WO2011034741A1 - Imidazopyridin-2-one derivatives - Google Patents

Abstract

The present invention is directed to imidazopyridin-2-one derivatives which are potentiators of metabotropic glutamate receptors, particularly the mGluR2 receptor, and which are useful in the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which metabotropic glutamate receptors are involved.

Description

TITLE OF THE INVENTION

IMIDAZOPYRIDIN-2-ONE DERIVATIVES

BACKGROUND OF THE INVENTION

The excitatory amino acid L-glutamate (sometimes referred to herein simply as glutamate) through its many receptors mediates most of the excitatory neurotransmission within the mammalian central nervous system (CNS). The excitatory amino acids, including glutamate, are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception.

Glutamate acts via at least two distinct classes of receptors. One class is composed of the ionotropic glutamate (iGlu) receptors that act as ligand-gated ionic channels. Via activation of the iGlu receptors, glutamate is thought to regulate fast neuronal transmission within the synapse of two connecting neurons in the CNS. The second general type of receptor is the G-protein or second messenger- linked "metabotropic" glutamate (mGluR) receptor. Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).

The present invention relates to potentiators of mGlu receptors, in particular mGluR2 receptors. The mGluR receptors belong to the Type III G- protein coupled receptor (GPCR) superfamily. This superfamily of GPCR's including the calcium-sensing receptors, GABAB receptors and pheromone receptors, which are unique in that they are activated by binding of effectors to the amino-terminus portion of the receptor protein. The mGlu receptors are thought to mediate glutamate's demonstrated ability to modulate intracellular signal transduction pathways. Ozawa, Kamiya and Tsuzuski, Prog. Neurobio., 54, 581 (1998). They have been demonstrated to be localized both pre- and post-synaptically where they can regulate neurotransmitter release, either glutamate or other neurotransmitters, or modify the post-synaptic response of neurotransmitters, respectively.

At present, there are eight distinct mGlu receptors that have been positively identified, cloned, and their sequences reported. These are further subdivided based on their amino acid sequence homology, their ability to effect certain signal transduction mechanisms, and their known pharmacological properties. Ozawa, Kamiya and Tsuzuski, Prog. Neurobio., 54, 581 (1998). For instance, the Group I mGluR receptors, which include the mGlulR and mGluR5, are known to activate phospho lipase C (PLC) via Gaq-proteins thereby resulting in the increased hydrolysis of phosphoinositides and intracellular calcium mobilization. There are several compounds that are reported to activate the Group I mGlu receptors including DHPG, (R/S)-3,5-dihydroxyphenylglycine. Schoepp, Goldworthy, Johnson, Salhoff and Baker, J.

Neurochem., 63, 769 (1994); Ito, et al, keurorep., 3, 1013 (1992). The Group II mGlu receptors consist of the two distinct receptors, mGluR2 and mGluR3 receptors. Both have been found to be negatively coupled to adenylate cyclase via activation of God-protein. These receptors can be activated by a selective compound such as lS,2S,SR,6S-2 aminobicyclo[3.1.0]hexane-2,6- dicarboxylate. Monn, et al, J. Med. Chem., 40, 528 (1997); Schoepp, et al, NeuropharmacoL, 36, 1 (1997). This activitation leads to inhibition of glutamate release in the synapse (Cartmell et al, J Neurochem 75, 889 (2000)). Similarly, the Group III mGlu receptors, including mGluR4, mGluR6, mGluR7 and mGluR8, are negatively coupled to adenylate cyclase via God and are potently activated by L-AP4 (L- (+) -2-amino-4-phosphonobutyric acid). Schoepp, Neurochem. Int., 24, 439 (1994).

Nonselective mGluR2/mGluR3 receptor agonists (Monn, et al, J. Med. Chem., 43, 4893, (2000)) have shown efficacy in numerous animal models of anxiety and psychosis as well as human clinical trials in schizophrenia patients; Patil et al, Nature Medicine, 13, 1102 (2007). Recent reports indicate that mGluR2 but not the mGluR3 receptor mediates the actions of the dual mGluR2/mGluR3 agonist LY379268 in mouse models predictive of antipsychotic activity. Woolley et al, Psycopharmacology, 196, 431 (2008). Additionally, recent animal studies demonstrate that selective potentiation of the mGluR2 receptor has similar effects to such nonselective agonists (Galici et al, Journal of Pharmacology and Experimental Therapeutics, 315, 1181 (2005)) suggesting an alternative strategy concerning the discovery of selective, positive allosteric modulators (PAMs or allosteric potentiators) of mGluR2 (Johnson et al, J. Med. Chem. 46, 3189, (2003); Pinkerton et al, J. Med. Chem., 47, 4595 (2004). These potentiators act by enabling the receptor to produce an enhanced response to endogenous glutamate. Such allosteric potentiators do not bind at the glutamate binding site also known as the "orthosteric site", and may benefit by binding to a site other than the highly conserved orthosteric site. A potential advantage to this approach includes the opportunity to have a distinct pharmacological profile by enhancing the activity of the endogenous ligand upon its binding to the orthosteric site. The pharmacological distinctions include the potential for pharmacological specificity between related receptor types that share the same endogenous ligand. In addition, positive allosteric modulators of mGluR2 have been shown to potentiate the response of mGluR2 agonists such as LY379268 (Johnson et. Al. Biochemical Soc. Trans. 32, 881 (2004) and this represents an alternative strategy for treatment using mGluR2 selective PAMs.

It has become increasingly clear that there is a link between modulation of excitatory amino acid receptors, including the glutamatergic system, through changes in glutamate release or alteration in postsynaptic receptor activation, and a variety of neurological and psychiatric disorders, e.g. Monaghan, Bridges and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365-402 (1989); Schoepp and Sacann, Neurobio. Aging, 15, 261-263 (1994); Meldrum and Garthwaite, Tr. Pharmacol. Sci., 11, 379-387 (1990). The medical consequences of such glutamate dysfunction make the abatement of these neurological processes an important therapeutic goal.

SUMMARY OF THE INVENTION

The present invention is directed to imidazopyridin-2-one derivatives which are potentiators of metabotropic glutamate receptors, particularly the mGluR2 receptor, and which are useful in the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which metabotropic glutamate receptors are involved.

DETAILED DESCRIPTION OF THE INVENTION

The invention encompasses a genus of compounds of Formula I

I or a pharmaceutically acceptable salt thereof, wherein: Xl is selected from the group consisting of: Cl-8alkyl, C2-8alkenyl, C2-8^alkynyl, C3-6cycloalkyl and C3-6cycloalkylCl-4alkyl, any of which may bear up to 5 halogen

substituents;

R1 represents H or Cl-4alkyl which is optionally substituted with OH, CN, CF3, C 1 -4alkoxy, amino, C 1 _4alkylamino or di(C 1 _4alkyl)amino;

R2 is selected from:

(i) Ci-8alkyl or C2-8alkenyl, either of which optionally bears up to 3 substituents independently selected from halogen, OH, CN, CF3, OR3, SR4, SO2R⁴, S02N(R3)2, COR3, C02R3, CON(R3)2, N( 3)_2s NR3COR4, NR3S02R⁴ and phenyl, said phenyl bearing 0 to 5 halogen substituents; and

(ii) C3-l0cycloalkyl, C3-l0cycloalkylCl-4alkyl, Het, HetCl-4alkyl, aryl or arylCi-4alkyl, any of which optionally bears up to 4 substituents independently selected from halogen, OH, oxo, CN, CF3, R4 OR3, SR4, SO2R⁴, S02N(R3)₂, COR3, C02R³, CON(R3)₂, N(R3)2, NR3COR4, NR3S02R⁴ and -P(0)-(OR3)2; where "aryl" refers to phenyl or 5- or 6- membered heteroaryl, either of which phenyl or heteroaryl is optionally fused to a 5- or 6- membered carbocycle or heterocycle, each "Het" independently refers to a nonaromatic or partially aromatic mono- or bicyclic heterocyclic system of up to 10 ring atoms and C3- lOcycloalkyl and the cyclic portion of C3-l0cycloalkylCl-4alkyl may be fused with phenyl or a 5- or 6-membered heteroaryl;

or R1 and R2 together may complete a non-aromatic monocyclic, a non-aromatic or partially aromatic bicyclic, or a non-aromatic spiro-linked heterocyclic system of up to 12 ring atoms which optionally bears up to 4 substituents independently selected from R3;

R3 is selected from the group consisting of: halogen, OH, oxo, CN, CF3, R5, OR4, SR5, SO2R⁵, S02N(R4)2, COR5, C02R⁴, CON(R4)₂, N(R4)₂, NR4COR5, NR4C02R⁴, NR4S02R⁵, -Ci_4alkyl-N(R4)₂, -Ci_4alkyl-NR4COR5 and -Ci_4alkyl-NR4C02R⁴,except that R3 is selected from R5, COR5 and C02R4 when substituted on a nitrogen atom and R3 is oxo when substituted on sulfur;

each R4 independently represents H , Cl-6alkyl, C3-I0cycloalkyl, C3- 10cycloalkylCl-4alkyl, C3-I0cycloalkenyl or C3-l0cycloalkenylCl-4alkyl, any of which except H optionally bear up to 3 halogen atoms or with OH, CN, CF3 and Cl-4alkoxy, or R4 represents phenyl, benzyl, 5- or 6-membered monocyclic heteroaryl optionally bridged with a methylene or a 9- or 10-membered bicyclic heteroaryl optionally bridged with a methylene, any of which optionally bear up to 3 substituents independently selected from halogen, OH, CN, CF3, Cl- 4alkyl, C3_6cycloalkyl, phenyl, Ci_4alkoxy, amino, Ci_4alkylamino and di(Ci_4alkyl)amino, or R4 represents Het, optionally bridged with a methylene and said Het optionally bearing up to 3 substituents independently selected from halogen, OH, oxo, CN, CF3, Cl-4alkyl, C3- gcycloalkyl, phenyl, a 5- or 6-membered monocyclic heteroaryl, Ci_4alkoxy, acetyl, amino, Ci_ 4alkylamino and di(Cl-4alkyl)amino; and

R5 has the same definition as R4 except that R5 is not H.

Within the genus, the invention encompasses a first sub-genus of compounds of Formula I wherein Xl is selected from 2,2-dimethylpropyl, [2,2-difluorocyclopropyl]methyl and [2,2-difluoro- 1 -methylcyclopropyl]methyl.

Also within the genus, the invention encompasses a second sub-genus of compounds of Formula I wherein Rl and R2 together complete a non-aromatic mono-cyclic, a nonaromatic or partially aromatic bi-cyclic, or a non-aromatic spiro-linked heterocyclic system of up to 12 ring atoms which optionally bears up to 4 substituents independently selected from R3.

Within the second sub-genus, the invention encompasses a first class of compounds of Formula la

la

or a pharmaceutically acceptable salt thereof.

Also within the second sub-genus, the invention encompasses a second class of compounds of Formula lb

lb

or a pharmaceutically acceptable salt thereof.

Within the second class, the invention encompasses a sub-class of compounds of Formula Ic wherein R3 is selected from NR4COR5, NR4C02R⁴ and NR3S02R⁴.

Also within the second sub-genus, the invention encompasses a third class of compounds of Formula Ic

Ic

or a pharmaceutically acceptable salt thereof. Within the third class, the invention encompasses compounds of Formula Ic wherein R3 is isoxazolylcarbonyl, optionally substituted with Cl- 4alkyl.

Also within the second sub-genus, the invention encompasses a fourth class of compounds of Formula Id

Id

or a pharmaceutically acceptable salt thereof.

Also within the second sub-genus, the invention encompasses a fifth class of compounds of Formula Ie

Ie

or a pharmaceutically acceptable salt thereof.

Also within the second sub-genus, the invention encompasses a sixth class of compounds of Formula If

If

or a pharmaceutically acceptable salt thereof.

The invention also encompasses a pharmaceutical composition comprising a compound of Formula la in combination with a pharmaceutically acceptable carrier.

The invention also encompasses a method for treating a neurological or psychiatric disorder associated with glutamate dysfunction in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula I. The invention also encompasses this method wherein the neurological or psychiatric disorder associated with glutamate dysfunction is schizophrenia.

"Alkyl", as well as other groups having the prefix "alk", such as alkoxy, alkanoyl, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.

"Alkenyl" means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2- butenyl, and the like.

"Alkynyl" means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3 -methyl- 1-pentynyl, 2-heptynyl and the like. "Cycloalkyl" means mono-, bi- or tri-cyclic structures, optionally combined with linear or branched structures, having the indicated number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, methylcyclopropyl, cyclopentyl, cycloheptyl, adamantyl, 2-ethyl-l- bicyclo[4.4.0]decyl, and the like.

"Cycloalkenyl" means cycloalkyl as defined above having at least one double bond, excluding aromatics.

"Alkoxy" means alkoxy groups of a straight or branched having the indicated number of carbon atoms. Cl-6alkoxy, for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.

"Cycloalkoxy" means cycloalkyl as defined above bonded to an oxygen atom, such as cyclopropyloxy.

Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl,

benzimidazolyl, benzofuranyl, benzothiophenyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, and the like.

"Halogen" and "halo" includes fluorine, chlorine, bromine and iodine.

With respect to "C3-6cycloalkylCi-4alkyl", said C3_6cycloalkyl may be substituted on any substitutable position on the Cl-4alkyl group and includes for example (1- methylcyclopropyl)methyl.

Unless indicated otherwise, the term "bicyclic" includes bridged bicyclic as well as fused ring systems.

A nitrogen atom forming part of a heteroaryl ring may be in the form of the N- oxide. A sulphur atom forming part of a nonaromatic heterocycle may be in the form of the S- oxide or S,S-dioxide.

A heteroaryl group may be attached to the remainder of the molecule via a ring carbon or a ring nitrogen, provided that this is consistent with preservation of aromaticity.

In formula I, Rl and R2 together with the nitrogen atom to which they are attached may complete a non-aromatic monocyclic, a non-aromatic or partially aromatic bicyclic, or a non-aromatic spiro-linked heterocyclic system of up to 12 ring atoms. The heterocyclic ring system may contain one or more heteroatoms in addition to nitrogen selected from N, O and S and the remainder are C. In the case of a bicyclic system, said heteroatoms may be confined to one of the rings or distributed over both of the rings. In the case of a partially aromatic bicyclic system, one of the rings is aromatic, for example 1, 2, 3, 4-tetrahydroquinoline. In the case of a monocyclic system, the ring typically comprises 5 or 6 ring atoms.

Examples of spiro-linked heterocyclic ring systems include 2,9- diazaspiro[5.5]undecane and the like.

Examples of bicyclic rings include 3,8-diazabicyclo[3.2. ljoctane, 2,3- diazabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2.1]heptane, 1,2, 3, 4-tetrahydroquinoline and 5,6,7,8 -tetrahy dro [ 1 ,2 ,4] triazo lo [4 , 3 -ajpyrazine .

It will be apparent to those skilled in the art that a hydroxyl substituent on an unsaturated ring may be capable of tautomerising to a ketone. In such circumstances, both tautomers are to be considered equivalent. Thus, for example, 2-hydroxypyridine is considered equivalent to 2-oxo-l,2-dihydropyridine.

The compounds of the present invention are potentiators of metabotropic glutamate (mGluR) receptor function, in particular they are potentiators of mGluR2 receptors. That is, the compounds of the present invention do not appear to bind at the glutamate recognition site on the mGluR receptor, but in the presence of glutamate or a glutamate agonist, the compounds of the present invention increase mGluR receptor response. The present potentiators are expected to have their effect at mGluR receptors by virtue of their ability to increase the response of such receptors to glutamate or glutamate agonists, enhancing the function of the receptors. It is recognized that the compounds of the present invention would be expected to increase the effectiveness of glutamate and glutamate agonists of the mGluR2 receptor. Thus, the potentiators of the present invention are expected to be useful in the treatment of various neurological and psychiatric disorders associated with glutamate dysfunction described to be treated herein and others that can be treated by such potentiators as are appreciated by those skilled in the art.

The compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers,

diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. Any formulas, structures or names of compounds described in this specification that do not specify a particular stereochemistry are meant to encompass any and all existing isomers as described above and mixtures thereof in any proportion. When stereochemistry is specified, the invention is meant to encompass that particular isomer in pure form or as part of a mixture with other isomers in any proportion.

The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray

crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

In the compounds of generic Formula I, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I. For example, different isotopic forms of hydrogen (H) include protium (iH) and deuterium (¾). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.

Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, Ν,Ν'-dibenzylethylene-diamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine,

isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like. It will be understood that, as used herein, references to the compounds of Formula I are meant to also include a pharmaceutically acceptable salts.

Exemplifying the invention are the examples described herein. The subject compounds are useful in a method of potentiating metabotorpic glutamate receptor activity in a patient such as a mammal in need of such inhibition comprising the administration of an effective amount of the compound. The present invention is directed to the use of the subject compounds disclosed herein as potentiators of metabotropic glutamate receptor activity. In addition to primates, especially humans, a variety of other mammals can be treated according to the method of the present invention.

The present invention is further directed to a method for the manufacture of a medicament for potentiating metabotropic glutamate receptor activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent. The subject treated in the present methods is generally a mammal, preferably a human being, male or female, in whom potentiation of metabotropic glutamate receptor activity is desired. The term "therapeutically effective amount" means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. It is recognized that one skilled in the art may affect the neurological and psychiatric disorders by treating a patient presently afflicted with the disorders or by prophylactically treating a patient afflicted with the disorders with an effective amount of the compound of the present invention. As used herein, the terms "treatment" and "treating" refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy of the mentioned conditions, particularly in a patient who is predisposed to such disease or disorder.

The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The terms "administration of and or "administering a" compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.

The utility of the compounds in accordance with the present invention as inhibitors of metabotropic glutamate receptor activity, in particular mGluR2 activity, may be demonstrated by methodology known in the art. Inhibition constants are determined as follows. The compounds of the present invention may be tested in a fluorescence laser imaging plate reader (FLIPR) based assay. This assay is a common functional assay to monitor Ca2+ mobilization in whole cells expressing recombinant receptor coupled with a promiscuous G- protein. CHO dhfr- cells stably expressing recombinant human mGluR2 and Gal 6 loaded with Fluo-4 AM (Invitrogen, Carlsbad CA) are treated with dose responses of compounds and the Ca2+ response is monitored on a FLIPR384 (Molecular Devices, Sunnydale CA) for agonist activity. The potentiation response is monitored after a subsequent addition of an EC20 concentration of glutamate (900 nM). The maximum calcium response at each concentration of compound for agonist or potentiation are plotted as dose responses and the curves are fitted with a four parameters logistic equation giving EC50 and Hill coefficient using the iterative non linear curve fitting software program.

The compounds of the present invention may also be tested in a [35s]-GTPyS assay. The stimulation of [35S]-GTPyS binding is a common functional assay to monitor Gai- coupled receptor in native and recombinant receptor membrane preparation. Membrane from cells stably expressing hmGlu2 CHO-Kl (50μg) are incubated in a 96 well plate for 1 hour in the presence of GTPyS35 (0.05nM), GDP (5μΜ) and compounds. The reaction is stopped by rapid filtration over Unifilter GF/B plate (Packard, Bioscience, Meriden CT) using a 96-well cell harvester (Brandel Gaithersburg, MD). The filter plates are counted using Topcount counter (Packard, Bioscience, Meriden CT, USA). When compounds are evaluated as potentiators they are tested in the presence of glutamate (ΙμΜ). The activation (agonist) or the potentiation of glutamate (potentiator) curves are fitted with a four parameters logistic equation giving EC50 and Hill coefficient using the iterative non linear curve fitting software GraphPad (San Diego CA, USA).

Compounds of the invention were tested and demonstrated activity in potentiating the mGluR2 receptor in the FLIPR assay, generally with an EC50 of less than about 10 μΜ. Compounds within the present invention had activity in potentiating the mGluR2 receptor in the FLIPR and GTPyS assays with an EC50 of less than about 1 μΜ. Each of the identified compounds resulted in a minimum 1.8-fold potentiation of glutamate response in the presence of an EC20 concentration of glutamate (900 nM). Such results are indicative of the intrinsic activity of the compounds in use as potentiators of mGluR2 receptor activity. Representative FLIPR EC50 Values

Metabotropic glutamate receptors including the mGluR2 receptor have been implicated in a wide range of biological functions. This has suggested a potential role for these receptors in a variety of disease processes in humans or other species.

The compounds of the present invention have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of neurological and psychiatric disorders associated with glutamate dysfunction, including one or more of the following conditions or diseases: acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine (including migraine headache), urinary incontinence, substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, ***e, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety (including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder), mood disorders (including depression, mania, bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), autism, autism spectrum disorders, attention deficit/hyperactivity disorder, and conduct disorder.

In an embodiment the present invention provides a method for treating migraine, comprising: administering to a patient in need thereof an effective amount of a compound of formula I. In another embodiment the present invention provides a method for preventing or treating anxiety, comprising: administering to a patient in need thereof an effective amount of a compound of formula I. Particular anxiety disorders of the invention are generalized anxiety disorder, panic disorder, and obsessive compulsive disorder. In another embodiment the present invention provides a method for treating schizophrenia, comprising: administering to a patient in need thereof an effective amount of a compound of formula I. In yet another embodiment the present invention provides a method for treating epilepsy, comprising: administering to a patient in need thereof an effective amount of a compound of formula I.

In an embodiment, the present invention provides a method for the treatment of schizophrenia comprising: administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutical composition thereof. In one of the available sources of diagnostic tools, The Merck Manual (2006-2007), schizophrenia is characterized by psychosis (loss of contact with reality), hallucinations (false perceptions), delusions (false beliefs), disorganized speech and behavior, flattened affect (restricted range of emotions), cognitive deficits (impaired reasoning and problem solving), and occupational and social dysfunction. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and

classification systems for neurological and psychiatric disorders, including migraine, and that these systems evolve with medical scientific progress

Thus, in an embodiment the present invention provides a method for treating migraine, comprising: administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutical composition thereof. In one of the available sources of diagnostic tools, Dorland's Medical Dictionary (23'd Ed., 1982, W. B. Saunders Company, Philidelphia, PA), migraine is defined as a symptom complex of periodic headaches, usually temporal and unilateral, often with irritability, nausea, vomiting, constipation or diarrhea, and photophobia. As used herein the term "migraine" includes these periodic headaches, both temporal and unilateral, the associated irritability, nausea, vomiting, constipation or diarrhea, photophobia, and other associated symptoms. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, including migraine, and that these systems evolve with medical scientific progress.

In another embodiment the present invention provides a method for treating anxiety, comprising: administering to a patient in need thereof an effective amount of a compound of Formula I or a pharmaceutical composition thereof. At present, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994, American Psychiatric Association, Washington, D.C.), provides a diagnostic tool including anxiety and related disorders. These include: panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive- compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder and anxiety disorder not otherwise specified. As used herein the term "anxiety" includes treatment of those anxiety disorders and related disorder as described in the DSM-IV. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, and particular anxiety, and that these systems evolve with medical scientific progress. Thus, the term "anxiety" is intended to include like disorders that are described in other diagnostic sources.

In another embodiment the present invention provides a method for treating depression, comprising: administering to a patient in need thereof an effective amount of a compound of Formula I or a pharmaceutical composition thereof. At present, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994, American Psychiatric Association, Washington, D.C.), provides a diagnostic tool including depression and related disorders. Depressive disorders include, for example, single episodic or recurrent major depressive disorders, and dysthymic disorders, depressive neurosis, and neurotic depression; melancholic depression including anorexia, weight loss, insomnia and early morning waking, and psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, anxiety and phobias; seasonal affective disorder; or bipolar disorders or manic depression, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder. As used herein the term "depression" includes treatment of those depression disorders and related disorder as described in the DSM-IV.

