OA17458A - Azabenzimidazole compounds as inhibitors of PDE4 isozymes for the treatment of CNS and other disorders. - Google Patents

Abstract

The present invention is directed to compounds of formula (I) : or a pharmaceutically acceptable salt thereof, wherein the substituents are as defined herein. The compounds of formula (I) are useful as inhibitors of PDE4 for the treatment of CNS and other disorders.

Description

The présent invention relates to azabenzimidazole compounds of formula I, which are inhibitors of PDE4 isozymes, especially with a binding affinity for the PDE4B isoform, and to the use of such compounds in methods for treating certain central nervous system (CNS), metabolic, autoimmune and înflammatory diseases or disorders.

Background of the Invention

Phosphodiesterases (PDEs) are a class of intracellular enzymes involved in the hydrolysis of the nucléotide cyclic adenosine monophosphate (cAMP) into adenosine 5’monophosphate (AMP). The cyclic nucléotide cAMP is synthesized by adenylyl cyclase, and serves as a secondary messenger in various cellular pathways.

cAMP functions as a second messenger regulating many intracellular processes within the body. An example is in the neurons of the central nervous system, where the activation of cAMP-dependent kinases and the subséquent phosphorylation of proteins is involved in acute régulation of synaptic transmission as well as neuronal différentiation and survival. The complexity of cyclic nucléotide signaling is indicated by the molecular diversity of the enzymes involved in the synthesis and dégradation of cAMP. There are at least ten families of adenylyl cyclases, and eleven familles of phosphodiesterases. Furthermore, different types of neurons are known to express multiple isozymes of each of these classes, and there is good evidence for compartmentalization and specificity of function for different isozymes within a given neuron.

A principal mechanism for regulating cyclic nucléotide signaling is via phosphodiesterase-catalyzed cyclic nucléotide catabolism. The 11 known families of PDEs are encoded by 21 different genes; each gene typically yields multiple splice variants that further contribute to the isozyme diversity. The PDE families are distinguished functionally 30 based on cyclic nucléotide substrate specificity, mechanism(s) of régulation, and sensitivity to inhibitors. Furthermore, PDEs are differentiaily expressed throughout the organisai, including in the central nervous system. As a resuit of these distinct enzymatic activities and localization, different PDEs' isozymes can serve distinct physiological functions. Furthermore, compounds that can selectively inhibit distinct PDE isozymes may offer 35 particular therapeutic effects, fewer side effects, or both (Deninno, M., Future Directions in

i

Phosphodiesterase Drug Discovery. Bioorganic and Médicinal Chemistry Letters 2012, 22, 6794-6800).

The présent invention relates to compounds having a binding affinity for the fourth family of PDEs (i.e., PDE4A, PDE4B, PDE4C, and PDE4D), and, in particular, a binding affinity for the PDE4B isoform. In addition to affinity for the PDE4B isoform, the compounds of the présent invention also hâve affinity for the PDE4A and PDE4C isoforms.

The PDE4 isozymes are characterized by sélective, high-affinity hydrolytic dégradation of the second messenger cyclic adenosine 3',5’-monophosphate (cAMP), and by sensitivity to inhibition by Rolipram™ (Schering AG); bénéficiai pharmacological effects resulting from that inhibition hâve been shown in a variety of disease models. A number of other PDE4 inhibitors hâve been discovered in recent years. For example, Roflumilast (Daliresp®), marketed by Forest Pharmaceuticals, Inc., is approved for severe chronic obstructive pulmonary disease (COPD) to decrease the number of flare-ups or the worsening of COPD symptoms (exacerbations). Apremilast (Celgene Corp.) is in Phase III development and clinical trials hâve shown apremilast to be effective for the treatment of psoriasis (Papp, K. et al., Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomized controlled trial. Lancet 2012; 380(9843):738-46).

While bénéficiai pharmacological activity of PDE4 inhibitors has been shown, a common side-effect of these treatments has been the induction of gastrointestinal side effects such as nausea, emesis, and diarrhea, which is currently believed to be associated with inhibition of the PDE4D isoform. Attempts were made to deveiop compounds with an 25 affinity for the PDE4B isoform over the PDE4D isoform (See: Donnell, A. F. et al.,

Identification of pyridazino[4,5-b]indolizines as sélective PDE4B inhibitors. Bioorganic & Médicinal Chemistry Letters 2010; 20:2163-7; and Naganuma, K. et al., Discovery of sélective PDE4B inhibitors. Bioorganic & Médicinal Chemistry Letters 2009; 19:3174-6).

However, there remains a need to deveiop PDE4 inhibitors, especially those having an affinity for the PDE4B isoform. In particular, there remains a need to deveiop compounds that hâve enhanced binding affinity for the PDE4B isoform over the PDE4D isoform for the treatment of various diseases and disorders of the central nervous System (CNS). The discovery of selected compounds of the présent invention addresses this continued need, and provides additional thérapies for the treatment of various diseases and disorders of the central nervous system (CNS), as well as metabolic, autoimmune and inflammatory diseases or disorders. Such diseases and disorders include, but are not limited to,

neurodegenerative or psychiatrie disorders, including psychosis, rmpaired cognition, schizophrenia, anxiety, dépréssion (e.g., major dépressive disorder), dementia, Alzheimer’s disease, Huntington's disease, multiple sclerosis, muscular dystrophy, sickle cell disease and diabètes.

Treatment with the PDE4B inhibitors of the présent invention may also lead to a decrease in gastrointestinal side effects (e.g., nausea, emesis and diarrhea) believed to be associated with inhibition of the PDE4D isoform (Robichaud, A. et al., Délétion of Phosphodiesterase 4D in Mice Shortens a2-Adrenoreceptor-Mediated Anesthésia, A Behavioral Correlate of Emesis. Journal of Clinical Investigation 2002, Vol. 110, 1045-1052).

In addition to the development of compounds having affinity for the PDE4B isoform, there remains a need to develop compounds having an affinity for the PDE4A and PDE4C isoforms. The discovery of selected compounds of the présent invention having affinity for the PDE4A and PDE4C isoforms also provides for the treatment of various diseases and disorders of the central nervous system (CNS), as well as treatment for various metabolic, autoimmune and inflammatory diseases or disorders,

Summarv of the Invention

The présent invention is directed to compounds of formula I:

or a pharmaceutically acceptable sait thereof, wherein:

R¹ is represented by a substituent selected from the group consisting of (C3C10)cycloalkyl, a (4- to 10-membered)heterocycloalkyl, (C6-C10)aryl, and a (5- to 10membered) heteroaryl; wherein said (C3-C10)cycloalkyl, (C6-Cw)aryl and (5- to 10membered)heteroaryl are optionally substituted with (R^a)b; and said (4- to 10membered)heterocycloalkyl is optionally substituted at one to five carbon atoms with a substituent independently selected from the group consisting of halogen, (Ci-C₆)alkyl, haloiCrCeialkyl, (CrCeJalkoxy, halo(CrC₆)alkoxy, (CrCeJalkylthio, -C(O)NR⁴R⁵, hydroxy, and cyano, and optionally substituted at each available nitrogen with (Ci-C₆)alkyl;

R² is represented by a substituent independently selected from the group consisting of halogen, (CrCeJalkyl, halo(Ci-C₆)alkyl, (CrC₆)alkoxy, haloiCrCeJalkoxy, (Ci-C₆)alkylthio;

-C(O)NR⁴R^E, hydroxy, and cyano;

R³, if présent, at each occurrence is represented by a substituent independently selected from the group consisting of halogen, (Ci-C₆)alkyl, haio(Ci-C₆)alkyl, (Ci-C₆)alkoxy, halo(Ci-C₆)alkoxy, (Ci-C_B)alkylthio, -C(O)NR⁴R⁵, hydroxy, and cyano;

R⁴ and R^s are each represented by a substituent independently selected from the group consisting of hydrogen, (CrC₆)alkyl, and (C₃-C₆)cycloalkyl;

R⁶ and R⁷ are each represented by a substituent independently selected from the group consisting of hydrogen, (CrC6)alkyl, -(CH2)m-(C3-C1o)cycloalkyl, -(CH2)m-(4- to 10membered) heterocycloalkyl, -(CH2)m-(C6-C10)aryl, and -(CH2)m-(5- to 10memberedjheteroaryl; wherein said (Ci-C6)alkyl, (C3-C10)cycloalkyl, (C6-Ci0)aryl, and (5- to 10-membered)heteroaryl are optionally substituted with one to five substituents independently selected from the group consisting of halogen, (CrC6)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy, halotCrCeialkoxy, (CrCeJalkylthio, -C(O)NR⁴R⁵, hydroxy, and cyano; and said (4- to 10-membered)heterocycloalkyl is optionally substituted at one to five carbon atoms with a substituent independently selected from the group consisting of halogen, (Cr C₆)alkyl, halo(Ci-C₆)alkyl, (C_rC₆)alkoxy, halo(C_rC₆)alkoxy, (Ci-C₆)alkylthio, -C(O)NR⁴R⁵, hydroxy, and cyano, and optionally substituted at each available nitrogen with (CrC6)alkyl; or R⁶ and R⁷ taken together with the nitrogen to which they are attached form a (4- to 10membered)heterocycloalkyl, wherein said (4- to 10-membered)heterocycloalkyl is optionally substituted at one to five carbon atoms with a substituent independently selected from the group consisting of halogen, (CrCeJalkyl, halo(CrC₆)alkyl, (Ci-C₆)alkoxy, haloiCrC^alkoxy, (CrCeJalkylthio, -C(O)NR⁴R^S, hydroxy, and cyano;

a is represented by an integer selected from 0, 1, 2 or 3;

b is represented by an integer selected from 0,1, 2, 3, 4 or 5; and m is represented by an integer selected from 0, 1, 2, or 3.

Compounds of the invention include Examples 1-92 or a pharmaceutically acceptable sait thereof as described herein.

The compounds of formula I are inhibitors of the PDE4B isoform.

In addition, the compounds of formula I are inhibitors of the PDE4A and PDE4C isoforms.

The compounds of formula I are useful for treating or preventing neurodegenerative or psychiatrie disorders, including, but not limited to, cognitive dysfunction, psychosis, 5 schizophrenia, dépréssion, dementia, anxiety, bipolar affective disorder, Parkinson’s disease, Alzheimer’s disease (AD), Huntington's disease (HD), multiple sclerosis (MS), and neuroinflammatory disorders as well as a host of other diseases or disorders in a mammal associated with PDE4B isoform activity. Additional diseases and disorders include, but are not limited to, pain, cancer, immunodeficiency diseases (e.g., psoriasis and arthritis), 10 inflammation, asthma, chronic obstructive pulmonary disease (COPD), diabètes, muscular dystrophy, sickle cell disease, cardiovascular diseases, cérébral vascular disease, stroke and allergie conjunctivitis.

The présent invention is also directed to the use of a compound of the présent invention, or a pharmaceutically acceptable sait thereof, in the préparation of a médicament 15 for the treatment or prévention of a condition amenable to modulation of the PDE4B gene family (i.e., PDE4B enzymes) which consists of various splice variants such as PDE4B1, B2, B3, PDE4B4, and B5 protein. Examples of conditions include, but are not limited to, cognitive dysfunction, psychosis, schizophrenia, dépréssion, dementia, anxiety, bipolar affective disorder, Parkinson’s disease, Alzheimer’s disease (AD), Huntington's disease 20 (HD), multiple sclerosis (MS), and neuroinflammatory disorders as well as a host of other diseases or disorders in a mammal associated with PDE4B isoform activity, such as, but not limited to, pain, cancer, immunodeficiency diseases (e.g., psoriasis and arthritis), inflammation, asthma, chronic obstructive pulmonary disease (COPD), diabètes, muscular dystrophy, sickle cell disease, cardiovascular diseases, cérébral vascular disease, stroke 25 and allergie conjunctivitis.

The présent invention is also directed to pharmaceutically acceptable formulations containing an admixture of a compound(s) of the présent invention and at least one excipient formulated into a pharmaceutical dosage form. Examples of such dosage forms include tablets, capsules, solutions/suspensions for injection, aérosols for inhalation and 30 solutions/suspensions for oral ingestion.

Detailed Description of the Invention

The headings within this document are only being utilized to expedite rts review by the reader. They should not be construed as limiting the invention or claims in any manner.

Définitions and Exemplifications

As used throughout this application, including the claims, the following terms hâve the meanings defîned below, unless specificaily indicated otherwise. The plural and singular should be treated as interchangeable, other than the indication of number:

“(Ci-C₆)alkyl” as used herein, refers to a branched- or straight-chain alkyl group contaîning from 1 to 6 carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyi, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

“halo” or “halogen” as used herein, refers to a chlorine, fluorine, bromine, or iodine atom.

“halo(Ci-C₆)alkyl” as used herein, refers to a (CrC^alkyl group, as defîned above, wherein at least one hydrogen atom is replaced with a halogen, as defîned above. Représentative examples of a halo(CrC₆)alkyl include, but are not limited to, chloromethyl,

2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.

“(CrCejalkoxy as used herein, refers to a (CrCgjalkyl group, as defîned above, 15 attached to the parent molecular moiety through an oxygen atom. Représentative examples of a (CrCejalkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, fert-butoxy, pentyloxy, and hexyloxy.

“halo(Ci-C₆)alkoxy as used herein, refers to a (Ci-C₆)alkoxy group, as defîned above, wherein at least one hydrogen atom is replaced with a halogen, as defîned above. 20 Représentative examples of a halofCi-Cejalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.

“thio as used herein, means -S (sulfur).

'‘(CrC₆)alkylthio” as used herein, means a (CrCgJalkyl group, as defîned herein, attached to the parent molecular moiety through a sulfur atom. Représentative examples of 25 a (Ci-C₆)alkylthio include, but are not limited to, methylthio, ethylthio, propylthio, and butylthio.

^,r(C3-C_1o)cycloalkyl” as used herein, refers to a saturated or partially saturated monocyclic, bicyclic, bridged bicyclic or tricyclic alkyl radical wherein the cyclic framework has 3 to 10 carbons. Examples of monocyclics include cyclopropyl, cyclobutyl, cyclopentyi, 30 cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyciodecyl. Alternatively, a cycloalkyl may be a bicyclic ring such as a bicycloalkyl. The bicycloalkyl may be a fused system, such as bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[2.2.0]hexane, bicyclo[3.1.0]hexane,

bicyclo[3.2.0]heptane, and bicyclo[3.3.0]octane. The term “bicycloalkyl” also includes bridged bicycloalkyl Systems such as, but not limited to, bicyclo[2.2.1]heptane and bicyclo[1.1.1]pentane. The cycloalkyl may also be a bicyclic ring such that a monocyclic ring is fused to an aryl or heteroaryl ring. In this case, a group having such a fused cycloalkyl group as a substituent is bound to a carbon atom of the saturated or partially saturated ring. For example, a cycloalkyl moiety may include, but is not limited to, 2,3-dihydro-1H-inden-2yi'‘heterocycloalkyl, as used herein, refers to a substituent obtained by removing a hydrogen from a saturated or partially saturated ring structure, wherein at least one of the

V ring atoms is a heteroatom selected from oxygen, nitrogen or sulfur. For example, as used herein, the term “(4- to 6-membered)heterocycloalkyl means the substituent contains a total of 4 to 6 ring atoms. A “(4- to 10-membered)heterocycloalkyl means the substituent contains a total of 4 to 10 ring atoms. A heterocycloalkyl may be a single ring with up to 10 total members. Alternatively, a heterocycloalkyl as defined above may comprise 2 or 3 rings fused together, wherein at least one such ring contains a heteroatom as a ring atom (i.e., nitrogen, oxygen, or sulfur). In a group that has a heterocycloalkyl substituent, the ring atom of the heterocycloalkyl substituent that is attached to the group may be the at least one heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom. Similarly, if the heterocycloalkyl substituent is in turn substituted with a group or substituent, the group or substituent may be bound to the at least one heteroatom, or it may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be rn a different ring from the at least one heteroatom.

The term ‘‘heterocycloalkyl” also includes substituents that are fused to a C₆-Ci₀ aromatic ring or a (5- to 10-membered)heteroaromatic ring, wherein a group having such a fused heterocycloalkyl group as a substituent is bound to a heteroatom of the heterocycloalkyl group or to a carbon atom of the heterocycloalkyl group. When such a fused heterocycloalkyl group is substituted with one or more substituents, the one or more 30 substituents, unless otherwise specified, are each bound to a heteroatom of the heterocycloalkyl group or to a carbon atom of the heterocycloalkyl group. The fused C₆-C₁₀ aromatic ring or a (5- to 10-membered)heteroaromatic ring may be optionally substituted with halogen, (Ci-C₆)alkyl, (C₃-Cio)cycloalkyl, (Ci-C₆)alkoxy or =O. Examples of heterocycloalkyl substituents include, but are not limited to, tetrahydroquinolyl, dihydrobenzofuryl and the like. Other heterocycloalkyl rings include: azetidinyl,

8'

dihydrofuranyl, tetra hydropyranyl, dihydrothiophenyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, azepane, azocane, morpholinyl, isochromyl, tetrahydrotriazine, tetrahydropyrazole, dihydro-1H-isoindole, tetrahydro-oxazolyl, tetrahydrooxazinyl, thiomorpholinyl, tetrahydropyrimidinyl, octahydrobenzofuranyl, octahydrobenzîmidazolyl, and octahydrobenzothiazolyl.

“(C₆-Cio)aryr refers to an aromatic substituent containing from 6 to 10 carbon atoms, including one ring or two fused rings such as phenyl, or naphthyl,. The term “aryl” also includes substituents such as phenyl and naphthyl that are fused to a (C₄-C₆)cycloalkyl or (C₄-C₁₀)heterocycloalkyl, wherein a group having such a fused aryl group as a substituent is 10 bound to an aromatic carbon of the aryl group. When such an aryl group is substituted with one or more substituents, the one or more substituents, unless otherwise specified, are each bound to an aromatic carbon of the fused aryl group. The fused (C₃-C₆)cycloalkyl or (C₄Cio)heterocycloalkyl ring may be optionally substituted with halogen, (Ci-C₆)alkyl, (C₃Cio)cycloalkyl, or = O. Examples of aryl groups include, but are not limited to, phenyl, 15 naphthyl, indanyl (e.g., 2,3-dihydro-l/-/-inden-5-yl), indenyl and dihydrobenzofuranyl (e.g.,

1,3-dihydro-2-benzofuran-5-yl),.

“(5- to 1O'membered)heteroaryl” refers to an aromatic ring having from 5 to 10 ring atoms in which at least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group 20 consisting of carbon, oxygen, nitrogen, and sulfur. A heteroaryl may be a single ring or 2 or 3 fused rings. In a group that has a heteroaryl substituent, the ring atom of the heteroaryl substituent that is bound to the group may be the at least one heteroarom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one 25 heteroatom. Similarly, if the heteroaryl substituent is in turn substituted with a group or substituent, the group or substituent may be bound to the at least one heteroarom, or it may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom, or where the ring carbon atom may be in a different ring from the at least one heteroatom.

The term “heteroaryl also includes substituents such as pyridyl and triazolyl that are fused to a (C₄-Ci₀)cycloalkyl group, or to a (4- to 10-membered)heterocycloalkyl group, wherein a group having such a fused heteroaryl group as a substituent is bound to an aromatic carbon of the heteroaryl group or to a heteroatom of the heteroaryl group. When such a fused heteroaryl group is substituted with one or more substituents, the one or more substituents, unless otherwise specified, are each bound to an aromatic carbon of the

heteroaryl group or to a heteroatom of the heteroaryl group. The fused (C₄-Ci₀)cycloalkyl group or (4- to 10-membered)heterocycloalkyl group may be optionally substitued with halogen, (CrC₆)alkyl, (C₃-C₁₀)cycloalkyl, or =0. Examples of heteroaryls include, but are not limited to, 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl and pyridazinyl; 5-membered heteroaryls such as triazolyl, imidazolyl, furanyl, isoxazolyl, isothîazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl, oxazolyl, thiophenyl, thiazolyl, and pyrazolyl. Représentative examples of bicyclic heteroaryls include, but are not limited to, benztmidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzothiazolyl (e.g., 1,3benzothiazol-6-yl and 2-methyl-1,3-benzothiazol-6-yl), benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, 1,4-benzoxazinyl, cinnolinyl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, purinyl, quinolinyl, quinazolinyl, 5,6,7,8-tetrahydroquinolrnyl, thienopyridinyl, and triazolopyridinyl (e.g., 5_l6,7,8-tetrahydro[1_l2,4]triazolo[1,5-a]pyridin-2-yl), hydroxy” or hydroxyl” as used herein, means an -OH group.

“cyano” as used herein, means a -CN group, which also may be depicted:

“optionally substituted as used herein, means that substitution is optional and therefore includes both unsubstituted and substituted atoms and moieties. A “substituted” atom or moiety indicates that any hydrogen on the designated atom or moiety can be replaced with a sélection from the indicated substituent group (up to and including that every hydrogen atom on the designated atom or moiety is replaced with a sélection from the 20 indicated substituent group), provided that the normal valency of the designated atom or moiety is not exceeded, and that the substitution results in a stable compound. For example, if a methyl group (i.e., CH₃) is optionally substituted, then up to 3 hydrogen atoms on the carbon atom can be replaced with substituent groups.

As used herein, unless specified, the point of attachment of a substituent can be from any suitable position of the substituent. For example, pyridinyl (or pyridyl) can be 2-pyridinyl (or pyridin-2-yl), 3-pyridinyl (or pyridin-3-yl), or 4-pyridinyl (or pyridin-4-yl).

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any of the ring-forming atoms in that ring that are substitutable (i.e., bonded to one or more hydrogen atoms). For example, as shown in 30 formula la below, R² may be bonded to any ring-forming atom that is substitutable (i.e., bonded to one or more hydrogen atoms).

“Therapeutically effective amount” refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.

Patient refers to warm blooded animais such as, for example, pigs, cows, chickens, horses, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, monkeys, chimpanzees, and humans.

Treating or treat”, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term treatment, 10 as used herein, unless otherwise indicated, refers to the act of treating as treating is defined immediately above. The term “treating” also includes adjuvant and neo-adjuvant treatment of a subject.

“Pharmaceutically acceptable îndicates that the substance or composition must be compatible, chemicaily and/or toxicologically, with the other ingrédients comprising a 15 formulation, and/or the mammal being treated therewith.

“Isoform” means any of several different forms of the same protein.

“Isozyme” or “isoenzyme” means a closely related variant of an enzyme that differs in amino acid sequence but catalyzes the same chemical reaction.

“Isomer” means “stereoisomer” and “géométrie isomer” as defined below.

“Stereoisomer” refers to compounds that possess one or more chiral centers, which may each exist in the R or S configuration. Stereoisomers include ail diastereomeric, enantiomeric and epimeric forms as well as racemates and mixtures thereof.

“Géométrie isomer refers to compounds that may exist in cis, trans, anti, entgegen (E), and zusammen (Z) forms as well as mixtures thereof.

This spécification uses the terms “substituent,” “radical, and group interchangeably.

If substituents are described as being “independently selected from a group, each instance of a substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s).

As used herein the terms formula I and ‘formula la” may be hereinafter referred to as a compound(s) of the invention.” Such terms are also defined to include ail forms of the compound of formulas I, and la, încluding hydrates, solvatés, isomers, crystalline and noncrystalline forms, isomorphe, polymorphs, and métabolites thereof. For example, the compounds of the invention, or pharmaceutically acceptable salts thereof, may exist in unsoivated and solvated forms. When the solvent or water is tighfly bound, the complex will hâve a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvatés and hygroscopic compounds, the water/solvent content will be dépendent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

The compounds of the invention may exist as clathrates or other complexes.

Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein the drug and host are présent in stoichiometrrc or nonstoichiometric amounts. Also included are complexes of the compounds of the invention 15 containîng two or more organic and/or inorganic components, which may be in stoichiometrrc or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J. Pharm. Scl, 64 (8), 1269-1288 by Haleblian (August 1975).

