WO2013060029A1 - Allosteric modulators of metabotropic glutamate receptors - Google Patents

Abstract

Formula (I), and salts thereof, wherein R¹, R^A2, R^A3 and R^A4, are defined herein, which have properties for positive allosteric modulation of mGluR-4 receptor sites. Also described are pharmaceutical formulations comprising the compounds of Formula (I) or their salts, and methods of treating Parkinson's disease and related disorders using the same.

Description

Allosteric

Modulators of Metabotropic Glutamate Receptors

Field of the Invention

[0001 ] This application discloses and claims novel compounds which have activity as positive allosteric modulators (PAMs) of metabotropic glutamate receptors, subtype 4 (mGluR4 receptors) and their use in preventing, managing, or treating diseases of the central nervous system and disorders modulated by mGluR4 receptors.

Background of the Invention

[0002] The excitatory amino acid L-glutamate (referred to herein also simply as glutamate) through its many receptors mediates most of the excitatory neurotransmissions within the mammalian central nervous system (CNS). Accordingly, glutamate is the major amino-acid transmitter in the mammalian CNS.

[0003] One general type of receptor through which glutamate acts is the G-protein, or secondary messenger-linked "metabotropic" glutamate receptors (mGluR's), which have a more modulatory role contributing to fine-tuning of synaptic efficacy. The mGluRs are G protein-coupled receptors (GPCRs) with seven-transmembrane spanning domains and belong to GPCR family along with the calcium-sensing GABAb and pheromone receptors. The mGluR family is composed of eight members. They are classified into three groups (group I comprising mGluRl and mGluR5; group II comprising mGluR2 and mGluR3; and group III comprising mGluR4, mGluR6, mGluR7 and mGluR8) according to sequence homology, pharmacological profile and nature of intracellular signalling cascades activated (Schoepp et al., (1999) Neuropharmacology, 38: 1431-1476). Glutamate activates the mGluRs through binding to the large extracellular amino- terminal domain of the receptor, herein called the orthosteric binding site. Both types of receptors are believed to mediate normal synaptic transmission along excitatory pathways and participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. Sci., 11, 508 (1990); McConald and Johnson, Brain Research Reviews, 15, 41 (1990). This activation induces a conformational change of the receptor which results in the activation of the G- protein and intracellular signalling pathways.

[0004] Symptoms of Parkinson's disease appear to be due to an imbalance in the direct and indirect output pathways of the basal ganglia and reduction of transmission at the inhibitory GABAergic striato-pallidal synapse in the indirect pathway may result in alleviation of these symptoms (Marino et al., (2002) Amino Acids, 23: 185-191). In striato-pallidal synapses, mGluR4 receptor subtypes are more abundant than in striato- nigral synapses, and its localization suggests it possibly functions as a presynaptic heteroreceptor on GABAergic neurons (Bradley et al., (1999) Journal of Comparative Neurology, 407:33-46). Further, this suggests that selective activation or positive modulation of mGluR4 would decrease GABA release in this synapse thereby decreasing output of the indirect pathway and reducing or eliminating Parkinson's disease symptoms. Classical treatment of Parkinsonism typically involves the use of Levodopa combined with carbidopa (SINEMET™) or benserazide (MADOPAR™). Dopamine agonists such as bromocriptine (PARLODEL™), lisuride and pergolide (CELANCE™) act directly on dopamine receptors and are also used for the treatment of Parkinsonism. These molecules have the same side-effect profile as L-dopa.

[0005] A new avenue for developing selective compounds acting at mGluR receptors is to identify molecules that act through allosteric mechanisms, modulating the receptor by binding to a site different from the highly conserved orthosteric binding site. Positive allosteric modulators of mGluRs have emerged recently as novel pharmacological entities offering this attractive alternative. This type of molecule has been discovered for mGluRl, mGluR2, mGluR4, mGluR5, mGluR7 and mGluR8 (Knofiach F. et al. (2001) Proc. Natl. Acad. Sci. USA, 98: 13402-13407; Johnson M.P. et al, (2002) Neuropharmacology, 43:799-808; O'Brien J.A. et al, (2003) Mol. Pharmacol, 64:731-740; Johnson M.P. et al, (2003) J. Med. Chem., 46:3189-3192; Marino M.J. et al, (2003) Proc. Natl. Acad. Sci. USA, 100: 13668-13673; Mitsukawa K. et al, (2005) Proc. Natl. Acad. Sci. USA, 102(51): 18712-18717; Wilson J. et al, (2005) Neuropharmacology, 49:278; for a review see Mutel V., (2002) Expert Opin. Ther. Patents, 12: 1-8; Kew J.N., (2004) Pharmacol. Ther., 104(3):233-244; Johnson M.P. et al, (2004) Biochem. Soc. Trans., 32:881-887; recently Ritzen A., Mathiesen, J.M. and Thomsen C, (2005) Basic Clin. Pharmacol. Toxicol, 97:202-213).

[0006] Particular molecules have been described as mGluR4 positive allosteric modulators (Maj et al, (2003) Neuropharmacology, 45:895-906; Mathiesen et al, (2003) British Journal of Pharmacology, 138: 1026-1030). It has been demonstrated that such molecules have been characterized in in vitro systems as well as in rat brain slices where they potentiated the effect of L-AP4 in inhibiting transmission at the striatopallidal synapse. These compounds do not activate the receptor by themselves (Marino et al, (2003) Proc. Nat. Acad. Sci. USA, 100: 13668-13673). Rather, they enable the receptor to produce a maximal response to a concentration of glutamate or the Group III orthosteric agonist L-AP4 which by itself induces a minimal response.

[0007] International patent publication WO2005/007096 describes mGluR4 receptor positive allosteric modulator useful, alone or in combination with a neuroleptic agent, for treating or preventing movement disorders. However, none of the specifically disclosed compounds are structurally related to the compounds of the invention.

[0008] PHCCC, a positive allosteric modulator of mGluR4 (tricyclic compound of Formula A) which is not active on other mGluRs (Maj et al, (2003) Neuropharmacology, 45:895-906), has been shown to be efficacious in animal models of Parkinson's disease thus representing a potential novel therapeutic approach for Parkinson's disease, as well as for other motor disorders and disturbances (Marino et al, (2003) Proc. Nat. Acad. Sci. USA, 100: 13668-13673), neurodegeneration in Parkinson's disease (Marino et al, (2005) Curr. Topics Med. Chem., 5:885-895; Valenti et al, (2005) J. Pharmacol. Exp. Ther., 313: 1296-1304; Vernon et al, (2005) Eur. J. Neurosc , 22: 1799-1806, Battaglia et al, (2006) J. Neuroscl, 26:7222-7229), and neurodegeneration in Alzheimer's disease or due to ischemic or traumatic insult (Maj et al, (2003) Neuropharmacology, 45:895-906). PHCCC has been shown also to be active in an animal model of anxiety (Stachowicz et al, (2004) Eur. J. Pharmacol, 498: 153-156). Previously, ACPT-1 has been shown to produce a dose-dependent anti-conflict effect after intrahippocampal administration and anti-depressant-like effects in rats after intracerebroventricular administration (Tatarczynska et al, (2002) Pol. J. Pharmacol, 54(6):707-710). When injected intraperitoneally, ACPT-1 has been shown also to have anxiolytic-like effects in stress- induced hyperthermia, in mice in the elevated-plus maze and in rats in the Vogel conflict test (Stachowicz et al., (2009) Neuropharmacology, 57(3):227-234).

Formula A

[0009] Modifications to PHCCC to improve activity and selectivity have been undertaken and reported, for example, Williams et al., ACS Chemical Neuroscience, Letters, published Online, March 8, 2010, which describes modifications to the substituent depending from the amide nitrogen, primarily altering the phenylacetamide substituent to pyridinyl acetamide (with various substituent patterns on the pyridine ring) and/or introducing substituents onto the aryl ring in the chroman core of the compound.

[0010] Other compounds have been reported to have mGluR4 activity wherein the core structure of the compound depart from that of PHCCC. For example, published international application, publication number WO2011/011722 (the '722 publication), Conn et al., describes compounds of the structure of the compound of Formula B. Compounds of Formula B replace the chroman core of PHCCC with a benzoimidazole core, the core having an arylsulfonamide substituent depending from its aryl ring portion. Other examples presented in the '722 publication include variously-substituted analogs of Formula B and a series of compounds replacing the pyridinyl substituent depending from the imidazole portion of the benzoimidazole with an aryl substituent.

Formula B

[001 1 ] More recently, new mGluR4 receptor positive allosteric modulators (PAMs) have been described: pyrazolo[3,4-d]pyrimidine derivatives ( iswender et al., (2008) Bioorganic & Medicinal Chemistry Letters, 18(20):5626-5630), functionalized benzylidene hydrazinyl-3-methylquinazoline and bis-2,3-dihydroquinazolin-4(lH)-one (Williams et al, (2009) Bioorganic 10 c & Medicinal Chemistry Letters, 19:962-966) and heterobiarylamides (Engers et al, (2009) Journal of Medicinal Chemistry, 52 (14), pp 4115-4118). Niswender et al, described (±)-cis-2-(3,5- dichlorophenylcarbamoyl)cyclohexane carboxylic acid ((2008) Molecular Pharmacology, 74(5): 1345-1358), as a positive allosteric modulator of mGluR4 also having agonist activity. This moderately active molecule has demonstrated evidence of efficacy following icv injection in rat models of Parkinson's disease. International patent publications WO2009/010454 and WO2009/010455 have mentioned amido derivatives and novel heteroaromatic derivatives, respectively, as positive allosteric modulators of metabotropic glutamate receptors. East et al. have also examined heteroaromatic derivatives as PAMs of mGlu receptors (East, Stephen P. et al., (2010) Expert Opin. Ther. Patents, 20(3): 441-445). Re-exploration of the PHCCC scaffold was described by Williams, R. et al. in (2010) ACS Chemical Neuroscience, 1(6): 411-419.

[0012] Additional examples of positive allosteric modulators of metabotropic glutamate receptors may be found in international patent application publication WO09/010454 (the *454 publication), WO09/010455 (the *455 publication) and WO 10/079238 (the '238 publication), which describe heteroaryl-amido-aryl compounds having mGluR4 activity. Additionally, International patent publication WO 10/079238 (the '238 publication) describes tricyclic compounds having mGluR4 activity and WO2006/040279 describes similar tricyclic compounds which have activity as PI3 kinase modulators. None of the aforementioned publications describe the inventive compounds presented herein.

[0013] Published international patent application nos. WO08/089307 (herein, "the '307 publication") and WO08/089310 (herein, "the '310 publication"), both describe numerous fused heterocyclic compounds of generic structure Formula Ca which have activity as inhibitors -desaturase:

Formula Ca,

wherein "n" is 1 to 4, m is 1 to 5, Ql and Q2 can be saturated or unsaturated carbon or nitrogen, X can be Oxygen, Sulfur, saturated carbon or saturated nitrogen, Y can be saturated or unsaturated carbon or nitrogen, "A" is either non-existant (direct bonding between nitrogen and the aryl ring) or is CH₂, S0₂ or C=0, and R¹, R², and R³ are independently selected from hydrogen, halogen, aryl, alkyl and a long list of other organo-functional substituents.

[0014] The compounds described in the '307 and '310 publications are said to be useful in the treatment of pain, inflammation, obesity, and cancer, and include describing and claiming lH-pyrazolo[3,4-b]pyridinyl amine compounds of Formula Da:

Formula Da; wherein R¹ is -H, -halogen, -alkoxy or an -alkyl-aryl substituent, R² is hydrogen or an -alkyl-aryl substituent, and R³ is hydrogen or halogen, and specifically exemplifying the compounds of Formula Db and Formula Dc:

Db; and Dc.

[0015] Neither the '307 publication nor the '310 publication identifies any of the compounds therein as having activity as an mGluR-4 positive allosteric modulator, nor does it describe or suggest how to identify and synthesize compounds having activity as an mGluR-4 positive allosteric modulators.

[0016] While the modifications of PHCCC and studies of mGluR4-active compounds which are structurally diverse from PHCCC have yielded compounds displaying mGluR4 activity, what is needed is a series of compounds providing potency toward the mGluR4 receptor and improved selectivity and solubility compared with PHCCC and the other families of compounds thus far identified with mGluR4 activity. Such compounds, and medicaments comprising such compounds, can be useful in the treatment, management, alleviation, amelioration or prevention of diseases or symptoms of diseases which are amenable to being so effected by the administration of a compound having activity as an mGluR4 positive allosteric modulator. What is needed also is a series of compounds which are structurally diverse from compounds heretofore identified as having mGluR4 positive allosteric modulator activity providing additional lattitude in the development of practical drug candidates.