In another embodiment the present invention provides a method for treating epilepsy, comprising: administering to a patient in need thereof an effective amount of a compound of Formula I or a pharmaceutical composition thereof. At present, there are several types and subtypes of seizures associated with epilepsy, including idiopathic, symptomatic, and cryptogenic. These epileptic seizures can be focal (partial) or generalized. They can also be simple or complex. Epilepsy is described in the art, such as Epilepsy: A comprehensive textbook. Ed. by Jerome Engel, Jr. and Timothy A. Pedley. (Lippincott-Raven, Philadelphia, 1997). At present, the International Classification of Diseases, Ninth Revision, (ICD-9) provides a diagnostic tool including epilepsy and related disorders. These include: generalized

nonconvulsive epilepsy, generalized convulsive epilepsy, petit mal status epilepticus, grand mal status epilepticus, partial epilepsy with impairment of consciousness, partial epilepsy without impairment of consciousness, infantile spasms, epilepsy partialis continua, other forms of epilepsy, epilepsy, unspecified, NOS. As used herein the term "epilepsy" includes these all types and subtypes. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, including epilepsy, and that these systems evolve with medical scientific progress.

The subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein.

The subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents, including an mGluR agonist.

The term "potentiated amount" refers to an amount of an mGluR agonist, that is, the dosage of agonist which is effective in treating the neurological and psychiatric disorders described herein when administered in combination with an effective amount of a compound of the present invention. A potentiated amount is expected to be less than the amount that is required to provided the same effect when the mGluR agonist is administered without an effective amount of a compound of the present invention.

A potentiated amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining a potentiated amount, the dose of an mGluR agonist to be administered in combination with a compound of formula I, a number of factors are considered by the attending diagnostician, including, but not limited to: the mGluR agonist selected to be administered, including its potency and selectivity; the compound of formula I to be coadministered; the species of mammal; its size, age, and general health; the specific disorder involved; the degree of involvement or the severity of the disorder; the response of the individual patient; the modes of administration; the bioavailability characteristics of the preparations administered; the dose regimens selected; the use of other concomitant medication; and other relevant circumstances.

A potentiated amount of an mGluR agonist to be administered in combination with an effective amount of a compound of formula I is expected to vary from about 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day and is expected to be less than the amount that is required to provided the same effect when

administered without an effective amount of a compound of formula I. Preferred amounts of a co-administered mGlu agonist are able to be determined by one skilled in the art.

The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of Formula I or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I. When a compound of Formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form may be utilized containing such other drugs and the compound of Formula I. However, the combination therapy may also includes therapies in which the compound of Formula I and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula I.

The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.

Likewise, compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention may be utilized. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.

The weight ratio of the compound of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000: 1 to about 1 : 1000, preferably about 200: 1 to about 1 :200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).

The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warmblooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention are effective for use in humans.

The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide

pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Oily suspensions may be formulated by suspending the active ingredient in a suitable oil. Oil-in-water emulsions may also be employed. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.

Pharmaceutical compositions of the present compounds may be in the form of a sterile injectable aqueous or oleagenous suspension. The compounds of the present invention may also be administered in the form of suppositories for rectal administration. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention may be employed. The compounds of the present invention may also be formulated for administered by inhalation. The compounds of the present invention may also be administered by a transdermal patch by methods known in the art. The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.

In the treatment, prevention, control, amelioration, or reduction of risk of conditions which require potentiation of metabotropic glutamate receptor activity an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

When treating, preventing, controlling, ameliorating, or reducing the risk of neurological and psychiatric disorders associated with glutamate dysfunction or other diseases for which compounds of the present invention are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligrams to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.

It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials are made according to procedures known in the art or as illustrated herein. The compounds of the present invention can be prepared in a variety of fashions.

All patents, publications and pending patent applications identified are hereby incorporated by reference.

Abbreviations used in the description of the chemistry and in the Examples that follow are: Ac20 (acetic anhydride); AcOH (acetic acid); AEBSF (p-aminoethylbenzenesulfonyl fluoride); Boc (di-tert-butyl carbamate); (Boc)₂0 (di-tert-butyl dicarbonate ); BSA (bovine serum albumin); BuLi (n-Butyl lithium); CDC13 (chloroform-d); Cul (copper iodide); CuS04 (copper sulfate); DBU (l,8-DIAZABICYCLO[5.4.0]UNDEC-7-ENE); DCE (dichloroethane); DCM (dichloromethane); DEAD (diethyl azodicarboxylate); DIPEA (diisopropylethylamine); DMBA (1,3-dimethylbarbituric acid ); DMF (Ν,Ν-dimethylformamide); DMP (Dess-Martin periodinane); DMSO (dimethyl sulfoxide); DPPA (diphenylphosphoryl azide); DTT

(dithiothreitol); EDTA (ethylene-diamine-tetra-acetic acid); EGTA (ethylene-glycol-tetra-acetic acid); Et20 (diethylether); EtOAc (ethyl acetate); EtOH (ethanol); HO Ac (acetic acid); HPLC (high-performance liquid chromatography); HRMS (high resolution mass spectrum); LAH (lithium aluminum hydride); LCMS (liquid chromatograph-mass spectrometer); LHMDS (lithium bis(trimethylsilyl)amide); LRMS (low resolution mass spectrum); mCPBA (3- chloroperoxybenzoic acid); MeOH (methanol); MP-B(CN)H3 (Macroporous cyanoborohydride); NaHC03 (sodium bicarbonate); Na2S04 (sodium sulfate); Na(OAc)3BH (sodium

triacetoxyborohydride); NH40Ac (ammonium acetate); NBS (N-bromosuccinamide); NFSi (N- fluorobenzenesulfonimide ); NMP (l-methyl-2-pyrrolidinone); NMR (nuclear magnetic resonance); PBS (phosphate buffered saline); PCR (polymerase chain reaction); Pd(dppf) ([Ι,Γ- bis(diphenylphosphino)ferrocene] palladium); Pd(Ph3)4 (palladium(O) tetrakis- triphenylphosphine); POC13 (phosphorous oxychloride); PS-DIEA (polystyrene

diisopropylethylamine); PS-PPh3 (polystyrene -triphenyl phosphine); PTSA (para-toluene sulfonic acid); Pyr (pyridine); Selectfluor (l-chloromethyl-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate); TBAF (tetrabutylammonium fluoride); T- BuOH (tert-butanol); THF (tetrahydrofuran); Tf (trifluoromethanesulfonyl); TFA (trifluoroacteic acid); and TMSCH2N2 (trimethylsilyldiazomethane).

The compounds of this invention may be prepared by employing reactions as shown in the following Reaction Schemes and Examples, in addition to other standard manipulations that are known in the literature or exemplified in the experimental procedures. The illustrative Reaction Schemes below, therefore, are not limited by the compounds listed or by any particular substituents employed for illustrative purposes. Substituent numbering as shown in the Reaction Schemes do not necessarily correlate to that used in the claims and often, for clarity, a single substituent is shown attached to the compound where multiple substituents are optionally allowed under the definitions of Formula I hereinabove.

Scheme 1

1 -(2,2-Dimethylpropyl)-3 -methyl-5 -piperidin- 1 -yl- 1 ,3 -dihydro-2H-imidazo [4,5 - blpyridin-2-one (1-5)

6-Chloro-N-methyl-3-nitropyridin-2-amine (1-1)

2,6-Dichloro-3-nitropyridine(2.0 g, 10.4 mmol) and sodium carbonate 2.75 g, 25.9 mmol) were added to a round bottom flask under nitrogen, and suspended in ethanol (100 mL). Methylamine in methanol (7.8 mL, 15.6 mmol, 2M) was then added and stirred at room temperature for 3 hours. The yellow solution was concentrated, and then re-dissolved in ethyl acetate followed by washing with sodium bicarbonate and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated. The yellow solid was then re-dissolved in ethanol and recrystalized to give 6-chloro-N-methyl-3-nitropyridin-2-amine (1-1) as a yellow solid.

6-Chloro-N²-methylpyridine-2,3-diamine (1-2)

6-Chloro-N-methyl-3-nitropyridin-2-amine (1-1, 10.5 g, 56 mmol) and tin(II) chloride dehydrate (50.5 g, 224 mmol) were suspended in concentrated HC1 (80 mL) and refiuxed overnight. The solution was cooled to room temperature and then added very slowly to a NaOH/ethyl acetate solution at -78 °C, until the solution had a slightly basic pH. The suspension was washed with sodium bicarbonate, brine, dried over sodium sulfate, filtered, and concentrated to produce 6-chloro-N²-methylpyridine-2,3-diamine (1-2) as a black solid.

5 -Chloro-3 -methyl- 1 ,3-dihvdro-2H-imidazor4,5-&1pyridin-2-one (1-3)

6-Chloro-N²-methylpyridine-2,3-diamine (1-2, 35 g, 222 mmol) and Ι,Γ- carbonyldiimidazole(63 g, 389 mmol) were added to a round bottom flask and suspended in DMF(150 mL). The solution was heated to 80 °C in an oil bath overnight. The reaction was then suspended in ethyl acetate and sodium bicarbonate. The suspension was washed with sodium bicarbonate, brine(x5), dried over sodium sulfate, filtered, and concentrated to produce 5-chloro-3-methyl-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one (1-3) as a white solid.

5-Chloro-l-(2,2-dimethylpropyl)-3-methyl-l,3-dihvdro-2H-imidazor4,5-

&1pyridin-2-one (1-4)

5-Chloro-3-methyl-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one (1-3, 2.97 g, 16.2 mmol) and cesium carbonate (15.8 g, 48.6 mmol) were added to a round bottom flask and suspended in NMP (25 mL) under nitrogen. Neopentyl iodide (6.4 g, 32.4 mmol) was added to the suspension and then refiuxed at 90 °C overnight. The reaction was then cooled to room temperature and suspended in ethyl acetate and sodium bicarbonate. The suspension was washed with sodium bicarbonate, brine(x5), dried over sodium sulfate, filtered, and

concentrated. The mixture was purified using normal phase chromatography(0-60% ethyl acetate/hexanes), and the desired fractions were collected to produce 5-chloro-l- (cyclopropylmethyl)-3-methyl-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one (1-4) as a tan solid.

1 -(2,2-Dimethylpropyl)-3 -methyl-5 -piperidin- 1 -yl- 1 ,3 -dihydro-2H-imidazo [4,5 - blpyridin-2-one (1-5)

5-Chloro-l-(2,2-dimethylpropyl)-3-methyl-l,3-dihydro-2H-imidazo[4,5-

£]pyridin-2-one (1-4, 20 mg, 0.079 mmol), potassium phosphate tribasic (33.5 mg, 0.158 mmol), bis(tri-t-butylphosphine)palladium(0) (1.6 mg, 3.15 μιηοΐ), and piperidine (11.7 μΐ,, 0.118 mmol) were added to a 1 mL vial and purged with nitrogen. Anhydrous dimethylacetamide (95 μί, degassed prior to use) was then added and the resulting suspension was heated to 100 °C for 18 h. Following this duration, the reaction contents were cooled to room temperature, filtered, and washed with acetonitrile. Purification using reverse phase chromatography (10-95%, 0.1% TFA in H₂0: acetonitrile) afforded 1 -(2, 2-dimethylpropyl)-3 -methyl-5 -piperidin- 1-yl- 1,3 -dihydro-2H- imidazo[4,5-b]pyridin-2-one (1-5) as a white solid. MS m/z (M+H): calculated = 303.2179; observed = 303.2174.

The following compounds were prepared from 1-4 by a reaction sequence analogous to that illustrated in Scheme 1 :

Table 1

Cmp Structure Name MS m z MS m/z

(M+H): (M+H): calc'd observed

1-6 1 -(2,2-dimethylpropyl)- 317.2336 317.2334

3-methyl-5-[(2S)-2- methylpiperidin- 1 -yl] - l,3-dihydro-2H-

imidazo [4,5 -b]pyridin- 2-one

1-7 1 - 2,2-dimeth l ropyl)- 331.2492 331.2492

- 1 - din-

2-one

1-8 ethyl-l-[l-(2,2- 375.2391 375.2391 dimethylpropyl)-3 - methyl-2-oxo-2,3- dihydro-lH- imidazo [4,5 -b]pyridin-

5 -yl]piperidine-2- carboxylate Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

1-9 393.2649 392.2650

1-10 351.2179 351.2180

1-11 345.2649 345.2648

2-one

1-12 1 -(2,2-dimethylpropyl)- 365.2336 365.2338

3 -methyl-5 -(8-methyl- 3 ,4-dihydroquinolin- l(2H)-yl)-l,3-dihydro- 2H-imidazo[4,5-

b]pyridin-2-one Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

1-13 1 -(2,2-dimethylpropyl)- 365.2336 365.2341

3 -me thy 1-5 -(6-methy 1- 3 ,4-dihydroquinolin- l(2H)-yl)-l,3-dihydro- 2H-imidazo[4,5- b]pyridin-2-one

1-14 1- (2,2-dimethylpropyl)- 303.2179 303.2186

3-methyl-5-[2- methylpyrrolidin- 1 -yl]- l,3-dihydro-2H-

imidazo [4,5 -b]pyridin-

2- one

1-15 1 -(2,2-dimethylpropyl)- 357.2649 357.2652

3-methyl-5-

[octahydroquinolin- l(2H)-yl]-l,3-dihydro-

2H-imidazo[4,5-

b]pyridin-2-one

1-16 1 -(2,2-dimethylpropyl)- 371.2053 371.2058

3-methyl-5-[2-

(trifluoromethyl)piperid

in- 1 -yl]- 1 ,3-dihydro-

2H-imidazo[4,5-

b]pyridin-2-one Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

1-17 1 -(2,2-dimethylpropyl)- 369.2285 369.2286

5 - [(4-methoxybenzyl)- (methyl)amino] -3 - methyl-l ,3-dihydro-2H-

imidazo[4,5-b]pyridin- 2-one

1-18 419.2053 419.2058

2-one

1-19 430.2813 430.2807

diazabicyclo[3.2.1]octa

ne-6-carboxylate tert-butyl {(3S)-1-[1- 418.2813 418.2801

(2,2-dimethylpropyl)-3

methyl-2-oxo-2,3- dihydro-lH-

imidazo [4,5 -bjpyridin-

5-yl]piperidin-3- Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed yl} carbamate

tert-butyl {(3R)-1-[1- 418.2813 418.2802

(2,2-dimethylpropyl)-3

methyl-2-oxo-2,3- dihydro-lH-

imidazo [4,5 -b]pyridin-

5-yl]piperidin-3- yl} carbamate

1 -(2,2-dimethylpropyl)- 438.2224 438.2242 5 - [5 ,5 -dimethyl-3 - (trifluoromethyl)-5,6- dihydro[l ,2,4]triazolo[4

,3 -a]pyrazin-7(8H)-yl] -

3-methyl- 1 ,3-dihydro- 2H-imidazo[4,5- b]pyridin-2-one

1 -(2,2-dimethylpropyl)- 379.2492 379.2486

3-methyl-5-[3- phenylpiperidin- 1 -yl] - l,3-dihydro-2H-

imidazo [4,5 -b]pyridin- 2-one Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

1-24 1 -(2,2-dimethylpropyl)- 379.2492 379.2492

3-methyl-5-(4- phenylpiperidin- 1 -yl)- l,3-dihydro-2H- imidazo [4,5 -b]pyridin-

2-one

1-25 tert-butyl 4-[l-(2,2- 404.2656 404.2648 dimethylpropyl)-3 - methyl-2-oxo-2,3- dihydro-lH- imidazo [4,5 -b]pyridin-

5 -yljpiperazine- 1 - carboxylate

1 -(2,2-dimethylpropyl)- 379.2492 379.2486 3-methyl-5-[2- phenylpiperidin- 1 -yl] - l,3-dihydro-2H-

imidazo [4,5 -b]pyridin- 2-one

1 -(2,2-dimethylpropyl)- 370.2350 370.2343

5-(3-ethyl-5,6- dihydro[l ,2,4]triazolo[4

,3-a]pyrazin-7(8H)-yl)- 3-methyl- 1 ,3-dihydro-

2H-imidazo[4,5-

¾]pyridin-2-one Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

1-28 441.2721 441.2721

1-29 484.3282 484.3267

1-30 414.2248 414.2249

tetrahydro[l ,2,4]triazolo

[4,3-a]pyrazine-3- carboxylate Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

1-31 5-(3,4-dihydro-l,5- 352.2132 352.2127 naphthyridin- 1 (2H)-yl)- 1 -(2,2-dimethylpropyl)- 3-methyl- 1 ,3-dihydro- 2H-imidazo[4,5-

b]pyridin-2-one

1-32 1 -(2,2-dimethylpropyl)- 366.2288 366.2284

3 -methyl-5 -(7-methyl- 3,4-dihydro-l,8- naphthyridin- 1 (2H)-yl)- l,3-dihydro-2H-

imidazo [4,5 -b]pyridin- 2-one

1-33 tert-butyl 7-[l-(2,2- 444.2969 444.2969 dimethylpropyl)-3 - methyl-2-oxo-2,3- dihydro-lH- imidazo [4,5 -b]pyridin-

5-yl]-3,7- diazabicyclo[3.3.1 ]nona

ne-3-carboxylate

1-34 tert-butyl ({l-[l-(2,2- 432.2969 432.2962 dimethylpropyl)-3 - methyl-2-oxo-2,3- dihydro-lH-

imidazo [4,5 -b]pyridin-

5-yl]piperidin-3- Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed yl}methyl)carbamate

1-35 1 -(2,2-dimethylpropyl)- 423.2115 423.2106

3 -methy 1-5 - [ 1 -methyl- 3 -(trifluoromethyl)- l,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridin-

5-yl]-l,3-dihydro-2H- imidazo [4,5 -b]pyridin- 2-one

1-36 - 353.1642 353.1634

1-37 418.2813 418.2805

-

methylpiperazine- 1 - carboxylate Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

1-38 418.2813 418.2805

-

methylpiperazine- 1 - carboxylate

1-39 432.3083 432.3083

dimethylpiperazine- 1 - carboxylate

1-40 444.2969 444.2961

Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

1-41 7-[l-(2,2- 400.2707 400.2696 dimethylpropyl)-3 - methyl-2-oxo-2,3- dihydro-lH-

imidazo [4,5 -b]pyridin-

5-yl]-2-ethyl-2,7- diazaspiro [4.5 ] decan- 1 - one

1-42 2-benzyl-7-[l-(2,2- 462.2864 462.2854 dimethylpropyl)-3 - methyl-2-oxo-2,3- dihydro-lH-

imidazo [4,5 -b]pyridin-

5-yl]-2,7- diazaspiro [4.5 ] decan- 1 - one

1-43 450.2500 450.2494

diazabicyclo [2.2.1 ]hept

ane-2-carboxylate Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

1-44 342.2288 342.2287

imidazo [4 , 5 -bjpyridin-

2-one

1- (2,2-dimethylpropyl)- 345.2649

5-[5-ethyl-2- methylpiperidin-l-yl]-3- methyl- 1 ,3-dihydro-2H-

imidazo [4,5 -b]pyridin-

2- one

1-46 l)- 410.2351 410.2352 pt-

imidazo [4,5 -b]pyridin- 2-one Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

1-47 426.2055 426.2052

1-48 392.2445 392.2447

2-one

1-49 426.2055 426.2054

2-one Scheme 2

l-(2,2-Dimethylpropyl)-3-methyl-2-oxo-5-{3-[(pyrimidin-2-ylamino)- methyl]piperidin-l-yl}-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium chloride (2- 2)

5-[3-(Aminomethyl)piperidin- 1 -yl - 1 -(2,2-dimethylpropyl)-3-methyl-l ,3- dihvdro-2H-imidazor4,5-&1pyridin-2-one (2-1)

tert-Butyl ( { 1 -[1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- 1H- imidazo[4,5-¾]pyridin-5-yl]piperidin-3-yl}methyl)carbamate (1-34, 500 mg, 1.16 mmol) was added to a mixture of dichloromethane (5 mL) and trifluoroacetic acid (5 mL) at room temperature. After stirring for 3 h, the solvent was removed in vacuo. The resulting residue was then diluted with ethyl acetate (15 mL) and washed sequentially with saturated sodium bicarbonate (2 x 10 mL), water (1 x 10 mL) and brine (1 x 10 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to give 5-[3-

(aminomethyl)piperidin- 1 -yl]- 1 -(2,2-dimethylpropyl)-3 -methyl- 1 ,3-dihydro-2H-imidazo[4,5- ¾]pyridin-2-one (2-1) as a white solid. The resulting material was carried on without further purification.

l-(2,2-Dimethylpropyl)-3-methyl-2-oxo-5-(3-r(pyrimidin-2-ylamino)- methyl1piperidin-l-yl|-2,3-dihydro-lH-imidazor4,5-b1pyridin-4-ium chloride (2-2)

5-[3-(Aminomethyl)piperidin- 1 -yl]- 1 -(2,2-dimethylpropyl)-3-methyl-l ,3- dihydro-2H-imidazo[4,5-£]pyridin-2-one (2-1, 200 mg, 0.603 mmol) and cesium carbonate (590 mg, 1.81 mmol) were added to anhydrous NMP (2 mL). To this reaction mixture was added 2- chloropyrimidine (138 mg, 1.21 mmol) and the contents were stirred for 20 min at 200 °C. Following this duration, the solvent was removed in vacuo and the resulting residue was partitioned between ethyl acetate (5 mL) and saturated sodium bicarbonate (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 3 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give an orange residue. Purification via reverse-phase HPLC (10-100%, 0.1% TFA in H₂0:acetonitrile) yielded 1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-5- {3-[(pyrimidin-2-ylamino)-methyl]piperidin- l-yl}-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium chloride (2-2) as a white solid. MS m/z (M+H): calculated = 410.2663; observed = 410.2657.