The compounds of the invention hâve asymmetric carbon atoms. The carbon-carbon 20 bonds of the compounds of the invention may be depicted herein using a solid line (------), a solid wedge ( ), or a dotted wedge ( ). The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that ail possible stereoisomers (e.g., spécifie enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to 25 indicate that the stereoisomer shown is présent. When présent in racemic compounds, solid and dotted wedges are used to define relative stereochemistry, rather than absolute stereochemistry. Racemic compounds possessing such indicated relative stereochemistry are marked with (+/-). For example, unless stated otherwise, it is intended that the compounds of the invention can exist as stereoisomers, which include cis and trans isomers, 30 optical isomers such as R and S enantiomers, diastereomers, géométrie isomers, rotational isomers, conformatîonal isomers, atropoisomers, and mixtures thereof (such as race mates and diastereomeric pairs). The compounds of the invention may exhibit more than one type of isomerism. Also included are acid addition or base addition salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or 35 DL-arginine.

When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.

The compounds of this invention may be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, a sait of the compound may be advantageous due to one or more of the salt’s physical properties, such as enhanced pharmaceutical stability in differing températures and humidifies, or a désirable 10 solubility in water or oil. In some instances, a sait of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.

Where a sait is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context), the sait preferably is pharmaceutically acceptable. The term pharmaceutically acceptable sait refers to a sait prepared by combining a compound 15 of the présent invention with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption. Pharmaceutically acceptable salts are particularly useful as products of the methods of the présent invention because of their greater aqueous solubility relative to the parent compound.

Suitable pharmaceutically acceptable acid addition salts of the compounds of the 20 présent invention when possible include those derived from inorganic acids, such as, but not limited to, hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphorîc, metaphosphoric, nitric, carbonic, sulfonic, and suifuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactîc, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, 25 toluenesulfonic, tartaric, and trifluoroacetic acids. Suitable organic acids generally include but are not limited to aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.

Spécifie examples of suitable organic acids include but are not limited to acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, 30 malate, tartrate, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilate, stéarate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminoulfonate, algenic acid, β-hydroxybutyric acid, galactarate, galacturonate, adîpate, alginate,

butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycérophosphate, heptanoate, hexanoate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, thiocyanate, and undecanoate.

Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali métal salts, e.g., sodium or potassium salts; alkaline earth métal salts, e.g., calcium or magnésium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. In another embodiment, base salts are formed from bases which form non-toxic salts, including 10 aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine, tromethamine and zinc salts.

Organic salts may be made from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine, Λ/,Λ/’-dibenzylethylenediamine, chloroprocaîne, choline, diethanol- amine, ethylenediamîne, meglumine (N-methylglucamine), and procaine. Basic 15 nitrogen- containing groups may be quaternized with agents such as lower alkyl (Ci-C₆) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and others.

In one embodiment, hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

Certain compounds of the invention may exist as géométrie isomers. The compounds of the invention may possess one or more asymmetric centers, thus existing as two, or more, stereoisomeric forms. The présent invention includes ail the individual 25 stereoisomers and géométrie isomers of the compounds of the invention and mixtures thereof. Individual enantiomers can be obtained by chiral séparation or using the relevant enantiomer in the synthesis.

In addition, the compounds of the présent invention can exist in unsolvated as well as soivated forms with pharmaceutically acceptable solvents such as water, éthanol and the 30 like. In general, the soivated forms are considered équivalent to the unsolvated forms for the purposes of the présent invention. The compounds may also exist in one or more crystalline states, i.e., polymorphs, or they may exist as amorphous solids. Ail such forms are encompassed by the claims.

Also within the scope of the présent invention are so-called “prodrugs of the compound of the invention. Thus, certain dérivatives of the compound of the invention that may hâve little or no pharmacological activity themselves can, when administered into or onto the body, be converted into the compound of the invention having the desired activity, for example, by hydrolytic cleavage. Such dérivatives are referred to as “prodrugs. Further information on the use of prodrugs may be found in “Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Sériés (T. Higuchi and W. Stella) and “Bioreversible Carriers in Drug Design,” Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association). Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities présent in the compounds of the présent invention with certain moieties known to those skilled in the art as “pro-moieties” as described, for example, in “Design of Prodrugs” by H. Bundgaard (Elsevier, 1985).

This invention also encompasses compounds of the invention containing protective groups. One skilled in the art will also appreciate that compounds of the invention can also 15 be prepared with certain protecting groups that are useful for purification or storage and can be removed before administration to a patient. The protection and deprotection of functional groups is described in “Protective Groups in Organic Chemistry, edited by J. W. F. McOmie, Plénum Press (1973) and “Protective Groups in Organic Synthesis”, 3rd édition, T. W. Greene and P. G. M. Wuts, Wiley-lnterscience (1999).

The présent invention also includes ail pharmaceutically acceptable isotopicallylabeled compounds, which are identical to those recited in formulas I and la, wherein one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which prédominâtes in nature. Examples of isotopes suitable for inclusion in the compounds of the présent invention include, but are not limited to, isotopes of hydrogen, such as ²H, ³H; carbon, such as ¹¹C, ¹³C, and ¹⁴C; chlorine, such as ³⁶CI; fluorine, such as ^,0F; iodine, such as ¹²³l and ¹²⁵l;

nitrogen, such as ¹³N and ¹⁵N; oxygen, such as ^1SO, ¹⁷O, and ¹⁸O; phosphorus, such as ^{20 * * * * 25 * * * * 30 * 32 * *}P;

and sulfur, such as ³⁵S. Certain isotopically-labeled compounds of the présent invention, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies (e.g., assays). The radioactive isotopes tritium, i.e., ³H, and carbon-14,

i.e., ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of détection. Substitution with heavier isotopes such as deuterium, i.e., ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-lîfe or reduced dosage requirements and, hence, may be preferred in some circumstances. Substitution with positron emitting isotopes, such as ¹¹C,

¹⁵F, ¹⁵0 and ¹³N, can be useful in positron émission tomography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of the présent invention can generally be prepared by conventîonal techniques known to those skilled in the art or by processes analogous to those described in the accompanying Schemes and/or in the 5 Examples and Préparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed. Pharmaceutically acceptable solvatés in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g., D₂O, acetone-d,₃, or DMSO-d₆. Compounds of formula l and formula 1a, as well as the compounds exemplified in Examples 1-92 described below, 10 include isotopically-labeled versions of these compounds, such as, but not limited to, the deuterated and tritiated isotopes and ail other isotopes dîscussed above.

Compounds

The présent invention is directed to azabenzimidazole compounds of formula I as described above. In certain embodiments, the pyridine ring of the imidazopyridine core does 15 not contain any substitutions on the ring. In these instances the “a of the (R³)_a substituent is represented by the integer 0.

To further elucidate the compounds of the présent invention, the following subgenus is described below.

Formula la depicted below is a subset of formula I as depicted, wherein R¹ is 20 represented by a phenyl optionally substituted with (R²)t>; and a is represented by the integer 0. In formula la, b is represented by an integer selected from 0, 1, 2, or 3; each R², if présent, is represented by a substituent independently selected from the group consisting of fluoro, chloro, cyano, methyl, trifluoromethyl, methylthio, methoxy, and trifluoromethoxy; R⁶ and R⁷ are each independently selected from the group consisting of hydrogen, (CpCeJalkyl, 25 -(CH2)m-(C3-Ci0)cycloalkyl, and -(CH2)m-(5- to 10-membered)heteroaryl, wherein said (Cr C6)alkyl, (C3-Ci0)cycloalkyl, and (5 to 10-membered)heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of halogen, (C,C6)alkyl, halo(Ct-C6)alkyl, (C;-C6)alkoxy, halofCrC^alkoxy, (Ci-C6)alkylthio, -C(O)NR⁴R^S, hydroxy, and cyano; or R⁶ and R⁷ taken together with the nitrogen to which they are attached 30 form a (4- to 6-membered)heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted at one to three carbon atoms with a substituent independently selected from the group consisting of halogen, (Ci-C6)alkyl, halo(Ci-C₆)alkyl, (CrC₆)alkoxy, halo(Ci-C₆)alkoxy, (Ci-C₆)alkylthio, -C(O)NR⁴R⁵, hydroxy, and cyano; wherein R⁴ and R^s are each

independently selected from the group consisting of hydrogen and (CrC₆)alkyl; and m is represented by an integer 0, 1, or 2:

In certain embodiments of the invention, in formula la as depicted above, b is represented by an integer selected from 0,1, 2, or 3; each R², if présent, is represented by a substituent independently selected from the group consisting of chloro, fluoro, methyl and cyano; one of R⁶ and R⁷ is represented by hydrogen, and the other is represented by a substituent selected from the group consisting of (Ci-C₆)alkyl, -(CH₂)_m-(C₃-C₁₀)cycloalkyl, and ~(CH₂)_m-(5- to 10-membered)heteroaryl, wherein said (C_rC₆)alkyl, (C3-C₁₀)cycloalkyl, 10 and (5 to 10-membered)heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of halogen, (Ci-C₆)alkyl, halofCrCsialkyl, (CrC₆)alkoxy, halo(Ci-C₆)alkoxy, (CrCeJalkylthio, -C(O)NR⁴R⁵, hydroxy, and cyano.

In certain embodiments of the invention, in formula la as depicted above, b is an integer selected from 0, 1, 2, or 3; each R², if présent, is represented by a substituent 15 independently selected from the group consisting of chloro, fluoro, methyl, and cyano; one of R⁶ and R⁷is represented by hydrogen, and the other is represented by (CrCeJalkyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, (Ci-C₆)alkyl, halo(Ci-C₆)alkyl, (Ci-C_e)alkoxy, halo(CrC₆)alkoxy, (C_rC₆)alkylthio, hydroxy, and cyano. In certain embodiments, one of R⁶ and R⁷ is represented by hydrogen, 20 and the other is represented by a substituent selected from the group consisting of ethyl and propyl. In certain embodiments, one of R⁶ and R⁷ is represented by hydrogen, and the other is represented by propyl.

In certain other embodiments of the invention, in formula la as depicted above, b is represented by an integer selected from 0, 1, 2, or 3; each R³, if présent, is represented by a 25 substituent independently selected from the group consisting of chloro, fluoro, methyl, and cyano; one of R⁶ and R⁷ is represented by hydrogen, and the other is represented by (CH₂)_m-(C₃-C₁₀)cycloalkyl optionally substituted with one to three substituents independently

selected from the group consisting of halogen, (Ci-C₆)alkyl, halo(Ci-C_B)alkyl, (CrC₆)alkoxy, halo(Ci-C_e)alkoxy, (Ci-C₆)alkylthio, hydroxy, and cyano; and m is represented by an integer selected from 0, 1, or 2. In certain embodiments, one of R⁵ and R⁷ is represented by hydrogen, and the other is represented by cyclopropyl.

In certain other embodiments of the invention, in formula la as depicted above, b is represented by an integer selected from 0, 1,2, or 3; each R², if présent, is represented by a substituent independently selected from the group consisting of chloro, fluoro, methyl, and cyano; one of R⁶ and R⁷ is represented by hydrogen, and the other îs represented by (CH2)m'(5- to 10-membered)heteroaryl optionally substituted with one to three substituents 10 independently selected from the group consisting of halogen, (CrC6)alkyl, haloiCrCejalkyl, (Ci-C6)alkoxy, halo(CrC6)alkoxy, (Ci-C6)alkylthio, hydroxy, and cyano, wherein m is represented by an integer selected from 0, 1, or 2. In certain embodiments, one of R⁶ and R⁷ rs represented by hydrogen, and the other is represented by pyrazolyl optionally substituted by a (Ci-C6)alkyl. In certain embodiments, one of R⁶ and R⁷ is represented by hydrogen, 15 and the other is represented by /V-methylpyrazolyl (e.g., N-methylpyrazol-3-yl).

In certain embodiments of the invention, in formula la, b is represented by an integer selected from 0, 1,2, or 3; each R², if présent, is represented by a substituent independently selected from the group consisting of fluoro, chloro, cyano, methyl, trifluoromethyl, methylthîo, methoxy, and trifluoromethoxy; R⁶ and R⁷ taken together with the nitrogen to 20 which they are attached form a (4- to 6'membered)heterocycloalkyl optionally substituted at one to three carbon atoms with a substituent independently selected from the group consisting of halogen, (Ci-CB)alkyl, hafoiCrCeJalkyl, (Ci-C6)alkoxy, halo(Ci-C6) alkoxy, (Cr C6)alkylthio, -C(O)NR⁴R⁵, hydroxy, and cyano, wherein R⁴ and R⁵ are each independently selected from the group consisting of hydrogen and (CrC₆)alkyl.

In certain other embodiments of the invention, in formula la as depicted above, b is represented by an integer selected from 0, 1,2, or 3; each R², if présent, is represented by a substituent independently selected from the group consisting of chloro, fluoro, methyl and cyano; and R⁶ and R⁷ taken together with the nitrogen to which they are attached form an azetidine ring optionally substituted with one to three halogen. In certain embodiments R⁶ 30 and R⁷ taken together with the nitrogen to which they are attached form 3-fluoro-azetidin-1yi.

In another embodiment, selected compounds of the présent invention may be useful for treating a PDE4B-mediated disorder, comprising administering to a mammal (preferably a human) in need thereof a therapeutically effective amount of a compound of the invention

effective in inhibiting PDE4B activity; more preferably, administering an amount of a compound of the invention having improved binding affinity for PDE4B while at the same time possessing less inhibitory activity toward PDE4D.

In another embodiment, selected compounds of the présent invention may be useful for treating a PDE4A-mediated disorder, comprising administering to a mammal (preferably a human) in need thereof a therapeutically effective amount of a compound of the invention effective in inhibiting PDE4A activity.

In yet another embodiment, selected compounds of the présent invention may be useful for treating a PDE4C-mediated disorder, comprising administering to a mammal 10 (preferably a human) in need thereof a therapeutically effective amount of a compound of the invention effective in inhibiting PDE4C activity.

In certain other embodiments, selected compounds of the présent invention may exhibit a binding affinity for the PDE4A, PDE4B and PDE4C isoforms or combinations thereof.

in certain embodiments, the compounds of the présent invention hâve an enhanced binding affinity for the PDE4B isoform over the PDE4D isoform such that the compounds display about a 2-fold to about a 120-fold binding affinity for the PDE4B isoform over the PDE4D isoform. In certain other embodiments, the compounds of the présent invention display about a 35-fold to about a 75-fold binding affinity for the PDE4B isoform over the

PDE4D isoform. In certain embodiments, the compounds of the présent invention display at least about a 2-fold binding affinity for the PDE4B isoform over the PDE4D isoform. In certain embodiments, the compounds of the présent invention display at least about a 5-fold binding affinity for the PDE4B isoform over the PDE4D isoform. In certain embodiments, the compounds of the présent invention display at least about a 10-fold binding affinity for the

PDE4B isoform over the PDE4D isoform. In certain embodiments, the compounds of the présent invention display at least about a 20-fold binding affinity for the PDE4B isoform over the PDE4D isoform. In certain other embodiments, the compounds of the présent invention display at least about a 40-fold binding affinity for the PDE4B isoform over the PDE4D isoform. In certain other embodiments, the compounds of the présent invention display at least about a 50-fold binding affinity for the PDE4B isoform over the PDE4D isoform. The binding affinities of the compounds of the présent invention for the PDE4B and PDE4D isoforms are shown in Table 4 of the Experimental Section below.

In another embodiment, the présent invention provides a pharmaceutical composition comprising a compound of the présent invention, or a pharmaceutically acceptable sait thereof, in admixture with at least one pharmaceutically acceptable excipient.

In yet another embodiment, administration of the compounds of the présent invention to a patient in need thereof may also lead to a decrease in gastrointestinal discomfort such as emesis, diarrhea, and nausea, which is currently believed to be associated with administration of compounds having binding affinity for other PDE4 isoforms, especially the PDE4D isoform, resulting in an increase in patient compliance as well as overall treatment outcome.

In another embodiment, the présent invention provides a method of treating central nervous system (CNS), metabolic, autoimmune and inflammatory diseases or disorders. comprising administering to the mammal, particularly a human, in need of such treatment a therapeutically effect amount of a compound of the présent invention, or a pharmaceutically acceptable sait thereof.

In another embodiment, the présent invention provides the use of a compound of the présent invention, or a pharmaceutically acceptable sait thereof, in the manufacture of a médicament for treating central nervous system (CNS), autoimmune and inflammatory diseases or disorders.

Pharmacoloqy

Phosphodiesterases (PDEs) of the PDE4 family are characterized by sélective, highaffinity hydrolytic dégradation of the second messenger cyclic nudeotide, adenosine 3',5'cyclic monophosphate (cAMP). The PDE4A, PDE4B and PDE4D subtypes are known to be widely expressed throughout the brain, with régional and intracellular distribution for the PDE4A, PDE4B and PDE4D subtypes being distinct, whereas the PDE4C subtype is expressed at lower levels throughout the central nervous system (See; Siuciak, J. A. et al., Antipsychotic profile of rolipram: efficacy in rats and reduced sensitivity in mice déficient in the phosphodiesterase-4B (PDE4B) enzyme, Psychopharmacology (2007) 192:415-424).

The location of the PDE4 subtypes makes them an interesting target for exploring new treatments for central nervous system diseases and disorders. For example, PDE4B has been identified as a genetic susceptibility factor for schizophrenia (See: Millar, J. K. et al., Disrupted in schizophrenia 1 and phosphodiesterase 4B: towards an understanding of psychiatrie illness, J. Physiol. 584 (2007) pp. 401-405).

The PDE4 inhibitor rolipram has been shown to be useful in treating or reversing Αβinduced memory déficits via the atténuation of neuronal inflammation and apoptosismediated cAMP/CREB signaling, and is a potential target for treatment of cognitive déficits associated with AD. (See: Wang, C. et al., The phosphodiesterase-4 inhibitor rolipram reverses Αβ-induced cognitive impairment and neuroinflammatory and apoptotic responses in rats, International Journal of Neuropsychopharmacology (2012), 15, 749-766).

PDE4 inhibitors hâve also been shown to possess antidepressant effects by decreasing brain levels of PDE4 in individuals with major dépressive disorder (MDD) (See: 10 Fujita, M. et al., C-(R-)-Rolipram Positron Emission Tomography in Major Dépressive Disorder, Biological Psychiatry, 71,2012, 548-554).

Furthermore, PDE4 inhibitors hâve been shown to possess therapeutic activity with implications for the treatment of multiple sclerosis (See: Sun, X. et al., Rolipram promûtes 15 remyelination possibly via MEK-ERK signal pathway in cuprizone-induced demyelination mouse, Experimental Neurology 2012;237:304-311).

In view of the above, in certain embodîments, the compounds of the présent invention hâve a wide range of therapeutic applications for the treatment of conditions or diseases of the central nervous system including, but not limited to, Niemann-Pick type C;

Batten Disease; neurological disorders (such as headache, migraine; epilepsy; Alzheimer’s disease; Parkinson's disease; brain injury (TBI); stroke; cerebrovascular diseases (including cérébral arteriosclerosis, cérébral amyloid angiopathy, hereditary cérébral hemorrhage, and brain hypoxia-ischemia); cognitive disorders (including amnesia, senile dementia, HIVassociated dementia, Alzheimer’s disease, Huntington’s disease, Lewy body dementia, 25 vascular dementia, drug-related dementia, tardive dyskinesia, myoclonus, dystonia, delirium,

Pick's disease, Creutzfeldt-Jacob disease, HIV disease, Gilles de la Tourette's syndrome, epilepsy, muscular spasms and disorders associated with muscular spasticity or weakness including tremors, and mild cognitive impairment); mental deficiency (including spasticity, Down syndrome and fragile X syndrome); sleep disorders (including hypersomnia, circadian 30 rhythm sleep disorder, insomnia, parasomnia, and sleep deprivation) and psychiatrie disorders such as anxiety (including acute stress disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, agoraphobia, and obsessive-compulsive disorder); factitious disorders (including acute hallucinatory mania); impulse control disorders (including compulsive gambling and intermittent explosive 35 disorder); mood disorders (including bipolar I disorder, bipolar II disorder, mania, mixed affective state, major dépréssion, chronic dépréssion, seasonal dépréssion, psychotic

dépréssion, premenstrual syndrome (PMS) premenstrual dysphorie disorder (PDD), and postpartum dépréssion); psychomotor disorders; psychotic disorders (including schizophrenia, schizoaffective disorder, schizophreniform, and delusional disorder); drug dependence and abuse (including narcotic dependence, alcoholism, amphétamine and methamphetamine dependence, opioid dependence, cocaine addiction, nicotine dependence, and drug withdrawal syndrome, and relapse prévention); eating disorders (including anorexia, bulimia, binge eating disorder, hyperphagia, obesity, compulsive eating disorders and pagophagia); sexual dysfunction disorders, urinary incontinence (e.g., bladder overactivity); neuronal damage disorders (including ocular damage, retinopathy or macular degeneration of the eye, tinnitus, hearing impairment and loss, and brain edema) and pédiatrie psychiatrie disorders (including attention déficit disorder, attention défieit/hyperactive disorder, conduct disorder, and autism) in a mammal, preferably a human, comprising administering to said mammal a therapeutically effective amount of a compound of the présent invention or a pharmaceutically acceptable sait thereof.

In certain embodiments, the présent invention is directed to methods for the treatment of schizophrenia by administration of a therapeutically effective amount of an azabenzimidazole compound of the présent invention to a patient in need thereof.

In certain other embodiments, the invention is further directed to a method for the treatment of cognitive impairment associated with schizophrenia by administration of a 20 therapeutically effective amount of an azabenzimidazole compounds of the présent invention to a patient in need thereof.

In addition to the central nervous system disorders mentioned above, there is extensive literature in the art describing the effects of PDE inhibitors on various înflammatory cell responses, which in addition to cAMP increase, include inhibition of superoxide 25 production, degranulation, chemotaxis and tumor necrosis factor (TNF) release in eosinophils, neutrophils and monocytes. Therefore, the azabenzimidazole compounds of the présent invention may be useful for treating autoimmune and Inflammatory diseases. (See: Schett, G. et al., Apremilast: A novel PDE4 Inhibitor in the Treatment of Autoimmune and Inflammatory Diseases, Ther. Adv. Musculoskeletal Dis. 2010; 2(5):271-278). For example, 30 the compounds of the présent invention may be useful for treatment of oral ulcers associated with Behçet’s disease (Id.). The compounds of the présent invention may also be useful for the treatment of pain associated with arthritis (See: Hess, A. et al., Blockade of TNF-a rapîdly inhibits pain responses in the central nervous System, PNAS, vol. 108, no. 9, 37313736 (2011) or for the treatment of psoriasis or psoriatic arthritis (See: Schafer, P., 35 Apremilast mechanism of action and application to psoriasis and psoriatic arthritis, Biochem.

Pharmacol. (2012), 15;83(12):1583-90). Accordingly, the azabenzimidazole compounds of the présent invention may also be useful for treatment of ankylosing spondylitis [see: Patan, E. et al., Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in ankylosing spondylitis, Ann. Rheum. Dis. (Sep. 14, 2102)]. Other conditions treatable by administration of the compounds of the présent invention include, but are not limited to, multiple sclerosis, burns, sepsis, asthma, chronic or acute bronchoconstriction, chronic bronchitis, bronchiectasis, small airways obstruction, emphysema, obstructive or inflammatory airways diseases, pneumoconiosis, seasonal allergie rhinitis or perennial allergie rhinitis or sinusitis, allergie conjunctivitis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), arthritis (e.g., rheumatoid arthritis and osteoarthritrs) goût, and fever and pain associated with inflammation, eosinophil-related disorders, dermatitis or eczema, urticaria, conjunctivitis, uveitis, psoriasis, inflammatory bowel disease, Crohn’s disease, septic shock, liver injury, pulmonary hypertension, bone loss disease, neuropathy, and infection.