Summary of the Invention

[0017] These and other objectives are met by the present invention which in one aspect is a pharmaceutical formulation comprising at least one compound (defined more specifically below with reference to the Detailed Description) which is a positive allosteric modulator of mGluR4 activity and which is described by Formula I:

Formula I,

wherein:

R¹ is: -H, -Br, -CN, -CH₃, or -0-CH₃, and preferably R¹ is -H;

R^A2 is: Ci-4-alkyl, optionally substituted with fluorine, preferably methyl or trifluoromethyl; Ci_₃-alkoxy, optionally substituted with fluorine, preferably methoxy or trifluoromethoxy; Ci_₃-alkyl-hydroxy; chloro; fluoro; cyano; or hydrogen;

R is: mmeetthhyl; trifluoromethyl; methoxy; trifluoromethoxy; chloro; fluoro; or hydrogen;

and

R^A4 is:

(i) -H; (ii) -alkyl, preferably Ci to C₃ alkyl, where the alkyl is optionally substituted with indazole, -OH, one or more fluorine substituents, or is

alkyl portion is optionally fluorine substituted; (xviii) a moiety of the Formula

r

a pharmaceutically acceptable salt thereof.

[0018] In another aspect, the invention is a pharmaceutical formulation comprising: the compound f Formula III, or a pharmaceutically acceptable salt thereof:

Formula III;

a compound of Formula IV, or a pharmaceutically acceptable salt thereof:

Formula IV,

wherein R is -CI or -O-CH₃, and R and R are independently -H or -C; or

a compound of Formula V, or a pharmaceutically acceptable salt thereof:

Formula V.

[0019] In one aspect the present invention is a medicament comprising at least one of the above-described compounds of Formula I, III, IV or V and one or more suitable excipients.

[0020] In another aspect the present invention is a method of providing treatment, management, alleviation or amelioration of conditions or disease states which can be treated, managed, alleviated or ameliorated by administration of one or more compounds of the invention exhibiting mGluR4 allosteric modulator activity, preferably a method of treating, managing, alleviating or ameliorating a condition, symptom or disease state associated with Parkinson's disease, and preferably where said at least one compound is administered in the form of a medicament of the invention.

[0021 ] In another aspect the present invention is one or more of the above-described compounds, or pharmaceutically acceptable salts thereof, except for compound A-9:

Compound A-9

or the compound of Formula C-l:

Formula C-l.

Detailed Description

[0022] The compounds provided by the present invention, defined in detail below, are believed to be positive allosteric modulators if mGluR4, and as such they do not appear to bind to the orthosteric glutamate recognition site. Accordingly, they do not activate the mGluR4 receptor by themselves, instead, the response of mGluR4 to a concentration of glutamate or mGluR4 agonist is increased when a compound of the invention is present. Accordingly, it is expected that the compounds of the invention will have an effect at mGluR4 by virtue of enhancing the function of the receptor.

[0023] There is strong motivation that mGluR4 receptor positive allosteric modulators are useful for treating or preventing a condition in a mammal, including a human, which treatment is affected or facilitated by the neuromodulatory effect of mGluR4 modulators. In the case of the treatment of movement disorders such as Parkinson's disease, the compounds of the invention can be used alone or in combination with an agent selected from the group consisting of: levodopa, levodopa with a selective extracerebral decarboxylase inhibitor, carbidopa, entacapone, a COMT inhibitor, a dopamine agonist, an anticholinergic, a cholinergic agonist, a butyrophenone neuroleptic agent, a diphenylbutylpiperidine neuroleptic agent, a heterocyclic dibenzazepine neuroleptic agent, an indolone neuroleptic agent, a phenothiazine neuroleptic agent, a thioxanthene neuroleptic agent, an NMDA receptor antagonist, an MAO-B inhibitor, an mGluR5 antagonist, for example, mavoglurant, or an A_2A antagonist, for example, istradefylline or preladenant.

[0024] As the term is used herein, alkyl comtemplates linear, branched or cyclic moieties, and when specified as, for example, "Ci__x-alkyl", means a linear alkyl of from one carbon atom (i.e. methyl) to "X" carbon atoms, a branched moiety of from 3 carbon atoms (i.e. isopropyl) to "X" carbon atoms, and a cycloalkyl of from 3-carbon atoms (i.e. cyclopropyl) to "X" carbon atoms. The meaning remains when used in conjunction with other terms, for example, aryl-alkyl- implies an alkyl moiety bonded to a substrate, and which has bonded to it an aryl group. Alkoxy- has its usual meaning, i.e., an alkyl chain bonded to a substrate through an oxygen atom, and alkyl-hydroxy means an alkyl group bonded to a substrate, and which is substituted with a hydroxyl group (i.e., an alcohol functional group).

[0025] In some embodiments, it is preferred for a pharmaceutical formulation to comprise at least one compound of the structure of Formula la, or a pharmaceutically accepta le salt thereof, for example, a trifluoromethylacetate salt of the compound:

Formula la,

wherein R¹ is "-H" and R², R³, and R⁴ have the values shown in Table I, below.

Table I

a compound of Formula III:

ormula III; a comp

Formula C-1,

a compound of Formula V:

[0026] With reference to Table I, in some embodiments of the present invention it is more preferred to provide a pharmaceutical formulation which comprises at least one of the following compound Nos.: A-2; A-4; A-5; A-9; A-10; A-16; A-19; A-22; A-25; A-32; A-33, A-40, A-43, A-45, A-46, A-47, A-48, A-49, A-51 , A-52, A-55, N-84, N-96, C-2, C- 3, or a pharmaceutically acceptable salt thereof, for example a trifluoromethyl acetate salt thereof..

[0027] In one aspect the invention comprises administering a therapeutically effective amount of a pharmaceutical formulation of the invention to a patient in need thereof, thereby providing treatment, management, alleviation, amelioration and/or prevention of a disease, condition and/or symptom associated with a disease state or condition, which can be so effected by administration of a positive allosteric modulator of mGluR4 receptor, and preferably for the treatment, management, alleviation, amelioration and/or prevention of Parkinson's disease and/or one or more of its associated symptoms.

[0028] Some embodiments provide treatment, management, alleviation, amelioration and/or prevention of a disease, condition and/or symptom which can be so effected by administration of a positive allosteric modulator of mGluR4 receptor, preferably, the pharmaceutical formulation administered comprises at least one of the compounds described herein above, or a pharmaceutically acceptable salt thereof, more preferably the formulation comprises at least one of the compounds, or a pharmaceutically acceptable salt thereof, for example, a trifluoromethyl acetate salt thereof, which is identified herein as compound Nos.: A-2; A-4; A-5; A-9; A-10; A-16; A-19; A-22; A-25; A-32; A-33; A- 40; A-43; A-45; A-46; A-47; A-48; A-49; A-51; A-52; A-55; N-84; N-96; C-2; or C-3 and preferably the administration of the compound is directed at treatment, management, alleviation, amelioration and/or prevention of a symptom related to Parkinson's disease.

[0029] Some embodiments provide treatment, management, alleviation, amelioration and/or prevention of a disease, condition and/or symptom which can be so effected by administration of a positive allosteric modulator of mGluR4 receptor, preferably the formulation administered comprises at least one of the compounds described herein above, or a pharmaceutically acceptable salt thereof, for example, a trifluoromethyl acetate salt thereof, which is identified herein as compound Nos.: A-l; A-6; A-7; A-8; A- 11; A-12; A-17; A-18; A-20; A-31; A-41; A-54; A-56; A-61; C-l; Formula III, or Formula V, and preferably the administration is directed at treatment, management, alleviation, amelioration and/or prevention of a symptom related to Parkinson's disease.

[0030] One aspect of the invention is a novel compound, or a salt thereof, which is a compound of Formula la, Formula III, Formula C-2, Formula C-3 or Formula V, as defined herein, or a salt thereof, excluding the compound described in Table I as Compound A-9.

[0031] It will be appreciated that various of the compounds provided by the reactions described herein, for example, the compounds of Formulae I, la, III, and V and compound Nos. C-l through C-3, described herein, can be provided as a salt, particularly a pharmaceutically acceptable salt, for example a trifiuoromethylacetate salt, and in various crystalline and amorphous forms, including solvates having crystalline or amorphous forms, in accordance with known methods. Accordingly, unless otherwise noted, identification of a particular compound is meant to encompass that compound in all crystalline and amorphous forms, including solvate forms, available from known methods. Examples of techniques for preparing crystalline and salt forms of compounds may be found in any edition of Remington, for example, The Science and Practice of Pharmacy, 21st edition.

[0032] In some embodiments, preferably a compound of the invention is a compound of Formula lb, or a salt thereof:

Formula lb,

wherein R², R³, and R⁴ are as defined in Table III.

Table III



or a compound of Formula C-2, or a salt thereof,

Formula C-2; or

or a compound of Formula C-3, or a salt thereof,

Formula C-2..

[0033] In some embodiments preferred compounds of the invention are those of Formula lb, or a salt thereof:

Formula lb, wherein R², R³, and R⁴ are defined in

Table IV

the compound of Formula V, or a salt thereof:

Compound V; the compound of Formula III, or a salt thereof:

Formula III.

[0034] In some embodiments preferred compounds of the invention are those of Formula lb :

Formula lb, wherein R², R³, and R⁴ are defined in Fable V.

Table V

, or

a pharmaceutically acceptable salt thereof.

[0035] It will be appreciated that the foregoing novel compounds are claimed in crude form as obtained from a reaction mixture as well as in pure form or in isolated form as defined herein. It will be appreciated also that these compounds can comprise multiple stereocenters, accordingly, stereoisomers and diastereomers in all possible combinations and racemates are included in the description of the compounds of the aforementioned Formulae.

[0036] It will be appreciated as well that all isolated forms, for example: isolated pure stereoisomers; mixtures of diastereomers; racemates; conventionally obtained amorphous forms; conventionally obtained crystalline forms; solvates, including hydrates; and tautomers of the compounds available via known methods are included in the description of the novel compounds of the Formulae described herein, as well as salt forms, preferably pharmaceutically acceptable salt forms, derived from the novel compounds of Formulae described herein obtained by known means.

[0037] In one aspect the invention provides treatment of conditions amenable to treatment via positive allosteric modulation of mGluR-4 receptors through administration of an effective amount of a pharmaceutical formulation comprising at least one of the compounds described herein as an mGluR-4 positive allosteric modulator, including compounds of Formula la, Formula lb (as defined in Tables III, IV, and V), Formula III, Formula V, or Compound Nos. C-1 through C-3. Preferably pharmaceutical compositions suitable for administration comprise 1 to 3 compounds described herein as an mGluR-4 positive allosteric modulator, or a pharmaceutically acceptable salt thereof, more prefereably 1 or 2 such compounds or their pharmaceutically acceptable salts and more preferably 1 such compound or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient.

[0038] Methods for establishing the safe and effective administration of compounds described herein as possitive allosteric modulators mGluR-4 receptor activity are known to those skilled in the art, for example, as described in the standard literature, for example, as described in the "Physicians' Desk Reference" (PDR), e.g., 1996 edition (Medical Economics Company, Montvale, NJ 07645-1742, USA), the Physician's Desk Reference, 56^th Edition, 2002 (published by Medical Economics company, Inc. Montvale, NJ 07645- 1742), or the Physician's Desk Reference, 57^th Edition, 2003 (published by Thompson PDR, Montvale, NJ 07645-1742); the disclosures of which is incorporated herein by reference thereto.

[0039] In one aspect the invention provides a pharmaceutical formulation comprising at least one compound of Formula la, Formula lb (as defined in Tables III, IV, and V), Formula III, Formula V, or Compound Nos. C-1 through C-3 and at least one excipient. It will be appreciated that excipients are themselves typically pharmaceutically inactive but their presence imparts to the formulation in which they are included properties which make it easier to handle or process, for example, lubricants or pressing aids in powdered medicaments intended to be tableted, or which adapts the formulation to a desired route of administration, for example, adapts the formulation to a solid form for oral delivery or liquid form for delivery via an injection route. Combined excipients providing a suitable form for administration are sometimes referred to collectively as "a carrier". Typically formulations may comprise up to about 95 percent active ingredient, although formulations with greater amounts may be prepared.

[0040] Examples of forms which may be selected for a pharmaceutical composition comprising at least one compound of Formula la, Formula lb (as defined in Tables III, IV, and V), Formula III, Formula V, or Compound Nos. C-1 through C-3 and at least one excipient include a form adapted for: (i) oral administration, e.g., a liquid, gel, powder, solid or semi-solid pharmaceutical composition which is loaded into a capsule or pressed into a tablet; (ii) a solution or suspension adapted for intramuscular administration (IM); (iii) a solution or suspension adapted for intravenous administration (IV), for example, as an IV solution or a concentrate to be injected into a saline IV bag; (iv) a lozenge form for administration through tissues of the oral cavity; (v) a solution, suspension or emulsion formulation for dispersion administration via the nasal mucosa or via tissues within the oral cavity including sublingual and buccal tissue; (vi) a suppository form for administration via the rectal or vaginal mucosa; (vii) in the form of an adhesive patch for administration through dermal tissue. It will be appreciated that other forms can be provided for use in administration by the foregoing routes and via other known routes. The use of a pharmaceutical composition comprising more than one compound of Formula I, and comprising more than one type of pharmaceutically active compound is also within the scope of this invention.