The following compounds were prepared from 2-1 by a reaction sequence analogous to that illustrated in Scheme 2: Table 2

Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

2-3 434.2663 434.2658

dihydro-lH- imidazo [4,5 -b]pyridin-

4-ium chloride

4-[({l-[l-(2,2- 434.2663 434.2654 dimethylpropyl)-3 - methyl-2-oxo-2,3- dihydro-lH-

imidazo [4,5 -b]pyridin-

5-yl]piperidin-3- yl}methyl)amino]pyridi

ne-2-carbonitrile Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

2-5 434.2590 434.2506

methyl-2-oxo-2,3- dihydro-lH- imidazo [4,5 -b]pyridin-

4-ium chloride

Scheme 3

l-(2,2-Dimethylpropyl)-3-methyl-2-oxo-5-(3-([(l,2,3-thiadiazol-4- ylcarbonyl)amino1methyl|piperidin-l-yl)-2,3-dihvdro-lH-imidazor4,5-b1pyridin-4-ium chloride

(Ml

5-[3-(Aminomethyl)piperidin- 1 -yl]- 1 -(2,2-dimethylpropyl)-3-methyl-l ,3- dihydro-2H-imidazo[4,5-£]pyridin-2-one (2-1, 131 mg, 0.397 mmol) was added to anhydrous 1,4-dioxane (2 mL). l,2,3-Thiadiazole-4-carboxylic acid (86 mg, 0.66 mmol), EDC (127 mg, 0.66 mmol) and ΗΟΒΤ (101 mg, 0.66 mmol) were added sequentially and the resulting reaction mixture was allowed to stir at 150 °C for 10 min. Following this duration, the contents were filtered and the resulting filtrate was purified via reverse-phase HPLC (10-100%, 0.1% TFA in H₂0:acetonitrile) to give l-(2,2-dimethylpropyl)-3-methyl-2-oxo-5-(3-{[(l,2,3-thiadiazol-4- ylcarbonyl)amino]methyl}piperidin- 1 -yl)-2,3-dihydro- lH-imidazo[4,5-b]pyridin-4-ium chloride (3-1) as a white solid. MS m/z (M+H): calculated = 444.2176; observed = 444.2166. The following compounds were prepared from 2-1 by a reaction sequence analogous to that illustrated in Scheme 3:

Table 3

Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

3-2 1 -(2,2-dimethylpropyl)- 426.2612 426.2602

3- methyl-2-oxo-5-(3- {[(lH-pyrazol-3- ylcarbonyl)amino]meth

yl}piperidin- 1 -yl)-2,3- dihydro-lH- imidazo [4,5 -b]pyridin-

4- ium chloride

3-3 1 -(2,2-dimethylpropyl)- 427.2452 427.2443

3- methyl-5-(3-{[(l,3- oxazol-5- ylcarbonyl)amino]meth

yl}piperidin- 1 -yl)-2- oxo-2,3 -dihydro- 1 H- imidazo [4,5 -b]pyridin-

4- ium chloride

3-4 1 -(2,2-dimethylpropyl)- 427.2452 427.2441

5-(3-{[(isoxazol-5- ylcarbonyl)amino]meth

yl} piperidin- 1 -yl)-3 -

methyl-2-oxo-2,3- dihydro-lH- imidazo [4,5 -b]pyridin-

4-ium chloride Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

1 -(2,2-dimethylpropyl)- 450.2864 450.2852

3 - methy 1-2-0X0-5 -(3-

{ [(phenylacetyl)amino]

methyl}piperidin- 1 -yl)-

2,3-dihydro-lH- imidazo [4,5 -b]pyridin-

4- ium chloride

1 -(2,2-dimethylpropyl)- 436.2707 436.2694

3 -methy 1-2-0X0-5 -(3- { [(phenylcarbonyl)amin

o]methyl}piperidin- 1 -

yl)-2,3-dihydro-lH- imidazo [4,5 -b]pyridin

4-ium chloride

Scheme 4

N-benzyl- 1 -[ 1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- 1H- imidazo[4,5-¾lpyridin-5-yllpiperidine-3-carboxamide (4-2)

1 -[1 -(2,2-Dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- lH-imidazo[4,5- &1pyridin-5-yl1piperidine-3-carboxyiic acid (4-1)

Ethyl l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5- ¾]pyridin-5-yl]piperidine-3-carboxylate (800 mg, 2.14 mmol) was added to a dichloromethane (25 ml). To this solution was added 6N NaOH (25 ml) and the resulting reaction mixture was stirred at RT for 1 h. Following this duration, concentrated aqueous HCl was added until the solution was acidic and the aqueous layer was extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered, and concentrated to give l-[l-(2,2- dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-¾]pyridin-5-yl]piperidine-3- carboxylic acid (4-1) as a white solid. MS m/z (Μ+Η): calculated = 347.2078; observed = 347.2072.

N-benzyl- 1 -[ 1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- 1H- imidazor4,5-&1pyridin-5-yl1piperidine-3-carboxamide (4-2)

1 -[1 -(2,2-Dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- lH-imidazo[4,5- £]pyridin-5-yl]piperidine-3-carboxylic acid (4-1, 60 mg, 0.173 mmol) was added to 1,4-dioxane (2 mL) in a microwave vial. 1-Phenylmethanamine (30 mg 0.289 mmol), EDC (53 mg, 0.289 mmol) and ΗΟΒΤ (44.2 mg, 0.289 mmol) were added sequentially. The resulting mixture was heated at 150 degrees for 10 min. Following this duration, the solution was cooled to RT and filtered. Purification by reverse-phase HPLC (10-100%, 0.1% TFA in F^Oiacetonitrile) afforded N-benzyl- 1 -[ 1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- lH-imidazo[4,5-£]pyridin-5- yl]piperidine-3-carboxamide (4-2) as a white solid. MS m/z (Μ+Η): calculated = 436.2707; observed = 436.2695.

The following compound was prepared from 4-1 by a reaction sequence analogous to that illustrated in Scheme 4: Table 4

Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

4-3 l-(2,2-dimethylpropyl)- 422.2551 422.2536

3-methyl-2-oxo-5-[3-

(phenylcarbamoyl)piper

idin- 1 -yl]-2,3-dihydro-

lH-imidazo[4,5- b]pyridin-4-ium

chloride

Scheme 5

5-r3-(lH-Benzimidazol-2-yl)piperidin-l-yl1-l-(2,2-dimethylpropyl)-3-methyl- 1 ,3-dihydro-2H-imidazo[4,5-¾lpyridin-2-one (5-1)

1 -[1 -(2,2-Dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- lH-imidazo[4,5- £]pyridin-5-yl]piperidine-3-carboxylic acid (4-1, 180 mg, 0.520 mmol), benzene- 1,2-diamine (56 mg, 0.520 mmol), EDC (80 mg, 0.520 mmol), and ΗΟΒΤ (100 mg, 0.520 mmol) were added to NMP (2 mL) in a microwave vial. The resulting mixture was heated to 100 °C in a microwave emitter for 10 min. Following this duration, acetic acid (1 mL) was added and the reaction was heated to 150 °C for 10 min. The contents were then cooled to RT, filtered, and purified by reverse-phase HPLC (10-100%, 0.1% TFA in H₂0:acetonitrile) to give 5-[3-(lH-benzimidazol- 2-yl)piperidin-l-yl]-l-(2,2-dimethylpropyl)-3-methyl-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2- one (5-1) as a white solid. MS m/z (Μ+Η): calculated = 419.2554; observed = 419.2547. Scheme 6

1 -(2,2-Dimethylpropyl)-3-methyl-5-[3-(3-methyl- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yll- 1 ,3-dihvdro-2H-imidazor4,5-¾1pyridin-2-one (6-1)

1 -[1 -(2,2-Dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- lH-imidazo[4,5-

¾]pyridin-5-yl]piperidine-3-carboxylic acid (4-1, 180 mg, 0.520 mmol), (\E)-N- hydroxyethanimidamide (115 mg, 1.55 mmol), EDC (80mg, .520 mmol) and ΗΟΒΤ (100 mg, 0.520 mmol) were added to NMP (2 mL) in a microwave vial. The resulting mixture was heated to 100 °C in a microwave emitter for 10 min. Following this duration, acetic acid (1 mL) was added and the contents were heated to 150 °C for 10 min. The reaction mixture was then cooled to RT, filtered, and purified by reverse-phase HPLC (10-100%, 0.1% TFA in H₂0:acetonitrile) to give 1 -(2,2-dimethylpropyl)-3-methyl-5-[3-(3-methyl- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yl]- 1 ,3-dihydro-2H-imidazo[4,5-£]pyridin-2-one (6-1)

as a white solid. MS m/z (Μ+Η): calculated = 385.2347; observed = 385.2343.

Scheme 7

1 -(2,2-Dimethylpropyl)-5- {3-[(l , 1 -dioxidothiomorpholin-4-yl)methyl]piperidin- 1 -yll -3-methyl- 1 ,3-dihydro-2H-imidazo[4,5-&lpyridin-2-one (7-2)

( 1 -[1 -(2,2-Dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- lH-imidazo[4,5- &1pyridin-5-yl1piperidin-3-yl|methyl methanesulfonate (7-1) Ethyl l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5- £]pyridin-5-yl]piperidine-3-carboxylate (1.67 g, 4.46 mmol) was added to anhydrous THF (20 mL). DIBAL (13.38 ml, 13.38 mmol) was then added and the resulting mixture was stirred at RT for 1 h. The contents were concentrated and re-dissolved in ethyl acetate (20 mL) followed by washing with saturated sodium bicarbonate (2 x 20 mL) and brine (1 x 20 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to give l-(2,2-dimethylpropyl)-5- [3-(hydroxymethyl)piperidin- 1 -yl]-3-methyl- 1 ,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one as a white solid

1 -(2,2-Dimethylpropyl)-5 -[3 -(hydroxymethyl)piperidin- 1 -yl] -3 -methyl- 1,3- dihydro-2H-imidazo[4,5-¾]pyridin-2-one (1.60 g, 4.81 mmol) was added to dichloromethane (100 mL) and treated with diisopropylethylamine (1.244g, 9.63 mmol). Methanesulfonyl chloride (551 mg , 4.81 mmol) was then added and the reaction was allowed to stir for 1 h at RT. The dark solution was concentrated and re-dissolved in ethyl acetate (20 mL) followed by washing with saturated sodium bicarbonate (2 x 20 mL) and brine (1 x 20 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to give {l-[l-(2,2- dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-¾]pyridin-5-yl]piperidin-3- yl}methyl methanesulfonate (7-1) as a pale yellow residue.

1 -(2,2-Dimethylpropyl)-5- (3-|Yl , 1 -dioxidothiomorpholin-4-yl)methyllpiperidin- 1 -yl} -3-methyl- 1 ,3-dihvdro-2H-imidazor4,5-&1pyridin-2-one (7-2)

{l-[l-(2,2-Dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-¾]pyridin-5- yl]piperidin-3-yl}methyl methanesulfonate (7-1, 85 mg, 0.207 mmol), diisopropylethylamine (66.9 mg, 0.518 mmol) and thiomorpho line- 1,1 -dioxide (28 mg, 0.207 mmol) were added to NMP (2 mL) in a microwave vial and heated to 200 °C for 10 min. Following this duration, the contents were cooled to RT, filtered, and purified by reverse-phase HPLC (10-100%, 0.1%> TFA in FLOiacetonitrile) to give l-(2,2-dimethylpropyl)-5-{3-[(l,l-dioxidothiomorpholin-4- yl)methyl]piperidin-l-yl}-3-methyl-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one (7-2) as a white solid. MS m/z (Μ+Η): calculated = 450.2533; observed = 450.2538.

The following compounds were prepared from 7-1 by a reaction sequence analogous to that illustrated in Scheme 7: Table 7

Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

7-3 5-({l-[l-(2,2- 449.3023 449.3028 dimethylpropyl)-3 - methyl-2-oxo-2,3- dihydro-lH-

imidazo [4,5 -b]pyridin-

4-ium-5-yl]piperidin-3- yl}methyl)-5,6,7,8- tetrahydro-1,5- naphthyridin- 1 -ium

dichloride

7-4 5-({l-[l-(2,2- 469.2744 469.2750 dimethylpropyl)-3 - methyl-2-oxo-2,3- dihydro-lH-

imidazo [4,5 -b]pyridin-

4-ium-5-yl]piperidin-3- yl}methyl)-2-methyl-

4,5,6,7- tetrahydro[l ,3]thiazolo[

5 ,4-c]pyridin-5 -ium

dichloride

7-5 6-({l-[l-(2,2- 449.3023 449.3028 dimethylpropyl)-3 - methyl-2-oxo-2,3- dihydro-lH-

imidazo [4,5 -b]pyridin-

4-ium-5-yl]piperidin-3- Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed yl}methyl)-5,6,7,8- tetrahydro-1,6- naphthyridin-6-ium

dichloride

1 -(2,2-dimethylpropyl)

3 - methy 1-2-0X0-5 -(3 - {[4-(4H-l,2,4-triazol-3

yl)piperidinium- 1 - yl]methyl}piperidin- 1 -

yl)-2,3-dihydro-lH- imidazo [4,5 -b]pyridin-

4- ium dichloride

Scheme 8

1 - ([2,2-Difluorocyclopropyl]methyl| -3-methyl-5-piperidin-l -yl- 1 ,3-dihydro-2H- imidazo[4,,5-b1pyridin-2-one (8-2)

5-Chloro-l-[(2,2-difluorocyclopropyl)methyll-3-methyl-l,3-dihydro-2H- imidazo Γ4.5 -&1pyridin-2-one (8-1)

5-Chloro-3-methyl-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one (1-3, 516 mg, 2.81 mmol) and cesium carbonate (4.97 g, 15.26 mmol) were added to a round bottom flask and suspended in NMP (4.6 mL) under nitrogen. 1 , 1 -Difluoro-2-(iodomethyl)cyclopropane (481 uL, 5.06 mmol) was added to the suspension and then heated to 100 °C in microwave reactor for 10 min. Following this duration, the reaction was cooled to room temperature and suspended in ethyl acetate and sodium bicarbonate. The suspension was washed with sodium bicarbonate, brine(x5), dried over sodium sulfate, filtered, and concentrated. The mixture was purified using reverse-phase chromatography (5-95% 0.1% TFA in H₂0:acetonitrile) to give 5-chloro-l-[(2,2- difluorocyclopropyl)methyl]-3-methyl-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one (8-1) as an off-white solid.

1 - (r2,2-DifluorocvclopropyHmethyl| -3-methyl-5-piperidin-l -yl- 1 ,3-dihvdro-2H- imidazo[4,5-blpyridin-2-one (8-2)

5-Chloro-l-[(2,2-difluorocyclopropyl)methyl]-3-methyl-l,3-dihydro-2H- imidazo[4,5-£]pyridin-2-one (8-1, 20 mg, 0.073 mmol), potassium phosphate tribasic (31.0 mg, 0.146 mmol), bis(tri-t-butylphosphine)palladium(0) (1.5 mg, 2.92 μιηοΐ), and piperidine (11.0 μί, 0.110 mmol) were added to a 1 mL vial and purged with nitrogen. Anhydrous

dimethylacetamide (88 μΐ,, degassed prior to use) was then added and the resulting suspension was heated to 100 °C for 18 h. Following this duration, the reaction contents were cooled to room temperature, filtered, and washed with acetonitrile. Purification using reverse phase chromatography (10-95%, 0.1% TFA in H₂0: acetonitrile) afforded l-{[2,2- difluorocyclopropyl]methyl}-3-methyl-5-piperidin-l-yl-l,3-dihydro-2H-imidazo[4,5-b]pyridin- 2-one (8-2) as a white solid. MS m/z (M+H): calculated = 323.1678; observed = 323.1676. The following compounds were prepared from 8-1 by a reaction sequence analogous to that illustrated in Scheme 8:

Table 8

Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

8-3 l-{[2,2- 337.1834 337.1830 difluorocyclopropyljmet

hyl}-3-methyl-5-[2- methylpiperidin- 1 -yl] - l,3-dihydro-2H-

imidazo [4,5 -b]pyridin- 2-one

8-4 l- [2,2- 337.1834 337.1824 t

2-one

8-5 l-{[2,2- 337.1834 337.1826 difiuorocyclopropyl]met

hyl}-3-methyl-5-(4- methylpiperidin- 1 -yl)- l,3-dihydro-2H-

imidazo [4,5 -b]pyridin- 2-one Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

imidazo[4,5-b]pyridin-

2- one

8-7 5- 351.1991 351.1984

imidazo[4,5-b]pyridin- 2-one

8-8 l-{[2,2- 309.1521 309.1520 difiuorocyclopropyl]met

hyl}-3-methyl-5- pyrrolidin- 1 -yl- 1,3- dihydro-2H-

imidazo [4,5 -b]pyridin- 2-one Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

8-9 337.1834 337.1834

8-10 371.1678 371.1676

8-11 398.1889 398.1888

Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

8-12 l-{[2,2- 337.1834 337.1836 difluorocyclopropyljmet

hyl}-3-methyl-5-[(2R)- 2-methylpiperidin- 1 -yl]- l,3-dihydro-2H-

imidazo [4,5 -b]pyridin- 2-one

8-13 5-azepan-l-yl-l-{[2,2- 337.1834 337.1836 t

8-14 371.1678 371.1677 propyljmet lin- 1 (2H)- l,3-

imidazo [4,5 -b]pyridin- 2-one Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

8-15 -azocan- 1 -yl- 1 - { [2,2- 351.1991 351.1993

/ t

F F

-one

8-17 486.2311 486.2323

8-18 449.5 450.4

Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed imidazo[4,5-£]pyridin- 5-yl}-2,5- diazabicyclo[2.2.2]octa ne-2-carboxylate

8-19 ethyl-l-(l-{[2,2- 351.1889 351.1891 difluorocyclopropyl]met

hyl}-3-methyl-2-oxo

2,3-dihydro-lH

imidazo [4,5 -b]pyridin- 5 -y l)pip eridine-2 -

carboxylate

Scheme 9

1 - {[2,2-Difluoro- 1 -methylcyclopropyl]methyl} -5-[2-ethylpiperidin- 1 -yl]-3- methyl-1 ,3-dihydro-2H-imidazo[4,5-b1pyridin-2-one (9-3) 5 -Chloro-3 -methyl- 1 -(2-methylprop-2-en- 1 -yl)- 1 ,3-dihydro-2H-imidazo[4,5- &1pyridin-2-one (9-1)

5-Chloro-3-methyl-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one (1-3, 20.18 g, 110 mmol) and cesium carbonate (107 g, 330 mmol) were added to NMP (300 mL). To this was cautiously added 3-bromo-2-methylprop-l-ene (14.84 g, 110 mmol) and the resulting mixture was stirred at RT for 2 h. The dark solution was concentrated and re-dissolved in ethyl acetate (200 mL) followed by washing with saturated sodium bicarbonate (2 x 100 mL) and brine (1 x 100 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated.

Purification by normal-phase HPLC gave 5 -chloro-3 -methyl- 1 -(2 -methylprop-2-en-l-yl)- 1 ,3- dihydro-2H-imidazo[4,5-£]pyridin-2-one (9-1) as a yellow solid.

5-Chloro-l-[(2,2-difluoro-l-methylcyclopropyl)methyll-3-methyl-l,3-dihydro- 2H-imidazor4,5-&1pyridin-2-one (9-2)

5 -Chloro-3 -methyl- 1 -(2-methylprop-2-en- 1 -yl)- 1 ,3-dihydro-2H-imidazo[4,5- £]pyridin-2-one (9-1, 5 g, 21.04 mmol) and sodium chloro(difluoro)acetate (32.1 g, 210 mmol) were heated neat to 200 °C for 1 h. The dark residue was re-dissolved in ethyl acetate (200 mL) followed by washing with saturated sodium bicarbonate (2 x 100 mL) and brine (1 x 100 mL).. The organic phase was dried over sodium sulfate, filtered, and concentrated. Purification by normal-phase HPLC gave5-chloro-l -[(2,2-difluoro- 1 -methylcyclopropyl)methyl] -3 -methyl- 1 ,3- dihydro-2H-imidazo[4,5-£]pyridin-2-one (9-2) was afforded as a white solid.

1 - ([2,2-Difluoro- 1 -methylcyclopropyl]methyl| -5-[2-ethylpiperidin- 1 -yl]-3- methyl-1 ,3-dihydro-2H-imidazor4,5-b1pyridin-2-one (9-3)

5-Chloro-l-[(2,2-difluoro-l-methylcyclopropyl)methyl]-3-methyl-l,3-dihydro- 2H-imidazo[4,5-£]pyridin-2-one (9-2, 20 mg, 0.070 mmol), potassium phosphate tribasic (29.5 mg, 0.139 mmol), bis(tri-t-butylphosphine)palladium(0) (1.4 mg, 2.78 umol), and 2-ethyl piperidine (14 μί, 0.104 mmol) were added to a 1 mL vial and purged with nitrogen.

Anhydrous dimethylacetamide (84 μί, degassed prior to use) was then added and the resulting suspension was heated to 100 °C for 18 h. Following this duration, the reaction contents were cooled to room temperature, filtered, and washed with acetonitrile. Purification using reverse phase chromatography (10-95%, 0.1% TFA in H₂0: acetonitrile) afforded 1- {[2,2-difluoro- 1- methylcyclopropyl]methyl} -5-[2-ethylpiperidin- 1 -yl]-3-methyl- 1 ,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one (9-3) as a white solid. MS m/z (M+H): calculated = 365.2147; observed = 365.2154. The following compounds were prepared from 9-2 by a reaction sequence analogous to that illustrated in Scheme 9:

Table 9

Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

9-4 tert-butyl {[l-(l-{[2,2- 465.2551 466.2626 difluoro-1- methylcyclopropyl]meth

yl}-3-methyl-2-oxo-2,3-

dihydro-lH- imidazo [4,5 -b]pyridin-

5-yl)piperidin-3- yljmethyl} carbamate

9-5 tert-butyl 5-{l-[(2,2- 463.5 463.4 difluoro-1- methylcyclopropyl)met

hyl]-3-methyl-2-oxo-

2,3-dihydro-lH-

imidazo[4,5-£]pyridin-

5-yl}-2,5- diazabicyclo[2.2.2]octa

ne-2-carboxylate

9-6 tert-butyl [l-(l-{[2,2- 499.2395 500.2474 difluoro-1- methylcyclopropyl]meth

yl}-3-methyl-2-oxo-2,3- dihydro-lH-

imidazo [4,5 -b]pyridin-

5-yl)-l,2,3,4- tetrahydroquinolin-3 - yl] carbamate

Scheme 10

N- { 1 -[1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- lH-imidazo[4,5- blpyridin-5-yll-l,2,3,4-tetrahydroquinolin-3-yl|benzamide (10-3) tert-Butyl ( 1 -[ 1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- 1H- imidazor4,5-b1pyridin-5-yl1-l, 2, 3,4-tetrahvdroquinolin-3-yl| carbamate (10-1)

Anhydrous dimethylacetamide (2.4 mL, degassed prior to use) was added to a mixture of 5-chloro-l-(2,2-dimethylpropyl)-3-methyl-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2- one (1-4, 500 mg, 1.971 mmol), potassium phosphate tribasic (837 mg, 3.94 mmol), bis(tri-t- butylphosphine)palladium(O) (40.3 mg, 0.079 mmol), and tert-butyl- 1,2,3, 4-tetrahydroquino lin- 3-yl)carbamate (489 mg, 1.971 mmol). The resulting suspension was heated to 100 °C for 18 h. Following this duration, the reaction contents were cooled to room temperature, filtered, and washed with acetonitrile. Purification using normal-phase chromatography (40% EtOAc in hexane) afforded tert-butyl {l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH- imidazo[4,5-b]pyridin-5-yl]-l,2,3,4-tetrahydroquinolin-3-yl}carbamate (10-1) as a white solid. MS m/z (Μ+Η): calculated = 466.2813; observed = 466.2823.

5-Γ3 - Amino-3 ,4-dihydroquinolin- 1 (2H)-yl1 - 1 -(2,2-dimethylpropyl)-3 -methyl- 1,3- dihydro-2H-imidazor4,5-b1pyridin-2-one (10-2) tert-Butyl { 1 -[ 1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- 1H- imidazo[4,5-b]pyridin-5-yl]-l,2,3,4-tetrahydroquinolin-3-yl}carbamate (10-1, 667 mg, 1.43 mmol) was added to a mixture of dichloromethane (6.1 mL) and trifluoro acetic acid (1.1 mL) at room temperature. After stirring for 18 h, the solvent was removed in vacuo. The resulting residue was then diluted with ethyl acetate (15 mL) and washed sequentially with saturated sodium bicarbonate (2 x 10 mL), water (1 x 10 mL) and brine (1 x 10 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to give 5-[3-amino-3,4- dihydroquinolin-1 (2H)-yl]- 1 -(2,2-dimethylpropyl)-3-methyl- 1 ,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one (10-2) as a white solid. The resulting material was carried on without further purification. MS m/z (M+H): calculated = 366.2288; observed = 366.2294.