In yet another embodiment, the compounds of the présent invention may be useful for treating cancer and tumors. For example, the compounds of the présent invention may be useful for treatment of brain cancer (e.g., medulloblastoma) (See: Schmidt, A. L., BDNF and PDE4, but not GRPR, Regulate Viability of Human Medulloblastoma Cells, J. Mol. Neuroscience (2010) 40:303-310). The compounds of the présent invention may also be useful for treating melanoma (See: Marquette, A. et al., ERK and PDE4 cooperate to induce RAF isoform switching in melanoma, Nature Structural & Molecular Biology, vol. 18, no. 5, 584-91, 2011). In certain embodiments, the compounds of the présent invention may be useful for treating leukemia, e.g., chronic lymphocytic leukemia, (See: Kim, D. H. et al., Type 4 Cyclic Adenosine Monophosphate Phosphodiesterase as a Therapeutic Target in Chronic

Lymphocytic Leulemia, Blood Journal of The American Society of Hematology, October 1, 1998, vol. 92, no. 7 2484-2494).

In certain other embodiments, the compounds of the présent invention may be useful for treating diabètes or conditions associated with diabètes (See: Vollert, S. et al., The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-Oxide in db/db 30 mice, Diabetologia (2012) 55:2779-2788. Wouters, E. F. M. et al., Effect of the

Phosphodiesterase 4 Inhibitor Roflumilast on Glucose Metabolism in Patients with

Treatment-Naïve, Newly Diagnosed Type 2 Diabètes Mellitus, Journal of Clinical

Endocrinology and Metabolism 2012, 97, 1720-1725). In certain embodiments, the compounds of the présent invention may be useful for treating diabetic macular edema 35 (DME) and diabetic neuropathy (DN).

Formulations

The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enfers the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.

In another embodiment, the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internai organ. Suitable means for parentéral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.

Suitable devices for parentéral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

In another embodiment, the compounds of the invention may also be formulated such that administration topically to the skin or mucosa (i.e., dermally or transdermally) leads to systemic absorption of the compound. In another embodiment, the compounds of 15 the invention can also be formulated such that administration intranasally or by inhalation leads to systemic absorption of the compound. In another embodiment, the compounds of the invention may be formulated such that administration rectally or vaginally leads to systemic absorption of the compound.

The dosage regimen for the compounds and/or compositions containing the 20 compounds is based on a variety of factors, including the type, âge, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus the dosage regimen may vary widely. Dosage levels of the order from about 0.01 mg to about 100 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions. In one 25 embodiment, the total daily dose of a compound of the invention (administered in single or divided doses) is typically from about 0.01 to about 100 mg/kg. In another embodiment, the total daily dose of the compound of the invention is from about 0.1 to about 50 mg/kg, and in another embodiment, from about 0.5 to about 30 mg/kg (i.e., mg compound of the invention per kg body weight). In one embodiment, dosing is from 0.01 to 10 mg/kg/day. 30 In another embodiment, dosing is from 0.1 to 1,0 mg/kg/day. Dosage unit compositions may contain such amounts or submultiples thereof to make up the daily dose. In many instances, the administration of the compound will be repeated a plurality of times in a day (typically no greater than 4 times). Multiple doses per day typically may be used to increase the total daily dose, if desired.

For oral administration, the compositions may be provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 and 500 milligrams of the active ingrédient for the symptomatic adjustment of the dosage to the patient. A médicament typically contains from about 0.01 mg to about 5 500 mg of the active ingrédient, or in another embodiment, from about 1 mg to about 100 mg of active ingrédient. Intravenously, doses may range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.

Suitable subjects according to the présent invention include mammalian subjects. Mammals according to the présent invention include, but are not limited to, canine, feline, 10 bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, and the like, and encompass mammals in utero. In one embodiment, humans are suitable subjects. Human subjects may be of either gender and at any stage of development.

In another embodiment, the invention comprises the use of one or more compounds of the invention for the préparation of a médicament for the treatment of the 15 conditions recited herein.

For the treatment of the conditions referred to above, the compounds of the invention can be administered as compound per se. Altematively, pharmaceutically acceptable salts are suitable for medical applications because of their greater aqueous solubility relative to the parent compound.

In another embodiment, the présent invention comprises pharmaceutical compositions. Such pharmaceutical compositions comprise a compound of the invention presented with a pharmaceutically acceptable carrier. The carrier can be a solid, a liquid, or both, and may be formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compounds. A compound of the invention may be coupled with suitable polymers as targetable drug carriers. Other pharmacologically active substances can also be présent.

The compounds of the présent invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The active compounds and compositions, 30 for example, may be administered orally, rectally, parenteraily, or topically.

Oral administration of a solid dose form may be, for example, presented in discrète units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the présent invention. In another

embodiment, the oral administration may be in a powder or granule form. In another embodiment, the oral dose form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the compounds of the présent invention are ordinarily combined with one or more adjuvants. Such capsules or tablets may contain a controlled-release formulation. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.

In another embodiment, oral administration may be in a liquid dose form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable émulsions, solutions, suspensions, syrups, and élixirs containing inert diluents commonly 10 used in the art (e.g., water). Such compositions also may comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.

In another embodiment, the présent invention comprises a parentéral dose form. Parentéral administration includes, for example, subcutaneous injections, intravenous injections, intraperitoneal injections, intramuscular injections, intrasternal injections, and 15 infusion. Injectable préparations (i.e., stérile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using suitable dispersing, wetting, and/or suspending agents.

In another embodiment, the présent invention comprises a topical dose form.

Topical administration includes, for example, transdermal administration, such as via 20 transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. A topical formulation may include a compound that enhances absorption or pénétration of the active ingrédient through the skin or other affected areas. When the compounds of this invention are administered by a 25 transdermal device, administration will be accomplished using a patch either of the réservoir and porous membrane type or of a solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include 30 alcohol, water, minerai oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Pénétration enhancers may be incorporated - see, for example, Finnin and Morgan, J. Pharm. Sci., 88 (10), 955-958 (1999).

Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this invention is dissolved or suspended in a suitable

carrier. A typical formulation suitable for ocular or aurai administration may be in the form of drops of a micronized suspension or solution in isotonie, pH-adjusted, stérile saline.

Other formulations suitable for ocular and aurai administration include ointments, biodégradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., 5 silicone) implants, wafers, lenses and particulate or vesicular Systems, such as niosomes or liposomes. A polymer such as crossed-lînked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as 10 benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aérosol spray présentation from a pressurized container or a nebulizer, with the use of a suitable 15 propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone; as a mixture, for example, in a dry blend with lactose; or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aérosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to 20 produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chrtosan or cyclodextrin.

In another embodiment, the présent invention comprises a rectal dose form. Such rectal dose form may be in the form of, for example, a suppository. Cocoa butter is a 25 tradîtional suppository base, but various alternatives may be used as appropriate.

Other carrier materials and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures. The above considérations in regard to effective formulations 30 and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishrng Co., Easton, Pennsylvania, 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients (3^rd Ed.), American 35 Pharmaceutical Association, Washington, 1999.

The compounds of the présent invention can be used, alone or in combination with other therapeutic agents, in the treatment of various conditions or disease states. The compound(s) of the présent invention and other therapeutic agent(s) may be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially. An exemplary therapeutic agent may be, for example, a metabotropic glutamate receptor agonist

The administration of two or more compounds “in combination” means that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other. The two or more compounds may be administered 10 simultaneously, concurrently or sequentially. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but at different anatomie sites or using different routes of administration.

The phrases “concurrent administration,” co-administration, “simultaneous 15 administration,” and “administered simultaneously mean that the compounds are administered in combination.

The présent invention includes the use of a combination of a PDE4 inhibitor compound of the présent invention and one or more additîonal pharmaceutically active agent(s). If a combination of active agents is administered, then they may be administered 20 sequentially or simultaneously, in separate dosage forms or combined in a single dosage form. Accordingly, the présent invention also includes pharmaceutical compositions comprising an amount of: (a) a first agent comprising a compound of the présent invention or a pharmaceutically acceptable sait of the compound; (b) a second pharmaceutically active agent; and (c) a pharmaceutically acceptable carrier, vehicle or diluent.

Various pharmaceutically active agents may be selected for use in conjunction with the compounds of the présent invention, depending on the disease, disorder, or condition to be treated. Pharmaceutically active agents that may be used in combination with the compositions of the présent invention include, without limitation:

(i) acetylcholinesterase inhibitors, such as donepezil hydrochloride (ARICEPT, 30 MEMAC), physostigmine salicylate (ANTILIRIUM), physostigmine sulfate (ESERINE), metrifonate, neostigmine, ganstigmine, pyridostigmine (MESTINON), ambenonium (MYTELASE), demarcarium, Debio 9902 (also known as ZT-1; Debiopharm), rivastigmine (EXELON), ladostigil, NP-0361, galantamine hydrobromide (RAZADYNE, RIMINYL,

NIVALIN), tacrine (COGNEX), tolserine, velnacrine maleate, memoquin, huperzine A (HUPA; NeuroHitech), phenserine, edrophonîum (ENLON, TENSILON), and INM-176;

(ii) amyloid-B (or fragments thereof), such as AB_V15 conjugated to pan HLA DRbinding epitope (PADRE), ACC-001 (Elan/Wyeth), ACI-01, ACI-24, AN-1792, Affitope AD-

01, CAD106, and V-950;

(iii) antibodies to amyloid-β (or fragments thereof), such as ponezumab, solanezumab, bapineuzumab (also known as AAB-001), AAB-002 (Wyeth/Elan), ACi-01Ab7, BAN-2401, intravenous Ig (GAMMAGARD), LY2062430 (humanized m266; Lilly), R1450 (Roche), ACU-5A5, huC091, and those disclosed in International Patent Publication

Nos WO04/032868, W005/025616, W006/036291, W006/069081, WO06/118959, in US Patent Publication Nos US2003/0073655, US2004/0192898, US2005/0048049,

US2005/0019328, in Européen Patent Publication Nos EP0994728 and 1257584, and in US Patent No 5,750,349;

(iv) amyloid-lowering or -inhibiting agents (including those that reduce amyloid production, accumulation and fibrillization) such as dimebon, davunetide, eprodisate, leuprolide, SK-PC-B70M, celecoxib, lovastatin, anapsos, oxiracetam, pramiracetam, varenicline, nicergoline, colostrînin, bisnorcymserine (also known as BNC), NIC5-15 (Humanetics), E-2012 (Eisai), pioglitazone, clioquinol (also known as PBT1), PBT2 (Prana Biotechnology), flurbiprofen (ANSAID, FROBEN) and its R-enantiomer tarenflurbil (FLURIZAN), nitroflurbiprofen, fenoprofen (FENOPRON, NALFON), îbuprofen (ADVIL, MOTRIN, NUROFEN), ibuprofen lysinate, meclofenamic acid, meclofenamate sodium (MECLOMEN), indomethacin (INDOCIN), diclofenac sodium (VOLTAREN), diclofenac potassium, sulindac (CLINORIL), sulindac sulfide, diflunisal (DOLOBID), naproxen (NAPROSYN), naproxen sodium (ANAPROX, ALEVE), ARC031 (Archer Pharmaceuticals),

CAD-106 (Cytos), LY450139 (Lilly), insulin-degrading enzyme (also known as insulysin), the gingko biloba extract EGb-761 (ROKAN, TEBONIN), tramiprosate (CEREBRIL, ALZHEMED), eprodisate (FIBRILLEX, KIACTA), compound W (3,5-bis(4nitrophenoxy)benzoic acid), NGX-96992, neprilysin (also known as neutral endopeptidase (NEP)), scyllo-inositol (also known as scyllitol), atorvastatin (LIPITOR), simvastatin (ZOCOR), KLVFF-(EEX)3, SKF-74652, ibutamoren mesylate, BACE inhibitors such as ASP1702, SCH-745966, JNJ-715754, AMG-0683, AZ-12304146, BMS-782450, GSK-188909, NB-533, E2609 and TTP-854; gamma secretase modulators such as ELND-007; and RAGE (receptor for advanced glycation end-products) inhibitors, such as TTP488 (Transtech) and TTP4000 (Transtech), and those disclosed in US Patent No 7,285,293, including PTI-777;

(v) alpha-adrenergic receptor agonîsts, such as guanfacine (INTUNIV, TENEX), clonidine (CATAPRES), metaraminol (ARAMINE), methyldopa (ALDOMET, DOPAMET,

NOVOMEDOPA), tizanidine (ZANAFLEX), phenylephrine (also known as neosynephrine), methoxamine, cirazoline, guanfacine (INTUNIV), lofexidine, xylazine, modafinîl (PROVIGIL), adrafinil, and armodafinil (NUVIGIL);

(vi) beta-adrenergic receptor blocking agents (beta blockers), such as carteolol, esmolol (BREVIBLOC), labetalol (NORMODYNE, TRANDATE), oxprenolol (LARACOR, TRASACOR), pindolol (VISKEN), propanolol (INDERAL), sotalol (BETAPACE, SOTALEX, SOTACOR), timolol (BLOCADREN, TIMOPTIC), acébutolol (SECTRAL, PRENT), nadolol 10 (CORGARD), metoprolol tartrate (LOPRESSOR), metoprolol succrnate (TOPROL-XL), atenolol (TENORMIN), butoxamine, and SR 59230A (Sanofi);

(vii) anticholinergics, such as amitriptyline (ELAVIL, ENDEP), butriptyline, benztropine mesylate (COGENT1N), trihexyphenidyl (ARTANE), diphenhydramine (BENADRYL), orphenadrine (NORFLEX), hyoscyamine, atropine (ATROPEN), scopolamine 15 (TRANSDERM-SCOP), scopolamine methylbromide (PARMINE), dicycloverine (BENTYL, BYCLOMINE, DIBENT, DILOMINE), tolterodine (DETROL), oxybutynin (DITROPAN, LYRINEL XL, OXYTROL), penthienate bromide, propantheline (PRO-BANTHINE), cyclizine, imipramine hydrochloride (TOFRANIL), imipramine maleate (SURMONTIL), lofepramine, desipramine (NORPRAMIN), doxepin (SINEQUAN, ZONALON), trimipramîne (SURMONTIL), and glycopyrrolate (ROBINUL);

(viii) anticonvulsants, such as carbamazepine (TEGRETOL, CARBATROL), oxcarbazepine (TRILEPTAL), phenytoin sodium (PHENYTEK), fosphenytoin (CEREBYX, PRODILANTIN), divalproex sodium (DEPAKOTE), gabapentin (NEURONTIN), pregabalin (LYRICA), topirimate (TOPAMAX), valproic acid (DEPAKENE), valproate sodium 25 (DEPACON), 1-benzyl-5-bromouracil, progabide, beclamide, zonisamide (TRERIEF, EXCEGRAN), CP-465022, retigabine, talampanel, and primidone (MYSOLINE);

(ix) antipsychotics, such as lurasidone (LATUDA, also known as SM-13496; Dainippon Sumitomo), arrpiprazole (ABILIFY), chlorpromazine (THORAZINE), haloperidol (HALDOL), iloperidone (FANAPTA), flupentixol decanoate (DEPIXOL, FLUANXOL), 30 reserpine (SERPLAN), pimozide (ORAP), fluphenazrne decanoate, fluphenazine hydrochloride, prochlorperazine (COMPRO), asenapine (SAPHRIS), loxapine (LOXITANE), molindone (MOBAN), perphenazine, thioridazine, thiothixine, trifluoperazine (STELAZINE), ramelteon, clozapine (CLOZARIL), norclozapine (ACP-104), rispéridone (RISPERDAL), paliperidone (INVEGA), melperone, olanzapine (ZYPREXA), quetiapine (SEROQUEL),

talnetant, amisulpride, ziprasidone (GEODON), blonanserin (LONASEN), and ACP-103 (Acadia Pharmaceuticals);

(x) calcium channel blockers such as lomerizine, ziconotide, nilvadipine (ESCOR, NIVADIL), diperdrpine, amlodipine (NORVASC, ISTIN, AMLODIN), felodtpine (PLENDIL), 5 nicardipine (CARDENE), nifedipine (ADALAT, PROCARDIA), MEM 1003 and its parent compound nimodipine (NIMOTOP), nisoldipine (SULAR), nitrendipine, lacidipine (LACIPIL, MOTENS), lercanidipine (ZANIDIP), lifarizine, diltiazem (CARDIZEM), verapamil (CALAN, VERELAN), AR-R 18565 (AstraZeneca), and enecadin;

(xi) catechol O-methyltransferase (COMT) inhibitors, such as nitecapone, tolcapone (TASMAR), entacapone (COMTAN), and tropolone;

(xii) central nervous system stimulants, such as atomoxetine, reboxetine, yohimbine, caffeine, phenmetrazine, phendimetrazine, pemoline, fencamfamine (GLUCOENERGAN, REACTIVAN), fenethylline (CAPTAGON), pipradol (MERETRAN), deanol (also known as dimethylaminoethanol), methylphenidate (DAYTRANA), methylphenidate hydrochloride 15 (RITALIN), dexmethylphenidate (FOCALIN), amphétamine (alone or in combination with other CNS stimulants, e.g., ADDERALL (amphétamine aspartate, amphétamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate)), dextroamphetamine sulfate (DEXEDR1NE, DEXTROSTAT), methamphetamine (DESOXYN), lisdexamfetamine (VYVANSE), and benzphetamine (DIDREX);

(xiii) corticosteroids, such as prednisone (STERAPRED, DELTASONE), prednisolone (PRELONE), predisolone acetate (OMN1PRED, PRED MILD, PRED FORTE), prednisolone sodum phosphate (ORAPRED ODT), méthylprednisolone (MEDROL); méthylprednisolone acetate (DEPO-MEDROL), and méthylprednisolone sodium succinate (A-METHAPRED, SOLU-MEDROL);

(xiv) dopamine receptor agonists, such as apomorphine (APOKYN), bromocriptine (PARLODEL), cabergoline (DOSTINEX), dihydrexidine, dihydroergocryptine, fenoldopam (CORLOPAM), lisuride (DOPERGIN), terguride spergolide (PERMAX), piribedil (TRIVASTAL, TRASTAL), pramipexole (MIRAPEX), quinpirole, ropinirole (REQUIP), rotigotine (NEUPRO), SKF-82958 (GlaxoSmithKIine), cariprazine, pardoprunox and 30 sarizotan;

(xv) dopamine receptor antagonists, such as chlorpromazine, fluphenazine, haloperidol, loxzpine, resperidone, thioridazine, thiothixene, trifluoperazine, tetrabenazine (NITOMAN, XENAZINE), 7-hydroxyamoxapine, droperidol (INAPSINE, DRIDOL,

DROPLETAN), domperidone (MOTILIUM), L-741742, L-745870, raclopnde, SB-277011A,

SCH-23390, ecopipam, SKF-83566, and metoclopramide (REGLAN);

(xvi) dopamine reuptake inhibitors such as bupropion, safinamide, nomifensine maleate (MERITAL), vanoxerine (also known as GBR-12909) and its decanoate ester DBL· 5 583, and amineptine;

(xvii) gamma-amino-butyric acid (GABA) receptor agonists, such as baclofen (LIORESAL, KEMSTRO), siclofen, pentobarbital (NEMBUTAL), progabide (GABRENE), and clomethiazole;

(xviii) histamine 3 (H3) antagonists such as ciproxifan, tiprolisant, S-38093, 10 irdabisant, pitolisant, GSK-239512, GSK-207040, JNJ-5207852, JNJ-17216498, HPP-404, SAR-110894, trans-3-fluoro-3-(3-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutane carboxylic acid ethylamide (PF-3654746 and those disclosed in US Patent Publication Nos US2005-0043354, US2005-0267095, US2005-0256135, US2008-0096955, US20071079175, and US2008O176925; International Patent Publication Nos W02006/136924, 15 W02007/063385, W02007/069053, W02007/088450, W02007/099423, W02007/105053,

W02007/138431, and W02007/088462; and US Patent No 7,115,600);

(xix) immunomodulators such as glatiramer acetate (also known as copolymer-1; COPAXONE), MBP-8298 (synthetic myelin basic protein peptide), dimethyl fumarate, fingolimod (also known as FTY720), roquinimex (LINOMIDE), laquinimod (also known as

ABR-215062 and SAIK-MS), ABT-874 (human anti-IL-12 antibody; Abbott), rituximab (RITUXAN), alemtuzumab (CAMPATH), daclizumab (ZENAPAX), and natalizumab (TYSABRI);

(xx) immunosuppressants such as methotrexate (TREXALL, RHEUMATREX), mitoxantrone (NOVANTRONE), mycophenolate mofetil (CELLCEPT), mycophenolate sodium (MYFORTIC), azathioprine (AZASAN, IMURAN), mercaptopurine (PURI-NETHOL), cyclophosphamide (NEOSAR, CYTOXAN), chlorambucil (LEUKERAN), cladribine (LEUSTATIN, MYLINAX), alpha-fetoprotein, etanercept (ENBREL), and 4-benzyloxy-5-((5undecyl-2H-pyrrol-2-ylidene)methyl)-2,2'-bi-1H-pyrrole (also known as PNU-156804);

(xxi) interferons, including interferon beta-1a (AVONEX, REBIF) and interferon beta30 1b (BETASERON, BETAFERON);

(xxii) levodopa (or its methyl or ethyl ester), alone or in combination with a DOPA decarboxylase inhibitor (e.g., carbidopa (SINEMET, CARBILEV, PARCOPA), benserazide

(MADOPAR), α-methyldopa, monofluromethyldopa, difluoromethyldopa, brocresine, or mhydroxybenzylhydrazine);

(xxiii) N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine (NAMENDA, AXURA, EBIXA), amantadine (SYMMETREL), acamprosate (CAMPRAL), 5 besonprodil, ketamine (KETALAR), delucemine, dexanabinol, dexefaroxan, dextromethorphan, dextrorphan, traxoprodil, CP-283097, himantane, idantadol, ipenoxazone, L-701252 (Merck), lancîcemine, levorphanol (DROMORAN), LY-233536 and LY-235959 (both Lrlly), methadone, (DOLOPHINE), neramexane, perzinfotel, phencyclidine, tianeptine (STABLON), dizocilpine (also known as MK-801), EAB-318 (Wyeth), ibogarne, 10 voacangine, tiletamine, riluzole (RILUTEK), aptiganel (CERESOTAT), gavestinel, and remacimide;

(xxiv) monoamine oxidase (MAO) inhibitors, such as selegiline (EMSAM), selegiline hydrochloride (l-deprenyl, ELDEPRYL, ZELAPAR), dimethylselegiiene, brofaromine, phenelzine (NARDIL), tranylcypromine (PARNATE), moclobemide (AUROR1X, MANERIX), 15 befloxatone, safinamide, isocarboxazid (MARPLAN), nralamide (NIAM1D), rasagiline (AZILECT), iproniazide (MARSILID, IPROZID, IPRONID), CHF-3381 (Chiesi Farmaceutici), iproclozide, toloxatone (HUMORYL, PERENUM), bifemelane, desoxypeganine, harmine (also known as telepathine or banasterine), harmaline, linezolid (ZYVOX, ZYVOXID), and pargyline (EUDATiN, SUPIRDYL);

(xxv) muscarinic receptor (particulariy M1 subtype) agonists, such as cevimeline, levetiracetam, bethanechol chloride (DUVOID, URECHOLINE), itameline, pilocarpine (SALAGEN), NGX267, arecoline, L-687306 (Merck), L-689660 (Merck), furtrethonium iodide (FURAMON, FURANOL), furtrethonium benzensulfonate, furtrethonium p-toluenesulfonate, McN-A-343, oxotremorine, sabcomeline, AC-90222 (Acadia Pharmaceuticals), and carbachol (CARBASTAT, MIOSTAT, CARBOPTIC);