[0041 ] By way of further examples, solid form pharmaceutical formulations can be adapted to a variety of modes of administration and include powders, dispersible granules, mini-tablets, beads, and the like for example, for tableting, encapsulation, or direct administration.

[0042] Liquid form preparations include solutions, suspensions and emulsions. Examples of liquid forms of medicament include, but are not limited to, water or water/surfactant mixtures, for example a water-propylene glycol solution, which can be employed in the preparation of formulations intended, for example, for parenteral injection, for example, as a solvent or as a suspending medium for the preparation of suspensions and emulsions where a medicament comprises constituents which are insoluble in water or water/surfactant mixtures. Liquid form preparations may also include solutions for intranasal administration which may also include, for example, viscosity modifiers to adapt the formulation to target application of the formulation to particular mucosa tissues accessible via nasal administration.

[0043] Aerosol preparations, for example, suitable for administration via inhalation or via nasal mucosa, may include solutions or solids in powder form, which may be in combination with a pharmaceutically acceptable propellant, for example, an inert compressed gas, e.g. nitrogen. Also included are solid form preparations which are intended to be converted, shortly before use, to a suspension, solution, or a solution, for example, for oral or parenteral administration. Examples of such solid forms include freeze dried formulations and liquid formulations adsorbed into a solid absorbent medium.

[0044] The compounds of the invention may also be deliverable transdermally or transmucosally, for example, from a liquid, suppository, cream, foam, gel, or rapidly dissolving solid form. It will be appreciated that transdermal compositions can take also the form of creams, lotions, aerosols and/or emulsions and can be provided in a unit dosage form which includes a transdermal patch of any known in the art, for example, a patch which incorporates either a matrix comprising the pharmaceutically active compound or a reservoir which comprises a solid or liquid form of the pharmaceutically active compound, with or without additional layers that function to regulate the rate of delivery of the pharmaceutically active compound(s) contained in the patch. It will be appreciated that a patch dosage form may contain additionally excipients which aid in passing the pharmaceutically active compound contained in the patch through the tissues through which it is being administered.

[0045] Additional examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions mentioned above and their incorporation into various of the dosage forms mentioned herein may be found in A. Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20^th Edition, (2000), Lippincott Williams & Wilkins, Baltimore, MD.

[0046] Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparations subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose over the desired treatment period. [0047] The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill in the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.

[0048] The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 0.04 mg/day to about 4000 mg/day, in two to four divided doses.

[0049] In general, in what ever form administered, the amount of a pharmaceutical composition comprising at least one compound of the invention that will be administered will be that amount providing a therapeutic serum level of the compound, or a metabolite or derivative thereof, for a period of at least 2 hours, preferably at least four hours, and preferably longer. In general, as is known in the art, dosages of a pharmaceutical composition providing a therapeutically effective serum level of a compound of the invention are spaced in time to provide serum level meeting or exceeding the minimum therapeutically effective serum level on a continuous basis throughout the period during which treatment is administered.

[0050] Administration of multiple pharmaceutically active compounds in connection with positive allosteric modulation of mGluR-4 receptors, or the administration of more than one compound of the invention in the provision of a treatment or management of a disease state, can comprise, administering a single pharmaceutical composition comprising all of the pharmaceutically active compounds or multiple compositions, each one comprising one or more different pharmaceutically active compounds. It will be appreciated that administration of more that one pharmaceutical composition can comprise simultaneous, contemporaneous, or sequential administration of said pharmaceutical compositions.

[0051 ] Pharmaceutical compositions of the invention may also include other compounds having pharmaceutical activity, that is, activity which treats, manages, mitigates, ameliorates, improves, eliminates, or cures a disease state or symptom associated with a disease state. Examples of additional therapeutic agents which may be included in a composition of the invention include, but are not limited to: L-DOPA; dopaminergic agonists, for example, quinpirole, ropinirole, pramipexole, pergolide and bromocriptine; MAO-B inhibitors, for example, rasagiline, deprenyl and selegiline; DOPA decarboxylase inhibitors, for example, carbidopa and benserazide; COMT inhibitors, for example, tolcapone and entacapone; adenosine A2a antagonists, for example, istradefylline or preladenant, and growth factors such as brain derived neurotrophic factor (BDNF). While these additional therapeutic agents can be incorporated into a single composition containing one or more compounds of the invention, the additional therapeutic agent and a pharmaceutically acceptable carrier, it will be appreciated that a pharmaceutical composition comprising one or more compounds of the invention can be co-administered with additional pharmaceutical compositions comprising one or more of the additional therapeutic agents. [0052] In one embodiment the invention provides a method of treating or managing at least one symptom associated with Parkinson's disease in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one compound of Formula la, Formula lb (as defined in Tables III, IV, and V), Formula III, Formula V, or Compound Nos. C-1 through C-3.

[0053] It will be appreciated that any of the methods of treating Parkinson's disease described herein, unless stated otherwise, can optionally include the administration of an effective amount of one or more (e.g., 1 , 2 or 3, or 1 or 2, or 1) agents effective in treating movement disorders associated with Parkinson's disease or side-effects arising from administering agents effective in treating Parkinson's disease. It will be appreciated also that when more than one pharmaceutically active compound is administered, pharmaceutically active compounds, including the administration of multiple compounds of this invention, can be administered together in the same formulation, or can be administered concurrently, contemporaneously, or sequentially in separate formulations.

[0054] It will be appreciated that some of the inventive positive allosgteric modulators of mGlu-R4 will have additional utility as therapeutic agents, for example, in the treatment of neuroinflamation, neurodegeneration, pain, and anxiety, for example, as mentioned by Lavereysen et al. in Current Medicinal Chemistry, 2008, 15, pp671-684 with regard to mGlu-R4 active compounds.

[0055] Compounds of Formula la, Formula lb (as defined in Tables III, IV, and V), Formula III, Formula V, or Compound Nos. C-1 through C-3 described herein may generally be prepared using one or more of the following synthetic schemes. Examples of the preparation of certain compounds of the invention are related further below.

[0056] Pyrazole[4,3b]pyridine compounds of the invention can be prepared in accordance with Schemes IA, IB and IIA, shown below, utilizing a pyrazolopyridine precursor and reacting it with an appropriately substituted analine compound.

Scheme IA

[0057] As shown in Scheme IA, Buchwald coupling of a protected pyrazolo-[4,3b]- pyridine compound with an analine moiety bearing a desired substitutent can be employed to provide certain compounds of the invention. Accordingly, palladium catalyzed cross-coupling of a suitable halo-pyrazolo-pyridine with a suitably substituted aniline can be conducted to furnish compounds of the product shown in Scheme IA, for example, using a precatalyst of Pd₂dba₃, Xantphos as ligand, and Cs₂C0₃ as base in refluxing dioxane. Deprotection of the PMB-group can be accomplished by heating the compound in TFA at 120 °C whilst irradiating the reaction mixture in a microwave to yield the product compound. It will be appreciated that employing a pyrazolopyridine having a pyridine portion bearing desired substituents in the reaction of Scheme IA will provide compounds comprising a pyridyl moiety comprising desired substituents on the pyridine portion of the pyrazolopyridine core.

[0058] For use in synthesis Scheme IA, halo-pyrazolopyridine precursors can conveniently be prepared as described in Scheme IA-1 starting with the desired pyrazolopyridine. For example,. lH-Pyrazolo[4,3-b]pyridine, an article of commerce, can be brominated on the pyrazole ring using bromine in MeOH/H₂0 at 0 °C to give IA- 1-2, and then the pyrazole ring can be protected with a protecting group, for example, as shown, a para-methoxybenzyl group, using PMBC1 and K₂C0₃ in DMF at 100 °C to yield a halo-pyrazolo-pyridine suitable for use in Scheme IA.

SCHEME IA-1

[0059] Suitably substituted analine precursors for use in the preparation of compounds of the invention can be purchased, or prepared, for example, by coupling suitably functionalized nitrobenzene sulfonyl chlorides to optionally substituted anilines to give nitro-sulfonamides, for example, the intermediate sulfonamides produced in Step 1 of Scheme IA-2, below. Subsequent reduction of the intermediate nitro group to an aniline substituent allows the resulting substituted analine product to be employed in the palladium catalyzed cross coupling reaction with a suitable pyrazolopyridine precursor shown in Scheme IA, above, thereby providing a compound of the invention.

Scheme IA-2

[0060] An analogous synthesis route to Scheme IA-2 is illustrated in Scheme IA-3, which shows the preparation of phthalate-substituted analine precursors suitable for use in preparing compounds of the invention utilizing the coupling reaction of Scheme IA

-3

[0061 ] As shown in Scheme IA3, Step 1 , coupling of an appropriately substituted nitro- phenylamine to a substituted phthalic anhydride in refluxing AcOH yields the corresponding diimide. The nitro substituent of the dimide intermediate is subsequently reduced, as shown in Step 2 of Scheme IA3, for example utilizing palladium-catalyzed hydrogenation, for example, palladium on carbon as catalyst, to give as a product phthalate-substituted aniline comopunds. In turn, these substituted analine compounds can be coupled with 3-bromo-lH-pyrazolo[4,3-b]pyridine as outlined in Scheme IA (shown above), then deprotected to yield compounds of the invention.

[0062] Scheme IA4 illustrates another general scheme for providing substitution on the aryl portion of a aryl-substituted pyrazolo-pyridine compound of the invention. As shown, this end is accomplished by providing an analine precursor functionalized with a labile substituent that can be reacted to incorporate additional functionality following a Buchwald coupling reaction (Step 3 of Scheme IA4) in which the substituted analine precursor is condensed with a pyrazolo-pyridine compound. This pathway is exemplified in Scheme IA4 by the reaction of an appropriately substituted nitro -phenylamine IA4-12 with acetyl chloride to provide a protected form of the analine compound (IA4-27). The nitro group of the compound of Formula IA4-27 is reduced, for example by using tin (II) chloride in HC1, to yield an aniline compound of the formula IA4-28. The compound of Formula IA4-28 can be coupled in subsequent Step 3 with a suitable 3-bromo-lH- pyrazolo[4,3-b]pyridine using the method described above in Scheme IA to provide IA4- 29, which is reacted to remove the acetamide protecting group, for example, by heating IA4-29 in acidic ethanol to yield intermediate IA4-30.

Scheme IA4

Ste l and Step 2

[0063] As shown in Scheme IA4-a, intermediate IA4-30 can be subsequently further derivatized, for example, by treatment with an appropriate anhydride, for example IA4- 31, to yield, for example, compounds of the Formula IA4-32. Deprotection of IA4-32, for example using trifluoroacetic and triflic acids, yields desirably substituted compounds having mGluR4 PAM activity.

Scheme IA4-a

[0064] Scheme IA-4b illustrates another scheme for further derivatizing a compound of Formula IA-4-30, wherein acyl functionality is added via reaction with an appropriate acyl chloride in the presence of a base, for example, pyridine, at the amino- substituent of the compound prior to deprotecting the pyrazolo nitrogen. In this manner an intermediate amide of Formula IA-4b-34 is provided. Subsequent removal of the PMB protecting group from the pyrazolo nitrogen, for example, by reaction with trifluoroacetic and triflic acids, yields amide compounds of the invention.

Scheme IA-4b

IA-4-30 IA-4b-34

[0065] An alternative process for the provision of substituted pyrazolo-[4,3b]-pyridines based on Wilcoxen, et al.,Bioorganic & Medicinal Chemistry Letters 13 (2003) pp3367- 3370, is illustrated in Scheme IB. Scheme IB utilizes pyrazole amines from which enolates are prepared then cyclized according to Scheme IB to provide derivatives of pyrazolo-[4,3b]-pyridine. It will be appreciated that the process of Scheme IB can provide directly pyrazolo-[4,3b]-pyridine compounds which are substituted both on the pyridine ring and on the aryl substituent of the product.

Scheme IB

[0066] The process of Scheme IIA, below, illustrates a process which can be employed to provide pyrazolo-[4,3b]-pyridine compounds having a labile substituent at C-5 on the pyridine ring. The related process of Scheme IIB, further below, provides pyrazolo- [3, 4b] -pyridine compounds. Both schemes utilize a reaction between thioamide precursors and hydrazine to provide the pyrazolo-pyridine core of the product.

[0067] As shown in Scheme IIA, a thioamide precursor containing a pyridine substituent comprising suitably located fluoro- and bromo- substituents yields a pyrazolo- [4,3b]-pyridine having a bromo-substituent on C-5 of the pyrazolo-pyridine moiety in the compound upon reaction with hydrazine.

Scheme IIA

It will be appreciated that the bromo-substituent present on the pyrazolo[4,3b]pyradine thus provided can be utilized in subsequent reactions to provide a number of different substituents at the C-5 position of the pyrazolo-pyridine moiety.