N- ( 1 -Γ 1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihvdro- lH-imidazo[4,5- b1pyridin-5-yl1-l,2,3,4-tetrahvdroquinolin-3-yl|benzamide (10-3)

5 - [3 - Amino-3 ,4-dihydroquinolin- 1 (2H)-yl] - 1 -(2,2-dimethylpropyl)-3 -methyl- 1,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one (10-2, 30 mg, 0.082 mmol) was added to anhydrous dimethylformamide (1 mL). Benzoic acid (11.0 mg, 0.09 mmol), EDC (15.74 mg, 0.082 mmol), HOBT (12.57 mg, 0.082 mmol) and triethylamine (23

0.164 mmol) were added sequentially and the resulting reaction mixture was allowed to stir at room temperature for 18 h. Following this duration, the contents were filtered and the resulting filtrate was purified via reverse-phase HPLC (10-100%, 0.1% TFA in H₂0:acetonitrile) to give N-{l-[l-(2,2-dimethylpropyl)-3- methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl]-l,2,3,4-tetrahydroquinolin-3- yl}benzamide (10-3) as a white solid. MS m/z (M+H): calculated = 470.2551; observed = 470.2553.

The following compounds were prepared from 10-2 by a reaction sequence analogous to that illustrated in Scheme 10:

Table 10

Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

10-4 434.2551 434.2556

-

tetrahydroquinolin-3 - yl} cyclopropanecarboxa

mide

448.2707 448.2714

-

tetrahydroquinolin-3 - yl} cyclobutanecarboxa

mide 462.2864 462.2871

-

tetrahydroquinolin-3 - yl} cyclopentanecarboxa

mide Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

462.2111 462.2120

-

tetrahydroquinolin-3 - yl}-2,2,2- trifluoroacetamide 450.2864 450.2872

-

tetrahydroquinolin-3 - yi}-2,2- dimethy lprop anamide 408.2394 408.2403

-

tetrahydroquinolin-3 - Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed yl}acetamide -10 476.3020 476.3030

-

tetrahydroquinolin-3 - yl}cyclohexane- carboxamide -11 466.2813 466.2823

tetrahydroquinolin-3 - yl} carbamate -12 466.2813 466.2823

-

tetrahydroquinolin-3 - yl} carbamate Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

484.2707 484.2707

-

tetrahydroquinolin-3 - yl} -4-methylbenzamide 472.2456 472.2462

-

tetrahydroquinolin-3 - yl}pyrazine-2- carboxamide

528.2329 528.2317

-

tetrahydroquinolin-3 - yl} -3-(trifluoromethyl)- Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed lH-pyrazole-5- carboxamide

10-16 474.2612 474.2601

-

tetrahydroquinolin-3 - yl}-l -methyl- 1H- imidazole-4- carboxamide

10-17 472.2456 472.2448

tetrahydroquinolin-3 - y 1 } pyrimidine-5 - carboxamide

10-18 N-{l-[l-(2,2- 477.2067 477.2056 dimethylpropyl)-3 - methyl-2-oxo-2,3- dihydro-lH- imidazo [4,5 -b]pyridin-

5-yl]-l,2,3,4- Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed tetrahydroquinolin-3 - yl}-l ,3-thiazole-4- carboxamide 471.2503 471.2489

tetrahydroquinolin-3 - yl}pyridine-3- carboxamide 471.2503 471.2490

tetrahydroquinolin-3 - yl}pyridine-4- carboxamide

N- { l-[l-(2,2- 460.2456 460.2450 dimethylpropyl)-3 - methyl-2-oxo-2,3- dihydro-lH- imidazo [4,5 -b]pyridin-

5-yl]-l ,2,3,4- Name MS m/z MS m/z

(M+H): (M+H): calc'd observed tetrahydroquinolin-3 - yl} - 1 H-pyrazole-5- carboxamide 460.2456 460.2445

-

tetrahydroquinolin-3 - yl} - 1 H-imidazole-2- carboxamide 460.2456 460.2449

tetrahydroquinolin-3 - yl} - 1 H-pyrazole-4- carboxamide N-{l-[l-(2,2- 474.2612 474.2599 dimethylpropyl)-3- methyl-2-oxo-2,3- dihydro-lH- imidazo[4,5-b]pyridin-

5-yl]-l,2,3,4- Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed tetrahydroquinolin-3 - yl} -2-( 1 H-pyrazol- 1 - yl)acetamide

Scheme 11

5-[3-(Benzylamino)-3,4-dihydroquinolin-l(2H)-yll-l-(2,2-dimethylpropyl)-3- methyl-l,3-dihvdro-2H-imidazor4,5-b1pyridin-2-one (11-1)

5 - [3 - Amino-3 ,4-dihydroquinolin- 1 (2H)-yl] - 1 -(2,2-dimethylpropyl)-3 -methyl- 1,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one (10-2, 30 mg, 0.082 mmol), benzaldehyde (8.71 mg, 0.082 mmol), and acetic acid (9.40 μί, 0.164 mmol) were added to anhydrous NMP (1 mL) and the resulting solution was stirred at room temperature for 30 min. Following this duration, sodium triacetoxyborohydride (20.9 mg, 0.099 mmol) was added. The resulting reaction mixture was stirred at room temperature for an additional 18 h. The contents were then filtered and purified by reverse-phase chromatography to give 5-[3-(benzylamino)-3,4-dihydroquinolin- 1 (2H)-yl]- 1 -(2,2-dimethylpropyl)-3-methyl-l ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (11-1) as a white solid. MS m/z (M+H): calculated = 456.2758; observed = 456.2759.

The following compounds were prepared from 10-2 by a reaction sequence analogous to that illustrated in Scheme 11 : Table 1 1

Cmp Structure Name MS m/z MS m z

(M+H): (M+H): calc'd observed

11-3 436.3071 436.3069 yl)-5 - [3 - yl)amino

quinolin- l(2H)-yl]-3-methyl- l,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one

11-4 554.3350 554.3363 4-

methyl- 1 ,3-dihydro- 2H-imidazo[4,5- b]pyridin-2-one

Scheme 12

N- { 1 -[1 -(2,2-Dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- lH-imidazo[4,5- b1pyridin-5-yl1-l,23^-tetrahvdroquinolin-3-yl|-4-methylbenzene-sulfonamide (12-1)

5 - [3 - Amino-3 ,4-dihydroquinolin- 1 (2H)-yl] - 1 -(2,2-dimethylpropyl)-3 -methyl- 1,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one (10-2, 30 mg, 0.082 mmol) was added to anhydrous DCM (1 mL) and treated with triethylamine (23 μί, 0.164 mmol) and 4-methylbenzenesulfonyl chloride (17.21 mg, 0.090 mmol) sequentially. The resulting mixture was stirred at room temperature for 18 h and concentrated in vacuo. Purification by reverse-phase HPLC

chromatography provided N- { 1 -[ 1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- 1H- imidazo[4,5-b]pyridin-5-yl]-l,2,3,4-tetrahydroquinolin-3-yl}-4-methylbenzene-sulfonamide (12- 1) as a white solid. MS m/z (Μ+Η): calculated = 520.2377; observed = 520.2371.

The following compounds were prepared from 10-2 by a reaction sequence analogous to that illustrated in Scheme 12:

Table 12

Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

12-2 444.2064 444.2055

-

tetrahydroquinolin-3 - y 1 } methanesulfonamide Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

12-3 498.1781 498.1775

-

tetrahydroquinolin-3 - yl}-l,l,l- trifluoromethanesulfona

mide

Scheme 13

Ethyl- ( 1 -[ 1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5- b1pyridin-5-yl1-l,2,3,4-tetrahvdroquinolin-3-yl| carbamate (13-1)

5 - [3 - Amino-3 ,4-dihydroquinolin- 1 (2H)-yl] - 1 -(2,2-dimethylpropyl)-3 -methyl- 1,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one (10-2, 30 mg, 0.082 mmol) was added to anhydrous DMF (1 mL) and treated with triethylamine (23 μί, 0.164 mmol) and isobutylchloroformate (12 μΐ_^, 0.090 mmol) sequentially. The resulting mixture was stirred at room temperature for 18 h and subsequently purified by reverse-phase HPLC chromatography to provide ethyl- { 1 -[ 1 -(2,2- dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl]-l,2,3,4- tetrahydroquinolin-3-yl} carbamate (13-1) as a white solid. MS m z (M+H): calculated = 438.2500; observed = 438.2496. Scheme 14

2-({ 1 -Γ 1 -(2,2-Dimethylpropyl)-3-methyl-2-oxo-2,3-dihvdro- lH-imidazo[4,5- &lpyridin-5-yll-l,23^-tetrahydroquinolin-3-yl|amino)pyridine-3-carbonitrile (14-1)

5 - [3 - Amino-3 ,4-dihydroquinolin- 1 (2H)-yl] - 1 -(2,2-dimethylpropyl)-3 -methyl- 1,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one (10-2, 30 mg, 0.082 mmol) and cesium carbonate (80 mg, 0.246 mmol) were added to anhydrous THF (820 μί). To this reaction mixture was added 2-chloro-3-cyano-pyridine (11.4 mg, 0.082 mmol) and the contents were stirred for 18 h at room temperature. Following this duration, the solvent was removed in vacuo and the resulting residue was partitioned between ethyl acetate (5 mL) and water (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 3 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give an orange residue. Purification via reverse-phase HPLC (10-100%, 0.1% TFA in H₂0:acetonitrile) yielded 2-({ 1 -[ 1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- lH-imidazo[4,5-£]pyridin-5-yl]- l,2,3,4-tetrahydroquinolin-3-yl}amino)pyridine-3-carbonitrile (14-1) as a white solid. MS m/z (Μ+Η): calculated = 468.2506; observed = 468.2496.

Scheme 15

l-(2,2-Dimethylpropyl)-3-methyl-5-[5-(pheny

diazabicyclor2.2.21oct-2-vH-l ,3-dihydro-2H-imidazor4,5-b1pyridin-2-one (15-3) fert-Butyl-5-Γ 1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- 1H- imidazor4,5-b1pyridin-5-yl1-2,5-diazabicvclor2.2.21octane-2-carboxylate (15-1)

Anhydrous dimethylacetamide (85 mL, degassed prior to use) was added to a mixture of 5-chloro-l-(2,2-dimethylpropyl)-3-methyl-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2- one (1-4, 17.89 g, 70.5 mmol), potassium phosphate tribasic (30.1 g, 142 mmol), bis(tri-t- butylphosphine)palladium(O) (1.45 g, 2.84 mmol), and tert-butyl-2,5-diazabicyclo[2.2.2]octane- 2-carboxylate (15.81 g, 74.5 mmol). The resulting suspension was heated to 100 °C for 18 h. Following this duration, the reaction contents were cooled to room temperature, filtered, and washed with acetonitrile. Purification using normal-phase chromatography (40% EtOAc in hexane) afforded tert-butyl-5-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH- imidazo[4,5-b]pyridin-5-yl]-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (15-1) as a white solid. MS m/z (M+H): calculated = 430.2813; observed = 430.2807.

5-(2,5-Diazabicyclor2.2.21oct-2-yl)-l-(2,2-dimethylpropyl)-3-methyl-l,3- dihydro-2-imidazo[4,5-&lpyridin-2-one (15-2)

tert-Butyl-5-[ 1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- 1H- imidazo[4,5-b]pyridin-5-yl]-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (15-1, 7.2 g, 16.76 mmol) was added to a mixture of dichloromethane (137 mL) and trifluoroacetic acid (30.5 mL) at room temperature. After stirring for 18 h, the solvent was removed in vacuo. The resulting residue was then diluted with ethyl acetate (200 mL) and washed sequentially with saturated sodium bicarbonate (2 x 100 mL), water (1 x 100 mL) and brine (1 x 100 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to give 5-(2,5- diazabicyclo[2.2.2]oct-2-yl)-l -(2,2-dimethylpropyl)-3-methyl-l ,3-dihydro-2-imidazo[4,5- ¾]pyridin-2-one (15-2) as a white solid. This material was carried on without further

purification.

l-(2,2-Dimethylpropyl)-3-methyl-5-[5-(phenylcarbonyl)-2,5- diazabicvclor2.2.21oct-2-yl1-l,3-dihvdro-2H-imidazor4,5-b1pyridin-2-one (15-3)

5-(2,5-Diazabicyclo[2.2.2]oct-2-yl)-l-(2,2-dimethylpropyl)-3-methyl-l,3- dihydro-2-imidazo[4,5-£]pyridin-2-one (15-2, 1.5 g, 4.55 mmol) was subsequently added to anhydrous dimethylformamide (45.5 mL). Triethylamine (1.27 mL, 9.11 mmol) and benzoyl chloride (0.58 mL, 5.01 mmol) were then added, and the resulting solution was stirred at room temperature for 3 h. Following this duration, the contents were filtered and the resulting filtrate was purified via reverse-phase HPLC (10-100%, 0.1% TFA in H₂0:acetonitrile) to give l-(2,2- dimethylpropyl)-3-methyl-5-[5-(phenylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]-l ,3-dihydro- 2H-imidazo[4,5-b]pyridin-2-one (15-3) as a white solid. MS m/z (M+H): calculated = 434.2551; observed = 434.2550.

Scheme 16

Ethyl 5-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5- &1pyridin-5-yl1-2,5-diazabicvclor2.2.21octane-2-carboxylate (16-1)

5-(2,5-Diazabicyclo[2.2.2]oct-2-yl)-l-(2,2-dimethylpropyl)-3-methyl-l,3- dihydro-2H-imidazo[4,5-£]pyridin-2-one (15-2, 30 mg, 0.091 mmol) was added to anhydrous DMF (1 mL) and treated with triethylamine (25 μί, 0.182 mmol) and ethylchloroformate (11 mg, 0.100 mmol) sequentially. The resulting mixture was stirred at room temperature for 18 h and subsequently purified by reverse-phase HPLC chromatography to provide ethyl 5-[l-(2,2- dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-¾]pyridin-5-yl]-2,5- diazabicyclo[2.2.2]octane-2-carboxylate (16-1) as a white solid. MS m/z (Μ+Η): calculated = 402.2500; observed = 402.2496.

The following compounds were prepared from 15-2 by a reaction sequence analogous to that illustrated in Scheme 16:

Table 16

Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

16-2 2-fluoroethyl 5-[l- 420.2405 420.2405

(2,2-dimethylpropyl)- 3-methyl-2-oxo-2,3- dihydro-lH- imidazo[4,5-

£]pyridin-5 -y 1] -2 , 5 - diazabicyclo[2.2.2]oct

ane-2-carboxylate

16-3 phenyl 5-[l -(2,2- 450.2500 450.2501 dimethylpropyl)-3 - methyl-2-oxo-2,3

dihydro-lH- imidazo[4,5-

£]pyridin-5 -y 1] -2 , 5 - diazabicyclo[2.2.2]oct

ane-2-carboxylate

16-4 propyl 5-[l -(2,2- 416.2656 416.2656 dimethylpropyl)-3- methyl-2-oxo-2,3- dihydro-lH- imidazo[4,5-

£]pyridin-5 -y 1] -2 , 5 - diazabicyclo[2.2.2]oct

ane-2-carboxylate Scheme 17

l-(2,2-Dimethylpropyl)-3-methyl-5-(5-[(4-methylphenyl)sulfonyll-2,5- diazabicvclor2.2.21oct-2-yl|-l,3-dihvdro-2H-imidazor4,5-&1pyridin-2-one (17-1)

5-(2,5-Diazabicyclo[2.2.2]oct-2-yl)-l-(2,2-dimethylpropyl)-3-methyl-l,3- dihydro-2H-imidazo[4,5-£]pyridin-2-one (15-2, 30 mg, 0.091 mmol) was added to anhydrous DCM (1 mL) and treated with triethylamine (25 μί, 0.182 mmol) and 4-methylbenzenesulfonyl chloride (19.08 mg, 0.100 mmol) sequentially. The resulting mixture was stirred at room temperature for 18 h and concentrated in vacuo. Purification by reverse-phase HPLC

chromatography provided 1 -(2,2-dimethylpropyl)-3-methyl-5- {5-[(4-methylphenyl)sulfonyl]- 2,5-diazabicyclo[2.2.2]oct-2-yl}-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one (17-1) as a white solid. MS m/z (Μ+Η): calculated = 483.6261; observed = 483.6382.

Scheme 18

l-(2,2-Dimethylpropyl)-5-r5-(isoxazol-3-ylcarbonyl)-2,5-diazabicvclo-r2.2.21oct- 2-yl1-3-methyl-l,3-dihvdro-2H-imidazor4,5-¾1pyridin-2-one (18-1)

5-(2,5-Diazabicyclo[2.2.2]oct-2-yl)-l-(2,2-dimethylpropyl)-3-methyl-l,3- dihydro-2-imidazo[4,5-£]pyridin-2-one (15-2, 35 mg, 0.106 mmol) was added to anhydrous dimethylformamide (1 mL). Isoxazole-3-carboxylic acid (12.0 mg, 0.106 mmol), EDC (20.37 mg, 0.106 mmol), ΗΟΒΤ (16.27 mg, 0.106 mmol) and triethylamine (30

0.212 mmol) were added sequentially and the resulting reaction mixture was allowed to stir at room temperature for 18 h. Following this duration, the contents were filtered and the resulting filtrate was purified via reverse-phase HPLC (10-100%, 0.1% TFA in H₂0:acetonitrile) to give l-(2,2- dimethylpropyl)-5-[5-(isoxazol-3-ylcarbonyl)-2,5-diazabicyclo-[2.2.2]oct-2-yl]-3-methyl-l,3- dihydro-2H-imidazo[4,5-¾]pyridin-2-one (18-1) as a white solid. MS m/z (Μ+Η): calculated = 425.2296; observed = 425.2301.

The following compounds were prepared from 15-2 by a reaction sequence analogous to that illustrated in Scheme 18:

Table 18

Cmp Structure Name MS m z MS m/z

(M+H): (M+H): calc'd observed

18-2 l-(2,2- 436.2456 436.2451 dimethylpropyl)-3 - methyl-5-[5- (pyrazin-2- ylcarbonyl)-2,5-

diazabicyclo [2.2.2]o

ct-2-yl]- 1 ,3-dihydro- 2H-imidazo[4,5- b]pyridin-2-one

424.2456 424.2446 dimethylpropyl)-5 - [5-(lH-imidazol-2- ylcarbonyl)-2,5- diazabicyclo[2.2.2]o

ct-2-yl]-3-methyl- l,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

18-4 l-(2,2- 424.2456 424.2446 dimethylpropyl)-5 - [5-(lH-imidazol-2- ylcarbonyl)-2,5- diazabicyclo[2.2.2]o

ct-2-yl]-3-methyl- l,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one

488.2268 488.2273

diazabicyclo [2.2.2]o

ct-2-yl}-l,3- dihydro-2H- imidazo[4,5- b]pyridin-2-one

452.2456 452.2457

ct-2-yl} -3 -methyl- l,3-dihydro-2H- imidazo[4,5- Cmp Structure Name MS m/z MS m z

(M+H): (M+H): calc'd observed b]pyridin-2-one

18-7 452.2456 452.2456

ct-2-yl} -3 -methyl- l,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one

18-8 470.2362 470.2364 2]o

3 - methyl-1 ,3-dihydro-

2H-imidazo[4,5- b]pyridin-2-one

18-9 470.2362 470.236 2]o

3 - Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed methyl-2-oxo-2,3- dihydro-lH- imidazo[4,5- b]pyridin-4-ium

trifluoroacetate -10 468.2161 468.2167

methyl-2-oxo-2,3- dihydro-lH- imidazo[4,5- b]pyridin-4-ium

trifluoroacetate -11 502.1771 502.1776 arb 2]o

3 - methyl-2-oxo-2,3- dihydro-lH- imidazo[4,5- b]pyridin-4-ium

trifluoroacetate Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

18-12 512.1656 512.1663

methyl-2-oxo-2,3- dihydro-lH- imidazo[4,5- b]pyridin-4-ium

trifluoroacetate

18-13 459.2503 459.2498

methyl-2-oxo-2,3- dihydro-lH- imidazo[4,5- b]pyridin-4-ium

trifluoroacetate

18-14 470.2362 470.2363

Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed methyl-2-oxo-2,3- dihydro-lH- imidazo[4,5- b]pyridin-4-ium

trifluoroacetate -15 459.2503 459.2501

methyl-2-oxo-2,3- dihydro-lH- imidazo[4,5- b]pyridin-4-ium

trifluoroacetate -16 459.2503 459.2495

methyl-2-oxo-2,3- dihydro-lH- imidazo[4,5- b]pyridin-4-ium

trifluoroacetate Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

18-17 l-(2,2- 520.233 520.234 dimethylpropyl)-5 -

(5-{[2-fluoro-4-

(trifluoromethyl)phe

ny 1] carbony 1 } -2 , 5 -

diazabicyclo[2.2.2]o

ct-2-yl)-3-methyl-2- oxo-2,3-dihydro- lH-imidazo[4,5- b]pyridin-4-ium

trifluoroacetate

18-18 l-(2,2- 520.233 520.2339 dimethylpropyl)-5 -

(5-{[2-fluoro-5-

(trifluoromethyl)phe

ny 1] carbony 1 } -2 , 5 -

diazabicyclo[2.2.2]o

ct-2-yl)-3-methyl-2- oxo-2,3-dihydro- lH-imidazo[4,5- b]pyridin-4-ium

trifluoroacetate

18-19 486.2067 486.2073 n o

Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed methyl-2-oxo-2,3- dihydro-lH- imidazo[4,5- b]pyridin-4-ium

trifluoroacetate

18-20 483.3078 483.3074 o

methyl-2-oxo-2,3- dihydro-lH- imidazo[4,5- b]pyridin-4-ium

trifluoroacetate

18-21 l-(2,2- 439.2452 439.2454 dimethylpropyl)-3 - methyl-5-{5-[(5- methylisoxazol-3- yl)carbonyl]-2,5-

diazabicyclo [2.2.2]o

ct-2-yl} -2-oxo-2,3- dihydro-lH- imidazo[4,5- b]pyridin-4-ium

trifluoroacetate Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

18-22 l-(2,2- 452.2769 452.2761 dimethylpropyl)-5 -

{5-[(l,3-dimethyl- lH-pyrazol-5- yl)carbonyl]-2,5-

diazabicyclo [2.2.2]o

ct-2-yl}-3-methyl-2- oxo-2,3-dihydro- lH-imidazo[4,5- b]pyridin-4-ium

trifluoroacetate

18-23 l-(2,2- 452.2769 452.2761 dimethylpropyl)-5 -

{5-[(l,5-dimethyl- lH-pyrazol-3- yl)carbonyl]-2,5-

diazabicyclo [2.2.2]o

ct-2-yl}-3-methyl-2- oxo-2,3-dihydro- lH-imidazo[4,5- b]pyridin-4-ium

trifluoroacetate

18-24 l-(2,2- 425.2408 425.2417 dimethylpropyl)-3 - methyl-5-[5-(lH- l,2,3-triazol-4- ylcarbonyl)-2,5-

diazabicyclo [2.2.2]o Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed ct-2-yl]- 1 ,3-dihydro- 2H-imidazo[4,5- b]pyridin-2-one

18-25 l-(2,2- 424.2456 424.2471 dimethylpropyl)-3 - methyl-5-[5-(lH- pyrazol-5- ylcarbonyl)-2,5-

diazabicyclo [2.2.2]o

ct-2-yl]- 1 ,3-dihydro-

2H-imidazo[4,5- b]pyridin-2-one

18-26 l-(2,2- 441.2067 441.2068 dimethylpropyl)-3 - methyl-5-[5-(l,3- thiazol-5- ylcarbonyl)-2,5-

diazabicyclo [2.2.2]o

ct-2-yl]- 1 ,3-dihydro-

2H-imidazo[4,5- b]pyridin-2-one

18-27 l-(2,2- 424.2456 424.2459 dimethylpropyl)-3 - methyl-5-[5-(lH- pyrazol-4- ylcarbonyl)-2,5-

diazabicyclo [2.2.2]o Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed ct-2-yl]- 1 ,3-dihydro-

