally substituted with at least one R; Y is CH, C-alkyl, N, or may form a 6-membered ring with X optionally sisbstitutcd with at least one R; Z is independently N, CH, C-alkyl, C-halogeti, C-Me, C-Oalkyl, C-

OMe; Xi is O or C-R ₅ : X ₂ is O or C-¾: R is independently H, halogen, CN, Me, alkyl, alkoxy, OMe, aryl heteroaryl, aikyl-aryl, alkyi .-heteroaryl, cycloalkyi, aikyl-cycloalkyi; Rt is independently H, alkoxy, ammo, alkyl-alkoxy, alkyi, CN, cycloalkyi aikyl-eyeloalky cycloheteroalkyl, alkyl*

eyclolieteroalkyl CF ₃ , halogen, CD ₃ , CD ₂ R, CDRRj, CONR.3R4, atyl, heteroaryl, aikyl-aryl, aikyl- heteroaryi, SO?.R ₂ , OR, ORj, Oaryl, Oheteroaryl, NHR, NR _S R ₄ , fluorinated alkyi, dtiteor ated aikyl trifluorinated aikyl, heteroalkyl, benzyl heteroaryi benzyl (C¾heterQarylj, propaaaraide,

diethylpropanamidc, C¾CONR ₃ R ; CHVNHR; CH3NHR3R ; ¾ is independently H, aikoxy, amino, alkyl-alkoxy, aikyl, CN, cycloa-kyJ, aikyl-cycloalkyi, cycloheteroalkyl, aikyl-cycloh teroaikyl, CF _; , halogen, CD ₃ , CD R _f CDRR CONR ₃ ¾, aryl, heteroaryi, aikyl-aryl, aikylheteroaryl, S0 ₂ R _t , OR, ORE, Oaryl, Oheteroaryl, NHR, NR ₃ R ₄ , iiuormated aikyl difluorinated aikyl, trifluorinated alkyL heteroalkyl, benzyl, heteroaryi benzyl (C%heteroaryJ), propanamide, diethylpropanamide,

CH ₂ NHR; CH2NH 3 4; R? is H, aikoxy, amino, alkyl-alkoxy. alkyk CN, cycloalkyl, alkyl-eye a!kyl, cycloheteroalkyl, alky!-cycloheteroalky!, CF _? , halogen, C¾, CD?.R, CDRR _2> aryl, heteroaryi, aikyl-aryl, alfcyl-heteroaryL S<¾R ₂ , OR, OR ₂ , Oaryl, Oheteroaryl, NHR, fluorinated aikyl, difluorinated aikyl, trifluorinated aikyl, heteroalkyl, benzyl, heteroaryi benzyl (C¾heteroaryl), propanamide.,

diethylpropanarnide, C¾NHR; R* is H, aikoxy, amino, alkyl-alkoxy, aikyl, CN, cycloalkyl, alky - eycloaikyi, cycloheteroalkyl , alky Cycloheteroalk l, CF ₃ , halogen, CD _S , CD ₂ R, CDRRj, aryl, heteroaryi, aikyl-aryl, aikyl-heieroary!, S0 ₂ R¾ OR, OR ₂ , Oaryl Oheteroaryl, NHR, fluorinated alky!, difluorinated. aikyl, tri fluorinated aikyl, heteroalkyl, benzyl, heteroaryi benzyl (CH^heteroaryl), propanamide, diemylpropanamide, CH3NHR; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof, in a dosage and amount effective to potentiate raGluR4 receptor activity in the subject.

|0012| Also disclosed are methods of potentiating xn 3lttR activity' in at least one ceil comprising the step of contacting at least one cell with at least one compound having a. structure represented by formula (I);

X is CH, C-alky!, N, NH, N-alkyl, aikoxy, or may form a 6-membered ring with Y optionally sisbstitutcd with at least one R; Y is CH, C-alkyI, N, or ma form a 6-membered ring with X optionally substituted with at least one R; Z is independently N, CH, C-alkyl, C-halogen, C-Me, C-Oalkyl C~

OMe; Xt is O or C-R , X ₂ is O or C¾ R is independently H, halogen, CN, Me, aikyl, aikoxy, OMe, aryl heteroaryi aikyl-aryl, aikyl -heteroar i, cycloalkyl alkyl-cyeloaikyl R _s is independently H, aikoxy, amino, aiky!-alkoxy, aikyl. CN, cycloalkyl, aikyl-eyeloalkyL cycloheteroalkyl, alkyl- cycloheteroalkyl, CF _¾ halogen, CD ₃ , CDjR, CDRR _¾ CONRsR*, aryl, heteroaryi, alkyl-aryl, alkyl- rteieroaryl SO _? .R ₂ , OR, OR?, Oaryl, Oheteroaryl, NHR, NR,R ₄ , fluoriaated alkyl, difluorinated alkyl trifluorinated alkyl, heteroalkyl, benzyl, heteroaryi benzyl (CHjheteroaryl), propanamide,

diethylpropanaraide, CH2CONR3R4; CH NHR; CBjNHRA; R ₂ is independently H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycioaikyl, alkyl-cycloalkyi, cycloheteroalkyl, alk l-cycloheteroaik l, CF _; , halogen, C¾ CD ₂ R, CD R _U CONRjRt, aryl, heteroaryi, alkyl-aryl, aikyi-heteroafyl, S0 ₃ R _T , OR, OR;, Oaryl, Oheteroaryl, NHR, NR _S R, _S , fluorinaied alkyl, difluorinated alkyl, tritluorinated. alky?, heteroalkyl, benzyl, heteroaryi benzyl (CHjheteroaryl), propanamide, diethylpropanamide, CH^CONRs *,

CHJNHR; CH2NHR3R ; R? is H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycioaikyl, alkyl-oycloalkyl, cycloheteroalkyl, alkyl-cycloheteroalkyl, CFj, halogen, C¾, CD ₂ R, CDRR ₂ , aryl, heteroaryi, alfcyi-aryl, aikyl-heteroaryl, SO ₃ R ₂ , OR, OR ₂ , Oaryl, Oheteroaryl, NHR, fluoridated alkyl, difluorinated alkyl, friflitorirtated alkyl, heteroalkyl, benzyl, heteroaryi benzyl (Cl¾heieroaryi), propanamide,

dieurylpropanamide, CH2 HR; R4 is H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycioaikyl, alkyl- cycioaikyl, cycloheteroalkyl, alkyl-cycloheteroalkyl, Cf 3, halogen, CD,, CD ₃ R, CD.RR _¾ aryl, heteroaryi, aikyl-aryi, alkyl-heteroaryl, S0 ₂ R ₂ , OR, OR ₂ , Oaryl, Oheteroaryl, NHR, fluorinaied alkyl, difluorinated alkyl trifluoriiiaied alkyl, heteroalkyl benzyl, heteroaryi benzyl (CHjheteroaryl), propanatnide, diethylpi'opananiide, CHjNHR; or a pharmaceutically acceptable salt thereof or a pnarmaeetriically acceptable derivative thereof, in an amount effective to potentiate roGluR.4 receptor activity in the at least one cell

|60i3J Also disclosed are compotinds having a structure represented by formula (I):

X is CH, C-alkyl, , NH, N-a?kyl, alkoxy, or may form a 6-membered ring with Y optionally substituted with at least one R; Y is CH, C-alkyl, , or may form a 6-membered ring with X optionall substituted with at least one R; Z is independently M CH, C-alkyl C-halogen, C-Me, C-Oaiky L C- OMe; Xi is O or C-R ₅ : X ₂ is O or C-R ₂ ; R is independently H, halogen, CN, Me, alkyl, alkoxy, OMe, aryl heteroaryi, alkyl-aryl, alkyl-heteroaryl, cycioaikyl alkyl -eye loalkyl R _s is independently H, alkoxy, ammo, alkyl-alkoxy, alkyl CN, cycioaikyl, alk l-cycloalkyl, cycloheteroalkyl, alkyl- cycloheteroalkyl, CF ₃ , halogen, CD ₃ , CDjR, CDRRj, CONR.3R4, aryl, heteroaryi, alkyl-aryl, aikyl- tietcroaryl SOjF , OR, ORj, Oaryl Oheteroaryl, NHR, NR _S R ₄ , fluorinated alkyl, dtiteorinated alkyl frifluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CHjheteroaryl), propanamide,

diemy!propananudc, CH ₂ CONR ₃ R ; CHVNHR; CH3NHR3R ; R∑ is independently H, aikoxv, amino, alkyl-alkoxy, aikyl, CN, cycloalkyi aikyl-cycloalkyl cycloheteroalkyl, aikyl-cycloheteroaikyl, CF _; , halogen, CD ₃ , CD R _f CDRR CONR ₃ ¾, aryl heteroaryl, aikyl-aryl, aikyl-heteroaryi, S0 ₂ Ri, OR, OR Oaryl, Oheteroaryl, NHR, NR ₃ R ₄ , iiuormated alkyl, difluorinated aikyl, trifluorinated alkyl, heteroalkyl benzyl heteroaryi benzyl (CHjheieroaryl), propanamide, dietlryipropanamide, CH^CONRsR*,

CH ₂ NHR; CH2NHR3R ₄ ; R? is H, alkoxy, amino, alkyl-alkoxy, aikyi, CN, cycloalkyi, aikyl-eyebalky cycloheteroalkyl, alky!-cydobeteroalky!, CF _? , halogen, C¾, CD ₂ R, CDR¾, aryl, heteroaryl aikyl-aryl, alkyl-heteroaryl, S<¾R ₂ , OR, OR ₂ , Oaryl, Oheteroaryl, NHR, fluormated aikyl, di fluorinated alkyl, trifluorinated aikyl, heteroalkyl benzyl, heteroaryl benzyl (CHjheteroaryl), propanamide,

diethylpropanamide, C¾NHR; R* is H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycioaikvl, alkyl- cycloalkyi, cycloheteroalkyl aikyl-cycloheteroaikyl, CF ₃ , halogen, CD _S , CD ₃ R, CDRRj, aryl, heteroaryl, aikyl-aryl, alkyl-heteroaryl S0 ₂ R ₂ , OR, OR ₂ , Oaryl, Oheteroaryl, NHR, fluormated aikyi, difttiorinated aikyl, trifluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CH ₂ heteroaryl), propanamide, dietlr} propaoa.niide, CH3NBR; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable deri ative thereof.

{00 J j Also disclosed pharmaceutical compositions comprising a compound having a structure represented by formula (I):

X is CH, C-aikyl, N, NH, N-alkyl, alkoxy, or may form a 6-membered ring with Y optionally substituted with at least one R; Y is CH, C-aikyl, N, or may form a 6-membered ring with X optionally substituted with at least one R; Z is independently N, CH, C-aikyl, C-halogeii, C-Me, C-Oalkyl, C- OMe; i is O or C-R ₅ ; X ₂ is 0 or C-R ₂ ; R is independently H, halogen, CN, Me, alkyl, alkoxy, OMe, aryl, heteroaryl, aikyl-aryl, alkyl-heteroaryl, cycloalkyi, alkyl-eycloalkyi; Rj is independently H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycloalkyi alkyl-eyeloalkyl cycloheteroalkyl, aikyl- cycloheteroaikyl CFs, halogen, 0¼, CDjR, CDRR¾ CONR3R , aryl, heteroaryl, aikyl-aryl, alkyi- hctcroary ^' j, S0 ₂ R ₃ , OR, OR ₂ , Oaryl Oheteroaryl, NHR, NR ₃ R , iiuormated aikyi, difluorraated aikyl trifluorinated aikyl, heteroaikyl, benzyl, heteroaryl benzyl (CH?heteroaryl), propanaraide, die lpropanamide, CH _; CON ₃ R ₄ ; CH ₂ NHR; CH2NHR3R ; R? is mdependettUy H, alkoxy, amino, alkyl-alkoxy, atkyl CN, cycloalkyl, al ^' kyl-cycloalkyl, cyeloheteroalkyl, alky!-cyclobcteroalkyl, CF¾, halogen, CD ₃ , CD R _f CDRR CONR ₃ R,, aryl, heteroaryl alkyl-aryl, aikylheteroaryi S0 ₂ R _t , OR, OR _* , Oaryl, Oheteroaryl M-IR, R ₃ R ₄ , fluorinated aikyl difiuorinated aikyl, trifluorinated aikyl, heteroaikyl, benzyl, heteroaryl benzyl (CH ₂ heteroaryl), propanamide, diethylpropanamide, CHjCONRjRf,

CH ₂ NHR; CH2NHR5R ; j is H, alkoxy, amino, alkyl-alkoxy, aikyl CN, cycloalkyl, alkyl-eye a!kyl, cyeloheteroalkyl, alkyl-eyelcheteroalkyl, CF ₃ , halogen, CDs, CD ₂ R, CDRR ₂ , aryl, heteroaryl, alkylaryl alkyl-beteroaryl, S0 ₂ R ₂ , OR, OR¾ Oaryl Oheteroaryi NHR, fluorraated aikyl, difluorinated aikyl trifluorinated aikyl, heteroaikyl, benzyl heteroaryl benzyl (CHjheteroaryl), propanamide,

diethylpropanamide, C¾NHR; R* is H, alkoxy, amino, alkyl-alkoxy, aikyl, CN, cycloalkyl, alkyl- cycloalkyi, cyeloheteroalkyl, alkyl-eycioheieroalkyl, CF ₅ , halogen, CD _3> CD ₂ R, CDRR _2> aryl, heteroaryl, alky!-aryl, aikyl-heteroaryl, S0 ₂ R ₂ , OR, OR ₂ , Oaryl Oheteroaryl NHR, fesorinated atkyl difiuorinated aikyl trifluorinated aikyl heteroaikyl benzyl, heteroaryl benzyl (CH ₂ heteroaryi}, propanamide, diethylpropanamide, CH ₂ NHR; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable deri ative thereof, and a pharmaeeutieaily acceptable carrier.

j¾OI5| Also disciosed are methods for potentiating mGtuR4 activity in at least one cell comprising the step of contacting at least one ceil with at least one disclosed compound in an amount effective to potentiate m01uR4 receptor activit in at least one ceil

(i)016| Also disciosed are methods for potentiating mGluR4 activity in a subject comprising the step of administering to the subject a therapeutically effective amount of at least one disclosed compound in a dosage and amount effecti ve to potentiate mOIuR4 receptor activity in the subject

|0017{ Also disclosed are methods for the treatment of a disorder associated with mGluR4 neurotransmission dysfunction or other mGluR4 mediated disease states in a mammal comprising the step of administering to the mammal at least one disclosed compound in a dosage and amount effective to treat the disorder in the mammal.

10018} Also disclosed are methods for making a compound comprising the steps of providing an amine compound having a structure represented by formula {!):

X is CH, C-alkyl, N, NH, N~alkyl, alkoxy, or may form a 6-mem ^' bered ring with Y optionally substituted with at least one R; Y is CH, C-alkyl, N, or may form a 6-merabered ring with X optionally substituted with at .least one R; Z is independently N, CH, C-alkyl, C- ^' halogen, C-Me, C-Oatkyl, C- OMe; X¾ is 0 or C-Rj; 2 is 0 or C-¾; R is independently H, halogen, CN, Me, alkyl, alkoxy, OMe, aryi, .heteroaryi, alkyl-aryl, aiky!-heteroary!, cycloalkyi, aikyl-cycloalkyi; i is independently H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycloalkyi, alkyi-eyeJoaJkyi, cyelolieteroalkyl, alkyl- cyclo!ieteroatky!, CF _Ss ^' halogen, CD ₃ , CD ₃ R, CDR ^' R ₂ , CONR _s R ₄ , aryl, heteroaryi, alkyl-aryl, aikyt- heteroaryl, SO2R2, OR, OR2, Oaryl, Oheteroaryl, NHR, RjR fluoriiiaied alkyl, difluorinated alkyl. trifluorinated alkyl, heteroalkyl, benzyl, heteroaryi benzyl (C¾heteroaryl), propanamide,

dieihylpropanarasde, CH2CONR3R ; CBjHER; CHJNHRJR*; ¾ is independently H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycioaikyk alkyl-cycloalkyl, cycloheteroaikyl, aikyi-cyclo ^' heteroaikyl, CF _;i , halogen, CDs, C 2R, C ^' D ^' RRs , CON 3R ₄ , aryl, heteroaryi alkyl-aryl, aikyl-heteroaryl, SOj u OR, OR; . Oaryl, Oheteroaryl, NHR, N sRi, fluoriiiaied aikyi, difluorinated alkyl, trifluorinated alkyl, heteroalkyl, benzyl, heteroaryi benzyl {C¾hetcroary ^' l), propanamide, dicthylpropanaraide, CH2CONR5R4,

CHVNHR; CHVNHR3R4; ¾ is H, alkoxy, amino, alkyl-alkoxy, aikyi, CN, cycloalkyi alkyi-cyctoatkyl, cycloheteroaikyl, alkyl-cycioheteroalkyL CF3, halogen, CD?, CD _; R, CDRRj, aryl heteroaryi, alkyl-aryl, alkyl-heteroaryl, SOjRj, OR, OR _? ., Oaryl, Oheteroaryl, NHR, fluorinated. alkyl, difluorinated aikyi, trifluorinated alkyl, heteroalkyl, benzyl, heteroaryi benzyl (C¾heferoaryl), propanarmde.

dietbyipropanamide, C¾NHR.; R ₄ is H, alkoxy, amino, alkyl-alkoxy, aikyi, CN, cycloalkyi, alkyl- cycloalkyi, cycloheteroalkyl, alkyl-cyc!oheteroalkyL CF _:; , halogen, CD ₃ , CD>R, CDRR _¾ aryl, heteroaryi alkyl-aryl, alkyl-heteroaryl, SOjR¾ OR, OR?, Oaryl, Oheteroaryl, NHR, fluorinated aikyi, difluorinated aikyi, trifluorinated aikyi, heteroalkyl, benzyl, heteroaryi benzyl (CHjheteroaryl), propanamide, diethylpropanamide, CHjNHR as shown in the .Examples below, wherein the variables are defined herein.

[0019J Also disclosed are the products of the disclosed methods of making. [0020] Also disclosed arc methods for the manufacture of a medicament for potentiating mGluR4 receptor activity in a mammal comprising combiaing a compound having a structure represented by formula (1) :

X is CH, C-alkyl, N, NH, N-alkyS, alkoxy, or may form a 6-membered. ring with Y optionally substituted with at. least one R; Y is CH, C-alkyl, , or may form a 6-membered ring with X optionally substituted with at least one R; Z is independently N, CH, C-alkyl, C-halogen, C-Me, C-Oalkyl, C- OM.e; j is O or OR-. ; X ₂ is O or C~R ; R is independently H, halogen, CN, Me, alkyl, alkoxy, OMe, aryl, heteroaryl, aikyl-aryl, alfcyl-heteroaryl, cycloalkyi, alkyl-cycloalkyl; R. ₅ is independently H, alkoxy, amino, alkyi-alkoxy, alkyl, CN, cycloalkyi, alkyl-cycloalkyl, cycloheteroalkyl, alkyl- cycloheteroalkyl, CFj, halogen, CDs, CD?R, CDRRj, CONR3R4, aryl, heteroaryl, aikyl-aryl, alkyl- heteroaryl, SO2R2, OR, O ₂ , Oaryl Oheteroaryl NHR, R3R ₄ , fluorinated alkyl, difluorinated alkyl, trifluorinated alkyl, heieroalkyl, benzyl, heteroaryl benzyl (CHjheteroaryl), propanamide,

diethy!propanamidc, CH ₂ CO j ; CH ₂ NHR: CH2NHR R4; ¾ is independently H, alkoxy, amino, alkyi-alkoxy, alkyl, CN, cycloalkyi, alkyl-cycloalkyl, cycloheteroalkyl, alky}-cycloheteroa.lkyl, CF¾, halogen, CD,, CDjR, CDRR;, CONR¾, aryl, heteroaryl aikyl-aryl, alkyl-heteroaryi SO ₂ R,, OR, OR;, Gary I, Oheteroaryl, NHR, NR3R ₄ , fluorinated alkyl, difluorinated alkyl, trifluorinated alkyl, heteroalk l, benzyl, heteroaryl benzyl (CHAeteroaryi), propanamide, diethylpropanamide, CH ₂ CONR ₃ R4,

CHjNHR; CH2NHR3R4; R¾ is li, alkoxy, amino, alkyi-alkoxy, alkyl CN, cycloalkyi, alkyl-cycloalkyl, cycloheteroalkyl, alkyl-cycioheteroalkyl, CF _; , halogen, CD;;, CD^R, CDRR ₂ , aryl, heteroaryl, aikyl-aryl, alkyi-heteroaryl, SO ₂ R ₂ , OR, OR ₂ , Oaryl Oheteroaryl NHR, fhiorinated alkyl, difluorinated alkyl, trifluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CHjheteroatyl), propanamide,

diethylpropanamide, C¾NHR; R. _t is H, alkoxy, amino, alkyi-alkoxy, alkyl, CN, cycloalkyi, alkyl- cycloalkyl cycloheteroalkyl alkyl-cyclo eteroalkyl, CF3, halogen, CDs, CD2R, CDRR2, aryl, heteroaryl, aikyl-aryl, alkyl-heteroary!, SO ₃ R2, OR, OR ₂ , Oaryl, Oheteroaryl, NHR, fluorinated alkyl, difluorinated alkyl. trifluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CH ₂ heteroaryl), propanamide, diethylpropanamide, C¾NHR; or pharmaceutically acceptable salt thereof or a pharmaceutically acceptable deri ative thereof [0021] Also disclosed arc the products of the disclosed methods for the manufacture of a medicament

{0022} Also disclosed are uses of a compound for potentiating mGluR4 receptor activity in a mammal, wherein the compound has a structure represented by formula (I):

X is CH, C-alkyl, N, NH, N~alkyl, alkoxy, or may form a 6-merabcred ring with Y optionally substituted with at least one R; Y is CH, C-alkyl, N, or may form a 6-membered ring with X optionally substituted with at least one R; Z is independently N, CH, C-alkyl C-halogen, C-Me, C-Oalky C- OMe; X, is 0 or C-R ₃ ; X ₃ is 0 or C-¾; R is independently H, halogen, CN, Me, alkyl alkoxy, OMe, aryl, hcteroaryl, alkyl-aryl, aikyt-heteroaryl cycloalkyl, alkyl-cycloalkyl; R _} is independently H ^" , alkoxy, am no, alkyl-alkoxy, alkyl CN, cycloalkyl alkyl-cycloalkyl cycloheteroalkyl alkyl- cycloheteroalkyl, CF _S> halogen, CDj, CD _? R, CDRRj, CO R3R4, aryl, heteroatyl alkyl-aryl alkyl heieroary SO3R2, OR, OR ₅ , Oaryl, Oheteroaryl NHR, NR3R4, fluorinated alkyl difluorinated alkyl trifluorinated alkyl, heteroalkyl benzy heteroaryl benzyl (CH^heteroaryl), propanamide,

diethylpropanaraide, CH2CONR3R4; CH NHR; C¾NHR ₅ R ₄ ; R ₂ is independently H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycloalkyl alkyl-cycloalkyl cycloheteroalkyl alkyl-cyeloheteroalky CF _? , halogen, CD*, CD ₂ R, CDRR ;, CONR,R ₄ , aryl hcteroaryl, alkyl-aryl, alkylheteroaryl SQ ₂ R _f , OR, OR _{ , Oaryl Oheteroaryl, NHR, NR _: 0¾, fluorinated alkyl, difluorinated alkyl tritlitorinated alkyl heteroalkyl, benzyl, heteroaryS benzyl (C¾heteroaryl), propanamide, dietnylpropanamide, CH2CONR3R4,

CH;; HR; CH ₂ NHR ₃ R ; R, is H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycloalkyl alkyl-cycloalkyl, cycloheteroalkyl alkyl-cycioheteroalkyl, CF ₃ , halogen, CD _? , CD^R, CDRR ₂ , aryl, hcteroaryl, alkyl-aryl alkyl-iieteroaryl SQjRa, OR, OR ₂ , Oaryl, Oheteroaryl, NHR, fluorinated alkyl difluorinated alkyl, trifluortnated alkyl, heteroalkyl benzyl heteroaryl benzyl (CHjheteroaryl), propanamide,

diethylpiopaaannde, C¾NHR; R4 is H, alkoxy, amino, alkyl-alkoxy, alkyl CN, cycloalkyl alkyl- cycloalkyl, cycloheteroalkyl alkyl-cye!oheteroaikyl CP ₃ , halogen, CD,, CD ₂ R, CDRR ₂ , aryl heteroaryl alkyl-aryl alk l-heteroar S0 ₂ R¾ OR, OR ₂ , Oaryl Oheteroaryl, NHR, fluorinated alkyl, difluorinated alkyl, triftuonnaied alkyl, heteroalkyl benzyl, heteroaryl benzyl (CH ₂ lieteroaryI), propanamide, dicthylpropanamide, CHjNHR; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof

{0023} Also disclosed are methods for the treatment of a neurotransmission dysfunction artd other disease states associated with mGmR4 activity in a mammal comprising the step of co-administering to the mammal at least one compound in a dosage and amount effective to treat the dysfunction in the mammal, the compound having a structure represented by formula (.! ^' }:

X is CH, C-alkyl, N, NH, N-alkyl, alkoxy, or may form a 6-mcmbcred ring with Y optionally substituted with at .least one R;Y is CH, C-alkyl, N, or may form a 6-mcmbered ring with X optionally substituted with at least one R; 2 is independently N, CH, C-atkyi, C-halogen, C-Me, C-Oatkyl, C- OMe; X _s is O or C-Ri; X ₂ is O or C-R?;, R is independently H, halogen, CN, Me, alkyl alkoxy, OMe, aryl, heteroaryl alkyl-aryl, aikyS-heteroaryS. cycioalkyi, aikyl-cycioalkyi; R _t is independently I

alkoxy, amino, alkyi-alkoxy, alkyl CN, cycioalkyi, alk l-ey oaik cyeioheteroaikyL alkyi- ey oheteroalkyl CF ₃ , halogen, CD.;, CD ₂ R, CDRR , CQNR ₃ R.t, aryl heteroaryl, alkyl-aryl, alkyl- heteroaryl, S0 ₂ R ₂ , OR, OR ₂ , Oaryl,. Oheteroaryi NHR, RjRi, fiuorinated alkyl, difluorinated alkyl trifluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CHjheteroaryl), propanamide,

diethylpropanamide, C¾CO R ₃ R Cf¾NHR; CFbNH ^; R ₂ is mdependentiy H, alkoxy, amino, alkyi-alkoxy, alkyl, CN, cycioalkyi alkyl-cycloalkyl, cycloheieroalkyi, alkyl-cyclobeteroalkyl, CFj, halogen, CDs, CD ₂ R, CDRR, , CONR,R ₄ , aryl heteroaryl alkyl-aryl, alkyl-heteroaryl, S0 ₂ R _s , OR, 0¾ , Oaryl, Oheteroaryi, NHR, NR3R , fiuorinated alkyl, difluorioated alkyl, tri fiuorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (Cf¾beteroaryl), propanamide, diethylpropanamide, CH2CONR.3R4,

CHjNHR; CH ₂ NHR ₃ R ₄ ; ¾ is H, alkoxy, amino, alkyi-aikoxy, alkyl, CN, cycioalkyi alkyl-cycloalkyl cycloheteroalkyl, alkyi-cycioheteroalkyl CFs, halogen, CDs, CD3R, CDRRj, aryl heteroaryl alkyl-aryl, alkyl-heteroaryl, S0 ₂ R ₂ , OR, OR¾ Oaryl Oheteroaryi, NHR, fiuorinated alkyl, difluorinated alkyl trifluorinated alkyl, heteroalkyl benzyl, heteroaryl benzyl (CH ₂ heteroaryl), propanamide,

dietfayipropanamide, CH _? .NHR; is H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycioalkyi alkyl- cycloalkyl cycloheteroalkyl, alkyi-cycioheteroalkyl CF _¾ halogen, CD ₃ , CDjR, CDRRj, aryl,

heteroaryl, alkyl-aryl, alkyl-heteroaryl, S0 ₂ R ₂ , OR, OR ₂ , Oaryl O eteroaryl, NHR, fiuorinated alkyl, difiuorinated alkyl iftuorinatcd alkyl, heteroaikyl, benzyl, heteroaryi benzyl (C¾he!eroaryl), propanaoiide, diethylpropanamide, C'HjNHR; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof with a drug having a known side-effect of increasing metaboiropic glutamate receptor activity.