[0068] As illustrated by Scheme IIA- la, below, the 5-bromo-pyrazolo[4,3b]-pyridine (IIA-la-42) provided by Scheme IIA can be used as a substrate in the preparation of, for example, C-5 alkyls, nitriles, and alkoxide compounds. It will be appreciated that further reactions utilizing some of these compounds to provide further substituents and derivatives are also possible. Thus, for example, Suzuki coupling of the C-5-bromo compound form Scheme IIA with a boronic acid under palladium catalysis gives compounds of the type IIA-la-43. In an additional example, reaction with zinc cyanide in NMP at 160 °C in the presence of palladium catalysis yields the corresponding nitrile IIA-la-44, and displacement of the bromide with an alkoxide ion provides compounds of the formula of II A- la -45.

Scheme IIA- la

[0069] Thioamide compounds suitable for use in preparing pyrazolopyridines in accordance with Scheme IIA can be can be prepared, for example, in accordance with Scheme IIA-lb. As exemplified in Scheme IIA-lb, 2-Bromo-5-fluoropyridine IIA-lb- 38 can be lithiated at the 6-position, for example, by treatment with n-BuLi at -78 °C in THF, and then quenched with C0₂ to yield the corresponding carboxylic acid IIA-lb-39. This intermediate acid can then be coupled with a variety of substituted anilines, for example, to give a carboxamide compound of Formula IIA-lb-40. This carboxamide intermediate can in turn be converted to a thioamide, for example, the compound of IIA- lb-41, for example, by treatment with Lawesson's reagent in refluxing dioxane. As shown in Scheme IIA, above, subsequent reaction of a thioamide of Formula IIA-lb-41 with hydrazine at 120 °C in a suitable solvent, for example, DMSO, yields pyrazolo- [4,3b]-pridine compounds of the invention. Scheme II A- lb

[0070] Scheme IIB illustates the preparation of pyrazolo-3,4b]-pyridine compounds from a different thioamide precursor than those utilized in Scheme IIA. The thioamide precursor utilized in Scheme IIB comprises a pyridine moiety bearing a single labile substituent which, upon reaction with hydrazine, yields a pyrazolo-[3,4b]-pyridine having a pyridine ring comprising only hydrogen substituents.

Scheme IIB

In some embodiments utilizing Scheme IIB, it is preferred to carry out the reaction with hydrazine by treating a DMSO solution of the thioamide maintained at 120 °C with hydrazine.

[0071 ] Thioamide precursors suitable for use in the process of Scheme IIB can be prepared in a manner analogous to the synthesis route described above for preparation of thioamide precursors used in Sheme IIA. Accordingly, reaction of a suitably mono- substituted pyridine-carboxylic acid, for example, 2-Chloropyridine-3-carboxylic, acid and an appropriately substituted analine precursor compound provide the corresponding carboxamide intermediate. Thus prepared, the carboxamide intermediate can be converted to the corresponding thioamide by treatment with Lawesson's reagent, as shown below in Scheme IIB1. It will be appreciated that reaction of the resulting mono- substituted pyridine -thioamide compound with hydrazine yields pyrolo-[3,4b]-pyradine compounds of the invention, as illustrated in Scheme IIB.

Scheme IIB1

[0072] Scheme IIIA, below, illustrates a process for preparing pyrazolo-[4,3-b]- pyrazine compounds of the invention from a suitably substituted pyrazine precursor by reaction with PMB-hydrazine in a process which is analogous to the process of Schemes IIA and IIB. In the process of Scheme III, PMB-protected pyrazolo-pyrazine is formed directly by reaction with PMB-hydrazine thus eliminating a need for a separate step to protect the pyrazolo-pyridine nitrogen employed in other schemes described above.

Scheme IIIA

Step I

[0073] As shown in Scheme IIIA, for example, 3-chloropyrazine-2-carbonitrile IIIA- 22 reacted with PMBNHNH₂ in the presence of K₂C0₃ in refluxing EtOH yields protected lH-pyrazolo[3,4-b]pyrazin-3-amine IIIA-23. Carrying out a Sandmeyer reaction with IIIA-23 using tert-butyl nitrite in MeCN in the presence of copper (II) bromide yields the heteroaryl bromide compound of Formula IIIA-24. In a subsequent reaction analogous to Scheme IA, the compound of Formula IIIA-24 can be reacted with a suitably substituted analine precursor in the presence of, palladium catalysis yielding a compound of Formula IIIA-25, which can subsequently be deprotected to provide a pyrazolo-pyrazine of the invention

[0074] Scheme IV-A illustrates a reaction useful for providing sulfonamide derivative compounds of the invention from aryl-pyrazolo-pyridine compounds. Accordingly, preparation of a aryl-pyrazolo-pyridine compound, for example, in accordance with any of Schemes IA, IB, IIA, IIB or IIIA, for example, the compound of Formula IV-A-5, can be sulfonylated using HSO₃CI to give the analogous sulfonyl chloride of Formula IV- A- 36. The intermediate Formula IV-A-36 can be reacted with an appropriately substituted amine or aniline, in the presence of a base such as pyridine, to give a sulfonamide of the invention, for example a sulfonamide compound of the Formula IV-A-37.

-A

[0075] It will be appreciated that various of the compounds provided by the reactions described herein, and the compounds listed in the Tables and formula above can be provided as a salt, particularly a pharmaceutically acceptable salt, and in various crystalline and amorphous forms, including solvate crystalline and amorphous forms, in accordance with known methods. Accordingly, unless otherwise noted, identification of a particular compound is meant to encompass that compound in all crystalline and amorphous forms, including solvate forms, available from known methods. Examples of techniques for preparing crystalline and salt forms of compounds may be found in any addition of Remington, for example, The Science and Practice of Pharmacy, 21st edition.

[0076] There follows examples of the preparation and characterization of specific compounds of the invention which are intended to be illustrative of the invention, and not limiting thereof. One of ordinary skill will appreciated from the provision of these examples that there are additional compounds which can be provided by application of the chemistry presented in the following examples to provide additional compounds of the invention.

Analytical equipments and methods:

[0077] LC-MS were recorded on Agilent 1200 RRLC equipped with 6110 MSD with the following conditions: Reversed phase HPLC was carried out on Zorbax SB-C18 analytical column (5 μηι, 2.1 x 50 mm) from Agilent, with a flow rate of 0.8 mL/min. The gradient conditions used are: 90 % A (water + 0.1 % of trifluoroacetic acid), 10% B (acetonitrile + 0.05 % of trifluoroacetic acid) to 100 % B at 3.5 minutes, maintained until 4.0 minutes and then equilibrated to initial conditions beginning at 4.01 minutes until 4.5 minutes. Injection volume 2-5 μL. ES MS detector was used, acquiring in positive ionization mode.

[0078] All mass spectra were taken under electrospray ionisation (ESI) methods.

[0079] Preparative HPLC was conducted using a Gilson GX-281 preparative HPLC (322 Binary Gradient Module, 156 UV/Visible detector GX-281 injector/fraction collector) Phenomenex Synergi Max-Rp (C12, 30x150mm, 4μηι) or Kromasil Eternity (C18, 30x150mm, 5μηι) columns and H₂0 + 0.1%TFA and CH₃CN as eluents. Gradients used cover the range from 0% CH₃CN to 100% CH₃CN.

[0080] ^!H NMR spectra were recorded on a Bruker Avance 400MHz or Varian 400MHz spectrometer. Chemical shifts are expressed in parts of million (ppm, δ units). Coupling constants are in units of hertz (Hz) Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quadruplet), quint (quintuplet), m (multiplet), br (broad).

mGluR4 Assay on HEK-expressing Human mGluR4

[0081 ] Since, as explained above, the compounds of the present invention are positive allosteric modulators of mGluR4 receptors, which activity was assayed by detecting changes in intracellular Ca⁺² ion concentration using a Ca⁺²-sensitive fluorescent dye (Fluo4-(AM)) and a fluorometric imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, CA) in accordance with the manufacturers instructions.

[0082] Accordingly, 24 hours prior to carrying out an analysis, human mGluR4 HEK- 293 cells were plated out in black- walled, clear-bottomed, poly-L-ornithine-coated 384- well plates at a density of 25,000 cells/well in a glutamine/glutamate-free DMEM medium containing fetal bovine serum (10%), penicillin (100 units/mL) and streptomycin (100 micrograms/mL) at 37°C under 5% C0₂. On the day of the assay, the medium was aspirated and the cells were loaded with a 3 micro-molar solution of Fluo4-AM (LuBioScience, Lucerne, Switzerland) in 0.03% pluronic acid. After maintaining the plate 1 hour at 37°C under 5% C0₂ the non-incorporated dye was removed by washing the cell plate with the assay buffer and the cells were left in the dark at room temperature for six hours before evaluating. All assays were performed in a pH 7.4 buffered-solution containing 20 mM HEPES, 142 mM NaCl, 6 mM KC1, 1 mM MgS0₄, 1 mM CaCl₂, 0.125 mM sulfapyrazone, and 1% glucose.

[0083] Basal fluorescence was recorded over 10 seconds, then aliquots of various concentrations of a compound of the invention were added to the cells. Changes in fluorescence level were first monitored for 180 seconds in order to detect any agonist activity attributable to the compound being assayed. Then the cells were stimulated for an additional 110 seconds by that concentration of glutamate yielding 25% of the maximal response to glutamate (EC₂₅). Concentration-response curves of compounds of the invention were generated using Prism GraphPad software (Graph Pad Inc., San Diego, USA). Curves generated were fitted to a four-parameter logistic equation allowing the determination of EC₅₀ values:

Y = Bottom+(Top - Bottom) / ( +1 o^logEC5°-^x) ^* Hill Slope

[0084] For each sample assayed, at least three independent measurements were performed. EC50 values thus determined are reported for each of the compounds of the invention in the respective Tables 1 to 3 herein above.

[0085] Accordingly, the compounds of the invention are believed to be effective in the treatment, prevention, or management of neurological or psychiatric diseases or disorders associated with glutamate dysfunction which are amenable to treatment, prevention, or management by administration of a positive allosteric modulator. It is believed that the compounds of the invention can be incorporated into dosage forms which lend themselves to administration via the alimentary canal (oral), through mucosal tissue (for example, administration by absorption through tissues of the oral cavity, rectal, and vaginal mucosa), via dermal absorption, or via intramuscular or intravenous injection. International application no. PCT/EP2010/050304, filed January 12, 2010 is incorporated by reference as if fully set forth herein for the purpose of illustrating various dosage forms suitable for the compounds of the present invention. It will be appreciated that other known methods of administration and other known dosage forms can be adopted for compounds of the present invention.

EXAMPLES

EXAMPLE 1 : Preparation of 3-[(4-Chloro-3-methoxyphenyl)amino]

pyrazolo [4,3-b]pyridin-4-ium trifluoroacetate

Ste 1 and 2:

Step 3:

St

Step 1 : Preparation of 3-bromo-lHpyrazolo[4,3-blpyridine (Exp-l-g2)

[0086] Into a vessel was placed a solution comprising 1.0 g of lH-pyrazolo[4,3- b]pyridine (Exp-l-gl , 8.4 mmol) in 12 mL of MeOH/H₂0 (1 : 1 , vol). Into the solution was added dropwise a solution of Br₂ (1.6 g, 10 mmol) in MeOH/H₂0 (1 : 1 , 5 mL) maintaining the solution temperature at 0 °C during the addition. The reaction mixture thus prepared was stirred at this temperature for 40 min. The resulting precipitate was collected by filtration and the filter cake thus obtained was neutralized with saturated Na₂C0₃ solution. The neutralized precipitate was filtered, washed with water and dried in vacuum. The crude product thus obtained (Exp-l-g2,l .2 g, 71 %) was used for the next step directly without purification. The identity of the product was verified by proton NMR in accordance with the procedures set forth above.

^NMR: (400 MHz, DMSO) δ 13.66 (br, 1H), 8.55 (d, 1H, J = 4.0 Hz), 8.03 (dd, 1H, J = 8.8 Hz, 1.2 Hz), 7.42-7.45 (m, 1H).

Step 2: Preparation of 3-Bromo-l-(4-methoxybenzyl)-lH-pyrazolo[4,3-b]pyridine

(Exp-l-g3)

[0087] Into 8 mL of DMF was placed 1.0 g of Exp-l-g2 (5 mmol) prepared in Step 1 , 0.94 g p-methoxybenzylchloride (PMBC1, 6 mmol) and 1.38g K₂C0₃ (10 mmol). The reaction mixture thus provided was stirred for 3 hours while maintaining it at 100 °C. At the end of this time the reaction mixture was diluted with 150 mL ethylacetate (EtOAc). The diluted mixture was washed sequentially with ali quotes of brine then water, dried over MgSC>4, filtered, and concentrated. The concentrate solution thus provided was purified via silica column chromatogram (PE:EtOAc = 8: 1) and after the eluting solvent was evaporated gave Exp-l-g3 as a yellow solid (1.2 g, 75 %).