(xxvi) neuroprotective drugs such as bosutinib, condoliase, airmoclomol, lamotrigine, perampanel, aniracetam, minaprime, viluzole 2,3,4,9-tetrahydro-1/+carbazol-3-one oxime, desmotepiase, anatibant, astaxanthin, neuropeptide NAP (e.g., AL-108 and AL-208; both Allon Therapeutics), neurostrol, perampenel, ispronicline, bis(4-p-D30 glucopyranosyloxybenzyl)-2-p-D-glucopyranosyl-2-isobutyltartrate (also known as dactylorhin B or DHB), formobactin, xaliproden (XAPRILA), lactacystin, dimeboline hydrochloride (DIMEBON), disufenton (CEROVIVE), arundic acid (ONO-2506, PROGLIA, CEREACT), citicoline (also known as cytidine 5'-diphosphocholine), edaravone (RADICUT), AEOL-10113 and AEOL-10150 (both Aeolus Pharmaceuticals), AGY-94806 (also known as

SA-450 and Msc-1), granulocyte-colony stimulating factor (also known as AX-200), BAY-38I 7271 (also known as KN-387271; Bayer AG), ancrod (VIPRINEX, ARWIN), DP-b99 (DPharm Ltd), HF-0220 (17-B-hydroxyepiandrosterone; Newron Pharmaceuticals), HF-0420 (also known as oligotropin), pyridoxal 5'-phosphate (also known as MC-1), microplasmin, S5 18986, piclozotan, NP031112, tacrolimus, L-seryl-L-methionyl-L-alanyl-L-lysyl-L-glutamylglycyl-L-valine, AC-184897 (Acadia Pharmaceuticals), ADNF-14 (National Institutes of Health), stilbazulenyl nitrone, SUN-N8075 (Daiichi Suntory Biomédical Research), and zonampanel;

(xxvii) nicotinic receptor agonists, such as epibatidine, bupropîon, CP-601927, varenicline, ABT-089 (Abbott), ABT-594, AZD-0328 (AstraZeneca), EVP-6124, R3487 (also known as MEM3454; Roche/Memory Pharmaceuticals), R4996 (also known as MEM63908; Roche/Memory Pharmaceuticals), TC-4959 and TC-5619 (both Targacept), and RJR-2403;

(xxviii) norepinephrine (noradrenaline) reuptake inhibitors, such as atomoxetine (STRATTERA), doxepin (APONAL, ADAPIN, SINEQUAN), nortriptyline (AVENTYL, 15 PAMELOR, NORTRILEN), amoxapine (ASENDIN, DEMOLOX, MOXIDIL), reboxetine (EDRONAX, VESTRA), viloxazine (VIVALAN), maprotiline (DEPRILEPT, LUDIOMIL, PSYMION), bupropîon (WELLBUTRIN), and radaxafine;

(xxix) phosphodiesterase (PDE) inhibitors, including but not limited to, (a) PDE1 inhibitors (e.g., vinpocetine (CAVINTON, CERACTIN, INTELECTOL) and those disclosed in 20 US Patent No 6,235,742, (b) PDE2 inhibitors (e.g., erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), BAY 60-7550, and those described in US Patent No. 6,174,884), (c) PDE3 inhibitors (e.g., anagrelide, ciiostazol, milrinone, olprinone, parogrelii, and pimobendan), (d) PDE4 inhibitors (e.g., apremilast, ibudilastroflumilast, rolipram, Ro 20-1724, ibudilast (KETAS), piclamilast (also known as RP73401), CDP840, cilomilast (ARIFLO), roflumilast, 25 tofîmilast, oglemilast (also known as GRC 3886), tetomilast (also known as OPC-6535), lirimifast, theophylline (UNIPHYL, THEOLAIR), arofylline (also known as LAS-31025), doxofylline, RPR-122818, or mesembrine), and (e) PDE5 inhibitors (e.g., sildenafil (VIAGRA, REVATIO), tadalafil (CIALIS), vardenafrl (LEVITRA, VIVANZA), udenafil, avanafil, dipyridamole (PERSANTINE), E-4010, E-4021, E-8010, zaprinast, iodenafil, mirodenaftl, DA30 8159, and those disclosed in International Patent Applications W02002/020521,

W02005/049616, W02006/120552, W02006/126081, W02006/126082, W02006/126083, and W02007/122466), (f) PDE7 inhibitors; (g) PDE8 inhibitors; (h) PDE9 inhibitors (e.g., BAY 73-6691 (Bayer AG) and those disclosed in US Patent Publication Nos US2003/0195205, US2004/0220186, US2006/0111372, US2006/0106035, and USSN 35 12/118,062 (filed May 9, 2008)), (i) PDE10 inhibitor such as 2-[4-(1-Methyl-4-pyridin-4-yl34

1H-pyrazol-3-y))phenoxymethyl]quinoline (PF-2545920), and SCH-1518291; and (j) PDE11 inhibitors;

(xxx) quinolines, such as quinine (including its hydrochloride, dihydrochloride, sulfate, bisulfate and gluconate salts), chloroquine, sontoquine, hydroxychloroquine (PLAQUENIL), mefloquine (LARIAM), and amodiaquine (CAMOQUIN, FLAVOQUINE);

(xxxi) β-secretase inhibitors, such as ASP-1702, SCH-745966, JNJ-715754, AMG-0683, AZ-12304146, BMS-782450, GSK-188909, NB-533, LY-2886721, E-2609, HPP-854, (+)phenserine tartrate (POSIPHEN), LSN-2434074 (also known as LY-2434074), KMI-574, SCH-745966, Ac-rER (N²-acetyl-D-arginyl-L-arginine), loxrstatin (also known as E64d), and 10 CA074Me;

(xxxii) γ-secretase inhibitors and modulators, such as BMS-708163 (Avagacest), W020060430064 (Merck), DSP8658 (Dainippon), ITI-009, L-685458 (Merck), ELAN-G, ELAN-Z, 4-chloro-A/-[2-ethyM(S)-(hydroxymethyl)butyl]benzenesulfonamide;

(xxxiii) serotonin (5-hydroxytryptamrne) 1A (5-HTi_A) receptor antagonists, such as spiperone, tevo-pindolol, BMY 7378, NAD-299, S(-)-UH-301, NAN 190, lecozotan;

(xxxiv) serotonin (5-hydroxytryptamine) 2C (5-HT2c) receptor agonists, such as vabicaserin, and zicronapine;

(xxxv) serotonin (5-hydroxytryptamine) 4 (5-HT₄) receptor agonists, such as PRX03140 (Epix);

(xxxvi) serotonin (5-hydroxytryptamine) 6 (5-HT₆) receptor antagonists, such as A964324, AVI-101, AVN-211, mianserin (TORVOL, BOLVIDON, NORVAL), methiothepin (also known as metitepine), ritanserin, ALX-1161, ALX-1175, MS-245, LY-483518 (also known as SGS518; Lilly), MS-245, Ro 04-6790, Ro 43-68544, Ro 63-0563, Ro 65-7199, Ro 65-7674, SB-399885, SB-214111, SB-258510, SB-271046, SB-357134, SB-699929, SB25 271046, SB-742457 (GlaxoSmithKIine), Lu AE58054 (Lundbeck A/S), and PRX-07034 (Epix);

(xxxvii) serotonin (5-HT) reuptake inhibitors such as alaproclate, citalopram (CELEXA, CIPRAMIL), escitalopram (LEXAPRO, CIPRALEX), clomipramine (ANAFRANIL), duloxetine (CYMBALTA), femoxetine (MALEXIL), fenfluramine (PONDIMIN), 30 norfenfluramine, fluoxetine (PROZAC), fluvoxamine (LUVOX), indalprne, milnacipran (IXEL), paroxetine (PAXIL, SEROXAT), sertraline (ZOLOFT, LUSTRAL), trazodone (DESYREL, MOLIPAXIN), venlafaxine (EFFEXOR), zimelidine (NORMUD, ZELMID), bicifadine,

desvenlafaxine (PRISTIQ), brasofensine, vilazodone, cariprazine, neuralstem and tesofensine;

(xxxviii) trophic factors, such as nerve growth factor (NGF), basic fibroblast growth factor (bFGF; ERSOFERMIN), neurotrophin-3 (NT-3), cardiotrophin-1, brain-derived neurotrophîc factor (BDNF), neublastin, meteorin, and glial-derived neurotrophic factor (GDNF), and agents that stimulate production of trophic factors, such as propentofylline, idebenone, PYM50028 (COGANE; Phytopharm), and AIT-082 (NEOTROFIN);

(xxxix) Glycine transporter-1 inhîbitors such as paliflutine, ORG-25935, JNJ17305600, and ORG-26041;

(xl) AMPA-type glutamate receptor modulators such as perampanel, mibampator, selurampanel, GSK-729327, /V-{(3S,4S)-4-[4'(5-cyanothiophen-2-yl)phenoxy]tetrahydrofuran-3-yl}propane-2'Sulfonamide, and the like.

The présent invention further comprises kits that are suitable for use in performing the methods of treatment described above. In one embodiment, the kit contains a first 15 dosage form comprising one or more of the compounds of the présent invention and a container for the dosage, in quantifies sufficient to carry out the methods of the présent invention.

In another embodiment, the kit of the présent invention comprises one or more compounds of the invention.

The compounds of the invention, or their pharmaceutically acceptable salts, may be prepared by a variety of methods that are analogously known tn the art. The reaction schemes described below, together with synthetic methods known in the art of organic chemistry, or modifications and derivatizations that are familiar to those of ordinary skill in the art, illustrate six (6) methods for preparing the compounds. Others, including modifications thereof, will be readily apparent to one skilled in the art.

The starting materials used herein are commercially available or may be prepared by routine methods known in the art (such as those methods disclosed in standard reference books such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol.

I-XII (published by Wiley-lnterscience)). Preferred methods include, but are not limited to, 30 those described below.

During any of the following synthetic sequences, it may be necessary and/or désirable to protect sensitive or reactive groups on any of the molécules concerned. This

can be achieved by means of conventional protecting groups, such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991 ; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John

Wiley & Sons, 1999, which are hereby incorporated by reference.

Compounds of the présent invention or their pharmaceutically acceptable salts of said compounds or tautomers and radioisotopes, can be prepared according to the reaction Schemes discussed herein below. Unless otherwise indicated, the substituents in the Schemes are defined as above. Isolation and purification of the products is 10 accomplished by standard procedures, which are known to a chemist of ordinary skill.

One skilled in the art will recognize that in some cases, the compounds in Schemes 1 through 6 will be generated as a mixture of diastereomers and/or enantiomers; these may be separated at various stages of the synthetic schemes using conventional techniques or a combination of such techniques, such as, but not limited to, crystallization, normal-phase 15 chromatography, reversed phase chromatography and chiral chromatography, to afford the single enantiomers of the invention.

It will be understood by one skilled in the art that the various symbols, superscripts and subscripts used in the schemes, methods and examples are used for convenience of représentation and/or to reflect the order in which they are introduced in the schemes, and 20 are not intended to necessarily correspond to the symbols, superscripts or subscripts in the appended claims. The schemes are représentative of methods useful in synthesizing the compounds of the présent invention. They are not to constrain the scope of the invention in any way.

Scheme 1 below illustrâtes one synthesis sequence for the préparation of 25 compounds of formula I. The initial step in the synthesis, as depicted, utilizes 2-chloro-3nitropyridine of formula 1 as an initial starting material. The 2-chloro-3-nitropyridine 1 undergoes S_NAr reactions with amine nucleophiles of formula 2 such as anilines, in the presence of base as a proton scavenger, at températures from room température to 200°C, to give aminonitropyridines of formula II. During the initial S_NAr reaction step the R¹ 30 substituent on the amine nucleophiles of formula 2 should be represented by the same moiety as is desired in the final product, or a protected variation thereof. For example, the final product of Example 1 (/V-cyclopropyl-3-(3-fluoro-4-methylphenyl)-3H-imidazo[4,5bJpyridine-2-carboxamidej can be prepared utilizing reaction scheme 1, wherein R¹ of the amine nucleophile of formula 2 is represented by 3-fluoro-4-methylphenyl.

The next step of the reaction is the réduction of the nitro group of formula II to the amine to give the diaminopyridîne compounds of formula III. This step can be effected through palladium or nickel réduction in the presence of a hydrogen source or through stoichiometric métal réductions, such as iron and zinc in the presence of mild acid.

In the next step, the half ester oxalamides of formula IV can be generated from amines of formula 3’ (i.e., HNR⁶R⁷) displacement on a half ester of oxalyl chloride of formula

3. During the amine displacement step, the R⁶ and R⁷ substituents on the amines of formula 3’ should be represented by the same moiety as is desired in the final product, or a protected variation thereof. For example, for the final product of Example 1 mentioned 10 above, one of R⁶ and R⁷ of the amines of formula 3’ is represented by hydrogen and the other is represented by cyclopropyl.

Following the amine displacement step, the compounds of formula V can be prepared by condensation of the diaminopyridines of formula III and the compounds of formula IV under thermal conditions, with reaction rates being increased under basic 15 conditions.

In the final step of scheme 1, conversion of the compounds of formula V to the compounds of formula I can be accomplished under dehydrating conditions such as heat, treatment with a Lewis acid, or amide coupling conditions.

Scheme 1

Scheme 2 below describes an alternative synthetic sequence for the préparation of compounds of formula I. Oxalic acids of formula VI can be generated in two steps from the

treatment of half esters of oxalyl chloride of formula 3 with an amine of formula 3’ in the presence of base, usually at room température or below. The résultant half ester oxalamides of formula IV can be hydrolyzed to the oxalic acids of formula VI by treatment under acidic or basic aqueous conditions at températures from 0 °C to 150 °C.

Next, the diaminopyridines of formula III can be mixed with the oxalic acids of formula

VI in the presence of amide coupling/dehydrating reagents, such as 2,4,6-tripropyl-

1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P), 0(7-azabenzotriazol-1-yl)-/V,N,A/',A/tetramethyluronium hexafluorophosphate (HATU), dicyclohexylcarbodiimide (DCC), etc., at températures ranging from -20 °C to 100 °C; subséquent heating up to 200 °C generates 10 compounds of formula I.

Scheme 2

R¹

N_X_,NH

R^{1 N}^-N O

O R⁷

VI

2. NaOH or HCl

O R⁷

3'

1. NHR⁶R⁷

Scheme 3 below illustrâtes an alternative synthetic sequence for the préparation of compounds of formula I. Diaminopyridines of formula III can be acylated by the nucleophilic 15 displacement of a leaving group on an ester-oxalate of formula 4 (wherein x is represented by chloride, alkoxy, succinimide, etc.) to generate the aminopyridine aminooxoacetate compounds of formula VII.

In the next step the compounds of formula VII can be cyclized under dehydrating conditions such as heat, treatment with a Lewis acid, or amide coupling conditions such as 20 ZAe-tripropyl-IAS^Ae-trioxatriphosphinane 2,4,6-trioxide (T3P), Q-(7-azabenzotrîazol-139

yl)-A/,A/,/V',/V-tetramethyluranium hexafluorophosphate (HATU), dicyclohexylcarbodiimide (DCC), etc., to generate the imidazopyridine esters of formula VIII.

Next, the conversion of imidazopyridine esters of formula VIII to amides of formula I may be carried out via addition of an amine of formula 3’ to imidazopyridine esters of formula 5 VIII at températures from 20 °C to 200 °C in the presence or absence of solvent.

Additionally, this transformation can be accomplished through the addition of a base or Lewis acid to the mixture of amine and imidazopyridine esters of formula VIII at températures ranging from 20 °C to 200 °C or under microwave irradiation at applicable températures.

Scheme 3

O

Scheme 4 below illustrâtes another alternative synthetic sequence for préparation of the compounds of formula I from the esters of formula VIII. In an initial step, esters of 15 formula VIII can be hydrolyzed to the corresponding imidazopyridine carboxylic acids of formula IX under basic or acidic aqueous conditions. During the initial step, the R¹ substituent on the esters of formula VIII should be represented by the same moiety as is desired in the final product, or a protected variation thereof.

Next, the imidazopyridine acids of formula IX can be reacted with an appropriate 20 amine of formula 3’ using any of a variety of amide coupling reagents such as 2,4,6-tripropyl-

1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P), 0-(7-azabenzotriazol-1-yl)-A/,/V,A/',/Vtetramethyluranium hexafluorophosphate (HATU), dicyclohexylcarbodiimide (DCC), etc., to provide the compounds of formula I.

Scheme 4

VIII

IX

3'

I

Scheme 5 below illustrâtes another alternative synthetic sequence for the préparation of compounds of formula I from the diaminopyridine compounds of formula lll. In the initial step, compounds of formula lll can be treated with methyl 2,2,2-trichloroacetimidate of formula 4’ in the presence of mild acid to form trichloromethyl-substituted imidazo[4,5-b]pyridines of formula X (see Venable, J. et al., Journal of Médicinal Chemistry 2005, 48, 8289).

Next, the compounds of formula X can be treated with amines of formula 3’ under mild basic aqueous conditions to provide compounds of formula I.

Scheme 5

lll ⁴' X i

Scheme 6 below illustrâtes another synthetic sequence for the prepratation of the compounds of formula I wherein R¹ is optionally substituted aryl.

In a first step, 2-amino-3-nitropyridine is coupled with a haloaryl compound of formula 5 in the presence of a métal catalyst (palladium, copper, rhodium, etc.), a ligand, and a base at températures ranging from room température to -200 °C, to generate anilinopyridine structures of formula XI. This general réaction is sometimes referred to as the BuchwaldHartwig amination. Similar couplings hâve been described previously (W02008/4117 A1 and Org. Lett. 2009, 11, 5502-5505). During this reaction, the R¹ substituent on the haloaryl compound of formula 5 should be represented by the same moiety as is desired in the final product, or a protected variation thereof. For example, the final product of Example 7 [3-(4cyano-3-fluorophenyl)-N-cyclopropyl-3H-imidazo[4,5-jb]pyridine-2-carboxamide] can be prepared utilizing réaction scheme 6, wherein R¹ of the diaminopyridine is represented by 4cyano-3-fluorophenyl.

In the next step, réduction of the nitro group to an amine to give the compounds of formula XII can occur through palladium or nickel réduction in the presence of a hydrogen source, or through stoichiometric métal réductions, such as iron and zinc in the presence of mild acid.

Next, compounds of formula XII can be converted to compounds of formula I through reaction of compounds of formula XII and a compound of formula IV (Scheme 2) under basic 30 conditions, at températures ranging from room température to 200 °C followed by the room

température addition of a dehydrating reagent/amide coupling reagent 2,4,6-tripropyl-

1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P), CHT-azabenzotriazol-l-yO-N.tyAKN- tetramethyluronium hexafluorophosphate (HATU), dicyclohexylcarbodiimide (DCC), etc., and subséquent reaction via appropriate heating (room température to 200 °C) to generate 5 compounds of formula I wherein R¹ is optionally substituted aryl, wherein the optional substituent is represented by (R²)_b.

Scheme 6

Experimental Procedures and Working Examples

The following illustrate the synthesis of various compounds of the présent invention. Additional compounds within the scope of this invention may be prepared using the methods illustrated in these Examples, either alone or in combination with techniques generally 15 known in the art.

Experiments were generally carried out under inert atmosphère (nitrogen or argon), particulariy in cases where oxygen- or moisture-sensitive reagents or intermediates were employed. Commercial solvents and reagents were generally used without further purification. Anhydrous solvents were employed where appropriate (generally Sure-Seal™ 20 products from the Aldrich Chemical Company, Milwaukee, Wisconsin, or solvents that had been dried and distilled using procedures familiar to those skilled in the art). Products were generally dried under vacuum before being carried on to further reactions or submitted for biological testing. Mass spectrometry data is reported from either liquid chromatographymass spectrometry (LCMS), atmospheric pressure chemical ionization (APCI) or gas 25 chromatography-mass spectrometry (GCMS) instrumentation. Chemical shifts for nuclear magnetic résonance (NMR) data are expressed în parts per million (ppm, 5) referenced to residual peaks from the deuterated solvents employed.

For synthèses referencing procedures in other Examples or Methods, reaction conditions (length of reaction and température) may vary. In general, reactions were followed by thin layer chromatography or mass spectrometry, and subjected to work-up when appropriate. Purifications may vary between experiments: in general, solvents and the solvent ratios used for eluents/gradients were chosen to provide appropriate R₍s or rétention times.

Préparation P1

Ethyl (cyclopropylamino)(oxo)acetate (P1).

A mixture of cyclopropylamine (1.39 g, 24.3 mmol) and triethylamine (3.5 g, 35 mmol) was added drop-wise to a 0 °C solution of ethyl chloro(oxo)acetate (3.5 g, 26 mmol) in tetrahydrofuran (25 mL). The reaction mixture was stirred at 0 °C for 10 minutes and filtered; the filtrate was concentrated in vacuo to afford the product as a yellow solid. Yield: 3.0 g, 19 mmol, 78%. ¹H NMR (400 MHz, CDCI₃) Ô 7.14 (br s, 1H), 4.34 (q, J=7.2 Hz, 2H), 2.78-2.86 (m, 1H), 1.38 (t, J=7.2 Hz, 3H), 0.83-0.90 (m, 2H), 0.59-0.65 (m, 2H).

Préparation P2 (Cyclopropylamino)(oxo)acetic acid (P2)

2) NaOH

P2

Ethyl chloro(oxo)acetate (96 mL, 0.86 mol) was added over 10 minutes to a -20 °C solution of cyclopropylamine (60 mL, 0.86 mol) and pyridine (70 mL, 0.86 mol) in dichloromethane (740 mL), and the reaction mixture was stirred at 0 °C for 1 hour, then at 20 °C for 20 hours. The reaction mixture was washed with aqueous hydrochloric acid (1 M, 3 / 185 mL), then the organic layer was stirred with aqueous sodium hydroxide solution (1 M, 930 mL, 0.93 mol) for 30 minutes. The resulting aqueous layer was acidified to pH 1 with concentrated hydrochloric acid (78 mL), treated with sodium chloride (100 g), and extracted with dichloromethane (6 x 500 mL) and ethyl acetate (6 x 500 mL). The combined organic layers were dried over magnésium sulfate, filtered, and concentrated in vacuo; the resulting

solid was mixed with ethyl acetate (150 mL) and warmed to reflux. After cooling to room température over 16 hours with stirring, the solid was collected via filtration and washed with ethyl acetate, affording the product as a sparkling white solid. Yield: 67.8 g, 0.525 mol, 61%. LCMS m/z 130.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 13.73 (br s, 1H), 8.83 (br d, J=4.0

Hz, 1H), 2.68-2.77 (m, 1H), 0.61-0.68 (m, 2H), 0.54-0.61 (m, 2H).

Examples

Example 1

N-Cyclopropyl-3-(3-fluoro-4-methylphenyl)-3iï -imidazo[4,5-b]pyridine-2-carboxamide (1)

Step 1. Synthesis ofl·)-(3-fluoro-4-methylphenyi)-3-nitropyridin-2-amine (C1).

A mixture of 2-chloro-3-nitropyridine (4.76 g, 30.0 mmol), 3-fluoro-4-methylaniline (3.75 g, 30.0 mmol) and potassium carbonate (8.29 g, 60.0 mmol) in dimethyl sulfoxide (30 mL) was stirred at 140 °C for 40 minutes. The reaction mixture was then cooled to room température, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with water, dried over magnésium sulfate, filtered, and concentrated in vacuo to afford the product as a black solid. Yield: 6.78 g, 27.4 mmol, 91%. ¹H NMR (400

MHz, CDCIa) δ 10.11 (br s, 1H), 8.54 (dd, J=8.3, 1.8 Hz, 1H), 8.51 (dd, J=4.6, 1.8 Hz, 1H), 7.59-7.64 (m, 1 H), 7.15-7.21 (m, 2H), 6.86 (dd, J=8.4, 4.6 Hz, 1H), 2.28 (d, J=2.0 Hz, 3H).

Step 2. Synthesis ofN²-(3-fluoro-4-methylphenyl)pyridine-2,3-diamine (C2).