{0024} Also disclosed are methods for the treatment of a neurotransmission dysfunction arid other disease states associa ted with mGlu.R4 activity in a mamma.! comprising the step of co-administering to the mammal at least one compound in a dosage d amount effective to treat the dysfunction in the mammal, the compound having a structure represented by formula (I):

X is C C-alkyl N _« NH, N-alkyl, alkoxy, or may form a 6-membered ring with Y optionally

substituted with at least one R; Y is CH, C-alkyl, N, or may form a 6-membered ring with X optionally substituted with at least one R; Z is independently N„ CH, C-alkyl, Ohalogen, O e, C-Oalkyl C- O e; Xt is O or C-Rr, X ₂ is O or C-Rj; R is independently H, halogen, CN, Me, alkyl, alkoxy, OMe, aryl, heteroaryi, a!ky!-aryl alkyl-heteroaryl, cyeloalkyl alkyl-cycloalkyl; R _} is independently H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cyeloalkyl alkyl-cycloalkyl. cycloheteroalkyl. alkyl- cycloheteroalkyl, CF _¾ halogen, C¾, 0¾R, CDRRj, CONR ₃ ¾, aryl, heteroaryi, aikyS-aryl, alkyl- heteroaryi, S<¾R ₂ , OR, 0¾, Oary!, Oheteroaryl, NHR, NR3R4, 6uorinated alkyl difiuorinated alkyl, trifluormated alkyl, heteroaikyl, benzyl, heteroaryi ^' benzyl (CHjheteroaryl), propanamide,

diethylpropanamide, CHjCONRjR*; CH2NHR; CI-fc HRsR,; R> is independently H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cyeloalkyl, alkyl-cycloalkyl, cycloheteroalkyl, aikyl-eycloheteroaikyl, CPs, halogen, CD ₃ , CD ₃ R, CDRR CONR3R4, ary!, heteroaryi, alkyl-aryl alk i-heteroaryL SO2R1, OR, OR OaryL Oheteroaryl NHR, NR ₃ R , fluorinat.ee! alkyl, difiuorinated alkyl, trifluorinat.ee! alkyl, heteroaikyl, benzyl, heteroaryi benzyl (CHjheteroaryl), propanamide, diethylpropanamide, CH3CONR3R ,

CH JNHR; CH2NRR3R4; R? is H, alkoxy, amino, alkyl-alkoxy, alkyl CN, cyeloalkyl, alkyl-cycloalkyl, cycloheteroalkyl, alkyl-cycloheteroalkyl, CF<, halogen, CD ₃ , CD ₂ R, CDR¾, aryi, heteroaryi, alky!-aryl alkyl-heteroaryl, SOsRj, OR, OR ₂ , Oaryl, Oheteroaryl, NHR, fiuorioated alkyl, difiuorinated alkyl, trifluorinated alkyl, heteroaikyl, benzyl, ^' heteroaryi benzyl (CHjheteroaryl), propanaimde,

diethylpropanamide, C¾ H ^' R; ¾ is H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cyeloalkyl alkyt- cyctoaikyl, cyclohcteroaikyl, alkyl-cyclohetoroaikyl, CF _¾ halogen, CD ₃ , CDjR, CORK* aryl, heteroaryi alkyi-aryL alkyl-heteroaryl, S<¼R¾ OR, OR¾ Oaryl, O ^' heteroaryl, NHR, fluoriaated alkyl difiuorinat d alkyl, rriftuonnated alkyl, hctcroalkyl, benzyl, heteroary! benzyl (CH¾heteroaryl), propanamide, diethylpropanamide., C¾NHR; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivati ve thereof with a dntg known to treat a disorder associated with increasing meiaboiropic giutamate receptor activity,

[0025] Also disclosed are methods for the treatment of a neurotransmission dysfunction and other disease states associated with mGluR4 activity in a -mammal eooiprising the step of co-administering to the m mma t at least one compound in a dosage and amount effective to treat the dysfunction in the mammal, the compound having a structure represented by a Also disclosed are methods for the treatment of a neurotransmission dysfunction and other disease states associated with raGiuR4 activity in a mammal comprising the step of co-administering to the mammal at least, one compound in a dosage and amount effective to treat the dysfunction in the mammal, the compound having a structure represented by formula (I):

X is CH, O-alkyl N, NH, -alkyl alkoxy, or may form a 6-membered ring with Y optionally substituted with at least one R; Y is CH, C-alkyl, ^' N, or may form a 6-membered ring with X optionally substituted with at least one R; Z is independently N„ CH, C-alky ^' L C-halogen, C-Me, C-Oalkyl C-

OMe; X, is 0 or C-R,; X ₂ is O or <¾; is independently II, halogen, CN, Me, alkyl, alkoxy, GMe, aryl, heteroaryi, alkyl-aryl, alky! -heteroary!, cycioaikyl, alky! -cycioaikyl; Rj is independently H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycloalkyL alkyl-cyeioalkyL cycloheteroalkyl aUcyl- cycloheteroalkyl CF ₃ , halogen, CI¼, CD ₂ R, CDRR ₂ , CONR.3R4, aryl, lieteroaryl, alkyl-aryl, alkyl - heteroaryi, SOjRj, OR, OR ₂ , OaryL Oiieteroaryl, NHR, NR3R4, fluoriualed alkyl dirktorinated alkyl, fcifluorroated alkyl, hetero&lkyl, benzyl, heteroaryi benzyl {CHsheteroaryl), propanamide,

diethylpropanamide, GffaCONlU CH ₂ NHR; CH ₂ NHR ₃ R ₄ ; R ₂ is independently H, alkoxy, amino, alky!-a!koxy, alkyl CN, cycloalkyL alkyl-cyc!oa!kyl cycloheteroalkyl, alkyl-cycloheteroalliyl, <¾ halogen, CD ₃ , CDjR, CDRRj, CONR ₃ R ₄ , aryl, heteroaryi, alkyl-aryl, alkyl-heteroaryl SO,R _t , OR, OR$,

OaryL Oheteroaryl NHR. NR3R4, fluorinated alkyl, difinorinated alkyl, trifiuorinated alkyl, heteroalkyL benzyl heteroaryl benzyl (CBjhcteroaryl), propaiiaraide, dicthylpropanamidc, CHjCONRsR*,

CHjNHR; CH ₂ NHR R ; R _} is H, alkoxy, amino, alkyl-alkoxy aik l, CN, cydoalkyl, alkyt-cydoalkyl cyclo!ieieroatky!, alkyl-cycloheteroalkyi, CPs, halogen, CDs, Q¾R, CDRRj, aryi, bcteroaryi, alkyl-aryl, alkyl-heteroary SO ₂ R ₂ , OR, OR _¾ Oaryl Oheteroaryl NHR, fluorinaied aikyl di fluorinaied aikyl, triffuorinated aikyl, heteroalkyl benzyl, heteroaryl benzyl (C¾heieroaryl), propanamide,

dierjiylpropanamide, CMj ^' NHR; R4 is H, alkoxy, amino, alkyl-alkoxy, aikyl CN, cycloalkyl, alkyi- cycloalkyl, eyeSoheteroalkyl, alkyl-cy oheteroalkyl, CPs, halogen, C s, CDiR, CDRRj, aryl bcteroaryi, alkyl-aryl, alkyl-heteroaryl, SO2R.2, OR, OR2, Oaryl, Oheteroaryl, NHR, fluorinaied aikyl, difluorinated alky!, tri fluorinaied aikyl heteroalkyl, benzyl, heteroaryl benzyl (CHjiieteroaryl}, propanamide, diethylpropanamide, Cf¼.NHR; or a pharmaceutically acceptable sal t thereof or a pharmaceutically acceptable derivati ve thereof with a drug known to treat the neurotransmission dysfunction or other disease states.

[0026] Also disclosed are kits comprising a compound having a structure represented by Also disclosed are methods for the treatment of a neurotransmission dysfunction and other disease states associated with raGluR4 activity in a mammal eomprisiog the step of co-administering to the mammal at least one compound in a dosage and amount effective to treat the dysfunction in the mammal, the compound having a structure represented by formula (Ϊ):

X is CM, C~a!kyi, N, NH, N-alkyl, alkoxy, or may form a 6-roenihered ring with Y optionally substituted with at least one R; Y is CH, C-alkyl, N, or may form a 6-raembered ring with X optionally substituted with at least one R; Z is independently N, CH, C-alkyl, C-halogen, C-Me, C-Oalkyl, C-

QMe; i is O or OR-. ; X ₂ is O or C-R ₃ ; R is independently H, halogen, CN, Me, aikyl alkoxy, OMe, ary ^; i, heteroary-'!, alkyl-aryl, alkyl-heteroaryL cycloalkyl, a!kyl-cycloalky!; R _} is independently H, alkoxy, amino, aikyi-alkoxy, aikyl CN, cycloalkyl, alkyl-cycioa!kyL cyeloheteroalkyl, aikyl- cyeloheteroalkyl, CF _;5 , halogen, CD ₅ , CD ₂ R, CDRR ₂ , CONR ₃ R4, aryl, heteroaryl, alkyl-aryl, alkyl- iieieroaryl SO;R _; >, OR, OR?, OaryL Oheteroaryl, NHR, NR ₃ R ₄ , fiuorinated aikyl, difluorinated aikyl, trifluorinated aikyl, heteroalkyl, benzyl, heteroaryl benzyl (CHjheteroaryl), propanamide,

diethylpropanamide, CH2CO R ₃ R ₄ ; CHjNHR; CH2NHR3R ; Rj is independently H, alkoxy, amino, alky!-a!koxy, alkyl, C , cycloalkyl, alkyl-cycloalkyi cycloheieroalkyl, alkyi-cyelohcteroalkyl 0¼ _> halogen., CD ₃ , CD ₂ R, CDRR _S> CONR ₃ R ₄ , aryl, heteroaryi, alkyl-aryl, alkyl -heteroaryi, SOjR _t , OR, OR$ _> Oaryl, Oheteroary ^' l, NHR, N .R4, fiuorinated alkyl, difluormated alkyl, trifitjorinat d alkyl heteroalkyl, benzyl heteroaryi benzyl (CHjheteioaryl), propanamide, dieihylpropanamide, CH ₂ CONR ₃ R ₄ ,

CHjNHR; CH ₂ NHR ₃ R ₄ ; R3 is H, alkoxy, amino, alkyl-alkoxy, aikyl, CN, cycloalkyl, alkyl-cycioalkyl, cycloheteroalkyl, alkyl-cycloheteroalkyl CF ₃ , halogen, CO,, CDjR, CDRRj, aryi, heteroaryi, alkyl-aryl, alkyl-heteroaryl, SO2R2, OR, OR ₂ , Oaryl, Qheteroaryi NHR, fluorinated alkyl, difluorinated alkyl trifloorinated alkyl, heteroalkyl, benzyl, heteroaryi benzyl (CHjheteroaryl), propanamide,

dierhylpropauamide, CHjNHR; 4 is H, alkoxy, amnio, alkyl-alkoxy, aikyl, CN, cycloalkyl alkyl- eycloalkyl cycloheteroalkyl, aikyl-eyeloheteroaikyl CF _S , halogen, CD ₃ , C.D ₂ R, CDRR ₂ , aryl heteroaryi, alkyl-aryl alkyl-heteroaryl, S0 ₂ R ₂ , OR, OR ₂ , Oaryl, Oheteroaryl, NHR, fiuorinated aikyl, difluorinated alkyl, trifluorinated alkyl, heteroalkyl, benzyl, heteroaryi benzyl (CH ₂ heteroaryl), propanamide, diefhylpropanamide, CH ^' jNHR; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof, and one or more of a drug having a known side-effect of increasing metabotropic glutamate receptor activity, a drug known to treat a disorder associated with increasing metabotropic glutamate receptor activity, and/or a drug known to treat the neurotransmission dysfunction.

{0027} Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained b means of the elements and

combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restricti ve of the in vention, as claimed.

^' DESCRIPTION

{0028} The present invention can be understood more readily by reference to the following detailed description of the inventio and the Examples included therein.

(00291 Before the present compounds, compositions, articles, systems, devices, and/or methods are disclosed and described, it is to be understood thai they are not limited to specific synthetic methods unless otherwise specified, or to particul r reagents unless otherwise specified, as such may, of course, vary . It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

- Ϊ 6 - [0030] All publications mentioned herein, are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing dare of t he present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication pro vided herein can be different from the actual publication dates, which need to be independently confirmed.

A. Definitions

{00311 As used to the specification and the appended claims, the singular forms *V "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a functional group," "an alkyl," or "a residue" includes mixtures of two or more such functional groups, alkyls, or residues, and the like.

{0032} Ranges can be expressed herein as from "about" one particular value, and or to "about" another partieuiar value. When such a range is expressed, a further aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as

approximations, b use of the antecedent "about," it will be understood that the particular value forms a further aspect, it will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpotnt, and independently of the ot her endpoint. it is also understood thai there are a number of values disclosed herein, and that each value is also herein disclosed as "about" that particular value in addition to the value itself For example, if the value "10" is disclosed, then "about 10" is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if i and 15 arc disclosed, then 1 1, 12, 13, and 14 are also disclosed.

{0033J As used herein, the terms "optional" or "optionally" means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

{0034} As used herein, the term "receptor positive ailosteric modulator" refers to any exogenous!}' administered compound or agent that directly or indirectly augments the activity of any form (for example, homomeric, heteromeric, o!igomerie, or interacting with other proteins or cellular components) of the receptor i n the presence or i n the absence of the endogenous Hgand (such as glutamate, L-scrine O-phosphate (L-SOP), other endogenous ligands, other neurotransmitters, etc.) in an animal, in particular a. mammal, for example a human. The term "receptor positive ailosteric modulator" includes a compound that is a "receptor ailosteric potentiator" or a "receptor ailosteric agonist," as well as a compound that has mixed activity as both a "receptor ailosteric potentiator" and an "mGlu receptor ailosteric agonist." [0035] As used herein, the term "receptor ailosteric potentiator" refers to any exogenonsSy

admittistered compound or agent that directly or indirectly augments the response of any form {for example, homoraeric, heterotnerte, oligomeric, or interacting with other proteins or cellular components) of the receptor produced by the endogenous hgand (such as glutamaie, L-serine O- phosphate (L-SOP), other endogenous iigands, other neurotransmitters, etc.) when it hinds to an aliostefic site of any form of receptor in an animal, in particular a mammal, for example a human. The receptor aUosterie potentiator binds to a site other than the orthosterie site (an ailosteric site) and positively augments the response of the receptor to an agonist. As it is predicted to induce less desensittzation of the receptor, activity of a compound as a receptor ailosteric potentiator provides advantages over the use of a pure receptor aUosterie agonist. Such advantages can include, for example, increased safety margin, higher tolerabihty, diminished potential for abuse, and reduced toxicity.

{0036} As used herein, the terra "receptor aUosterie agonist" refers to any exogenously administered compound or agent th t directly augments the activity of any form (for example, homoraeric, fieteromerie, oligomeric, or interacting with other proteins or cellular components) of the receptor in the absence of the endogenous !igand (such as glutamate, L-serine Q-phosphate (L-SOP), other endogenous Iigands, other neurotransmitters, etc) in an animal, in particular a mammal, for example a human. The receptor aUosterie agonist binds to the aliostcric glutamate site of the receptor and directly influences the orthosterie site of the receptor, the term "receptor positive ailosteric modulator" refers to any exogenously administered compound or agent that directly or indirectly augments the activity of the receptor in the presence or in the absence of the endogenous iigand ( such as glutamate, L-serine O- phosphate (L-SOP). other endogenous iigands, other neurotransmitters, etc.) in an animal, in particular a mammal, for example a human. The term "receptor positive ailosteric modulator" includes a compound that is a "receptor ailosteric potentiator" or a "receptor ailosteric agonist," as well as a compound that has mixed activity as both a "receptor aliostcric potentiator" and an "raGluR receptor ailosteric agonist,"

{0037} in some aspects of the disclosed methods, the subject has been diagnosed with a need for treatment of one or more neurological and/or psychiatric disorder and/or any other disease state associated with glutamate dysfunction prior to the administering step, in some aspects of the disclosed method, the subject has been diagnosed with a need for potentiation of metabotropic glutamate receptor activity prior to the administering step, in some aspects of the disclosed method, the subject has been diagnosed with a need for partial agonism of metabotropic glutamate receptor activity prior to the administering step. In some aspec ts, the disclosed methods can further comprise a step of identifying a subject having a need for treatment of a disclosed disorder. [0038] As used herein, the term "GrcatracnC refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.

{0039} As used herein, the term "prevent' ^' or "preventing" refers to precluding, averting, ob viating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressl disclosed.

{0040} As used herein, the term "diagnosed" means having been subjected to a physical examination by a person of skill, for example, a physician, and found to ha ve a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein. For example, "diagnosed with a disorder treatable by potentiation of mGiuR.4 activity" means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by a compound or composition that can favorably potentiate mGluR4 activity. As a further example, "diagnosed with a need for potentiation of mGluR4 activity" refers to having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition characterized by abnormal mGluR4 activity. Such a diagnosis can be in reference to a disorder, such as Parkinson's disease, and the like, as discussed herein.

[0041 { As used herein, the phrase "identified to be in need of treatment for a disorder," or the like, refers to selection of a subject based upon need for treatment: of the disorder. For example, a subject can be identified as having a need for treatment of a disorder (e.g., a disorder related to t»GluR4 acti vity) based upon an earlier diagnosis by a person of skill and thereafter subjected to treatment for the disorder. It is contemplated that the identification can, in one aspect, be performed by a person different from the person making the diagnosis, it i also contemplated, in a further aspect, that the

administration can be performed by one who subsequently performed the administration. As used herein, the terra "receptor allostcric agonist", as used herein, is generally defined as a ligand that functions as both an allosteric oioduiator and as an agonist on its own (though the iatter is usually onl at higher concentratious).

{0043} As used herein, the term "diagnosed with a need for potentiation of meiabotropic glutamate receptor activity" refers to having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by potentiation of metabotropic glutamate receptor activity.

[0044] As used herein, "diagnosed with a need for partial agonism of metabotropic glutamate receptor activity" means having been, subjected to a physical examination, by a person of skill, for example, a physician, and found to ha ve a condition that can be diagnosed or treated by partial agonism of metabotropic glutamate receptor activity,

[0045] As used herein, "diagnosed with a need for treatment of one or more neurological and/or psychiatric disorder or any disease state associated with glutamate dysfunction" means having been subjected to a physical examination by a person of skill for example, a physician, and .{bund to have one or more neurological and or psychiatric disorder associated with glutamate dysfunction.

{0046} As used herein, the terms "administering" and "administration" refer to an method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled, in tie art and include, but are not limited to, oral administration, transdermal administration,

administration b inhalation, nasal administration, topical administration, hitravaginal administration, ophthalmic administration, intraaura! administration, intracerebral administration, rectal administration, and parenteral administration, including injectable such as intravenous administration, intra -arterial, administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition, in further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0047] As used herein, the term "effective amount" refers to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a "therapeutically effective amount" refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on. undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder: the specific composition employed; the age, body weight, general health , sex and diet of the patient.; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with, the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved, if desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or suhtmtltiples thereof to make up the daily dose. The dosage can he adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products, in further various aspects, a preparation can be administered in a "prophylactic-ally effective amount"; that is, an amount effective for prevention of a disease or condition.

j00 8| As used herein, the term "pharmaceutically acceptable carrier" refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for

reeonstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, soivents or vehicles include water, ethanol, poiyois (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethyleellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured b the inclusion of various antibacterial and antifungal agent such as paraben, chlorobutanol, phenol, sorbic acid and die like. It can also he desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum -monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming mieroencapsnle matrices of the drug in biodegradable polymers such as polylactide- polyglyeolide, poly(orthoesters) and poSy(auhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemitlsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers. (00 A residue of a chemical species, as used in the specification and concluding claims, refers to the moiety that is the resulting product of the chemical species in & particular reaction scheme or subseq uent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more - O H ₂ CH ₂ O- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more - O(CH;) _s CO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.

[0050] As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranehed, carbocyclic and heterocyclic, and aromatic and nonaroraatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. In other words, all substitutions are "independent." For example, "substituted with at least one R" means that each R group is independent from the other one, and as such may be the same or different. For purposes of this disclosure, the heteroatoms, such, as nitrogen, c an have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms "substitution" or "substituted with" include the implicit proviso that such substitution is tn accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cycUzation, elimination, etc.

[0051 J in defining various terms, ⁴ⁱ A ⁴ⁱ A ^" _} " ⁴ⁱ A ^J ," and "A ^'' " ^* are used herein a generic symbols to represent various specific substituents. ^' These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.

[t}052 ( The term "alky!" as used herei is a branched or unbranehed saturated hydrocarbon group of 1 to 24 carbon atoms, such, as methyl, ethyl, «-propyl, isopropyl, «¾ttyl, tsobutyl, s-hutvl, /-butyl, n- pentyf isopentyl, .v-pentyi, neopentyl, hexyi, heptyl, octyl, nonyl, deeyl, dodecyl, tetradecyf hexadecyl, eicosyf tetracosyf and the like. The alky} group can be cyclic or acyclic. The a kyl group can be branched or unbranehed. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, optionally substituted alkyl, eycloalkyl, aSkoxy, amino, ether, halide, hydroxy, nitro, silyl, su fo-oxo, or thiol, as described herein. A "lower alkyl" group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms.

{0053} Throughout the specification "alkyl" is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyi groups are also specifically referred to herein by identifying the specific sisbstituent(s) on the alkyi group. For example, the term "halogenated alkyl" specifically refers to an alkyl group that is substituted with one or more haiide, e.g., fluorine, chlorine, bromine, or iodine. The term "alkoxyaUcyl" specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described beiow. The term "alkylattiino" specifically refers to an alkyl group that is substituted with one or more amino groups, as described beiow, and the like. When "alkyl" is used in one instance and a specific term such as "alkylalcohol" is used in another, it is not meant to imply that the term "alkyl" docs not also refer to specific terms such as "alkylalcohol" and the like.

[0054] This practice is also used for other groups described herein. That is, while a term such as "cycloalkyi" refers to both unsubstituted and substituted cycloalkyi moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyi can be referred to as. e.g. , an "aikyleycioaikyt" Similarly, a substituted alkoxy can be specifically referred to as, e.g., a "halogenated alkoxy," a particular substituted alkenyl can be, e.g., an "aikenylalcohol," and the like. Again, the practice of using a general term, such as "cycloalkyi," and a specific term, such as "alkyieyeloalkyt" is not meant to imply that the general term does not also include the specific term.

[0055] The term "cycloalkyi" as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyi groups include, but are not limited to, cyelopropy!, cyclobutyl, eyclopentyi, eye!ohexyi, norbonryl, and the like. The term 'lieterocycloalkyi" is a type of cycloalkyi group as defined above, and is included within the meaning of the term "cycloalkyi," where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyi group and heterocyeloalkyi group can be substituted or unsubstituted. The cycloalkyi group and heterocyeloalkyi group can be substituted with one or more groups including, but not limited to, optionally substituted alkyl cycloalkyi, alkoxy, amino, ether, haiide, hydroxy, nitre, sifyi, sulib-oxo, or thiol as described herein.

|0O56[ The term "polyalkylene group" as used herein is a group having two or more C¾ groups linked to one another. The polyalkylene group can be represented by a formula «¾)*· , where "a" is an integer of from. 2 to 500.