2H-imidazo[4,5- b]pyridin-2-one

18-28 l-(2,2- 425.2296 425.2297 dimethylpropyl)-3 - methyl-5-[5-(l,3- oxazol-5- ylcarbonyl)-2,5-

diazabicyclo [2.2.2]o

ct-2-yl]- 1 ,3-dihydro- 2H-imidazo[4,5- b]pyridin-2-one

18-29 l-(2,2- 425.2296 425.2295 dimethylpropyl)-5 -

[5-(isoxazol-5- ylcarbonyl)-2,5- diazabicyclo [2.2.2]o

ct-2-yl]-3-methyl- l,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one

18-30 l-(2,2- 424.2456 424.2461 dimethylpropyl)-3 - methyl-5-[5-(lH- pyrazol-5- ylcarbonyl)-2,5-

diazabicyclo [2.2.2]o Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed ct-2-yl]- 1 ,3-dihydro- 2H-imidazo[4,5- b]pyridin-2-one

18-31 l-(2,2- 442.202 442.2018 dimethylpropyl)-3 - methyl-5-[5-(l,2,3- thiadiazol-4- ylcarbonyl)-2,5-

diazabicyclo [2.2.2]o

ct-2-yl]- 1 ,3-dihydro-

2H-imidazo[4,5- b]pyridin-2-one

18-32 l-(2,2- 435.2503 435.2503 dimethylpropyl)-3 - methyl-5-[5-

(pyridin-2- ylcarbonyl)-2,5-

diazabicyclo [2.2.2]o

ct-2-yl]- 1 ,3-dihydro-

2H-imidazo[4,5- b]pyridin-2-one

18-33 l-(2,2- 435.2503 435.2504 dimethylpropyl)-3 - methyl-5-[5-

(pyridin-3- ylcarbonyl)-2,5-

diazabicyclo [2.2.2]o Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed ct-2-yl]- 1 ,3-dihydro-

2H-imidazo[4,5- b]pyridin-2-one

18-34 l-(2,2- 435.2503 435.2502 dimethylpropyl)-3 - methyl-5-[5-

(pyridin-4- ylcarbonyl)-2,5-

diazabicyclo [2.2.2]o

ct-2-yl]- 1 ,3-dihydro-

2H-imidazo[4,5- b]pyridin-2-one

18-35 439.2452 439.2464

o

18-36 460.2456 460.2467

Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed b]pyridin-5-yl]-2,5- diazabicyclo[2.2.2]o

ct-2- yl} carbonyl)pyridin

e-2-carbonitrile

453.2409 453.2417 5 -

2]o

ct-2-yl} -3 -methyl- l,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one

18-38 l-(2,2- 503.2377 503.2392 dimethylpropyl)-3 - methyl-5-(5-{[6- (trifluoromethyl)pyr

idin-3-yl]carbonyl} - 2,5- diazabicyclo [2.2.2]o

ct-2-yl)- 1 ,3-dihydro- 2H-imidazo[4,5- b]pyridin-2-one Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

18-39 5-{5-[(5- 513.1608 513.1633 bromopyridin-3 - yl)carbonyl]-2,5- diazabicyclo [2.2.2]o

c_t-2-yl}-l-(2,2-

dimethylpropyl)-3 - methyl-1 ,3-dihydro- 2H-imidazo[4,5- b]pyridin-2-one l-(2,2- 449.2660 449.2666 dimethylpropyl)-3 - methyl-5-{5-[(6- methy lpyridin-3 - yl)carbonyl]-2,5-

diazabicyclo [2.2.2]o

ct-2-yl}-l,3- dihydro-2H- imidazo[4,5- b]pyridin-2-one

18-41 l-(2,2- 438.2612 438.2613 dimethylpropyl)-3- methyl-5-{5-[(l- methyl- 1H- imidazol-2-

yl)carbonyl]-2,5- diazabicyclo [2.2.2]o

ct-2-yl}-l,3- dihydro-2H- Structure Name MS m/z MS m z

(M+H): (M+H): calc'd observed imidazo[4,5- b]pyridin-2-one -42 l-(2,2- 456.2176 456.2180 dimethylpropyl)-3 - methyl- methyl-1,3,4

thiadiazol-2-

yl)carbonyl]-2,5- diazabicyclo [2.2.2]o

ct-2-yl}-l,3- dihydro-2H- imidazo[4,5- b]pyridin-2-one -43 l-(2,2- 441.2067 441.2072 dimethylpropyl)-5- [5-<iso<hiazol-5- ylcarbonyl)-2,5- diazabicyclo[2.2.2]o

ct-2-yl]-3-methyl- l,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

18-44 l-(2,2- 441.2067 441.2077 dimethylpropyl)-5 -

[5-(isothiazol-4- ylcarbonyl)-2,5- diazabicyclo [2.2.2]o

ct-2-yl]-3-methyl- l,3-dihydro-2H- imidazo[4,5- b]pyridin-2-one

18-45 l-(2,2- 455.576 456.2 dimethylpropyl)-3 - (LRMS) methyl-5-{5-[(5- methyl- 1,2,3 - thiadiazol-4-

yl)carbonyl]-2,5- diazabicyclo [2.2.2]o

ct-2-yl}-l,3- dihydro-2H- imidazo[4,5- b]pyridin-2-one

18-46 l-(2,2- 425.2296 425.2304 dimethylpropyl)-3 - methyl-5-[5-(l,3- oxazol-2- ylcarbonyl)-2,5-

diazabicyclo [2.2.2]o

ct-2-yl]- 1 ,3-dihydro-

2H-imidazo[4,5- Cmp Structure Name MS m/z MS m z

(M+H): (M+H): calc'd observed b]pyridin-2-one

l-(2,2- 501.2609 501.2630 dimethylpropyl)-3 - methyl-5-{5-[(5- phenylisoxazol-3- yl)carbonyl]-2,5-

diazabicyclo [2.2.2]o

ct-2-yl}-l,3- dihydro-2H- imidazo[4,5- b]pyridin-2-one 467.2765 467.2782

diazabicyclo [2.2.2]o

ct-2-yl)- 1 ,3-dihydro- 2H-imidazo[4,5- b]pyridin-2-one Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

18-49 519.1172 519.1191 o

methyl-1 ,3-dihydro- 2H-imidazo[4,5- b]pyridin-2-one

18-50 l-(2,2- 438.2612 438.2619 dimethylpropyl)-3 - methyl-5-{5-[(4- methyl-lH- imidazol-2-

yl)carbonyl]-2,5- diazabicyclo [2.2.2]o

ct-2-yl}-l,3- dihydro-2H- imidazo[4,5- b]pyridin-2-one

18-51 l-(2,2- 425.2408 425.2419 dimethylpropyl)-3 - methyl-5-[5-(lH- l,2,4-triazol-5- ylcarbonyl)-2,5-

diazabicyclo [2.2.2]o

ct-2-yl]- 1 ,3-dihydro-

2H-imidazo[4,5- Cmp Structure Name MS m/z MS m z

(M+H): (M+H): calc'd observed b]pyridin-2-one

509.1288 509.1308 o

dimethylpropyl)-3 - methyl-1 ,3-dihydro- 2H-imidazo[4,5- b]pyridin-2-one

5-{5-[(3- 464.2769 464.2786 cyclopropyl-lH- pyrazol-5- yl)carbonyl]-2,5- diazabicyclo [2.2.2]o

c_t-2-yl}-l-(2,2- dimethylpropyl)-3 - methyl-1 , 3-dihydro- 2H-imidazo[4,5- b]pyridin-2-one

466.2925 466.2940 dimethylpropyl)-3- methyl-5-(5-{[3-(l- methylethyl)-lH- pyrazol-5-

yl]carbonyl}-2,5- Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed diazabicyclo [2.2.2]o

ct-2-yl)- 1 ,3-dihydro- 2H-imidazo[4,5- b]pyridin-2-one

18-55 l-(2,2- 439.2564 439.2580 dimethylpropyl)-3 - methyl-5-{5-[(3- methyl- 1H- 1,2,4- triazol-5-

yl)carbonyl]-2,5- diazabicyclo [2.2.2]o

ct-2-yl}-l,3- dihydro-2H- imidazo[4,5- b]pyridin-2-one

18-56 l-(2,2- 442.2020 442.2030 dimethylpropyl)-3 - methyl-5-[5-(l,2,5- thiadiazol-3- ylcarbonyl)-2,5-

diazabicyclo [2.2.2]o

ct-2-yl]- 1 ,3-dihydro-

2H-imidazo[4,5- b]pyridin-2-one Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

18-57 l-(2,2- 492.2329 492.2348 dimethylpropyl)-3 - methyl-5-(5-{[3-

(trifluoromethyl)- lH-pyrazol-5-

yl]carbonyl}-2,5- diazabicyclo [2.2.2]o

ct-2-yl)- 1 ,3-dihydro-

2H-imidazo[4,5- b]pyridin-2-one

^■58* 442.202 442.2018

o

ct-2-yl]- 1 ,3-dihydro- 2H-imidazo[4,5- £]pyridin-2-one

^■59* 442.202 442.2018

o

ct-2-yl]- 1 ,3-dihydro- 2H-imidazo[4,5- £]pyridin-2-one Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

18-60* 425.2296 425.2301

5 -

2]o

ct-2-yl]- 1 ,3-dihydro- 2H-imidazo[4,5- £]pyridin-2-one

18-61* l-(2,2- 425.2296 425.2301 dimethylpropyl)-5 -

(isoxazol-3- ylcarbonyl)-2,5-

diazabicyclo [2.2.2]o

ct-2-yl]- 1 ,3-dihydro- 2H-imidazo[4,5- ¾]pyridin-2-one

18-62* l-(2,2- 435.2503 435.2504 dimethylpropyl)-5 - [(lR,4R)-5-(pyridin- 3-ylcarbonyl)-2,5- diazabicyclo [2.2.2]o

ct-2-yl]- 1 ,3-dihydro- 2H-imidazo[4,5- Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

£]pyridin-2-one

435.2503 435.2504 dimethylpropyl)-5 -

[(15,4S)-5-(pyridin-

3-ylcarbonyl)-2,5- diazabicyclo [2.2.2]o

ct-2-yl]- 1 ,3-dihydro-

2H-imidazo[4,5-

£]pyridin-2-one

* prepared via chiral chromatographic separation of racemic counterpart

Scheme 19

2-{5-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo-[4,5- &1pyridin-5-yl1-2,5-diazabicvclor2.2.21oct-2-yl|pyridine-3-carbonitrile (19-1)

5-(2,5-diazabicyclo[2.2.2]oct-2-yl)-l-(2,2-dimethylpropyl)-3-methyl-l,3-dihydro- 2-imidazo[4,5-¾]pyridin-2-one (15-2, 30 mg, 0.091 mmol) and cesium carbonate (89 mg, 0.273 mmol) were added to anhydrous THF (911 μί). To this reaction mixture was added 2-chloro-3- cyano-pyridine (12.6 mg, 0.091 mmol) and the contents were stirred for 18 h at room

temperature. Following this duration, the solvent was removed in vacuo and the resulting residue was partitioned between ethyl acetate (5 mL) and water (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 3 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give an orange residue. Purification via reverse-phase HPLC (10-100%, 0.1% TFA in H₂0:acetonitrile) yielded 2-{5-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo-[4,5-¾]pyridin-5-yl]-2,5- diazabicyclo[2.2.2]oct-2-yl}pyridine-3-carbonitrile (19-1) as a white solid. MS m/z (Μ+Η): calculated = 432.2506; observed = 432.2515.

The following compounds were prepared from 15-2 by a reaction sequence analogous to that illustrated in Scheme 19: Table 19

Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

19-2 1 -(2,2-dimethylpropyl)- 408.2506 408.25

3-methyl-5-(5- pyrimidin-2-y 1-2 , 5 - diazabicyclo[2.2.2]oct-

2-yl)-l,3-dihydro-2H-

imidazo [4,5 -b]pyridin-

2-one

19-3 432.2506 432.25

carbonitrile Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

19-4 432.2506 432.2499

2-yl}pyridine-3- carbonitrile

19-5 432.2506 432.2499

carbonitrile

19-6 432.2506 432.2495

2-yl}pyridine-3- carbonitrile Scheme 20

l-(2,2-Dimethylpropyl)-3-methyl-5-(5-phenyl-2,5-diazabicyclo[2.2.21oct-2-yl)- 1 ,3-dihvdro-2H-imidazor4,5-&1pyridin-2-one (20-1)

5-(2,5-Diazabicyclo[2.2.2]oct-2-yl)-l-(2,2-dimethylpropyl)-3-methyl-l,3- dihydro-2-imidazo[4,5-£]pyridin-2-one (15-2, 35 mg, 0.106 mmol) in anhydrous, degassed DMA (128 μί) was treated with bis(tri-t-butylphosphine)palladium(0) (2.17 g, 4.25 μιηοΐ), potassium phosphate (45.1 mg, 0.212 mmol), and bromobenzene (16.68 mg, 0.106 mmol). The resulting reaction mixture was warmed to 100 °C and stirred for 18 h. The resulting contents were diluted with acetonitrile, filtered, and purified by reverse-phase chromatography (0-100% 0.1% TFA in H₂0: acetonitrile) to give to give l-(2,2-dimethylpropyl)-3-methyl-5-(5-phenyl-2,5- diazabicyclo[2.2.2]oct-2-yl)-l ,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one (20-1) as a white solid. MS m/z (Μ+Η): calculated = 406.2601; observed = 406.2591.

Scheme 21

l-(2,2-Dimethylpropyl)-3-methyl-5-[5-(lH-pyrazol-5-ylmethyl)-2,5- diazabicyclo[2.2.2loct-2-yll-l,3-dihydro-2H-imidazo[4,5-blpyridin-2-one (21-1)

5-(2,5-diazabicyclo[2.2.2]oct-2-yl)-l-(2,2-dimethylpropyl)-3-methyl-l,3-dihydro- 2-imidazo[4,5-£]pyridin-2-one (15-2, 30 mg, 0.091 mmol), lH-pyrazole-5-carbaldehyde (9.63 mg, 0.100 mmol), and acetic acid (10.4 μΐ,, 0.182 mmol) were added to anhydrous NMP (1 mL) and the resulting solution was stirred at room temperature for 30 min. Following this duration, sodium triacetoxyborohydride (23.2 mg, 0.109 mmol) was added. The resulting reaction mixture was stirred at room temperature for an additional 18 h. The contents were then filtered and purified by reverse-phase chromatography (0-100% 0.1% TFA in JH^Oiacetonitrile) to give 1- (2,2-dimethylpropyl)-3-methyl-5-[5-(lH-pyrazol-5-ylmethyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]- l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (21-1) as a white solid. MS m/z (M+H): calculated = 410.2663; observed = 410.2657.

The following compounds were prepared from 15-2 by a reaction sequence analogous to that illustrated in Scheme 21 : Table 21

Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

21-2 420.2758 420.2748

- imidazo [4,5 -b]pyridin- 2-one l-(2,2-dimethylpropyl)- 410.2663 410.2657 5-[5-(lH-imidazol-2

ylmethyl)-2,5- diazabicyclo[2.2.2]oct-

2-yl]-3-methyl-l,3- dihydro-2H- imidazo [4,5 -b]pyridin- 2-one Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

21-4 1 -(2,2-dimethylpropyl)- 410.2663 410.2657

3-methyl-5-[5-(lH- pyrazol-5-ylmethyl)-

diazabicyclo[2.2.2]oct- 2-yl]-l ,3-dihydro-2H- imidazo [4 , 5 -bjpyridin- 2-one

21-5 1 -(2,2-dimethylpropyl)- 425.2660 425.2652

3-methyl-5-{5-[(5- methylisoxazol-3- yl)methyl]-2,5-

diazabicyclo[2.2.2]oct- 2-yl}-l,3-dihydro-2H- imidazo [4,5 -b]pyridin- 2-one

436.3071 436.3064

dimethylpropyl)-3 - methyl- 1 ,3-dihydro-2H- imidazo [4,5 -b]pyridin- 2-one Scheme 22

l-(2,2-Dimethylpropyl)-3-methyl-5-[9-(l,3-thiazol-4-ylcarbonyl)-2,9- diazaspiror5.51undec-2-yl1-l,3-dihvdro-2H-imidazor4,5-&1pyridin-2-one (22-3) tert-Butyl 2-Γ 1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- 1H- imidazo[4,5-¾lpyridin-5-yll-2,9-diazaspiro[5.51undecane-9-carboxylate (22-1)

Anhydrous dimethylacetamide (95 μί, degassed prior to use) was added to a mixture of 5-chloro-l-(2,2-dimethylpropyl)-3-methyl-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2- one (1-4, 20 mg, 0.079 mmol), potassium phosphate tribasic (33.5 mg, 0.158 mmol), bis(tri-t- butylphosphine)palladium(O) (1.61 mg, 3.15 μιηοΐ), and tert-butyl 2,9-diazaspiro-[5.5]undecane- 9-carboxylate (30.1 mg, 0.118 mmol). The resulting suspension was heated to 100 °C for 18 h. Following this duration, the reaction contents were cooled to room temperature, filtered, and washed with acetonitrile . Purification using reverse-phase chromatography (10-100%, 0.1% TFA in F£₂0: acetonitrile) affordedJert-butyl 2-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3- dihydro-lH-imidazo[4,5-¾]pyridin-5-yl]-2,9-diazaspiro[5.5]undecane-9-carboxylate (22-1) as a white solid. MS m/z (Μ+Η): calculated = 472.3282; observed = 472.3275.

5-(2,9-Diazaspiro[5.5^"|undec-2-yl)- 1 -(2,2-dimethylpropyl)-3-methyl- 1 ,3-dihydro- 2H-imidazor4,5-&1pyridin-2-one (22-2)

tert-Butyl 2-[ 1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- 1H- imidazo[4,5-¾]pyridin-5-yl]-2,9-diazaspiro[5.5]undecane-9-carboxylate (22-1, 200 mg, 0.437 mmol) was added to a mixture of dichloromethane (3.4 mL) and trifluoro acetic acid (874 μΐ.) at room temperature. After stirring for 18 h, the solvent was removed in vacuo. The resulting residue was then diluted with ethyl acetate (10 mL) and washed sequentially with saturated sodium bicarbonate (2 x 5 mL), water (1 x 5 mL) and brine (1 x 5 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give 5-(2,9-diazaspiro[5.5]undec-2- yl)-l-(2,2-dimethylpropyl)-3-methyl-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one (22-2) as a white solid. This material was carried on without further purification.

l-(2,2-Dimethylpropyl)-3-methyl-5-[9-(l,3-thiazol-4-ylcarbonyl)-2,9- diazaspiror5.51undec-2-yl1-l,3-dihvdro-2H-imidazor4,5-&1pyridin-2-one (22-3)

5-(2,9-Diazaspiro[5.5]undec-2-yl)- 1 -(2,2-dimethylpropyl)-3-methyl- 1 ,3-dihydro- 2H-imidazo[4,5-£]pyridin-2-one (22-2, 20 mg, 0.054 mmol) was added to anhydrous

dimethylformamide (354

Thiazole-3-carboxylic acid (6.95 mg, 0.054 mmol), EDC (10.32 mg, 0.054 mmol), ΗΟΒΤ (8.24 mg, 0.054 mmol) and triethylamine (15

0.108 mmol) were added sequentially and the resulting reaction mixture was allowed to stir at room temperature for 18 h. Following this duration, the contents were filtered and the resulting filtrate was purified via reverse-phase HPLC (10-100%, 0.1% TFA in H₂0:acetonitrile) to give l-(2,2- dimethylpropyl)-3-methyl-5-[9-(l,3-thiazol-4-ylcarbonyl)-2,9-diazaspiro[5.5]undec-2-yl]-l,3- dihydro-2H-imidazo[4,5-¾]pyridin-2-one (22-3) as a white solid. MS m/z (Μ+Η): calculated = 483.2537; observed = 483.2530.

The following compound was prepared from 22-2 by a reaction sequence analogous to that illustrated in Scheme 22:

Table 22

Cmp Structure Name MS m/z MS m/z

(Μ+Η): (Μ+Η): calc'd observed

22-4 1- (2,2-dimethylpropyl)- 466.2925 466.2917

5-[9-(lH-imidazol-2- ylcarbonyl)-2,9- diazaspiro [5.5 ]undec-2-

yl]-3-methyl-l,3- dihydro-2H- imidazo [4,5 -b]pyridin-

2- one Scheme 23

l-(2,2-Dimethylpropyl)-3-methyl-5-[2-(l,3-thiazol-4-ylcarbonyl)-2,7- diazaspiror4.51dec-7-yl1-l,3-dihydro-2H-imidazor4,5-b1pyridin-2-one (23-3) tert-Butyl 7-[ 1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- 1H- imidazor4,5-b1pyridin-5-yl1-2,7-diazaspiror4.51decane-2-carboxylate (23-1)

Anhydrous dimethylacetamide (2.4 mL, degassed prior to use) was added to a mixture of 5-chloro-l-(2,2-dimethylpropyl)-3-methyl-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2- one (1-4, 500 mg, 1.971 mmol), potassium phosphate tribasic (837 mg, 3.94 mmol), bis(tri-t- butylphosphine)palladium(O) (40.3 mg, 0.079 mmol), and tert-butyl 2,7-diazaspiro[4.5]decane-2- carboxylate (710 mg, 2.96 mmol). The resulting suspension was heated to 100 °C for 18 h. Following this duration, the reaction contents were cooled to room temperature, filtered, and washed with acetonitrile. Purification using reverse-phase chromatography (10-100%, 0.1% TFA in H₂0: acetonitrile) afforded tert-butyl 7-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3- dihydro-lH-imidazo[4,5-b]pyridin-5-yl]-2,7-diazaspiro[4.5]decane-2-carboxylate (23-1) as a white solid. MS m/z (M+H): calculated = 458.3126; observed = 458.3119.

5-(2,7-Diazaspiro[4.51dec-7-yl)-l-(2,2-dimethylpropyl)-3-methyl-l,3-dihydro- 2H-imidazor4,5-¾1pyridin-2-one (23-2)

tert- utyl 7-[ 1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- 1Η- imidazo[4,5-b]pyridin-5-yl]-2,7-diazaspiro[4.5]decane-2-carboxylate (23-1, 200 mg, 0.437 mmol) was added to a mixture of dichloromethane (3.4 mL) and trifluoro acetic acid (874 μί) at room temperature. After stirring for 18 h, the solvent was removed in vacuo. The resulting residue was then diluted with ethyl acetate (10 mL) and washed sequentially with saturated sodium bicarbonate (2 x 5 mL), water (1 x 5 mL) and brine (1 x 5 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give 5-(2,7-diazaspiro[4.5]dec-7-yl)- l-(2,2-dimethylpropyl)-3-methyl-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one (23-2) as a white solid. This material was carried on without further purification.

l-(2,2-Dimethylpropyl)-3-methyl-5-[2-(l,3-thiazol-4-ylcarbonyl)-2,7- diazaspiror4.51dec-7-yl1-l,3-dihydro-2H-imidazor4,5-b1pyridin-2-one (23-3)

5-(2,7-Diazaspiro[4.5]dec-7-yl)-l-(2,2-dimethylpropyl)-3-methyl-l,3-dihydro- 2H-imidazo[4,5-£]pyridin-2-one (23-2, 20 mg, 0.056 mmol) was added to anhydrous

dimethylformamide (368

Thiazole-3-carboxylic acid (7.22 mg, 0.056 mmol), EDC (10.72 mg, 0.056 mmol), ΗΟΒΤ (8.57 mg, 0.056 mmol) and triethylamine (11

0.112 mmol) were added sequentially and the resulting reaction mixture was allowed to stir at room temperature for 18 h. Following this duration, the contents were filtered and the resulting filtrate was purified via reverse-phase HPLC (10-100%, 0.1% TFA in H₂0:acetonitrile) to give l-(2,2- dimethylpropyl)-3-methyl-5-[2-(l,3-thiazol-4-ylcarbonyl)-2,7-diazaspiro[4.5]dec-7-yl]-l,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one (23-3) as a white solid. MS m/z (M+H): calculated = 469.2380; observed = 469.2373.