Zinc dust (14,3 g, 219 mmol) was added to a stirring mixture of A/-(3-fluoro-4methylphenyl)-3-nitropyridin-2-amine (C1 ) (6.78 g, 27.4 mmol) and ammonium chloride (11.7 g, 219 mmol) în tetrahydrofuran (55 mL) and water (55 mL), which caused the température of the mixture to rise to 45 °C. The reaction mixture was stirred for 10 minutes, and then filtered through a pad of Celite, rinsing with ethyl acetate. The organic layer from the filtrate was further diluted with ethyl acetate, washed with aqueous ammonium chloride solution and with saturated aqueous sodium chloride solution, dried over magnésium sulfate, and filtered. The filtrate was concentrated in vacuo to afford the product as a black solid (6.6 g), the bulk 10 of which was taken directly to the following step. LCMS m/z 218.1 [M+H]⁺. ¹H NMR (400

MHz, CDCI₃), characteristic product peaks: δ 7.84 (dd, J=4.9, 1.6 Hz, 1H), 7.01 (dd, J=7.6,

1.6 Hz, 1H), 6.82 (br dd, J=8, 2 Hz, 1H), 6.77 (dd, J=7.6, 4.9 Hz, 1H), 2.20 (d, J=2 Hz, 3H).

Step 3. Synthesis ofN-cyclopropyl-N'-{2-[(3-fluoro-4-methylphenyl)amino]pyridin-315 yl/ethanediamide (C3).

Potassium tert-butoxide (4.54 g, 40.5 mmol) was added to a solution of A^-(3-fluoro4-methylphenyl)pyridine-2,3-diamine (C2) (from the previous step, 5.87 g, <24.4 mmol) and ethyl (cyclopropylamino)(oxo)acetate (P1) (6.36 g, 40.5 mmol) in 1-methylpyrrolidin-2One (27 mL). The reaction mixture was heated at 120 °C for 10 minutes, cooled to room 20 température and diluted with aqueous ammonium chloride solution. Tetrahydrofuran was added to assist solubilization, followed by ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnésium sulfate, filtered, and concentrated in vacuo to provide the crude product (13.0 g). A portion of this material was used directly in the following step. LCMS m/z 329.0 [M+H]⁺.

Step 4. Synthesis ofN-cyclopropyl-3-(3-fluoro-4-methylphenyl)-3M-imidazo[4,5-b]pyridine-2carboxamide (1).

A mixture of /V-cyclopropyl-/V'-{2-[(3-fluoro-4-methylphenyl)amino]pyrïdin-3-yl}ethanediamide (C3) (from the preceding step, 8.86 g, £16.6 mmol) and ethane-1,2-diol (27 mL) was 30 stirred at 200 °C for 1 hour. After cooling to room température, the reaction mixture was diluted with water (100 mL) and aqueous sodium hydroxide solution (1 M, 100 mL), then extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnésium sulfate, filtered, and concentrated under reduced pressure. Purification using silica gel chromatography (Gradient: 5% to 50% 35 ethyl acetate in heptane) was followed by recrystallization from 3:1 toluene / heptane, to afford the product as a solid. Yield: 2.52 g, 8.12 mmol, 49% over three steps. LCMS m/z

311.0 [M+H]⁺. ¹H NMR (400 MHz, CDCI₃) δ 8.50 (dd, J=A.7, 1.5 Hz, 1H), 8.13 (dd, J=8.1, 1.5

Hz, 1H), 7.68 (br s, 1H), 7.37 (dd, J=8.1, 4.7 Hz, 1 H), 7.34-7.40 (m, 1H), 7.10-7.15 (m, 2H),

2.83-2.90 (m, 1H), 2.37 (br d, J=2 Hz, 3H), 0.83-0.89 (m, 2H), 0.67-0.72 (m, 2H).

Example 2

3-Cyclopentyl-N -cyciopropyl-3H -imidazo[4,5-bJpyridine-2-carboxamide (2)

Step 1. Synthesis of N-cyclopentyl-3-nttropyridin-2-amine (C4).

Cyclopentanamine (2.7 g, 32 mmol) was added to a solution of 2-chloro-310 nitropyridine (5.0 g, 32 mmol) in tetrahydrofuran (200 mL), and the reaction mixture was stirred at reflux for 18 hours. After removal of solvent under reduced pressure, the residue was purified via silica gel chromatography to give the product as a yellow solid. Yield: 5.5 g, 26 mmol, 81%. ¹H NMR (400 MHz, CD₃OD) δ 8.42 (dd, half of ABX pattern, J=8.3, 1.8 Hz, 1H), 8.40 (dd, half of ABX pattern, J=4.5, 1.8 Hz, 1H), 6.69 (dd, J=8.3, 4.5 Hz, 1 H), 4.5115 4.59 (m, 1H), 2.07-2.17 (m, 2H), 1.62-1.85 (m, 4H), 1.51-1.62 (m, 2H)

Step 2. Synthesis of N^z-cyclopentylpyridine-2,3-diamine (C5).

To a solution of /V-cyclopentyl-3-nitropyridin-2-amine (C4) (4.7 g, 23 mmol) in methanol (100 mL) was added palladium on carbon (0.5 g), and the mixture was degassed 20 with hydrogen. After stirring under hydrogen at room température for 4 hours, the reaction mixture was filtered; the filtrate was concentrated in vacuo to afford the product as a black solid. Yield: 3.6 g, 20 mmol, 87%. ¹H NMR (400 MHz, DMSO-d₆) δ 7.35 (dd, J=5, 1 Hz, 1H), 6.63 (dd, J=7.3, 1.0 Hz, 1 H), 6.30 (dd, J=7.3, 5.0 Hz, 1H), 5.31 (br d, J=6.3 Hz, 1H), 4.69 (br s, 2H), 4.18-4.28 (m, 1H), 1.88-2.00 (m, 2H), 1.61-1.75 (m, 2H), 1.36-1.60 (m, 4H).

Step 3. Synthesis of ethyl {[2-(cyclopentylamino)pyridin-3-yl]amino}(oxo)acetate (C6).

To a solution of A^-cyclopentylpyridine-Z.S-diamine (C5) (1.78 g, 10.0 mmol) and triethylamine (1.52 g, 15.0 mmol) in dichloromethane (100 mL) was added ethyl chloro(oxo)acetate (1.49 g, 10.9 mmol), and the reaction mixture was stirred at room température for 18 hours. Removal of volatiles in vacuo afforded the crude product (2 g) as a brown solid, which was used in the next step without further purification.

Step 4. Synthesis of ethyl 3-cyc!opentyl-3H-imidazo[4,5-b]pyridine-2-carboxylate (C7).

A solution of crude ethyl {[2-(cyclopentylamino)pyridin-3-yl]amino}(oxo)acetate (C6) (from the previous step, 2 g) in toluene (100 mL) was stirred at reflux for 18 hours. The reaction mixture was concentrated in vacuo and the residue was purified using silica gel chromatography (Gradient; 9% to 50% ethyl acetate in petroleum ether) to provide the product as a brown solid. Yield: 0.70 g, 2.7 mmol, 27% over 2 steps. ¹H NMR (400 MHz, 15 CD₃OD) 6 8.53 (dd, J=4.6, 1.4 Hz, 1H), 8.14 (dd, J=8.2, 1.4 Hz, 1H), 7.40 (dd, J=8.2, 4.7 Hz, 1H), 5.79-5.89 (m, 1H), 4.51 (q, J=7.1 Hz, 2H), 2.48-2.61 (m, 2H), 2.07-2.20 (m, 4H), 1.701.83 (m, 2H), 1.46 (t, J=7.2 Hz, 3H).

Step 5. Synthesis of 3-cyclopentyl-N-cyclopropyl-3H-imidazo[4,5-b]pyridine-2-carboxamide 20 (2).

To a solution of ethyl 3-cyc)opentyl-3H-imidazo[4,5-b]pyridine-2-carboxylate (C7) (0.12 g, 0.46 mmol) in éthanol (10 mL) was added cyclopropylamine (0.55 g, 9.6 mmol), and the reaction mixture was stirred at room température for 18 hours. After concentration in vacuo, purification was effected via préparative thin layer chromatography on silica gel 25 (Eluent: 5:1 petroleum ether / ethyl acetate) to afford the product as a yellow solid. Yield: 36 mg, 0.13 mmol, 28%. LCMS m/z270.9 [M+H]⁺. Ή NMR (400 MHz, CDCI₃) δ 8.47 (dd, J=4.6, 1.5 Hz, 1H), 8.02 (br d, J=8 Hz, 1H), 7.85 (br s, 1H), 7.27 (dd, J=8.2, 4.6 Hz, 1H, assumed; partially obscured by solvent peak), 6.16-6.27 (m, 1H), 2.89-2.97 (m, 1H), 2.51-2.64 (m, 2H), 2.06-2.19 (m, 4H), 1.69-1.81 (m, 2H), 0.87-0.95 (m, 2H), 0.69-0.76 (m, 2H).

Example 3

3-(4-Chlorophenyi)-N-cyclopropyl-3'r\-imidazo[4.5-ï)]pyridine-2-carboxamide (3)

Step 1. Synthesis ofN-(4-chloropheny!)-3-nitropyridin-2-amine (C8).

To a solution of 2-chloro-3-nitropyridine (15.4 g, 97.1 mmol) in Ν,Νdimethylformamide (100 mL) were added 4-chloroaniline (12.4 g, 97.2 mmol) and potassium carbonate (20 g, 140 mmol). The reaction mixture was stirred at 100 °C for 18 hours, and then poured into ice-water (200 mL). The precipitate was collected via filtration and washed with water (3 x 30 mL) to provide the product as a black solid. Yield: 15 g, 60 mmol, 62%. ¹H

NMR (400 MHz, DMSO-cfe) S 9.97 (br s, 1 H), 8.47-8.57 (m, 2H), 7.69 (d, J=8.8 Hz, 2H), 7.41 (d, J-8.8 Hz, 2H), 7.01 (dd, J=8.2, 4.6 Hz, 1H).

Step 2. Synthesis of N^z-(4-chlorophenyl)pyridine-2,3-diamine (C9).

To a solution of M-(4-chlorophenyl)-3-nitropyridin-2-amîne (CB) (2.68 g, 10.7 mmol) in 20 ethyl acetate (100 mL) was added Raney nickel (1.5 g), and the mixture was degassed with hydrogen. After 6 hours of hydrogénation at room température, the reaction mixture was filtered; concentration of the filtrate in vacuo afforded the product as a black solid. Yield: 1.8

g, 8.2 mmol, 77%. ¹H NMR (400 MHz, DMSO-cfe) δ 7.88 (br s, 1H), 7.67 (d, J=8.9 Hz, 2H),

7.50 (br d, J=4 Hz, 1H), 7.25 (d, J=8.9 Hz, 2H), 6.91 (br d, Z7.5 Hz, 1H), 6.64 (dd, J=7.3,

4.8 Hz, 1H), 5.08 (brs, 2H).

Step 3. Synthesis of ethyl 3-(4-chlorophenyl)-3H -imidazo[4,5-b]pyridine-2-carboxyla te (C10).

A mixture of /^-(4-chlorophenyl)pyridine-2,3-diamine (C9) (1.8 g, 8.2 mmol) and diethyl ethanedioate (18 g, 123 mmol) was stirred at 140 °C for 18 hours. Purification using silica gel chromatography (Gradient: 16% to 50% ethyl acetate in petroleum ether) provided the product as a brown solid, containing approximately 30% of a contaminant by ¹H NMR 10 analysis. Yield: 250 mg, 0.83 mmol, 10%. ¹H NMR (400 MHz, CD₃OD), product peaks only: δ 8.49 (dd, J=4.8, 1.5 Hz, 1H), 8.31 (dd, J=8.2, 1.4 Hz, 1H), 7.61 (br d, J=8.9 Hz, 2H), 7.52 (dd, J=8.2, 4.6 Hz, 1 H), 7.49 (br d, 7=8.9 Hz, 2H), 4.34 (q, 7=7.2 Hz, 2H), 1.25 (t, 7=7.2 Hz, 3H).

Step 4. Synthesis of 3-(4-ch!orophenyl)-N-cyciopropyl-3H -imidazo[4,5-b]pyridine-2carboxamide (3).

Ethyl 3-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-2-carboxylate (C10) was converted to the product using the method described for synthesis of 2 in Example 2. The product was obtained as an off-white solid. Yield: 34.5 mg, 0.110 mmol, 28%. LCMS m/z 20 312.9 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.42 (dd, 7=4.8, 1.5 Hz, 1H), 8.24 (dd, 7=8.2,

1.4 Hz, 1H), 7.58 (br d, 7=8.8 Hz, 2H), 7.43-7.49 (m, 3H), 2.76-2.83 (m, 1H), 0.77-0.84 (m, 2H), 0.63-0.69 (m, 2H).

Example 4

3-(4-Chloro-3-fluorophenyl)4<-cyclopropy!-3H-imidazo[4_l5-b]pyridine-2-carboxamide (4)

Cl Cl

C11 C12

Step 1. Synthesis ofN-(4-chloro-3-fluorophenyl)-3-nitropyridin-2-amine (C11).

4-Chloro-3-fluoroaniline (10.0 g, 68.7 mmol) was heated to 180 °C in an oil bath. 2Chloro-3-nitropyridÎne (11.0 g, 69.4 mmol) was added, and the resulting mixture was stirred 5 at 180 °C for 10 minutes. The reaction mixture was then cooled to 15 °C and washed with petroleum ether, providing the product as a salmon-pink solid. Yield: 15 g, 56 mmol, 82%. ¹H NMR (400 MHz, CDCI₃) Ô 10.20 (br s, 1H), 8.57 (dd, J=8.3, 1.6 Hz, 1H), 8.54 (dd, J=4.6, 1.7 Hz, 1H), 7.90 (dd, J=11.3, 2.4 Hz, 1H), 7.38 (dd, J=8.5, 8.3 Hz, 1H), 7.23-7.28 (m, 1H, assumed; partially obscured by solvent peak), 6.94 (dd, J=8.3, 4.5 Hz, 1H).

Step 2. Synthesis of^-(4-chioro-3-fluorophenyl)pyridine-2,3-diamine (C12).

A mixture of /V-(4-chloro-3-fluorophenyl)-3-nitropyridin-2-amine (C11) (5.0 g, 19 mmol) and Raney nickel (3 g) in ethyl acetate (400 mL) was degassed three times with hydrogen. The reaction mixture was then hydrogenated at room température for 20 hours.

After removal of the catalyst via filtration, the filtrate was concentrated in vacuo. Purification via silica gel chromatography afforded the product as a gray solid. Yield: 3.1 g, 13 mmol, 68%. ¹H NMR (400 MHz, CDCI₃) δ 7.87 (dd, J=4.9, 1.6 Hz, 1H), 7.38 (dd, J=11.5, 2.5 Hz, 1H), 7.24 (dd, <7=8.5, 8.4 Hz, 1H), 7.06 (dd, J=7.6, 1.6 Hz, 1H), 6.92 (ddd, J=8.7, 2.5, 1.0 Hz, 1H), 6.82 (dd, J=7.6, 4.9 Hz, 1H), 6.37 (brs, 1H), 3.38 (brs, 2H).

Step 3. Synthesis of 3-(4-chloro-3-fIuorophenyl)-N-cyclopropyl-3iï-imidazo[4,5-b]pyridine-2carboxamide (4).

A mixture of the mono-tosylate sait of /V^?-(4-chloro-3-fluorophenyl)pyridine-2,3diamine (C12) [prepared via treatment of C12 with p-toluenesulfonic acid monohydrate (1.5 équivalents) in éthanol at 80 °C, followed by cooling to room température and isolation via filtration] (1.003 g, 2.447 mmol), (cyclopropylamîno)(oxo)acetic acid (P2) (0.304 g, 2.35 mmol), 2,6-dimethylpyridine (0.91 mL, 0.84 g, 7.8 mmol), and 2-methyltetrahydrofuran (10 mL) was cooled to -10 °C and treated with 2,4₁6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane

2,4,6-trioxide (50 weight% solution in ethyl acetate, 4.3 mL, 4.6 g, 7.2 mmol). The reaction mixture was warmed to 0 °C and held for 1 hour, heated at reflux for 20 hours, and then cooled to 0 °C and filtered, rinsing with 2-methyltetrahydrofuran. The filtrate was sequentially washed with water (10 mL, 5 mL), with aqueous ammonium hydroxide solution (15%, 3x5 mL), with aqueous hydrochloric acid (0.1 M, 10 mL, 5 mL), and with water (10 mL). The organic layer was distilled to a volume of approximately 4 mL, diluted with 2methyltetrahydrofuran (13 mL), and again distilled to approximately 4 mL, whereupon it was cooled to 50 °C and treated with heptane (3 mL). The resulting slurry was stirred at 50 °C for 2 hours, cooled to 20 °C, and stirred for 12 hours. The solid was collected via filtration and washed with a mixture of heptane and 2-methyltetrahydrofuran (2:1, 5 mL). The resulting material (0.488 g) was reslurried in a mixture of 2-propanol and ethyl acetate (9:1, 4.9 mL), warmed to 40 °C, cooled to 20 °C, and stirred for 16 hours. Filtration and washing with 2propanol (3 mL) afforded the product as an off-white solid. Yield: 410 mg, 1.24 mmol, 53%. LCMS m/z 330.9, 332.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.17 (d, J=4.8 Hz, 1H), 8.45 (d, J=4.5 Hz, 1H), 8.27 (d, A8.0 Hz, 1H), 7.71-7.80 (m, 2H), 7.47 (dd, J=8.0, 4.8 Hz, 1H), 7.40 (br d, A8.5 Hz, 1 H), 2.77-2.86 (m, 1H), 0.65-0.69 (m, 4H).

Example 5

3-(4-Chloro-3-fluorophenyl)-N-( 1 -methyl-1H -pyrazol-3-yl)-3iï-imidazo[4,5-b ]pyridine-2carboxamide (5)

C12 C13 5

Step 1. Synthesis of ethyl 3-(4-chloro-3-fluorophenyl)-3H-imidazo[4,5-b]pyridine-2carboxylate (C13).

Conversion of 7/-(4-chloro-3-fluorophenyl)pyridine-2,3-diamine (C12) to the product was effected using the method described for synthesis of C10 in Example 3. The product was obtained as a brown solid. Yield: 700 mg, 2.2 mmol, 17%. ¹H NMR (400 MHz, CDCI₃) δ

8.55 (dd, J=4.6, 1.4 Hz, 1H), 8.29 (dd, J=8.2, 1.4 Hz, 1H), 7.61 (dd, J=8.3, 8.0 Hz, 1H), 7.42 (dd, J=8.2, 4.8 Hz, 1H), 7.29 (dd, J=8.9, 2.3 Hz, 1H, assumed; partially obscured by solvent peak), 7.18-7.22 (m, 1H), 4.44 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H).

Step 2. Synthesis of 3-(4-chloro-3-fluorophenyl)-N-(1-methyl-1H-pyrazol-3-yl)-3\-\imidazo[4,5-bJpyridine-2-carboxamide (5).

To a solution of ethyl 3-(4-chloro-3-fluorophenyl)-3H-imidazo[4,5-b]pyridine-2carboxylate (C13) (32 mg, 0.10 mmol) and 1-methyl-1H-pyrazol-3-amrne (29 mg, 0.30 mol) in toluene (3 mL) was added trîmethylaluminum (2 M solution in toluene, 0.3 mL, 0.6 mmol) at room température. The reaction mixture was irradiated in a microwave reactor at 150 °C for 1 hour, whereupon it was partitioned between water (20 mL) and ethyl acetate (50 mL). The organic layer was washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via reversed phase HPLC (Column: Agella Venusil ASB-C18, 5 pm; Mobile phase A: 0.225% formic acid in water; Mobile phase B: 0.225% formic acid in acetonitrile; Gradient: 33% to 63% B) afforded the product as a yellow solid. Yield: 2.0 mg, 5.4 pmol, 5%. LCMS m/z371.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.47 (br d, J=4.6 Hz, 1H), 8.32 (br d, J=8 Hz, 1H), 7.69 (dd, J=8, 8 Hz, 1H), 7.48-7.56 (m, 3H), 7.35 (br d, J=8 Hz, 1H), 6.52-6.55 (m, 1H), 3.83 (s, 3H).

Example 6

3-(4-Chloro-3-fluorophenyl)-l··!-propyl-3H-imidazo[4,5-b]pyridine-2-carboxamide (6)

n-Propylamine (148 mg, 2.5 mol) was added to a solution of ethyl 3-(4-chloro-325 fluorophenyl)-3H-imidazo[4,5-b]pyridine-2-carboxylate (C13) (80 mg, 0.25 mmol) in éthanol (5 mL) and the reaction mixture was stirred at room température for 18 hours. After concentration under reduced pressure, the residue was purified by préparative thin layer chromatography on silica gel (Eluent: 1:1 petroleum ether / ethyl acetate) to provide the product as a pale yellow solid. Yield: 28 mg, 84 pmol, 34%. LCMS m/z 332.9 [M+H]⁺. ¹H 30 NMR (400 MHz, CD₃OD) δ 8.43 (dd, J=4.8, 1.4 Hz, 1H), 8.26 (dd, J=8.2, 1.5 Hz, 1 H), 7.67

(dd, 4=8.4, 8.2 Hz, 1H), 7.45-7.50 (m, 2H), 7.30 (ddd, 4=8.5, 2.3, 1.2 Hz, 1H), 3.28-3.34 (m,

2H, assumed; partially obscured by solvent peak), 1.58-1.68 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).

Example 7

3-(4-Cyano-3-fluorophenyl)-N-cyclopropyl-3H-imidazo[4,5-b]pyridine-2-carboxamide (7)

Step 1. Synthesis of2-fluoro-4-[(3-nitropyridin-2-yl)amino]benzonitrile (C14).

A mixture of 3-nitropyridin-2-amine (3.44 g, 24.7 mmol), 4-bromo-2-fluorobenzonitrile (4.95 g, 24.7 mmol), tris(dibenzylideneacetone)dipalladium(0) (226 mg, 0.247 mmol), 4,5bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos, 286 mg, 0.494 mmol) and césium carbonate (32.3 g, 99.0 mmol) in 1,4-dioxane (124 mL) was degassed, placed under 5 nitrogen and stirred at 100 °C for 30 minutes. The reaction mixture was filtered through a pad of Celite using tetrahydrofuran, and the filtrate was concentrated in vacuo. A 1:1 mixture of heptane and ethyl acetate was added to the residue, and the mixture was cooled in an ice/water bath. The solid was coliected via filtration and washed with cold 1:1 heptane / ethyl acetate to afford the product as a gray solid. Yield: 6.2 g, 24 mmol, 97%. LCMS m/z 259.1 10 [M+H]⁺. ¹H NMR (400 MHz, CDCI₃) 8 10.46 (br s, 1H), 8.60-8.63 (m, 2H), 8.16 (dd, J=11.8,

2.1 Hz, 1H), 7.59 (dd, J=8.5, 7.2 Hz, 1H), 7.40 (br dd, J=8.6, 2 Hz, 1H), 7.05-7.09 (m, 1H).

Step 2. Synthesis of 4-[(3-aminopyridin-2-yl)amino]-2-fluorobenzonitrile (C15).

To a solution of 2-fluoro-4“[(3-nitropyridin-2-yl)amino]benzonitrile (C14) (5.4 g, 21 mmol) in a 1:1 mixture of tetrahydrofuran and water (40 mL) was added ammonium chloride (8.9 g, 170 mmol), foliowed by zinc (10.8 g, 165 mmol). The mixture was stirred at 60 °C for 30 minutes, whereupon it was filtered through a pad of Celite. The organic layer from the filtrate was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo; the residue was washed with heptane to afford the product as a brown solid. Yield: 4.2 g, 18 mmol, 86%. LCMS m/z 229.1 [M+H]⁺. Ή NMR (400 MHz, DMSO-d_e) δ 8.68 (br s, 1H), 7.82 (dd, J=13.6, 2.0 Hz, 1H), 7.66 (dd, J=8.4, 8.3 Hz, 1H), 7.61 (dd, J=4.8, 1.6 Hz, 1H), 7.37 (dd, J=8.8, 2.0 Hz, 1 H), 7.03 (dd, J=7.8, 1.6 Hz, 1 H), 6.82 (dd, J=7.8, 4.8 Hz, 1 H), 5.24 (br s, 2H).