[0057] The terms "alkoxy" and "alkoxy 1." as used herein to refer to an alkyi or cycloalkyi group bonded through an ether linkage; that is, an "alkoxy ^" " group can be defined as OA ¹ where A ^} is alkyl or cycloalkyi as defined above. "Alkoxy" also includes polymers of alkoxy groups as just described; that is, an alkoxy can he a polyeihcf such as OA ¹ OA or OA ¹ (OA ² ) _a - OA ³ , where "a" is an integer of from I to 200 and A', A ^" , and A ^'! are alkyl and/or cyeloalkyl groups.

{0058} The term "alkenyl" as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A'A^C-CCA'A*) arc intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C-C. The alkenyl group can be substituted with one or more groups including, but not limited to, optionally substituted alkyl, cyeloaikyl, alkoxy, alkerryi, cyeloaikerryi, aikynyl, cycioalkynyl, aryl, heieroaryl, aldehyde, amino, carboxylic acid, ester, ether, haiide, hydroxy, ketone, azide, nitro. silyl, sulfo-oxo, or thiol, as described herein.

{0059} The term "cycloalkeriyF ^' as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e. , OC. Examples of cycloaikenyl groups include, but are not limited to. cyclopropenyl, cycSobirtenyl, cyclopentenyl, cyclopentadienyl, eyclohexenyl, cyclohexadienyl, norbomenyl, and the like. The terra

"heterocycioaikenyT is a type of cycloaikenyl group as defined above, and is included within the meaning of the term "cycloaikenyl " where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloaikenyl group and heterocyeioalkenyi group can be substituted or nnsubstituted. The cycloaikenyl group and heterocycloalkcnyl group can be substituted with one or more groups including, but not limited to, optionally substituted alkyl, cyeloalkyl, alkoxy, alkenyl, cycloaikenyl, aikynyl, cycioalkynyl, aryl, lieteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halkle, hydroxy, ketone, azide, nit.ro, silyl, sulfo-oxo, or thiol as described herein.

{0060} The term "alkynyf as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The aikynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, optionally substituted alkyl, cyeloalkyl, alkoxy, alkenyl, cycloaikenyl, aikynyl, cycioalkynyl aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, haiide, hydroxy, ketone, azide, uitro, silyl, sulfo-oxo, or thiol, as described herein.

{0061} The term "cycioalkynyl" as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound. Examples of cycioalkynyl groups include, but are not limited to, eycioheptynyL cyeiooctynyi, eyc!ononynyi, and the like. The term "heterocycloalkynyl" is a type of cycloaikenyl group as defined above, and is included within the meaning of the term "cycioalkynyl," where at: least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not: limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyi group and heteroeycloalkyiiyl group can he substituted or uusubstituted. The cycS.oalky.oyS. group aod heterocycloalkynyi group caa be substituted with one or more groups including, but not limited to, optionally substituted alkyl, cycloalkyl, aikoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyi, aryl. heteroaryl, aldehyde, amino, carboxyiie acid, ester, ether, halide, hydroxy, ketone, azide, nitro. silyi. sulfo-oxo, or thiol as described herein.

[ _. 0062] The term "aryF as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, phenoxybenzene, and the like. The term "ar r aiso includes "heteroaryl," which is deiioed as a group that contains an aromatic group that has at least one heteroaiom incorporated within, the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus. Likewise, the term "aon-heteroaryl,' ^' which is also included in the term "aryl," defines a group that contains an aromatic group that does not contain a heteroatom. The aryl group can be substituted or ^substituted. The ary! group can be substituted with one or more groups including, but not limite to, optionally substituted alkyl, cycioaikvl, aikoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyi, aryl, heteroaryl, aldehyde, amino, carboxyiie acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyi sulfo-oxo, or thiol as described herein. The term "biaryP is a specific type of aryl group and is included in the definition of"aryl." Biaryi refers to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon, bonds, as in biphenyl.

[0063] The term "aldehyde" as used herein is represented by a formula— C(0)H. Throughout this specification "C(0>" is a short hand notation for a carbonyl group, i.e., C=0.

j¾064j The terras "amine' ⁵ or "amino" ⁵ as used herein are represented by a formula N A ^f A' ^: A ^" , where A ¹ , A ² , and A ^' can be, independently, hydrogen or optionall substituted alkyl cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyi, aryl or heteroaryl group as described herein.

[0065] The term "carboxyiie acid" as used herein is represented by a formula ~~C(O)OH.

[0066J The term "ester" as used herein is represented by a formula— OC(0)A ¹ or— Cf 0)0 A , where A ^! can be an optionally substituted alkyl, cycloalkyl alkenyl, cycloalkenyl, alkynyl,

cycloalkynyi, aryl, or heteroaryl group as described herein. The term "polyester" as used herein is represented by a formula→ ^" A k3(0)C~A ⁵ ~C(0)0) _a ~- or— A ^l O(0)C-A ² -OC(0)) _¾ --, where A ¹ and A ³ can he, independently, an optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl alkynyl cycloalkynyi, aryl, or heteroaryl group described herein and "a" is an integer from 1 to 500, "Polyester" is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxyiie acid groups with a compound having at least two hydroxy! groups. pMH>7] The term "ether" as used herein is represented by a formula ΑΌΑ\ where A ^! and A ² can he, uidependentfy, an optionally substituted a!kyl, eycloalkyl, alkenyl, cycioalkenyi, alkynyk cycloalkynyi, aryl, or heteroaryl group described herein. The term "po ^' lyether" as used herein is represented by a formula— (A ^l O-AO) _a — , where A ^f and A" can be, independently, an optionally substituted alkyl, eycloalkyl, alkenyl, cycioalkenyi, alkynyl, cycloalkynyl, aryl, or heteroary} group described herein and "a" is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0068] The term "halide" as used herein refers to the halogens fluorine, chlorine, bromine, and iodine.

{0069} The terra "heteroeycle," as used herein refers to single and multi-cyclic aromatic or non- aromatic ring systems in which at least one of the ring members is other than carbon. Heierocyele includes pyridinde, pyrimidme, furan, thiophene, pyrrole, isoxazole, isothiazolc, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1 ,2,5 -o adi azoic and 1,3,4- oxadiazole,thiadiazoie, including, i,2,3-tliiadiazole, 1 ,2,5-thiadiazoie, and 1 ,3,4-thiadiazoie, triazole, including, 1 ,2,3-triazo!e, 1 ,3,4-triazoie, telrazole, including 1,2,3,4-tetrazoie and 1 ,2,4,5-tetrazole, pyridine, pyridazine, pyrimidine, pyrazme, triazine, including .1 ,2,4-triazme and 1,3,5-triazme, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholirte, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like.

(0 7 ^β { The term ^hydroxyT as used herein is represented, by a formula— OH.

{Θ071| The term "ketone" as used herein is represented by a formula A'CiO A ⁵ , where A ¹ and A ^* ' can be, independently, an optionally substituted alkyl, eycloalkyl, alkenyl cycioalkenyi, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

(0072J The term "azide" as used herein is represented by a formula—-K ,

[00731 The term "nitro" as used herein is represented by a formula NO?.

f0074| The terra "niirile" as used herein is represented by a formula— C .

{0075} The term "silyl" as used herein is represented by a formula— SiA'A ^' A*, where A\ A and A' can be, independently, hydrogen or an optionally substituted alkyl, eycloalkyl, alkoxy, alkenyl, cycioalkenyi, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

00?6] The terra "sulfo-oxo" as used herein is represented by a formulas— S(0)A' ,— S(OjjA ' ,— OS(0)jA ¹ , or— OSiOjOA', where A ^! can be hydrogen or an optionally substituted alkyl, eycloalkyl, alkenyl, cycioalkenyi, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. Throughout this specification "S(O)" is a short hand notation for S-O. The term "sulfonyl" is used herein to refer to the sulfo-oxo group represented by a formula S(OhA ^! , where A ^! can be hydrogen or an optionally substituted alkyl, cydoaikyi aikenyi, eycioaikeoyl, alkynyl, cycloalkynyl, aryi, or beteroarvi group as described herein. The term "sulfone" as used herein is represented by a formula A'Sf ^' QlsA", where A ¹ and A" can be, independently, an optionally substituted alkyl, cycloalkyl, aikenyi, cycloalkenyi, alkynyl, cycloalkynyl, aryi, or heteroaryl group as described herein. The term "sulfoxide" as used herein is represented by a f rrauia A'SfOiA ^" where A ¹ and A can be, independently, an optionally substituted alkyl, cycloalkyl, aikenyi cycloalkenyl, alkynyl, cycloalkynyl, aryi, or heteroaryl group as described, herein.

[00771 The term "thiol" as used herein is represented by a formula™~SH.

{0078} The term " ^" organic residue" defines a carbon containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-eoiitainmg groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkySs, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc. Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect, an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms

[0079] A very close synonym of the term '"residue" is the term "radical which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4-fhiazolidinediotie radical in a particular compound has the structure

regardless of whether thiazolidinedione is used, to prepare the compound. In some aspects the radical (for example art alkyl) can be further modified (i.e., substituted alkyl) by having bonded thereto one or more "substituent radicals," The number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.

|O080{ "Organic radicals," as the term is defined and used herein, contain one or more carbon atoms. An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, .1 -6 carbon atoms, or 1-4 carbon atoms, in a further aspect, an organic radical can have 2-26 carbon atoms, 2- 18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic .radical One example, of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8Heirahydro-2~naphthyl radical. n some aspects, an organic radical can contain 1 -iO inorganic heteroatoms bound thereto or therein, including halogens, oxygen, suifor, nitrogen, phosphorus, and the like. Examples of organic radicals include but arc not limited to an alk l, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di-substituted amino, aeyloxy, cyano, earhoxy, carboalkoxy, alkylearboxamide, substituted alkylearboxamide, di alkylearboxamide, substituted dialkylcarboxanikle, alkylsulfonyl, alkylsulfiuyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, ha!oa!kyt, haloalkoxy, aryl substituted aryl, heteroaryL heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non-limiting examples of organic radicals that include heteroatoms include alkoxy radicals, trifiuoromethoxy radicals, acetoxy radicals, dtmethylatnioo radicals and the like.

[0081] "Inorganic radicals " as the term is defined and used herein, contain no carbon atoms and therefore comprise only atoms oilier than carbon. Inorganic radicals comprise bonded combinations of atoms selected from hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens such as fluorine, chlorine, bromine, and iodine, which can be present individually or bonded together in their chemically stable combinations. Inorganic radicals have 10 or fewer, or preferably one to six or one to four inorganic atoms as listed above bonded together. Examples of inorganic radicals include, but not limited to, amino, hydroxy, halogens, nitro, thiol sulfate, phosphate, and like commonly known inorganic radicals. The inorganic radicals do not have bonded therein die metallic elements of the periodic table (such as the alkali metals, alkaline earth metals, transition metals, fanthanide metals, or actinide metals), although such metal ions can sometimes serve as a pharmaceutically acceptable cation for anionic inorganic radicals such as a sulfate, phosphate, or like anionic inorganic -radical. Typically, inorganic radicals do not comprise metalloids elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gas elements, unless otherwise specifically indicated elsewhere herein,

[80821 The term "pharmaceutically acceptable" describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

f 00831 As used herein, the term "derivative" refers to a compound having a structure derived from the structure of a parent compound (e.g., a compounds disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives incl ude salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

{0084} The term "hydmiysabie residue" is meant to refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions. Examples of hydrolysabie residues include, without limitation, residues of acid haiides or activated carboxylic acids, residues of

tria.lkyJsilyl haiides, residues of alkytoxymeth l haiides, and various other protecting groups known in the art (see, for example, "Protective Groups in Organic Synthesis," T. W. Greene, P. G. M. Wuts, Wiley-lnterscience, 1 99).

[0085] The term "leaving group" refers to art atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons. Examples of suitable leaving groups include sulfonate esters, including, but not limited to, inflate, mesylate, tosylate, brosylate, and haiides.

[0086] Compounds described herein can contain one or more double bonds and, thus, potentially give rise to eis/trans (E/Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.

{0087} Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and

diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and. thus, potentially give rise to diastereomers and opttcat isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomcrs, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic

procedures used to prepare such compounds, or in using racemization or epimerization proeedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers. Additionally, unless expressly described as "unsubstituted", all substituents can be substituted or itnsuhstituted.

[0088] In some aspects, a structure of a compound can be represented by a formula:

^• i> . which is understood to be equivalent to a formula:

wherein n is typically an integer. That is, R ^" is understood to represent five independent substituents, R' ^!i¾) , Κ" ^ίιϊ) , R . By 'Independent substituents " it is meant that each R substituent can be independently defined. For example, if in one instance R" ^<ai is halogen, then R" ^bi is not necessarily halogen in iiiai instance. Likewise, when a group R is defined as four substituents, R is understood to represent four independent substituents, R\ R ^h , R ^e , and R ^d , Unless indicated to the contrary, the substituents are not limited to any particular order or arrangement.

|00S9| The following abbreviations are used herein. DMF: dimethyl formamide. EiOAc: ethyl acetate. THF: tetrahydrofutan. D1PEA or DIE A: dlisopropylethyJamine. HOBt: 1 - hydroxybenzotriazole. EDO 1 -e jyl-3- -dimediylammopropyl jearbodiimide hydrochloride. DM.SO: diraeihylsul&xide. DMAP: 4-Dimethylamu )pyridine. RT: Room temperature, h: Hours. Min:

Minutes. DCM: Dichloromethane. MeCN: Aceto itnle. MeOH: methanol. iPrOH: 2-PropanoL n- BuOFi: l-ButanoL

j0090| Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications thai can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specificaiiy indicated to the contrary. Thus, if a class of molecules A , B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C- D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E. B-F, and C-E would be considered disclosed. This concept applies to ail aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific aspect or combination of aspects of the methods of the invention. [0091] : is understood that: the compositions disclosed herein have certain functions. Disclosed herein are certain, structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that, can perform the same functio that are related to the disclosed structures, and that these structures will typically achieve the same result.

B, Compounds

|6 92j in one aspect, the invention relates to compounds, or pharmaceutically acceptable derivatives thereof, useful as potentiators of r»GluR4 activity. In general, it is contemplated that each disclosed deri vative can be optionally further substituted. It is also contemplated that any one or more derivative can he optionally omitted from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. t is also understood that the disclosed compounds can be employed in the disclosed methods of using. It is also understood that the disclosed compounds can all be employed as corresponding pharmaceutical compositions.

j0093| In one aspect, the invention relates to compounds having a structure represented by formula

X is CH, C-aikyi, N, NH, ^' N-alkyl, aik.oxy, or may form a 6-membered ring with Y optionally substituted with at least one R;

Y is CH, C-alk I, N, or may form a 6-membered ring with X optionally substituted with at least one R;

2 is independently K CH, C-alkyl, C-halogen, C-Me, C-Oalkyl, C-O e;

2. is 0 or C-¾;

R is independently H, halogen, C ,. Me, alkyl, alkoxy, OMe, aryi heteroaryi alkyl-aryl, alky I ~ heteroaryl , cycioaikyl, alkyl-eycloaiky!; ; is independently H, alkoxy, amino, alkyl-aikoxy, aikyl, CN, cycloalkyl, alkyl-cycloalkyl, cycloheteroalfcyl, alkyi-cycloheteroalkyl CF,, halogen, C¾, CD _? .R, CDRR ₂ , CON ₃ R ₄ , aryl,

heteroaryi, a kyl-aryl alkyl-heaeroaryl, SOjR ₂ , OR, OR _¾ Oaryl Oheteroaiyl NHR, NR3R , fluorinated alkyl, difiuorinated alkyl, trifluorinated alkyl, lieteroaikyl benzyl, heteroaryi benzyl (CH ₂ heteroaryi), propanamide, diethylpropanamide, CH ₂ CON ^" R _s R ₄ ; C¾NHR; CH ₂ NHR ₃ R _t ;

2 is independently H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycloalkyl, alk l-cycloalkyl, cycloheteroalkyl, alkyi-cycloheteroalkyl, CF ₅ , halogen, CD ₃ , CD ₂ R, CDRRu CONR5R4, aryl

heteroaryi, alkyl-aryl alkyl-heteroaryl, S0 ₂ R _} , OR, ORi, Oaryl Oheteroaryl NHR, NR ₃ R ₄ , fluorinated alkyl, difiuorinated aiky trifiuorinated alkyl, lieteroaikyl benzyl, heteroaryi benzyl (CHjheteroatyl), propanamide, diethylpropanamide, CHa !ONRjR.!, CH ₂ NHR; C-H2NHR3R4;

j is H, alkoxy, ammo, alkyl-alkoxy, alkyl, CN, cycloalkyl, alkyl-cycloalkyl, cycioheteroalkyl, alkyl-cyclohcteroalkyl, CF _¾ , halogen, CD ₃ , CD,R, CDRR3, aryl, heteroaryi, alkyl-aryl, alkyl-hcteroaryi, S0 ₂ R _2> OR, OR ₂ , Oaryl, Oheteroaryl, NHR, fluorinated alkyl, difiuorinated alkyl, trifluorinated alkyl, heteroalkyl, benzyl, heteroaryi benzyl (Cl-fcheteroaryl), propanamide, diethylpropanamide, CHjNHR

R,! is H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycloalkyl, alkyl-cycloalkyl, cycioheteroalkyl, alkyi-cycloheteroalkyl, CF _3> halogen, CD ₃ , CD ₂ R, GDRR _2j aryi, iieteroaryi, alkyl-aryl, alkyl-heteroaryf, SO2R2, OR, OR ₂ , Oaryl Oheteroaryl NHR, fluorinated alkyl, difiuorinated alkyl trifluorinated alkyl, lieteroaikyl benzyl, heteroaryi benzyl (CH ₂ heteroaryl), propanamide, djethylpropanamide, CH ₂ NHR; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof j(MK>4| Also disclosed are compounds of the following formula:

or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof

[0095J Also disclosed arc compounds of the following formula: or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof,

[0096] Also disclosed are compounds of the following formula.:

or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

wherein R _lA is H, alkyl, cvcloalkyi, alkyl-eyeloalkyl, tetrahydrofuran, tetrahydropyran, alkyi- tetrahydropyran, cyclopropy alkyl-cyclopropyi, eyclobufyl, alkyl-cyclo ^' butyl, fluoroaikyl-cyciobutyl, alkoxy, oxetari, alkyl-oxetan, thian, dioxotrtiart, alkylHtnethyldioxothiaa, hydroxy!; and wherein is H, alkyl cycloalkyl, alkyl-cyc!oaikyi propananiide, diethylpropanaraide.

0097j Also disclosed are compounds of the following formula:

[0098] The compounds disclosed herein can include ail salt forms, for example, salts of both basic- groups, inter aha, amines, as well as salts of acidic groups, inter aim, carboxylic acids. The following arc aon-liraitmg examples of anions that can form salts with protonatcd basic groups: chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, citrate, and the like. The following are non-limiting examples of cations that can form salts of acidic groups: ammonium, sodium, lithium, potassium, calcium, magnesium, bismuth, lysine, and the like.

[0099] The analogs (compounds) of the present disclosure are arranged into several categories to assist the fcrmuJator in applying a rational synthetic strategy for the preparation of analogs which are not expressly exampled herein. The arrangement into categories does not imply increased or decreased efficacy for any of the compositions of matter described herein.

C. Pharmaceutical compositions

1001001 in one aspect, the invention relates to pharmaceutical -compositions comprising the disclosed compouads. That is, a pharniaceutical composition can be provided comprising a therapeutically effective amount of at least one disclosed compound or at least one product of a. disclosed method and pharmaceutically acceptable carrier.

{OIOIJ in certain aspects, the disclosed pharmaceutical compositions comprise the disclosed compounds {including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutical ly acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants. The instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given ease will depend on the particular host, and nature and severity of the conditions for which the active ingredient: is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

101.02 j As used herein, the term "'pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present in vention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (-ic and -ous), ferric, ferrous, lithium, magnesium, manganese

(-ic and -ous), potassium, sodium, zinc- and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, a well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, argmine, betaiae, caffeine, choline, N,N - di eozylethyleoediamine, diethylaaiine, 2-dietliylaniinoethiaioL 2-dimeihylaniinoethanoi _i ethanolamine, cthyleaediamine, N-ethylmorpholine, N-ethylpiperidine, glucamrac, glucosamiae, histidine, hydrabamine, isopropylamine, lysine, niethylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, tnethySaniine, triroethyiainrae, tri propyl amine, tromeihamine and the like.

{0103} As used herein, the term "pharmaceutically acceptable non-toxic adds" includes inorganic acids, organic acids, and salts prepared merefrom, for example, acetic, benzenes lfonic, benzoic, camphorsulfomc, citric, ethanesulfomc, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethiomc, lactic, maleic, malic, mandelic, methanesulfonic, mucie, nitric, paraoie, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toiuetiesulfooic acid and the like. Preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids,

{0104} In practice, the compounds of the invention, or phamiaeeutically acceptable sails thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in- arer emulsion or as a ater-in-otl liquid emulsion. In addition to the common dosage forms set out above, the compounds of the invention, and/or pharmaceutically acceptable salt(s) thereof can also be administered by controlled release means and/or delivery devices. The compositions can be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients, in general, the compositions are prepared by uniformly and intimatel admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation,

(01O5| Thus, the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the compounds of the invention. The compounds of the invention, or pharmaceutically acceptable salts thereof can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds. The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.

Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia. magnesium stearate. and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

|0I06{ in preparing the compositions for oral dosage form, arty convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservati ves, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, roieroerystailine cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, aad the like can be used to form orai solid preparations such as powders, capsules and tablets. Becau se of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated, by standard aqueous or nonaqueous techniques

{0107} A tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the acti ve ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened, with an inert liquid diluent.

{0.108} The pharmaceutical compositi ons of the presen t invention can comprise a compound of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants. The instant compositions include compositions suitable for oral, rectal topical, and parenteral (including subcutaneous, mtramuseular, and intra venous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severit of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy,

[0109] Pharmaceutical compositions of the present in vention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcelhilose. Dispersions can also he prepared in glycerol, liquid poly ethylene glycols, and mixtures thereof in oils. Further, a preservative can be included, to prevent the detrimental growth of microorganisms.

{0110} Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions, hi all cases, the final injectable 'form must be sterile and must be effectively fluid for easy syringabiiity. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against: the contaminating action of microorganisms such as bacteria and fungi. The earner can be a solvent or dispersion medium containing, for example, water, ethanol polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

{01111 Pharmaceutical compositions of the presen t invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouth washes, gargles, and the like. Further, the compositions can be in a. form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophi!ic material and water, together with, about 5 wt% to about 1.0 wt% of the compound, to produce a cream or ointment having a desired consistency,

{0112J Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted earrier(s) followed by chilling and shaping in molds.

{0113} In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other ad juvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of the invention, and/or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form,

(01 14J A potentiated amount of an niGlo.R agonist to be administered in combination with an effective amount of a disclosed compound is expected to vary from about 0, 1 milligram per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg day and is expected to be less than the amount that is required to provide the same effect when administered without an effective amount of a disclosed compound. Preferred amounts of a co-administered mGluR agonist are able to be determined by one skilled in the art.

{0115} In the treatment conditions which require potentiation of met botropic glntamate receptor activity an appropriate dosage level will generally be about 0.01 to 500 mg pe kg patient body weight per day and can be administered in single or multiple doses. Preferably, the dosage level will be about

0.1 to abou 250 mg kg per day; more preferably 0,5 to 100 mg/kg per day, A suitable dosage level can be about 0.01 to 250 mg kg per day, about 0.05 to 100 mg kg per day, or about 0.1 to 50 mg kg per day. Within this range the dosage can be 0.05 to 0,5, 0,5 to 5.0 or 5.0 to 50 rng kg per day. For oral acUmnistration, the compositions are preferabl provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly Ϊ .0, 5.0, Ϊ , 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 milligrams of the acti ve ingredient f r the symptomatic adjustment of the dosage of the patient to be treated. The compound can be administered on a regimen of I to 4 times per day , preferably once or twice per day . This dosing regimen can be adjusted to provide the optimal therapeutic response.

[0116] It is understood, however, that the specific dose level for any particular- patient will depend upon a variety of factors. Such factors include the age, body weight, genera! health, sex, and diet of the patient. Other factors include the time and route of administration, rate of excretion, drug combination, and the type and severity of the particular disease undergoing therapy.

{0117] The disclosed pharmaceutical compositions can further comprise other therapeutically active compounds, which are usually applied in the treatment of the above mentioned pathological conditions,

[0118] It is understood that the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using.

{01 !9J Further disclosed herein are pharmaceutical compositions comprising one or more of the disclosed mGIuR.4 potentiators and a pharmaceutically acceptable carrier,

[0120] Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention.

{0121 { The above combinations include combinations of disc losed compound not only with one other active compound, but also with two or more other active compounds. Likewise, disclosed compounds may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which disclosed compounds are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preierred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.

[0122] The weight ratio of the compound of the present invention to the second active ingredient can be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight -ratio of the compound o f the present invention to the other agent will generally range from about 1000: 1 to about 1 : 1000, preferably about 200:1 to about 1:200.

Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

[ _. 0123] In such combinations the compound of the present -invention and other acti ve agents may be administered separately or in conjunction. In addition, the administration of one element can be prior to, concurrent to, or subsequent to the administration of other agentis).

|0124] Accordingly, the subject compounds can be used alone or in combination with, other agents which are known to be beneficial in the subject indications or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the disclosed compounds. The subject compound and the other agent ma e coadministered, either in concomitant therap or in fixed combination.