Step 3: Preparation of N-(4-Chloro-3-methoxyphenyl)-l-(4-methoxybenzyl)-lH- yrazolof 4, 3-b]pyridin-3-amine (Exp- 1 -g4)

[0088] Into a vessel containing 1.5 mL dioxane was placed 63 mg of the crude Exp-1- g3 prepared in Step 2 (0.2 mmol). To the vessel was added 39 mg of 4-chloro-3- methoxy-phenylamine (0.25 mmol), 18 mg Pd₂dba₃ (0.02 mmol), 23 mg Xantphos (0.04 mmol) and 130 mg Cs₂C0₃ (0.4 mmol). The reaction mixture thus provided was refluxed under a nitrogen atmosphere for 4 hours, then filtered and concentrated under reduced pressure. The residue was subjected to Prep-TLC (PE:EtOAc = 2: 1) to obtain Exp-l-g4 (52 mg, 66 %).

Step 4: Preparation of 3-[(4-Chloro-3-methoxyvhenyl)aminol-lH-pyrazolo[4,3- bJpyridin-4-ium trifluoroacetate (Exp-1 -q5)

[0089] An aliquot of the compound of Formula Exp-l-g4 prepared in Step 3 (52 mg, 0.13 mmol) was dissolved in 4 mL of trifluoroacetic acid (TFA) with stirring while maintaining the solution temperature at 120 °C using microwave radiation. The reaction mixture thus provided was heated with stirring for 20 minutes, then the mixture was concentrated under reduced pressure and the residue was purified by Prep. HPLC to give 22 mg of the compound of Formula Exp-l-g5 (calculated 61 % yield). The identity of the product was confirmed via mass spectroscopy and proton NMR in accordance with the above-described procedures.

MS (ESI) m z: (M+H) 275.

^XH NMR (400 MHz, CD₃OD) δ 8.47 (d, 1H, J= 3.6 Hz), 8.04 (d, 1H, J= 8.4 Hz), 7.49- 7.53 (m, 2H), 7.19 (d, 1H, J= 8.4 Hz), 7.03-7.06 (m, 1H), 3.89 (s, 3H).

EXAMPLE 2: Preparation of 3-{[3-Chloro-4-(4-methyl-l,3-dioxo-l,3-dihydro-2H- isoindol -2-yl)phenyl]amino}-lH-pyrazolo[4,3-b]pyridin-4-ium trifluoroacetate

Step 1 S

S

Step 4

Step 1 : Preparation of 2-{2-Chloro-4-nitroDhenyl)-4-methyl- 1 H-isoindole-

1 ,3(2H)-dione (Exp-2-g 14)

[0090] Into a vessel containing 10 mL of acetic acid was placed 480 mg of 4-methyl-2- benzofuran-l ,3-dione (Exp-2-gl3, 3 mmol) and 344 mg of 2-chloro-4-nitro-phenylamine (Exp-2-gl2, 2 mmol), and the mixture was brought to reflux under a nitrogen atmosphere. Refluxing was maintained for 48 h under N₂, then cooled to ambient temperature (about 25 °C) and concentrated under reduced pressure to afford the crude Exp-2-gl6 (570 mg, calculated 90 % yield). The crude product was used in the next step without purification.

Step 2: Preparation of 2-(4-Amino-2-chlorophenyl)-4-methyl-lH-isoindole-l ,3(2H)- dione (Ex -2- g 15)

[0091 ] Into a vessel containing 40 mL of EtOAc was placed 570 mg of Exp-2-gl4 prepared in Step 1 , and 100 mg of Pd/C hydrogenation catalyst (article of commerce) was added. The resulting mixture was stirred at room temperature for 24 h under hydrogen atmosphere, then it was filtered and concentrated under reduced pressure. The residue thus obtained was purified by Prep-TLC (PE:EtOAc = 2: 1) to afford 100 mg of Exp-2- gl5 (calculated yield 19 %). The identity of the product was confirmed by mass spectroscopy in accordance with the procedures described herein. MS (ESI) m/z 287, 289 (M+H)⁺

Step 3: Preparation of 2-(2-Chloro-4-{[l-(4-methoxybenzyl)-lH-yyrazolo[4,3bl- pyridin-3-yl]amino}phenyl)-4-methyl-lH-isoindole-l,3(2H)-dione (Exp-2-gl6)

[0092] Into a vessel containing 1.5 mL dioxane was placed 57 mg of EXP-2-gl5 prepared in Step 2 (0.2 mmole), 80 mg 3-bromo-l-(4-methoxy-benzyl)-lH-pyrazolo[4,3- b]pyridine (Exp -l-g3 prepared in Example 1 , 0.25 mmol), 18 mg Pd₂dba₃ (0.02 mmol), 23 mg Xantphos (0.04 mmol), and 130 mg Cs₂C0₃ (0.4 mmol), and this reaction mixture was refluxed for 3 hours under an N₂ atmosphere, then the reaction mixture was cooled to ambient temperatue (RT), filtered, and concentrated under reduced pressure. The residue thus provided was purified by Prep-TLC (PE:EtOAc=l : l) to afford 62 mg of Exp-2-gl6 (calculated yield 59 %). The identity of the product was confirmed by mass spectroscopy using the procedures described herein. MS (ESI) m/z 524, 526 (M+H)⁺

Step 4: Preparation oi3-{[3-chloro-4-(4-methyl-l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)vhenyllamino}-lH-vyrazolo[4,3-blvyridin-4-ium trifluoroacetate (Exp-2- g!7)

[0093] Into a vessel containing 4 mL of trifluoroacetic acid (TFA) was dissolved 62 mg of Exp-2-gl6 (0.12 mmol) prepared in Step 3. This solution was stirred at 120 °C under microwave irradiation for 20 min, then cooled to RT and concentrated under reduced pressure. The residue thus obtained was purified by Prep. HPLC to give 20 mg of Exp-2- gl7 (calculated yield 41%). The identity of the product was confirmed by mass spectroscopy and proton NMR using the procedures described herein. MS (ESI) m/z 404, 406 (M+H)⁺

^XHNMR (400 MHz, DMSO-d6): δ 12.42 (s, 1H), 9.67 (s, 1H), 8.44-8.45 (m, 1H), 8.17 (d, 1H, J = 2.4 Hz), 7.89 (d, 1H, J= 8.4 Hz), 7.74-7.77 (m, 3H), 7.68-7.70 (m, 1H), 7.38- 7.41 (t, 2H, J= 4.4 Hz), 2.64 (s, 3H).

EXAMPLE 3: Preparation of 3-({4-[(2-Chlorophenyl)sulfamoyl]-phenyl}amino)-lH- pyrazolo[4,3-b]pyridin-4-ium trifluoroacetate

Step 1 :

Step 1 : Preparation of N-(2-Chlorophenyl)-4-nitrobenzenesulfonamide (Exp-3-g8)

[0094] Into a vessel containing 10 mL of pyridine was placed 1.0 g of 4- nitrobenzenesulfonyl chloride (Exp-3-g-6, 4.5 mmol) and 0.5g 2-chlorophenylamine (Exp-3-g7, 4.3 mmol). The mixture was stirred at RT for one hour, then washed with 5 % HC1 and subsequently extracted with 3 aliquots of CH₂CI₂ (50 mL). The combined methylene chloride extracts were dried over Na₂S0₄, filtered and concentrated under reduced pressure to afford 1.1 g of crude Exp -3-g8 (calculated yield 79 %) which was used for the next step directly without further purification.

Step 2: Preparation of 4-Amino-N-(2-chlorophenyl)benzenesulfonamide (Exp-3-g9)

[0095] Into a solution prepared by dissolving 174 mg of SnCl₂ (0.77 mmol) in 2 mL of cone. HC1 was added 100 mg of crude Exp-3-g8 (0.32 mmol) prepared in Step 1. The resulting mixture was stirred at RT for 1 h, then basified with NaOH and extracted sequentially with three 10 mL aliquots of EtOAc. The ethyl acetate extrats were combined, dried over Na₂SC>4, filtered and concentrated under reduced pressure. The residue thus provided was purified by Prep-TLC (PE:EtOAc= 2: 1) to give 70 mg of Exp- 3-g9 (calculated yield 78 %). The identity of the product was confirmed by mass spectroscopy and proton NMR in accordance with the proceedures described herein. MS (ESI) m/z 283, 285 (M+H)⁺

^NMR: (400 MHz, CD₃OD) δ 7.47 (dd, 1H, J = 1.2 Hz, J = 8.0 Hz), 7.36 (d, 2H, J = 8.8 Hz), 7.26 (dd, 1H, J = 1.2 Hz, J = 8.0 Hz), 7.18-7.22 (m, 1H), 7.05-7.09(m, 1H), 6.54 (d, 2H, J = 8.8 Hz).

Step 3: Preparation of 3-({4-[ (2-Chlorophenyl)sulfamoyl]phenyl}amino)-lH- pyrazolo[4,S-b]pyridin-4-ium trifluoroacetate via N-(2-Chlorophenyl)-4-i[l-(4- methoxybenzyl)-lH-pyrazolo[43-b pyridin-3-yl amino}benzenesulfonamide

(Ε^χρ-3-glO

[0096] Into a vessel containing 1.5 mL dioxane was placed 66 mg of Exp-3-g9 prepared in Step 3 (0.23 mmol), 50 mg 3-bromo-l-(4-methoxy -benzyl)- lH-pyrazolo [4,3- b]pyridine (Exp-l-g3 prepared in Example 1, 0.16 mmol), 18 mg Pd₂dba₃ (0.02 mmol), 23 mg Xantphos (0.04 mmol) and 130 mg Cs₂C0₃ (0.4 mmol). The reaction mixture thus provided was refluxed for 3 hours under a nitrogen atmosphere, cooled to ambient temperature, filtered and concentrated under reduced pressure. The residue thus provided was purified via Prep-TLC (PE:EtOAc=2: l) to afford 40 mg of Exp-3-glO (calculate yield 34%). The identity of the product was confirmed by mass spectroscopy using the procedures described herein. MS (ESI) m/z 520, 522 (M+H)⁺

Step 4: Deprotection of Exp-3-glO

[0097] Into a vessel containing 3 mL of TFA was dissolved 40 mg of Exp-3-glO ( 0.077 mmol) prepared and purified in the previous step. This solution was stirred and heated to 120 °C using a microwave oven, and was maintained at that temperature, with stirring, for 20 minutes. After 20 minutes the mixture was cooled to ambient temperature, concentrated under reduced pressure, and the residue thus obtained was purified by Prep.HPLC to give 10 mg of 3-({4-[( 2-chlorophenyl)-sulfamoyl]phenyl}- amino)-lH- pyrazolo[4,3-b]pyridin-4-ium trifluoroacetate (33% calculated yield). The identity of the produce was confirmed by mass spectroscopy and proton NMR in accordance with the procedures described herein. MS (ESI) m/z 400, 402 (M+H)⁺

[0098] ^XHNMR (400 MHz, CD₃OD): δ 8.41 (d, 1H, J = 3.2 Hz), 7.88 (d, 1H, J = 8.8 Hz), 7.58-7.64 (m, 4H), 7.51 (d, 1H, J = 6.8 Hz), 7.37-7.40(m, lH), 7.21-7.28 (m, 2H) , 7.09 (t, 1H, J = 7.6 Hz).

[0099] Using the process of Example 3 and an appropriately substituted analine in Step 3 in place of the comopund of Formula Exp-3-g9, the following compounds were also synthesized and characterized as indicated in the table below:

EXAMPLE 4: Preparation of 3-[(4-Chloro-3-methoxyphenyl)amino]-lH- pyrazolo[3,4-b]pyridin-7-ium trifluoroacetate

Step 1 :

Exp-4-g1

Step 1 : preparation of 2-Chloro-N-(4-chloro-3-methoxyphenyl)pyridine-3- carboxamide (Exp-4-g3)

[0100] Into a vessel containing a solution prepared by dissolving 1 g of 2- chloropyridine-3-carboxylic acid (Exp-4-gl, 6.37 mmol) and 1 g of 4-chloro-3- methoxy-phenylamine (Exp-4-g2, 6.4 mmol) in 30 mL of DMF was added 6.05 g 0- 7- Azabenzotriazol-l-yl)-N,N,N'N'-tetramethyluronium hexafluorophosphate (HATU, 15.9 mmol), and 1.93 g triethylamine (TEA, 19.1 mmol). The reaction mixture thus provided was stirred at ambient temperature (RT) overnight then the mixture was poured into cool water and the resulting mixture extracted with sufficient amounts of EtOAc to obtain the product from the reaction mixture. The organics were combined, washed with brine, dried over MgSC>4, filtered and concentrated under reduced pressure. The residue thus provided was purified on silica column chromatogram (PE:EtOAc = 50: 1-1 : 1) to give 1.1 g of Exp-4-g3 (calculated yield 58%).

Step 2: preparation of 2-Chloro-N-(4-chloro-3-methoxyphenyl)pyridine-3- carbothioamide (Exp-4-g4)

[0101 ] Into a vessel containing a solution made by dissolving 1 g of Exp-4-g3 prepared in Step 1 in 40 mL of a 1 : 1 (vol) mixture of toluene (Tol) and tetrahydrofuran (THF) was added 1.5 g of Lawesson's reagent (2,4-bis(4-methoxyphenyl)-l,3,2,4- dithiadiphosphetane-2,4-dithione, 3.7 mmol.). The reaction mixture thus provided was heated to 90 °C with stirring and maintained for two hours under a nitrogen atmosphere, then concentrated under reduced pressure and cooled to RT. The crude prduct thus provided was purified via silica column chromatogram (PE:EtOAc = 15: 1-1 : 1) to yield 400 mg of Exp-4-g4 (38% calculated yield).