Step 3. Synthesis of3-(4-cyano-3~fluorophenyl)-N-cyclopropyl-3H-imidazo[4,5-b]pyridine-2carboxamide (7).

To a mixture of 4-[(3-aminopyridin-2-yl)amino]-2-fluorobenzonitrile (C15) (3.9 g, 17 mmol) and ethyl (cyclopropylamino)(oxo)acetate (P1) (4.03 g, 25.6 mmol) in 1methylpyrrolidin-2-one (17 mL) was added potassium terf-butoxide (2.88 g, 25.7 mmol). The 30 reaction mixture was stirred at 120 °C for 30 minutes, cooled to room température, and treated with 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P) (-50% weight solution, 20.3 mL, 32 mmol). After the réaction mixture had been stirred at 120 °C for 18 hours, it was allowed to cool. Water (10 mL) was added and stirring was continued for 10 minutes. Saturated aqueous sodium bicarbonate solution (20 mL) was introduced, and the 35 mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, filtered, and concentrated in

vacuo. Silica gel chromatography (Gradient; 10% to 50% ethyl acetate in petroleum ether) afforded the product as a white solid. Yield: 2.29 g, 7.13 mmol, 42%. LCMS m/z 322.2 [M+H]⁺. ¹H NMR (400 MHz, CDCI₃) δ 8.50 (dd, J=4.7, 1.4 Hz, 1H), 8.17 (dd, J=8.2, 1.5 Hz,

H), 7.79-7.85 (m, 1H), 7.69 (br s, 1H), 7.38-7.45 (m, 3H), 2.83-2.90 (m, 1H), 0.87-0.93 (m,

2H), 0.68-0.73 (m, 2H).

Example 8

4-[2-(Azetidin-1 -ylcarbonyl)-3H-imidazo[4,5-b]pyridin-3-ylJ-2-fluorobenzonitrile (8)

Step 1. Synthesis of ethyl 3-(4-cyano-3-fluorophenyl)-3V\-imidazo[4,5-b]pyridine-2carboxylate (C16).

To a 0 °C solution of 4-[(3-aminopyridin-2-yl)amino]-2-fluorobenzonitrile (C15) (300 mg, 1.31 mmol) and triethylamine (270 mg, 2.67 mmol) in dichloromethane (20 mL) was added ethyl chloro(oxo)acetate (220 mg, 1.61 mmol), and the solution was stirred at 0 ^DC for 15 2 hours. After addition of water (20 mL), the mixture was extracted with dichloromethane (3 x mL); the combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by préparative thin layer chromatography on silica gel (Eluent: 10:1 dichloromethane / methanol) to afford the product as a yellow solid. Yield: 40 mg, 0.13 20 mmol, 10%. ¹H NMR (400 MHz, CDCI₃), characteristic peaks: δ 8.55 (d, J=5 Hz, 1H), 4.46 (q, J=7 Hz, 2H), 1.43 (t, J=7 Hz, 3H).

Step 2. Synthesis of 4-[2-(azetidin-1-ylcarbonyl)-3H-imidazo[4,5-b]pyridin-3-yl]-2fluorobenzonitrile (8).

A mixture of azetidine hydrochloride (120 mg, 1.3 mmol) and N,Ndiisopropylethylamine (168 mg, 1.30 mmol) in methanol (2 mL) was stirred at room température for 1 hour. At this point, ethyl 3-(4-cyano-3-fluorophenyl)-3A/-imidazo[4,5ô]pyrîdine-2-carboxylate (Cl6) (40 mg, 0.13 mmol) and calcium chloride (15 mg, 0.13 mmol) were added, and the reaction mixture was stirred at room température for an additional 2 hours. After removal of solvents in vacuo, the residue was purified by reversed phase HPLC (Column: DIKMA Diamonsil C18(2), 5 pm; Mobile phase A: 0.225% formic acid in water;

Mobile phase B: 0.225% formic acid in acetonitrile; Gradient: 15% to 45% B) to provide the product as a yellow solid. Yield: 4.0 mg, 12 pmol, 9%. LCMS m/z 322,1 [M+H]⁺. ¹H NMR (400 MHz, CDCIa) Ô 8.49 (dd, J=4.8, 1.3 Hz, 1H), 8.20 (dd, J=8.2, 1.4 Hz, 1H), 7.77-7.82 (m,

1H), 7.36-7.43 (m, 3H), 4.80-4.89 (m, 2H), 4.18-4.26 (m, 2H), 2.39-2.50 (m, 2H).

Example 9

Azetidin-1 -yl[3-(4-chloro-3,5-difluorophenyl)-3H -imidazo[4,5-b]pyridin-2-yl]methanone (9)

Step 1. Synthesis ofN-(4-chloro-3,5-dif!uoropheny/)-3-nitropyridin-2-amine (C17).

A mixture of 4-chloro-3,5-difluoroaniline (1.64 g, 10.0 mmol), 2-chloro-3-nîtropyridine (1.56 g, 9.84 mmol) and césium carbonate (6.56 g, 20.1 mmol) in Ν,Ν-dimethylformamide (30 mL) was stirred at 80 °C for 36 hours. The reaction mixture was cooled to room température, diluted with water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (5 x 50 mL), dried over sodium sulfate, filtered, concentrated in vacuo and purified by chromatography on silica gel (Gradient: 0% to 5% ethyl acetate in petroleum ether) to provide the product as a yellow solid. Yield: 200 mg, 0.70 mmol, 7%. ¹H NMR (400 MHz,

CDCIa) δ 10.23 (br s, 1H), 8.55-8.61 (m, 2H), 7.52 (brd, J=Q Hz, 2H), 6.96-7.01 (m, 1H).

i

Step 2. Synthesis ofN²-(4-chloro-3,5-difluorophenyl)pyridine-2,3-diamine (C18).

To a solution of /V-(4-chloro-3,5-difluorophenyl)-3-nitropyridin-2-amine (C17) (100 mg, 0.35 mmol) in a 1:1 mixture of tetrahydrofuran and water (20 mL) was added ammonium chloride (148 mg, 2.77 mmol) followed by zinc (182 mg, 2.78 mmol), and the reaction 15 mixture was stirred at room température for 2 hours. It was then diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the product as a yellow solid. This material was used directly in the following step. Yield: 80 mg, 0.31 mmol, 89%.

Step 3. Synthesis of ethyl 3-(4-chloro-3,5-difluorophenyl)-3[-i-imidazo[4_!5-b]pyridine-2carboxylate (C19).

/y-(4-Chloro-3,5-difluorophenyl)pyridine-2,3-diamine (C18) was converted to the product using the method described for synthesis of C16 in Example 8. The product was 25 obtained as a yellow solid. Yield: 40 mg, 0.12 mmol, 41%. Ή NMR (400 MHz, CDCI₃) δ 8.56 (dd, J=4.7, 1.3 Hz, 1H), 8.30 (dd, J=8.1, 1.5 Hz, 1H), 7.44 (dd, J=8.2, 4.7 Hz, 1H), 7.11-7.15 (m, 2H), 4.46 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H).

Step 4. Synthesis of azetidin-1-yl[3-(4-chloro-3,5-difluorophenyl)-3H-imidazo[4,5-b]pyridin-230 yljmethanone (9).

Ethyl 3-(4-chloro-3,5-difluorophenyl)-3H-imidazo[4,5-b]pyridine-2-carboxylate (C 19) was converted to the product using the method described for synthesis of 8 in Example 8. The product was obtained as a yellow solid. Yield: 7.9 mg, 23 pmol, 39%. LCMS m/z 349.1 [M+H]⁺. ’H NMR (400 MHz, CDCI₃) δ 8.50 (dd, J=A.7. 1.4 Hz, 1H), 8.19 (dd, J=8.1, 1.4 Hz, 35 1H), 7.39 (dd, J=8.1, 4.7 Hz, 1H), 7.10-7.15 (m, 2H), 4.80-4.85 (m, 2H), 4.19-4.25 (m, 2H),

2.40-2.49 (m, 2H).

Example 10

Azetidin-1 -y![3-(4-chloro-3-f!uorophenyl)-3b\-imidazo[4,5-b]pyridin-2-yl]methanone (10)

C12

Step 1. Synthesis of 3-(4-chloro-3-fluorophenyl)-2-(trichloromethyl)-3H-imidazo[4,5bjpyridine (C20).

Methyl 2,2,2-trichloroethanimidoate (0.743 mL, 6.00 mmol) was added to a solution of /V^?-(4-chloro-3-fluorophenyl)pyridine-2I3-diamine (C12) (951 mg, 4.00 mmol) in acetic acid (4 mL), and the reaction mixture was stirred at room température for 5 hours. After 10 concentration în vacuo, the residue was purified via chromatography on silica gel (Gradient: 5% to 100% ethyl acetate in heptane) to afford the product as a white solid. Yield: 1.04 g, 2.85 mmol, 71%. LCMS m/z 366.0 [M+H]*. ¹H NMR (400 MHz, CDCI3) δ 8.49 (dd, J=4.7, 1.5 Hz, 1H), 8.27 (dd, >8.1, 1.5 Hz, 1H), 7.64 (ddd, >8.5, 7.8, 0.3 Hz, 1H), 7.42 (dd, J=8.1, 4.7 Hz, 1H), 7.39 (ddd, >8.8, 2.4, 0.2 Hz, 1 H), 7.32 (ddd, >8.5, 2.4, 1.3 Hz, 1H).

Step 2. Synthesis ofazetidin-1-yl[3-(4-chloro-3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2yljmethanone (10).

3-(4-Chloro-3-fluorophenyl)-2-(trichloromethyl)-3H-imidazo[4,5-b]pyridine (C20) (50 mg, 0.14 mmol) was dissolved in a 3:1 mixture of acetonitrile and water (1.4 mL). Azetidine 20 hydrochloride (25.6 mg, 0.274 mmol) was added, followed by an aqueous solution of potassium carbonate (4 M, 0.15 mL, 0.60 mmol), and the reaction mixture was heated at 50 °C for 22 hours, then at 80 °C for 3 hours, and finally at 100 °C for 18 hours. The layers were separated, and the organic layer was concentrated in vacuo; purification via reversed phase HPLC (Column: Waters Sunfire C18, 5 pm; Mobile phase A: 0.05% trifluoroacetic acid in 25 water (v/v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 30% to 50% B) afforded the product. Yield: 17 mg, 51 pmol, 36%. LCMS m/z 331.1, 333.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 8.45 (dd, >4.6, 1.5 Hz, 1H), 8.30 (dd, >7.9, 1.3 Hz, 1 H), 7.76 (dd, >8.3, 8.3 Hz, 1H), 7.73 (dd, >10.1, 2.2 Hz, 1H), 7.46 (dd, >8.1, 4.6 Hz, 1H), 7.40-7.43 (m, 1H), 4.64-4.68 (m, 2H), 4.02-4.07 (m, 2H), 2.29-2.35 (m, 2H).

Method A

Synthesis of Examples from 2-Chloro-3-nitropyridine and Amines

The requisite amine (0.20 mmol) was combined with a solution of 2-chloro-3nitropyridine (31.7 mg, 0.200 mmol) in tetrahydrofuran (0.1 mL) and polyethylene glycol 400 5 (PEG 400, 0.1 mL); if an amine sait was used, triethylamine (28 pL, 0.20 mmol) was also added. The reaction mixture was shaken at 150 °C for 1-1.5 hours, then cooled to room température, To this was added tetrahydrofuran (0.4 mL) and a solution of ammonium chloride (85.6 mg, 1.60 mmol) in water (0.4 mL), followed by zinc (approximately 105 mg,

1.6 mmol). The reaction mixture was shaken at 65 °C for 1.5 hours, then partitioned between 10 water (1 mL) and ethyl acetate (2.5 mL). The organic layer was eluted through a 6 mL solid phase extraction cartridge filled with sodium sulfate (approximately 1 g). This extraction was repeated twice, and the combined eluates from the cartridge were concentrated in vacuo. To the crude residue was added a solution of ethyl (cyclopropylamino)(oxo)acetate (PI ) (47 mg, 0.30 mmol) in 1-methylpyrrolidin-2-one (0.2 mL) and a solution of potassium te/ï-butoxide in 15 tetrahydrofuran (1 M, 0.3 mL, 0.3 mmol); this reaction mixture was shaken at 120 °C for 30 minutes, then cooled to room température and treated with acetic acid (18 pL, 0.31 mmol).

2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P, 50% weight solution in ethyl acetate, 254 mg, 0.40 mmol) was added, and the reaction mixture was shaken at 120 °C for 24 hours. The reaction mixture was then partitioned between ethyl acetate (2.5 mL) 20 and aqueous sodium hydroxide solution (1 M, 1.5 mL); the organic layer was eluted through a 6 mL solid phase extraction cartridge filled with sodium sulfate (approximately 1 g). This extraction was repeated twice, and the combined eluates from the cartridge were concentrated in vacuo and purified via reversed phase HPLC using one of the following Systems: 1) Column: Waters XBridge C18, 5 pm; Mobile phase A: 0.03% ammonium 25 hydroxide in water (v/v); Mobile phase B: 0.03% ammonium hydroxide in acetonitrile (v/v);

Gradient: 20% to 60% B or 10% to 100% B; 2) Column: Waters Sunfire C18, 5 pm; Mobile phase A: 0.05% trifluoroacetic acid in water (v/v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 10% to 100% B.

Using the methodology described above for Examples 1-10, the compounds in Table and Table 2 were also made (See Tables 1 and 2 for characterization data).

Table 1

Example Number	Structure	Method of Préparation ; Noncommercial Starting Materials	1H NMR (400 MHz, CDCI3), δ (ppm); Mass spectrum, observed ion m/z [M+Hf or HPLC rétention time1 (minutes); Mass spectrum m/z [M+H]+ (unless otherwise indicated)
11	Cl çr fxw N— /	Example 12;C12	1H NMR (600 MHz, DMSO-de), δ 8.46 (dd, J=4.6, 1.5 Hz, 1H), 8.28 (dd, J=8.1, 1.5 Hz, 1 H), 7.81 (dd, J=8.3, 8.3 Hz, 1H), 7.74 (dd, J=1O.1, 2.2 Hz, 1 H), 7.47 (dd, J=8.1,4.6 Hz, 1H), 7.41-7.44 (m, 1H), 3.15 (s, 3H), 2.98 (S, 3H); 319.0, 321.0
12	Cl AY-N n (Xh O • CF3COOH	Example 10	1H NMR (600 MHz, DMSO-cfe), δ 8.46-8.49 (m, 1H), 8.32-8.36 (m, 1H), 7.90-7.96 (m, 2H), 7.47-7.51 (m, 1H), 4.71 (dd, J=7.7, 7.7 Hz, 2H), 4.06 (dd, J=7.7, 7.4 Hz, 2H), 2.30-2.37 (m, 2H); 349.1,351.1
13	Cl 0 Y-v-N O d	Example 6; C10	characteristic peaks: 8.46-8.53 (m, 1 H), 8.15 (br d, J=8 Hz, 1 H), 7.63- 7.73 (br m, 1H), 7.53 (br d, J=8 Hz, 2H), 7.39 (br d, J=8 Hz, 2H), 3.33- 3.43 (m, 2H), 0.99 (t, J=7.3 Hz, 3H); 314.8
14	N 9	C73	10.09 (brs, 1H), 8.49 (dd, J=4.6, 1.5 Hz, 1H), 8.07 (dd, J=8.2, 1.5 Hz, 1H), 7.32 (d, J=2.3 Hz, 1H), 7.29 (dd, J=8.2, 4.6 Hz, 1H), 6.78 (d, J=2.3 Hz, 1H), 6.22-6.33 (m, 1H), 3.87 (s, 3H), 2.55-2.67 (m, 2H), 2.08-2.21 (m, 4H), 1.70-1.83 (m,2H); 311.0

I

15	P	Example 2	1H NMR (400 MHz, CD3OD), δ 8.47 (dd, J=4.7, 1.4 Hz, 1H), 8.09 (dd, J=8.2, 1.4 Hz, 1H), 7.36 (dd, J=8.2, 4.6 Hz, 1H), 5.68 (tt, J=12, 4 Hz, 1H), 4.13 (dd, J=11.5, 4.5 Hz, 2H), 3.60 (ddd, J--12.4,11.8, 1.5 Hz, 2H), 3.03- 3.15 (m, 2H), 2.89-2.96 (m, 1H), 1.81-1.89 (m, 2H), 0.83-0.90 (m, 2H), 0.69-0.76 (m, 2H); 286.9
16	Cl 0 N p □	Example 10; C9	1H NMR (600 MHz, DMSO-tf6), δ 8.44 (dd, J=4.7, 1.3 Hz, 1 H), 8.28 (dd, J=8.1, 1.3 Hz, 1H), 7.56 (br AB quartet, JAB=8.7 Hz, ΔνΑΒ=39.2 Hz, 4H), 7.45 (dd, J=8.1, 4.7 Hz, 1H), 4.63 (dd, J=7.8, 7.7 Hz, 2H), 4.04 (dd, J=7.8, 7.7 Hz, 2H), 2.28-2.35 (m, 2H); 313.1,315.1
17	Cf çr Qw \U'N NH2	Example 7; C12	8.52 (dd, J=4.7, 1.3 Hz, 1 H), 8.19 (dd, J=8.2, 1.3 Hz, 1H), 7.59 (dd, J-8.2, 8.2 Hz, 1H), 7.41 (dd, J=8.1, 4.7 Hz, 1 H), 7.28-7.32 (m, 1 H), 7.20- 7.24 (m, 1 H); 290.8
18	XF AVN P L X aa UN N-, O	Example 34	8.49 (d, J=4.4 Hz, 1H), 8.15 (d, J=7.6 Hz, 1H), 7.31-7.38 (m, 2H), 7.10- 7.16 (rn, 2H), 4.73-4.80 (m, 2H), 4.16-4.24 (m, 2H), 2.36 (s, 3H), 2.36- 2.45 (m,2H);311.0
19	n k lYh0 Un n-, A F	Example 34	8.45 (dd, J=4.8, 1.3 Hz, 1H), 8.30 (dd, J=8.2, 1.1 Hz, 1H), 7.38-7.49 (m, 3H), 7.23-7.27 (m, 1H), 5.49 (br d, Jhf=57 Hz, 1H), 4.93-5.05 (m, 1H), 4.63-4.76 (m, 1 H), 4.32-4.44 (m, 1H), 4.04-4.16 (m, 1H), 2.33 (s, 3H); 329.0

20	c CN ÿ-F |[ΝγΝΛο HN~O	Example 7	8.50 (dd, >4.7, 1.5 Hz, 1H), 8.17 (dd, >8.2,1.5 Hz, 1H), 7.67 (br d, 1 H), 7.44 (dd, >8.1,4.7 Hz, 1 H), 7.21-7.25 (m, 2H), 2.83-2.90 (m, 1 H), 0.88-0.94 (m, 2H), 0.69-0.74 (m, 2H); 340.1
21	Cl Y N-. Y F	Example 34	8.51 (dd, >4.6, 1.2 Hz, 1H), 8.19 (dd, >8.2, 1.1 Hz, 1H), 7.57 (dd, >8.3, 8.0 Hz, 1H), 7.39 (dd, J=8.2, 4.6 Hz, 1H), 7.27 (dd, J=8.8, 2.3 Hz, 1H), 7.16-7.22 (m, 1H), 5.33-5.54 (m, Jhf=57 Hz, 1H), 5.08-5.20 (m, 1H), 4.85-4.98 (m, 1 H), 4.40-4.52 (m, 1H), 4.23-4.36 (m, 1H); 348.9
22	Cl F-0 ζΎΎ N—, O	Example 34	8.49 (dd, >4.7, 1.4 Hz, 1H), 8.18 (dd, J=8.2, 1.4 Hz, 1 H), 7.47 (dd, >8.4, 7.4 Hz, 1H), 7.37 (dd, >8.1, 4.8 Hz, 1H), 7.28-7.35 (m, 2H), 4.69- 4.96 (br m. 2H), 4.16-4.26 (m, 2H), 2.37-2.47 (m, 2H); 331.0
23	Cl	Example 34	8.50 (dd, J=4.8, 1.5 Hz, 1 H), 8.15 (dd, J=8.1, 1.4 Hz, 1 H), 7.66 (br s 1H), 7.45 (dd, >9.0, 7.4 Hz, 1H), 7.40 (dd, >8.1, 4.7 Hz, 1H), 7.31- 7.37 (m, 2H), 2.83-2.89 (m, 1H), 0.84-0.91 (m, 2H), 0.68-0.73 (m, 2H); 330.9
24	Cl 0 o UH »N HN-ÇJj	Example 5; C10	characteristic peaks: 9.94 (br s, 1 H), 8.52 (dd, >4.8, 1.5 Hz, 1H), 8.20 (dd, >8.2, 1.4 Hz, 1H), 7.56 (br d, J-8.8 Hz, 2H), 7.43 (br d, >8.7 Hz, 2H), 7.40 (dd, >8.2, 4.6 Hz, 1H), 6.68 (d, >2.1 Hz, 1H), 3.85 (s, 3H); 352.9

25	Cl γ ÔcW5 N--. F	Example 34	8.51 (dd, J=4.8, 1.4 Hz, 1H), 8.20 (dd, 0=8.2, 1.4 Hz, 1H), 7.46 (dd, 0=8.4, 7.9 Hz, 1H), 7.39 (dd, 0=8.2, 4.8 Hz, 1H), 7.29-7.37 (m, 2H), 5.33- 5.54 (m, JHf=57 Hz, 1H), 4.8-5.3 (v br m, 2H), 4.40-4.54 (m, 1H), 4.23- 4.37 (m, 1H); 348.9
26	Cl -0 ÔX	Example 34	8.49 (dd, 0=4.8, 1.1 Hz, 1H), 8.15 (dd, J=7.9,1.1 Hz, 1H), 7.66 (br s, 1H), 7.32-7.43 (m, 3H), 7.19 (d, 0=8.2 Hz, 1H), 2.81-2.89 (m, 1H), 1.98 (s, 3H), 0.83-0.89 (m, 2H), 0.66- 0.71 (m, 2H); 327.0
27	Cl 0_CI	Method A	2.97 minutes; 347.0, 349.0
28	0 XX N H N—<3	Method A	2.59 minutes; 311.1
29	N 0 Cxw. xX n hn—<]	Method A	2.51 minutes; 293.1
30	.x, j1 -h T LA o o 1 i A	Method A	2.70 minutes; 333.0

31	F Ç^y-cN	Method A	2.46 minutes; 322.1
32	Ç>CI	Method A	2.53 minutes; 331.0, 333.0
33	ÇÇci .0 CXM-o	Method A	2.90 minutes; 327.0, 329.0
34	Cl G Olw n-, □	Example 34	8.48 (dd, J=4.8, 1.5 Hz, 1H), 8.18 (dd, J=8.2, 1.4 Hz, 1H), 7.30-7.40 (m, 3H), 7.17 (d, J=8.3 Hz, 1 H), 4.754.92 (m, 2H), 4.15-4.22 (m, 2H), 2.36-2.46 (m, 2H), 1.99 (s, 3H); 327.0
35	CI -fj1 F	Example 34	presumed to be a mixture of rotamers; 8.50 (dd, J=4.6, 1.4 Hz, 1 H), 8.20 (br d, J=8.0 Hz, 1 H), 7.31 - 7.42 (m, 3H), 7.14-7.19 (m, 1H), 5.32-5.52 (m, JHf=57 Hz, 1H), 5.04- 5.26 (m, 1H), 4.82-5.03 (m, 1H), 4.38-4.50 (m, 1H), 4.21-4.34 (m, 1H), 1.99 and 1.97 (2 s, total 3H); 345.0
36	p Cl Z GH.<	Example 9	8.51 (dd, J=4.6, 1.5 Hz, 1 H), 8.15 (dd, J=8.2,1.5 Hz, 1H), 7.68 (br s, 1H), 7.41 (dd, J=8.2, 4.8 Hz, 1 H), 7.11-7.16 (m, 2H), 2.82-2.90 (m, 1H), 0.86-0.92 (m, 2H), 0.68-0.73 (m, 2H); 349.1