Scheme 24

l-(2,2-Dimethylpropyl)-3-methyl-5-[9-(phenylcarbonyl)-2,9- diazaspiro Γ5.5 lundec-2-νΠ - 1 ,3 -dihydro-2H-imidazo Γ4.5 -blpyridin-2-one (24-1)

5-(2,9-Diazaspiro[5.5]undec-2-yl)- 1 -(2,2-dimethylpropyl)-3-methyl- 1 ,3-dihydro- 2H-imidazo[4,5-£]pyridin-2-one (22-2, 20 mg, 0.054 mmol) was added to anhydrous dimethylformamide (708

Triethylamine (15 0.108 mmol) and benzoyl chloride (7 0.059 mmol) were then added, and the resulting solution was stirred at room temperature for 3 h. Following this duration, the contents were filtered and the resulting filtrate was purified via reverse-phase HPLC (10-100%), 0.1%> TFA in H₂0:acetonitrile) to give l-(2,2-dimethylpropyl)- 3-methyl-5-[9-(phenylcarbonyl)-2,9-diazaspiro[5.5]undec-2-yl]-l,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one (24-1) as a white solid. MS m/z (M+H): calculated = 476.3020; observed = 476.3011. The following compound was prepared from 23-2 by a reaction sequence analogous to that illustrated in Scheme 24:

Table 24

Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

24-2 1 -(2,2-dimethylpropyl)- 462.2864 462.2856

3-methyl-5-[2-

(phenylcarbonyl)-2,7- diazaspiro [4.5 ] dec-7- yl]-l,3-dihydro-2H-

imidazo [4,5 -b]pyridin-

2-one

Scheme 25

2-{2-ri-(2,2-Dimethylpropyl)-3-methyl-2-oxo-2,3-dihvdro-lH-imidazo-r4,5- blpyridin-5-yll-2,9-diazaspiro[5.51undec-9-yl|pyridine-3-carbonitrile (25-1)

5-(2,9-Diazaspiro[5.5]undec-2-yl)- 1 -(2,2-dimethylpropyl)-3-methyl- 1 ,3-dihydro- 2H-imidazo[4,5-¾]pyridin-2-one (22-2, 20 mg, 0.054 mmol) and cesium carbonate (52.6 mg, 0.161 mmol) were added to anhydrous THF (269 μί). To this reaction mixture was added 2- chloro-3-cyano-pyridine (14.9 mg, 0.108 mmol) and the contents were stirred for 18 h at room temperature. Following this duration, the solvent was removed in vacuo and the resulting residue was partitioned between ethyl acetate (5 mL) and water (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 3 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give an orange residue. Purification via reverse-phase HPLC (10-100%, 0.1% TFA in H₂0:acetonitrile) yielded 2- {2-[ 1 -(2,2-dimethylpropyl)-3-me^^

diazaspiro[5.5]undec-9-yl}pyridine-3-carbonitrile (25-1) as a white solid. MS m/z (M+H): calculated = 474.2976; observed = 474.2971.

The following compound was prepared from 23-2 by a reaction sequence analogous to that illustrated in Scheme 25:

Table 25

Cmp Structure Name MS m z MS m/z

(M+H): (M+H): calc'd observed

25-2 2-{7-[l-(2,2- 460.2819 460.2813 dimethylpropyl)-3 - methyl-2-oxo-2,3- dihydro-lH-

imidazo [4,5 -b]pyridin-

5-yl]-2,7- diazaspiro[4.5]dec-2- yl}pyridine-3- carbonitrile

Scheme 26

l-(2,2-Dimethylpropyl)-3-methyl-5-[8-(pyridin-3-ylcarbonyl)-3,8- diazabicvclor3.2.11oct-3-yl1-l,3-dihvdro-2H-imidazor4,5-¾1pyridin-2-one (26-3) tert-Butyl 3-[ 1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- 1H- imidazor4,5-&1pyridin-5-yl1-3,8-diazabicvclor3.2.11octane-8-carboxylate (26-1)

Anhydrous dimethylacetamide (4.75 mL, degassed prior to use) was added to a mixture of 5-chloro-l-(2,2-dimethylpropyl)-3-methyl-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2- one (1-4, 1.0 g, 3.94 mmol), potassium phosphate tribasic (1.67 g, 7.88 mmol), bis(tri-t- butylphosphine)palladium(O) (81 mg, 0.158 mmol), and tert-butyl 3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (1.26 g, 5.91 mmol). The resulting suspension was heated to 100 °C for 18 h. Following this duration, the reaction contents were cooled to room temperature, filtered, and washed with acetonitrile. Purification using reverse-phase chromatography (20-100%, 0.1% TFA in H₂0: acetonitrile) afforded tert-butyl 3-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3- dihydro-lH-imidazo[4,5-¾]pyridin-5-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (26-1) as a white solid. MS m/z (Μ+Η): calculated = 430.2813; observed = 430.2817.

5 -(3 , 8-Diazabicyclo [3.2.1 ]oct-3 -yl)- 1 -(2,2-dimethylpropyl)-3 -methyl- 1,3- dihvdro-2H-imidazor4,5-&1pyridin-2-one (26-2)

tert- utyl 3-[ 1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- 1H- imidazo[4,5-¾]pyridin-5-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (26-1, 247 mg, 0.575 mmol) was added to a mixture of dichloromethane (4.6 mL) and trifluoro acetic acid (1.15 mL) at room temperature. After stirring for 18 h, the solvent was removed in vacuo. The resulting residue was then diluted with ethyl acetate (50 mL) and washed sequentially with saturated sodium bicarbonate (2 x 25 mL), water (1 x 25 mL) and brine (1 x 25 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give 5-(3,8- diazabicyclo[3.2.1]oct-3-yl)-l-(2,2-dimethylpropyl)-3-methyl-l,3-dihydro-2H-imidazo[4,5- £]pyridin-2-one (26-2) as a white solid. MS m/z (Μ+Η): calculated = 330.2288; observed = 330.2286. This material was carried on without further purification.

l-(2,2-Dimethylpropyl)-3-methyl-5-r8-(pyridin-3-ylcarbonyl)-3,8- diazabicvclor3.2.11oct-3-yl1-l,3-dihvdro-2H-imidazor4,5-¾1pyridin-2-one (26-3)

5 -(3 , 8-Diazabicyclo [3.2.1 ]oct-3 -yl)- 1 -(2,2-dimethylpropyl)-3 -methyl- 1,3- dihydro-2H-imidazo[4,5-¾]pyridin-2-one (26-2, 20 mg, 0.061 mmol) was added to anhydrous dimethylformamide (607 μί). Pyridine-3-carboxylic acid (8.22 mg, 0.067 mmol), EDC (11.64 mg, 0.061 mmol), HOBT (9.30 mg, 0.061 mmol) and triethylamine (17 μί, 0.121 mmol) were added sequentially and the resulting reaction mixture was allowed to stir at room temperature for 18 h. Following this duration, the contents were filtered and the resulting filtrate was purified via reverse-phase HPLC (5-95%, 0.1% TFA in H₂0:acetonitrile) to give l-(2,2-dimethylpropyl)- 3-methyl-5-[8-(pyridin-3-ylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-l,3-dihydro-2H- imidazo[4,5-£]pyridin-2-one (26-3) as a white solid. MS m/z (Μ+Η): calculated = 435.2503; observed = 435.2510.

The following compounds were prepared from 26-2 by a reaction sequence analogous to that illustrated in Scheme 26:

Table 26

Cmp Structure Name MS m/z MS m/z

(Μ+Η): (Μ+Η): calc'd observed

26-4 l)- 451.2452 451.2459

t-

dihydro-2H- imidazo [4,5 -b]pyridin- 2-one

26-5 l)- 451.2452 451.2457

t-

dihydro-2H- imidazo [4,5 -b]pyridin- Cmp Structure Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

2-one

26-6 1 -(2,2-dimethylpropyl)- 442.2020 442.2026

3-methyl-5-[8-(l,2,3- thiadiazol-4- ylcarbonyl)-3,8- diazabicyclo[3.2.1]oct-

3-yl]-l,3-dihydro-2H-

imidazo [4,5 -b]pyridin-

2- one

26-7 1 -(2,2-dimethylpropyl)- 425.2296 425.2298

5-[8-(isoxazol-3- ylcarbonyl)-3,8- diazabicyclo[3.2.1]oct-

3- yl]-3-methyl-l,3- dihydro-2H-

imidazo [4,5 -b]pyridin- 2-one

Scheme 27

l-(2,2-Dimethylpropyl)-3-methyl-5-[8-(phenylcarbonyl)-3,8- diazabicyclo [3.2.1 ]oct-3 -yl] - 1 ,3 -dihydro-2H-imidazo [4,5 -b^"|pyridin-2-one (27-1) 5 -(3 , 8-Diazabicyclo [3.2.1 ]oct-3 -yl)- 1 -(2,2-dimethylpropyl)-3 -methyl- 1,3- dihydro-2H-imidazo[4,5-£]pyridin-2-one (26-2, 30 mg, 0.091 mmol) was added to anhydrous dimethylformamide (911 μί). Triethylamine (13 μί, 0.091 mmol) and benzoyl chloride (11 μί, 0.091 mmol) were then added, and the resulting solution was stirred at room temperature for 3 h. Following this duration, the contents were filtered and the resulting filtrate was purified via reverse-phase HPLC (10-100%, 0.1% TFA in H₂0:acetonitrile) to give l-(2,2-dimethylpropyl)- 3-methyl-5-[8-(phenylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-l,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one (27-1) as a white solid. MS m/z (M+H): calculated = 434.2551; observed = 434.2558.

Scheme 28

2-{3-[l-(2,2-Dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo-[4,5- b1pyridin-5-yl1-3,8-diazabicvclor3.2.11oct-8-yl|pyridine-3-carbonitrile (28-1)

5 -(3 , 8-Diazabicyclo [3.2.1 ]oct-3 -yl)- 1 -(2,2-dimethylpropyl)-3 -methyl- 1,3- dihydro-2H-imidazo[4,5-£]pyridin-2-one (26-2, 30 mg, 0.091 mmol) and cesium carbonate (89 mg, 0.273 mmol) were added to anhydrous THF (455 μί). To this reaction mixture was added 2-chloro-3-cyano-pyridine (25.2 mg, 0.182 mmol) and the contents were stirred for 18 h at room temperature. Following this duration, the solvent was removed in vacuo and the resulting residue was partitioned between ethyl acetate (5 mL) and water (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 3 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give an orange residue. Purification via reverse-phase HPLC (10-100%, 0.1% TFA in H₂0:acetonitrile) yielded 2-{3-[l-(2,2-Dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo-[4,5-b]pyridin-5-yl]-3,8- diazabicyclo[3.2.1]oct-8-yl}pyridine-3-carbonitrile (28-1) as a white solid. MS m/z (M+H): calculated = 432.2506; observed = 432.2511. Scheme 29

l-(2,2-Dimethylpropyl)-3-methyl-5-[(15^*,45)-5-(l,2,3-thiadiazol-4-ylcarbonyl)- 2,5-diazabicyclo[2.2.1]hept-2-yl]-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one (29-3) tert-ButvUlS.4S -5-ri-(2,2-dimethylpropyn-3-methyl-2-oxo-2,3-dihvdro-lH- imidazo[4,5-blpyridin-5-yll-2,5-diazabicyclo[2.2.1lheptane-2-carboxylate (29-1)

Anhydrous dimethylacetamide (2.4 mL, degassed prior to use) was added to a mixture of 5-chloro-l-(2,2-dimethylpropyl)-3-methyl-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2- one (1-4, 500 mg, 1.97 mmol), potassium phosphate tribasic (837 mg, 3.94 mmol), bis(tri-t- butylphosphine)palladium(O) (40.3 mg, 0.079 mmol), and tert-butyl (lS,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (586 mg, 2.96 mmol). The resulting suspension was heated to 100 °C for 18 h. Following this duration, the reaction contents were cooled to room temperature, filtered, and washed with acetonitrile. Purification using reverse-phase

chromatography (20-100%, 0.1% TFA in H₂0: acetonitrile) afforded tert-butyl (lS,4S)-5-[l-(2,2- dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (29-1) as a white solid. MS m/z (M+H): calculated = 416.2656; observed = 416.2651.

5-r(l_tS'.4^-2,5-Diazabicvclor2.2.11hept-2-yl1-l-(2,2-dimethylpropyl)-3-methyl- 1 ,3-dihvdro-2H-imidazor4,5-&1pyridin-2-one (29-2)

tert-Butyl (lS,4S)-5-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH- imidazo[4,5-b]pyridin-5-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (29-1, 656.9 mg, 1.58 mmol) was added to a mixture of dichloromethane (12.6 mL) and trifluoroacetic acid (3.16 mL) at room temperature. After stirring for 18 h, the solvent was removed in vacuo. The resulting residue was then diluted with ethyl acetate (50 mL) and washed sequentially with saturated sodium bicarbonate (2 x 25 mL), water (1 x 25 mL) and brine (1 x 25 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give 5-[(lS, S)-2,5- diazabicyclo[2.2.1]hept-2-yl]-l-(2,2-dimethylpropyl)-3-methyl-l,3-dihydro-2H-imidazo[4,5- ¾]pyridin-2-one (29-2) as a white solid. This material was carried on without further

purification.

l-(2,2-Dimethylpropyn-3-methyl-5-r(l_tS'.4^-5-(1.2,3-thiadiazol-4-ylcarbonvn- 2,5-diazabicvclor2.2.11hept-2-yl1-l,3-dihvdro-2H-imidazor4,5-&1pyridin-2-one (29-3)

5-[(15^*,45)-2,5-diazabicyclo[2.2.1]hept-2-yl]-l-(2,2-dimethylpropyl)-3-methyl- l,3-dihydro-2H-imidazo[4,5-£]pyridin-2-one (29-2, 25 mg, 0.079 mmol) was added to anhydrous dimethylformamide (793

l,2,3-thiadiazole-4-carboxylic acid (11.4 mg, 0.087 mmol), EDC (15.19 mg, 0.079 mmol), ΗΟΒΤ (12.14 mg, 0.079 mmol) and triethylamine (22 pL, 0.159 mmol) were added sequentially and the resulting reaction mixture was allowed to stir at room temperature for 18 h. Following this duration, the contents were filtered and the resulting filtrate was purified via reverse-phase HPLC (5-95%, 0.1% TFA in H₂0:acetonitrile) to give 1- (2,2-dimethylpropyl)-3-methyl-5-[(15^*,45)-5-(l,2,3-thiadiazol-4-ylcarbonyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one (29-3) as a white solid. MS m/z (Μ+Η): calculated = 428.1863; observed = 428.1860.

The following compounds were prepared from 29-2 or ent-29-2 by a reaction sequence analogous to that illustrated in Scheme 29:

Table 29

Cmp Structure Name MS m/z MS m/z

(Μ+Η): (Μ+Η): calc'd observed

29-4 1 -(2,2-dimethylpropyl)- 411.2139 411.2136

5-[(15,4S)-5-(isoxazol-

3-ylcarbonyl)-2,5- diazabicyclo [2.2.1 ]hept-

2-yl]-3-methyl-l,3-

dihydro-2H- imidazo[4,5-£]pyridin-

2-one

29-5 1 -(2,2-dimethylpropyl)- 412.1952 412.1979

3-methyl-5-[(lS,4S)-5-

(l,3-oxazol-2- ylcarbonyl)-2,5- diazabicyclo [2.2.1 ]hept-

2-yl]-l,3-dihydro-2H- imidazo[4,5-£]pyridin- 2-one 421.2347 421.2350

imidazo[4,5-£]pyridin- 2-one Cmp Structure Name MS m/z MS m/z

(Μ+Η): (Μ+Η): calc'd observed

29-7 1 -(2,2-dimethylpropyl)- 428.1863 428.1860

3-metnyl-5-[(lR,4R)-5-

(l,2,3-thiadiazol-4- ylcarbonyl)-2,5- diazabicyclo [2.2.1 ]hept-

2-yl]-l,3-dihydro-2H- imidazo[4,5-£]pyridin-

2-one

29-8 1- (2,2-dimethylpropyl)- 411.2139 411.2136

5-[(lR,4R)-5-(isoxazol- 3-ylcarbonyl)-2,5- diazabicyclo [2.2.1 ]hept-

2- yl]-3-methyl-l,3-

dihydro-2H- imidazo[4,5-£]pyridin- 2-one l-(2,2-dimethylpropyl)- 412.1952 412.1979

3-metnyl-5-[(lR,4R)-5- (l,3-oxazol-2- ylcarbonyl)-2,5- diazabicyclo [2.2.1 ]hept-

2-yl]-l,3-dihydro-2H- imidazo[4,5-£]pyridin- 2-one Cmp Structure Name MS m/z MS m z

(Μ+Η): (Μ+Η): calc'd observed

29-10 421.2347 421.2350

imidazo[4,5-£]pyridin- 2-one

Scheme 30

l-(2,2-Dimethylpropyn-3-methyl-5-r(l_tS'.4^-5-(phenylcarbonvn-2,5- diazabicvclor2.2.11hept-2-yl1-l ,3-dihvdro-2H-imidazor4,5-&1pyridin-2-one (30-1)

5-[(15^*,45)-2,5-Diazabicyclo[2.2.1]hept-2-yl]-l-(2,2-dimethylpropyl)-3-methyl- l ,3-dihydro-2H-imidazo[4,5-£]pyridin-2-one (29-2, 25 mg, 0.079 mmol) was subsequently added to anhydrous dimethylformamide (793 μί). Triethylamine (1 1.1 μί, 0.079 mmol) and benzoyl chloride (9.2 μΐ,, 0.079 mmol) were then added, and the resulting solution was stirred at room temperature for 1 h. Following this duration, the contents were filtered and the resulting filtrate was purified via reverse-phase HPLC (10-100%, 0.1% TFA in H₂0:acetonitrile) to give l-(2,2-dimethylpropyl)-3-methyl-5-[(15',45)-5-(phenylcarbonyl)-2,5-diazabicyclo[2.2.1]hept-2- yl]-l ,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one (30-1) as a white solid. MS m/z (Μ+Η):

calculated = 420.2394: observed = 420.2396. The following compound was prepared from ent-29-2 by a reaction sequence analogous to that illustrated in Scheme 30:

Table 30

Cmp Structure Name MS m/z MS m/z

(Μ+Η): (Μ+Η): calc'd observed

30-2 l-(2,2- 420.2394 420.2396 dimethylpropyl)-3 - methyl-5-[(lR,4R)-5-

(phenylcarbonyl)-2,5- diazabicy clo [2.2.1 ] he

pt-2-yl]- 1 ,3-dihydro-

2H-imidazo[4,5-

£]pyridin-2-one

Scheme 31

Ε&ν1 (1^4^-5-Π-(2,2-ά 6&ν1ρΓορνη-3^6&ν1-2-οχο-2,3-ά^νάΓθ-1^ imidazor4,5-&1pyridin-5-yl1-2,5-diazabicvclor2.2.11heptane-2-carboxylate (31-1)

5-[(15^*,45)-2,5-Diazabicyclo[2.2.1]hept-2-yl]-l-(2,2-dimethylpropyl)-3-methyl- l ,3-dihydro-2H-imidazo[4,5-£]pyridin-2-one (29-2, 26.4 mg, 0.084 mmol) was added to anhydrous DMF (837 μί) and treated with triethylamine (12 μΤ, 0.084 mmol) and

ethylchloroformate (8 μί, 0.084 mmol) sequentially. The resulting mixture was stirred at room temperature for 60 min and subsequently purified by reverse-phase HPLC chromatography to provide ethyl (15',45)-5-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5- ¾]pyridin-5-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (31-1) as a white solid. MS m/z (Μ+Η): calculated = 388.2343; observed = 388.2344. The following compound was prepared from ent-29-2 by a reaction sequence analogous to that illustrated in Scheme 31 :

Table 31

Cmp Structure Name MS m/z MS m/z

(Μ+Η): (Μ+Η): calc'd observed

31-2 ethyl (lR,4R)-5-[l- 388.2343 388.2344

(2,2-dimethylpropyl)- 3-methyl-2-oxo-2,3- dihydro-lH- imidazo[4,5-

£]pyridin-5 -y 1] -2 , 5 - diazabicy clo [2.2.1 ] he

ptane-2-carboxylate

Scheme 32

1 - r(2,2-Difluorocvclopropyl)methyl1 -5 -Γ5 -(isoxazol-3 -ylcarbonyl)-2,5 - diazabicvclor2.2.21oct-2-yl1-3-methyl-l,3-dihvdro-2H-imidazor4,5-&1pyridin-2-one (32-2)

tert-Butyl 5- { 1 -[(2,2-difluorocyclopropyl)methyl]-3-methyl-2-oxo-2,3-dihydro- lH-imidazo[4,5-¾]pyridin-5-yl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (8-18, 113.8 mg, 2.53 mmol) was added to a mixture of dichloromethane (2.0 mL) and trifluoroacetic acid (0.5 mL) at room temperature. After stirring for 1 h, the solvent was removed in vacuo. The resulting residue was then diluted with ethyl acetate (5 mL) and washed sequentially with saturated sodium bicarbonate (2 x 5 mL), water (1 x 5 mL) and brine (1 x 5 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give 32-1 as a white solid, This material was carried on without further purification.

Amine 32-1 (73 mg, 0.209 mmol) was added to anhydrous dimethylformamide (2.0 mL). Isoxazole-3-carboxylic acid (23.6 mg, 0.209 mmol), EDC (40.1 mg, 0.209 mmol), HOBT (32 mg, 0.209 mmol) and triethylamine (58

0.418 mmol) were added sequentially and the resulting reaction mixture was allowed to stir at room temperature for 18 h. Following this duration, the contents were filtered and the resulting filtrate was purified via reverse-phase HPLC (5-95%, 0.1% TFA in H₂0:acetonitrile) to give 32-2 as a white solid. MS m/z (M+H): calculated = 445.1794; observed = 445.1808. Ή NMR δ (ppm)(CHCl₃-d): 8.50-8.43 (1 H, m), 7.14 (1 H, d, J = 8.42 Hz), 6.79-6.75 (1 H, m), 6.03 (1 H, d, J = 8.47 Hz), 5.10-5.01 (2 H, m), 4.18-4.08 (2 H, m), 3.90 (1 H, dd, J = 13.05, 3.18 Hz), 3.83-3.66 (3 H, m), 3.58-3.50 (1 H, m), 3.41 (3 H, d, J = 10.20 Hz), 2.15 (2 H, t, J = 14.76 Hz), 1.96 (4 H, d, J = 20.07 Hz).

Scheme 33

1 - [(2,2-Difluoro- 1 -methylcyclopropyl)methyl]-5 - [5 -(isoxazol-3 -ylcarbonyl)-2,5 - diazabicvclor2.2.21oct-2-yl1-3-methyl-l,3-dihvdro-2H-imidazor4,5-&1pyridin-2-one (33-2)

tert- vXy\ 5- { 1 -[(2,2-difluoro- 1 -methylcyclopropyl)methyl]-3-methyl-2-oxo-2,3- dihydro-lH-imidazo[4,5-¾]pyridin-5-yl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate

(9-5, 152.2 mg, 0.33 mmol) was added to a mixture of dichloromethane (2.6 mL) and trifluoroacetic acid (0.6 mL) at room temperature. After stirring for 1 h, the solvent was removed in vacuo. The resulting residue was then diluted with ethyl acetate (5 mL) and washed sequentially with saturated sodium bicarbonate (2 x 5 mL), water (1 x 5 mL) and brine (1 x 5 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give 33-1 as a white solid. This material was carried on without further purification.