Step 3: Preparation of 3-f (4-Chloro-3-methoxyvhenyl)aminol-lH-pyrazolo[3,4- bJpyridin-7-ium trifluoroacetate via (Exp-4-g5)

[0102] Into a solution of 2-chloro-N-(4-chloro-3-methoxyphenyl)pyridine-3- carbothioamide (100 mg, 0.32 mmol) in DMSO (20 mL) was added solution of hydrazine in THF (1M, 2 mL, 2 mmol) in one portion. The mixture was stirred at 120 °C for 3 h. After the reaction was finished, the mixture was diluted with saturated aqueous aHCOs solution and extracted with EtOAc. The combined organic layers were dried over MgSC>4, filtered and concentrated under reduced pressure. The crude product was purified by Prep. HPLC (water + 1% TEA/ CH₃CN eluents) to yield 20 mg of Exp-4-g5 as the TFA-salt (calculated yield 23 %). The identity of the product was verified via MS and proton NMR using the procedures described herein. MS (ESI) m/e 275, 277 (M+H)⁺

[0103] ^XH NMR (400 MHz, CD₃OD): δ 8.50-8.40 (m, 2H), 7.56 (d, 1H, J = 2.0Hz), 7.16-7.20 (m, 2H), 7.09-7.11 (m, 1H), 3.88 (s, 3H).

EXAMPLE 5: 3-[(4-Chloro-3-methoxyphenyl)amino]-lH-pyrazolo[3,4-b]pyrazin-4- ium trifluoroacetate

Step 1 :

Step 3:

Step 1 : Preparation of 1 ^' -(4-Methoxybenzyl)-l H-pyrazolo[3 ,4-b] pyrazin-3-amine

(Exp-5-g23

[0104] Into a vessel containing 50 mL ethanol was added 1.0 g of 3-chloropyrazine-2- carbonitrile (Exp-5-g22, 7.2 mmol), 1.1 g PMBNHNH₂ (7.3 mmol) and 1.9 g K₂C0₃ (14.2 mmol). The reaction mixture thus provided was heated to reflux and refluxing was continued for 6 hours, then the mixture was cooled to ambient temperature, filtered and the solid was washed sequentially with 10 mL H₂0 and 10 mL of methanol and dried yielding 1.0 g Exp-5-g23 (calculated yield 56%).

Step 2: Preparation of 3-Bromo-l -(4-methoxybenzyl)-lH-pyrazolo [3 ,4-b 'pyrazine

[0105] Into a vessel containing 3 mL CH₃CN was added 300 mg of Exp-5-g23 prepared in the previous step (1.2 mmol) and 379 mg CuBr₂ (1.7 mmol). The reaction mixture thus provided was stirred at ambient temperature for 2 hours then the mixture was purified by Prep-TLC (PE:EtOAc = 3:2) yielding 150 mg of Exp-5-g24 (calculated yield 40%).

Step 3: Preparation of N-(4-Chloro-3-methoxyphenyl)-l-(4-methoxybenzyl)-lH- pyrazolo[3,4-b]pyrazin-3-amine (Exp-5-g25)

[0106] Into a vessel containing 3 mL of dioxane was added 60 mg of Exp-5-g24 prepared in Step 2 (0.19 mmol), 31 mg of 4-chloro-3-methoxy-phenylamine (0.2 mmol), 18 mg of Pd₂dba₃ (0.02 mmol), 23 mg of Xantphos (0.04 mmol) and 130 mg Cs₂C0₃ (0.4 mmol). The reaction mixture thus provided was maintained under an N₂ atmosphere, refluxed for 3 hours, then cooled to ambient temperature, filtered and concentrated under reduced pressure. The residue thus provided was purified by Prep-TLC (PE:EtOAc = 1 :2) yielding 65 mg of Exp-5-g25 (calculated yield 70 %).

Step 4: Preparation oi3-[(4-Chloro-3-methoxyphenyl)amino]-lH-pyrazolo[3,4- bJpyrazin-4-ium trifluoroacetate

[0107] Into a vessel containing 4.4 mL of a mixture of TfOH and TFA (1 : 10, vohvol) was dissolved 65 mg of Exp-5-g25 prepared in Step 3 with heating and stirring. The solution was maintained at 100 °C with stirring for 30 minutes, then cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by prep. HPLC yielding 27 mg of the title compound (calculated yield 62 %). The identity of the product was confirmed by mass spectroscopy and proton NMR in accordance with the procedures described herein. MS (ESI) m/z 276, 278 (M+H)⁺

[0108] ^NMR: (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 9.55 (s, 1H), 8.53 (d, 1H, J = 2.4 Hz), 8.48 (d, 1H, J = 2.4 Hz), 7.67 (d, 1H, J = 2.0 Hz), 7.37 (dd, 1H, J = 2.0 Hz, 8.8 Hz), 7.24 (d, 1H, J = 8.8 Hz), 3.80 (s, 3H). EXAMPLE 6: 3-[(3,4-Dichlorophenyl)amino]-lH-pyrazolo[4,3-b] pyridin-4-ium

Step 1 : Preparation of N-(3,4-Dichlorophenyl)-l ^' -(4-methoxybenzyl)-l H- pyrazolof 4, 3-b]pyridin-3-amine

[0109] Into a vessel containing 8 mL dioxane was dissolved 100 mg of 3-bromo-l-(4- methoxybenzyl)-lH-pyrazolo[4,3-¾]pyridine (0.32 mmol) and 101 mg 3,4-dichloro- phenylamine (0.63 mmol). To this solution was added 14 mg Pd(dba)₂ (0.025 mmol), 18 mg xantphos (0.032 mmol) and 309 mg Cs₂C0₃ (95 mmol). The reaction mixture thus provided was heated under a nitrogen atmosphere to 100 °C (with stirring), maintained at that temperature under a nitrogen atmosphere and stirred for two hours then the mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by Prep. TLC (PE/EtOAc = 1 :3) to give the titled product (43 mg, 34 %). The identity of the product was confirmed by mass spectroscopy in accordance with the procedures described herein. MS (ESI) m/z 399, 401 (M+H)⁺

Step 2: Preparation of 3- [(3.4-Dichlorophenyl)amino] -lH-pyrazolo[4 ,3-b] pyridin-4- ium trifluoroacetate

[01 10] Into a vessel containing 6 mL of a mixture of TfOH and TFA (1 :5, vohvol) was dissolved 43 mg of of N-(3,4-dichlorophenyl)-l-(4-methoxybenzyl)-lH-pyrazolo[4,3-¾] pyridin-3 -amine prepared in Step 1 (0.11 mmol) by heating the solvent to 100 °C, with stirring, for lhour. After 1 hour the reaction mixture was concentrated under reduced pressure and purified by Prep. HPLC to give 17 mg of the titled product (calculated yield 56 %). The identity of the product was confirmed by mass spectroscopy and proton NMR in accordance with the procedures described herein. MS (ESI) m/z 279 (M+H)⁺

[01 1 1 ] ^XH NMR (400 MHz,CD₃OD) δ 8.47 (d, 1H, J=7.6 Hz), 8.01 (d, lH, J=8.8 Hz), 7.59 (s, 2H), 7.46- 7.50 (m, 1H), 6.86 (s, 1H).

Example 7: 2-[2-Chloro-4-(lH-pyrazolo[4,3-¾pyridin-3-ylamino) phenyl]-lH-

Part I: Preparation of N-(2-Chloro-4-{[l-(4-methoxybenzyl)-lH-pyrazolo[4,3-blvyridin- 3-ylj ' amino IphenvDacetamide (Exp-7-g4)

Preparation of N-(2-Chloro-4-nitrophenyl)acetamide

[01 12] Into a vessel containing a solution prepared by dissolving l .Og of 2-chloro-4- nitroaniline (5.8 mmol) in 22 mL of a solvent which was a mixture of dichloromethane (DCM) and pyridine (10: 1 vol:vol DCM:pyridine) was added dropwise 1.0 mL of Acetyl chloride (with stirring) at ambient temperature (RT). The reaction mixture thus provided was stirred at RT overnight, then the mixture was poured into cool water and extracted with DCM. The extracts were combined washed sequentially with water and brine, dried over a₂S04, filtered, then concentrated under reduced pressure, providing 0.9 g of N-(2- Chloro-4-nitrophenyl)acetamide (calc. yield 75 %) which was used directly in the next step without further purification.

Preparation of N-(4-Amino-2-chlorophenyl)acetamide

[01 13] Into a vessel containing 50 mL of HC1 was added a mixture of 25 g of N-(2- chloro-4-nitrophenyl)acetamide, prepared in the previous step, (11.7 mmol) and 6.6 g SnCl₂-2H₂0 (29.2 mmol), which was stirred for 2 hours at RT. After the reaction was finished, aqueous NaOH solution was added to pH = 8 and extracted with EtOAc. The combined organics were washed sequentially with water then brine, dried over Na₂SC>4, filtered, and concentrated under reduced pressure to afford 0.9 g of N-(4-Amino-2- chlorophenyl)acetamide, (calculated yield 42 %), used directly for the next step without further purification. The identity of the product was confirmed by mass spectroscopy using the procedures described herein MS (ESI) m/z 185, 187 (M+H)⁺

Preparation of N-(2-Chloro-4-{[l-(4-methoxybenzyl)-lH-pyrazolo[4.3-b]pyridin-3- ylJaminolphenvDacetamide

[01 14] Into a vessel containing 10 mL dioxane was placed 139 mg of N-(4-amino-2- chlorophenyl)acetamide prepared in the previous step (0.75 mmol), 200 mg of 3-bromo- l-(4-methoxybenzyl)-lH-pyrazolo[4,3-¾]pyridine (Exp-l-g3, prepared in Example 1 , 0.63 mmol), 25 mg of Pd₂dba₃ (0.025 mmol), 31 mg of Xantphos (0.05 mmol) and 410 mg of Cs₂C0₃ (1.26 mmol). The reaction mixture thus provided was refluxed for 4 hours under a nitrogen atmosphere, then filtered and concentrated under reduced pressure. The residue thus provided was purified by Prep-TLC (PE:EtOAc = 1 : 1) to afford 129 mg of N-(2-Chloro-4- {[l -(4-methoxybenzyl)-lH-pyrazolo[4,3-b]pyridin-3- yl] amino }phenyl)acetamide (Exp-7-g4, calculated yield 49 %). The identity of the product was confirmed by mass spectrocopy using the procedures described herein. MS (ESI) m/z 422, 424 (M+H)⁺

Part II: Preparation of 2-[2-Chloro-4-(lH-pyrazolo[4,3-b]pyridin-3-ylamino)phenyl]-lH- pyrrolo [3, 4-c] pyridine- 1 ,3(2H)-dione(Exp7-g7)

Preparation of 2-Chloro-N⁴-[l-(4-methoxybenzyl)-lH-pyrazolo[4,3-b]pyridin-3-yl]

benzene- 1 A-diamine

[01 15] Into a vessel containing 20 mL of ethanolic HC1 solution (1 : 1 vol:vol, EtOH onc. HC1) was placed 500 mg Exp-7-g4 prepared in the previous step and the mixture was heated to reflux and maintained at reflux for 2 hours. After two hours the reaction mixture was concentrated under reduced pressure, basified using NaOH to pH = 8 and extracted with EtOAc. The extracts were washed sequentially with water and brine, dried over Na₂SC>4, filtered, and concentrated under reduced pressure to provide 400 mg of crude 2-Chloro-N⁴-[l -(4-methoxybenzyl)-lH-pyrazolo[4,3-b]pyridin-3-yl] benzene- 1 ,4-diamine (calculated 88% yield) which was used for the next step directly without further purification. The identity of the product was confirmed by mass spectroscopy according to the procedures described herein. MS (ESI) m/z 380, 382 (M+H)⁺

Preparation of 2-(2-Chloro-4-{[l-(4-methoxybenzyl)-lH-pyrazolo[4,3-blpyridin-3- yll^' 'amino}phenyl)-lH-pyrrolo [3, 4-c] pyridine- 1 ,3(2H)-dione

[01 16] Into a reaction vessel containing 10 mL of acetic acid (AcOH) was added, with stirring, 100 mg of 2-chloro-7V⁴-[l-(4-methoxybenzyl)-lH-pyrazolo[4,3-¾]pyridin-3- yl]benzene -1 ,4-diamine prepared in the previous step (0.26 mmol) and 78 mg of furo[3,4-c]pyridine-l ,3-dione (0.52 mmol). The reaction mixture thus prepared was heated to 110 °C with continued stirring and maintained at temperature for 20 hours. After 20 hours the reaction mixture was concentrated in vacuo to provide 92 mg of cride 2-(2-Chloro-4- {[l -(4-methoxybenzyl)-lH-pyrazolo[4,3-b]pyridin-3-yl]amino}phenyl)- lH-pyrrolo[3,4-c]pyridine-l ,3(2H)-dione (calculated yield 69.7 %) which was used directly for the next step without purification. The identity of the product was confirmed by mass spectroscopy. MS (ESI) m/z 511 , 513 (M+H)⁺

Preparation oi 2-[2-Chloro-4-(lH-pyrazolo[4,3-b pyridin-3-ylamino)phenyl -lH- pyrrolo[3,4-c]pyridine-l,3(2H)-dione(Exp7-g,7)

[01 17] In a vessel containing 5 mL of TFA and 0.25 mL of trifiic Acid (TfOH), with stirring at 110 °C, was dissolved 92 mg of 2-(2-chloro-4- {[l -(4-methoxybenzyl)-lH- pyrazolo [4,3 -¾]pyridin-3-yl] amino} phenyl)- lH-pyrrolo[3,4-c]pyridine-l ,3(2H)-dione prepared in the previous step (0.18 mmol). After dissolution, the reaction mixture thus provided was maintained at 110°C and stirred for 2 hours, then the mixture was concentrated in vacuum. The residue thus provided was dissolved in DMSO and purified by Prep HPLC to provide 23 mg of Exp-7-g7 (the titled compound, calculated yield 33 %). The identity of the product was confirmed by mass spectroscopy and proton NMR in accordance with the procedures described herein. MS (ESI) m/z 391 , 393 (M+H)⁺

[01 18] ^XH NMR: (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.87 (s, 1H), 9.29 (s, 1H), 9.22 (d, 1H, J= 4.8 Hz), 8.50 (d, 1H, J= 4.4 Hz), 8.23 (s,lH), 8.06 (d, 1H, J= 4.8 Hz), 7.95 (d, 1H, J= 8.8 Hz), 7.83 (d, 1H, J= 8.8 Hz), 7.43-7.47 (m, 2H).