[0125| In one aspect; the compound can be employed in combination with anti- Alzheimer's agents, beta-secretase inhibitors, gannna-secretase inhibitors, HMG-CoA reductase inhibitors, NSAiDS's (nonsteroidal anti-inflammatory drugs) including ibuprofen, vitamin E, and anti-amyloid antibodies, !n a further aspect, the subject, compound may be employed in combination with sedati ves, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, i idazopyridines, pyrazoSopyrimidhies, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as: adsnazolam, ailobarbital, alontmid, alprazolam, amisuipride, amifripfyline, amobarbital, amoxapine, ariptpra oie, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butaJbitai, capitri.de, earbocloral chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidoue, clorazepate, chiordiazepoxide, clorethate, chlorpromazine, clozapine, cypiazepam, desipramine, dexcla ol, diazepam, dichioralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethehlorvynol, etomidate, fenobam, flun tazepam, fiupentixol, flup ^' henazine, tlurazepam, fiuvoxamine, fluoxetine, fosazepam, glotettiimide, ha!azepam, halqperidol, hydroxyzine, imipramine, lithium, !orazepam, lormetazepam, map.rotil.me, mecloquaione, melatonin, raephobarbital, rneprobarnate, rnethaqualone, raidailur, midazolam, ncfazodonc, nisobamate, nitrazepam, nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlaptnc, perphenazine, phenelzine, phenobarbitai, prazepam, promethazine, propofol. protriptyline, quazepam, quetiapnie, reclazepara, risperidone, .roletarnide, secobarbital, sertraline, suprocl ne, temazepam, thioridazine, thiothixene, fracazo!ate, tranylcypromaine, trazodone, triazolam, trepipam, tricefamide, triclofos, trifluoperazine, trimetozine, trimiprarnme, itldazepam, venlafaxine, zaleplort, ziprasidone, zolazepam. Zolpidem, and salts thereof, and combinations thereof, and the like, or the subject compound may he administered in conjunction with die use of physical methods such as with light therap or electrical stimulation.

|0126] in a further aspect, the compound can be employed in combination with levodopa (with or without a selective e tracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as bipe.rid.en (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopanx lisuride, naxagolide, pergolide and pramipexole. it will be appreciated that the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrohromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate . Lisuride and pramipexol are commonly used in a non-salt form.

[0127] In a further aspect, the compound can be employed in combination with a compound from the phenoihiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbufylpiperidine and indolone classes of neitroieptic agent. Suitable examples ofphenothiazines include chSorproniazine, raesoridazine, thioridazine, aeetophenazine, fluphenazine, perphenazine and trifluoperazine- Suitable examples of thioxanthenes include ehlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of a buryrophenone is haloperidol. An example of a diphenylbuty ipiperidine is pimozide. An example of an indolone is molindolone. Other neuroleptic agents include loxapine, sulpiride and risperidone, it will be appreciated that the neuroleptic agents when used in combination with the subject compound may be in the form of a pharmaceutically acceptable salt, for example, cMorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, aeetophenazine maieate, fiuphenazine hydrochloride, flutphenazme enathafe, fiuphenazine decanoate, trifluoperazine hydrochloride, thiothixene .hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, ch!orprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form.. Thus, the subject compound may be employed in combination with aeetophenazine, alentemol, aripiprazole. aniisulpride, benzhexol, bromocriptine, biperiden, cMorpromazine, ehlorprot xene, clozapine, diazepam, fenoldopam, fiuphenazine, haloperidol, levodopa, levodopa with henserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide. pramipexole, quetiapine, risperidone, sulpiride, tetnsbertazine, trihexyphenidyl, thioridazine, thiothixene, trifluoperazine or ziprasidone.

|¾128| In one aspect, the compound can be employed in combination with an anti-depressant or anti-anxiety agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selecti ve serotonin reuptake inhibitors (SSRls), monoamine oxidase inhibitors (MAO ^' lsj, reversible inhibitors of monoamine oxidase (R As), serotonin and noradrenaline reuptake inhibitors (SNRls), corticotropin releasing factor (CRFj antagonists, a- adrenoreceptor antagonists, neurokinin- 1 receptor antagonists, atypical anti-depressants, benzodiazepines,, 5-HTJA agonists or antagonists, especially 5-ΗΊΊ A partial agonists, and corticotropin releasing factor (CRF) antagonists. Specific agents include; amitriptyline, clomipramine, doxepin, itmpramme and

trimipramine; amoxapine, desipramine, maprotiiine, nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide: vctuaiaxinc. duloxeiine; aprepitant; bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam, ehlordiazepoxide, clonazepam, chiorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.

[0129] in the treatment of conditions which require potentiation of mGluR.4 activity an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0,5 to about 100 mg/kg per day. A suitable dosage level may be about 0,01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0, 1 to 50 mg kg per day. Within this range the dosage may be 0,05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the composi tions arc preferably pro vided the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1 ,0, 5,0, 10, 15. 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosage regimen may be adjusted to provide the optimal therapeutic response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be v aried and will, depend upon a variety of factors including the acti vity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

[01301 In one aspect, the invention relates to a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable deri ative thereof; and a pharmaceutically acceptable earner.

[0131 { in one aspect, the in ention relates to pharmaceutical compositions comprising a compound having a structure represented by a compound of the .following formula:

X is CH, C-alkyl, N, NH, N-alkyi, aikoxy, or may form a 6-mem ^' bered ring with Y optionally substituted with at least one R;

Y is CH, C-alkyl, N, or may form a 6-membered ring with X optionally substituted with at least one R ;

Z is independently N, CH, C-alkyl, C-halogea, C-Me, C-Oaikyi, C-OMe;

], is O or C- _t ;

X; is O or C-R?;

R is independently H, halogen, CN, Me, alkyi, aikoxy, OMe, aryl, heteroaryi alkyi-aryl, alkyi- heteroaryi , cycioalkyl, alkyl-cycioalkyl;

j is independently H, aikoxy, amino, alkyl-alkoxy, alkyi, CN, cycioalkyl, alk l-eycloalkyi, cycloheteroalkyl, alkyl-cycloheteroalkyL CF ₃ , halogen, CD ₃ , CD _; R, CDRRj, CO R ₃ R , aryl, heteroaryi, alkyi-aryl, alkyl-heteroaryl, S0 ₂ R ₂ , OR, OR ₂ , Oaryl, Oheteroaryl, NHR, NR ₃ R ₄ , fluorinated alkyl, difluorinated alkyl, trifluorinated alkyl, heteroalkyl, benzyl, heteroaryi benzyl (CHAeteroaryi), propanamide, diethyl propanamide, CH>CX) R;;Ri; G-1:?NHR; CHjNHRs *;

Rz is independently H, aikoxy, amino, alkyl-alkoxy, alkyl, CN, cycioalkyl, aikyl-eycioaifcyl, cycloheteroalkyl, aftyl-cycioheteroalkyl CF ₃ , halogen, CDs, CD _;? R, CDRRs, CONR .R4, aryl, heteroaryi, alkyi-aryl, alkyl-heieroaryl, SOjRt, OR, OR), Oaryl, Oheteroar l, NHR, NR3R , fluorinated alkyl, di fluorinated alkyl, trifluorinated alkyl, heteroalkyl, beazyi, heteroaryi benzyl (CH ₂ heteroaryl), propanamide, diethylpropanaroide, CH2CONR3R4, CH ₂ NHR; CH2NHR3R*;

Rs is H, aikoxy, amino, alkyl-alkoxy, alky 1 , CN, cycloalkyl, alkyl-eycloalkyi, cycloheteroalkyl, alkyl-cycloheteroalkyl, CP;?, halogen, CDj, C1¾R, CDRRi, aryl, heteroaryi, alkyi-aryl, alkyi -heteroaryi, SO2R.2, OR, OR2, Oaryl, Oheteroaryl, NHR, fluorinated alkyl, difluorinated alkyl, trifluorinated alkyi, heteroalkyl, beazyi, heteroaryi benzyl (CHjheteroaryl), propanamide, diethyipropanarnide, CBjNHR; ₄ is H, alkoxy, amino, alkyl-alkoxy, aikyl C , cyc!oa!kyl alkyl-cycloaikyl, eyclohetcroalfcyi alkyl-cydoheteroalkyl, CFj, halogen, CD ₃ , CDjR, CDRRs, aryl, heteroaryl, alkyi-ary!, alkyl-heteroaiyl, SO3R2, OR, ORj, Oaryl, Oheteroaryl, NHR, fluorinated atkyl, difluorinated alkyi, trifluorinat d alkyi, hetcroalkyl, benzyl, heteroaryi benzyl (CHiheteroaryf), propana.mide _f diethylpropanamkk, Clij HR; or a pharmaceutically acceptable salt, thereof or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptabie carrier.

|¾J 32] Also disclosed are pharmaceutical compositions comprising a compound of the following formula;

or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof; and a pharmaceutically acceptable carrier,

{013J| Also disclosed are pharmaceutical compositions comprising a compound of the following formula: or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof; and a pharmaceutically acceptabie carrier,

|M34| Also disclosed are pharmace tical compositions comprising a compound of the following formula:

or a pharmaceutically acceptabie salt thereof or a pharmaceutically acceptable derivative thereof; and a pharmaceutically acceptable carrier; wherein .S A is H, alkyi, cycloalkyl, alkyl-cycloalkyl,

fefxahydrofuran, tetrahydropyran, aikyi-tetrahydropyran, cyclopropyl, aik l-cyclopropyl, cyclobiityl, alkyl-eyelohuryl, fluoroalkyl-cyclobutyl, alkoxy, oxetan, alkyl-oxetan, thian, dioxothian, aikyl- methyldioxothian, hydroxyl; and wherein _!a is il alkyi eycloalkyL alkyl-eycloalkyl propanaraide, diethyipropanainjde.

£01.35] Also disclosed are pharmaceutical compositioas wherein the compouftd is of the following .formula:

D. Methods of using the compounds aad compositions

l ^' 0136 ^' j m01uR4 belongs to the group 10 raGluR. subfamily and is iocaied in predominantly in presynaptic locations in the central nervous system where it is functions as an auto- and heieroreceptor to regulate the release of both GABA and g!utaraate. In addition. mGIttR4 is also expressed at a low level in some postsynaptic locations. mGhiR4 is expressed in most brain regions, particularly in neurons known to play key roles in the following functions of the C S:

a) learning and memory;

b) regulation of voluntary movement and other motor functions

c) motor learning

d) emotional responses

e) habit formation, including repetitive tasks and perseverative thought processes f) reward systems

g) vision and olfaction

h) cerebellar functions;

i) feeding and t he regulation of hypothalamic hormones; and

j) sleep and wakefulness.

As such, mGiuR4 plays a major role in the modulation of C S-related diseases, syndromes and non- CNS related diseases or conditions the like, for example:

a) Parkinson's disease, parkinsonism, and other disorders invol ving akinesia or bradykinesia

b) Dystonia

c) Huntington's diseases and other disorders involving involuntary movements and dyskinesias

d) Tourette's syndrome and related ticking disorders

e) Obsessive/compulsive disorder and other persevcrative behavioral disorders

f) Addictive disorders (including drug abuse, eating disorders, and.)

g) Schizophrenia and other psychotic disorders

h) Posttraumatic stress disorder

i) Anxiety disorders;

j) motor effects after alcohol consumption or other drug-induced motor disorders; k) neurogenic fate commitment and neuronal survival;

i) epilepsy; m) certain cancers, for example, mcduiloblasto a;

n) type 2 diabetes, and/or other metabolic disorders; and

o) taste enhancement blockade.

|6137J The disclosed compounds can act as potentiators of the metabo ropic glutamate receptor activity (mGluR4). Therefore, in one aspect, die disclosed compounds cart he used to treat one or .more mGl 4 associated disorders that, result in dysfunction ia a mammal.

{0138| The disclosed compounds can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration or reduction of risk of the aforementioned diseases, disorders and conditions for which compounds of formula I or the other drugs have utility, where the combination of drugs together are safer or more effective than either drug alone. The other drug(s) can be administered by a route and in an amount commonly nsed therefore, contemporaneously or sequentially with a disclosed compound. When a disclosed compound is used contemporaneousl with one or more other drugs, a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compound is preferred. However, the combination therapy cart also be administered on overlapping schedules. It is also en visioned that the combination of one or more active ingredients and a disclosed compound will be more efficacious than either as a single agent.

l. TREATMENT METHOBS

The compounds disclosed herein are useful for treating, pre venting, ameliorating, control ling or reducing the risk of a variety of neurological and psychiatric disorders associated with glutamate dysfunction. Thus, provided is a method of treating or preventing a disorder in a subject comprising the step of administering to the subject at least, one disclosed compound; at least one disclosed

pharmaceutical composition; and/or at least one disclosed product in a dosage and amount effective to treat the disorder in. the subject.

014 | Also provided is a method for the treatment of one or more neurological and/or psychiatric disorders associated with glutamate dysfunction in a subject comprising the step of administering to the subject at least one disclosed compound; at least one disclosed pharmaceutical composition; and/or at least one disclosed product in a dosage and amount effective to treat the disorder in the subject.

(111411 Examples of disorders associated with glutamate dysfunction include: acute and chronic neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AiDS-induced dementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, multiple sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine

(iaciuding migraine headache), urinary iircoatiaence, substance tolerance, addictive behavior, including addiction to substances (including opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics,, etc.), withdrawal from such addictive substances (including substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc), obesity, psychosis, schizophrenia, anxiety (including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder), mood disorders (including depression, mania, bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, eroesis, brain edema, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, and posttraumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention

deficit/¾yperaetivity disorder, conduct disorder, diabetes and other metabolic disorders, taste alteration, and cancer.

i _. 0142] Anxiety disorders that can be treated or prevented by the compositions disclosed herein include generalized anxiety disorder, panic disorder, and obsessive compulsive disorder. Addictive behaviors include addiction to substances (including opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedati ves, hypnotics, etc.), withdrawal from such addictive substances (including substances such, as opiates, nicotine, tobacco products, alcohol benzodiazepines, cocaine, sedatives, hypnotics, etc.) and substance tolerance.

10143} Thus, in some aspects of the disclosed method, the disorder is dementia, delirium, amnestic disorders, age-related cognitive decline, schizophrenia, psychosis including schizophrenia,

schizopfaremform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, substance-related disorder, movement disorders, epilepsy, chorea, pain, migraine, diabetes, dystonia, obesity, eating disorders, brain edema, sleep disorder, narcolepsy, anxiety, affective disorder, panic attacks, unipolar depression, bipolar disorder, psychotic depression.

(01441 Also provided is a method for treating or prevention anxiety, comprising: administering to a subject at least one disclosed compound; at least one disclosed pharmaceutical composition; and/or at least one disclosed product in a dosage and amount effective to treat the disorder in the subject. At present, the fourth edition of the Diagnostic and Statistical Manual of Mental Di sorders (DSM-S V) (1 94, American Psychiatric Association, Washington, .C.), provides a diagnostic tool including anxiety and related disorders. These include: panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder and anxiety disorder not otherwise specified. [0145] In one aspect, the invention relates to methods for the treatment of a neurotransmission dysfunction and other disease states associated with raGI« 4 activit in a mammal comprising the step of administering to the mammal at least one compound of the present invention in a dosage and amount effective to treat the dysfunction in the mammal, in certain embodiments, the compound has a structure represented by formula:

wherein X is CH, C-aikyl, N„ NE, N-alky!, alkoxy, or may form a 6-mem ered ring with Y optionally substituted with at least one R;

Y is CH, C-alkyl, N, or may form a 6-membered ring with X optionally substituted with at least otie ;

Z is independently N, CH, C-alkyl, C-halogen, C-Me, C-Oalkyl, C-O e;

Xi ^j s O or -R _t ;

R is independently H, halogen, CN, Me, alkyl, alkoxy, OMe, aryl, heteroaryi alkyl-aryl, alkyl- heieroaryl, cyc!oa!kyl alkyl-cye!oa!kyl;

R; is independently H, alkoxy, amino, alkyt-atkoxy, alkyl CN, cycloaikyl, aikyl-eycioaikyl, eycloheteroalkyl, alkyi-cycloheteroalkyi, CF.-?, halogen, CDs, CI¾R, CDRRj, CONR R4, aryl,

heteroaryl, alkyl-aryl aSkyl-rteieroaryl SO _? R ₂ , OR, QR _¾ OaryL OheteroaryL NHR, H : _{5 ?} fluormated alkyl, di fhtorinated alkyl, trifluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CH ₂ heteroaryl), propanamide, dicthylpropanamide. CH2CONR3 4; C¾NMR; CH ₂ NHR. ₃ R ₄ ;

;; is independently H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycloalkyl, alkyl-cycloalkyl, eycloheteroalkyl, alkyl-cycloheteroalkyl, CF ₃ , halogen, CD?, CO2R, CDRR CONR3R4, aryl,

heteroaryl, alkyl-aryl aikyl-lieteroaryl, S0 ₂ R _t , OR, ORj, Oary , Oneteroaryl, NHR, NR. _; R _4: fluorinated alkyl, difluorinaied alkyl trifluorinated alkyl, heteroalkyl, benzyl heteroaryl benzyl (CHjheteroaryl), propanamide, diethylpropana ide, CH2CONR3R , CH ₂ NHR; CHjNHR^R*; ;; is H, alkoxy, amino, alkyl-alkoxy, aikyl C , cye!oalkyl, alkyl-cye!oalkvi eyclohetcroalkyl, alkyl-cyeloheteroalkyl, CFj, halogen, CDs, CDjR, CDRRs, aryl, heteroaryi, alkyi-ary!, alkyi- ^' heteroaiyl, SO3R2, OR, ORj, Oaryl, Oheteroaryi, NHR, fluorirtated aikyl, difluorinated alkyi, tri iorinatcd alkyi, heteroaikyl, benzyl, heteroaryi benzyl (CHiheteroaryl), propanamide, diethylpropamrmide, CBjNilR;

R* is H, alkoxy, amino, alkyl-alkoxy, alkyi, CN, cyeioaikyL alkyl-eyeioaikyL cyeloheteroaikyL alkyl-cyeloheteroalkyl, CF¾, halogen, CD3, CD ₂ .R, CD ^' R ₂ , aryl, heteroaryi, alkyl-aryl, alkyl-heteroaryl, SO2R2, OR, OR.2, Oaryl, Oheteroaryi, NHR, fiaorinated alkyi, difluorinated alkyi, trifluormated. alkyi, heteroaikyS, benzyl, heteroaryi benzyl (CHjheteroaryl), propaoamkle, dietiiylpropanaroide, CHjNHR; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

|0146| in one aspect, the invention relates to methods for potentiating raGluR4 activity in a subject comprising the step of administering to the subject at least one compound of the present invention in a dosage and amount effective to treat the dysfimction in. the mammal , In certain embodiments, the compound has a structure represented by formula:

wherein X is CH, C-alkyl, , NIL N-aikyS, alkoxy, or may form a 6-nierabe.t'ed rin with Y optionally substituted with at least one R;

Y is CH, C-alkyl, N, or may form a 6-raera ered ring with X optionally substituted with at least one R;

Z is independently N, CH, C-alkyl, C-halogen, C-Me, C-Oalkyi, C-OfVie;

X _\ is O or C>Ri

X ₂ is O or C-R^;

R is independently H, halogen, CN, Me, alkyi, alkoxy, OMe, aryl,. heteroaryi, aJkyl-aryl, aikyl- heteroaryi , eycioaikyl, alkyi-eycioaikyl;

Rs is independently H, alkoxy, amino, alkyl-alkoxy, aikyl, CN, cycloalkyl, alkyl-cyeloalkyl, cycloheteroalkyl, alkyl-cyeloheteroalkyl, CF,, halogen, CD,, CD ₂ R, CDRR,. CONR ₃ R ₄ , aryl, heteroaryl, alky!-aryi, alkyl-heteroaryl, S0 ₃ R _¾ OR, OR ₂ , Oaryi Oheteroaryi, NHR, NR ₃ R ₄ , fluoridated alkyl, dstlucrinated alky), trifluorinated alky 1, heteroalkyl benzyl, heteroaryl benzyl {CHjheteroaryi), propanamide, dictiiylpropanaraide,€¾CON ¾ ; CHjNH ^' R; CH2 HR3R ;

¾ is independently H, aikoxy, attu.no, alkyL-alkoxy, alkyl, CN, cycloalkyl, alkyl-cyc oalkyl, cycloaeteroalkyl, alkyl-eycioheieroalkyl, CF.-?, halogen, CD3, CD;R, CDRR;, CO R .R.1, aryl, heteroaryl, alkyl-aryl, alkyl -heteroaryl, SO R OR, ORj, Oaryl, Oheteroaryi, NHR, NR3R4, iiuorinated alkyl, difiuorinated alkyl, trifluoririated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CH>heieroary , propanamide, die rylpropanamide, CHjCONRsR*, CH?.NHR CH;HHR ₃ R ;

Ri is H, aikoxy, amino, alkyl-alkoxy, alkyl CN, cycloalkyl, aikyl-cyc oa kyl, cycloheteroalkyl, alkyl-cyc!oheteroalkyl, CF ₃ , halogen, CD _? ,, CD _? R, CDRRj, aryl, heteroaryl, alkyl-aryl, alky! -heteroaryl, SOjR¾ OR, OR2, OaryL Oheteroaryi, NHR, Iiuorinated alkyl, difiuorinated alkyl, trrlluorinated alkyl, heteroalkyl. benzyl, heteroaryl benzyl (CHjteteroaryi), propanamide, diethylpropanarnide, CHjNHR;

R is Fi, aikoxy, amino, alkyl-alkoxy, alkyl, CN, cycloalkyl ai.kyl-cycloal.kyL cycloheteroalkyl, alkyi-cycloheteroalkyi, CF?., halogen, CDs, CDjR, CDRRj, aryl, heteroaryl, alkyl-aryl, alkyMieteroaryl, SO2R.2, OR, OR2, Oaryl, Oheteroaryi, NHR, fiuortaared alkyl, difiuorinated alkyl, trifluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (C¾heteroaryl), propanamide, diethylpropanarnide, CBjNHR; or a pharmaceutically acceptable salt thereof or a paarmaceutically acceptable derivative thereof in a dosage and amount effective to potentiate mGiuR4 receptor activity in the subject.

[0147] l.n one aspect, the invention relates to methods of potentiating mGlitR4 activity in at least one ceil comprising the step of contacting the at least one cell with at least one compound having a. structure represented by formula:

wherein X is CFi C-alkyl, N, NH, N-afl yl, aikoxy, or may form a 6-membeted ring with Y optionally substituted with at least one R;

Y is Cli. C-alkyl. N. or may form a 6-membered ring with X optionally substituted with at least one R; Z is independently , CfL C-alkyl, C-halogen, C-Me, C-Oalky.l, C-O e;

R is independently H, halogen, CN, e, alkyl, alkoxy, OMe, aryl, heteroaryl aikyl-aryl, aikyl- heteroaryl, cyeloalkyL alkyl-cyeloalkyl;

R _\ is independently H, alkoxy, amino, alkyl-a koxy, alky I, CM, cyeloaikyl, alkyi-eyeloaikyl, eycloheteroaikyl alkyl-cycioheteroalkyi CF _;{ , halogen, C¾ CD ₂ R ₍ CD.RR;, CONR ₅ R ₄ , ar J,

heteroaryl alkyi-aryi alkyl-heteroaryl, SO>R ₂ , OR, OR;, Garyl, Oheteroaryl, NHR, M R , fluorraated alkyl, difluorinaied alky trifluorinaied alkyl, heteroalkyl benzyl heteroaryl benzyl (CHjheteroaryi), propanamide, dietlrySpropanamide, Ci¾CONR ₃ R ₄ : CH ₂ NHR; C¾NHR.jR ₄ ;

;j is independently H, alkoxy, ammo, alkyl-alkoxy, alkyl, CN, cycioaikyl alkyl-cYcloaikyl eycloheteroalkyl, alkyl-cycloheieroalkyl CF _;{ , halogen, CD _? , CD?R, CDRRj, CONR ₃ R , aryl, heteroaryl alkyl-aryl, alkyl-heteroaryl, S0 ₂ R _{ , OR, OR _is Oaryl, Oheteroaryl, NHR, NRd fluofinated alkyl, diffctorinaied alkyl, trifluorinated alkyl, heteroalkyl, benzyl, heteroaryl benzyl (CHjheteroaryl), propanamtde, diethylpropanamide, C¾CONR ₃ R , CHj ^' HR; CHVNHR R4;

R;s is H, alkoxy, amino, alkyl-alkoxy, alkyi, CN, cyeloaikyl alkyl-cyeloalkyl, eycloheteroaikyl alkyl-cydoheteroalkyl, CF¾ halogen, CDs, Gt¾R, CDRR?, aryl, heteroaryl, aikyl-aryl, alkyl-heteroaryl, SOjR ₂ , OR, OR¾ Oaryl Oheteroaryl, NHR, fluo inated alkyl difiuorinated alkyl, irifiuorraated alkyl heteroalkyl benzyl, heteroaryl benzyl (C¾heteroary1) ₅ propanamide, diethylpropanamide, C¾NHR;

Rs is H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cydoa!kyl, aikyl-eyeloalkyl cycloheteroalk l, alkyl-eycioheteroalkyl, CF _S , halogen, CD ₃ , CD ₂ R, CDRR ₃ , aryl, ^' heteroaryl, alkyl-aryl, alkyl-heteroaryl, O2R , OR, QR.2, Oary Oheteroaryl, NHR, flaoriaated alkyl, difluormated alkyl, trifluorinated alkyi heteroalkyl, benzyl heteroaryl benzyl (C¾heteroaryl), propanamide, diethylpropanamide, CHjNHR; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof, in an amount effecti ve to potentiate mGluR4 receptor activity in the at least one cell

|0148] in certain aspects, a subject, for example a mammal or a human, has been diagnosed with the dysfunction prior to the administering step. In further aspects, a disclosed method can further comprise the step of identifying a subject, for example a mammal or a human, having a need for treatment of a dysfunction. In further aspects, a subject, for example a mammal or a human, has been diagnosed with a need for potentiation of mGluR4 receptor activity prior to the administering step. In further aspects, a disclosed method can further comprise the step of identifying a subject, for example a mammal or a human, having a need for potentiation of mGiuR4 receptor activity. In further aspects, a cell (e.g., a mammalian cell or a human cell) has been isolated from a subject, for example a mammal or a human, prior to (he contacting step. In further aspects, contacting is via administration to a subject, for example a mammal or a human.