Amine 33-1 (115 mg, 0.316 mmol) was added to anhydrous dimethylformamide (3.2 mL). Isoxazole-3-carboxylic acid (35.8 mg, 0.316 mmol), EDC (60.7 mg, 0.316 mmol), ΗΟΒΤ (48.5 mg, 0.316 mmol) and triethylamine (64 0.633 mmol) were added sequentially and the resulting reaction mixture was allowed to stir at room temperature for 18 h. Following this duration, the contents were filtered and the resulting filtrate was purified via reverse-phase HPLC (5-95%, 0.1% TFA in H₂0:acetonitrile) to give 33-2 as a white solid. MS m z (M+H): calculated = 459.1951; observed = 459.1958.

Scheme 34

5-[5-(Isoxazol-3-ylcarbonyl)-2,5-diazabicyclo[2.2.2loct-2-yll-3-methyl-l -(4,4,4- trifluoro-2,2-dimethylbutvD- 1 ,3-dihvdro-2H-imidazor4,5-&1pyridin-2-one (34-5)

5 -Chloro-3 -methyl- 1 -(4,4,4-trifluoro-2,2-dimethyrbutyiy 1 ,3-dihydro-2H- imidazor4,5-¾1pyridin-2-one (34-2)

5-Chloro-3-methyl-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one (1-3, 500 mg, 2.72 mmol) was added to 1,4-dioxane (13 mL). Added sequentially alcohol 34-1 (497 μί, 4.09 mmol), triphenylphosphine (2.2 g, 8.17 mmol), and di-tert-butyl-azo-dicarboxylate (DTBAD, 1.9 g, 8.17 mmol) and heated to 80 °C for 18 h. Following this duration, cooled to RT, filtered through celite and concentrated in vacuo. Purified by reverse-phase HPLC to give a white solid. MS m/z (M+H): calculated = 458.5; observed = 458.4.

tert-Butyl 5-r3-methyl-2-oxo-l-(4,4,4-trifluoro-2,2-dimethylbutyl)-2,3-dihvdro- lH-imidazo[4,5-¾lpyridin-5-yll-2,5-diazabicyclo[2.2.21octane-2-carboxylate (34-3)

Anhydrous dimethylacetamide (655 mL, degassed prior to use) was added to a mixture of 5 -chloro-3 -methyl- 1 -(4,4,4-trifluoro-2,2-dimethylbutyl)- 1 ,3-dihydro-2H-imidazo[4,5- £]pyridin-2-one (34-2, 175 mg, 0.544 mmol), potassium phosphate tribasic (231 mg, 1.09 mmol), bis(tri-t-butylphosphine)palladium(0) (11.2 mg, 0.02 mmol), and tert-butyl-2,5- diazabicyclo[2.2.2]octane-2-carboxylate (115 g, 0.54 mmol). The resulting suspension was heated to 100 °C for 18 h. Following this duration, the reaction contents were cooled to room temperature, filtered, and washed with acetonitrile. Purification using normal-phase

chromatography (40% EtOAc in hexane) afforded tert-butyl 5-[3-methyl-2-oxo-l -(4,4,4- trifluoro-2,2-dimethylbutyl)-2,3-dihydro-lH-imidazo[4,5-¾]pyridin-5-yl]-2,5- diazabicyclo[2.2.2]octane-2-carboxylate (34-3) as a white solid. MS m/z (Μ+Η): calculated = 497.5; observed = 498.5.

5-(2,5-Diazabicvclor2.2.21oct-2-vn-3-methyl-l-(4,4,4-trifiuoro-2,2- dimethylbutyP- 1 ,3-dihydro-2H-imidazo[4,5-¾lpyridin-2-one (34-4)

Amine (34-3, 91 mg, 0.18 mmol) was added to a mixture of dichloromethane (1.5 mL) and trifluoroacetic acid (0.4 mL) at room temperature. After stirring for 1 h, the solvent was removed in vacuo. The resulting residue was then diluted with ethyl acetate (5 mL) and washed sequentially with saturated sodium bicarbonate (2 x 5 mL), water (1 x 5 mL) and brine (1 x 5 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give 34-4 as a white solid. MS m/z (Μ+Η): calculated = 397.4; observed = 398.4.

5-[5-(Isoxazol-3-ylcarbonyl)-2,5-diazabicyclo[2.2.21oct-2-yll-3-methyl-l- (4,4,4-trifluoro-2,2-dimethylbutyl)- 1 ,3-dihydro-2H-imidazo[4,5-&lpyridin-2-one (34-5)

Amine 34-4 (119 mg, 0.298 mmol) was added to anhydrous dimethylformamide (3.0 mL). Isoxazole-3-carboxylic acid (33.7 mg, 0.298 mmol), EDC (57.2 mg, 0.298 mmol), ΗΟΒΤ (45.7 mg, 0.298 mmol) and triethylamine (83 μί, 0.596 mmol) were added sequentially and the resulting reaction mixture was allowed to stir at room temperature for 18 h. Following this duration, the contents were filtered and the resulting filtrate was purified via reverse-phase HPLC (5-95%, 0.1% TFA in H₂0: acetonitrile) to give 34-5 as a white solid. MS m z (M+H): calculated = 493.2170; observed = 493.2172.

The following compounds were prepared from 1-3 and the appropriate alcohol by a reaction sequence analogous to that illustrated in Scheme 34: Name MS m/z MS m/z

(M+H): (M+H): calc'd observed

1- 409.1983 409.1979

(cyclopropylmethyl)-

5-[5-(isoxazol-3- ylcarbonyl)-2,5-

diazabicyclo[2.2.2]oct

-2-yl]-3-methyl-l,3- dihydro-2H- imidazo[4,5-

£]pyridin-2-one

5-[5-(isoxazol-3- 423.2139 423.2147 ylcarbonyl)-2,5- diazabicyclo[2.2.2]oct

-2-yl]-3-melhyl-l-[(l -

methylcyclopropyl)me

thyl]-l,3-dihydro-2H- imidazo[4,5- £]pyridin-2-one

34-8 l-(cyclobutylmethyl)- 423.2139 423.2136

5-[5-(isoxazol-3- ylcarbonyl)-2,5- diazabicyclo[2.2.2]oct

-2-yl]-3-methyl-l,3- dihydro-2H- imidazo[4,5- £]pyridin-2-one

Claims

WHAT IS CLAIMED IS:

1. A compound according to Formula I

X¹

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is selected from the group consisting of: Cl-8alkyl, C2-8alkenyl, C2-8^alkynyl, C3-6cycloalkyl and C3-6cycloalkylCi_4alkyl, any of which may bear up to 5 halogen

substituents;

R1 represents H or Ci_4alkyl which is optionally substituted with OH, CN, CF3, Cl-4alkoxy, amino, Cl-4alkylamino or di(C 1-4 alky l)amino;

R2 is selected from:

(i) Cl-8alkyl or C2-8alkenyl, either of which optionally bears up to 3 substituents independently selected from halogen, OH, CN, CF3, OR3, SR4, SO2R⁴, S02N(R3)2, COR3, C02R3, CON(R3)2, N( 3)_2s NR3COR4, NR3S02R⁴ and phenyl, said phenyl bearing 0 to 5 halogen substituents; and

(ii) C3-iocycloalkyl, C3-iocycloalkylCi_4alkyl, Het, HetCi_4alkyl, aryl or arylCl-4alkyl, any of which optionally bears up to 4 substituents independently selected from halogen, OH, oxo, CN, CF3, R4 OR3, SR4, SO2R⁴, S02N(R3)2, COR3, C02R³, CON(R3)2, N(R3)2, NR3COR4, NR3S02R⁴ and -P(0)-(OR3)2; where "aryl" refers to phenyl or 5- or 6- membered heteroaryl, either of which phenyl or heteroaryl is optionally fused to a 5- or 6- membered carbocycle or heterocycle, each "Het" independently refers to a nonaromatic or partially aromatic mono- or bicyclic heterocyclic system of up to 10 ring atoms and C3- lOcycloalkyl and the cyclic portion of C3-l0cycloalkylCl-4alkyl may be fused with phenyl or a 5- or 6-membered heteroaryl; or R1 and R2 together may complete a non-aromatic monocyclic, a non-aromatic or partially aromatic bicyclic, or a non-aromatic spiro-linked heterocyclic system of up to 12 ring atoms which optionally bears up to 4 substituents independently selected from R3;

R3 is selected from the group consisting of: halogen, OH, oxo, CN, CF3, R5, OR4, SR5, SO2R⁵, S02N(R4)2, COR5, C02R⁴, CON(R4)2, N(R4)2, NR4COR5, NR4C02R⁴, NR4S02R⁵, -Cl_4alkyl-N(R4)2, -Cl-4alkyl-NR4COR5 and -Cl-4alkyl-NR4C02R⁴,except that R3 is selected from R5, COR5 and C02R4 when substituted on a nitrogen atom and R3 is oxo when substituted on sulfur; each R4 independently represents H , Cl-6alkyl, C3-I0cycloalkyl, C3- 1 OcycloalkylC 1 _4alkyl, C3- 1 ocycloalkenyl or C3- 1 ocycloalkenylC 1 _4alkyl, any of which except H optionally bear up to 3 halogen atoms or with OH, CN, CF3 and Cl-4alkoxy, or R4 represents phenyl, benzyl, 5- or 6-membered monocyclic heteroaryl optionally bridged with a methylene or a 9- or 10-membered bicyclic heteroaryl optionally bridged with a methylene, any of which optionally bear up to 3 substituents independently selected from halogen, OH, CN, CF3, Cl- 4alkyl, C3_6cycloalkyl, phenyl, Ci_4alkoxy, amino, Ci_4alkylamino and di(Ci_4alkyl)amino, or R4 represents Het, optionally bridged with a methylene and said Het optionally bearing up to 3 substituents independently selected from halogen, OH, oxo, CN, CF3, Cl-4alkyl, C3- gcycloalkyl, phenyl, a 5- or 6-membered monocyclic heteroaryl, Ci_4alkoxy, acetyl, amino, Ci_ 4alkylamino and di(Cl-4alkyl)amino; and

R5 has the same definition as R4 except that R5 is not H.

2. The compound according to Claim 1 wherein Xl is selected from 2,2- dimethylpropyl, [2,2-difluorocyclopropyl]methyl and [2,2-difluoro-l-methylcyclopropyl]methyl.

3. The compound according to Claim 1 wherein Rl and R2 together complete a non-aromatic mono-cyclic, a nonaromatic or partially aromatic bi-cyclic, or a non- aromatic spiro-linked heterocyclic system of up to 12 ring atoms which optionally bears up to 4 substituents independently selected from R3.

4. The compound according to Claim 3 of Formula la

or a pharmaceutically acceptable salt thereof.

5. The compound according to Claim 3 of Formula lb

lb or a pharmaceutically acceptable salt thereof.

6. The compound according to Claim 5 wherein R3 is selected from NR4COR5, NR4CC-2R⁴ and NR3S02R⁴.

7. The compound according to Claim 3 of Formula Ic

or a pharmaceutically acceptable salt thereof.

8. The compound according to Claim 7 wherein R3 is isoxazolylcarbonyl, optionally substituted with Cl-4alkyl.

The compound according to Claim 3 of Formula Id

or a pharmaceutically acceptable salt thereof.

10. The compound according to Claim 3 of Formula Ie

or a pharmaceutically acceptable salt thereof.

11. The compound according to Claim 3 of Formula If

If or a pharmaceutically acceptable salt thereof.

12. A compound according to Claim 1 selected from the following group:

1 -(2,2-dimethylpropyl)-3-methyl-5-piperidin- 1 -yl- 1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[(2S)-2-methylpiperidin-l-yl]-l,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one;

1 -(2,2-dimethylpropyl)-5-[2-ethylpiperidin- 1 -yl] -3 -methyl- 1 ,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one; ethyl-l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5- yl]piperidine-2-carboxylate;

5-[2-benzylpiperidin-l-yl]-l-(2,2-dimethylpropyl)-3-methyl-l,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one;

5-(3,4-dihydroquinolin-l(2H)-yl)-l-(2,2-dimethylpropyl)-3-methyl-l,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one;

1 -(2,2-dimethy lpropyl)-3 -methyl-5 - [2-propylpiperidin- 1 -yl] - 1 ,3 -dihydro-2H-imidazo [4,5 - b]pyridin-2-one; 1 -(2 ,2-dimethylpropyl)-3 -methyl^

imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-(6-methyl-3,4-dihydroquinolin-l(2H)-yl)-l,3-d

imidazo[4,5-b]pyridin-2-one;

1 -(2,2-dimethylpropyl)-3-methyl-5-[2-methylpyrrolidin- 1 -yl]- 1 ,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one;

1 -(2,2-dimethylpropyl)-3-methyl-5-[octahydroquinolin- 1 (2H)-yl]- 1 ,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one;

1 -(2,2-dimethylpropyl)-3-methyl-5-[2-(trifluoromethyl)piperidin- 1 -yl]- 1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-5-[(4-methoxybenzyl)-(methyl)amino]-3-methyl-l,3-dihyd

imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[7^

dihydro-2H-imidazo[4,5-b]pyridin-2-one; tert-butyl-3-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyri yl]-3,6-diazabicyclo[3.2.1]octane-6-carboxylate; tert-butyl {(3S)-l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5- b]pyridin-5-yl]piperidin-3-yl}carbamate; tert-butyl {(3R)- 1 -[ 1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- lH-imidazo[4,5- b]pyridin-5-yl]piperidin-3-yl}carbamate; l-(2,2-dimethylpropyl)-5-[5,5-dimethyl-3-(trifluoromethyl)-5,6-dihydro[l,2

a]pyrazin-7(8H)-yl]-3-methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; 1 -(2,2-dimethylpropyl)-3-methyl-5-[3-phenylpiperidin- 1 -yl]- 1 ,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one;

1 -(2,2-dimethylpropyl)-3-methyl-5-(4-phenylpiperidin- 1 -yl)- 1 ,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one; tert-butyl 4-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5- yl]piperazine- 1 -carboxylate;

1 -(2,2-dimethylpropyl)-3-methyl-5-[2-phenylpiperidin- 1 -yl]- 1 ,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one; l-(2,2-dimethylpropyl)-5-(3-ethyl-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-3-m l,3-dihydro-2H-imidazo[4,5-£]pyridin-2-one;

N-tert-butyl-7-[l-(2,2-dimethylpropyl)^^

5-yl]-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]pyrazine-3-carboxamide; tert-butyl- -[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyr yl]-8H-spiro[8-azabicyclo[3.2.1]octane-3,3'-pyrrolidine]-8-carboxylate; ethyl 7-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl]- 5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]pyrazine-3-carboxylate;

5 -(3 ,4-dihydro- 1 ,5 -naphthyridin- 1 (2H)-yl)- 1 -(2,2-dimethylpropyl)-3 -methyl- 1 ,3 -dihydro-2H- imidazo[4,5-b]pyridin-2-one;

1 -(2,2-dimethylpropyl)-3-methyl-5-(7-methyl-3,4-dihydro- 1 ,8 -naphthyridin- 1 (2H)-yl)- 1,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one; tert-butyl 7-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5- yl]-3,7-diazabicyclo[3.3.1 ]nonane-3 -carboxylate; tert-butyl ({l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridm^ yl]piperidin-3-yl}methyl)carbamate;

1- (2,2-dimethylpropyl)-3-methyl-5-[l-methyl-3-(trifluoromethyl)-l,4,6,7-tetrahydro-^ pyrazolo[4,3-c]pyridin-5-yl]-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

1 -(2,2-dimethylpropyl)-5-(l , 1 -dioxidothiomorpholin-4-yl)-3-methyl- 1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one; tert-butyl (2R)-4-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5- b]pyridin-5-yl]-2-methylpiperazine-l-carboxylate; tert-butyl (2S)-4-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5- b]pyridin-5-yl]-2-methylpiperazine-l-carboxylate; tert-butyl 4-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5- yl]-2,2-dimethylpiperazine- 1 -carboxylate; tert-butyl 2-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5- yl] -2,6-diazaspiro [3.5 ]nonane-6-carboxylate;

7-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl]-2-ethyl- 2 , 7-diazaspiro [4.5] decan- 1 -one;

2- benzyl-7-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5- y 1] -2 , 7-diazaspiro [4.5 ] decan- 1 -one ; benzyl 5-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl]- 2 , 5 -diazabicy clo [2.2.1] heptane -2-carboxy late ; l-(2,2-dimethylpropyl)-3-methyl-5-(l-methyl-2,4,6,6a-tetrahydropyrrolo[3,4-b]pyrrol-5(lH)-yl) 1 , 3 -dihy dro-2H-imidazo [4 , 5 -b ]pyridin-2-one ; 1 -(2,2-dimethylpropyl)-5-[5-ethyl-2-methylpiperidin- 1 -yl]-3-methyl- 1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-5-[(lS,4S)-5-(4-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-3- methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

5-[(lS,4S)-5-(2-chlorophenyl)-2,5-diazabicyclo[2.2 ]hept-2-yl]-l-(2,2-dimethylpropyl)-3- methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[(lS,4S)-5-phenyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-l,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one;

5-[(lS,4S)-5-(3-chlorophenyl)-2,5-diazabicyclo[2.2 ]hept-2-yl]-l-(2,2-dimethylpropyl)-3- methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-2-oxo-5-{3-[(py

2 , 3 -dihy dro- 1 H-imidazo [4 , 5 -b ]pyridin-4-ium chloride;

5 -(3 - { [(3 -cyanopyridin-2-yl)amino]methyl} piperidin- 1 -yl)- 1 -(2,2-dimethylpropyl)-3 -methyl-2- oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium chloride;

4- [({l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5- yl]piperidin-3-yl}methyl)amino]pyridine-2-carbonitrile;

5- (3-{[(4-cyanopyridin-2-yl)amino]methyl}piperidin-l-yl)-l-(2,2-dimethylpropyl)-3-methyl-2- oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium chloride; l-(2,2-dimethylpropyl)-3-methyl-2-oxo-5-(3-{[(l,2,3-thiadiazol-4- ylcarbonyl)amino]methyl}piperidin-l-yl)-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium chloride; l-(2,2-dimethylpropyl)-3-methyl-2-oxo-5-(3-{[(lH-pyrazol-3- ylcarbonyl)amino]methyl}piperidin-l-yl)-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium chloride; 1 -(2,2-dimethylpropyl)-3-methyl-5-(3- {[(1 ,3-oxazol-5-ylcarbonyl)amino]methyl}piperidin- 1 - yl)-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium chloride; l-(2,2-dimethylpropyl)-5-(3-{[(isoxazol-5-ylcarbonyl)amino]methyl}piperidin-l-yl)-3-m oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium chloride;

1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-5-(3- {[(phenylacetyl)amino]methyl}piperidin- 1 -yl)-2,3- dihydro- 1 H-imidazo [4,5 -b]pyridin-4-ium chloride;

1 -(2 ,2-dimethylpropy l)-3 -methyl-2-oxo-5 -(3 - { [(pheny lcarbonyl)amino]methyl} piperidin- 1 -yl)- 2 , 3 -dihy dro- 1 H-imidazo [4 , 5 -b ]pyridin-4-ium chloride;

N-benzyl- 1 -[1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- lH-imidazo[4,5-b]pyridin-5- yl]piperidine-3-carboxamide ;

1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-5-[3-(phenylcarbamoyl)piperidin- 1 -yl]-2,3-dihydro- 1Η- imidazo[4,5-b]pyridin-4-ium chloride;

5-[3-(lH-benzimidazol-2-yl)piperidin- 1 -yl]- 1 -(2,2-dimethylpropyl)-3-methyl- 1 ,3-dihydro-2H- imidazo[4,5-£]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[3-(3-methyl-l,2,4-oxadiazol-5-yl)piperidin-l-yl]-l,3- dihydro-2H-imidazo[4,5-£]pyridin-2-one;

1 -(2,2-dimethylpropyl)-5- {3-[(l , 1 -dioxidothiomorpholin-4-yl)methyl]piperidin-l -yl} -3-methyl- l,3-dihydro-2H-imidazo[4,5-£]pyridin-2-one;

5-({l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium-5- yl]piperidin-3-yl}methyl)-5,6,7,8-tetrahydro-l,5-naphthyridin-l-ium dichloride;

5-({l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium-5- yl]piperidin-3-yl}methyl)-2-methyl-4,5,6,7-tetrahydro[l,3]thiazolo[5,4-c]pyridin-5-ium dichloride; 6-({ 1 -[ 1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- lH-imidazo[4,5-b]pyridin-4-ium-5 yl]piperidin-3-yl}methyl)-5,6,7,8-tetrahydro-l,6-naphthyridin-6-ium dichloride;

1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-5-(3- {[4-(4H- 1 ,2,4-triazol-3-yl)piperidinium- 1 - yl]methyl}piperidin-l-yl)-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium dichloride;

1 - {[2,2-difluorocyclopropyl]methyl} -3-methyl-5-piperidin-l -yl- 1 ,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one;

1 - {[2,2-difluorocyclopropyl]methyl} -3-methyl-5-[2-methylpiperidin- 1 -yl]- 1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one;

1 - {[2,2-difluorocyclopropyl]methyl} -3-methyl-5-[3-methylpiperidin- 1 -yl]- 1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one;

1 - {[2,2-difluorocyclopropyl]methyl} -3-methyl-5-(4-methylpiperidin- 1 -yl)- 1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one;

5-[benzyl(methyl)amino]- 1 - {[2,2-difluorocyclopropyl]methyl} -3-methyl- 1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one;

5 - [cyclohexyl(methyl)amino]- 1 - { [2 ,2-difluorocyclopropyl]methy 1} -3-methyl- 1 ,3 -dihydro-2H- imidazo[4,5-b]pyridin-2-one; l-{[2,2-difluorocyclopropyl]methyl}-3-methyl-5-pyrrolidin-l-yl-l,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one;

1 - {[2,2-difluorocyclopropyl]methyl} -3-methyl-5-[(2S)-2-methylpiperidin- 1 -yl]- 1 ,3-dihydro-2H imidazo[4,5-b]pyridin-2-one; l-{[2,2-difluorocyclopropyl]methyl}-5-(3,4-dihydroisoquinolin-2(lH)-yl)-3-methyl-l,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one; ethyl- 1 -(1 - {[2,2-difluorocyclopropyl]methyl} -3-methyl-2-oxo-2,3-dihydro- 1 H-imidazo [4, 5- b]pyridin-5-yl)piperidine-3-carboxylate;

1 - {[2,2-difluorocyclopropyl]methyl} -3-methyl-5-[(2R)-2-methylpiperidin- 1 -yl]- 1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one;

5-azepan-l -yl- 1 - {[2,2-difluorocyclopropyl]methyl} -3-methyl- 1 ,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one; l-{[2,2-difluorocyclopropyl]methyl}-5-(3,4-dihydroquinolin-l(2H)-yl)-3-methyl-l,3-dihydro- 2H-imidazo [4 , 5 -b]pyridin-2-one ;

5-azocan-l -yl- 1 - {[2,2-difluorocyclopropyl]methyl} -3-methyl- 1 ,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one;

1 - {[2,2-difluorocyclopropyl]methyl} -5-[2-ethylpiperidin- 1 -yl]-3-methyl- 1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one; tert-butyl [l-(l-{[2,2-difluorocyclopropyl]methyl}-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5- b]pyridin-5 -yl)- 1,2,3 ,4-tetrahydroquinolin-3 -yl] carbamate; ethyl- 1 -(1 - {[2,2-difluorocyclopropyl]methyl} -3-methyl-2-oxo-2,3-dihydro- 1 H-imidazo [4,5- b]pyridin-5-yl)piperidine-2-carboxylate;