37		Example 25	8.72 (d, J=2.0 Hz, 1H), 8.60 (d, J=2.1 Hz, 1H), 8.51 (dd, J=4.6, 1.4 Hz, 1H), 8.16 (dd, J=8.2, 1.4 Hz, 1H), 7.86 (dd, J=2.1,2.0 Hz, 1H), 7.69 (brs, 1H), 7.42 (dd, J=8.3, 4.6 Hz, 1H), 2.83-2.91 (m, 1H), 0.86-0.92 (m, 2H), 0.68-0.73 (m, 2H); 314.1, 316.0
38	cXK ο	Example 37	8.69 (d, J=2.3 Hz, 1H), 8.56 (d, J=1.9 Hz, 1H), 8.50 (dd, J=4.6, 1.3 Hz, 1H), 8.20 (dd, J=8.1, 1.3 Hz, 1H), 7.85- 7.88 (m, 1H), 7.40 (dd, J=8.2, 4.6 Hz, 1H), 4.82-4.87 (m, 2H), 4.19-4.25 (m, 2H), 2.39-2.49 (m, 2H); 313.9, 315.9
39	CN 0 Y N ,0	Example 76	8.84 (br d, J=2.4 Hz, 1H), 8.50 (dd, J=4.7, 1.4 Hz, 1H), 8.18 (dd, J=8.2, 1.4 Hz, 1H), 8.03 (dd, half of ABX pattern, J=8.3, 2.4 Hz, 1H), 7.91 (dd, half of ABX pattern, J=8.3, 0.5 Hz, 1H), 7.72 (br s, 1H), 7.44 (dd, J=8.2, 4.8 Hz, 1H), 2.82-2.90 (m, 1H), 0.87- 0.93 (m, 2H), 0.68-0.73 (m, 2H); 305.1
40	faQ'cn Y N 0 ( T/M HN—0	Example 7	8.50 (dd, J=4.9, 1.4 Hz, 1H), 8.17 (dd, J=8.3, 1.3 Hz, 1H), 7.81-7.87 (m, 2H), 7.68 (br s, 1H), 7.39-7.45 (m, 2H), 2.82-2.89 (m, 1H), 0.86-0.92 (m, 2H), 0.68-0.74 (m, 2H); 322.2
41	Cl VF w	Example 77	8.51 (dd, J=4.6, 1.5 Hz, 1H), 8.16 (dd, J=8.o, 1.3 Hz, 1H), 7.64 (brs, 1H), 7.32-7.43 (m, 3H), 2.83-2.90 (m, 1H), 0,85-0.92 (m, 2H), 0.68-0.74 (m, 2H); 349.1

42	CN 0 /A-n p Cqa-<i	Method A	2.32 minutes; 304.1
43	p Oaa	Method A	2.47 minutes; 315.1
44	pr ,-Ύ-n p	Method A	2.54 minutes; 311.1
45	O Â ,-Ύ-n p CAA]	Method A	2.44 minutes; 327.1
46	P (VA . >An hn<.	Method A	2.34 minutes; 309.1
47	f œ-p	Method A	3.25 minutes; 319.1
48	pF (W. AA UN—0	Method A	2.55 minutes; 315.0

49	A Οχ	Method A	2.66 minutes; 343.0, 345.0
50	ç!n ftVA HNYJ	Method A	2.60 minutes; 323.1
51	O’- A ΓχΑΑ hnY]	Method A	2.60 minutes; 323.1
52	« & ΓχΑΑ HN-O	Method A	2.71 minutes; 307.1
53	ÇA ΓχΝΧΑ HN-<]	Method A	2.30 minutes; 304.1
54	M1 ΓχΑΑ \sVN HN~<]	Method A	2.85 minutes; 327.1, 329.1
55	F ΓχΑθ hn-<]	Method A	2.40 minutes; 327.1
56	M ôVa ^'N HNYJ	Method A	2.52 minutes; 318.1

A

57	9	Method A	2.13 minutes; 279.1
58	0- . J ΧχΝ/Μ°^ι HN-<	Method A	2.33 minutes; 309.1
59	X AV . HN—<]	Method A	2.74 minutes; 307.1
60	M <N n p	Method A	2.55 minutes; 311.1
61	S ftw . HN^O	Method A	2.10 minutes; 321.1
62	çl· CL·	Method A	2.52 minutes; 315.0
63	Ck L·01 CiML· YY-N HN Yj	Method A	3.06 minutes; 347.0, 349.0

64		Method A	2.83 minutes; 319.1
65	Y	Method A	2.39 minutes; 297.1
66		Method A	2.46 minutes; 339.1
67	Z X-Y---N .0	Method A	2.69 minutes; 311.1
68		Method A	2.35 minutes; 297.1
69	çr CY° T/N hn—<3	Example 7Θ	8.50 (dd, J=4.8, 1.3 Hz, 1H), 8.14 (dd, J=8.2,1.1 Hz, 1H), 7.69 (br s, 1H), 7.47-7.53 (m, 2H), 7.45 (br s, 1H), 7.33-7.41 (m, 2H), 2.83-2.90 (m, 1H), 0.83-0.90 (m, 2H), 0.67-0.73 (m, 2H); 312.9
70	Y TY-N HN-<0	Method A	2.48 minutes; 293.1

71	An V CF	Method A	2.13 minutes; 336.0
72	ÇA	Method A	2.65 minutes; 325.0
73	SÙ U ΓχΑΑ ZZ hn—<j	Method A	2.27 minutes; 350.0
74	Ci 0CcAA ZZ hnA	Method A	2.85 minutes; 327.1,329.0
75	Çj^°'cf3 Azj P (X^A	Method A	2.95 minutes; 363.0
76	F cz	Method A	2.71 minutes; 307.1
77	ÇA3 OhL	Method A	2.88 minutes; 347.0

©

78	cl Y γΝ N O ί X ac . YAn hn—<] • cf3cooh	Method A	2.79 minutes; 331.0, 333.0
79	YCI • CF3COOH	Method A	2.76 minutes; 331.0, 333.0
80	rp (M • cf3cooh	Method A	1.59 minutes; 330.1

1. Conditions for analytical HPLC. Column: Waters Atlantis dC18, 4.6 x 50 mm, 5 pm; Mobile phase A: 0.05% trifluoroacetic acid in water (v/v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 5.0% to 95% B, linear over 4.0 minutes; Flow rate: 2 mL/minute.

2. Ethyl (dimethylamîno)(oxo)acetate was employed in place of ethyl (cyclopropylamino) (oxo)acetate (P 1 ).

3. Hydrolysis of C7 with lithium hydroxide afforded the corresponding carboxylic acid; this was condensed with 1-methyl-1 H-pyrazol-3-amine using 1-[3-(drmethylamino)propyl]-3ethylcarbodiimide hydrochloride and 1H-benzotriazol-1-ol.

4. W,/V-Diisopropylethylamine was utilized in the final step.

5. The requisite N²-(5-chloropyridin-3-yl)pyridine-2,3-diamine was prepared via reaction of

2-chloro-3-nitropyridine with 5-chloropyridin-3-amine using palladium(ll) acetate and 4,5bis(diphenylphosphino)-9,9-dimethylxanthene, followed by treatment with Raney nickel.

6. 5-[(3-Nitropyridin-2-yl)amino]pyridine-2-carbonitrile was prepared by the method used for 15 synthesis of C17 in Example 9.

7. A/-(4-Chloro-2,5-difluorophenyl)-3-nitropyridin-2-amine was prepared by the method used for synthesis of C17 in Example 9.

8. A/-(3-Chlorophenyl)-3-nitropyridin-2-amine was prepared by heating 2-chloro-3nitropyridine with 3-chloroaniline at 150 °C.

Table 2

Example Number	Structure	Method of Préparation; Noncommercial Starting Materials	Mass spectrum, observed ton m/z[M+H]+
81	ζΎΎ AA N HN--y	Example 21	302.0
82	p \AN HN^C	Example 72	348.2

83	(W . ΧΦ ΗΝφ]	Example 7	309.9
84	<φ5	Method A	345.0, 347.0
85		Method A	294.1
86	X CA	Method A	333.1
87	η X υΑν ρ χΧφ-<	Method A	339.1
88	ci^ÇS	Method A	327.1,329.0
89	θ'” A (ΎΆ° . ΑΑ^ν ΗΝφ]	Method A	323.1

90	(ÏW - HN—O	Method A	331.0,333.0
91	CI^^Y An o CUnxi	Method A	327.1, 329.0
92	Y L	Method A	347.1

1. See footnote 5 in Table 1.

2, 3-Nitro-/V-[2-(trifluoromethyl)pyridin-4-yl]pyridin-2-amine was prepared from 2-chloro-3nitropyridine and 2-(trifluoromethyl)pyridin-4-amine using the method for synthesis of C17 in Example 9.

The binding affinity of the compounds in Examples 1-92 for the PDE4B isoform is shown in column 2 of Table 3 below, and the affinity of these compounds for the PDE4D isoform is shown în column 3. A review of the data shows that selected compounds hâve an enhanced binding affinity for the PDE4B isoform over the PDE4D isoform. For example, the data for Examples 2, 15, 17, 81, 82, 83, 85, 90 and 91 shows that these compounds display 10 at least about a 2-fold selectivity over the PDE4D isoform. The data for Examples 13, 14, 21,

25, 35, 40, 47, 77, 88, 89 and 92 shows that these compounds display at least about a 5-fold selectivity over the PDE4D isoform. The data for Examples 19, 20, 33, 38, 41,44, 49, 57, 61,

72, 75, 79 and 87 shows that these compounds display at least about a 10-fold to selectivity over the PDE4D isoform. The data for Examples 6, 9, 10, 11, 12, 22, 27, 31, 34, 37, 39, 43,

56, 59, 60, 63, 66, 69, 70, 73, 74, 78 and 80 shows that these compounds display at least about a 20-fold selectivity over the PDE4D isoform. The data for Examples 4, 7, 18, 36, 46, 62, 67 and 71 shows that these compounds display at least about a 40-fold selectivity over the PDE4D isoform. The data for Examples 1, 3, 8, 16, 23, 26, 28, 30, 32, 33, 42, 45, 48, 50, 51, 52, 54, 55, 58, 64, 65, 68 and 76 shows that these compounds display at least about a 50-fold selectivity over the PDE4D isoform.

The PDE4B and PDE4D binding affinity for the compounds of the présent invention was determîned utilizing the following biological assay(s):

Biological Assavs

A portion of the human PDE4D3 coding sequence (amino acids 50 to 672 from the sequence with accession number Q08499-2) was cloned into the baculovirus expression vector pFastBac (Invitrogen) engineered to include a C-terminal His6 affinity tag to aid in purification as described in Seeger, T. F. et al., Brain Research 985 (2003) 113-126. The recombinant Bacmid was isolated and used to transfect insect cells to generate a viral stock.

To generate cell paste for purification, insect cells were infected and cells were harvested 72 hours after infection. Insect cell paste was lysed and after centrifugation, the supernatant was chromatographed on Ni-NTA agarose (Qiagen) as described in Seeger, T. F. et al., 10 Brain Research 985 (2003) 113-126. Ni-NTA agarose eluting fractions containing PDE4 were pooled, diluted with Q Buffer A (50 mM Tris HCl pH 8, 4% glycerol, 100 mM NaCI, 1 mM TCEP, Protease inhibitors EDTA-free (Roche)) to reduce NaCI to -200 mM, and loaded on a Q Sepharose (GE Healthcare) column. After washing with Q buffer A to baseline, PDE4D was eluted with a gradient from 10% to 60% of Buffer B (50 mM Tris HCl pH 8, 1 M 15 NaCI, 4% glycerol, 1 mM TCEP). PDE4D fractions were analyzed by SDS-PAGE Coomassie blue staining, pooled based on purity, frozen and stored at -80 °C.

Human PDE4B1 coding sequence (amino acids 122 to 736 from the sequence with accession number Q07343) with the mutations resulting in the amino acid substitutions S134E, S654A, S659A, and S661A was cloned into the baculovirus expression vector 20 pFastBac (Invitrogen) engineered to include a N-terminal His6 affinity tag to aid in purification followed by a thrombin cleavage site. The recombinant Bacmid was isolated and used to transfect insect cells to generate a viral stock. To generate cell paste for purification, insect cells were infected with the virus stock and cells were harvested 72 hours after infection as described in Seeger, T. F. et al., Brain Research 985 (2003) 113-126. Insect cell 25 paste was lysed and after centrifugation, the supernatant was chromatographed on Ni-NTA agarose (Qiagen) as described in Seeger, T. F. et al., Brain Research 985 (2003) 113-126. Ni-NTA agarose eluting fractions containing PDE4 were pooled, diluted with Q buffer A (20 mM Tris HCl pH 8, 5% glycerol, 1 mM TCEP) to reduce NaCI to -100 mM and loaded on a Source 15Q (GE Healthcare) column. After washing with Q buffer A/10% buffer B to 30 baseline, PDE4D was eluted with a gradient from 10% to 60% of Buffer B (20 mM Tris HCl pH 8, 1 M NaCI, 5% glycerol, 1 mM TCEP). PDE4D fractions were analyzed by SDS-PAGE Coomassie blue staining, pooled based on purity, frozen and stored at -80 °C.

The PDE4B and 4D assays use scintillation proximity assay (SPA) technology to measure the inhibition of human recombinant PDE4B and PDE4D enzyme activity by 35 compounds in vitro. The PDE4B and 4D assays are run in parallel using identical

parameters, except for the concentration of enzyme (—32 pM PDE4B and ~16 pM PDE4D). The assays are performed in a 384-well format with 50 pL assay buffer (50 mM Tris pH 7.5;

1.3 mM MgCI₂; 0.01% Brij) containing enough PDE4B and PDE4D to convert -20% of substrate (1 μΜ cAMP consisting of 20 nM ³H-cAMP + 980 pM cold cAMP) and a range of 5 inhibitors. Reactions are incubated for 30 min at 25 °C. The addition of 20 pL of 8 mg/mL yttrium silicate SPA beads (PerkinElmer) stops the reaction. The piates are sealed (TopSeal, PerkinElmer) and the beads are allowed to settle for 8 hrs, after which they are read on the Trilux Microbeta ovemight.

Table 3

Example Number	Human PDE4B FL; IC50 (nM)a	Human PDE4D FL; IC50 (pM)a	IUPAC Name
1	31.8b	2.21b	W-Cyclopropyl-3-(3-fluoro-4-methylphenyl)-3/7- imidazo[4,5-b]pyridine-2-carboxamide
2	426	1.27b	3-Cyclopentyl- /V-cyclop ropyl-3H-i m idazo[4,5d]pyridrne-2-carboxamide
3	131b	7.95b	3-(4-Chlorophenyl)-A/-cyclopropyl'3H- imidazo[4,5-b]pyridine-2-carboxamide
4	18.4b	0.908b	3-(4-Chloro-3-fluorophenyl)-/V-cyclopropyl-3H- imidazo[4,5-f)]pyridine-2-carboxamide
5	54.1	5.64	3-(4-Chloro-3-fluorophenyl)-/V-(1 -methyl-1 H-

			pyrazol-3-yl)-3H-imidazo[4,5-b]pyridine-2carboxamide
6	38.1b	0.778b	3-(4'Chloro-3-fluorophenyl)-N-propyl-3H- imidazo[4,5-b]pyridine-2-carboxamide
7	40.8b	1.88b	S-^-Cyano-S-fluorophenylJ-N-cyclopropyl-SHi m rdazo[4,5-b] pyridi ne-2-carboxamide
8	16.0	0.910	4-[2-(Azetidin-1-ylcarbonyl)-3H-imidazo[4,5- b]pyridin-3-yl]-2-fluorobenzonitrile
9	14.2b	0.420b	Azetidin-1-yl[3'(4-chloro-3,5-difluorophenyl)- 3H-imidazo[4,5-£)]pyridin-2-yl]methanone
10	15.2b	0.567b	Azetidin-1-yl[3-(4-chloro-3-fluorophenyl)-3Himidazo[4,5'ib]pyridin-2-yl]methanone
11	405	9.64	3-(4-Chloro-3-fluorophenyl)-/VIN-dimethyl-3H- imrdazo[4,5-i)]pyridine-2-carboxamide
12	99.4	1.52	Azetidin-1-yl[3-(4-chloro-2,5-difluorophenyl)3/7-imidazo[4,5-b]pyridin-2-yl]methanone, trifluoroacetate sait
13	944	6.64b	3-(4-Chlorophenyl)-/V-propyl-3H-imidazo[4,5- bJpyridine-2-carboxamide
14	822	4.38	3-Cyclopentyl-/V-(1-rriethyl-1H-pyrazol-3-yl)- 3H-imidazo[4,5-b]pyridine-2-carboxamide
15	1730	6.90	/V-Cyclopropyl-3-(tetrahydro-2/7'pyran-4-yl)- 3H-imidazo[4,5-b]pyridine-2-carboxamide
16	196	5.50	Azetidin-1-yl[3-(4-chlorophenyl)-3Hrmidazo[4,5-b]pyridin-2-yl]methanone
17	8510	>30.0	3-(4-Chloro-3-fluorophenyl)-3H-imidazo[4,5- b]pyrîdine-2-carboxamide
18	48.7	2.14	Azetidin-1-yl[3-(3-fluoro-4-methylphenyl)-3H- imidazo[4,5-b]pyridin-2-yl]methanone
19	281	5.28	(3-Fluoroazetrdin-1-yl)[3-(3-fluoro-4methylphenyl)-3/7-imidazo[4,5-b]pyridin-2yljmethanone
20	13.8	0.262b	3“(4-Cyano-3,5-difluorophenyl)-/V-cyc)opropyl-

η

			3H-imidazo[4,5-b]pyrÎdine-2-carboxamide
21	42.6	0.316	[3-(4-Chloro-3-fluorophenyl)-3H-imidazo[4,5- b]pyridin-2-yl](3-fluoroazetrdin-1-yl)methanone
22	273	5.59	Azetidin-1-yl[3-(4-chloro-2-fluorophenyl)-3/7- imidazo[4,5-b]pyridin-2-yl]methanone
23	632	>30.0	3-(4-Chloro-2-fluorophenyl)-N-cyclopropyl-3H- imidazo[4,5-b]pyridine-2-carboxamide
24	211	>24.1	3-(4-Chlorophenyl)-N-(1 -methyl-1 H-pyrazol-3- yl)-3H-imidazo[4,5-i)]pyridine-2-carboxamide
25	910	5.84	[3-(4-Chloro-2-fluorophenyl)-3H-imidazo[4,5- b]pyridin-2-yl](3-fluoroazetidin-1-yl)methanone
26	319	>17.9	3-(4-Chloro-2-methylphenyl)-N-cyclopropyl- 3H-imidazo[4,5-b]pyridine-2-carboxamide
27	12.2b	0.511b	N-Cyclopropyl-3-(3,4-dichlorophenyl)-3H- imidazo[4,5-d]pyridine-2-carboxamide
28	114	8.23	N-Cyclopropyl-3-(4-fluoro-3-methylphenyl)-3H- imidazo[4,5-b]pyridine-2-carboxamide
29	225	>28.0b	/V-Cyclopropyl-3-(4-methylphenyl)-3Himidazo[4,5-b]pyridine-2-carboxamide
30	5.77	0.333	/V-Cyclopropyl-3-(3,4,5-trifluorophenyl)-3Himidazo[4,5-b]pyridine-2-carboxamide, trifluoroacetate sait
31	87.5	2.55	3-(3-Cyano-4-f[uorophenyl)-/V-cyclopropyl-3/-/- imidazo[4,5-b]pyridine-2-carboxamide
32	15.7	0.886	3-(3-Chloro-4-fluorophenyl)-N-cyclopropyl-3H- imidazo[4,5-i?]pyridine-2-carboxamide
33	15.9	1.23b	3-(3-Chloro-4-methylphenyl)-/V-cyclopropyl- 3H-imidazo[4,5-b]pyridine-2-carboxamide
34	399	10.2	Azetidin-1 -yl[3-(4-chloro-2-m ethylph eny I) -3Himidazo[4,5-b]pyridin-2-yl]methanone
35	1130	8.28	[3-(4-Chloro-2-methylphenyl)-3W-imidazo[4,5b]pyridin-2-yl](3-fluoroazetidin-1-yl)methanone
36	5.65	0.255	3-(4-Chloro-3,5-difluorophenyl)-N-cyclopropyl-

			3H-imidazo[4,5-b]pyridine-2-carboxaniide
37	409	10.7	3-(5-Chloropyridin-3-yl)-/V-cyclopropyl-3H- imidazo[4,5-b]pyridine-2-carboxamide
38	466	6.67	Azetidin-1-yl[3-(5-chloropyridin-3-yl)-3H- imidazo[4,5-b]pyridin-2-yl]rnethanone
39	363	10.2	3-(6-Cyanopyridin-3-yl)-/V-cyclopropyl-3H- imidazo[4,5-b]pyridine-2-carboxamide
40	1710	15.2	3-(5'Cyano-2“fluorophenyl)-A/-cyc(opropyl-3H- imidazo[4,5-i)]pyridine-2-carboxamide
41	100	1.17	3-(4-Chloro-2,5-difluorophenyl)-N-cyclopropyl- 3H-imidazo[4,5-b]pyridine-2-carboxamide
42	276b	>22.4b	3-(4-Cyanophenyl)-/V-cyclopropyl-3Hi m idazo[4,5- b] pyridine-2-carboxam ide
43	927	>26.6	/V-Cyclopropyl-3-(2,4-difluorophenyl)-3Hirnidazo[4,5-£j]pyridine-2-carboxamide
44	1660	>29.0	/V-Cyclopropyl-3-(5-fluoro-2-methylphenyl)-3Himidazo[4,5'b]pyridine-2-carboxamide
45	205	14.8	N-Cyclopropyl-3-(3-fluoro-4-methoxyphenyl)- 3H-imidazo[4,5-b]pyridine-2-carboxamide
46	329	13.8	N-Cyclopropyl-3“(3-methoxyphenyl)-3Himidazo[4,5-b]pyridine-2-carboxamide
47	1260	6.39	N-Cyclopropyl-S-ÎS^-dihydro-IH-inden-a-yl)- 3H-imidazo[4,5-ù]pyridine-2-carboxamide
48	88.9	4.82	N-Cyclopropyl-3-(3,5-difluorophenyl)-3H- imidazo[4,5-b]pyridrne-2-carboxamide
49	629	12.3	3-(3-Chloro-4-methoxyphenyl)-A/-cyciopropyl- 3H-imidazo[4,5-b]pyridine-2-carboxamide
50	339	>30.0	/V-Cyclopropyl-3-(3-methoxy-4-methylphenyl)- 3H-imidazo[4,5-b]pyridine-2-carboxamide
51	207	13.2	AACyclopropyl-3-(4-methoxy-3-methylphenyl)- 3H-imidazo[4,5-b]pyridine-2-carboxamide
52	271	25.8	/V-Cyclopropyl-3-(3,4-dimethylphenyl)-3Himidazo[4,5-b]pyridine-2-carboxamide
53	287	3.40	3-(3-Cyanophenyl)-/V-cyclopropyl'3H-

			imidazo[4,5-b]pyridine-2-carboxamide
54	329	19.2	3-(5-Chloro-2-methylphenyl)-N-cyclopropyl- 3H-imidazo[4,5-b]pyridine-2-carboxamide
55	304	>23.7	N-Cyclopropyl-3-(4-fluoro-3-methoxyphenyl)- 3H-imidazo[4,5“b]pyridine-2-carboxamide
56	167	4.85	3-(3-Cyano-4-methylphenyl)-N-cyclopropyl- 3H-imidazo[4,5-b]pyridine-2-carboxamide
57	1160	>19.7	AACyclopropyl-3-phcnyl-3H-imidazo[4,5- b]pyrid i ne-2-carboxam ide
58	506	>30.0	A/-Cyclopropyl-3-(4-methoxyphenyl)-3Himidazo[4,5-b]pyridine-2-carboxamide
59	1020	>30.0	/V-Cyclopropyl-3-(2,4-dimethylphenyi)-3Himidazo[4,5-b]pyridine-2-carboxamide
60	1200	>30.0	/V-Cyclopropyl'3-(4-fluoro-2-methylphenyl)-3Himidazo[4,5-b]pyridine-2-carboxamrde
61	1580	>30.0	MCyclopropyl-3-(1,3-dihydro-2-benzofuran-5- yl)-3H-imidazo[4,5-b]pyridine-2-carboxamide
62	34.9	1.49b	N-Cyclopropyl-3-(3,4-difluoropheny))'3H- imidazo[4,5-b]pyridine-2-carboxamide
63	68.0	2.55	/V-Cyclopropyl-3-(3,5-dichlorophenyl)-3Himidazo[4,5-b]pyridine-2-carboxamide
64	206	15.7	/V-Cyclopropyl-3-(2,3'dihydro-lH-inden-5-yl)- 3H-imidazo[4,5-b]pyridine-2-carboxamide
65	188	10.9	N-Cyclopropyl-3-(3'fluorophenyl)-3Hrmidazo[4,5-b]pyridine-2-carboxamÎde
66	759	19.4	/V-Cyclopropyl-3-(3,5-dimethoxyphenyl)-3Himidazo[4,5-b]pyridÎne-2-carboxamide
67	619	>30.0	N-Cyclopropyl-3-(2'fluoro-4-methylphenyl)-3/7- imidazo[4,5-b]pyridine-2-carboxamide
68	219	11.9	A7Cyclopropyl-3-(4-fluorophenyl)-3/7imidazo[4,5'b]pyridine-2-carboxamide
69	70.9b	1.91b	3-(3-Chlorophenyl)-/V-cyclopropyl-3H- imidazo[4,5-d]pyridine-2-carboxamide
70	421	14.9	N-Cyclopropyl'3-(3-methylphenyl)-3Himidazo[4,5-b]pyridine-2-carboxamide