EXAMPLE 8: 3-[(3-Chloro-4-{[(2-chloro-4-fluorophenyl)carbonyl]amino} phenyl)amino]-lH-pyrazolo[4,3-b]pyridin-4-ium trifluoroacetate

Preparation of 2-Chloro-N-(2-chloro-4-{fl-(4-methoxybenzyl)-lH-pyrazolof4,3- b]pyridin-S-yl]amino}phenyl)-4-fluorobenzamide

[01 19] Into a vessel containing 10 mL of SO₂CI₂ was added 174 mg of 2-chloro-4- fluoro-benzoic acid (1 mmol) with stirring at 90 °C. Stirring was continued for 1 hr. then the mixture was concentrated in vacuum yielding crude 2-chloro-4-fluoro-benzoyl chloride. Into 6 mL of a 5: 1 vohvol mixture of dichloromethane (D CM): pyridine was dissolved 50 mg of 2-chloro-7V⁴-[l-(4-methoxybenzyl)-lH-pyrazolo [4,3-&]pyridin-3-yl] benzene- 1 ,4-diamine (0.13 mmol) at RT. Into this solution was added, dropwise, 50 mg of the crude 2-chloro-4-fluoro-benzoyl chloride previously prepared. The reaction mixture thus provided was stirred overnight at ambient temperature (RT) then the reaction mixture was washed with HQ (aq) and extracted with DCM. The combined organics were washed sequentially with water and brine, dried over Na₂S04, filtered, then concentrated under reduced pressure yielding 48 mg of Exp-8-g3 (calculated yield 68.5 %). The crude material was used directly in the next step without purification. The identity of the product was confirmed by mass spectroscopy in accordance with the procedures described herein. MS (ESI) m/z 536, 538 (M+H)⁺

Preparation of 3-[(3-Chloro-4-{[(2-chloro-4-fluorovhenyl)carbonyllamino}- phenyl)amino]-lH-pyrazolo[4,3-b]pyridin-4-ium trifluoroacetate

[0120] Into a vessel containing 5 mL of TFA and 0.25 mL TfOH at 110 °C was dissolved, with stirring, 48 mg 2-chloro-N-(2-chloro-4-{[l-(4-methoxybenzyl)-lH- pyrazolo[4,3-b] pyridin-3-yl] amino }phenyl)-4-fluorobenzamide (0.089 mmol) previously prepared. The reaction mixture was stirred for 2 hours then the mixture was concentrated in vacuum and the residue was dissolved in DMSO then purified by Prep HPLC to give 12 mg of the title compound (calculated yield 33 %). The identity of the product was confirmed by mass spectroscopy and proton NMR using the procedures described herein. MS (ESI) m/z 416, 418 (M+H)⁺

[0121 ] ^XH NMR: (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 9.98 (s, 1H), 9.45 (s, 1H), 8.42 (d, 1H, J= 4.0 Hz), 8.09 (d, 1H, J= 2.4 Hz), 7.88 (d, 1H, J= 8.4 Hz), 7.63-7.69 (m, 2H), 7.54 (d, 1H, J= 8.4 Hz), 7.29-7.41 (m, 3H).

EXAMPLE 9: N-(2,6-Dimethylphenyl)-4-(lH-pyrazolo[4,3-b]pyridin-3-yl amino)benzenesulfonamide

Preparation of 4-(lH-Pyrazolof4,3-bJpyridin-3-ylamino)benzenesulfonyl chloride (Exp- 9-g2)

[0122] Into a vessel containing 2 mL of CISO₃H was added 40 mg of N-phenyl- 1 H- pyrazolo[4,3-b]pyridin-3-amine (Exp-9-gl, 0.2 mmol) and the mixture was stirred at RT for 30 mins. After thirty minutes the reaction mixture was poured into ice water and extracted with EtOAc. The combined organics were washed with water and brine, dried over a₂S04, filtered and concentrated under reduced pressure to afford 22 mg of Exp-9- g2 (calculated yield 36 %), which was used directly in the next step without further purification.

Preparation of N-(2,6-dimethylphenyl)-4-(lH-pyrazolo[4,3-b]pyridin-3- ylamino)benzenesulfonamide (Exp-9-g3)

[0123] Into a vessel containing 2 mL pyridine was dissolved 22 mg of 4-(lH- pyrazolo[4,3-¾]pyridin-3-ylamino)benzenesulfonyl chloride (Exp-9-g2, previously prepared, 0.2 mmol) and 8.6 mg of 2,6-dimethylphenylamine (0.14 mmol) and the reaction mixture was stirred overnight, then the mixture was washed with HCl and extracted with EtOAc. The combined organics were washed with water and brine, dried over Na₂SC>4, filtered, and concentrated under reduced pressure. The crude product thus provided was purified by Prep HPLC to give 12 mg of the title compound (Exp-9-g3, calculated yield 44 %). The identity of the product was confirmed by mass spectroscopy and proton NMR in accordance with procedures described herein. MS (ESI) m/z 394 (M+H)⁺

[0124] ^XH NMR (400 MHz, CD₃OD) δ 8.43 (d, 1H, J= 3.6 Hz), 7.89 (d, 1H, J= 8.4 Hz), 7.70 (d, 2H, J= 8.4 Hz), 7.56 (d, 1H, J= 8.8 Hz), 7.38-7.42 (m, 1H), 6.96-7.05 (m, 3H), 2.04 (s, 6H).

EXAMPLE 10: 5-Bromo-3-[(3,5-dichlorophenyl)amino]-lH-pyrazolo [4,3-b]pyridin- 4-ium trifluoroacetate

Preparation of 6-Bromo-3-fluoropyridine-2-carboxylic acid (Exp-10-g2)

[0125] Into a vessel containing 80 mL of THF was dissolved 2 g of 2-Bromo-5- fluoropyridine (Exp-10-gl, 0.01 mol) and the solution was cooled to -78 °C. To the solution was added a slight mole excess of n-BuLi relative to the compound of Formula Exp-10-gl present, while maintaining the temperature of the reaction mixture thus provided at -78 °C, then the reaction mixture was stirred for ½ hour while maintaining the temperature at -78 °C. At the end of ½ hour 0.75 g dry ice (0.75 g, 0.02 mol) was added in one portion to the reaction mixture and the mixture was warmed to ambient (RT) while continuing stirring for another 1 hour. At the end of 1 hour the mixture was poured into cool water, the solution was acidified with cone. HC1 to pH=l~2 and the acidified mixture was extracted with EtOAc. The combined organics were washed with brine, dried over MgSC>4, filtered and concentrated under reduced pressure to give 1.68 g of Exp-10-g2 (calculated yield, 74 %). The identity of the product was confirmed by mass spectroscopy a in accordance with procedures described herein. MS (ESI): m/z 220, 222 (M+H)⁺

Preparation of 6-Bromo-N-(3,5-dichlorophen l)-3-fluorop ridine-2-carboxamide (Exp- 10-g3)

[0126] Into a vessel containing 50 mL of dimethylformamide (DMF) was dissolved lg Exp-10-g2 prepared in the previous step (4.55 mmol) and 0.70g of 3,5- dichlorobenzenamine. Into this solution were added 2.76 g HATU (7.27 mmol) and 1.39g triethylamine (TEA, 13.64 mmol). The reaction mixture thus prepared was stirred at RT overnight, then the mixture was poured into cool water and extracted with EtOAc. The combined organics were washed with brine, dried over MgSC>4, filtered, and concentrated under reduced pressure. The crude product thus obtained was purified on silica column chromatogram (PE/EtOAc = 15: 1-1 : 1) to give 1.28 g of Exp-10-g3 (calculated yield 77.5%). The identity of the product was confirmed by mass spectroscopy in accordance with procedures described herein. MS (ESI): m/z 363, 365, 367, 369 (M+H)⁺

Preparation of 6-Bromo-N-(3,5-dichlorophenyl)-3-fluoropyridine-2-carbothioamide

(Exp-10-g4)

[0127] Into a vessel containing 40 mL of dioxane was dissolved lg of 6-bromo-N-(3,5- dichlorophenyl)-3-fiuoropyridine-2-carboxamide (Exp-10-g3 previously prepared, 2.76 mol) and 1.23 g of Lawesson's reagent (3.03 mmol) was added into the solution. The reaction mixture thus provided was stirred at 100 °C for 5h under a nitrogen atmosphere, then the reaction mixture was concentrated under reduced pressure and the crude product was purified on silica column chromatogram (PE/EtOAc = 15: 1-5: 1) to yield 0.67 g of Exp-10-g4 (calculated yield 64 %). The identity of the product was confirmed by mass spectroscopy in accordance with procedures described herein. MS (ESI): m/z 379, 381 , 383, 385 (M+H)⁺

Preparation of 5-Bromo-3-[ (3,5-dichlorophenyl)amino]-lH-pyrazolo[ 4, 3-b]pyridin-4- ium trifluoroacetate (Exp-10-g5)

[0128] In a vessel containing 15 mL of DMSO was dissolved 350 mg of 6-bromo-N- (3,5-dichlorophenyl)-3-fiuoropyridine-2-carbothioamide (Exp-10-g4, prepared in the previous step, 0.921 mmol). Into this solution was added, in one portion, 9.5 mL of 1M hydrazine in THF, and the reaction mixture thus provided was stirred at 120 °C for 3 hours. After 3 hours the reaction mixture was diluted with saturated aqueous NaHC0₃ solution and extracted with EtOAc. The combined organics were dried over MgS04, filtered, and concentrated under reduced pressure. The crude product thus provided was purified by Prep. HPLC to give 125 mg of Exp-10-g5, the title compound (calculated yield 38 %). The identity of the product was confirmed by mass spectroscopy and proton NMR in accordance with procedures described herein. MS (ESI): m/z 357, 359, 361 , 363 (M+H)⁺

[0129] ^XH NMR(400 MHz, CD₃OD) δ 7.78 (d, 1H, J= 8.8Hz), 7.68 (d, 2H, J= 1.6Hz), 7.48 (d, 1H, J= 8.8Hz), 6.85 (s, 1H).

[0130] Examples 11, 12, and 13 exemplify the chemistry described in general Scheme IIA-la above.

EXAMPLE 11: 3-[(3,5-Dichlorophenyl)amino]-5-methyl-lH-pyrazolo b]pyridin-4-ium trifluoroacetate

[0131 ] Into a vessel containing 0.8 mL water mixed with 8 mL dioxane was dissolved 40 mg of 5-bromo-N-(3,5-dichlorophenyl)-lH-pyrazolo[4,3-¾]pyridin-3-amine (0.11 mmol) and 10 mg of methylboronic acid (0.17 mmol). To this solution was added 8 mg Pd(dppf)Ci2 (0.011 mmol) and K₂C0₃ (46 mg, 0.34 mmol). The reaction mixture was stirred at 100 °C for 3h under a nitrogen atmosphere, then the mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by Prep. HPLC to give 10 mg of the titled product as the TFA salt (calculated yield 31 %). The identity of the product was confirmed by mass spectroscopy and proton NMR in accordance with procedures described herein. MS (ESI): m/z 293, 295, 297 (M+H)⁺

[0132] ^XH NMR (400 MHz, CD₃OD) δ 7.96 (d, 1H, J = 8.4 Hz), 7.54 (d, 2H, J = 1.6 Hz), 7.42 (d, 1H, J= 8.4 Hz), 7.21 (d, 1H, J= 8.8 Hz), 2.71 (s, 3H).