1 - {[2,2-difluoro- 1 -methylcyclopropyl]methyl} -5-[2-ethylpiperidin-l -yl] -3 -methyl- 1 ,3-dihydro- 2H-imidazo [4 , 5 -b]pyridin-2-one ; tert-butyl { [ 1 -( 1 - { [2,2-difluoro- 1 -methylcyclopropyljmethyl} -3 -methyl-2-oxo-2,3-dihydro- 1 H- imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl]methyl} carbamate; tert-butyl [ 1 -( 1 - { [2,2-difluoro- 1 -methylcyclopropyl]methyl} -3-methyl-2-oxo-2,3-dihydro- 1 H- imidazo[4,5-b]pyridin-5-yl)-l,2,3,4-tetrahydroquinolin-3-yl]carbamate; N-{l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridm^ l,2,3,4-tetrahydroquinolin-3-yl}benzamide;

N-{l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl] l,2,3,4-tetrahydroquinolin-3-yl}cyclopropanecarboxamide;

N-{l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl] l,2,3,4-tetrahydroquinolin-3-yl}cyclobutanecarboxamide;

N-{l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl] l,2,3,4-tetrahydroquinolin-3-yl}cyclopentanecarboxamide;

N-{l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl] l,2,3,4-tetrahydroquinolin-3-yl}-2,2,2-trifluoroacetamide;

N-{l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl] l,2,3,4-tetrahydroquinolin-3-yl}-2,2-dimethylpropanamide;

N-{l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl] l,2,3,4-tetrahydroquinolin-3-yl}acetamide;

N-{l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl] l,2,3,4-tetrahydroquinolin-3-yl}cyclohexane-carboxamide; tert-butyl {(3S)-l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5- b]pyridin-5-yl]-l,2,3,4-tetrahydroquinolin-3-yl}carbamate; tert-butyl {(3R)- 1 -[ 1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- lH-imidazo[4,5- b]pyridin-5-yl]-l,2,3,4-tetrahydroquinolin-3-yl}carbamate; N-{l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridm^ l,2,3,4-tetrahydroquinolin-3-yl}-4-methylbenzamide;

N-{l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl]- l,2,3,4-tetrahydroquinolin-3-yl}pyrazine-2-carboxamide;

N-{l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl]- l,2,3,4-tetrahydroquinolin-3-yl}-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide;

N-{l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl]- 1 ,2,3 ,4-tetrahydroquinolin-3-yl} - 1 -methyl- 1 H-imidazole-4-carboxamide;

N-{l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl]- l,2,3,4-tetrahydroquinolin-3-yl}pyrimidine-5-carboxamide;

N-{l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl]- 1 ,2,3,4-tetrahydroquinolin-3-yl} - 1 ,3-thiazole-4-carboxamide;

N-{l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl]- l,2,3,4-tetrahydroquinolin-3-yl}pyridine-3-carboxamide;

N-{l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl]- l,2,3,4-tetrahydroquinolin-3-yl}pyridine-4-carboxamide;

N-{l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl]- l,2,3,4-tetrahydroquinolin-3-yl}-lH-pyrazole-5-carboxamide;

N-{l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl]- 1 ,2,3 ,4-tetrahydroquinolin-3-yl} - 1 H-imidazole-2-carboxamide;

N-{l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl]- 1 ,2,3 ,4-tetrahydroquinolin-3-yl} - 1 H-pyrazole-4-carboxamide; N-{l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyri 1 ,2,3 ,4-tetrahydroquinolin-3-yl} -2-( 1 H-pyrazol- 1 -yl)acetamide;

5-[3-(benzylamino)-3,4-dihydroquinolin- 1 (2H)-yl]- 1 -(2,2-dimethylpropyl)-3-methyl- 1 ,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one;

1 -(2,2-dimethylpropyl)-5 - [3 - [(2,2-dimethylpropyl)amino] -3 ,4-dihydroquinolin- 1 (2H)-yl]-3- methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

5 - [3 - {bis [( 1 -methyl- 1 H-imidazol-4-yl)methyl]amino } -3 ,4-dihydroquinolin- 1 (2H)-yl]-l-(2,2- dimethylpropyl)-3-methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

N-{l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl]- l,2,3,4-tetrahydroquinolin-3-yl}-4-methylbenzene-sulfonamide;

N-{l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl]- l,2,3,4-tetrahydroquinolin-3-yl}methanesulfonamide;

N-{l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl]- 1 ,2,3 ,4-tetrahydroquinolin-3-yl} -1 ,1,1 -trifluoromethanesulfonamide; ethyl- {l-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-5-yl]- l,2,3,4-tetrahydroquinolin-3-yl}carbamate;

2-({ 1 -[ 1 -(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro- lH-imidazo[4,5-¾]pyridin-5-yl]- l,2,3,4-tetrahydroquinolin-3-yl}amino)pyridine-3-carbonitrile; l-(2,2-dimethylpropyl)-3-methyl-5-[5-(phenylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]-l,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one; ethyl 5-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-¾]pyridin-5-yl]- 2,5-diazabicyclo[2.2.2]octane-2-carboxylate; 2-fluoroethyl 5-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-¾]pyridin- 5-yl]-2,5-diazabicyclo[2.2.2]octane-2-carboxylate; phenyl 5-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-¾]pyridin-5-yl]- 2,5-diazabicyclo[2.2.2]octane-2-carboxylate; propyl 5-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-¾]pyridin-5-yl]- 2,5-diazabicyclo[2.2.2]octane-2-carboxylate;

1- (2,2-dimethylpropyl)-3-methyl-5-{5-[(4-methylphenyl)sulfonyl]-2,5-diazabicyclo[2.2.2]oct-2- yl}-l,3-dihydro-2H-imidazo[4,5-£]pyridin-2-one l-(2,2-dimethylpropyl)-5-[5-(isoxazol-3- ylcarbonyl)-2,5-diazabicyclo-[2.2.2]oct-2-yl]-3-methyl-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-

2- one; l-(2,2-dimethylpropyl)-3-methyl-5-[5-(pyrazin-2-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]- l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-5-[5-(lH-imidazol-2-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]-3- methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-5-[5-(lH-imidazol-2-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]-3- methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-{5-[(2,4,6-trifluorophenyl)carbonyl]-2,5- diazabicyclo[2.2.2]oct-2-yl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-5-{5-[(3-fluorophenyl)carbonyl]-2,5-diazabicyclo[2.2.2]oct-2-yl}-3- methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-5-{5-[(4-fluorophenyl)carbonyl]-2,5-diazabicyclo[2.2.2]oct-2-yl}-3- methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; 5-{5-[(2,6-difluorophenyl)-carbonyl]-2,5-di^

methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

5-{5-[(2,4-difluorophenyl)-carbonyl]-2,5-diazabicyclo[2.2.2]oct-2-yl}-l-(2,2-dimethylpropyl)-3 methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium trifluoroacetate;

5-{5-[(2-chlorophenyl)carbonyl]-2,5-diazabicyclo[2.2.2]oct-2-yl}-l-(2,2-dimethylpropyl)-3- methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium trifluoroacetate;

5-{5-[(2,4-dichlorophenyl)carbonyl]-2,5-diazabicyclo[2.2.2]oct-2-yl}-l-(2,2-dimethylpropyl)-3- methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium trifluoroacetate;

5-{5-[(4-bromophenyl)carbonyl]-2,5-diazabicyclo[2.2.2]oct-2-yl}-l-(2,2-dimethylpropyl)-3- methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium trifluoroacetate;

5-{5-[(4-cyanophenyl)carbonyl]-2,5-diazabicyclo[2.2.2]oct-2-yl}-l-(2,2-dimethylpropyl)-3- methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium trifluoroacetate;

5-{5-[(2,5-dif uorophenyl)carbonyl]-2,5-diazabicyclo[2.2.2]oct-2-yl}-l-(2,2-dimethylpropyl)-3- methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium trifluoroacetate;

5-{5-[(3-cyanophenyl)carbonyl]-2,5-diazabicyclo[2.2.2]oct-2-yl}-l-(2,2-dimethylpropyl)-3- methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium trifluoroacetate;

5-{5-[(2-cyanophenyl)carbonyl]-2,5-diazabicyclo[2.2.2]oct-2-yl}-l-(2,2-dimethylpropyl)-3- methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium trifluoroacetate; l-(2,2-dimethylpropyl)-5-(5-{[2-f uoro-4-(trif uoromethyl)phenyl]carbonyl}-2,5- diazabicyclo[2.2.2]oct-2-yl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium trifluoroacetate; 1 -(2,2-dimethylpropyl)-5 -(5 - { [2-fluoro-5 -(trifluoromethyl)phenyl] carbonyl} -2,5 - diazabicyclo[2.2.2]oct-2-yl)-3-methyl-2-ox

trifluoroacetate;

5-{5-[(5-chloro-2-fluorophenyl)carbonyl]-2,5-diazabicyclo[2.2.2]oct-2-yl}-l-(2,2- dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium trifluoroacetate;

5-{5-[(l-acetylpiperidin-4-yl)carbonyl]-2,5-diazabicyclo[2.2.2]oct-2-yl}-l-(2,2- dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium trifluoroacetate; l-(2,2-dimethylpropyl)-3-methyl-5-{5-[(5-methylisoxazol-3-yl)carbonyl]-2,5- diazabicyclo[2.2.2]oct-2-yl} -2-0X0-2, 3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium

trifluoroacetate; l-(2,2-dimethylpropyl)-5-{5-[(l,3-dimethyl-lH-pyrazol-5-yl)carbonyl]-2,5- diazabicyclo[2.2.2]oct-2-yl}-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium trifluoroacetate; l-(2,2-dimethylpropyl)-5-{5-[(l,5-dimethyl-lH-pyrazol-3-yl)carbonyl]-2,5- diazabicyclo[2.2.2]oct-2-yl}-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridin-4-ium trifluoroacetate; l-(2,2-dimethylpropyl)-3-methyl-5-[5-(lH-l,2,3-triazol-4-ylcarbonyl)-2,5- diazabicyclo[2.2.2]oct-2-yl]-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[5-(lH-pyrazol-5-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2- yl]-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[5-(l,3-thiazol-5-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2- yl]-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[5-(lH-pyrazol-4-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2- yl]-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[5-(l,3-oxazol-5-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2- yl]-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-5-[5-(isoxazol-5-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]-3-methyl- l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[5-(lH-pyrazol-5-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2- yl]-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[5-(l,2,3-thiadiazol-4-ylcarbonyl)-2,5- diazabicyclo[2.2.2]oct-2-yl]-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[5-(pyridin-2-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]- l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[5-(pyridin-3-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]- l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[5-(pyridin-4-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]- l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-{5-[(5-methylisoxazol-3-yl)carbonyl]-2,5- diazabicyclo[2.2.2]oct-2-yl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

5-({5-[l-(2,2-dimethylpropyl)-3-meth^^

diazabicyclo[2.2.2]oct-2-yl}carbonyl)pyridine-2-carbonitrile; l-(2,2-dimethylpropyl)-5-{5-[(2-fluoropyridin-3-yl)carbonyl]-2,5-diazabicyclo[2.2.2]oct-2-yl}- 3-methyl- 1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-(5-{[6-(trifluoromethyl)pyridin-3-yl]carbonyl^

diazabicyclo[2.2.2]oct-2-yl)-l ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; 5-{5-[(5-bromopyridin-3-yl)carbonyl]-2,5-diazabicyclo[2.2.2]oct-2-yl}-l-(2,2-dimethylpropyl)- 3-methyl- 1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

1 -(2,2-dimethylpropyl)-3 -methyl-5 - {5 - [(6-methylpyridin-3 -yl)carbonyl] -2,5 - diazabicyclo[2.2.2]oct-2-yl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

1 -(2,2-dimethylpropyl)-3 -methyl-5 - {5- [(1 -methyl- lH-imidazol-2 -yl)carbonyl] -2,5 - diazabicyclo[2.2.2]oct-2-yl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

1 -(2,2-dimethylpropyl)-3-methyl-5- {5-[(5-methyl- 1 ,3 ,4-thiadiazol-2-yl)carbonyl]-2,5- diazabicyclo[2.2.2]oct-2-yl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-5-[5-(isothiazol-5-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]-3- methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-5-[5-(isothiazol-4-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]-3- methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

1 -(2,2-dimethylpropyl)-3-methyl-5- {5-[(5-methyl- 1 ,2,3-thiadiazol-4-yl)carbonyl]-2,5- diazabicyclo[2.2.2]oct-2-yl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[5-(l,3-oxazol-2-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2- yl]-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-{5-[(5-phenylisoxazol-3-yl)carbonyl]-2,5- diazabicyclo[2.2.2]oct-2-yl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-(5-{[5-(l-methylethyl)isoxazol-3-yl]carbonyl}-2,5- diazabicyclo[2.2.2]oct-2-yl)-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

5-{5-[(4-bromoisothiazol-3-yl)carbonyl]-2,5-diazabicyclo[2.2.2]oct-2-yl}-l-(2,2- dimethylpropyl)-3-methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-{5-[(4-methyl-lH-imidazol-2-yl)carbonyl]-2,5- diazabicyclo[2.2.2]oct-2-yl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[5-(lH-l,2,4-triazol-5-ylcarbonyl)-2,5- diazabicyclo[2.2.2]oct-2-yl]-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

5-{5-[(4,5-dichloroisothiazol-3-yl)carbonyl]-2,5-diazabicyclo[2.2.2]oct-2-yl}-l-(2,2- dimethylpropyl)-3-methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

5-{5-[(3-cyclopropyl-lH-pyrazol-5-yl)carbonyl]-2,5-diazabicyclo[2.2.2]oct-2-yl}-l-(2,2- dimethylpropyl)-3-methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-(5-{[3-(l-methylethyl)-lH-pyrazol-5-yl]carbonyl}-2,5- diazabicyclo[2.2.2]oct-2-yl)-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

1 -(2,2-dimethylpropyl)-3-methyl-5- {5-[(3-methyl- 1H- 1 ,2,4-triazol-5-yl)carbonyl]-2,5- diazabicyclo[2.2.2]oct-2-yl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[5-(l,2,5-thiadiazol-3-ylcarbonyl)-2,5- diazabicyclo[2.2.2]oct-2-yl]-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

1 -(2,2-dimethylpropyl)-3 -methyl-5 -(5 - { [3 -(trifluoromethyl)- 1 H-pyrazol-5 -yljcarbonyl} -2,5 - diazabicyclo[2.2.2]oct-2-yl)-l ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

1- (2,2-dimethylpropyl)-5-[(li?,4i?)-5-(l,2,3-thiadiazol-4-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-

2- yl]- 1 ,3-dihydro-2H-imidazo[4,5-£]pyridin-2-one;

1- (2,2-dimethylpropyl)-5-[(15',45)-5-(l,2,3-thiadiazol-4-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct^

2- yl]- 1 ,3-dihydro-2H-imidazo[4,5-£]pyridin-2-one; l-(2,2-dimethylpropyl)-5-[(li?,4i?)-5-(isoxazol-3-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]- l,3-dihydro-2H-imidazo[4,5-£]pyridin-2-one; l-(2,2-dimethylpropyl)-5-[(15',45)-5-(isoxazol-3-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]- l,3-dihydro-2H-imidazo[4,5-£]pyridin-2-one; l-(2,2-dimethylpropyl)-5-[(li?,4i?)-5-(pyridin-3-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]- l,3-dihydro-2H-imidazo[4,5-£]pyridin-2-one;

1- (2,2-dimethylpropyl)-5-[(15',45)-5-(pyridin-3-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]-l,3- dihydro-2H-imidazo[4,5-£]pyridin-2-one;

2- {5-[l-(2,2-dimethylpropyl)-3-methy^

diazabicyclo[2.2.2]oct-2-yl}pyridine-3-carbonitrile;

1- (2,2-dimethylpropyl)-3-methyl-5-(5-pyrimidin-2-yl-2,5-diazabicyclo[2.2.2]oct-2-yl)-l_^ dihydro-2H-imidazo[4,5-b]pyridin-2-one;

4-{5-[l-(2,2-dimethylpropyl)-3-methyl^^

diazabicyclo[2.2.2]oct-2-yl}pyridine-2-carbonitrile;

4-{5-[l-(2,2-dimethylpropyl)-3-methyl^^

diazabicyclo[2.2.2]oct-2-yl}pyridine-3-carbonitrile;

2- {5-[l-(2,2-dimethylpropyl)-3-methyl^^

diazabicyclo[2.2.2]oct-2-yl}pyridine-4-carbonitrile;

6-{5-[l-(2,2-dimethylpropyl)-3-methy^

diazabicyclo[2.2.2]oct-2-yl}pyridine-3-carbonitrile; l-(2,2-dimethylpropyl)-3-methyl-5-(5-phenyl-2,5-diazabicyclo[2.2.2]oct-2-yl)-l,3-dihydro imidazo[4,5-¾]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[5-(lH-pyrazol-5-ylmethyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]- l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; 5-[5-benzyl-2,5-diazabicyclo[2.2.2]oct-2-yl]-l-(2,2-dimethylpropyl)-3-methyl-l,3-dihydra imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-5-[5-(lH-imidazol-2-ylmethyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]-3- methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[5-(lH-pyrazol-5-ylmethyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]- l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

1 -(2,2-dimethylpropyl)-3 -methyl-5 - {5 - [(5 -methylisoxazol-3 -yl)methyl] -2,5 - diazabicyclo[2.2.2]oct-2-yl}-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

5-[5-(bicyclo[2.2.1]hept-5-en-2-ylmethyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]-l-(2,2- dimethylpropyl)-3-methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[9-(l,3-thiazol-4-ylcarbonyl)-2,9-diazaspiro[5.5]undec-2-yl^ l,3-dihydro-2H-imidazo[4,5-£]pyridin-2-one; l-(2,2-dimethylpropyl)-5-[9-(lH-imidazol-2-ylcarbonyl)-2,9-diazaspiro[5.5]undec-2-yl]-3- methyl-l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[2-(l,3-thiazol-4-ylcarbonyl)-2,7-diazaspiro[4.5]dec-7-yl]- l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[9-(phenylcarbonyl)-2,9-diazaspiro[5.5]undec-2-yl]-l,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one;

1- (2,2-dimethylpropyl)-3-methyl-5-[2-(phenylcarbonyl)-2,7-diazaspiro[4.5]dec-7-yl]-l,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one;

2- {2-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo-[4,5-b]pyridin-5 diazaspiro[5.5]undec-9-yl}pyridine-3-carbonitrile; 2-{V-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyri diazaspiro [4.5 ] dec-2-y 1 } pyridine-3 -carbonitrile; l-(2,2-dimethylpropyl)-3-methyl-5-[8-(pyridin-3-ylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]- 1 ,3-dihydro-2H-imidazo[4,5-£]pyridin-2-one ;

1 -(2,2-dimethylpropyl)-5- {8-[(6-hydroxypyridin-3-yl)carbonyl]-3,8-diazabicyclo[3.2.1 ]oct-3- yl} -3-methyl- 1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

1 -(2,2-dimethylpropyl)-5- {8-[(6-hydroxypyridin-3-yl)carbonyl]-3,8-diazabicyclo[3.2.1 ]oct-3- yl} -3-methyl- 1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[8-(l,2,3-thiadiazol-4-ylcarbonyl)-3,8- diazabicyclo [3.2.1 ]oct-3 -yl] - 1 ,3 -dihydro-2H-imidazo [4,5 -b]pyridin-2-one;

1- (2,2-dimethylpropyl)-5-[8-(isoxazol-3-ylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-3-methyl- l,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

1 -(2,2-dimethylpropyl)-3-methyl-5-[8-(phenylcarbonyl)-3 ,8-diazabicyclo[3.2.1 ]oct-3-yl]- 1,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one;

2- {3-[l-(2,2-Dimethylpropyl)-3-methyl-2-oxo-2,3-dm^

diazabicyclo[3.2.1]oct-8-yl}pyridine-3-carbonitrile; l-(2,2-Dimethylpropyl)-3-methyl-5-[(15^*,45)-5-(l,2,3-thiadiazol-4-ylcarbonyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[(15^*,45)-5-(l,2,3-thiadiazol-4-ylcarbonyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one; l-(2,2-dimethylpropyl)-5-[(15',45)-5-(isoxazol-3-ylcarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-

3- methyl- 1 ,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[(15^*,45)-5-(l,3-oxazol-2-ylcarbonyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one;

1 -(2,2-dimethylpropyl)-3 -methyl-5 - [( 15^*,45)-5 -(pyridin-3 -ylcarbonyl)-2,5 - diazabicyclo[2.2.1]hept-2-yl]-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[(li?,4i?)-5-(l,2,3-thiadiazol-4-ylcarbonyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one; l-(2,2-dimethylpropyl)-5-[(li?,4i?)-5-(isoxazol-3-ylcarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]- 3-methyl- 1 ,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[(li?,4i?)-5-(l,3-oxazol-2-ylcarbonyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[(li?,4i?)-5-(pyridin-3-ylcarbonyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[(15^

yl]-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one; l-(2,2-dimethylpropyl)-3-methyl-5-[(li?,4^

yl]-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one; ethyl (15',45)-5-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-¾]pyridin- 5 -y 1] -2 , 5 -diazabicy clo [2.2.1] heptane -2-carboxy late ; ethyl (li?,4i?)-5-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5-¾]pyridin- 5 -y 1] -2 , 5 -diazabicy clo [2.2.1] heptane -2-carboxy late ; tert-butyl 5- { 1 -[(2,2-difluorocyclopropyl)methyl]-3-methyl-2-oxo-2,3-dihydro- lH-imidazo[4,5- ¾]pyridin-5-yl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate; tert-butyl 5- { 1 -[(2,2-difluoro- 1 -methylcyclopropyl)methyl]-3-methyl-2-oxo-2,3-dihydro- 1H- imidazo[4,5-¾]pyridin-5-yl}-2,5-diazabicyclo[2.2.2]octane-2-carboxylate; l-[(2,2-Difluorocyclopropyl)methyl]-5-[5-(isoxazol-3-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2 yl]-3-methyl-l ,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one;

1 - [(2,2-Difluoro- 1 -methylcyclopropyl)methy 1] -5 - [5 -(isoxazol-3 -ylcarbonyl)-2,5 - diazabicyclo[2.2.2]oct-2-yl]-3-methyl-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2-one;

5-[5-(Isoxazol-3-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]-3-methyl-l-(4,4,4-trifluoro-2,2- dimethylbutyl)- 1 ,3-dihydro-2H-imidazo[4,5-£]pyridin-2-one; l-(cyclopropylmethyl)-5-[5-(isoxazol-3-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]-3-methyl- l,3-dihydro-2H-imidazo[4,5-£]pyridin-2-one;

5-[5-(isoxazol-3-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]-3-methyl-l-[(l- methylcyclopropyl)methyl]- 1 ,3-dihydro-2H-imidazo[4,5-£]pyridin-2-one; and l-(cyclobutylmethyl)-5-[5-(isoxazol-3-ylcarbonyl)-2,5-diazabicyclo[2.2.2]oct-2-yl]-3-methyl- l,3-dihydro-2H-imidazo[4,5-£]pyridin-2-one; or a pharmaceutically acceptable salt of any of the foregoing compounds.

13. A pharmaceutical composition comprising a compound according to Claim 1 in combination with a pharmaceutically acceptable carrier.

14. A method for treating a neurological or psychiatric disorder associated with glutamate dysfunction in a patient in need thereof comprising administering to the patient therapeutically effective amount of a compound according to Claim 1.

15. The method according to Claim 14 wherein the neurological or psychiati disorder associated with glutamate dysfunction is schizophrenia.