£01.49] in one aspect, the invention relates to methods for potentiating mG!uR4 activity in. at least one cell comprising the step of contacting the at least one ceil with at least one disclosed compound in an amount effective to potentiate «sGluR4 receptor activity in the at least one cell.

|¾ J 50] In one aspect,, the invention relates to methods for potentiating rnGhtR.4 acti vity in a subject comprising the step of administering to the subject a therapeuticall effective amount of at least one disclosed compound in a dosage and amount effective to potentiate mGiu.R4 receptor activity in. the subject.

10151] In one aspect, the invention relates to methods for the treatment of a disorder associated with mGluR4 neurotransmission dysfunction or other disease state in a mammal comprising the step of administering to the mammal at least one disclosed compound in a dosage and amount effective to treat the disorder in the mammal.

{01521 The disclosed compounds can be used to trea t a wide range of neurological and psy chia tric disorders and oilier disease states associated with giutamate dysfunction. Non-limiting examples of these diseases includes movement disorders, including akinesias and akinetic-rigid syndromes (including Parkinson's disease), dystonia, epilepsy, chorea, neurogenerative diseases such as dementia,

Huntington ^' s disease. Amyotrophic Lateral Sclerosis, Alzheimer's disease. Pick's disease, Creutzfeklt- Jakob disease, pain, migraines, diabetes, obesity and eating disorders, sleep disorders including narcolepsy, and anxiet or affective disorders, including generalized anxiety disorder, panic attacks, unipolar depression, bipolar disorder, psychotic depression, and related disorders, cognitive disorders including dementia (associated with Alzheimer's disease, ischemia, trauma, stroke, HIV disease, Parkinson ^'' s disease, Huntington ^' s disease and other genera! medical conditions or substance abuse), delirium, amnestic disorders, age-related cognitive decline, schizophrenia or psychosis including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, substance-related disorder, cancer and inflammation (including MS). Of the disorders above, the treatment of Parkinson's disease, movement disorders, cognitive disorders, neurodegenerative diseases, obesity and pain are of particular importance.

|0153] la one aspect, the disclosed compounds can be used to treat or can be a component of a pharmaceutical composition used to treat movement disorders. As such, disclosed herein in a method for treating a movement disorder, comprising the step of administering to a mammal in need of treatment at least one compound in a dosage and amount effective to treat the disorder in the mammal wherein the disorder is selected from Parkinson's disease, Huntington's disease, dystonia, Wilson's disease, chorea, ataxia, ballism, akathcsia, athetosis, hradykincsia, rigidity, postural instability, inherited ataxias such as Friedreich's ataxia, Maehado-Joseph disease, spinocerebellar ataxias, Tourette syndrome and other tie disorders, essential tremor, cerebral patsy, stroke, encephalopathies, and intoxication. j0154| In a further aspect, the di sclosed compounds can he used to treat, or can be a component of a pharmaceutical composition used to treat cognitive disorders. As such, disclosed herein in a method tor treating a cognitive disorder, comprising the step of administering to a mammal in need of treatment at least one compound in a. dosage and amount effective to treat the disorder in the mammal, wherein the disorder is selected from dementia (associated with Alzheimer's disease, ischemia, trauma, stroke, HIV disease, Parkinson's disease, Huntington's disease and other general medical conditions or substance abuse), delirium, amnestic disorders and age-related cognitive decline. The fourth edition (Revised) of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides a diagnostic tool for cognitive disorders including dementia (associated with Alzheimer's disease, ischemia, trauma, stroke, HIV disease, Parkinson ^' s disease, Huntington's disease and other general medical, conditions or substance abuse), delirium, amnestic disorders and age-related cognitive decline.

{0155} In a further aspect, the disclosed compounds can be used to treat,, or ca be a component of a pharmaceutical composition used to neurodegenerative disorders. As such, disclosed, herein in a method for treating a neurodegenerative disorder, comprising the step of administering to a mammal io. need of treatment at least one compound in a dosage aud amount effective to treat a neurodegenerative disorder i the mammal

|Q156| in a still further aspect, the disclosed compounds provide a method for treating

schizophrenia or psychosis. As such, disclosed herein in a method for treating a disorder related to schizophrenia or psychosis, comprising the step of administering to a mammal in need of treatment at least one compound in a dosage and amount effective to treat the disorder in the mammal, wherein the disorder related to schizophrenia or psychosis is selected from paranoid, disorganized, catatonic or undifferentiated, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, substance-induced psychotic disorder. The fourt edition (Revised) of the

Diagnostic and Statistical Manual of Menial Disorders (DSM-IV-TR) (2000, America Psychiatric Association, Washington DC) provides a diagnostic tool for e include paranoid, disorganized, catatotiic or undifferentiated, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, substance-induced psychotic disorder.

[0157J The subject compounds are further useful in the prevention, treatment, control, amelioration or -reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents, including an niGtuR agonist. 2. COADMINISTRATION ETHOBS

|0158| The disclosed compounds may be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration or reduction of risk of the aforementioned diseases, disorders and conditions for which compounds of formula 1 or the other drugs ave utility, where the combination of drugs together are safer or more efiective than either drug alone. The other dmg(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a disclosed compound. When a. disclosed compound is used contemporaneousl with one or more other drugs, a pharmaceutical composition in unit dosage form containing such drugs and the compound is preferred. However, the combination therapy can also be administered on overlapping schedules. It is also envisioned that the combination of one or more active ingredients and. a disclosed compound can. be more efikacious than either as a single agent.

{0159J In one aspect, the compounds ca be coadministered with anti-Alzheimer's agents, heta- secretase inhibitors,, ga ma-secreiase inhibitors, muscarinic agonists, muscarinic potentiators HMG- CoA reductase inhibitors, NSAIDs and anti-amyloid antibodies. n a further aspect, the compounds can be administered in combination with sedatives, hypnotics, anxiolytics, antipsychotics, selective seroto in reuptake inhibitors (SS !s). monoamine oxidase inhibitors (MAOis), 5-HT2 antagonists, GlyTi inhibitors and the like such as, but not limited to: risperidone, clozapine, haioperidoL fluoxetine, prazepam, xanometine, lithium, phenobarhitol, and salts thereof and combinations thereof,

(016β{ In a further aspect, the subject compound may be used in combination with Levodopa (with or without a selective extracerebral decarboxyiase inhibitor), anticholinergics such as biperideii, COMT inhibitors such as entaeapone, A2a adenosine antagonists, cholinergic agonists, NM ^' DA receptor antagonists and dopamine agonists.

{0161 { In one aspect, the invention relates to methods for the treatment of a neurotransmission dysfunction and. other disease states associated with mGluR.4 activity in a mamma! comprising the step of co-administering to the mammal at least one compound in a dosage and amount effective to treat the dysfunction in the mammal, the compound having a structure represented by formula:

X wherein X is CH, C-alkyl, N, MH, N-alkyl alkoxy, or may form a 6-raembered ring with Y optionally substituted with at least one R;

Y is CH, C-alkyl, N, or may form a 6-roerobered ring with X optionally substituted with at least one R;

Z is inde endently N ₍ CH, C-alkyl, C-halogea, C-Me, C-Oa ^' lkyl, C-OMe;

, is O 0r C-R _¾

is independently H, halogen, CN, Me, alkyL alkoxy, OMe, ary!, heteroaryi, aikyi-aryl, aJkyl- heteroaryi, cycloalkyi, alkyl-cycloalkyl;

Rs is independently H, alkoxy, amino, alkyl-alkoxy, alkyl CN, cycloalkyi, aikyl-cveloaikyl, eycloheteroalkyL alkyl-cycloheteroalkyl CF ₃ , halogen, CDs, CD ₂ R, CDRR ₂ , CONR _s R ₄ , atyl,

heteroaryi, aikyi-aryl, alkyl-heteroaryi, S0 ₂ R _2f OR, OR,, Oaryl, Oheteroaryl, NHR, NR. _; R ₄ , fluormated alkyl difiuorinaied aikyi, trifluorinated aikyl, heteroalkyl, benzyl, heteroaryi benzyl (Ck heteroaryi), propanamide, diethylpropanamide, CH ₂ CONR ₃ R ₄ ; C¾NHR; CH ₂ NHR _;? R ₄ ;

R ₂ is independently H, alkoxy, amino, alkyl-alkoxy, aikyl, CN, cycloalkyi, alkyl-cycloalkyl, cyeloheteroalkyl, alkyl-cycloheteroalkyl, CF. _?> halogen, CD,, CDjR, CDRRj, CONR ₃ R ₄ , aryi, heteroaryi, alkyl-aryl, alkyl-heteroaryl, S0 ₂ R _f , OR, OR Oaryl Oheteroaryl, NHR, NR ₃ R , fluortnaied alkyi, diiTuoriftated aikyl, trifltiormated alkyl, lieteroalkyl, benzyl heteroaryi benzyl (C¾hetcroaryl), propanamide, diethylpropanamide, Q-kCON ^' RjR}, CH ₂ NHR; CH2 HR3R4;

j. is H, alkoxy, amino, alkyl-alkoxy, alkyl, CN, cycloalkyi, alkyl-cycloalkyl, cyeloheteroalkyl, alkyl-cycloheteroalkyl, C ^' Fj, halogen, CDs, CD ₂ R, CD ^' RR ₂ , aryi, heteroaryi alkyl-aryl, alkyl-heteroaryi, SO;R ₃ , OR, ORj, Oaryl, Oheteroaryl, NHR, fluorinaied alkyl diiluorinated alkyl, trifluorinated alkyl, heteroalkyl benzyl, ^' heteroaryi benzyl (CH; heteroaryi), propanamide, die hylpropanamide- CH ₂ NHR:

R,! is H, alkoxy, amino, alkyl-alkoxy, alkyi, CN, cycloalkyi, alkyl-cycloalkyl, cyeloheteroalkyl, alkyi-eycioheteroalkyl CF ₃ , halogen, C¾, CD _; R, CDRRj, aryi, heteroaryi, aikyi-aryl alk l-heteroar l, SO _{2 2} , OR, OR _¾ Oaryl, Oheteroaryl NHR, fluormated aikyl, diiluorinated alkyl trifluorinated alkyl, heteroalkyl, benzyl, heteroaryi benzyl (CH ₂ heteroaryl), propanamide, diethylpropanamide, CH ₂ NHR; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof with a drug having a known side-effect of tnereasiag metaboiropic glutaraate receptor activity,

{0162 j in one aspect, the invention relates to methods for the treatment of a neurotransmission dysfunction and other disease states associated with mCHuR4 activity in a mammal comprising the step of co-administering to the mammal at least: one eo.rapound in a dosage and amount effective to treat the dysfunction in the mammal, the compound having a structure represented by formula:

wherein X is CM, C-alkyL K NH, N-aikyl, alkoxy, or may form a 6-memhe-red ring with Y optionally substituted with at least one R;

Y is CH, C-aikyl, N, or may form a 6-membered ring with X optionally substituted with at least one R;

Z is independently N, CH, C-aikyl, C-halcgen, C-Me, C-Oalkyl, C-OMe;

is independently H, halogen, CN, Me. alkyi, alkoxy, O e, aryl, heteroaryl, alkyi-aryl a!kyl- heteroaryl, cydoaikyl, alky l-cydoalkyl ;

Rj is independently H, alkoxy, amino, alkyl-alkoxy, alkyi, CN, cydoaikyl, alkyl-cycloalkyl, cycloheteroaikyl, alkyl-cycioheteroalkyl CF _if halogen, CD ₃ , CD ₂ R, CDRR ₂ , CONR ₅ R4, aryl,

heteroaryl, alky!-aryl, alk l-heteroaryl, SQaRj, OR, OR2, Oaryi Oheteroaryi, NMR, R ₃ R4, fluorinaled alkyi, diiluorinated alkyi, trill uorinated alkyi, heteroaiky ^' L benzyl, heteroaryl benzyl (GFfeheteroaryl), propanamide, diethylpropanamide, CH2CONR3R4; C%NHR; CH2NHR3R ;

r; is independently H, alkoxy, amino, alkyt-atkoxy, alkyi, CN, cydoaikyl, alkyl-cyetoatkyl, cycloheteroaikyl, alkyl-cycioheterx>alkyl. CF ₅ , halogen, CD;;, CD^R, CDRR _; , CONR ₅ R ₄ , aryl, heteroaryl, alkyl-aryl, alkyl-heteroaryl SOs j. OR, OR _lf Oaryl, Oheteroaryi, NHR, NR3R4, fiuorinated alkyi, difTuorinated alkyi, trifluorinated alkyi, heteroalkyl, benzyl, heteroaryl benzyl (CHjheteroaryS), propanamide, diethylpropanamide, CH2CONR3R4, Ct¾NHR; H H jR,!;

R.j is H, alkoxy, amino, aikyl-alkoxy, alkyi, CN, cydoaikyl, alkyl-cycloalkyl, cycloheteroaikyl, alkyl-eyeioheteroalkyl, CP,?, halogen, CDs, C¾R, CDRRj, aryl, heteroaryl, alkyl-aryl, alkyi-heteroaryi. SOjR;?, OR, OR?, Oaryl, Qheteroaryl, NHR, fiisorinaied alkyl difluorinated alkyl, triftuorinated alkyl, faeteroaikyi benzyl heteroaryi benzyl (CHjheteroatyl), propanamide, diediylpropaaamide, CHjNHR;

R is H, alkoxy, amino, alkyl-alkoxy, alkyl CN, eycioaikyi, alky l -eycioaikyi, cycloheteroaikyl, aJkyl-cyc oheteroalkyl, G¼, halogen, CD?,, CD?R, CDRRj, aryl, heteroaryi, alkyi-aryL alkyl-heteroaryi, S<¾R¾ OR, OR ₂ , Oaryl Oheteroaryl, NHR, iluorinated alkyl, difluorinated alkyl, triiluorinated alkyl heteroalkyl, benzyl, heteroaryi benzyl (CH ₂ heteroaryl), propanamide, diethylpropanamide, CH ₂ NHR; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivati e thereof with a drug known to treat a disorder associated with increasing raetabotropic g!utamate receptor activity.

[0163] in one aspect, the invention relates to methods for the treatment of a neurotransmission dysfunction and oilier disease states associated with mGluR4 activity in a mammal comprising the step of co-administering to the mammal at least one compound m a dosage and amount effective to treat, the dysfunction in the mammal, the compound having a structure represented by formula:

wherein X is CH, C-alkyl, N, NE, N-alkyi, alkoxy, or may form a 6-merabered ring with Y optionally substituted with at least one R;

Y is CH, C-alkyl, N, or may form a 6-membered ring with X optionally substituted with at least one R;

Z is independently N, CH, C-alkyl, C-halogen, C-Me, C-Qalkyl, C-QMe;

Xz is 0 or C~R ,

R is independently H, halogen, CN, Me, alkyl, alkoxy, OMe, aryl heteroaryi alkyl -aryl, alkyl- heteroaryi, eycioaikyi alkyl -eycioaikyi;

R is independently 11 alkoxy, amino, a!kyl-alkoxy, alkyl CN, eycioaikyi, alkyl-cycloalkyl, cyeloheteroaikyl, alkyl-cycloheteroalkyl, C¾ halogen, CD3, CD ₂ R, CDRR ₂ , CO R ₃ R , aryl

heteroaryi, alky!-aryi, alkyl-heteroaryl, S0 ₂ R ₂ , OR, OR ₂ , Oaryl, Oheteroaryl, NHR, NR ₃ R , iluorinated alkyl, diflnorinated alkyl, trifluorinated alkyl, heteroaikyl, benzyl heteroaryi benzyl (CBjhcisroaryl), propanamide, (Jicthylpropanamide, CHjCONRsR*; CH ₂ NHR; CH? HRj¾;

R ₂ is independently H, aikoxy, ammo, alkyl-alkoxy, alkyl CN, cycloalkyl, alkyl-cycloalkyl, cycloaeteroalkyt, alkyl-eycioheisroalkyi, CF _3> halogen, CD¾ CD _;? R, CDRR _; , CO R .R4, aryl, heteroaryi, alkyl-aryl alkyl-heieroaryl SO R _f , OR, OR,, Gary I Oheteroaryl, HER, NRsR*, fluoridated alkyl, difluonnated alkyl, trifluorinated alkyl, heteroaikyl, benzyl, heteroaryi benzyl (CH ₂ heteroaryl), propanamide, diethylpropana ide, CH2CONR3R4, <¾NFIR; CH2NHR3R ;

Rs is H, aikoxy, amino, alkyl-alkoxy, alky!., CN, cycioalkyl, aikyl-cycioalkyl, eycloheteroaikyl, alkyl-cyc!oheteroalkyl, CF _! , halogen, CD _? , CD ₂ R, CDRR ₂ , aryl, .heteroaryi, alkyl-aryl, alky!-heteroaryl, S ¾R¾ OR, OR _; >, Oaryl, Oheteroaryl, NHR, fluorinated alkyl difkorirsated alkyl, aifluorinated alkyl heteroaikyl, benzyl heteroaryi benzyl (C'Hjheteroaryl), propanamide, diethylpropanamide, C'HjJNHR;

R is H, aikoxy, amino, alkyl-alkoxy, alkyl, CN, cycioalkyl. alkyl-cycloalkyl, eycloheteroaikyl alkyl-cydoheteroalkyl, CFj, halogen, CDs, CD-R, CDRRj, aryl, heteroaryi, alkyl-aryl, alkyl-lieteroaryl, SO3R2, OR, OR¾ Oaryl Oheteroaryl, NHR, flaoriaated alkyl difluorinated alkyl, irifluorraaied alkyl heteroaikyl, benzyl, heteroaryi benzyl (CHiheteroaryl), propanamide, diethylpropanamide, CH2NH.R; or a pharmaceutically acceptable salt thereof or a puamiaceutically acceptable derivative thereof -with a drug known to treat the neurotransmi sion dysfunction and other disease states.

E. eiabotroptc gltitainate receptor activity

{0.164} The disclosed compounds and compositions can be evaluated for their ability to act as a potentiator of metabotropic glutamate receptor activity, in particular niGluR4 activity, by any suitable known methodology known in the art.For example, Chinese Hamster Ovary (CHO) cells transfecte with human raGluR4 or HEK ceils co-transfected with rat roGluR4 and t e G-protein regulated inwardly Rectifying Potassiaai channel (G1RK) were plated in clear bottom assay plates for assay in a Haniamatsu FDSS Fluorometric Plate Reader. The ceils were loaded with either a Ca2÷-sensitive fluorescent dye or the thallium responsive dye and the plates were washed and placed into a suitable kinetic plate reader. For human mG1uR4 assays, a fluorescence baseline was established for 3-5 seconds, the disclosed compounds were then added to the cells, and the response in cells was measured. Approximately two and a half minutes later, a concentration of mGSuR4 orthosteric agonist (e.g.

glutamate or L-AP4) eliciting a proximately 20% (EC20) of the maximal agonist response was added to the cells, and the response was measured. ^' TWO minutes later, a concentration. o mGI«R4 agonist (e.g. glutamate or L-AP4) eliciting 80% (EC80) of the maxtmai agonist response was added to the cells, and die response was measured. For rat mGluR4/CiIR experiments, a baseline was established for approximately five seconds, disclosed compounds were added, and either an EC20 or EC80 concentration of agonist was added approximately two and one half minutes later. Potentiation of the agonist response of .raGiuR4 by the disclosed compounds was observed as an ^' increase hi response to die EC20 concentration of agon ist in the presence of compound compared to the response to agon ist in the absence of compound. Similarly, antagonism of the agonist response ofmGluR4 by the disclosed compounds was observed as a decrease in response to the EC80 concentration of agonist irt the presence of compound compared to the response to agonist irt the absence of compound.

[016SJ The above described assay operated in two modes, in the first mode, a range of concentrations of the disclosed compounds are added to ceils, followed by a single fixed concentration of agonist. If the compound acts as a potentiator, an ECx _> value for potentiation and a maximum extent o -potentiation by the compound at this concentration of agonist is determined b non-linear curve fitting. If the compound acts as a noncompetitive antagonist, an JC$o value is determined by non-linear curve fitting. In the second mode, several fixed concentrations of the disclosed compounds are added to various wells on a plate, followed by a range in concentrations of agon ist for each concen trat ion of disclosed compound. The EC _¾ s values for the agonist at each concentration of compound are determined by non-linear curve fitting. A decrease in the EC _$ value of the agonist with increasing concentrations of the sample compound (a leftward shift of the agonist concentration-response curve) is an indication of the degree of roGhiSM potentiation at a given concentration of the sample compound, A decrease in the maximal response of the agonist with increasing concentrations of the sample compounds, with or without a rightward shift in agonist potency, is an indication of the degree of noncompetitive antagonism at mGIuR4.The second mode also indicates whether the sample compounds also affect the maximum response to mGluR4 to agonists.

[0166! In particular, the compounds of the folio wing examples were found to have activity in potentiating the mGluR4 receptor in the aforementioned assays, generally with an ECs for potentiation of less than about 1.0 μΜ. One aspect of the disclosed compounds have activity in potentiating rat and human mGluR4 receptors with an ECse for potentiation of less than about 500 oM. These compounds further caused a leftward shift of the agonist EC» by greater than 3-fold. These compounds are positive allosteric modulators (potentiators) of human and rat mGloR4 and were selective for mGluR4 compared to the other seven subtypes of metabotropic glutamate receptors.

F. Manufacture of a medicament

[01.67 in one aspect, the invention relates to methods for the manufacture of a medicament for potentiating mGluR4 receptor activity in a mammal comprising combining a compound having a structure represented by formula:

X is CH, C-alkyl, N, NH, N~alkyl, aikoxy, or may form a 6-mem ^' bered ring with Y optionally substituted with at least one R;

Y is CH, Oalkyi, N, or may form a 6-membered ring with X optionally substituted with at least one R ;

Z is independently N, CH, C-alkyl, C-halogen, C-Me, C-Oaikyk C-OMe;

], is O or C- _t ;

X; is O or C-R?;

R is independently H, halogen, CN, Me, aiky.1, aikoxy, OMe, aryi heteroaryi alkyi-aryl, alkyl- heteroaryi , eycioaikyl, aikyl-cycloaikyi;

j is independently II, aikoxy, amino, alkyl-alkoxy, aikyl CN, eycioaikyl, alk l~eycloaIkyI ₅ eycloheteroalkyl, alkyi-eycSoheteroalkyk CF ₃ , halogen, CD ₃ , CD _; R, CDRRj, CONR ₃ R , aryi, heteroaryi, aiky!-aryi, alkyl-heteroaryl, S0 ₂ R ₂ , OR, OR ₂ , OaryL Oheteroaryi, NHR, NR ₃ R , fluorinated alkyl, difluorinated alkyl, trifluorinated alkyl, heteroalkyl, benzyl, heteroaryi benzyl (CHjheteroaryl), propanamide, diethylpropanamide, CH>CX) R;;Ri; G-1:?NHR; CHjNHRsR*;

Rz is independently H, aikoxy, amino, alkyl-alkoxy, aikyl CN, eycioaikyl, alkyl-eycioaikyl, eycloheteroalkyl, alkyl-cyclohetm>alkyl CPs, halogen, CDs, CI¼R, CDRRs, CONR .R4, aryi, heteroaryi, alkyi-aryl alkyd-heteroaryl, SOjR OR, QR), OaryL Oheteroaryi, NHR, NR3R4, fluorinated aikyl, di fluorinated alkyl, trifluorinated alkyl, heteroalkyl, beazyi, heteroaryi benzyl (CH ₂ heteroaryl), propanamide, diethylpropanamide, CH2CONR3R4, CH ₂ NFIR; CH2 HR3R*;

Rs is H, aikoxy, amino, alkyl-alkoxy, alky 1 , CN, eycioaikyl, aikyl-cycloalkyl, eycloheteroalkyl, alkyl-cycloheteroalkyl, CP;?, halogen, CD ₃ , C1¾R, CDRRi, aryi, heteroaryi, alkyi-aryl, alkyi -heteroaryi, SO2R.2, OR, OR2, Oaryl, Oheteroaryi, NHR, fluorinated aikyl difluorinated alkyl, trifluorinated alkyl, heteroalkyl, beazyi, heteroaryi benzyl (CHjheteroaryl), propanamide, diethylpropanamide, CBjNHR; ₄ is H, alkoxy, amino, alkyl-alkoxy, aikyl C , cyc!oa!kyl alkyl-cycfoaikyi eyclohetcroalfcyi alkyl-cydoheteroalkyl, CFj, halogen, CD ₃ , CDjR, CDRRs, aryi, heteroaryi, alkyi-ary!, alkyl-heteroaryl, SO3R2, OR, ORj, Oaryl, Oheteroaryl, NHR, fluorinated alky I, difluorinated alkyi, trifluorinat d alkyi, heteroaikyl, benzyl, heteroaryi benzyl (CHiheteroaryf), propanamide diethyipropaaamkie, CBjNHR; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable deri vative thereof with a pharmaceutically acceptable carrier.

[0168] Thus, the disclosed compounds and compositions can be further directed to a method for the aaufacture of a medicament for potentiating glistaraate receptor activity (e.g., treatment of one or more neurological and/or psychiatric disorder and other disease states associated with glutamate dysfunction) in mammals (e.g., humans) comprising combining one or more disclosed compounds, products, or compositions with a pharmaceutically acceptabie carrier or diluent.