EXAMPLE 12: 5-Cyano-3-[(3,5-dichlorophenyl)amino]-lH-pyrazolo [4,3-b]pyridin- 4-ium trifluoroacetate

[0133] Into a vessel containing 4 mL N-methylpyrollidine ( MP) was dissolved 40 mg 5-bromo-N-(3,5-dichlorophenyl)-lH-pyrazolo[4,3-¾]pyridin-3-amine (0.11 mmol) and 28 mg Zn(CN)₂ (0.28 mmol). Into this solution was added 8 mg Pd(dppf)Cl₂ (0.01 mmol) and the reaction mixture thus provided was stirred at 160 °C for 0.5h under microwave irradiation, then the mixture was poured into cold water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSC>4, filtered, and concentrated under reduced pressure. The crude product was purified by Prep. HPLC to give 11 mg of the titled product as the TFA salt (calculated yield 33 %). The identity of the product was confirmed by mass spectroscopy and proton NMR in accordance with procedures described herein. MS (ESI): m/z 304, 306, 308 (M+H)⁺

[0134] ^XH NMR (400 MHz, CD₃OD) δ 7.93 (d, 1H, J= 8.8 Hz), 7.78 (d, 2H, J= 1.6 Hz), 7.73 (d, 1H, J= 8.8 Hz), 6.88 (s, 1H).

EXAMPLE 13: 3-[(3,5-Dichlorophenyl)amino]-5-methoxy-lH-pyrazolo [4,3- b]pyridin-4-ium trifluoroacetate

[0135] Into a vessel containing 8 mL of methanol at 90 °C under a nitrogen atmosphere was added 40 mg of 5-bromo-N-(3,5-dichlorophenyl)-lH-pyrazolo[4,3-¾]pyridin-3- amine (0.112 mmol) and 25 mg of Na. The reaction mixture thus provided was stirred overnight then poured into cool water and extracted with EtOAc. The combined organics were washed with brine and dried, filtered, concentrated under reduced pressure and the crude product was purified by Prep. HPLC to give 6 mg of the titled compound as the TFA salt (calculate yield 18 %). The identity of the product was confirmed by mass spectroscopy and proton NMR in accordance with procedures described herein. MS (ESI): m/z 309, 311 , 313 (M+H)⁺

[0136] ^XH NMR (400 MHz, CD₃OD) δ 7.75 (d, lH, J= 9 Hz), 7.55 (s, 2H), 6.85 (d, 1H, J= 9 Hz), 6.79 (s, 1H), 3.98(s, 3H).

EXAMPLE 14: 3-{[4-(4-Chlorophenoxy)phenyl]amino}-lH-pyrazolo [4,3-b]pyridin- -ium trifluoroacetate

Step 1 : Preparation of l-Chloro-4-(4-nitroyhenoxy)benzene (Exp-14-g2)

[0137] Into a vessel containing 8 mL DMF and 12 mL CH₃CN was added 19 g of 4- chlorophenol (7.8 mmol), 1.21 g of l -fluoro-4-nitrobenzene (8.59 mmol) followed by 3.82 g Cs₂C0₃ (11.7 mmol). The reaction mixture thus provided was stirred at ambient temperature overnight, then filtered, and the filtrate was diluted with brine then extracted with EtOAc. The combined extracts were dried over MgS0₄ and concentrated under reduced pressure to give 1.95 g of the crude Exp-14-g2 (100 % yield) which was used in the next step without purification.

Step 2: Preparation of 4-(4-Chlorophenoxy)aniline(Exp-14-g3)

[0138] Into a vessel containing 30 mL of 1 : 1 , vol:vol ethanol and water was added 0.56 g acetic acid (9.40 mmol), 1.95 g of Exp-14-g2 prepared in Step 1 (7.8 mmol) followed by 2.19 g of iron powder (39.1 mmol). The reaction mixture thus provided was heated to 80 °C, and maintained at that temperature with stirring for 0.5 hour, then the mixture was filtered, the filtrate was washed with saturated aqueous NaHC0₃ solution, and extracted with EtOAc. The organic phase was separated and dried over MgSC>4, then concentrated, yielding 1.72 g of crude Exp-14-g3 (100% yield) used in Step 3 without further purification. The identity of the product was confirmed by mass spectroscopy in accordance with procedures described herein. MS (ESI) m/z 220, 222 (M+H)⁺

Step 3: Preparation of 3-1 ^' [4-(4-Chlorophenoxy)phenyli^' ' amino Ϊ- IH-pyrazolo [4,3- bJpyridin-4-ium trifluoroacetate

[0139] Using the procedures of Example 6, Step 1 , the entire amount of Exp-14-g3 prepared in Step 2 was reacted with 3-bromo-l-(4-methoxybenzyl)-lH-pyrazolo[4,3- ¾]pyridine, prepared as described in Example 1 for compound Exp-l-g3, to yield the coupled, PMB-protected product Exp-14-g4. The entire amount of Exp-14-g4 thereby produced was treated with TfOH and TFA in accordance with Example 6, Step 2 to provide the freebase title compound as a product. The identity of the product was confirmed by mass spectroscopy and proton NMR in accordance with procedures described herein. MS (ESI): m/z 338 (M+H)⁺ [0140] ^XH NMR (400 MHz, CD₃OD) δ 8.48 (d, 1H, J = 4.4 Hz), 8.02 (d, 1H, J=8.4 Hz), 7.65 (d, 2H, J=8.4 Hz), 7.49-7.53 (m, 1H), 7.30 (d, 2H, J = 8.8 Hz), 7.00 (d, 2H, J = 4.8 Hz), 6.84 (d, 2H, J = 4.8 Hz).

[0141 ] Compounds of the invention were assayed for activity as positive allosteric modulators of mGluR4 receptors in accordance with the assay described herein. The following results were obtained (EC₅₀ in nM):

[0142] Compounds A- 1 to A-25

A-l, 470 nM; A-2, 25 nM; A-3, 3273 nM; A-4, 12 nM; A-5, 36 nM; A-6, 280 nM; A-7, 478 nM; A-8, 559 nM; A-9, 25 nM; A-10, 113 nM; A-ll,

470 nM; A-12, 496 nM; A-13, 914 nM; A-14, 3340 nM; A-15, 1386 nM;

A-16, 240 nM; A-17, 465 nM; A-18, 501 nM; A-19, 148 nM; A-20, 472 nM; A-21, 6444 nM; A-22, 194 nM; A-23, 5486 nM; A-24, 575 nM; A- 25, 244 nM.

[0143] Compounds A-26 to A-61 :

A-26, 5506 nM; A-28, 1132 nM; A-31, 781 nM; A-32, 61 nM; A-33,

184 nM; A-34, 1586 nM; A-37, 1143 nM; A-40, 90 nM; A-41, 693 nM;

A-42, 1545 nM; A-43, 191 nM; A-45, 62 nM; A-46, 101 nM; A-47, 112 nM; A-48, 53 nM; A-49, 54 nM; A-50, 3590 nM; A-51, 40 nM; A-52,

38 nM; A-53, 1043 nM; A-54, 475 nM; A-55, 196 nM; A-56, 403 nM;

A-57, 1876 nM; A-61, 752 nM.

[0144] Compounds N- 14 to N- 101 :

N-146, 1584 nM; N-80, 482 nM; N-81, 1797 nM; N-82, 8059 nM; N-83, 1955 nM; N-84, 45.5 nM; N-85, 7109 nM; N-86, 4794 nM; N-87, 1352 nM; N-88, 6528 nM; N-89, 1477 nM; N-92, 633 nM; N-94, 295 nM; N- 96, 19.9 nM; N-97, 2597 nM; N-98, 1140 nM; N-99, 1266 nM; N-101,

1216 nM.

[0145] Compounds of Formula III, Formula IVa (Table II, compounds C-1, C-2 and C- 3), Formula V, and Formula VI:

Formula III, 706 nM; Formula IVa: C-1, 420 nM; C-2, 39 nM; C-3, 29 nM; Formula V, 706 nM; Formula VI, 5624 nM.

Claims

A compound of:

(i) Formula C-I

wherein R¹ is "-H" and R², R³, and R⁴ are defined in Table C-I:

Table C-I

or a salt thereof;

Formula C-III, or a salt thereof:

Formula C-III;

Formula C-C-2 or a salt thereof:

Formula C-C-2;

(iv) Formula C-C-3 or a salt thereof:

a compound of Formula CC-V, or a salt thereof:

A pharmaceutical formulation comprising at least one excipient and at least one compound which is:

(i) the compound of Formula C-Vaa or a pharmaceutically acceptable salt thereof:

Formula C-Vaa;

the compound of Formula Formulae C-C-1 or a pharmaceutically acceptable salt thereof:

Formula C-C-1; or

(iii) a compound of Claim 3, or a pharmaceutically acceptable salt thereof.

3) A method of providing treatment, management, alleviation or amelioration of symptoms or conditions associated with Parkinson's disease comprising administering, in a therapeutically effective amount, at least one medicament comprising the pharmaceutical formulation of Claim 2.

4) A compound of:

Formula C-Ic, or a salt thereof:

Formula C-Ic, wherein R 2 , R 3 , and R 4 are as defined in Table

Table C-III

Formula C-IV, or a salt thereof,

Formula C-IV,

wherein R ' is -H or -CI.

5) A pharmaceutical composition comprising at least one excipient and at least one compound of Claim 4 or a pharmaceutically acceptable salt thereof.

6) A method of providing treatment, management, alleviation or amelioration of symptoms or conditions associated with Parkinson's disease comprising administering, in a therapeutically effective amount, at least one medicament comprising the pharmaceutical formulation of Claim 5.

7) A compound of:

(i) Formula C-Id, or a salt thereof:

Formula C- wherein R 2 , R 3 , and R 4 are defined in Table C-IV:

Table C-IV

; or

Formula C-III; or a salt thereof

Compound C-III.

8) A pharmaceutical composition comprising at least one excipient and at least < compound of Claim 7 or a pharmaceutically acceptable salt thereof.

9) A method of providing treatment, management, alleviation or amelioration of symptoms or conditions associated with Parkinson's disease comprising administering, in a therapeutically effective amount, at least one medicament comprising the pharmaceutical formulation of Claim 8.

10) A compound of:

(i) Formula C-Ig or a salt thereof:

2 3

Formula C-Ig, wherein R , R , and R⁴ are defined in Table C-V:

Table C-V

11) A pharmaceutical composition comprising at least one excipient and at least one compound of Claim 10, or a pharmaceutically acceptable salt thereof.

12) A method of providing treatment, management, alleviation or amelioration of symptoms or conditions associated with Parkinson's disease comprising administering, in a therapeutically effective amount, at least one compound, or a pharmaceutically acceptable salt thereof, of any of Claims 1, 4, 7, or 10.

13) A compound of the Formula CG-I:

Formula CG-I,

wherein:

R¹ is: -H, -Br, -CN, -CH₃, or -0-CH₃, and preferably R¹ is -H; R is: Ci-4-alkyl, optionally substituted with: fluorine; Ci-3-alkoxy, optionally substituted with fluorine; Ci_₃-alkyl-hydroxy; chloro; fluoro; cyano; or hydrogen;

R^A3 is: methyl; trifluoromethyl; methoxy; trifluoromethoxy; chloro; fluoro; or hydrogen; and

R A4 ·

(i) -H; (ii) Ci-6-alkyl, where the alkyl is optionally substituted with indazole, - OH, one or more fluorine substituents, or is perfluorinated; (iii) -0-R'^a, where R'^a is: (a) alkyl, optionally fluorinated or perfluorinated; (b) aryl; or (c) substutited aryl with 1 to 3 substituents; (iv) halogen, which is -chloro, -fluoro or -bromo; (v) -CN; (vi) -S0₂-NH-R"^a, wherein R"^a is: (a) Ci_₃ linear or branched; or (b) aryl, optionally substituted with 1 or 2 moieties which are independently -CI, -Br, or -CH₃; (vii) isoindoledione; (viii) -N(CH₃)₂; (ix) -NH- (C=0)-R'^b, wherein R'^b is -CH₃, aryl, or aryl, optionally substituted with 1 or 2 moieties which are independently -CI or -F; (x) lH-pyrollo-[3,4c]pyridine- (l,3)-dione; (xi) isoindoline-l,3-dione; (xii) imidazole; (xiii) a moiety of the formula:

, wherein (Q') is -N(CH₃)-, -0-, or -(CH₂)-; (xiv) a 1- methylene -piperidine -sulfonylmorpholine moiety; or (xv) a moiety of the formul

; (xvi) an amido moiety; (xvii) a Ci_₃-alkyl- sulfane- onally fluorine substituted; (xviii) a moiety of the

Formula

a pharmaceutically acceptable salt thereof.