71	155	6.34	3-(1,3-Be nzothiazol-6-yl) - /V-cyclopropyl-3Himidazo[4,5-d]pyricline-2-carboxamide
72	40.9	0.753	/V-Cyclopropyl-3-[3-(methylsulfanyl)phenyl]- 3H-imidazo[4,5-b]pyridine-2-carboxamide
73	516	12.6	N-Cyclopropyl-3-(2'methyl-1,3-benzothiazol-6- yl)-3H-imidazo[4,5-<b]pyridine-2-carboxamide
74	58.8	1.99	3-(4-Chloro-3-methylphenyl)-N-cyclopropyl- 3H-imidazo[4,5-£)]pyndine-2-carboxamide
75	389	3.98	Λ/-Cyclopropyl·3-[3-(trifluoromethoxy)phenyl]- 3H-imidazo[4,5-b]pyndine-2-carboxamide
76	374	>18.8	A/-Cyclopropyl-3-(3,5-dimethylphenyl)-3H- imidazo[4,5-b]pyridine-2-carboxamide
77	1150	8.64	/V-Cyclopropyl-3-[3-(trifluoromethyl)phenyl]- 3H- i m idazo[4,5-d]pyridi ne-2-carboxa m ide
78	387	11.4	3-(3-Chloro-2-fluorophenyl)-/V-cyclopropyl-3Himidazo[4,5-b]pyridine-2-carboxamide, trifluoroacetate sait
79	106	1.76	3-(5-Chloro-2-fluorophenyl)-A/-cyclopropyl-3Himidazo[4,5-jb]pyrïdine-2-carboxamide, trifluoroacetate sait
80	1470	>30.0	A/-Cyclopropyl-3-(quinolin-6-yl)-3Himidazo[4,5-d]pyridine-2-carboxamide, trifluoroacetate sait
81	8270	>30.0	3-(5-Chloropyridin-3-yl)-/V-ethyl-3/-/imidazo[4,5-£j]pyridine-2-carboxamide
82	6070	17.5	/V-Cyclopropyl-3-[2-(trifluoromethyl)pyridin-4- yl]-3/7-imidazo[4,5-b]pyridrne-2-carboxamide
83	13600	>29.3	N-Cyclopropyl-3-(5-methoxypyridin-3-yl)-3H- imidazo[4,5-ù]pyridine-2-carboxamide
84	16600	>30.0	3-(2-Chloro-4-fluoro-5-methylphenyl)-/\/cyclopropyl-3H-imidazo[4,5-b]pyridine-2carboxamide
85	7730	>30.0	/V-Cyclopropyl-3-(6-methylpyridin-3-yl)-3Himidazo[4,5-ij]pyridine-2-carboxamide

86	24500	>30.0	N-Cyclopropy 1-3-(1 -methyl-1 /7-indazol-6-yl)- 3H-im id azo[4,5-b]pyrid ine-2-carboxam ide
87	2720	>30.0	M-Cyclopropyl-3-(3,4-dimethoxyphenyl)-3/7- imidazo[4t5-b]pyridine-2-carboxamîde
88	3700	>30.0	3-(2-Chloro-4-methylphenyl)-/\/-cyclopropyl- 3/7-imidazQ[4,5-b]pyridine-2-carboxamide
89	3520	>30.0	/V-Cyclopropyl-3-(4-methoxy-2- methylphenyl)-3H-imidazo[4,5-b]pyridine-2carboxamide
90	9230	>30.0	3-(2-Chloro-5-fluorophenyl)-W-cyclopropyl- 3H-imidazo[4,5-b]pyridine-2-carboxamide
91	9420	>30.0	3-(2-Chloro-5-methylphenyl)-W-cyclopropyl- 3H-im idazo[4,5-b]pyrid i ne-2-carboxam ide
92	3110	>30.0	W-Cyclopropyl-3-[4-(trifluoromethyl)phenyl]- 3/-/-imidazo[4,5-b]pyridine-2-carboxamide

a. Values represent the géométrie mean of 2 - 6 déterminations.

b. Value represents the géométrie mean of £7 déterminations.

Claims (33)

1. A compound of formula i:

or a pharmaceutically acceptable sait thereof, wherein:

R¹ is represented by a substituent selected from the group consisting of (C3C1D)cycloalkyl, a (4- to 10-membered)heterocycloalkyl, (C6-C10)aryl, and a (5- to 10membered) heteroaryl; wherein said (C3-C10)cycloalkyl, (C6-C10)aryl and (5- to 10memberedjheteroaryl are substituted with (R²)b; and said (4- to 10membered)heterocycloalkyl is optionally substituted at one to five carbon atoms with a substituent independently selected from the group consisting of halogen, (CrC₆)alkyl, halo(Ci-C₅)alkyl, (CrC₆)alkoxy, halo(CrC₆)alkoxy, (CrC_e)alkylthio, -C(O)NR⁴R⁵, hydroxy, and cyano, and optionally substituted at each available nitrogen with (Ci-C₆)alkyl;

R² is represented by a substituent independently selected from the group consisting of halogen, (CrC₆)alkyl, halo(Ci-C₅)alkyl, (CrC₆)alkoxy, halo(CrC₆)alkoxy, (C,-C₆)alkylthio; -C(O)NR⁴R⁵, hydroxy, and cyano;

R³, if présent, at each occurrence is represented by a substituent independently selected from the group consisting of halogen, (Ci-C₆)alkyl, halo(CrC₆)alkyl, (C_r C₅)alkoxy, halo(CrC₆)alkoxy, (CrC₆)alkylthio, -C(O)NR⁴R⁵, hydroxy, and cyano;

R⁴ and R⁵ are each represented by a substituent independently selected from the group consisting of hydrogen, (CrCeJalkyl, and (C₃-C₆)cycloalkyl;

one of R⁶ and R⁷ is represented by a substituent selected from the group consisting of hydrogen, (CrCeJalkyl, -(CH₂)_m-(C₃-C₁₀)cycloalkyl, -(CH₂)_m-(4- to 10memberedj-heterocycloalkyl, -(CH₂)_m-(C_e-C₁₀)aryl, and -(CH^m-ÎS- to 10membered)heteroaryl and the other is represented by a substituent selected from the group consisting of (Ci-C₆)alkyl,

-(CH₂)_m-(C₃-C₁₀)cycloalkyl, -(CH₂)_m-(4- to 10-membered)-heterocycloalkyl, -(CH₂)_m-(C_sCiojaryl, and -(CH₂)_m-(5- to 10-membered)heteroaryl; wherein:

i) said R⁶ and R⁷ (CrCeJalkyl substituent is optionally substituted with one to five substituents independently selected from the group consisting of halogen, (CrC₆)alkyl, halotCrCeJalkyl, (CrC_B)alkoxy, halo(CrC₆)alkoxy, (CrC₆)alkylthio,

-C(O)NR⁴R⁵, and cyano;

ii) said R⁶ and R⁷ (C₃-Ci₀)cycloalkyl substituent is optionally substituted with one to five substituents independently selected from the group consisting of halogen, (Cr C₆)alkyl, halofC^OeJalkyl, (C_rC₆)alkoxy, halo(CrC₆)alkoxy, (Ci-C_e)alkylthio, -C(O)NR⁴R⁵, hydroxy and cyano;

iii) said R⁶ and R⁷ (C₆-C₁₀)aryl substituent is optionally substituted with one to five substituents independently selected from the group consisting of halogen, (CrC₆)alkyl, halo(C-i-C₆)alkyl, (CrCeJalkoxy, halofCrCejalkoxy, (Ci-C₆)alkylthio,

-C(O)NR⁴R⁵, hydroxy and cyano;

iv) said R⁶ and R⁷ (5- to 10-membered)heteroaryl substituent is optionally substituted with one to five substituents independently selected from the group consisting of halogen, (CrCgJalkyl, halotCi-C^alkyl, (Ci-C^alkoxy, halofC-î-Cyalkoxy, (C_r Ce)alkylthio, -C(O)NR⁴R⁵, hydroxy, and cyano; and

v) said R^e and R⁷ (4- to 10-membered)heterocycloalkyl substituent is optionally substituted at one to five carbon atoms with a substituent independently selected from the group consisting of halogen, (Ci-C6)alkyl, halo(Ci-C6)alkyl, (CrCeJalkoxy, haloiCr C6)alkoxy, (CpCeialkylthio, -C(O)NR⁴R⁵, hydroxy, and cyano, and optionally substituted at each available nitrogen with (CrCsJalkyl; or R⁶ and R⁷ taken together with the nitrogen to which they are attached form a (4- to 10-membered)heterocycloalkyl, wherein said (4- to 10-membered) heterocycloalkyl is optionally substituted at one to five carbon atoms with a substituent independently selected from the group consisting of halogen, (CrC6)alkyl, halo(CrC₆)alkyl, (Ci-C_B)alkoxy, halotCrCeJalkoxy, (Ci-C₆)alkylthio, -C(O)NR⁴R⁵, hydroxy, and cyano;

a is represented by an integer selected from 0,1, 2 or 3;

b is represented by an integer selected from 0,1, 2, 3, 4 or 5; and m is represented by an integer selected from 0,1,2, or 3.

2. The compound according to claim 1, or a pharmaceutically acceptable sait thereof, wherein a is represented by the integer 0.

3. The compound according to claim 1, or a pharmaceutically acceptable sait thereof, wherein R¹ is represented by a (5 to 10-membered)heteroaryl and b is an integer selected from 0,1, 2 or 3.

4. The compound according to claim 3, or a pharmaceutically acceptable sait thereof, wherein R¹ is represented by pyridinyl; b is an integer selected from 1, 2, or 3;

and each R² is independently selected from the group consisting of chloro, fluoro, methyl, methoxy, trifluoromethyl, trifluoromethoxy, cyano, and methylthio.

5. The compound according to claim 4, or a pharmaceutically acceptable sait thereof, wherein R¹ is represented by the group consisting of 5-chloropyridin-3-yl, 6methylpyridin-3-yl, 5-methoxypyridin-3-yl, 2-trifluoromethylpyridin-4-yl, and 6cyanopyridin-3-yl.

6 The compound according to claim 3, or a pharmaceutically acceptable sait thereof, wherein R¹ is represented by 1-methyl-1H-indazol-5-yl, quinolin-6-yl, 1,3benzothîazol-6-yl, and 2-methyl-1,3-benzothiazol-6-yl.

7. The compound according to claim 1, or a pharmaceutically acceptable sait thereof, wherein R¹ is represented by (C₃-C₁₀)cycloalkyl, and b is and integer selected from 0,1, 2, or 3,

8. The compound according to claim 7, or a pharmaceutically acceptable sait thereof, wherein R¹ is represented by cyclopentyl; b is an integer selected from 1, 2, or 3; and each R² is independently selected from the group consisting of chloro, fluoro, methyl, methoxy, trifluoromethyl, trifluoromethoxy, cyano, and methylthio.

9. The compound according to claim 1, or a pharmaceutically acceptable sait thereof, wherein R¹ is represented by a (4 to 10-membered)heterocycloalkyl optionally substituted at one to three carbon atoms with a substituent independently selected from the group consisting of halogen, (Ci-C_e)alkyl, halofCrCeJalkyl, (CrCeJalkoxy, halo(C-C₆)alkoxy, (CrC^alkylthio, -C(O)NR⁴R⁵, hydroxy, and cyano, and optionally substituted at each available nitrogen with a (CrCeJalkyl.

10. The compound according to claim 9 or a pharmaceutically acceptable sait thereof, wherein R¹ is represented by tetrahydropyranyl optionally substituted at one to three carbon atoms with a substituent independently selected from the group consisting of chloro, fluoro, methyl, methoxy, trifluoromethyl, trifluoromethoxy, cyano, and methylthio.

11. The compound according to claim 1, or a pharmaceutically acceptable sait thereof, wherein R¹ is represented by (Ce-C10)aryl; b is an integer selected from 0, 1,2, or 3; and when présent each R² is independently selected from the group consisting of halogen, (Ci-C6)alkyl, halo(Ci-C₆)alkyl, (Ci-C₆)alkoxy, halofCrCeOalkoxy, (Ci-C₆)alkylthio, -C(O)NR⁴R⁵, hydroxy, and cyano.

12. The compound of claim 11, wherein said (C_B-C₁₀)aryl is selected from the group consisting of 2,3-dihydro-1 H-inden-5-yl and 1,3-dihydro-2-benzofuran-5-yl.

13. A compound of formula la:

or a pharmaceutically acceptable sait thereof, wherein:

b is represented by an integer selected from 0,1, 2, or 3;

each R^z, if présent, is represented by a substituent independently selected from the group consisting of fluoro, chloro, cyano, methyl, trifluoromethyl, methylthio, methoxy, and trifluoromethoxy;

one of R^e and R⁷ is selected from the group consisting of hydrogen, (C-rCejalkyl, -(CH2)_m“(C₃-C₁₀)cycloalkyl, and -(CHi)_m-(5- to 10-membered)heteroaryl and the other is selected from the group consisting of (Ci-C₅)alkyl, -(CH₂)_m-(C₃-Cio)cycloa[kyl, and (CH₂)_m-(5-to 10-membered)heteroaryl; wherein:

i) said R⁶ and R⁷ (CrCgJalkyl substituent is optionally substituted with one to three substituents independently selected from the group consisting of halogen, (C_n-C₆)alkyl, halofCrCeJalkyl, (Ci-C₆)alkoxy, halo(Ci-C₆)alkoxy, (Ci-C₆)alkylthio, and cyano;

ii) said R^s and R⁷ (C₃-C io)cycloalkyl substituent is optionally substituted with one to three substituents independently selected from the group consisting of halogen, (C_r C₆)alkyl, halo(CrC_e)alkyl, (C_rC₆)alkoxy, halo(C_rC₆)alkoxy, (CrC_e)alkylthio, hydroxy, and cyano; and iii) said R⁶ and R⁷ (5- to 10-membered)heteroaryl substituent is optionally substituted with one to three substituents independently selected from the group consisting of halogen, (CrCgJalkyl, halo(Ci-C6)alkyl, (C^-Cyalkoxy, halo(Ci-C6)alkoxy, (Cf-C6)alkylthior hydroxy, and cyano; or R⁶ and R⁷ taken together with the nitrogen to which they are attached form a (4 to 6-membered)heterocycloalkyl, in which up to three carbon atoms of said heterocycloalkyl are optionally substituted with a substituent independently selected from the group consisting of halogen, (CrCgJalkyl, halo(C-iC6)alkyi, (Ci-C₆)alkoxy, halo(CrC₆)alkoxy, (Ci-C₆)alkylthio, -C(O)NR⁴R⁵, hydroxy, and cyano, wherein R⁴ and R^E are each independently selected from the group consisting of hydrogen and (CpCeJalkyl;

and m is represented by an integer selected from 0,1, or 2.

14. The compound according to claim 13, or a pharmaceutically acceptable sait thereof, wherein R⁶ and R⁷ taken together with the nitrogen to which they are attached form a (4- to 6-membered)heterocycloalkyl optionally substituted at one to three carbon atoms with halogen.

15. The compound of claim 14, wherein R⁶ and R⁷ taken together with the nitrogen to which they are attached form azetidinyl, optionally substituted with one to three halogen.

16. The compound according to claim 15, wherein said azetidinyl is selected from azetidin-1 -yl or 3-fluoroazetidin-1-yl.

17. The compound according to claim 13, or a pharmaceutically acceptable sait thereof, wherein b is represented by an integer selected from 0, 1, 2, or 3; each R², if présent, is represented by a substituent independently selected from the group consisting of fluoro, chloro, cyano, methyl, trifluoromethyl, methylthio, methoxy, and trifluoromethoxy; one of R⁶ and R⁷ is represented by hydrogen and the other represented by a substituent selected from the group consisting of (CrCeJalkyl, -(CH2)_m-(C₃-C₆)cycloalkyl, and -(CH₂)_m(5- to 10-membered)heteroaryl; wherein:

i) said (CrCXalkyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, (C₃-Ce)alkyi, halo(Cr C₆)alkyl, (CrCeJalkoxy, halofCi-CeJalkoxy, (Ci-C₆)alkylthio, and cyano;

ii) said (C₃-C₁₀)cycloalkyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, (Ci-C₆)alkyl, halo(C-iCsjalkyl, (Ci-C_s)alkoxy, halo(C₁-C₆)alkoxy, (CrC₆)alkylthio, hydroxy, and cyano; and iii) said (5- to 10-membered)heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, (C_rC₆)alkyl, halo(Ci-C₆)alkyl, (Ci-C₆)alkoxy, halo(C-i-C₆)alkoxy, (C₁-C₆)alkylthio, hydroxy, and cyano; and m is represented by.an integer selected from 0, 1, or 2.

18. The compound according to claim 17, or a pharmaceutically acceptable sait thereof, wherein b is represented by an integer selected from 0, 1,2, or 3; and each R², if présent, is represented by a substituent independently selected from the group consisting of chloro, fluoro, methyl, and cyano; and one of R⁶ and R⁷is represented by hydrogen and the other is represented by (Ci-C₆)alkyl.

19. The compound according to claim 18, or a pharmaceutically acceptable sait thereof, wherein one of R⁶ and R⁷ is represented by hydrogen and the other is represented by the group consisting of ethyl or propyl,

20. The compound according to claim 17, or a pharmaceutically acceptable sait thereof, wherein b is represented by an integer selected from 0, 1,2, or 3; and each R², if présent, is represented by a substituent independently selected from the group consisting of chloro, fluoro, methyl, and cyano; and one of R⁶ and R⁷ is represented by hydrogen and the other is represented by

-(CH₂)_m-(C₃“C₆)cycloalkyl.

21. The compound according to claim 20, or a pharmaceutically acceptable sait thereof, wherein one of R⁶ and R⁷is represented by hydrogen and the other is represented by cyclopropyl.

22. The compound according to claim 17, or a pharmaceutically acceptable sait thereof, wherein b is represented by an integer selected from 0, 1,2, or 3; and each R², if présent, is represented by a substituent independently selected from the group consisting of chloro, fluoro, methyl, and cyano; and one of R⁶ and R⁷ is represented by hydrogen and the other is represented by -(0-12^-(5 -to 10-membered)heteroaryl optionally substituted by a (C-rCsJalkyl.

23. The compound according to claim 22, or a pharmaceutically acceptable sait thereof, wherein one of R^e and R⁷ is represented by hydrogen and the other is represented by pyrazolyl optionally substituted by methyl.

24. The compound according to claim 23, or a pharmaceutically acceptable sait thereof, wherein one of R⁶ and R⁷ is represented by hydrogen and the other is represented by M-1-methyl-1 H-pyrazol-3-yl.

25. Use of a compound of Formula I according to claim 1, or a pharmaceutically acceptable sait thereof in the manufacture of a pharmaceutical composition for treating a patient suffering from a disease or condition mediated by the PDE4B isoform, wherein said disease or condition is selected from the group consisting of schizophrenia, dépréssion, anxiety, and Alzheimer's disease.

26. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable excipient.

27. A compound selected from the group consisting of: N-Cyclopropyl-3-(3-fluoro-4-methylpheny!)-3H-imidazo[4,5-b]pyridine-2- carboxamide;

S-Cyclopentyl-N-cyclopropylXH-imidazolA.S-bJpyridine-S-carboxamide;

3-(4-Chlorophenyl)-N-cyclopropyl-3H-imidazo[4,5-b]pyridine-2-carboxamide: 3-(4-Chloro-3-fluorophenyl)-N-cyclopropyl-3H-imidazo[4,5-b]pyridine-2carboxamide;

3-(4-Chloro-3-fluorophenyl)-N-(1-methyl-1H-pyrazol-3-yl)-3H-imidazo[4,5b]py ridi ne-2-carboxam ide ; 3-(4-Chloro-3-fluorophenyl)-N-propyl-3H-imidazo[4,5-b]pyridme-2-carboxamide;

3- (4-Cyano-3-fluorophenyl)-N-cyclopropyl-3H-imidazo[4,5-b]pyridine-2carboxamide;

4- [2-(Azetidin-1-yîcarbonyl)-3H-imidazo[4,5-b]pyrïdin-3-yl]-2-fluorobenzonitrïle; azetid i n-1 -y l[3-(4-ch loro-3,5-difl uorophenyl)-3H-imidazo[4,5-b]pyrid i n-2- yl]methanone; and azetidin-1-yl[3-(4-chloro-3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl]methanone; or a pharmaceutically acceptable sait thereof.

28. A pharmaceutical composition comprising a compound of claim 27, or a pharmaceutically acceptable sait thereof, and at least one pharmaceutically acceptable excipient.

29. N-Cyclopropyî-3-(3-fIuoro-4-methylphenyl)-3H-imidazo[4,5-b]pyridine-2carboxamide, or a pharmaceutically acceptable sait thereof.

30. 3-Cyclopentyl-N-cyclopropyl-3H-imidazo[4,5-b]pyridine-2-carboxamide, or a pharmaceutically acceptable sait thereof.

31. 3-(4-0 hloro-3-fluorophenyl)-N-cyclopropyl-3H-imidazo[4,5-b]pyridine-2carboxamide, or a pharmaceutically acceptable sait thereof.

32. 3-(4-Chloro-3-fluorophenyl)-N-(1-methyl-1 H-pyrazol-3-yl)-3H-imidazo[4,5b]pyridine-2-carboxamide, or a pharmaceutically acceptable sait thereof.

33. 4-[2-(Azetidin-1-ylcarbonyl)-3H-imidazo[4,5-b]pyridin-3-yl]-2-fluorobenzonitrile, or a pharmaceutically acceptable sait thereof.