G. Uses of compounds

{O.M>9| In one aspect, the inventio relates to uses of caaipouad for poteatiating aiGluR4 receptor activity in a aianimaL wherein the compound has a structure represented by formula:

wherein X is CH, C-aikyi, N, MH, -alkyl alkoxy, or may form a 6-mernbered ring with Y optionally substituted with at least one R;

Y is CH, C-alkyi, , or may form a 6-membered ring with X optionally substituted with at least one R;

2 is independently K CH, C-alkyl, C-halogen, C-Me, C-Oalkyl, C-O c;

2. is 0 or ø¾

R is indepeadentiy H, halogen, CN, e _s aikyl, alkoxy, OMe, aryi heteroaryi alkyl-aryl, aikyl- heteroaryi , eycioalkyi, alkyl-eycloalkyl; ; is independently H, alkoxy, amino, aikyl-alkoxy, alkyl, CN, cycloalkyl, alkyl-cycloalkyl, cycloheteroalkyl, alkyl-cydoheteroalkyL CF,, halogen, C¾, CD ₂ R, CDRRa, CONR ₃ R ₄ , aryl, heieroaryl, a kyl-ary alkyl-heteroary SOjR ₂ , OR, OR _¾ Oaryl Oheteroaiyl NHR, NR3R , fluorinated alkyl, difiuorinated alkyl, trifiuorinated alkyl, heteroalkyl benzyl, heteroaryi benzyl (CHiheteroaryi), propanamide, diethylpropanamide, CH ₂ CON ^" R _s R ₄ ; C¾NHR; CH2NHR3R4;

2 is independently H, alkoxy, amino, aikyl-alkoxy, alkyl, CN, cycloalkyl, alk l-cycloalkyl, cycloheteroalkyl, alkyi-cycloheteroalkyl, CF ₃ , halogen, CD ₃ , CD ₂ R, CDR¾ , CONR?R ₄ , aryl,

heicroaryl alkyl-aryl alkyl-heteroaryl S<¼R _} , OR, QR _U Oaryl Oheteroaryl, NHR, NR ₃ R , fluorinated alkyl diiluorinated aikyl triflnorinated alkyl heteroalkyl benzyl, heteroaryi benzyl (CHjheteroaryl), propanamide, diethylpropanamide,. CH ₂ CONR. ₅ R. _i5 CH ₂ NHR;

Rj is H, alkoxy, ainrao, aikyl-alkoxy, aikyl C , cycloalkyl, alky!-eyeloalkyL cycloheteroalkyl, alkyf-cyclohcteroalkyf, CF _¾S halogen, CD ₃ , CD,R, CDRRj, aryl, heteroaryi, alkyi-aryl, alkyl-hcteroaryl, S0 ₂ R _2> OR, OR ₂ , Oaryl Oheteroaryl, NHR, fluorinated alkyl, difiuorinated alkyl, irifluorinated alkyl heteroalkyl, benzyl, heteroaryi benzyl (Cl-fcheteroaryl), propanamide. diethylpropanamide, CHjNHR

R,! is H, alkoxy, amino, aikyl-alkoxy, alkyl, CN, cycloalkyl, alkyl-cycloalkyl, cycloheteroalkyl, alkyi-cycloheteroalkyl CF _3> halogen, CD ₃ , C1¾R, CDRR ₂ , aryl heteroaryi, alkyl-aryl alkyl -heteroaryi, SO ₂ R ₂ , OR, OR ₂ , Oaryl, Oheteroaryl NHR, fluorinated alkyl, difiuorinated alkyl trifluorinated alkyl heteroalkyl, benzyl, heteroaryi benzyl (CH ₂ heteroaryl), propanamide, diethylpropanamide, Ct¾NHR; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof

JO170] The disclosed uses for potentiating mGh»R4 receptor activity in a mammal can further be directed for use in treating one or more disorders, for example neurological and psychiatric disorders and other disease states associated with gluiamate dysfunction (e.g., Parkinson ^' s disease) in a subject, for example a mamma! or a human.

H. KITS

10171] In one aspect, the invention relates to kits comprising a compound having a structure represented by formula:

wherein X is CH, C-alkyl, N, NH, N~alkyL alkoxy, or may form a oVraembered ring with Y optionally substituted with at least one R;

Y is CH, Oalkyi, N, or may form a 6-membered ring with X optionally substituted with at least one ;

Z is independently N, CH, C-alkyl, C-halogeu, C-Me, C-Oalkyl, C-OMe;

], is O or C- _t ;

X; is O or C-R?;

R is independently H, halogen, CN, Me, aikyi, alkoxy, OMe, aryi heteroaryi alkyl-aryl, aikyi- heteroaryi , cycioalkyl, alkyl-cyeloalkyi:

j is independently H ₅ alkoxy, ammo, aikyl-alkoxy, aikyi, CN, cycioalkyl, alk l-cycloalkyl, cycloheteroaikyl, alkyi-eycioheieroalkyk CF _3> halogen, CD ₃ , CD _; R, C ^' RR ₃ , CONR ₃ R , aryi, heteroaryi, alkyi-aryl, alkyl-heteroaryi, S0 ₂ .2- OR, R ₂ , Oaryi Oheteroaryl, HR, NR. ₃ R , fluorinated alkyl, difluorinated aikyi, trifluormated alkyl, heteroaikyl, benzyl, heteroaryi benzyl (CHAeteroaryl), propanamide, diethyl propanamide, CHjCONRsRt; CHj HR; CHjNHRs *;

Rz is independently H, a!koxy, amino, alkyl-alkoxy, alkyl, CN, eyci.oai.kyl, alkyl~eyci.oai.kyl, cycloheteroaikyl alkyl-cycioheteroalkyl CF ₃ , halogen, CD ₃ , CD _;? R, CDRRs, CONR .R4, aryi,

heteroaryi, alkyi-aryi aSkyHieieroaryL SOjRt, OR, OR), Oaryi, OheteroaryL NHR, NR3R , fluorinated alkyl, difluorinated aikyi, trifluoriaated alkyl, heteroaikyl, beazyi, heteroaryi benzyl (CH ₂ heteroaryi), propanamide, diethylpropanaroide, Ci¾CONR ₃ R4, CH ₂ NF1R; CH2NHR3R*;

Rs is H, alkoxy, amino, alkyl-alkoxy, aikyi, CN, cycioalkyl, alkyl-cyeloalkyi, cycloheteroaikyl, alkyl-cycloheteroalkyi, CP;?, halogen, CD ₃ , C1¾R, CDRRi, aryi, heteroaryi, alkyi-aryl, aikyi -heteroaryi, SO2R.2, OR, OR2, Oaryi, Oheteroaryi, NHR, fluorinated aikyi, difluorinated alkyl, trifluorinated alkyl, heteroaikyl, beazyi, heteroaryi benzyl (CBjheteroaryl), propaiiatnide, diethylpropananiide, CHjNHR;

- 7.1 - ₄ is M, alkoxy, amino, alkyl-alkoxy, alkyl, C , cycloaifcyl, alkyt-cycloaikvi eycloheicroalfcyl, alkyl-cydoheteroalkyl, CFj, halogen, CD ₃ , CDjR, CDRRs, aryl, heteroaryl, alkyi-aryl, alkyl-heteroaryl, SO3R2, OR, ORj, Oaryl, Oheteroaryl, NHR, fluorinated alkyl, difltwrinated alkyi, trifluorinat d alkyi, hetcroalkyl, benzyl, heteroaryi benzyl (Q¾heteroaryS} ₅ propanamide, diethyipropanamkk, CBjNHR; or a pharmaceutically acceptable salt, thereof or a pharmaceutically acceptable derivative thereof and one or more of a drag having a known side-effect of increasing metabotropic glutamate receptor activity, a drug known to treat a disorder associated with increasing metabotropic gluiamate receptor activity, and/or a drug known to treat ike neurotransmission dysfunction and other disease siates.

[01:72] In various aspects, the kits can comprise disclosed compounds, compositions, and/or products co-packaged, co- formulated, and/or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, or a pharmacist can provide a kit comprising a disclosed oral dosage forms and another component for delivery to a patient.

J0173J In further aspects, the kits ca comprise one or more other components (e.g., one or more of a drug having a known side-effect of increasing metabotropic gluiamate receptor activity, a drug known to treat a disorder associated with increasing metabotropic gluiamate receptor activity, and/or a drag known to treat the neurotransmission dysfunction and other disease states) and instructions for coadministration to a patient with one or more disclosed compounds, compositions, and/or products. For example, a drug manufacturer, a drug reseller, a physician, or a pharmacist can provide a kit comprising one or more other components (e.g., one or more of a drug having a known side-effect of increasing metabotropic gluiamate receptor activity, a drug known to treat a di order associated with increasing metabotropic gluiamate receptor activity, and/or a drug known to treat the neurotransmission dysfunction and other disease states) and instructions for coadministration to a patient with one or more disclosed compounds, compositions, and/or products.

H. Experimental

[01.74} The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, de vices and/or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.

|¾175] Several methods for preparing the compounds of this invention are illustrated in the following Examples. Starting materials and the requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures or as illustrated herein. All NMR spectra were recorded on either a Varian. Ittovs 400 (400 MHz) or Varian. Inova 500 {500 MHz)

spectrophotometer. ' H chemical shifts are reported in δ values in ppm dowtifteld from Me* Si as the internal standard in CDC1 _? . Data are reported as follows: chemical shift, multiplicity (s - singlet, d ~ doublet, t - triplet, q ~ quartet, br - broad, m ~ mitldplet), integration, coupling constant (Hz). ^!' C chemical shifts are reported in 3 values in ppm with the CDCL carbon peak set to 77.23 ppm. Low resolution mass spectra were obtained on an HPi 1.00 MSD with eleetrospray ionization. High

resolution mass spectra were recorded on a Broker Dai tonics 3Ϊ Fourier transform ion cyclotron resonance mass spectrometer (FT/ICR) with eleetrospray ionization. Analytical thin layer

chromatography was performed on EM Reagent 0.25 mm silica gel 60-F plates. Analytical HPLC was performed on an HP! 1 0 with UV detection at 214 and 254 run along with ELSD detection, LC/MS (J- Sphere80-C18, 3.0 x 50 mm, 4.1 rain gradient, 5 |;0.05%TFAC¾CN]:95%};0.05%TFA/¾O] to 100% [0.05%TFA/CH;tC ^" j. Preparative purification was performed on a custom HPI 100 purification system (reference 16) with collection triggered fay mass detection. Solvents for extraction, washing and chromatography were HPLC grade.N-Boe-p~phenylenediamine was purchased from Fluka and 1,2- beozeoedisu fonyi diehloride was purchased irom TCI America. Ail other reagents were purchased from Aldrieh Chemical Co. and were used without purification.

Genera! Scheme 1

¼

General Procedures: (2). To a solution of 3-bromophcnol (I) (1.0 cq) in Diehloroeihane (1.2 ) was added Α!(¾ ( 1.5 cq) in three e ual portions over 5 rain period. After 5 rain, the acid chloride (1.02 eqj was added dropwise and the rxn was heated to reflux. After 12b, the heat was removed. The rxn was poured onto tee/ IN HO (1: 1 , 50 rsL). The mixture was extracted with EtOAc (3x) and the combined organic layers were washed with brine, dried (MgSO,<) and filtered. After the solvent was removed, the crude residue was purified by norma! phase chromatography (Biotage, 0-10% EtOAc/hexanes) to afford the desired product.

(3). A. solution of ?M NH in MeOH (5 eq) was added to (2) (leq) at rt. After 30 min, a bright yellow precipitate was observed. After an additional 30 min, the rxn was filtered and the yellow precipitate was washed with cold MeOH. After the solid was dried overnight, the desired hydroxy), inline was obtained and taken through without any further purification.

(4&5). To a solution of (3.) ( cq) and K ₂ CO ₃ (2eq.i in THE (0,15 M) at rt was added N- ehlorosucehiiniide (1 .5eq). After 12h at rt, LCMS confirmed product. The rxn was added to

EtOAcrwater (1:1) and the organic layer was separated. The organic layer was further washed with water (2x1 brine and dried (MgSO^). After filtration, the solvent was removed under reduced pressure. The crude residue was purified by normal phase chromatography (Biotage, 1 0% DCM) to afford pure material (4) and when observed the chlorinated (5).

(6) in a microwave vial, was added (leq), NaO'Bu (2. J eq), 'BuXPhos (1 mo! %) and ^' 'BuXPhos Pailadaeycle (l mol%). The vial was sealed and evacuated and purged with Argon (3s). A solution of (4) { icq) in ^l BuOH was added and the rxn was heated to 60°C. After 4h, the rxn was added to Et0Ae;Nl¾ (aoj (1 :1). The organic layer was separated and washed with water (2x), brine and dried (MgSO*). After filtration, the solvent was removed under reduced pressure. The crude residue was redlssoived in TF A. 'toluene (! :1 ) and subjected to microwave irradiation at 140°C for 20 min. The solvent was removed and the crude residue was purified by reverse phase chromatography (Gilson, 20-80% acetonitrile:water w/ .1 % TFA). The collected fractions were neutralized with NaHCO _? (aq); EtOAc ( 1 :1) and the organic layers were concentrated to provide desired product.

General Scheme 11

' i

¾

2} i ^' F ^' A. toEuerie

3

General Procedures:

(7) . A solution of 7M N¾ in MeOH (5 eq) was added to hydroxyketone (ieq) at rt. After 30 mm, a bright yello precipitate was observed. After 12h, the rxn was filtered and the yellow precipitate was washed with cold MeOH, After the solid was dried overnight in a vacuum dessicator, the desired hydroxy! iraine was obtained and taken through without any further purification.

(8) . To a solution of (7) ( ieq) aad K ₂ CO ₃ (2eq) in THF (0.15 ) at rt was added -ch!orosucciftitnide (1 .5eq). After 12h at rt, LCMS confirmed product. The rxn was added to EtOAc:water (1:1) and the organic layer was separated. The organic layer was further washed with water (2x) ₅ brine and dried (Mg${¾). After filtration, the solvent was removed under reduced pressure. The crude residue was purified b normal phase chromatography (Biotage, 1 0% DCM) to afford pure material (8).

(9) in a microwave vial, was added H -.metlK) yben^l)-lH- TazoloH "b.| > din^-amme (ieq).

NaO'Bu (2.1 eq), 'BuXFhos (1 mol %) and 'BuXPhos Palladaeycle (imoi%). The vial was sealed and evacuated and purged with Argon (3x). A solution of (8) ( Icq) in 'BuQH was added and the mi was heated to 60°C. After 4h, the rxn was added to .EtOAc:NH. _t Cl (aq) (1 :1 ). The organic layer wa separated and washed with water (2x), brine and dried (MgSO*). After filtration, the solvent was removed under reduced pressure. The crude residue was redissoived in TFA;tohsene (1 : 1) and subjected to microwave irradiation at: 140°C for 20 min. The solvent was removed and the crude residue was purified by reverse phase chromatography (Glison, 20-80% acetonitriie: water w/0.1% TFAj. The collected fractions were neutralized wtth NaHC i (aq): EtOAc and the organic layers were concentrated to provide desired product.

General Scheme 111;

IS i«

Genera] Procedures:

(10) To a solution of 4-bromo-2-hydroxy benzoic acid (1 eq) in Methanol (0.2 M) at tt was added sulfuric acid (1 eq) . The dark red brown solution was heated to 75 for 12 h. LCMS confirms product. The rxtt was concentrated and crude residue was partitioned between EfOAe: water (1 : 1 }. The organic layer was washed wiih NaHCO.? faq), water and dried (MgSC ). After filtration, the organic layer was concentrated to give a tan solid (58%).

(11) To a solution of hydroxy laraiiie hydrochloride (1.5 eqjand NaOH (3.5 eq) in water (0,25 M) was added Methyl 4-bromc-2-hydroxyben2oate (1 eq)in L4-dioxa«e (2,0 M) dropwise. The reaction turns light yellow shortly after addition. The solution is stirred at rt for 1 8hrs. 1 ,4-dioxane was removed in vacuo and HQ (2N) was added until a precipitate was formed. The heterogenous mixture was filtered and washed with water. The solid was dried overnight in a vacuum oven to give the title compound.

(12) A solution of ί ,Γ-earbonyidiimidazoie (2.0 eq) in THF (0,1 M) was added dropwise to a rcfluxing solution of 4-bromo~2~hydroxy~be:nzertecari ohydfoxar)iie acid (1.0 eq) in THF (0.15 M) and then stirred for 2h at reihrxing conditions. The THF was removed under vacuum and the residue was suspended ia water. HO (2 ) was added dropwise at rt. A precipitate formed and was collected by filtration, washed with water and dried overnight ia a vacuum ovea to afford 6-bromo- 1 ,2-benzoxazol- 3-0.1 (95% yield).

(13) 6-bron¾ .l _i 2-benzoxazoi-3-ol (L0 eq), potassium carbonate f 1.5 eq) were added to a bf, followed by DMF (0.2 M). 4-Methoxybeayl chloride ( i.l eq) was added and the rxn was stirred overnight at rt. LCMS shows both product regioisoraers, Rxn is added to water (0.1 M) and extracted with EtO Ac (2x). The combined extracts are washed with water (3x), brine, and dried over MgSO.*. Solvent was removed in vacuo and the residue was purified by normal phase chromatography ( 15-30%

EiOAciiexaoes). The two regioisomers were collected separately. The major product, 6-bronio-3-{(4- methoxyphenyl }methoxy] ^« 1 ,2-benzoxazo e (39% yield)and the minor product 6~bromo-2-i(4~

methoxyphenyl)methyl ^' j-l,2-benzoxazol-3-one (.15% yield).

(14) To a rxn viat was added - ^ mio-3-|(4~methoxyphe» l)methoxy}-l ,2-bei oxazole (I .0 eq), cesium carbonate (2.0 eq), l-{ ^' (4^methox 9hen )niemyl]pyrazolo(4,3-bipyridiu-3-anune (1.1 eq), XPhos (0.15 eq), Pd _? (dba).¾ {0,075 eq). The rxn was evacuated aod purged with Nitrogen (3x) _> followed by the addition of I,4~Dioxane (0.0? M). The heterogenous rxa was heated to 100 ° After 24h, the rxrt was added t N¾C! (aq):EtOAc, the organic layer was collected, washed with water, brine, dried over MgSO. _t and the solvent was removed. Residue was purified by normal phase chromatography (.1 - 65% BtOAcihexanes). The product was dissolved in Trichloroacetic acid (7,5 mL) and Toluene (5 mL) and the solution were transferred to a 20 mL MW vial, The rxn was subjected to 150 °C in the MW for 45 min. After LCMS confirms complete loss of the PMB protecting group, the solvent was removed. The material was carried through withou t further purification.

15 16

(IS) & (16) AikyS haiide (.1.0 eq) and potassium carbonate (3.0 eq) were added to a 2 ml, ₍ uW vial A solution of eKl H- yrazoloiA^bjp r din-S-ylam no^I- -benzo a/ il-S-ol; 2,2,2-trifluoroacenc acid (1.0 eq) in DMF (1.5raL) was added to the MW vial. The mixture was subjected to 120 ¹ € in the MW for 15 rain. LCMS shows two products formed, Rxri was syringe filtered and purified by GOson HPLC ( 15-85% acetonitrilervvater with 0.1 %TFA). The two products were collected separately, free based aHCOj (aq), extracted with EtOAe and washed with water (2x). The solvent was removed to afford the products (IS a d 16).

General Scheme IV;

19

General Procedures:

(17) To a suspension of pyridine (3.0 eq) and 6-brorao-l _« 2-benzoxaaol-3-ol (1.0 eq) in DCM (0,05 M) at 0"C under nitrogen was added triflooromethanesoifonic anndride (1 ,5 eq, 1 M in DCM), dropwise. After 10 rain, the ice bath was removed, it was stirred for an additional 45 rain at rt.Rxti was added to DCM: Water (1 : i ), The organic layer was separated with the hydrophobic phase separator, solvent was removed and the product (6-brorao-i ,2-benzoxazol-3-yl ) trifluororaedianesulfonate was carried forward without further purification.

(18) To a 2mL μ\¥ vial was added amine (5.0 eq), (6-bromo-.l ,2-benzoxazol-3-yl)

trifl«oromcthaiiestilfoiiate ( 1.0 eq), and l-methy]-2pyrroHdirtone (0.5 M), The rxn was heated to 130 ' ^' C for 15mm in the MW. LCMS confirmed product and the rxn was added to ΕίΟΑει .Η (1:1). The organic layer was collected and the aq. layer re-extracted with EtOAc (2x). The combined organic extracts were washed with water, brine, and dried over MgSO,*, filtered and concentrated. The crude residue was purified by normal phase chromatography (25-85% EtOAe:hexanes to yield desired product (9-20% yield).

(19) In a microwave vial, was added Ϊ -(4-methoxybeiizyI)- ^■ lH-p razo!.o| _> 3-b]pyridis-3-amise ( cq), NaO'Bu (2.1 eq), TiuXPhos (1 mol %) and ^l BuXPhos Pailadaeycle (l moi%). The vial was sealed and evacuated and purged with Argon (3s). A solution of (18) ( icq) in 'SuOH was added and the rxn was heated to 90°C. After 4h, the rxn was added to EtOAc :ΝΗ Ί (aq) (1:1). The organic layer was separated and washed with water (2x), brine and dried (MgSO^. After filtration, the solvent was removed under reduced pressure. The crude residue was redissoived in TFA. olu ne (1 :1 ) and subjected to microwave irradiation at I40°C tor 20 min. The solvent was removed and the crude residue was purified by reverse phase chromatography (Gilson, 20-80% aeetonitriie:water w/0.1 % TFA). The coUeeted fractions were neutralized with NaHCOj (aq): EtOAc (1 :1) and the organic layers were concentrated to provide desired product.

General Scheme V;

(20). A solution of methyl 2-(4-brarao-2-mtropbenyl )acetate (3.43 g, 12.5 .ramoi, 1.0 eq.) in ethanol (62.5 mL, 0.2 M) was treated with isoa yl nitrite (2.1 mL, 16.25 mmol, 1.3 eq.) a d- sodium ethoxide (893 mg, 13.13 mmol, 1.05 eq.). The reaction mixture was stirred at 60 °C. After 24 h, the mixture was neutralized with 1M HO solution and concentrated. The residue was extracted with EiOAc (3X). The combined extracts were washed with brine, dried over Na SO,*, filtered and concentrated. Purification using Hash chromatography an silica ge! (0-35% EtOAc/hexanes) to provide the title compound as a pale yellow solid (1.73 g, 51% yield): ES-MS ( - 1 f : 270.2

(21). Iris{dibenzylideneacetoae)dipailadiuffi (123.6 mg, 0.14 mmol, 9.0 MO1%), XantPhos ( 104 mg, 0. Ϊ 8 mmo ^' l. 12 moi%), ethyl 6-bromobenzo|d]isoxazole-3-carboxylate (608 mg, 2.25 mmol, 1.5 eq.),l- jX4 raemoxypheny1)me&yI}pyjrazofo^ _^ (381 mg, 1.5 mmol, 1.0 eq.) and cesium carbonate (731 rag, 2.25 mmol. 1 ,5 eq.) were charged in a microwave vial. The vial was evacuated and purged with nitrogen (3X) and 1,4-dioxane (7.5 mL) was added. The reaction mixture was subjected to a microwave reactor tor 140 "C. After 2 h, the reaction mixture was cooled and filtered through a pad of Celite which was washed with EtOAc. Solvents were removed. Purification using reverse phase (Giison HPLC, acidic method (ACN water/0.1% TFA), gradient; 61-91%). Giison fractions were neutralized with sat solo. NaHC<¼ and extracted with EtOAc (3X). The combined extracts were washed with brine, dried over Na-jSCu, filtered, and concentrated to provide the titie compound as a light yellow solid (370 mg, 55 % yield): ¾ NMR (400 MHz, DMSO~<¾) 3 10.1 (s, 1 H), 8.49 (dd, 1.2, 4.3 Hz, IK), 8.4? (4 J ~ 1 .5 Hz, i H), 8.1 S (dd, J- 1.2, 8.6 Hz, 1H), 7.88 (d, ~ S.8 Hz, 1 H), 7.75 (dd, J ^::: 1.8, 8.8 H¾ IH), 7.48 (dd, ./ - 4.3, 8.6 Hz, l H), 730 (d, J ^::: 8.7 Hz, 2H), 6.88 (ddd, J - 2.9, 4.9, 8.7 Hz, 2H), 5.56 (s, 2H), 4.87 (q, 7.0 Hz, 2H), 3.70 (s, 3H), 1.41 (t, J = 3.2 Hz, 3H). ES-MS ΓΜ+l f : 443.3.

(22). To a solution of ethyl 6 ^« (( \ ^« (4-methoxybeozyl)-lH-pyTazoloi4,3-hJpyridin-3 ^«

yl)attuao)bettzo[djisoxazole-3-carboxylate (300 mg, 0,79 mmol, 1.0 eq) in 1 ,4-dioxane (3,9 mL) at 0 was added a solution of IN LtOH (2.76 mL, 2.76 mmol, 3.5 eq.), ^' The reaction mixture was stirred at rt. for 45 min. Solvent was removed. The aqueous layer was adjusted to p ^' H 3-4 with IM HC! solution.

The resulting mixture was extracted witli CHCViPA (3: 1, v/v, 3 ),T e combined extracts were concentrated to provide the title compound as a yellow solid (280 mg, 85.4% yield): ES-MS (M-H : 41 .2. Note: Decarboxylation will occur upon heating the sample.

General Procedure (23): A mixture of 6-((l-(4-methoxy benzyl)- I H-pyrazoioj 4,3-bjpyridin-3- yi}amino)beazoS ^' d|isoxazole-3-earboxy1:fe acid (.14,45 mg, 0.035 mmol, 1 ,0 eq.), amine (0.07 mmol. 2.0 eq.) and HATU ( 19,96 m , 0.05 mmol, 1.5 eq.) in DM.P (.1 .0 mL) was stirred tor 5 min at rt and DIEA (9.55 uL, 0.07 mmol, 2.0 eq.) was added. The reaction mixture was continued to stir at rt for 45 min. U n completion by LCMS, the reaction mixture was purified using reverse phase Giison HPLC system with acidic method (ACNAvater/O.1 % TFA). The Giison fractions were concentrated. The resulting residue was dissolved in TFA (0.1 M) and heated in a microwave reactor for 30 min at 150 "C. Solvent was removed. The crude product was purified using reverse phase Giison HPLC system with acidic method (ACN water/0, 1% Tf A). The sample was concentrated and submitted as a TFA salt.

Scheme V :

(24) . equiv), ! ~(6- bromo- 1 _> 2-benzoxiU»l-3-yI)erhanone (1 equiv), cesium carbonate (3 equiv), XantPhos (0.05 equiv), and -.is(dibenzyIideneacetone)dipalladjui»(0)-chlorofonti adduct (0,05 equiv) were added. The vial was evacuated and purged with Nitrogen, three times. Then, dtoxanc (10 mh) was added info the vial The mixture was stirred at room temperature for 3 min, and heated under microwave irradiation at 140 °C for 30 rain. The mixture was filtered through celite _f and the filtrate was concentrated under reduced pressure. Then, the resulting residue was purified by column chromatography, eiuted with 0% - 70% ethyl acetate in he ane, to afford the -product.

(25) . To a solution of H _. e^ I ^mc&ox Dcn^lVlH-p r z^loH^-bl yridi -S- yi)anitno)benzo|d]isoxazot-3-yl}cihati-l-one (1 equiv) to methanol (0.25 )„ 4- methy!ben^eriesiilfonohydrazide (.! equiv) was charged. The solution was stirred at room temperature for Ih or until all starting material was consumed. The mixture was then concentrated under reduced pressure and purified by column cinematography, eiuted with O%-50% ethyl acetate in hexane, to afford the product.

(26) . To a solution of (E)-N'-(l~(6-((.l

yi)amiiio)beazo d]isoxazoi-3-yl)eihyitdeue)-4-met >4 (] equiv) in dioxane

(0.07 M), boronie acid (1.5 equiv) and potassium carbonate (3 equiv) were charged. The mixture was stirred at 1 1 °C for overnight. After stirring, the mixture was filtered through syringe filter, and the filtrate was concentrated The residue was purified by HPLC, eiuted with 15% - 100% aceio trik in water with 0.5 mL L NH ₄ OH. The resulting solid was dissolved m TFA (0.07 ) and stirred under microwave irradiation at 130 "C for 30 mia. The solution was concentrated, and the residue was purified by HPLC, elated with 15% - 100% acetonitriie in water with 0,5 mL L N¾OH„ to obtain the final product.

Scheme VT!:

1.

2. T

(27) . To a solution of6-b£omoben2»|d]jsoxazole-3-carbaldehyde (1 equiv) in methanol (0.25 M), 4- methylbeftzenesulfotjohydfazide (.! eqaiv) was charged. The solution was stirred at room temperature for ih or until all starting material was consumed. The mixture was then concentrated under reduced pressure and purified by column chromatography, eiuted with 0%-50% ethyl acetate in hexane to afford the product.

(28) . To a solution of (Z)-N' (6-bromobenzo|d]isoxazol-3-yl)ri5ethylene) ^« - niethyiherrzenesttlfoiiohydrazide (I equiv) in dioxane (0.07 M), boronic acid ( 1.5 equiv) and potassium carbonate (3 equiv) were charged. ^' The mixture was stirred at 1 1 *C for overnight. After stirring, the mixture was filtered with syringe filter. The filtrate was purified by HPLC. eiuted with 15% - 100% acetonitriie in water with 0.5 mL/L Ν¾ΟΗ, to obtain the product, I.

(29) . To a microwave vial, i-(4-methoxybenzyl)-l H-pyrazoioj _. 4,3-b ^' jpyridin-3-atnine (1.1 equiv), J (1 equiv), caesium carbonate (3 equiv), XantPhos (0.05 equiv), and

tris(dibenzylidmeacetone)dipalladmm(0H^h1oroforra adduct (0.05 equiv) were added. The vial was evacuated and purged with Nitrogen three times. Then, dioxane (0.07M) was added into the vial The mixture was stirred at room, temperature for 3 min, and heated under microwave irradiation at 140 "C for 30 mm. The mixture was filtered through syringe .filter, and the filtrate was concentrated. Then, the resulting residue was purified by HPLC, eiuted with 15% - 100% acetonitriie in water with 0.1 % TFA, The resulting solid was dissolved in TFA (0,07 M) and stirred under microwave irradiation at 130 "C for 30 mm. The solution was concentrated, and the .residue was purified by HPLC, cmted with 15% · 300% acetooiirile in water with 0.5 tuL/L NH ₄ OH, to obtain the fiaai product.

General Scheme VOI:

(30) . To a solution of l-(6½x>mobenzo[d)isoxazoi-3-yl)ethai -!-one {1.0 eq) in THF (0.15M) at -78 was added a solution of cycJoproylmagnesium bromide (2.0 eq) m THF ( .5M). After 2h at ~78 ^* C, N¾C1 (aq) was added dropwise and the cold bath was removed. The rxn was extracted with EtOAc (2x) and the organic iayer was washed with water, brine and concentrated. The residue was purified using normal phase Biotage Isolera (0-i5% EtOAc hexanes) to afford .1 -(6~bromobenzo[dJisoxazo!-3~ yl)~i-cyelopropySethan~i~ol (85% yield).

LCMS (90 sec. method); T ^::: 0,912 min, m ^' Na- 304.0

(31) . To a solution of l ^' 6-biOmobenzo| ^" d|isosa2o!-3-yl)-l-cyciopropykthan-i-oi (Ϊ .0 eq) in DCM

(0. i.M) was added DAST (3.0 eq) at 0 ^ci C. The ice bath was removed. After 2h, NaHCOs (aq) was added dropwise to the rxn. The rxn was extracted with DCM (2x) and the organic layer was passed through a phase separator. After concentration _f the residue was purified using normal phase Biotage Isolera ( Ig column, liquid loading, gradient: 0-15% EtOAc/hexanes) to rovide 6-bronio-3-(I- cyelopropyS - 1 -fl uoroethyS )benzo|d] isoxazo!e (40% yield) .

LCMS (90 sec. method); RT=== 1.274 mill m H- 284.2

(32). In a microwave vial was added e-tero ^SKi^ c it ^y yl-i-f aoiOediyiJ eRzoldjjsoxazoIe (LO eq), Fd;(db j3 (0.18 eq), Xanfphos (0.24 eq), Cesium Carbonate (2.1 eq) and l-(4-meiliOxybeiiz l)-.l H- pyrazolo 4,3 >}pyridin~3-amine ( 1 .0 eq). The mixture was evacuated and purged with Nitrogen (3x), followed by the addition of 1 ,4-dioxane (0.1 M). The rxn was heated to 150°C for 1 h i the microwave. After confirmation of product via LCMS, the mixture was filtered throiigh a pad of Ceiite and washed with EtOAc. After the solvent, was removed, the crude residue was purified by reversed phase Gilson HPLC (60-90% acefconiirile/water with 0.1 % TFA). The collected fractions were neutralized with

MaHCO _.? (aq _. ) and extracted with EtOAc (3x). The combioed extracts were washed with brine, dried (MgSO^), filtered and concentrated under reduced pressure. The residue was dissolved in toluene :TF A (1 : 1 ) and heated to 150 ^' C in the microwave. After the solvent was removed, the material was purified by reversed phase Gilson HPLC (60-90% acetonitrile/water with 0.1% TFA). The collected fractions ere neutralized with NaHC<¼ (aq) and extracted with EtOAc (3x). The combined extracts were washed with brine, dried ( gSO*), filtered and concentrated under reduced pressure to afford 1~(6-((1H-

LCK'fS (90 sec. method): RT~ 0.754 mm, +H= 336.2

General Scheme ΪΧ:

33 3

(33). in a microwave vial was added ¾ t»0-3- 2-fliiofohexati''2*'yl) enzoidj}s xazoie (TO eq), Pdj(d.ba)3 (0.1 eq), Xantphos (0.24 eq). Cesium Carbonate (2, i eq) and ferr-butyl carbamate (1.0 eq). The mixture was evacuated and purged with Nitrogen (3x), followed by the addition of L4-dioxa«c (0.1 M). The rx.u. was heated to 140 ^':i C for ih in the microwave. After c aiftrraation of product via LCMS, the mixture was Filtered through a pad of Celite and washed with EtOAc. After the solvent was removed, the erode residue was taken forward without further purification.

LCMS (90 sec. method): RT ^:::: 1.152 rai m+H= 337.2

The above materia! was disso! ved in TFA:DCM (1 :5; 0.1 M) at rt. The rxn was monitored by LCMS. After complete consumption of starting material, the solvent was removed. The crude residue was purified by reversed phase Gtlsoo HPLC (60-90% acetoiiitnleAvater with 0.1% TFA). The collected fractions were neutralized with NaHC<¼ (aq) and extracted with EfOAc (3x). The combined extracts were washed with brine, dried ( gSO.i), filtered and concentrated under reduced pressure to afford 3<2-fluoiX hexan-2-yl)bei^o{d|isoxa5Eol-6-arame.

LCMS (90 sec. method): RT- 0.930 min, m÷H= 237.2

(34). In a vial was added 3-(2-rIuorohexan-2-yl)benzo[d]isoxazo!-6-amine (1.0 eq), Pck(dba)3 (0.18 eq), Xantphos (0,24 eq), Cesium Carbonate (2.1 eq _. ) and 3-bromo- .l-(tetrahydro-2H-pyrau-2-yl.)-Ill- pyrazolo[4J-b]pyridine (1.0 eq). The mixture was evacuated and purged with Nitrogen (3x1 followed by the addition of .1 ,4-dioxane (0.1 M). The rxn was heated to 1 OfPC. After 12h, the reaction was removed from the heat and cooled to rt. The rxn was added to EiOAcrNHtCl (aq) (! : 1 ). The organic layer was separated and washed with water (2x), brine aud dried (MgSO*). After filtration, the solvent was removed under reduced pressure. The crude residue was purified by reversed phase Gilson HPLC (35-95% aeetonitrile/water with 0.1 % TFA). The collected fractions were concentrated.

LCMS (90 sec, method): RT= 1.21 min, m÷H= 438,2

The above material was dissolved in 4N HQ in MeOH (O.IM.) at rt. The rxrt was heated to 55 ^a C, After complete consumption of starting material, the solvent was removed. The crude residue was purified by reversed phase Giison HPLC (25-95% acetonitriie/water with 0.1% TFA). The collected fractions were neutralized with NaHC<¼ (aq) and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried (MgS0 ₄ ), filtered and concentrated under reduced pressure to afford

amine.

LCMS (90 sec. method): RT= 1 ,038 rain, .m+H= 354.2

General Scheme X:

(35) Acid Chloride method: To a solution of 3-neopentyl-N-(.l H-pymzoio[4 ₅ 3-b]pyri.dijJ-3- yi)benzo[d]isoxazol-6-amine (1.0 eq) ia DMA (0.2M) at ft was added C¾C<¾ (2,0 eq). After 15 mm, acid chloride (1,5 eq) was added. After an additional 30 min, the rxn mixture was diluted with BtOAc:water (1 : 1 ). The organic layer was separated and washed with water (4χ}„ dried (M SO^, filtered and concentrated. The crude residue was purified by reversed phase Giison HPLC (60-85% aeetonitrile/waier with 0.1% TFA). The collected fractions were neutralized with NaHCOj (aq) and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried {.MgSQ*}, filtered and concentrated under reduced pressure to afford the desired amide,

(35) arboxylk Acid Method: To a vial was eharged carboxylie acid (3,0 eq), HOBt (3,0 eq), EDC (3.0 eq) and NMP (0.3 ) at rt. Once a solution was achieved, a solution of ^' S-neopentyl- - -iH- pyrazolo[4 ₅ 3-b]pyridi -3-yi)bcnzoj ^' d isoxa^ (.1.0 eq) in NMP (0.5M was added dropwise.

DMAP (3,0eq) was added. After 30 rain, TFA was added until a solution was obtained. The crude rxn was purified by reversed phase Giison HPLC (30-60% aeeionitrile/water with 0.1% TFA). The collected fractions svere neutralized with NaHCOj (aq) and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried ( gSO. , filtered and concentrated under reduced pressure to afford the desired amide.

General Scheme XI:

38

H ₂ H

BO

(36) . A solution of .1 -( ~bfosTio-2-liydroxyphe«yl)etban-l-orte ( 1 .0 eq) in toluene (0.5 ) was added dropwise to a stirred suspension of sodium hydride (2.8 eq) in toluene (0.5M) at reflux. Hie mixture was stirred for 10 min and then dietl lcarbonate (2,0 eq) was added dropwise over 30 mm. After 18h at reflux, the rxn mixture was removed from heat source . Once at it, the rxn was cooled to 0° and 2N HO (0,01M) was added dropwise. After an additional 1 rain, white solid forms in the aqueous layer. The .rxn mixture was extracted with EtOAc (2x). The combined organic layers were washed with, water, brine arid dried (MgSC¾). After filtration, the solvent was removed and the crude residue was carried forward without purification.

The above residue was dissolved in toluene (0.2M) and refiitxed. After 12h, the heat source was removed and upon cooling the resulting precipitate was collected by vacuum filtration. The white solid was washed with ether and dried to provide 7-broino*4-hydroxy-2H-chrome.n-2-oiie (49% yield).

(37) . To a solution of NaOEt (2.0 eq) in ElOH (0.8M) was added hydroxyianiine hydrochloride (2.0 eq), A solution of 7-bromo-4-hydroxy-2H~chromen-2-one ( i .O eq) in EtOH (1. M) was added to the rxn. The mixture was heated to reflux. After 4h at reflux, the solution was cooled to rt. The mixture was poured into a saturated solution of sodium bicarbonate { f .DM). WatenDC (1 :1 ; 0.3 were added and the aqueous layer was collected. The aqueous layer was washed with DCM (I . CM) and acidified with 2N HCl, dropwise. until precipitate forms. The precipitate was collected by filtration and dried m the oven to afford 2- 6-bromobenzo[d jisoxazol-3- l)acetic acid (79% yield).

(38). To a solution of 2-(6-bromobenzo[djisoxazol-3-yi)acetic acid (1 ,0eq) in DMF was added amine (13 eq), DIEA (4,0 eq), HOBt (1.0 eq) and HATU ^' (1 .3 eq). The solution was heated to 5 X and monitored, by LCMS. After 3h, the rxn was filtered nd purified, by reverse phase Oilson HPLC (35- 95% accto mle/water with 0.05% NH ₄ OH). The solvent was removed to afford desired product (50- 85% yield).

(39). In a microwave vial was added the previously mentioned aryl bromide (1 .0 eq), Pdaidba ^ (0.09 eq), Xantphos (0, 12 eq), Cesium Carbonate (2.1 eq) and l-(4-memoxybenzyl)- I H-pyrazolo[4,3- blpyridm-3-amine ( 1.0 eq). The mixture was evacuated and purged with itrogen (3x), followed by the addition of 1 ,4-dioxane (0.1 M). The reaction mixture was subjected to a microwave reactor for 45 min at 150 "C. After confirmation of product via LCMS, the mix ture was fi ltered through a pad of Ceiite and washed with EtOAc, After the solvent was removed, the crude residue was dissolved in

TFA: toluene (1 : 1; 0.03M). The reaction mixture was subjected to a microwave reaetor for 30 min at .150 "C. LCMS confirmed loss of starting material, so solvent was removed. The crude residue was purified by reversed phase Gil son HPLC (60-90% acetonitri ^' le/water with 0.1% TFA). The fractions were concentrated to afford the desired product.

General Scheme ΧΪΙ; tBuOH, oC, 2 h

2. TFA. 150 OC, 15 m«i. t;W

(40). To a solution of 2~(6-((iR-pyrazoioj ^' 4 -b^

N-methylaceta ide (1.Oeq) in DMF (O. IM) was added Boc ₂ 0 (1.5 eq) and F¾N (1.5 eq) at rt. After .12 h, rxn was added to water and extracted with a solution of CHClj'iPA (3; J ). The organic layer was washed with water (2x) and the solvent was removed. The material was carried forward without further purification,

LCMS (90 see. method);

(41).

pyrazoIo 4,3-b]py«dttie- Ϊ -carboxylate (1.0 eq) was dissolved in TH (0.2M) and the solution was cooled to °C. LL8H4 (5.0 eq) was added slowly, followed by eOH (5.0 eq), dropwise. The ice bath was removed. After 3h at rt, IN HQ was added slowly. The rxn was added to EtO Ac ".water ( 1 : i) and die organic layer was separated. The aqueous layer was further extracted with EtOAe (2x j. The combined organic layers were washed with water, brine and dried (MgSO ). The solvent was removed and the residue was carried forward without further purification.

LCMS (90 see. method); RT=== 1.050 min, m+Hh 396.2

(42). To a solution of text-butyl 3-((3-(2-hydroxyethyl)bcnzol ^' d]isoxazol-<S-yl)ainino)- Ϊ H-pyrazolo(4,3- b]pyndine- l -carboxylate (1.0 eq) in DCM ( .1M) was added (diethyl amino)suiiur irifiuoride

(DASTX4.0 eq) dropwise. The rxn was added to ice water and the mixture was extracted with EtOAe (3x), The combined organic layers were washed with water, brine and dried (MgS04). After filtration and concentration, the residue was dissolved in DCM:TFA (2: 1) and stirred at rt. After LCMS confirms the loss of starting material, the solvent was removed. The erode residue was purified by reversed phase Gilson HPLC (15-55% acetomtriie/water with 0.1% TFA) to afford 3-(2-fluoroethyl N-(lH- p>^x>lo[4,3-b]pyridin-3-yl)benzo[d]isoxazol-6-amine (22% yield).

LCMS (90 sec. method): RT- 0.773 into, m÷H=== 298.4

General Scheme X iU.

- 9.1 - , t-BuXPhos *0.

44

{ ^' 43). To a solution of the starting material (75 mg, 0,3500mmoi) and triethy!am e (0.06 mL, 0.42 mmoij in DCM (3 raL, 0, ί 1 M) was added ptvaloyi chloride (0,05 mL, 0.42 romot j , After 3 hours at it, the reaction was heated to 30 "C for 12 hrs, and monitored via LCMS. The reaction was concentrated, and purified using flash chromatography on silica gel (8-30% EtOAc in hexanes) to provide 43 (41.7 mg, 0.14 ramoi, 40% yield).

(44). In a via! was added 43 (20 mg, 0.07 romol), i-^me ho y l^ yOmethyll y ilo ^-bJ rid nr 3 -amine (20 mg, 0.07 mmol), NaOtBu (17 rag, 0.18 roraolk tBuXPhos (0.31 rag, 0.001 mmol), and tBuXPhos-Paliadacycle (0.5 mg, 0,001 inraoi). The sealed vial was evacuated and backfilled with dry Nitrogen 3X. To the vial was added tBuOH (1 mL, 0.07 M). After i hr at 60 "C, The rxn was added to a mixture of EtOAc and water. The aqueous layer was extracted with EtOAc SX (25 mL), and the organic extractions were washed with water I X ( 10 mL), The organic extractions were concentrated in vacuo, and the residue was dissolved in TFA and toluene. The solution was heated to 150 ^!> C in f*W for .15 roin. The solvent was removed in vacuo, and compound was purified with reverse phase chromatography via HPLC ( eCN in 0. !% TFA and water). The fractions were added to water and NaHCOS solution. The water was extracted with EtOAc. The solvent was removed, and the residue was dissolved in DCM and filtered through a hydrophobic membrane to yield the product. (6.4 mg, 0.018 mmol, 27% yield).

General Scheme XIV:

48 2Π ^' ΡΑ, toSuene, 150* C, MW

(45) . A solution of the starting material in THF (58.5 mL, 0.2 M) was cooled to 0 °C. To the reaction was added a solution ofLiBHt in THF and MeOH. After 30 min at 0 *€, the reaction was quenched with .15% NaOH aqueous solution. The reaction was allowed to warm to room temp, and the filtrate was coilecicd and eoiiceiitrated. The residue was added to water and EtOAc. The aqueous layer was extracted with EtOAc 3X. The organic extraction was washed with brine 1 X and dried over gSO*. The solution, was concentrated to afford the product which was used for future reactions without further purification.

(46) . To a solution of 45 {2.00 g, 8.77 mmol) in DCM (43.9 mL, 0.2 M) was added Dess-Mattin Periodmane (5.58 g, 13.2 mmol). After 90 min at room temp, to die reaction was added water. The water layer was extracted the DCM. The DCM extractions were combined and concentrated. The product was purified by flash chromatography on silica gel (10-45% EtOAc in hexanes) to yield 30 (1.60 g, 7.08 mmol 81% yield).

(47) . A solution of 46 (60 mg, 0,26 mmol) and 4-methoxypiperdme (0.164 mL, .1.33 mmol) in DCE (2.4 mL, 0.07 mmol) and AcOH (1.6 mL, 0.07 mmol) was heated to 45 After 45 min at 45 ^C C,

N tCllsCOO Bi i _t (84 mg. 0.40 mmol) was added to the solution. After 1 min, the solution was diluted with DCE and quenched with aMC03 aqueous solution. The aqueous mixture was extracted with DCE 2X. The organic extractions were combined and filtered through a hydrophobic membrane to yield 47 (61 mg, 0.1 8 mmol, 71% yield).

(48) . in a 2 mL vial, was added NaOtBu (28 mg, 0.30 mmol), tBuXPhos-Palladaeyele (2.5 mg, 0.02 mmol), tBuXPhos (1.6 mg, 0,02 mmol), I -{(4-methoxyphenyi)metliy 1 jpyrazolo[4,3- bjpyridin-3-amine (47 mg, 0.18 mmol), and 31 (60 mg, 0.1 S mmol). The reaction was evacuated and purged with Nitrogen (3x). To the vial was added tBuOH (2mL). The heterogeneous mixture was heated to 75 °C for 12 hrs. The reaction was added to a mixture of ^' ExOAc and water. The aqueous mixture was extracted with EtOAc 5X. The organic mixture was washed with water 3X. The organic extractions were combined and concentrated. The residue was dissolved in TFA (1 ml.,} and transferred to a 2 mL MW vial After 15 mm at 150 ^a C in the MW, the solvent was removed under reduced pressure. The fractions were separated by reverse phase chromatography (ACN/ ater/0.1%TFA). The combined fractions were added to a mixture of water and NaHC03. The aqueous layer was extracted with EtOAc 3X, and the organic layer was washed with water IX. Solvent was removed under reduced pressure, and solids were dissolved in a mixture of DCM:MeOH (1:1) and filtered through a hydrophobic frit to yield the product (7.2mg, 0.02 mmol, i 0.3% yield). ES-MS |M + Hp 379.4.

General Scheme XV:

C

(49) . To a IM solution of chloro(2, 2-dimettjy Ipropy l)magnesium in THF ( .86 mL, 9.86 mmol) was added 33 (1000 mg. 4.90 mmol) at 0* C. The reaction was removed from the ice bath, and stirred at room tempt for 24 hrs. The reaction was diluted with EtOAc ( 10 mL). The organic mixture was washed with aqueous NH4C1. solution I X, and water 2X, The reaction, was concentrated in vacuo to yield yellow oil. The residue was dissolved in DCM.. To the DCM solution was added DMP (2080 mg. 4.90 mmol). After 1 hr at room temp, the rxn was diluted with DCM. To the reaction was added saturated aS203 and saturated NaH C03 solution. The organic layers were filtered through a hydrophobic membrane to yield the product which was taken forward without purification and assumed to yield 100% product.

(50) , To a solution of 49 (1340 mg. 4.9 mmol) in MeOH (50 mL, 0, 1 M) was added hydroxylamine hydrochloride (1 60 mg, 1 .6 mmol) and NaOAc (2009 mg, 24.5 mmol). After 1 hrs at 50° C, the reaction was cooled to room temperature and filtered over a ceiite pad. The filtrate was added to water and the aqueous mixture was extracted with EtOAc IX and dried over anhydrous a2S04, The solution was concentrated in vacuo to yield 50 as crude product. The product was taken forward without further purification. (51) . A solution of NaH (336 rag, 60%w/v) in DMF (5 mL) was cooled to 0° C in an ice-bath under a nitrogen environment. To the solution was added dropwise a solution of 50 (1420 rag, 4.9 mraol) in DMF (5 mL), The ice bath was removed, and the reaction was stirred for another hour at room temp. After .1 hour, the reaction was cooled to 0° C, and a mixture of EtOB '.water (.1 : 1) was added dropwise until no gas evolution was noticed. The solution was added to water, and extracted with EtOAc 2X. The organic extractions were washed with water 3X. The solution was concentrated in vacuo, and fractions were separated by reverse phase H.PLC in a gradient of MeCN in water and 0.1%TFA. The fractions were added to water and treated with NaHCOS solution. The aqueous solution was extracted with EtOAc 2X. The organic extractions were washed with water 3X, brine 1 , and dried over anhydrous Na2S04. The solution was concentrated to yield 51. ( 130 mg, 0.48 mmol, 9.8% yield): ! H NMR (400 MHz, CDC ) S 8.65 (d, J- 1 .80 Hz, 1 H), 7.99 (d _f J- i .S Hz, III), 2.92 (s, 2H) _f 0.994 (s, H).

(52) . in 2 mL vial, was added NaOtBu (28 mg, .3( ) mmol), t ^' BuXPhos-PaUadacycle (2.5mg, 0.02 mmol)., tBuXPhos (1. > mg, 0.02 mmol), 1 -[(4~methox phen i)methyl ]pyrazolo[4 _v 3~ bjpyridin-3-araine (57 mg, 0.22 mmol), and 36 (60 mg, 0.22 mmol). The reaction was evacuated and purged with Nitrogen (3s), To the vial was added t-butanol (2mL), The heterogeneous mixture was heated to 75 °C for 12 hrs. The reaction was added to a mixture of ExOAc and water. The aqueous mixture was extracted with. EtOAc 5X, The organic mixture was washed with water SX, The organic extractions were combined and concentrated. The residue was dissolved in TFA ( 1 .mL) and transferred to a 2 mL MW vial. After ί 5 min at ί 50 °C in the MW, the solvent was removed under reduced pressure. The tractions were separated by reverse phase chromatography (AC water/0.1 %TFA). The combined fractions were added to a mixture of water and NaHCOS. The aqueous layer was extracted with EtOAc 3X, and the organic layer was washed with water 1 X, Solvent was remo ved under reduced pressure, and solids were dissolved in a mixture of DCM: eOH (1 :1) and filtered through a hydrophobic frit to yield 52 (8.1 mg, 0.03 mmol, 1 1.3% yield). ES-MS (M+l \+: 323.9.

Scheme XV

(S3). To a solution of ethyl ^- fomo-l ,2-benzoxazole-3-cai¾oxyiate (540.16 rag, 2 mmol, J .0 eq.) in THF ( iO mL) at -78 "C was added a solution of methyltnagncsiuja bromide in diethyl ether (3

M, 3.33 HiL 10 mmol, 5.0 eq. _. ). The resulting mixture was stirred at -78 °C for 3 h. Sat. solo NH CI was added. The mixture was warmed to rt and extracted with EiOAc (3x). The combined extracts were washed with brine, dried over ajSO*, filtered and concentrated, under reduced pressure. The crude material was purified using normal phase flash chromatography on silica gel (0-50% EtOAc/hexanes) to provide die title compound (410 mg„ 85.4% yield) as a white powder. ^! H- MR (400 MHz, DMSO~<¾}: S 8.33 (s, IH), 8.06 (d, J=- 8.4 Hz, IH), 7,71 (dd, ,/ - 8.5, 1 A Hz, H), 2.73 (s _« 3H).

(54). To a solution of l~(6-bron¾>-i,2-be»zoxazoi-3-yl)ethanotie (60.0! g, 0.25 mmol, .1.0 eq.) in DCE (1.25 mL) was added drop wise DAST (132.12 uL, i .O mmol, 4,0 eq.). The reaction mixture was stirred at 90 ^i! C for 3 h. DAST (132.12uL, 1.0 mmol, 4.0 eq.) was added and continued to stir for i k The mixture was cooied to rt and poured over to an ice/wafer mixture. The mixture was extracted with DCM (3s). Combined extracts were filtered through a phase separator and ewcentrated.

Purification using flash chromatography on silica gei (0-50% EtOAc/hexanes) to provide the title compound (45 mg, 68.7% yield) as a reddish oil 'fi-NMR (400 MHz, DMSO-tif): «5 8.34 (d, 7 ^» 0,6 Hz, iH), 7,90 (d, ,/ 8.5 Hz, IH), 7.71 (dd, J 8,5, 1 .4 Hz, iH), 2.24 (dd, J 19.6, 19.6 Hz, 3H). General Procedure for Coupling and Deprotection:

(55)» l-[X4-methoxypIicnyl)methyllpyra2olo{ _. 4,3- Jpyridin-3-aJt»iS ⁾ C (25.43 mg, 0. Ϊ0 nimoi, 1.0 eq,), 6- brorao-3-Cl, i-difi«oroethyl)- 1 ,2-bcnzoxazole (32.76 mg, 0.13 rornot, 1.25 eq.},

iris(dibe»zyiiderieactQ».e)dipa!ladium(0) (8.24 mg, 0,01 mmo.1, 0.09 eq.) _} 4 _> 5-bis(d.iphenylp.hosphiiio)~ 9,9-dimeihy!xantnene (6,94 nig, 0.01 mural, 0, 12 eq,} and cesium carbonate (48.87 mg, 0, 15 rainol, J .5 eq.) were charged in a reaction vial which was evacuated and purged with (3x). 1 ,4-Dioxanc (1 mL) was added. The reaction was stirred to 100 ¹ C. After 4 h, die mixtiire was cooled to rt, iikered through a pad of Ce!ite which was washed with EtOAc and concentrated under reduced pressure. The residue was then re-dissolved in TFA (-0.5 mL) and subjected to a mtcrowave reactor for 30 mm at 150 "C. TFA was removed under reduced pressure. Purified using reverse phase Gilson HPLC system with acidic method (AC Avater/0.1% TFA), gradient; 34-65% and free based with sat. soln, NaHC<¾ to provide the title compound (5.7 m , 18.1 % yield). ES-MS jM+f f .' 316.2, RT = 0.925 mis, 98% at 2 5 mil and 254 am.

Scheme X V 11

(56). To a solution of 6-hromo- i ,2-benzoxazole-3~carbaldehyde (678.09 mg, 3.0 mmoi, 1.0 eq,) in THF (30ml,) at -78 °C was added a solution of tert-butylnmgnesiutn chloride in THF (2.0 M, 2.25 mL, 4.5 mmol, J .5 eq). The resulting mixture was stirred at -78 °C. After 2 h, sat. soln NIi,Q was added. The mixture was warmed to rt aod extracted with EtOAc (3x). The combined extracts were washed with brine, dried over Na^SO^ filtered and concentrated. Purification using flash

chromatography on silica gel (0-30% EtOAc/hexancs) to provide the title compound (600 mg, 70.4% yield) as a viscous oil. ES-MS [M+l] ^* : 284.2, RT - 1.128 rain, >80% at 254 nm.

(57). To a solution of .1 ^« (6~bromo- 1 ^-benzoxazol-S- l^j -dimetljyl- ro an-l^ol (600 mg, 2.11 rariioi, 1.0 eq.) in DCM (10.6 mL) was added Dess-!Vl artisi periodinane ( 1 ,34 g, 3.2 mmol, 1 .5 eq.). After stirring at rt for 1 h, water was added slowly. ^" The mixture was extracted with DCM (3s). The combined extracts were washed with brine, dried over Na^SC^, filtered and concentrated. ^' Purification using flash chromatography on silica gel (0-30% EtOAc/hexanes) to provide die title compound (380 mg, 63.8% yield) as a white crystalline solid. ES-MS [M+lf : 284.2, RT - 1.371 ram, >98% at 21 5 and 2 4 ma).

(58). Same procedure as 6-brom:0-3-(i,.l -difiuoroet l)-l ₅ 2^enzoxazole in Scheme XVI. ES-MS M-H. : 304,2, RT === 1 ,372 min, >98% at 215 and 254 nm).

(59). Same procedure as 3-{I,l-di. .uoroctl.r>d)- -( l H-pyrazoioj ,3-blpyrid

amine in Scheme XVI ES-MS [M+l] ^* : 358.4, RT = I . I .I 3 min, >98% at 215 and 254 nm).

Scheme XViii

(60). To a solution of 6-broroo-} ,2-benzoxazole-3-cari>a!dehyde (750.mg„ 3.32 mmol, 1 .0 eq.) in THF

(1 .6 mL) at -78 ^*' C was added a solution of n^ utylraagnesiurn chloride in THF (2,0 M„ 4.98 mL, 9.95 mmol, 3,0 eq). The resulting mixture was stirred at -78 ' ^' C, After 2 h, sat. solo NH ₄ CI was added. The mixture was warmed to rt and extracted with EtOAc (3x). The combined extracts were washed with brine, dried over NajSO,*, filtered and concentrated- Purification using flash chromatography ort silica gel (0-30% EtOAc hexanes) to provide the title compound (360,2 mg, 38.2% yield) as a viscous oil, ES- MS [M+lf: 284.2, RT ~ 1 , 147 miu, >9 % at 215 and 254 am

(61). To a solution of .1 -(6-bromo- 1 ,2~be«zoxazoS~3-y1)pentan~i~oi. (.100 mg, 0.35 mmol, 1 .0 eq.) in DCE (2.64 mL) was added dropwtse DAST (0.86 mL, .1 .41 ramol, 4.0 eq.). After stirring at rt for 1 it, the mixture was poured over an iee/water mixture and extracted with DCM. The combined extracts were washed with brine, dried over NajSO*. tittered and concentrated. Purification using flash chromatography ort silica gel (0-30 EiOAc/hexartes) to provide the tide compound (85.8 mg _f 85.2% yield) as an oil,

ES- S j +l f: 284.2 , RT === 1,332 mm, >%% at 215 and 254 am.

(62), 6-bromo~3-( 1 -fluoropentyl)-l ,2-benzoxazoie (85. S mg, 0.30 mmol, 1 .0 eq.), cesium carbonate (1 4,9 m , 0.60 mmol, 2.0 eq.), tris(diben2j ideoeacetoi!te)dipalSadium(( ⁾ ) (10.43 mg, 0,01 mmoL 0.034 eq.), XantPhos ( 15.63 mg, 0,03 mmol, 0.09 eq.) and t-butyl carbamate (42.15 mg _t 0,36 mmol, 1 .2 eq.) were charged in a reaction vial The vial was evacuated and purged with Ν _¾ (3x). 1,4-Dioxane (1.5 mL) was added. The mixture was subjected to microwave reactor for 1 h at 140 "C. The mixture was cooled to rt and filtered through a pad of Ceiite which was washed with EtOAc. Filtrate was concentrated. Purification using flash chromatography on silica gel ( 10-30% EtO Ac/he anes) to provide the title compound (60.7 mg, 63% yield). ES-MS JM-H f : 323.4 . RT - 1.331 mm, >75% at 215 and 254 nm

(63). To a solution of tert-butyl N-|3^!-fluowpea{yl)-l,2-beiTzoxazol-6-yi]carbaiT}ate (60.7 mg, 0,19 mmol, 1.0 eq.) in 1,4-Dioxane (0.47 mL) at 0 ^'"' C was added 4M HC1 in 1,4-dioxane solution (0.24 mL. 0.94 inmol, 5.0 eq.). The reaction mixture wa wanned to rt for 1 h. 4M HQ in Dioxane (0,24 mL, 0.94 mmol, 5.0 eq.) was added and continued to stir for 2 h. Once the reaction was completed by

LC ^' S, solution was concentrated under reduced pressure. The residue was dissolved in MeQH and loaded onto an SCX cartridge, washed with MeQH (20 mL) and eluted with 2M N¾ in MeQH

solution. Desired fractions were collected and concentrated to provide the title compound (31.6 mg, 75.5% yield) a dark oil. ES-MS (M-H† 223.4 , RT - 0.992 min, >70% at 215 and 254 nm

General procedure for coupling:

(64). Tris(diben2ylideneacetone)dipaiiadium(i)) (31.01 mg, 0.03 mmoi, 0.1 S eq.), XantPhos (23.13 mg, 0.04 mmol, 0.2 eq.), cesium carbonate (1 13.62 mg, 0.35 mmol, 2.1 eq.) and 3-bromo-l- tetrahydropyran>2-yl-pyrazolo(4,3-"b ^' |pyridine (46,97 mg, 0.1 7 mmol, 1.0 eq.) were charged into a reaction vial. The vial was evacuated and purged with Nitrogen (3x), followed by the addition of a solution of 3~( l -fluoropen†.yl)-l ₅ 2-benzoxazol-6-amine (37. mg, 0.17 mmol, .1.0 eq.) in 1,4-Dioxane (0.83 tiiL), The reaction mixture was stirred at .100 "C. After 6 fa, the reaction mixture was cooled to rt and a mixture ofEtOAcrNlitCI (aq) (1 : 1) was added. The organic layer was separated and washed with water (2xj, brine, dried over MgSG*, filtered aad concentrated. Purified using reverse phase Gilson HPLC system with acidic method (ACN/water/0.1 % TFA), gradient: 34-65% and free based with sat. soln. NaHCOa to provide the title compound (42.6 rug, 60.4% yield) ES-MS (M-hl j ' : 424.4 , RT - 1.328 rain, >98% at 2 i 5 and 254 nm

(65). To a solution of 3 ~( 1 -fl «oropentyl)- -( J -tetrahydropyraa-2-y S yrazoloj 4,3 ~b jpyrkfin~3 ~yi)~ 1.2- be.ozoxazol-6-amjoe (40.0 rag, 0.09 mmol eq.) in 1,4-Dioxane (0,24 tnL) at it was added 4M HCl in dioxane (0.24 niL ₅ 0.94 mmol, 10 eq.). The orange solution was stirred at rt overnight and at 45 ^& C for 3 h. Solvent was removed. The crude material reverse phase Gilson HPLC system with acidic method (AC /water/0, 1% TFA), gradient; 34-65% and free based with sat. soln. NaHCOs to provide the title compound (25.5 mg, 79.6% yield). ES-MS jLM-Hf: 340.4 , RT = 1.094 min, >95% at 215 and 254 nm.

Scheme XIX

(66). Same procedure as 3 iJ -difiuoroethyl}~^

amine in Scheme XVI ES-MS I ^' M-Mf: 310.2, RT - 0,759 min, >90% at 215 and 254 nm

(67). A mixture of methyl 6~(fH-pyrazolo{4,3-b ^' jpyridin-3-ylammo _> 2-te^

(164.0 mg, 0.53 mraol, L eq), di-tert-butyi dicarbonate (138.83 mg, 0.64 nunoi, 1.2 eq.) and irimethylamiiie (88.8 luL, 0.64 mmol, L2 eq) in DCM (2.65 mL) was stirred at it overnight Di-ter- buryl dicarbonate (138.83 mg, 0.64 ramol L2 eq.) and trioiethyiamioe {88.8 !uL _> 0.64 mmol, 1.2 eq) were added and continued to stir for 2 . Purification using flash column chromatography on silica gel (1 -100% EtOAc/hexanes) io provide the title compound. (MMS-B-122) ES-MS fM÷l : 4 0.1 , T 1 .2 J 6 mm, >98% at 215 and 254 am

(68). To a solution of meth l 6-{(l -†.ert¾}toxyearbo«ylpyTazolo[4^^ ,2- beiizoxazole-j-carbox late ( 119,0 mg, 0.29 mrooi, 1.0 eq.) in THF (1.45 mL) ai 0 ^e C was added a solution of iifhitim borobydride in THF (2.0 M, 0.298 mL, 0,58 mmol, 2.0 eq.) and methanol (23.55uL„ 0.58 mtrto ^' l, 2,0 eq,). The resulting mixture was stirred at 0 °C for 30 nun. Water ( 10 mL) was added. The mixture was stirred for 20 min at r and diluted with EtOAc. The mixture was extracted with EtOAc (2K), The combined organic layers were washed with brine, dried over NajSCXj, filtered atid concentrate. Purification using flash column chromatography on silica gel (10-60% EiGAc/hexanes) to provide the title compound. ES-MS +l ; 382.3 , RT ~ 1.038 min, >98% at 15 and 254 nm

(69). To a suspension of test-butyl 3-j J -(hydroxymethyi)-l _f 2-berizoxa^l-6-yiiamrao]pyrazoio[4,3- bjpyridine- l-ca oxylate (9.0 .mg, 0,02 mmo!, 1.0 eq..), 5-bydro-2-.oieihylpyridine (5.15 mg, 0.05 .mmol,

2.5 eq.) and triphenylphosphine (13.63 mg, 0.05 mmol, 2.5 eq.) in DCM. (0.12 mL) at 0 °C was added di-teri-but l. azodicarboxy!ate (8.7 org, 0,04 mmol, .1.6 eq.). The mixture was warmed to rt and stirred for 15 mm. TEA (0.10 mL) was added and the reaction was allowed io stir at rt for 2 h. The reaction was concentrated and. purified using reverse phase Gilson M.PLC system with acidic method (ACN water/0.1 % TP A), gradient: 11 -42%. The desired fraction was concentrated to provide the title compouttd as a IF A salt (3.6 tug mg, 25.4% yield). ES-MS {UHf 373.3, RT - 0.668 nun, >98% at 215 and 254 am

Scheme XX

(70). To a sohition of methyl 6- roniobeiizoidjisoxazole-3-carboxy!.ate~( l .123169-23-2) (Sg,

19.53raraol) in THP (25mL) at if C was added a solution of lithium borohydride-( 16949-15-8) (2M, 19.53.oiL, 39.05mmol) in THF and methanol. After 30 min at 0° C, water (30mL) was added. After 20 min at ft, the reaction was diluted with EtOAc, The organic layer was extracted, and washed with water, briiie, and dried over MgSO* to yield (6-bronio~l,2-beiizoxa2:o!~3-y].)methano]. (4.3g, .l8.86mmo.1, 97%yieid). ES-MS {MHf : 230.3, RT - 0.807 rain, >98% at 254 «m.

(71). In a microwave vial to a sohition of m-cresoS. (108-39-4) (22.16nL, 0.220mrao!) and (6-bromo- l,2-be.azoxa oI-3-yl)t.nethaiioi (l Omg, 0.440mraol) in THF (3tnL.) was added tripheny ^' Iphosphtnc (603 35-0) (! l Smg, 0.440mmol). After 5 rain at 0° C, di-tert-bittyl azodicatboxviate (870-50-8) {lOlmg, 0.440nmiol) was added. The vial was capped, and the mixture was stirred at room temp to yield 6- bromo-3- (3-methylphemixy)methyl]-l ,2-benzoxazole (40mg _f 0.126mmol„ 57%yieid).

(73). A mixture of 6-broino-3- (3-.rae&ylphenoxy)methylj-l ,2-benzoxazoie (40mg, CU 26mraol

P (dba)i-CHC1¾ (52522-40-4) (6.5mg, O.OQSmmoO, Xantplios (16.1265-03-8) (3.6n¾, O.MfosaoIX CS _J CO _J (534- 17-8) (122, :mg, 0.377_nmol), and 1 -( 4-n^¾oxypbeny ^th l] yra^lo[4 - ]p r din-3- amine (35.2mg, .138ramol) was sealed in a vial and purged and backfilled with argon. To the vial was added 1,4-dtoxaite (3mL). After 3 min at ft, the reaction was heated to 140* C in MW for 30 min. The solution was concentrated and fractions were separated via automated reverse phase HPLC in a gradient of MeCN in water (0.5mL NH ₄ OH IL water). The fractions were concentrated and suspended in TFA. The TFA solution was heated to 130° C in MW for 30 min. The reaction was concentrated, and iraclions were separated by automated reverse phase HPLC in. a gradient ofMcC in water (0,5mL NH ₄ OH IL water). The fractions were concentrated to yield 3-j (3-metlwlpiienoxy):methylj~ --(iH- pyraz:olo(4,3-bjpyridiu-3-yi)-I,2-berizoxazol-6-annue.

Scheme XXI

TFA, (iwav«. 130 "C, 30 min

(74). 2-raethyl-2-propanesulfi.namide (L07g, 8.849mmol _. ) was added to a solution of 6-bromo-! _? 2- benzoxazole-3-carbaldehyde (2g, S.84Sin. ioi) in toluene (50 niL). After 15 min at room temp, NaOH (353.9mg, 8.848mmol) was added to the solution. After stirring overnight at room temp, the reaction was diluted with EtOAc. The organic mixture was washed with water, dried over MgSQ* _> and concentrated. Fractions were separated by automated normal phase flash chromatography on silica gei in a gradient of EtOAc in hexanes. The fractions were combined and concentrated to yield ( E)- -j(6- bromo~l ,2~benzoxa?.ol~3-yl)ffiethylen^ ^{^} (2.24g„ 6.804mmoi _f

7?%yield).

(75). A mixture ofTBAT (2.7 ig, 5.01 tnmol) and (N.E}- -[(6-bromo~ ^' l _! 2~benzoxazol~3-yl)nieth\dene]-2- methyi-propane-2-sulfmamide ( 1 .5g, 4.56mmo!) was sealed the vessel was evacuated and backfilled with dry nitrogen 3X, The vessel was cooled to 0* C and THE (30mL) and

trii»cthy1(trifluorom thyl)silanc (81290-20-2) (0,876:mL, 5,92rarooi) was added. The reaction was maintained at ( C. After 30 min, the reaction was quenched with saturated N.H4CI solution, and diluted with EtOAc. The organic layer was extracted, dried over MgS0 ₄ , and concentrated. Fractions were separated by automated normal phase Hash chromatography on silica gel in a gradient of EtOAc in hexanes. The fractions were concentrated to yield N^l -(^bronK^l.^-bej oxai^W- l^^^-rrifiuoro- edi ri^-met yl- o ne^-sul.finamjde (1.57g, 3.93mmol, 86%yield>. ES-MS [M+lf: 401.0, RT = 1.138 min, >98% at 254 nm.

To a solution of -{ i -(6-bromo- 1 ,2-benzoxa2oi-3-yi)-2,2,2-trifluoro-etlr l]-2-meihyI-propaae-2- sulfinamide (1.57g, 3.93mmol) in methanol (iSniL) was added HC1 (4 in dioxanes, 3.93mL,

15,73nimol). After 4 hrs at room temp, the reaction was concentrated. The crude residue wa sonicated with EtOAc, and the product was coliected as solids by filtration to yield l-(6"bromo- l ,2-henzoxazol-3- y1 2,2,2-trifluoro-ethanamme hydrochloride (1 i ⁾ 3g, 3. lOTtnmol, 79%yield). ES-MS fM+lf: 297.2, RT = 0.875 min, >90 at 254 nm.

(76). To a solution of l-(6-bromo-l^-bcnzoxazo!-3-yi)-2,2 _> 2-trit¾ioro- hanaraine hydrochloride

(lOOmg, 0.300mraoi) in N _f N-d.iisopropylethy ^' iaraine {7087-68-5) (iOSuL, O.60Omrao!) and DCE { ImL), was added a solution of b iyraldehyde (123-72-8) (271-uL, 3.02mmol) in Acetic acid (2mL). The reaction was heated to 90° C in MW for Ihr. The reaction was monitored by TLC (30%

BtOAc/TIexanes). To the reaction mixture, sodium triacetoxyborohydride (56553-60-7) (95.9mg, 0.450nuaol) was added. The mixture was stirred for 30 min at room temp. Then, the mixture was quenched with a saturated NaHCOa solution (2:roL), and diluted with DCM. The organic Saver was extracted with DCM and concentrated. Fractions were separated with automated normal phase flash chromatography on silica gel in a gradient of EtOAc in hexanes. Fractions were concentrated to yield N~] l~(6 >romo ,2-h^ (50mg, 0J42mmoL

47%yie!d). ES-MS (M-hl f: 353.3, RT - 1 .322 min, >98% at 254 am.

(77). In a 2 mL vial was added 'BuONa (865-48-5) (21.9mg, 0.230mmo!) _s Pd-'BuXPhos (2mg, 0.003mmoi), 'BuXPhos (1.2mg _« O,0G3mmo ^' l), l-{ 4-ir»euioxypbcnyl)nieJliyl]pyrazolo{43-b ^' ]pyridin-3- amine (39.8, 0.1.57mmol), and N-j J-i6-brorao-.l ,2-benzoxazol-3-yl)-2 _s 2,2-trirluoro-ethyl}butan-l-aniine (50mg, 0,I42.ramoi). The reaction was e acuated and purged with Nitrogen 3X, To the vial was added ^l BuOH (2mL). The heterogeneous mixture was heated to 60" C for 3 hrs. The reaction was added to water, and extracted with EtOAc. The organic extractions were combined and concentrated in vacuo. The residue was dissolved in DMSO, and fractions were separated via automated reverse phase HPLC in a gradient of MeCN in water (0.1 TFA in water). The fractions were concentrated, and the residue was suspended in TFA (2 mL) and transferred to a 2 mL MW via!. The reaction was heated to 130° C for 30 min in MW. The solvent was removed under reduced pressure, and residue was dissolved in DMSO (5 mL). Fractions were separated by re verse phase HPLC ^" in a gradient of MeCN in water (MeCN/Q. %TFA in water). The fractions were concentrated and extracted with DCM to yield 3-( 1 - (birtylani)no)~2,2,2-trif!iioro~ethylj-N-(l.H 2,2,2- trifluoroacetic acid (3.2mg, Ο.ΟΟόηηηοΙ, 4%yieid). ES-MS [M-H : 405.3, RT = 1.034 min, >98% at 215 and 254 nm. Scheme XXII

(78). 1 -(6-bromo- \ _> 2-ben2X>xazol-3-y1 2 _> 2,2-to ^* fluo.«>-etha»amine was prepared as previously described. To a solution of 1 -{6-bro.rno- 1 _> 2-bej£zoxazol-3-yI 2 _> 2,2-trifi oiX -edmnaniine (50mg, O. iSroraol) and triraethyla ine (Q.084 L, 0.6mmol) in DCM (iroL) was added pivaioyl chloride (0.0.19axL, 0.1 Smrnol). After 1 hour at room temp, the reaction was concentrated, and fractions were separated by reverse phase KPLC in a gradient of MeCN in water (O.SmL ΝΗ4ΟΗ Ί L water). The ^■ fractions were concentrated to yield -j ^-(6-bramo-1.2-benzoxazol~3~yI)~2.2,2-trif1«oro-eih.yl -2 _? 2- dimethyi-propaiiamide (40mg, 0.1 Immof 70% yield). ES-MS |M+ i j ^! ; 379.2, T === 1,215 mi» _« >98% at 215 and 254 nm.

(79). A mixture ofN-f i-(6-brQmo-!,2-beo20xazol-3-y^

propanamide (40mg, 0.1 irranoi), Pd;(dba) _; rCHCii (Sing, O.OOS mol), Xantphos (161265-03-8) (Sing, O.OOSmmol), CS2CO3 ( 103mg, 0,317ramol), and l-| 4-me&oxy henyl)nietlrylJpy a-»lo[4 -b ^' ]pyridin-3- amine- (30mg, 0.1.16mmof) was sealed m a vial and purged and backfilled with argon. To the vial was added .1 ,,4-dioxane (2mL). After 3 min at rt, the reaction was heated to 140° C m MW for 30 min. The solution was concentrated and fractions were separated via automated reverse phase If PLC in a gradient of MeCN in water (O.SmL NH ₄ OH/l L water). The fractions were concentrated and suspended in TFA. The TFA solution was heated to 130° C in MW for 30 min. The reaction was concentrated, and fractions were separated by automated reverse phase HPLC in a gradient of McC in water (0.5mL NH4OH IL water). The fractions were coircentrated to yield

pyra∞loj43~b]pyridio-3~y ^^^

and 254 em.

4 iiiii

[0176J It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention, without departing from the scope or spirit of the invention. Oilier aspecis of the invention will be apparent to those skilled in the art. from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, wit a true scope and spirit of the invention being indicated by the foi lowing claims.

|¾ J 77] Unless otherwise indicated, ail numbers expressing quantities of ingredients,, properties such as reaction conditions, and so forth used herein are to be understood as being modified in ail instances by the term "about," Accordingly, unless indicated to the contrary, the numerical parameters set forth in the herein are approximations that, may vary depending upon the desired properties sought to be determined by the present invention.